Pharmacology

A suspicion from retrospective data has now been confirmed by a prospective clinical trial: Adding panitumumab (Vectibix) to standard chemotherapy in left-sided RAS wild-type metastatic colorectal cancer (mCRC) is more effective than adding bevacizumab (Avastin).

Patients treated with panitumumab alongside chemotherapy saw a 16% improvement in overall survival versus those given bevacizumab after a median follow-up of over 5 years.

The overall survival benefit rose to 18% in those with left-sided tumors.

However, there was no difference in overall survival between the two treatment groups in the small subgroup of patients with right-sided primary tumors.

These findings come from the PARADIGM trial conducted in Japan.

The results were presented during a plenary session at the annual meeting of the American Society of Clinical Oncology.

“If gene testing shows that a tumor is RAS wild-type, the choice of initial treatment with panitumumab plus mFOLFOX6 chemotherapy is superior ... for those people with left-sided tumors,” said lead researcher Takayuki Yoshino, MD, PhD, department of gastrointestinal oncology, National Cancer Center Hospital East, Chiba, Japan, in an ASCO press release.

“It has long been believed that the sequence of metastatic colorectal cancer treatment does not matter as long as patients had access to the drugs at some point, which has now been disproven,” he noted.

Dr. Yoshino added in a press conference about the trial that the results establish “a standard first-line combination regimen for patients with RAS wild-type, left-sided mCRC.”

This is the “longest survival ever reported in a first-line unresectable metastatic colorectal cancer prospective phase 3 trial,” commented Cathy Eng, MD, ASCO Expert in gastrointestinal cancers.

The findings “emphasize the importance of taking into account sidedness, as well as including comprehensive biomarker testing,” she said.

Dr. Eng underlined that this is especially the case for RAS gene status testing, “which is critical for all colorectal cancer patients at the time of diagnosis of metastatic disease.”

These results are of particular relevance in the United States, where the choice between an anti-EGFR or anti-VEGF antibody for the treatment of mCRC has been an area of “controversy” because of the lack of supporting data.

Panitumumab is a human monoclonal antibody that targets EGFR. It was approved in 2006 for use in mCRC by the U.S. Food and Drug Administration and also approved in 2014 for use in combination with FOLFOX for the first-line treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) mCRC, having previously been shown to be equally effective as cetuximab (another EGFR inhibitor) in this population.

In contrast, bevacizumab is a monoclonal antibody that targets the VEGF receptor. It was approved by the FDA for use in mCRC in 2004 in combination with intravenous 5-fluorouracil–based chemotherapy.

Dr. Yoshino explained that around 36% of patients with CRC have metastatic tumors at diagnosis and that adding an anti-EGFR or anti-VEGF antibody to chemotherapy improves overall survival in these patients by up to 30 months.

There has been “accumulating” evidence from retrospective studies suggesting that patients with RAS wild-type mCRC whose primary tumor is on the left side, which accounts for approximately 35% of mCRC cases, have a longer survival benefit with an anti-EGFR antibody, he commented.

Despite this, both antibody types continue to be used in these patients, he added.

PARADIGM was the first prospective trial to compare the two antibody types. Patients were randomized to receive either panitumumab or bevacizumab plus the combination chemotherapy regimen modified FOLFOX6 (mFOLFOX6).

The trial involved 823 Japanese patients with previously untreated wild-type mCRC with unresectable disease. Most patients had left-sided primary tumors (312 of 400 patients in the panitumumab group, and 292 of 402 patients in the bevacizumab group).  

After a median follow-up of 61 months, panitumumab was associated with a significant improvement in overall survival in the overall study population, at a hazard ratio of 0.84 (P = .030, with the boundary of significance set at P < .05).

In addition, panitumumab was associated with a significant improvement in overall survival in the large subgroup of patients with left-sided primary tumors, at 37.9 versus 34.3 months, or a hazard ratio of 0.82 (P = .031).

However, there was no significant difference in overall survival between the two treatment groups in the smaller subgroup of patients with right-sided tumors, at a hazard ratio of 1.09.

Median progression-free survival was no different between the panitumumab and bevacizumab groups, at 13.7 versus 13.2 months in patients with a left-sided tumor and 12.9 versus 12.0 months in the overall cohort.

There was, however, a difference in response rates in left-sided patients between those receiving the two antibodies, at 80.2% with panitumumab versus 68.6% with bevacizumab, and in curative resection rates, at 18.3% and 11.6%, respectively.

These results demonstrate the “superiority of first-line panitumumab versus bevacizumab in combination with mFOLFOX6 in the left-sided and overall populations,” Dr. Yoshino concluded.

He also highlighted that the team has undertaken a large-scale biomarker analysis of pre- and posttreatment plasma and tissue samples from patients in the PARADIGM study to identify potential biomarkers of treatment response.

At the plenary session, discussant for this abstract Chiara Cremolini, MD, PhD, professor of medical oncology, Pisa (Italy) University Hospital, commented that “location matters” when it comes to mCRC tumors.

Dr. Cremolini pointed out that the separation of the survival curves at 28 months suggests that the 40% of patients with left-sided tumors who survived only up until that time point receive an equal benefit from panitumumab and bevacizumab.

In contrast, the remainder who survived for longer showed better outcomes with panitumumab.

Overall, she said, in her opinion and based on the findings from other studies, the current results support the use of panitumumab plus mFOLFOX6 as first-line therapy in patients with microsatellite stable RAS wild-type and with BRAF wild-type left-sided mCRC.

Dr. Cremolini emphasized that patients should be warned that, if they opt for doublet chemotherapy plus bevacizumab, they could face a median 3.6-month loss in overall survival, as well as poorer treatment activity.

However, patients with high microsatellite instability should receive immunotherapy up front, she added, while those with BRAF mutations should be given FOLFOX upfront plus bevacizumab, followed by encorafenib plus cetuximab in the case of progression.

Dr. Cremolini ended by noting that there has, as yet, been no prospective comparison of doublet chemotherapy plus an anti-EGFR antibody with triplet chemotherapy plus bevacizumab in this population.

The study was funded by Takeda. Dr. Yoshino has reported relationships with Bayer Yakuhin, Chugai Pharmaceutical, Merck, and MSD. Dr. Eng has reported relationships with Bayer Health, Gilead/Forty Seven, GlaxoSmithKline, Hookipa Biotech, Mirati Therapeutics, Natera, Pfizer, Elevar, Fruquitinib, Merck, and Pfizer.

A version of this article first appeared on Medscape.com.

A suspicion from retrospective data has now been confirmed by a prospective clinical trial: Adding panitumumab (Vectibix) to standard chemotherapy in left-sided RAS wild-type metastatic colorectal cancer (mCRC) is more effective than adding bevacizumab (Avastin).

Patients treated with panitumumab alongside chemotherapy saw a 16% improvement in overall survival versus those given bevacizumab after a median follow-up of over 5 years.

The overall survival benefit rose to 18% in those with left-sided tumors.

However, there was no difference in overall survival between the two treatment groups in the small subgroup of patients with right-sided primary tumors.

These findings come from the PARADIGM trial conducted in Japan.

The results were presented during a plenary session at the annual meeting of the American Society of Clinical Oncology.

“If gene testing shows that a tumor is RAS wild-type, the choice of initial treatment with panitumumab plus mFOLFOX6 chemotherapy is superior ... for those people with left-sided tumors,” said lead researcher Takayuki Yoshino, MD, PhD, department of gastrointestinal oncology, National Cancer Center Hospital East, Chiba, Japan, in an ASCO press release.

“It has long been believed that the sequence of metastatic colorectal cancer treatment does not matter as long as patients had access to the drugs at some point, which has now been disproven,” he noted.

Dr. Yoshino added in a press conference about the trial that the results establish “a standard first-line combination regimen for patients with RAS wild-type, left-sided mCRC.”

This is the “longest survival ever reported in a first-line unresectable metastatic colorectal cancer prospective phase 3 trial,” commented Cathy Eng, MD, ASCO Expert in gastrointestinal cancers.

The findings “emphasize the importance of taking into account sidedness, as well as including comprehensive biomarker testing,” she said.

Dr. Eng underlined that this is especially the case for RAS gene status testing, “which is critical for all colorectal cancer patients at the time of diagnosis of metastatic disease.”

These results are of particular relevance in the United States, where the choice between an anti-EGFR or anti-VEGF antibody for the treatment of mCRC has been an area of “controversy” because of the lack of supporting data.

Panitumumab is a human monoclonal antibody that targets EGFR. It was approved in 2006 for use in mCRC by the U.S. Food and Drug Administration and also approved in 2014 for use in combination with FOLFOX for the first-line treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) mCRC, having previously been shown to be equally effective as cetuximab (another EGFR inhibitor) in this population.

In contrast, bevacizumab is a monoclonal antibody that targets the VEGF receptor. It was approved by the FDA for use in mCRC in 2004 in combination with intravenous 5-fluorouracil–based chemotherapy.

Dr. Yoshino explained that around 36% of patients with CRC have metastatic tumors at diagnosis and that adding an anti-EGFR or anti-VEGF antibody to chemotherapy improves overall survival in these patients by up to 30 months.

There has been “accumulating” evidence from retrospective studies suggesting that patients with RAS wild-type mCRC whose primary tumor is on the left side, which accounts for approximately 35% of mCRC cases, have a longer survival benefit with an anti-EGFR antibody, he commented.

Despite this, both antibody types continue to be used in these patients, he added.

PARADIGM was the first prospective trial to compare the two antibody types. Patients were randomized to receive either panitumumab or bevacizumab plus the combination chemotherapy regimen modified FOLFOX6 (mFOLFOX6).

The trial involved 823 Japanese patients with previously untreated wild-type mCRC with unresectable disease. Most patients had left-sided primary tumors (312 of 400 patients in the panitumumab group, and 292 of 402 patients in the bevacizumab group).  

After a median follow-up of 61 months, panitumumab was associated with a significant improvement in overall survival in the overall study population, at a hazard ratio of 0.84 (P = .030, with the boundary of significance set at P < .05).

In addition, panitumumab was associated with a significant improvement in overall survival in the large subgroup of patients with left-sided primary tumors, at 37.9 versus 34.3 months, or a hazard ratio of 0.82 (P = .031).

However, there was no significant difference in overall survival between the two treatment groups in the smaller subgroup of patients with right-sided tumors, at a hazard ratio of 1.09.

Median progression-free survival was no different between the panitumumab and bevacizumab groups, at 13.7 versus 13.2 months in patients with a left-sided tumor and 12.9 versus 12.0 months in the overall cohort.

There was, however, a difference in response rates in left-sided patients between those receiving the two antibodies, at 80.2% with panitumumab versus 68.6% with bevacizumab, and in curative resection rates, at 18.3% and 11.6%, respectively.

These results demonstrate the “superiority of first-line panitumumab versus bevacizumab in combination with mFOLFOX6 in the left-sided and overall populations,” Dr. Yoshino concluded.

He also highlighted that the team has undertaken a large-scale biomarker analysis of pre- and posttreatment plasma and tissue samples from patients in the PARADIGM study to identify potential biomarkers of treatment response.

At the plenary session, discussant for this abstract Chiara Cremolini, MD, PhD, professor of medical oncology, Pisa (Italy) University Hospital, commented that “location matters” when it comes to mCRC tumors.

Dr. Cremolini pointed out that the separation of the survival curves at 28 months suggests that the 40% of patients with left-sided tumors who survived only up until that time point receive an equal benefit from panitumumab and bevacizumab.

In contrast, the remainder who survived for longer showed better outcomes with panitumumab.

Overall, she said, in her opinion and based on the findings from other studies, the current results support the use of panitumumab plus mFOLFOX6 as first-line therapy in patients with microsatellite stable RAS wild-type and with BRAF wild-type left-sided mCRC.

Dr. Cremolini emphasized that patients should be warned that, if they opt for doublet chemotherapy plus bevacizumab, they could face a median 3.6-month loss in overall survival, as well as poorer treatment activity.

However, patients with high microsatellite instability should receive immunotherapy up front, she added, while those with BRAF mutations should be given FOLFOX upfront plus bevacizumab, followed by encorafenib plus cetuximab in the case of progression.

Dr. Cremolini ended by noting that there has, as yet, been no prospective comparison of doublet chemotherapy plus an anti-EGFR antibody with triplet chemotherapy plus bevacizumab in this population.

The study was funded by Takeda. Dr. Yoshino has reported relationships with Bayer Yakuhin, Chugai Pharmaceutical, Merck, and MSD. Dr. Eng has reported relationships with Bayer Health, Gilead/Forty Seven, GlaxoSmithKline, Hookipa Biotech, Mirati Therapeutics, Natera, Pfizer, Elevar, Fruquitinib, Merck, and Pfizer.

A version of this article first appeared on Medscape.com.

A suspicion from retrospective data has now been confirmed by a prospective clinical trial: Adding panitumumab (Vectibix) to standard chemotherapy in left-sided RAS wild-type metastatic colorectal cancer (mCRC) is more effective than adding bevacizumab (Avastin).

Patients treated with panitumumab alongside chemotherapy saw a 16% improvement in overall survival versus those given bevacizumab after a median follow-up of over 5 years.

The overall survival benefit rose to 18% in those with left-sided tumors.

However, there was no difference in overall survival between the two treatment groups in the small subgroup of patients with right-sided primary tumors.

These findings come from the PARADIGM trial conducted in Japan.

The results were presented during a plenary session at the annual meeting of the American Society of Clinical Oncology.

“If gene testing shows that a tumor is RAS wild-type, the choice of initial treatment with panitumumab plus mFOLFOX6 chemotherapy is superior ... for those people with left-sided tumors,” said lead researcher Takayuki Yoshino, MD, PhD, department of gastrointestinal oncology, National Cancer Center Hospital East, Chiba, Japan, in an ASCO press release.

“It has long been believed that the sequence of metastatic colorectal cancer treatment does not matter as long as patients had access to the drugs at some point, which has now been disproven,” he noted.

Dr. Yoshino added in a press conference about the trial that the results establish “a standard first-line combination regimen for patients with RAS wild-type, left-sided mCRC.”

This is the “longest survival ever reported in a first-line unresectable metastatic colorectal cancer prospective phase 3 trial,” commented Cathy Eng, MD, ASCO Expert in gastrointestinal cancers.

The findings “emphasize the importance of taking into account sidedness, as well as including comprehensive biomarker testing,” she said.

Dr. Eng underlined that this is especially the case for RAS gene status testing, “which is critical for all colorectal cancer patients at the time of diagnosis of metastatic disease.”

These results are of particular relevance in the United States, where the choice between an anti-EGFR or anti-VEGF antibody for the treatment of mCRC has been an area of “controversy” because of the lack of supporting data.

Panitumumab is a human monoclonal antibody that targets EGFR. It was approved in 2006 for use in mCRC by the U.S. Food and Drug Administration and also approved in 2014 for use in combination with FOLFOX for the first-line treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) mCRC, having previously been shown to be equally effective as cetuximab (another EGFR inhibitor) in this population.

In contrast, bevacizumab is a monoclonal antibody that targets the VEGF receptor. It was approved by the FDA for use in mCRC in 2004 in combination with intravenous 5-fluorouracil–based chemotherapy.

Dr. Yoshino explained that around 36% of patients with CRC have metastatic tumors at diagnosis and that adding an anti-EGFR or anti-VEGF antibody to chemotherapy improves overall survival in these patients by up to 30 months.

There has been “accumulating” evidence from retrospective studies suggesting that patients with RAS wild-type mCRC whose primary tumor is on the left side, which accounts for approximately 35% of mCRC cases, have a longer survival benefit with an anti-EGFR antibody, he commented.

Despite this, both antibody types continue to be used in these patients, he added.

PARADIGM was the first prospective trial to compare the two antibody types. Patients were randomized to receive either panitumumab or bevacizumab plus the combination chemotherapy regimen modified FOLFOX6 (mFOLFOX6).

The trial involved 823 Japanese patients with previously untreated wild-type mCRC with unresectable disease. Most patients had left-sided primary tumors (312 of 400 patients in the panitumumab group, and 292 of 402 patients in the bevacizumab group).  

After a median follow-up of 61 months, panitumumab was associated with a significant improvement in overall survival in the overall study population, at a hazard ratio of 0.84 (P = .030, with the boundary of significance set at P < .05).

In addition, panitumumab was associated with a significant improvement in overall survival in the large subgroup of patients with left-sided primary tumors, at 37.9 versus 34.3 months, or a hazard ratio of 0.82 (P = .031).

However, there was no significant difference in overall survival between the two treatment groups in the smaller subgroup of patients with right-sided tumors, at a hazard ratio of 1.09.

Median progression-free survival was no different between the panitumumab and bevacizumab groups, at 13.7 versus 13.2 months in patients with a left-sided tumor and 12.9 versus 12.0 months in the overall cohort.

There was, however, a difference in response rates in left-sided patients between those receiving the two antibodies, at 80.2% with panitumumab versus 68.6% with bevacizumab, and in curative resection rates, at 18.3% and 11.6%, respectively.

These results demonstrate the “superiority of first-line panitumumab versus bevacizumab in combination with mFOLFOX6 in the left-sided and overall populations,” Dr. Yoshino concluded.

He also highlighted that the team has undertaken a large-scale biomarker analysis of pre- and posttreatment plasma and tissue samples from patients in the PARADIGM study to identify potential biomarkers of treatment response.

At the plenary session, discussant for this abstract Chiara Cremolini, MD, PhD, professor of medical oncology, Pisa (Italy) University Hospital, commented that “location matters” when it comes to mCRC tumors.

Dr. Cremolini pointed out that the separation of the survival curves at 28 months suggests that the 40% of patients with left-sided tumors who survived only up until that time point receive an equal benefit from panitumumab and bevacizumab.

In contrast, the remainder who survived for longer showed better outcomes with panitumumab.

Overall, she said, in her opinion and based on the findings from other studies, the current results support the use of panitumumab plus mFOLFOX6 as first-line therapy in patients with microsatellite stable RAS wild-type and with BRAF wild-type left-sided mCRC.

Dr. Cremolini emphasized that patients should be warned that, if they opt for doublet chemotherapy plus bevacizumab, they could face a median 3.6-month loss in overall survival, as well as poorer treatment activity.

However, patients with high microsatellite instability should receive immunotherapy up front, she added, while those with BRAF mutations should be given FOLFOX upfront plus bevacizumab, followed by encorafenib plus cetuximab in the case of progression.

Dr. Cremolini ended by noting that there has, as yet, been no prospective comparison of doublet chemotherapy plus an anti-EGFR antibody with triplet chemotherapy plus bevacizumab in this population.

The study was funded by Takeda. Dr. Yoshino has reported relationships with Bayer Yakuhin, Chugai Pharmaceutical, Merck, and MSD. Dr. Eng has reported relationships with Bayer Health, Gilead/Forty Seven, GlaxoSmithKline, Hookipa Biotech, Mirati Therapeutics, Natera, Pfizer, Elevar, Fruquitinib, Merck, and Pfizer.

A version of this article first appeared on Medscape.com.

Cannabis-based products may control chronic pain as effectively as opioids, but adverse effects are common, and long-term safety remains unknown, according to a new study.

Several other systematic reviews have recently evaluated cannabinoids for treating chronic pain, but the new study’s methodology was “distinct” in “important ways,” leading to “conclusions that differ from other reviews,” according to the authors of the paper published in the Annals of Internal Medicine.

In the new systematic review, synthetic products with high THC:CBD ratios were associated with moderate improvements in pain, whereas plant-based products with comparable THC:CBD ratios offered less relief, said study author Marian S. McDonagh, PharmD, professor of medical informatics and clinical epidemiology, and codirector of the Evidence-based Practice Center at Oregon Health & Science University, Portland, and colleagues.

Specifically, the investigators stratified cannabis-based interventions according to relative content of two key cannabinoids: THC and CBD. Products were sorted into five categories: high THC:CBD ratio (at least 2:1), comparable THC:CBD ratio (less than 2:1 but more than 1:2), low THC:CBD ratio (no more than 1:2), whole-plant cannabis products, and other cannabinoids.

“In preclinical studies, THC and related compounds have demonstrated analgesic properties, although its psychoactive effects and addiction potential may limit its suitability as an analgesic,” the investigators wrote. “CBD and other cannabinoids may also have some analgesic or anti-inflammatory properties and are not believed to be psychoactive or addictive. Given the variation in analgesic effect with THC and CBD, response may differ according to the ratio of THC to CBD in products used to treat pain.”

The final analysis included 18 randomized placebo-controlled trials involving 1,740 individuals and 7 cohort studies involving 13,095 individuals. Most of the studies were short-term, lasting 1-6 months.

Pain was scored on a ten-point scale, with improvements reported as the mean difference from baseline to post treatment. A mean difference in pain score of 0.5-1.0 was considered a “small effect,” an improvement of 1-2 points was considered a “moderate effect,” and an improvement greater than 2 points was considered a “large effect.”
 

Cannabis-based products with relatively high THC:CBD ratios showed efficacy

Synthetic products with high THC:CBD ratios offered moderate pain relief, based on a mean difference in pain score of –1.15 (95% confidence interval, –1.99 to –0.54), whereas products with comparable THC:CBD ratios were associated with a small effect on pain, with a mean difference of –0.52 (95% CI, –0.95 to –0.19).

According to Dr. McDonagh, treatment response rates were on par with response rates for more conventional treatments, “such as opioids or specific antidepressant drugs,” but data for the cannabis-based products are weaker.

“The amount of evidence available for cannabis-related products is very limited for [response rates], and therefore less certain,” Dr. McDonagh said in an interview. “The average reduction in pain severity is also similar to some other treatments, but we do not have studies directly comparing these treatments to draw conclusions.”

Although the cannabis-based products with relatively high and comparable THC:CBD ratios showed efficacy, they were also associated with “moderate to large increased risk for dizziness, sedation, and nausea,” the investigators wrote, noting that evidence was insufficient to characterize other “key adverse event outcomes” that may occur with long-term use, such as “psychosis, cannabis use disorder, and cognitive deficits.”

For products with low THC:CBD ratios, or without reported THC:CBD ratios, data were too scarce to reach any conclusions at all about safety or efficacy, highlighting the sizable knowledge gaps that remain in the area, the authors said.

“The current evidence on cannabis-related products for chronic pain is quite limited,” Dr. McDonagh said in an interview. “Patients with chronic pain should consult with their doctor to discuss which of the many options for treating chronic pain is best for them to start with.”
 

Patients may face resistance when asking about cannabis

According to Kevin F. Boehnke, PhD, and Daniel J. Clauw, MD, of the anesthesiology department and Chronic Pain and Fatigue Research Center at the University of Michigan, Ann Arbor, patients with chronic pain may face resistance, or even risk of being reported, when asking about cannabis-based products.

“Some physicians cite lack of data as rationale for not engaging with patients who wish to use or currently use cannabis,” Dr. Boehnke and Dr. Clauw wrote in an accompanying editorial. “Such practices may reflect consideration of cannabis solely as a drug of misuse (even in the 37 states where medical cannabis is legal) and requirements to refer patients who disclose or test positive for cannabis use to addiction services or decline to refill opioid prescriptions.”

Instead of shutting patients out, Dr. Boehnke and Dr. Clauw suggested clinicians engage in an “open information exchange” with their patients that focuses on “pragmatism, patient experience, known cannabinoid effects, and harm reduction.” In these conversations, the editorialists recommend noting that, “as with other analgesics, some persons will benefit, and others will not.”

They also offered some practical guidance: “Clinicians could suggest using tinctures (effect onset, 15-45 minutes) for breakthrough pain and edibles or capsules (which last about 6-8 hours) for extended relief. ... The scientific literature suggests that CBD doses could start at 5-10 mg twice daily and increase to 40-50 mg daily, whereas THC doses could start at 0.5-3 mg (initially at night) and increase to 30-40 mg/day.”

David Copenhaver, MD, MPH, clinical professor and chief of the division of pain medicine at UC Davis Health, Sacramento, shared a similar clinical mindset for patients choosing between opioids and cannabis-based products, specifically, CBD.

Compared with opioids, “the side-effect profile for CBD is less and the risk of mortality is less,” Dr. Copenhaver said in an interview, pointing out that nobody, to his knowledge, has ever died from an overdose of cannabis alone, and that CBD doses up to 1,000 mg/kg have been safely tolerated in people. “You present that, and most patients will say, ‘You know, I’d like to give this a try.’”

If so, Dr. Copenhaver makes sure patients know about a nonmedical risk: “The risk to the pocketbook.” Unlike opioids, which are covered under most insurance policies, most cannabis-based therapies are self-pay.

Buyers may get what they pay for, Dr. Copenhaver said, since products vary in quality, as do the dispensaries, from “very modest,” to highly sophisticated, with some even using chromatographic datasets to support the purity of their products.

Dr. Copenhaver steers his patients toward these more sophisticated retailers. Their expertise appears to be paying off, he said, not only in relief for patients, but also in market share. “Survival of the most fit will occur in the marketplace based on the results,” he said. “Unfortunately, some of that information doesn’t get percolated out into the literature.”

For investigators to fully uncover what cannabis-based products can do for chronic pain, Dr. Copenhaver said they need to get as “granular” as the leading dispensaries, which may first require recognition of the “very expansive opportunity” that less-studied cannabinoids may provide.

The study was supported by the Agency for Healthcare Research and Quality, U.S. Department of Health & Human Services. The investigators, Dr. Boehnke, Dr. Clauw, and Dr. Copenhaver, disclosed no conflicts of interest.

Cannabis-based products may control chronic pain as effectively as opioids, but adverse effects are common, and long-term safety remains unknown, according to a new study.

Several other systematic reviews have recently evaluated cannabinoids for treating chronic pain, but the new study’s methodology was “distinct” in “important ways,” leading to “conclusions that differ from other reviews,” according to the authors of the paper published in the Annals of Internal Medicine.

In the new systematic review, synthetic products with high THC:CBD ratios were associated with moderate improvements in pain, whereas plant-based products with comparable THC:CBD ratios offered less relief, said study author Marian S. McDonagh, PharmD, professor of medical informatics and clinical epidemiology, and codirector of the Evidence-based Practice Center at Oregon Health & Science University, Portland, and colleagues.

Specifically, the investigators stratified cannabis-based interventions according to relative content of two key cannabinoids: THC and CBD. Products were sorted into five categories: high THC:CBD ratio (at least 2:1), comparable THC:CBD ratio (less than 2:1 but more than 1:2), low THC:CBD ratio (no more than 1:2), whole-plant cannabis products, and other cannabinoids.

“In preclinical studies, THC and related compounds have demonstrated analgesic properties, although its psychoactive effects and addiction potential may limit its suitability as an analgesic,” the investigators wrote. “CBD and other cannabinoids may also have some analgesic or anti-inflammatory properties and are not believed to be psychoactive or addictive. Given the variation in analgesic effect with THC and CBD, response may differ according to the ratio of THC to CBD in products used to treat pain.”

The final analysis included 18 randomized placebo-controlled trials involving 1,740 individuals and 7 cohort studies involving 13,095 individuals. Most of the studies were short-term, lasting 1-6 months.

Pain was scored on a ten-point scale, with improvements reported as the mean difference from baseline to post treatment. A mean difference in pain score of 0.5-1.0 was considered a “small effect,” an improvement of 1-2 points was considered a “moderate effect,” and an improvement greater than 2 points was considered a “large effect.”
 

Cannabis-based products with relatively high THC:CBD ratios showed efficacy

Synthetic products with high THC:CBD ratios offered moderate pain relief, based on a mean difference in pain score of –1.15 (95% confidence interval, –1.99 to –0.54), whereas products with comparable THC:CBD ratios were associated with a small effect on pain, with a mean difference of –0.52 (95% CI, –0.95 to –0.19).

According to Dr. McDonagh, treatment response rates were on par with response rates for more conventional treatments, “such as opioids or specific antidepressant drugs,” but data for the cannabis-based products are weaker.

“The amount of evidence available for cannabis-related products is very limited for [response rates], and therefore less certain,” Dr. McDonagh said in an interview. “The average reduction in pain severity is also similar to some other treatments, but we do not have studies directly comparing these treatments to draw conclusions.”

Although the cannabis-based products with relatively high and comparable THC:CBD ratios showed efficacy, they were also associated with “moderate to large increased risk for dizziness, sedation, and nausea,” the investigators wrote, noting that evidence was insufficient to characterize other “key adverse event outcomes” that may occur with long-term use, such as “psychosis, cannabis use disorder, and cognitive deficits.”

For products with low THC:CBD ratios, or without reported THC:CBD ratios, data were too scarce to reach any conclusions at all about safety or efficacy, highlighting the sizable knowledge gaps that remain in the area, the authors said.

“The current evidence on cannabis-related products for chronic pain is quite limited,” Dr. McDonagh said in an interview. “Patients with chronic pain should consult with their doctor to discuss which of the many options for treating chronic pain is best for them to start with.”
 

Patients may face resistance when asking about cannabis

According to Kevin F. Boehnke, PhD, and Daniel J. Clauw, MD, of the anesthesiology department and Chronic Pain and Fatigue Research Center at the University of Michigan, Ann Arbor, patients with chronic pain may face resistance, or even risk of being reported, when asking about cannabis-based products.

“Some physicians cite lack of data as rationale for not engaging with patients who wish to use or currently use cannabis,” Dr. Boehnke and Dr. Clauw wrote in an accompanying editorial. “Such practices may reflect consideration of cannabis solely as a drug of misuse (even in the 37 states where medical cannabis is legal) and requirements to refer patients who disclose or test positive for cannabis use to addiction services or decline to refill opioid prescriptions.”

Instead of shutting patients out, Dr. Boehnke and Dr. Clauw suggested clinicians engage in an “open information exchange” with their patients that focuses on “pragmatism, patient experience, known cannabinoid effects, and harm reduction.” In these conversations, the editorialists recommend noting that, “as with other analgesics, some persons will benefit, and others will not.”

They also offered some practical guidance: “Clinicians could suggest using tinctures (effect onset, 15-45 minutes) for breakthrough pain and edibles or capsules (which last about 6-8 hours) for extended relief. ... The scientific literature suggests that CBD doses could start at 5-10 mg twice daily and increase to 40-50 mg daily, whereas THC doses could start at 0.5-3 mg (initially at night) and increase to 30-40 mg/day.”

David Copenhaver, MD, MPH, clinical professor and chief of the division of pain medicine at UC Davis Health, Sacramento, shared a similar clinical mindset for patients choosing between opioids and cannabis-based products, specifically, CBD.

Compared with opioids, “the side-effect profile for CBD is less and the risk of mortality is less,” Dr. Copenhaver said in an interview, pointing out that nobody, to his knowledge, has ever died from an overdose of cannabis alone, and that CBD doses up to 1,000 mg/kg have been safely tolerated in people. “You present that, and most patients will say, ‘You know, I’d like to give this a try.’”

If so, Dr. Copenhaver makes sure patients know about a nonmedical risk: “The risk to the pocketbook.” Unlike opioids, which are covered under most insurance policies, most cannabis-based therapies are self-pay.

Buyers may get what they pay for, Dr. Copenhaver said, since products vary in quality, as do the dispensaries, from “very modest,” to highly sophisticated, with some even using chromatographic datasets to support the purity of their products.

Dr. Copenhaver steers his patients toward these more sophisticated retailers. Their expertise appears to be paying off, he said, not only in relief for patients, but also in market share. “Survival of the most fit will occur in the marketplace based on the results,” he said. “Unfortunately, some of that information doesn’t get percolated out into the literature.”

For investigators to fully uncover what cannabis-based products can do for chronic pain, Dr. Copenhaver said they need to get as “granular” as the leading dispensaries, which may first require recognition of the “very expansive opportunity” that less-studied cannabinoids may provide.

The study was supported by the Agency for Healthcare Research and Quality, U.S. Department of Health & Human Services. The investigators, Dr. Boehnke, Dr. Clauw, and Dr. Copenhaver, disclosed no conflicts of interest.

Cannabis-based products may control chronic pain as effectively as opioids, but adverse effects are common, and long-term safety remains unknown, according to a new study.

Several other systematic reviews have recently evaluated cannabinoids for treating chronic pain, but the new study’s methodology was “distinct” in “important ways,” leading to “conclusions that differ from other reviews,” according to the authors of the paper published in the Annals of Internal Medicine.

In the new systematic review, synthetic products with high THC:CBD ratios were associated with moderate improvements in pain, whereas plant-based products with comparable THC:CBD ratios offered less relief, said study author Marian S. McDonagh, PharmD, professor of medical informatics and clinical epidemiology, and codirector of the Evidence-based Practice Center at Oregon Health & Science University, Portland, and colleagues.

Specifically, the investigators stratified cannabis-based interventions according to relative content of two key cannabinoids: THC and CBD. Products were sorted into five categories: high THC:CBD ratio (at least 2:1), comparable THC:CBD ratio (less than 2:1 but more than 1:2), low THC:CBD ratio (no more than 1:2), whole-plant cannabis products, and other cannabinoids.

“In preclinical studies, THC and related compounds have demonstrated analgesic properties, although its psychoactive effects and addiction potential may limit its suitability as an analgesic,” the investigators wrote. “CBD and other cannabinoids may also have some analgesic or anti-inflammatory properties and are not believed to be psychoactive or addictive. Given the variation in analgesic effect with THC and CBD, response may differ according to the ratio of THC to CBD in products used to treat pain.”

The final analysis included 18 randomized placebo-controlled trials involving 1,740 individuals and 7 cohort studies involving 13,095 individuals. Most of the studies were short-term, lasting 1-6 months.

Pain was scored on a ten-point scale, with improvements reported as the mean difference from baseline to post treatment. A mean difference in pain score of 0.5-1.0 was considered a “small effect,” an improvement of 1-2 points was considered a “moderate effect,” and an improvement greater than 2 points was considered a “large effect.”
 

Cannabis-based products with relatively high THC:CBD ratios showed efficacy

Synthetic products with high THC:CBD ratios offered moderate pain relief, based on a mean difference in pain score of –1.15 (95% confidence interval, –1.99 to –0.54), whereas products with comparable THC:CBD ratios were associated with a small effect on pain, with a mean difference of –0.52 (95% CI, –0.95 to –0.19).

According to Dr. McDonagh, treatment response rates were on par with response rates for more conventional treatments, “such as opioids or specific antidepressant drugs,” but data for the cannabis-based products are weaker.

“The amount of evidence available for cannabis-related products is very limited for [response rates], and therefore less certain,” Dr. McDonagh said in an interview. “The average reduction in pain severity is also similar to some other treatments, but we do not have studies directly comparing these treatments to draw conclusions.”

Although the cannabis-based products with relatively high and comparable THC:CBD ratios showed efficacy, they were also associated with “moderate to large increased risk for dizziness, sedation, and nausea,” the investigators wrote, noting that evidence was insufficient to characterize other “key adverse event outcomes” that may occur with long-term use, such as “psychosis, cannabis use disorder, and cognitive deficits.”

For products with low THC:CBD ratios, or without reported THC:CBD ratios, data were too scarce to reach any conclusions at all about safety or efficacy, highlighting the sizable knowledge gaps that remain in the area, the authors said.

“The current evidence on cannabis-related products for chronic pain is quite limited,” Dr. McDonagh said in an interview. “Patients with chronic pain should consult with their doctor to discuss which of the many options for treating chronic pain is best for them to start with.”
 

Patients may face resistance when asking about cannabis

According to Kevin F. Boehnke, PhD, and Daniel J. Clauw, MD, of the anesthesiology department and Chronic Pain and Fatigue Research Center at the University of Michigan, Ann Arbor, patients with chronic pain may face resistance, or even risk of being reported, when asking about cannabis-based products.

“Some physicians cite lack of data as rationale for not engaging with patients who wish to use or currently use cannabis,” Dr. Boehnke and Dr. Clauw wrote in an accompanying editorial. “Such practices may reflect consideration of cannabis solely as a drug of misuse (even in the 37 states where medical cannabis is legal) and requirements to refer patients who disclose or test positive for cannabis use to addiction services or decline to refill opioid prescriptions.”

Instead of shutting patients out, Dr. Boehnke and Dr. Clauw suggested clinicians engage in an “open information exchange” with their patients that focuses on “pragmatism, patient experience, known cannabinoid effects, and harm reduction.” In these conversations, the editorialists recommend noting that, “as with other analgesics, some persons will benefit, and others will not.”

They also offered some practical guidance: “Clinicians could suggest using tinctures (effect onset, 15-45 minutes) for breakthrough pain and edibles or capsules (which last about 6-8 hours) for extended relief. ... The scientific literature suggests that CBD doses could start at 5-10 mg twice daily and increase to 40-50 mg daily, whereas THC doses could start at 0.5-3 mg (initially at night) and increase to 30-40 mg/day.”

David Copenhaver, MD, MPH, clinical professor and chief of the division of pain medicine at UC Davis Health, Sacramento, shared a similar clinical mindset for patients choosing between opioids and cannabis-based products, specifically, CBD.

Compared with opioids, “the side-effect profile for CBD is less and the risk of mortality is less,” Dr. Copenhaver said in an interview, pointing out that nobody, to his knowledge, has ever died from an overdose of cannabis alone, and that CBD doses up to 1,000 mg/kg have been safely tolerated in people. “You present that, and most patients will say, ‘You know, I’d like to give this a try.’”

If so, Dr. Copenhaver makes sure patients know about a nonmedical risk: “The risk to the pocketbook.” Unlike opioids, which are covered under most insurance policies, most cannabis-based therapies are self-pay.

Buyers may get what they pay for, Dr. Copenhaver said, since products vary in quality, as do the dispensaries, from “very modest,” to highly sophisticated, with some even using chromatographic datasets to support the purity of their products.

Dr. Copenhaver steers his patients toward these more sophisticated retailers. Their expertise appears to be paying off, he said, not only in relief for patients, but also in market share. “Survival of the most fit will occur in the marketplace based on the results,” he said. “Unfortunately, some of that information doesn’t get percolated out into the literature.”

For investigators to fully uncover what cannabis-based products can do for chronic pain, Dr. Copenhaver said they need to get as “granular” as the leading dispensaries, which may first require recognition of the “very expansive opportunity” that less-studied cannabinoids may provide.

The study was supported by the Agency for Healthcare Research and Quality, U.S. Department of Health & Human Services. The investigators, Dr. Boehnke, Dr. Clauw, and Dr. Copenhaver, disclosed no conflicts of interest.

NATIONAL HARBOR, MD. -- Over 25 years of clinical research, phase 3 trials of approved disease-modifying therapies (DMTs) for multiple sclerosis (MS) were overwhelmingly made up of White subjects, a new analysis finds, and many studies failed to report percentages of non-White subjects at all. Researchers also found that the websites of multiple major drug manufacturers don’t include any trial data about how medications may affect people of different races and ethnicities.

It’s clear that “non-White participants are significantly underreported and unrepresented,” said study corresponding author and Dell Medical School/The University of Texas at Austin neurologist Leorah Freeman, MD, PhD, in an interview. “Despite the globalization of MS trials over time, we do not see that trials are enrolling more diverse populations.”

The study was presented at the annual meeting of the Consortium of Multiple Sclerosis Centers and published in Neurology.

“The lack of diversity in MS research is something that has been sporadically discussed in the past. By conducting this systematic review of MS phase 3 trials, we wanted to put numbers on this issue and review the evidence systematically,” Dr. Freeman said. “By doing so, we hoped to raise awareness about the problem of underreporting and underrepresentation of non-White participants in trials so that we, as a community involved in MS research, can start having the difficult conversations needed for change to occur.”
 

25 years of clinical research

The researchers reviewed 44 phase 3 studies from 1995-2020 that represented 45 trials. “We wanted to capture data from the very first global trials being conducted for the approval of MS DMTs, and the first was published in 1995,” Dr. Freeman said. “We were interested in understanding the impact of trial globalization over a long period of time on diversity of enrollment.”

The studies include trials of mainstays of MS treatment such as interferon, glatiramer acetate, teriflunomide, dimethyl fumarate, diroximel fumarate, fingolimod, natalizumab, and others.

The researchers found that 17 (37.8%) of the trials did not report race or ethnicity, 14 (31.1%) reported race and ethnicity as proportion of White participants only, and 14 (31.1%) reported 2 or more races/ethnicities.

Of the 28 trials with racial breakdowns, the median percentage of White participants was 93.8% (range 78.5-99.6% across 28 studies), 1.9% for Black participants (range 0.1-8.1% across 14 studies), and 0.5% for Asian participants (range 0.1-14.5% across 11 studies).

The studies often failed to account for non-White subjects even though “Black people, in particular, have been shown to have a more severe disease course,” Dr. Freeman said.

A 2022 study of more than 2.6 million Southern California adults finds that prevalence of MS was similar among White and Black people at about 230 per 100,000. “Taken together with previous studies, these findings indicate that the burden of MS in the United States Black community has long been underrecognized,” the researchers wrote.

According to Dr. Freeman, it’s unclear why the studies were so dominated by White subjects. “Lack of awareness about the importance of this information likely explains why this information often goes unreported.”

She highlighted the TOWER (teriflunomide) and DEFINE and CONFIRM (dimethyl fumarate) studies as positive examples. “We noted the inclusion of trial sites in Asia and consequently a higher representation of Asian people with MS in those trials. We felt these studies were examples of how trial globalization can support better representation of underrepresented groups.”

And she noted that the ongoing CHIMES trial is examining the use of ocrelizumab in Black and Hispanic people with MS. “This study was designed in partnership with MS patients and advocacy groups to bridge gaps in clinical trial participation in these communities,” she said. “Innovative strategies were developed to increase participation of Black and Hispanic patients in this trial.”
 

What should happen next?

Going forward, Dr. Freeman said, “MS researchers, DMT manufacturers, sponsors, and publishers need to set better standards for racial and ethnic representation and reporting in trial publications.”

In an interview, epidemiologist Luisa N. Borrell, DDS, PhD, a professor who studies race and medicine at City University of New York, said the new study is valid and useful. She noted that it reflects the findings of a 2022 analysis of more than 20,500 clinical trials in the U.S. from 2000-2020: Only 43% reported racial/ethnic breakdowns, and the subjects were much more White than the population at large.

Possible reasons for the disparity include distrust among possible participants and lack of health literacy, she said, which are both “modifiable issues.”

Dr. Borrell added: “Clinical trials should aim to recruit populations affected by the outcome of interest. That would allow for the intervention to effectively treat those who need it the most. Moreover, the lack of diversity of trials brings issues of generalizability and transportability of the findings.”

No funding is reported. Dr. Freeman and some of the other study authors report various disclosures.

NATIONAL HARBOR, MD. -- Over 25 years of clinical research, phase 3 trials of approved disease-modifying therapies (DMTs) for multiple sclerosis (MS) were overwhelmingly made up of White subjects, a new analysis finds, and many studies failed to report percentages of non-White subjects at all. Researchers also found that the websites of multiple major drug manufacturers don’t include any trial data about how medications may affect people of different races and ethnicities.

It’s clear that “non-White participants are significantly underreported and unrepresented,” said study corresponding author and Dell Medical School/The University of Texas at Austin neurologist Leorah Freeman, MD, PhD, in an interview. “Despite the globalization of MS trials over time, we do not see that trials are enrolling more diverse populations.”

The study was presented at the annual meeting of the Consortium of Multiple Sclerosis Centers and published in Neurology.

“The lack of diversity in MS research is something that has been sporadically discussed in the past. By conducting this systematic review of MS phase 3 trials, we wanted to put numbers on this issue and review the evidence systematically,” Dr. Freeman said. “By doing so, we hoped to raise awareness about the problem of underreporting and underrepresentation of non-White participants in trials so that we, as a community involved in MS research, can start having the difficult conversations needed for change to occur.”
 

25 years of clinical research

The researchers reviewed 44 phase 3 studies from 1995-2020 that represented 45 trials. “We wanted to capture data from the very first global trials being conducted for the approval of MS DMTs, and the first was published in 1995,” Dr. Freeman said. “We were interested in understanding the impact of trial globalization over a long period of time on diversity of enrollment.”

The studies include trials of mainstays of MS treatment such as interferon, glatiramer acetate, teriflunomide, dimethyl fumarate, diroximel fumarate, fingolimod, natalizumab, and others.

The researchers found that 17 (37.8%) of the trials did not report race or ethnicity, 14 (31.1%) reported race and ethnicity as proportion of White participants only, and 14 (31.1%) reported 2 or more races/ethnicities.

Of the 28 trials with racial breakdowns, the median percentage of White participants was 93.8% (range 78.5-99.6% across 28 studies), 1.9% for Black participants (range 0.1-8.1% across 14 studies), and 0.5% for Asian participants (range 0.1-14.5% across 11 studies).

The studies often failed to account for non-White subjects even though “Black people, in particular, have been shown to have a more severe disease course,” Dr. Freeman said.

A 2022 study of more than 2.6 million Southern California adults finds that prevalence of MS was similar among White and Black people at about 230 per 100,000. “Taken together with previous studies, these findings indicate that the burden of MS in the United States Black community has long been underrecognized,” the researchers wrote.

According to Dr. Freeman, it’s unclear why the studies were so dominated by White subjects. “Lack of awareness about the importance of this information likely explains why this information often goes unreported.”

She highlighted the TOWER (teriflunomide) and DEFINE and CONFIRM (dimethyl fumarate) studies as positive examples. “We noted the inclusion of trial sites in Asia and consequently a higher representation of Asian people with MS in those trials. We felt these studies were examples of how trial globalization can support better representation of underrepresented groups.”

And she noted that the ongoing CHIMES trial is examining the use of ocrelizumab in Black and Hispanic people with MS. “This study was designed in partnership with MS patients and advocacy groups to bridge gaps in clinical trial participation in these communities,” she said. “Innovative strategies were developed to increase participation of Black and Hispanic patients in this trial.”
 

What should happen next?

Going forward, Dr. Freeman said, “MS researchers, DMT manufacturers, sponsors, and publishers need to set better standards for racial and ethnic representation and reporting in trial publications.”

In an interview, epidemiologist Luisa N. Borrell, DDS, PhD, a professor who studies race and medicine at City University of New York, said the new study is valid and useful. She noted that it reflects the findings of a 2022 analysis of more than 20,500 clinical trials in the U.S. from 2000-2020: Only 43% reported racial/ethnic breakdowns, and the subjects were much more White than the population at large.

Possible reasons for the disparity include distrust among possible participants and lack of health literacy, she said, which are both “modifiable issues.”

Dr. Borrell added: “Clinical trials should aim to recruit populations affected by the outcome of interest. That would allow for the intervention to effectively treat those who need it the most. Moreover, the lack of diversity of trials brings issues of generalizability and transportability of the findings.”

No funding is reported. Dr. Freeman and some of the other study authors report various disclosures.

NATIONAL HARBOR, MD. -- Over 25 years of clinical research, phase 3 trials of approved disease-modifying therapies (DMTs) for multiple sclerosis (MS) were overwhelmingly made up of White subjects, a new analysis finds, and many studies failed to report percentages of non-White subjects at all. Researchers also found that the websites of multiple major drug manufacturers don’t include any trial data about how medications may affect people of different races and ethnicities.

It’s clear that “non-White participants are significantly underreported and unrepresented,” said study corresponding author and Dell Medical School/The University of Texas at Austin neurologist Leorah Freeman, MD, PhD, in an interview. “Despite the globalization of MS trials over time, we do not see that trials are enrolling more diverse populations.”

The study was presented at the annual meeting of the Consortium of Multiple Sclerosis Centers and published in Neurology.

“The lack of diversity in MS research is something that has been sporadically discussed in the past. By conducting this systematic review of MS phase 3 trials, we wanted to put numbers on this issue and review the evidence systematically,” Dr. Freeman said. “By doing so, we hoped to raise awareness about the problem of underreporting and underrepresentation of non-White participants in trials so that we, as a community involved in MS research, can start having the difficult conversations needed for change to occur.”
 

25 years of clinical research

The researchers reviewed 44 phase 3 studies from 1995-2020 that represented 45 trials. “We wanted to capture data from the very first global trials being conducted for the approval of MS DMTs, and the first was published in 1995,” Dr. Freeman said. “We were interested in understanding the impact of trial globalization over a long period of time on diversity of enrollment.”

The studies include trials of mainstays of MS treatment such as interferon, glatiramer acetate, teriflunomide, dimethyl fumarate, diroximel fumarate, fingolimod, natalizumab, and others.

The researchers found that 17 (37.8%) of the trials did not report race or ethnicity, 14 (31.1%) reported race and ethnicity as proportion of White participants only, and 14 (31.1%) reported 2 or more races/ethnicities.

Of the 28 trials with racial breakdowns, the median percentage of White participants was 93.8% (range 78.5-99.6% across 28 studies), 1.9% for Black participants (range 0.1-8.1% across 14 studies), and 0.5% for Asian participants (range 0.1-14.5% across 11 studies).

The studies often failed to account for non-White subjects even though “Black people, in particular, have been shown to have a more severe disease course,” Dr. Freeman said.

A 2022 study of more than 2.6 million Southern California adults finds that prevalence of MS was similar among White and Black people at about 230 per 100,000. “Taken together with previous studies, these findings indicate that the burden of MS in the United States Black community has long been underrecognized,” the researchers wrote.

According to Dr. Freeman, it’s unclear why the studies were so dominated by White subjects. “Lack of awareness about the importance of this information likely explains why this information often goes unreported.”

She highlighted the TOWER (teriflunomide) and DEFINE and CONFIRM (dimethyl fumarate) studies as positive examples. “We noted the inclusion of trial sites in Asia and consequently a higher representation of Asian people with MS in those trials. We felt these studies were examples of how trial globalization can support better representation of underrepresented groups.”

And she noted that the ongoing CHIMES trial is examining the use of ocrelizumab in Black and Hispanic people with MS. “This study was designed in partnership with MS patients and advocacy groups to bridge gaps in clinical trial participation in these communities,” she said. “Innovative strategies were developed to increase participation of Black and Hispanic patients in this trial.”
 

What should happen next?

Going forward, Dr. Freeman said, “MS researchers, DMT manufacturers, sponsors, and publishers need to set better standards for racial and ethnic representation and reporting in trial publications.”

In an interview, epidemiologist Luisa N. Borrell, DDS, PhD, a professor who studies race and medicine at City University of New York, said the new study is valid and useful. She noted that it reflects the findings of a 2022 analysis of more than 20,500 clinical trials in the U.S. from 2000-2020: Only 43% reported racial/ethnic breakdowns, and the subjects were much more White than the population at large.

Possible reasons for the disparity include distrust among possible participants and lack of health literacy, she said, which are both “modifiable issues.”

Dr. Borrell added: “Clinical trials should aim to recruit populations affected by the outcome of interest. That would allow for the intervention to effectively treat those who need it the most. Moreover, the lack of diversity of trials brings issues of generalizability and transportability of the findings.”

No funding is reported. Dr. Freeman and some of the other study authors report various disclosures.

CHICAGO – New results from a trial in patients with newly diagnosed multiple myeloma (MM) offer some answers to questions about which treatment route to choose.

The trial, known as DETERMINATION, found that newly diagnosed patients treated with a triplet of drugs had longer progression-free survival (PFS) if they received an autologous stem cell transplant (ASCT) soon after the drug therapy than if they simply had their stem cells collected for a possible future transplant.

Patients who received the triplet of lenalidomide, bortezomib, and dexamethasone (RVD) plus ASCT had a median PFS of 67.5 months, compared with 46.2 months for those who received RVD but did not have a transplant soon after.

However, patients were just as likely to be alive more than 6 years after treatment regardless of whether or not they underwent an immediate stem cell transplant.

In addition, treatment-related adverse events of grade 3 or above were higher in the group that received the transplant immediately after the triplet therapy.  

The results were presented during a plenary session at the American Society of Clinical Oncology annual meeting and simultaneously published in the New England Journal of Medicine.

“Our findings confirm the PFS benefit of transplantation as first-line treatment for patients with myeloma and confirms stem cell transplant as a standard of care with certain triplet therapy,” said lead author Paul G. Richardson, MD, professor of medicine, Harvard Medical School, and clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana Farber Cancer Institute, Boston.

Another finding from the trial was that the use of maintenance lenalidomide in both groups continuously until progression conferred substantial clinical benefit.

“We can also say that the use of lenalidomide maintenance therapy is also a standard of care,” he added.
 

Study details

In this trial, Dr. Richardson and colleagues randomly assigned 873 patients newly diagnosed with multiple myeloma to the RVD-alone group (n = 357) or the transplantation group (n = 365). All patients had received one cycle of RVD prior to randomization and then received two additional RVD cycles plus stem-cell mobilization followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Lenalidomide was administered to all patients until disease progression, unacceptable side effects, or both.

At a median follow-up of 76.0 months, the risk of disease progression or death was 53% higher among patients who received RVD alone versus the transplantation group (hazard ratio [HR], 1.53; P < .001). The median duration of PFS among patients with a high-risk cytogenetic profile was 55.5 vs. 17.1 months, favoring the transplantation group.

The percentage of patients who were alive without progression at 5 years was 58.4% vs 41.6%, respectively (HR, 1.66) and median duration of response was 56.4 vs 38.9 months, also favoring transplantation (HR, 1.45).

The estimated 5-year overall survival was similar between groups: 80.7% for transplantation and 79.2% for RVD alone (HR for death, 1.10; P > .99). For patients with a high-risk cytogenetic profile, 5-year survival was 63.4% versus 54.3%, respectively.

“This tells us that for patients who had kept transplant in reserve, they had the same overall survival as those who had had a transplant right away, despite there being such impressive initial disease control for the patients in whom transplant was used early,” Dr. Richardson said in a press release from his institution.

Patients who did not undergo immediate transplant received treatment when their disease progressed with newer and active therapies, such as monoclonal antibodies and/or next-generation novel agents, he noted. Only 28% of patients used the reserve option of a transplant.

“It demonstrates the extent to which patients now have options and that we have new data to guide them in balancing the pluses and minuses of each approach,” he added.

When looking at safety, the authors noted that the most common treatment-related adverse events of grade 3 or higher occurred in 279 patients (78.2%) in the RVD-alone group and 344 patients (94.2%) in the transplantation group. Of those patients, 60.5% and 89.9%, respectively, reported hematologic events of grade 3 or higher (P < .001). The 5-year cumulative incidence of invasive second primary cancers was similar in both cohorts (RVD-alone group, 4.9%; transplantation group, 6.5%).

However, while the risk of secondary cancers was similar between groups, Dr. Richardson noted that there was a higher incidence of acute myeloid leukemia and myelodysplastic syndromes in the transplant cohort.

“There was also a significant drop in quality of life across transplant procedures, but the good news is that it was recoverable rapidly,” he said. “What is also really important is that we have prospective, multicenter, national comparative data on toxicity. That’s very important for providing patients with a choice as they move forward with their treatment plan.”

He noted that treatment continues to evolve. “This study was designed in 2009, begun in 2010, and now there is mature data in 2022,” Dr. Richardson said. “This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies and novel next-generation therapies. The results from these studies are extremely exciting.

“Now more than ever, treatment for multiple myeloma can be adapted for each patient,” Dr. Richardson said. “Our study provides important information about the benefits of transplant in the era of highly effective novel therapies and continuous maintenance, as well as the potential risks, to help patients and their physicians decide what approach may be best for them. This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies, such as RVD combined with daratumumab.”
 

Lack of difference in overall survival

These new results further support an already established role of autologous hematopoietic stem cell transplantation in the management of patients with multiple myeloma, said Samer Al-Homsi, MD, clinical professor of medicine and director of the blood and marrow transplant program at Perlmutter Cancer Center, NYU Langone, New York, who was approached for comment.

“The treatment regimen is applicable to patients who are determined by an expert in transplantation to be fit to receive autologous hematopoietic transplantation,” he added. “Although this study, like many others, establishes hematopoietic stem cell transplantation as part of the standard of care in multiple myeloma, only a fraction of patients are actually offered this important modality of treatment for a variety of reasons, including provider bias,” he noted. “In fact, although improvement in supportive care has enhanced the safety of the procedure, many patients are denied this therapy.” 

Dr. Al-Homsi noted that the lack of difference in overall survival might be due to the fact that some patients (28%) in the RVD-alone group did end up undergoing transplantation at the time of progression. “Also, longer follow-up might reveal a difference in overall survival,” he said.

The toxicities are manageable, and the incidence of secondary malignancies was not significantly different between cohorts. “However,” he emphasized, “lenalidomide has been associated in other studies with increased incidence of secondary malignancies and it must be noted that this study used extended administration of lenalidomide until progression.” 

Support for this study was provided by grants to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute, the National Cancer Institute, R. J. Corman Multiple Myeloma Foundation, Celgene/Bristol Myers Squibb, and Millennium/Takeda Pharmaceutical. Dr. Richardson has reported relationships with Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm Therapeutics, Oncopeptides, Sanofi, Secura Bio, Takeda, and Bristol Myers Squibb. Dr. Al-Homsi has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

CHICAGO – New results from a trial in patients with newly diagnosed multiple myeloma (MM) offer some answers to questions about which treatment route to choose.

The trial, known as DETERMINATION, found that newly diagnosed patients treated with a triplet of drugs had longer progression-free survival (PFS) if they received an autologous stem cell transplant (ASCT) soon after the drug therapy than if they simply had their stem cells collected for a possible future transplant.

Patients who received the triplet of lenalidomide, bortezomib, and dexamethasone (RVD) plus ASCT had a median PFS of 67.5 months, compared with 46.2 months for those who received RVD but did not have a transplant soon after.

However, patients were just as likely to be alive more than 6 years after treatment regardless of whether or not they underwent an immediate stem cell transplant.

In addition, treatment-related adverse events of grade 3 or above were higher in the group that received the transplant immediately after the triplet therapy.  

The results were presented during a plenary session at the American Society of Clinical Oncology annual meeting and simultaneously published in the New England Journal of Medicine.

“Our findings confirm the PFS benefit of transplantation as first-line treatment for patients with myeloma and confirms stem cell transplant as a standard of care with certain triplet therapy,” said lead author Paul G. Richardson, MD, professor of medicine, Harvard Medical School, and clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana Farber Cancer Institute, Boston.

Another finding from the trial was that the use of maintenance lenalidomide in both groups continuously until progression conferred substantial clinical benefit.

“We can also say that the use of lenalidomide maintenance therapy is also a standard of care,” he added.
 

Study details

In this trial, Dr. Richardson and colleagues randomly assigned 873 patients newly diagnosed with multiple myeloma to the RVD-alone group (n = 357) or the transplantation group (n = 365). All patients had received one cycle of RVD prior to randomization and then received two additional RVD cycles plus stem-cell mobilization followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Lenalidomide was administered to all patients until disease progression, unacceptable side effects, or both.

At a median follow-up of 76.0 months, the risk of disease progression or death was 53% higher among patients who received RVD alone versus the transplantation group (hazard ratio [HR], 1.53; P < .001). The median duration of PFS among patients with a high-risk cytogenetic profile was 55.5 vs. 17.1 months, favoring the transplantation group.

The percentage of patients who were alive without progression at 5 years was 58.4% vs 41.6%, respectively (HR, 1.66) and median duration of response was 56.4 vs 38.9 months, also favoring transplantation (HR, 1.45).

The estimated 5-year overall survival was similar between groups: 80.7% for transplantation and 79.2% for RVD alone (HR for death, 1.10; P > .99). For patients with a high-risk cytogenetic profile, 5-year survival was 63.4% versus 54.3%, respectively.

“This tells us that for patients who had kept transplant in reserve, they had the same overall survival as those who had had a transplant right away, despite there being such impressive initial disease control for the patients in whom transplant was used early,” Dr. Richardson said in a press release from his institution.

Patients who did not undergo immediate transplant received treatment when their disease progressed with newer and active therapies, such as monoclonal antibodies and/or next-generation novel agents, he noted. Only 28% of patients used the reserve option of a transplant.

“It demonstrates the extent to which patients now have options and that we have new data to guide them in balancing the pluses and minuses of each approach,” he added.

When looking at safety, the authors noted that the most common treatment-related adverse events of grade 3 or higher occurred in 279 patients (78.2%) in the RVD-alone group and 344 patients (94.2%) in the transplantation group. Of those patients, 60.5% and 89.9%, respectively, reported hematologic events of grade 3 or higher (P < .001). The 5-year cumulative incidence of invasive second primary cancers was similar in both cohorts (RVD-alone group, 4.9%; transplantation group, 6.5%).

However, while the risk of secondary cancers was similar between groups, Dr. Richardson noted that there was a higher incidence of acute myeloid leukemia and myelodysplastic syndromes in the transplant cohort.

“There was also a significant drop in quality of life across transplant procedures, but the good news is that it was recoverable rapidly,” he said. “What is also really important is that we have prospective, multicenter, national comparative data on toxicity. That’s very important for providing patients with a choice as they move forward with their treatment plan.”

He noted that treatment continues to evolve. “This study was designed in 2009, begun in 2010, and now there is mature data in 2022,” Dr. Richardson said. “This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies and novel next-generation therapies. The results from these studies are extremely exciting.

“Now more than ever, treatment for multiple myeloma can be adapted for each patient,” Dr. Richardson said. “Our study provides important information about the benefits of transplant in the era of highly effective novel therapies and continuous maintenance, as well as the potential risks, to help patients and their physicians decide what approach may be best for them. This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies, such as RVD combined with daratumumab.”
 

Lack of difference in overall survival

These new results further support an already established role of autologous hematopoietic stem cell transplantation in the management of patients with multiple myeloma, said Samer Al-Homsi, MD, clinical professor of medicine and director of the blood and marrow transplant program at Perlmutter Cancer Center, NYU Langone, New York, who was approached for comment.

“The treatment regimen is applicable to patients who are determined by an expert in transplantation to be fit to receive autologous hematopoietic transplantation,” he added. “Although this study, like many others, establishes hematopoietic stem cell transplantation as part of the standard of care in multiple myeloma, only a fraction of patients are actually offered this important modality of treatment for a variety of reasons, including provider bias,” he noted. “In fact, although improvement in supportive care has enhanced the safety of the procedure, many patients are denied this therapy.” 

Dr. Al-Homsi noted that the lack of difference in overall survival might be due to the fact that some patients (28%) in the RVD-alone group did end up undergoing transplantation at the time of progression. “Also, longer follow-up might reveal a difference in overall survival,” he said.

The toxicities are manageable, and the incidence of secondary malignancies was not significantly different between cohorts. “However,” he emphasized, “lenalidomide has been associated in other studies with increased incidence of secondary malignancies and it must be noted that this study used extended administration of lenalidomide until progression.” 

Support for this study was provided by grants to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute, the National Cancer Institute, R. J. Corman Multiple Myeloma Foundation, Celgene/Bristol Myers Squibb, and Millennium/Takeda Pharmaceutical. Dr. Richardson has reported relationships with Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm Therapeutics, Oncopeptides, Sanofi, Secura Bio, Takeda, and Bristol Myers Squibb. Dr. Al-Homsi has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

CHICAGO – New results from a trial in patients with newly diagnosed multiple myeloma (MM) offer some answers to questions about which treatment route to choose.

The trial, known as DETERMINATION, found that newly diagnosed patients treated with a triplet of drugs had longer progression-free survival (PFS) if they received an autologous stem cell transplant (ASCT) soon after the drug therapy than if they simply had their stem cells collected for a possible future transplant.

Patients who received the triplet of lenalidomide, bortezomib, and dexamethasone (RVD) plus ASCT had a median PFS of 67.5 months, compared with 46.2 months for those who received RVD but did not have a transplant soon after.

However, patients were just as likely to be alive more than 6 years after treatment regardless of whether or not they underwent an immediate stem cell transplant.

In addition, treatment-related adverse events of grade 3 or above were higher in the group that received the transplant immediately after the triplet therapy.  

The results were presented during a plenary session at the American Society of Clinical Oncology annual meeting and simultaneously published in the New England Journal of Medicine.

“Our findings confirm the PFS benefit of transplantation as first-line treatment for patients with myeloma and confirms stem cell transplant as a standard of care with certain triplet therapy,” said lead author Paul G. Richardson, MD, professor of medicine, Harvard Medical School, and clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana Farber Cancer Institute, Boston.

Another finding from the trial was that the use of maintenance lenalidomide in both groups continuously until progression conferred substantial clinical benefit.

“We can also say that the use of lenalidomide maintenance therapy is also a standard of care,” he added.
 

Study details

In this trial, Dr. Richardson and colleagues randomly assigned 873 patients newly diagnosed with multiple myeloma to the RVD-alone group (n = 357) or the transplantation group (n = 365). All patients had received one cycle of RVD prior to randomization and then received two additional RVD cycles plus stem-cell mobilization followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Lenalidomide was administered to all patients until disease progression, unacceptable side effects, or both.

At a median follow-up of 76.0 months, the risk of disease progression or death was 53% higher among patients who received RVD alone versus the transplantation group (hazard ratio [HR], 1.53; P < .001). The median duration of PFS among patients with a high-risk cytogenetic profile was 55.5 vs. 17.1 months, favoring the transplantation group.

The percentage of patients who were alive without progression at 5 years was 58.4% vs 41.6%, respectively (HR, 1.66) and median duration of response was 56.4 vs 38.9 months, also favoring transplantation (HR, 1.45).

The estimated 5-year overall survival was similar between groups: 80.7% for transplantation and 79.2% for RVD alone (HR for death, 1.10; P > .99). For patients with a high-risk cytogenetic profile, 5-year survival was 63.4% versus 54.3%, respectively.

“This tells us that for patients who had kept transplant in reserve, they had the same overall survival as those who had had a transplant right away, despite there being such impressive initial disease control for the patients in whom transplant was used early,” Dr. Richardson said in a press release from his institution.

Patients who did not undergo immediate transplant received treatment when their disease progressed with newer and active therapies, such as monoclonal antibodies and/or next-generation novel agents, he noted. Only 28% of patients used the reserve option of a transplant.

“It demonstrates the extent to which patients now have options and that we have new data to guide them in balancing the pluses and minuses of each approach,” he added.

When looking at safety, the authors noted that the most common treatment-related adverse events of grade 3 or higher occurred in 279 patients (78.2%) in the RVD-alone group and 344 patients (94.2%) in the transplantation group. Of those patients, 60.5% and 89.9%, respectively, reported hematologic events of grade 3 or higher (P < .001). The 5-year cumulative incidence of invasive second primary cancers was similar in both cohorts (RVD-alone group, 4.9%; transplantation group, 6.5%).

However, while the risk of secondary cancers was similar between groups, Dr. Richardson noted that there was a higher incidence of acute myeloid leukemia and myelodysplastic syndromes in the transplant cohort.

“There was also a significant drop in quality of life across transplant procedures, but the good news is that it was recoverable rapidly,” he said. “What is also really important is that we have prospective, multicenter, national comparative data on toxicity. That’s very important for providing patients with a choice as they move forward with their treatment plan.”

He noted that treatment continues to evolve. “This study was designed in 2009, begun in 2010, and now there is mature data in 2022,” Dr. Richardson said. “This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies and novel next-generation therapies. The results from these studies are extremely exciting.

“Now more than ever, treatment for multiple myeloma can be adapted for each patient,” Dr. Richardson said. “Our study provides important information about the benefits of transplant in the era of highly effective novel therapies and continuous maintenance, as well as the potential risks, to help patients and their physicians decide what approach may be best for them. This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies, such as RVD combined with daratumumab.”
 

Lack of difference in overall survival

These new results further support an already established role of autologous hematopoietic stem cell transplantation in the management of patients with multiple myeloma, said Samer Al-Homsi, MD, clinical professor of medicine and director of the blood and marrow transplant program at Perlmutter Cancer Center, NYU Langone, New York, who was approached for comment.

“The treatment regimen is applicable to patients who are determined by an expert in transplantation to be fit to receive autologous hematopoietic transplantation,” he added. “Although this study, like many others, establishes hematopoietic stem cell transplantation as part of the standard of care in multiple myeloma, only a fraction of patients are actually offered this important modality of treatment for a variety of reasons, including provider bias,” he noted. “In fact, although improvement in supportive care has enhanced the safety of the procedure, many patients are denied this therapy.” 

Dr. Al-Homsi noted that the lack of difference in overall survival might be due to the fact that some patients (28%) in the RVD-alone group did end up undergoing transplantation at the time of progression. “Also, longer follow-up might reveal a difference in overall survival,” he said.

The toxicities are manageable, and the incidence of secondary malignancies was not significantly different between cohorts. “However,” he emphasized, “lenalidomide has been associated in other studies with increased incidence of secondary malignancies and it must be noted that this study used extended administration of lenalidomide until progression.” 

Support for this study was provided by grants to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute, the National Cancer Institute, R. J. Corman Multiple Myeloma Foundation, Celgene/Bristol Myers Squibb, and Millennium/Takeda Pharmaceutical. Dr. Richardson has reported relationships with Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm Therapeutics, Oncopeptides, Sanofi, Secura Bio, Takeda, and Bristol Myers Squibb. Dr. Al-Homsi has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients with relapsed or refractory B cell non-Hodgkin lymphoma responded positively to a new therapy based on genome editing in early results from a phase 1 study, according to a news release from manufacturer Caribou Biosciences.

In the first-in-human, phase 1 open-label study, known as ANTLER, 5 out of 5 patients with relapsed or refractory B cell non-Hodgkin lymphoma (r/r B-NHL) responded to a single dose of CB-010, an allogeneic CAR-T cell therapy designed to boost antitumor activity, according to the company.

The use of chimeric antigen receptor (CAR) T-cell therapy involves taking T cells out of the body, reprogramming them with CAR to better equip them to kill cancer cells, and putting them back into the body.

The study consists of two sections: an initial dose escalation following a 3 + 3 design, with prespecified, increasing doses, followed by an expanded trial in which all patients receive CB-010 at the dose determined in the first section.

The study population included 6 adults with r/r B-NHL who had relapsed after previous treatment with a median of 3 prior therapies. At baseline, all 6 patients underwent a lymphodepletion regimen consisting of cyclophosphamide at 60 mg/kg/day for 2 days, followed by 5 days of fludarabine at 25 mg/m²/day.

Then all patients received a single dose of 40x106 CAR-T cells. As of the Feb. 23, 2022, data cutoff date, 5 of the 6 patients had completed the 28-day dose-limiting toxicity (DLT) evaluation period. All 5 patients (100%) achieved a response; 4 achieved complete response and 1 achieved partial response. All 4 of the complete responders had ongoing complete response at 3 months, and the longest measured complete response was 6 months, according to the company.

“We are excited to see a 100% overall response rate with CB-010 at dose level 1 for these patients who have limited treatment options,” said Dr. Syed Rizvi, chief medical officer for Caribou Biosciences, in the press release. “We believe this initial level of activity is unparalleled for a single, starting dose of cell therapy. CB-010 was generally well-tolerated, with adverse events routinely observed in autologous or allogeneic anti-CD19 CAR-T cell therapies,” he said.

Based on the promising safety and efficacy results, the company is enrolling patients in a second cohort for treatment at dose level 2 (80x106 CAR-T cells), according to the news release.

Another allogeneic CAR-T cell therapy known as ALLO-501A is being studied in a similar trial conducted by the Moffitt Cancer Center.

Overall, CB-010 was well-tolerated, according to Caribou Biosciences. No cases of graft-versus-host disease were reported. A total of 3 patients developed grade 3 or 4 adverse events (AEs) within the first 28 days; the most common were neutropenia (50%), thrombocytopenia (33%), anemia (17%), and hypogammaglobulinemia (17%). One patient experienced both grade 1 cytokine release syndrome (CRS) and grade 3 Immune effector cell-Associated Neurotoxicity Syndrome (ICANS). This response was characterized as a dose-limiting toxicity. The patient was treated with tocilizumab and steroids, recovered within 39 hours, and went on to achieve a complete response, according to the company.

Although the safety profile in the current study was promising, prior research suggest that concerns associated with CRS and ICANS should not be ignored and may be barriers to treatment.

In an article published in Bone Marrow Transplant in 2021, Dr. Vipul Sheth and Dr. Jordan Gauthier of the Fred Hutchinson Cancer Center, Seattle, noted that adverse effects may remain a challenge to widespread use of CAR-T in patients with refractory or relapsed acute lymphoblastic leukemia, for which it has been approved by the U.S. Food and Drug Administration and several European agencies. However, “there is mounting evidence that earlier, and potentially more targeted, interventions can reduce these toxicities,” they wrote.
 

Study provides solid stepping stone

“CRS and ICANS are mild in most patients but can be severe and sometimes life-threatening in a subset of patients undergoing CD19 CAR T-cell therapy,” Dr. Gauthier said in an interview. “Different strategies are being investigated to mitigate or treat severe toxicities, such as the use of prophylactic corticosteroids, anakinra, lenzilumab, itacitinib. I am hopeful we will soon manage to prevent toxicities while maintaining potent anti-tumor effects,” he said.

“While autologous CD19 CAR-T cells have high efficacy in patients with refractory/relapsed large B-cell lymphoma, product manufacturing remains a complicated and lengthy process in the autologous setting,” Dr. Gauthier noted. “Commercial CAR T-cell manufacturing takes approximately 3-4 weeks, sometimes longer. Some patients won’t survive long enough to receive their infusion. In some patients, T-cell function is dramatically impaired, due to prior therapies or to the disease itself,” he said.

Dr. Gauthier said he was not surprised but that he was encouraged by the apparent early success of the ANTLER study. “The proof-of-concept that allogeneic CD19-targeted CAR T cells can induce high response rates in r/r LBCL has already been established,” he said. “Having said that, it is comforting to see prior findings confirmed by this new study, and those results are exciting for the field,” he added.

As for additional research, “we need longer follow-up after allogeneic CD19-targeted CAR T-cell therapy to ensure responses are durable,” Dr. Gauthier explained. “We also need to better understand the biology driving the antitumor effects and the side effects of CAR T-cells. This will help us build more efficacious and safer CAR T-cell therapies,” he said.
 

Response and side effects show promise for future research

The therapy is “the best CAR-T product” that clinicians can provide for patients knowing that autologous CAR-T works, said Dr. Ahmed Galal, of Duke University, Durham, N.C., in an interview. The current research supports the use of this treatment immediately for patients, he added.

Dr. Galal said he was somewhat surprised, but pleasantly so, by the 100% response rate. This rate is likely because of the small number of patients and may not hold up in further research, but “even 90% would be an amazing achievement,” he said. The tolerable safety profile is encouraging as well, he emphasized. Dr. Galal said that he did not foresee any real barriers to expanded use of the therapy and that technology should make it easier to deliver at authorized centers.

Limitations to the current study are those common to all phase 1 trials, such as the strict inclusion criteria, Dr. Galal said. As research progresses to phase 2, “I don’t think it will be an obstacle to find patients,” he said. However, patients should be aware of side effects, and clinicians should maintain a culture of education to help them understand the value of the therapy, he added.

The complete data from the preliminary findings are scheduled to be presented at the European Hematology Association (EHA) 2022 Hybrid Congress, Vienna, in June, as abstract P1455, titled “First-in-human trial of CB-010, a CRISPR-edited allogeneic anti-CD19 CAR-T cell therapy with a PD-1 knock out, in patients with relapsed or refractory B cell non-Hodgkin lymphoma (ANTLER study).” The findings are scheduled to be presented by Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center, according to Caribou Biosciences.

Dr. Gauthier had no financial conflicts to disclose. Dr. Galal had no financial conflicts to disclose.

Patients with relapsed or refractory B cell non-Hodgkin lymphoma responded positively to a new therapy based on genome editing in early results from a phase 1 study, according to a news release from manufacturer Caribou Biosciences.

In the first-in-human, phase 1 open-label study, known as ANTLER, 5 out of 5 patients with relapsed or refractory B cell non-Hodgkin lymphoma (r/r B-NHL) responded to a single dose of CB-010, an allogeneic CAR-T cell therapy designed to boost antitumor activity, according to the company.

The use of chimeric antigen receptor (CAR) T-cell therapy involves taking T cells out of the body, reprogramming them with CAR to better equip them to kill cancer cells, and putting them back into the body.

The study consists of two sections: an initial dose escalation following a 3 + 3 design, with prespecified, increasing doses, followed by an expanded trial in which all patients receive CB-010 at the dose determined in the first section.

The study population included 6 adults with r/r B-NHL who had relapsed after previous treatment with a median of 3 prior therapies. At baseline, all 6 patients underwent a lymphodepletion regimen consisting of cyclophosphamide at 60 mg/kg/day for 2 days, followed by 5 days of fludarabine at 25 mg/m²/day.

Then all patients received a single dose of 40x106 CAR-T cells. As of the Feb. 23, 2022, data cutoff date, 5 of the 6 patients had completed the 28-day dose-limiting toxicity (DLT) evaluation period. All 5 patients (100%) achieved a response; 4 achieved complete response and 1 achieved partial response. All 4 of the complete responders had ongoing complete response at 3 months, and the longest measured complete response was 6 months, according to the company.

“We are excited to see a 100% overall response rate with CB-010 at dose level 1 for these patients who have limited treatment options,” said Dr. Syed Rizvi, chief medical officer for Caribou Biosciences, in the press release. “We believe this initial level of activity is unparalleled for a single, starting dose of cell therapy. CB-010 was generally well-tolerated, with adverse events routinely observed in autologous or allogeneic anti-CD19 CAR-T cell therapies,” he said.

Based on the promising safety and efficacy results, the company is enrolling patients in a second cohort for treatment at dose level 2 (80x106 CAR-T cells), according to the news release.

Another allogeneic CAR-T cell therapy known as ALLO-501A is being studied in a similar trial conducted by the Moffitt Cancer Center.

Overall, CB-010 was well-tolerated, according to Caribou Biosciences. No cases of graft-versus-host disease were reported. A total of 3 patients developed grade 3 or 4 adverse events (AEs) within the first 28 days; the most common were neutropenia (50%), thrombocytopenia (33%), anemia (17%), and hypogammaglobulinemia (17%). One patient experienced both grade 1 cytokine release syndrome (CRS) and grade 3 Immune effector cell-Associated Neurotoxicity Syndrome (ICANS). This response was characterized as a dose-limiting toxicity. The patient was treated with tocilizumab and steroids, recovered within 39 hours, and went on to achieve a complete response, according to the company.

Although the safety profile in the current study was promising, prior research suggest that concerns associated with CRS and ICANS should not be ignored and may be barriers to treatment.

In an article published in Bone Marrow Transplant in 2021, Dr. Vipul Sheth and Dr. Jordan Gauthier of the Fred Hutchinson Cancer Center, Seattle, noted that adverse effects may remain a challenge to widespread use of CAR-T in patients with refractory or relapsed acute lymphoblastic leukemia, for which it has been approved by the U.S. Food and Drug Administration and several European agencies. However, “there is mounting evidence that earlier, and potentially more targeted, interventions can reduce these toxicities,” they wrote.
 

Study provides solid stepping stone

“CRS and ICANS are mild in most patients but can be severe and sometimes life-threatening in a subset of patients undergoing CD19 CAR T-cell therapy,” Dr. Gauthier said in an interview. “Different strategies are being investigated to mitigate or treat severe toxicities, such as the use of prophylactic corticosteroids, anakinra, lenzilumab, itacitinib. I am hopeful we will soon manage to prevent toxicities while maintaining potent anti-tumor effects,” he said.

“While autologous CD19 CAR-T cells have high efficacy in patients with refractory/relapsed large B-cell lymphoma, product manufacturing remains a complicated and lengthy process in the autologous setting,” Dr. Gauthier noted. “Commercial CAR T-cell manufacturing takes approximately 3-4 weeks, sometimes longer. Some patients won’t survive long enough to receive their infusion. In some patients, T-cell function is dramatically impaired, due to prior therapies or to the disease itself,” he said.

Dr. Gauthier said he was not surprised but that he was encouraged by the apparent early success of the ANTLER study. “The proof-of-concept that allogeneic CD19-targeted CAR T cells can induce high response rates in r/r LBCL has already been established,” he said. “Having said that, it is comforting to see prior findings confirmed by this new study, and those results are exciting for the field,” he added.

As for additional research, “we need longer follow-up after allogeneic CD19-targeted CAR T-cell therapy to ensure responses are durable,” Dr. Gauthier explained. “We also need to better understand the biology driving the antitumor effects and the side effects of CAR T-cells. This will help us build more efficacious and safer CAR T-cell therapies,” he said.
 

Response and side effects show promise for future research

The therapy is “the best CAR-T product” that clinicians can provide for patients knowing that autologous CAR-T works, said Dr. Ahmed Galal, of Duke University, Durham, N.C., in an interview. The current research supports the use of this treatment immediately for patients, he added.

Dr. Galal said he was somewhat surprised, but pleasantly so, by the 100% response rate. This rate is likely because of the small number of patients and may not hold up in further research, but “even 90% would be an amazing achievement,” he said. The tolerable safety profile is encouraging as well, he emphasized. Dr. Galal said that he did not foresee any real barriers to expanded use of the therapy and that technology should make it easier to deliver at authorized centers.

Limitations to the current study are those common to all phase 1 trials, such as the strict inclusion criteria, Dr. Galal said. As research progresses to phase 2, “I don’t think it will be an obstacle to find patients,” he said. However, patients should be aware of side effects, and clinicians should maintain a culture of education to help them understand the value of the therapy, he added.

The complete data from the preliminary findings are scheduled to be presented at the European Hematology Association (EHA) 2022 Hybrid Congress, Vienna, in June, as abstract P1455, titled “First-in-human trial of CB-010, a CRISPR-edited allogeneic anti-CD19 CAR-T cell therapy with a PD-1 knock out, in patients with relapsed or refractory B cell non-Hodgkin lymphoma (ANTLER study).” The findings are scheduled to be presented by Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center, according to Caribou Biosciences.

Dr. Gauthier had no financial conflicts to disclose. Dr. Galal had no financial conflicts to disclose.

Patients with relapsed or refractory B cell non-Hodgkin lymphoma responded positively to a new therapy based on genome editing in early results from a phase 1 study, according to a news release from manufacturer Caribou Biosciences.

In the first-in-human, phase 1 open-label study, known as ANTLER, 5 out of 5 patients with relapsed or refractory B cell non-Hodgkin lymphoma (r/r B-NHL) responded to a single dose of CB-010, an allogeneic CAR-T cell therapy designed to boost antitumor activity, according to the company.

The use of chimeric antigen receptor (CAR) T-cell therapy involves taking T cells out of the body, reprogramming them with CAR to better equip them to kill cancer cells, and putting them back into the body.

The study consists of two sections: an initial dose escalation following a 3 + 3 design, with prespecified, increasing doses, followed by an expanded trial in which all patients receive CB-010 at the dose determined in the first section.

The study population included 6 adults with r/r B-NHL who had relapsed after previous treatment with a median of 3 prior therapies. At baseline, all 6 patients underwent a lymphodepletion regimen consisting of cyclophosphamide at 60 mg/kg/day for 2 days, followed by 5 days of fludarabine at 25 mg/m²/day.

Then all patients received a single dose of 40x106 CAR-T cells. As of the Feb. 23, 2022, data cutoff date, 5 of the 6 patients had completed the 28-day dose-limiting toxicity (DLT) evaluation period. All 5 patients (100%) achieved a response; 4 achieved complete response and 1 achieved partial response. All 4 of the complete responders had ongoing complete response at 3 months, and the longest measured complete response was 6 months, according to the company.

“We are excited to see a 100% overall response rate with CB-010 at dose level 1 for these patients who have limited treatment options,” said Dr. Syed Rizvi, chief medical officer for Caribou Biosciences, in the press release. “We believe this initial level of activity is unparalleled for a single, starting dose of cell therapy. CB-010 was generally well-tolerated, with adverse events routinely observed in autologous or allogeneic anti-CD19 CAR-T cell therapies,” he said.

Based on the promising safety and efficacy results, the company is enrolling patients in a second cohort for treatment at dose level 2 (80x106 CAR-T cells), according to the news release.

Another allogeneic CAR-T cell therapy known as ALLO-501A is being studied in a similar trial conducted by the Moffitt Cancer Center.

Overall, CB-010 was well-tolerated, according to Caribou Biosciences. No cases of graft-versus-host disease were reported. A total of 3 patients developed grade 3 or 4 adverse events (AEs) within the first 28 days; the most common were neutropenia (50%), thrombocytopenia (33%), anemia (17%), and hypogammaglobulinemia (17%). One patient experienced both grade 1 cytokine release syndrome (CRS) and grade 3 Immune effector cell-Associated Neurotoxicity Syndrome (ICANS). This response was characterized as a dose-limiting toxicity. The patient was treated with tocilizumab and steroids, recovered within 39 hours, and went on to achieve a complete response, according to the company.

Although the safety profile in the current study was promising, prior research suggest that concerns associated with CRS and ICANS should not be ignored and may be barriers to treatment.

In an article published in Bone Marrow Transplant in 2021, Dr. Vipul Sheth and Dr. Jordan Gauthier of the Fred Hutchinson Cancer Center, Seattle, noted that adverse effects may remain a challenge to widespread use of CAR-T in patients with refractory or relapsed acute lymphoblastic leukemia, for which it has been approved by the U.S. Food and Drug Administration and several European agencies. However, “there is mounting evidence that earlier, and potentially more targeted, interventions can reduce these toxicities,” they wrote.
 

Study provides solid stepping stone

“CRS and ICANS are mild in most patients but can be severe and sometimes life-threatening in a subset of patients undergoing CD19 CAR T-cell therapy,” Dr. Gauthier said in an interview. “Different strategies are being investigated to mitigate or treat severe toxicities, such as the use of prophylactic corticosteroids, anakinra, lenzilumab, itacitinib. I am hopeful we will soon manage to prevent toxicities while maintaining potent anti-tumor effects,” he said.

“While autologous CD19 CAR-T cells have high efficacy in patients with refractory/relapsed large B-cell lymphoma, product manufacturing remains a complicated and lengthy process in the autologous setting,” Dr. Gauthier noted. “Commercial CAR T-cell manufacturing takes approximately 3-4 weeks, sometimes longer. Some patients won’t survive long enough to receive their infusion. In some patients, T-cell function is dramatically impaired, due to prior therapies or to the disease itself,” he said.

Dr. Gauthier said he was not surprised but that he was encouraged by the apparent early success of the ANTLER study. “The proof-of-concept that allogeneic CD19-targeted CAR T cells can induce high response rates in r/r LBCL has already been established,” he said. “Having said that, it is comforting to see prior findings confirmed by this new study, and those results are exciting for the field,” he added.

As for additional research, “we need longer follow-up after allogeneic CD19-targeted CAR T-cell therapy to ensure responses are durable,” Dr. Gauthier explained. “We also need to better understand the biology driving the antitumor effects and the side effects of CAR T-cells. This will help us build more efficacious and safer CAR T-cell therapies,” he said.
 

Response and side effects show promise for future research

The therapy is “the best CAR-T product” that clinicians can provide for patients knowing that autologous CAR-T works, said Dr. Ahmed Galal, of Duke University, Durham, N.C., in an interview. The current research supports the use of this treatment immediately for patients, he added.

Dr. Galal said he was somewhat surprised, but pleasantly so, by the 100% response rate. This rate is likely because of the small number of patients and may not hold up in further research, but “even 90% would be an amazing achievement,” he said. The tolerable safety profile is encouraging as well, he emphasized. Dr. Galal said that he did not foresee any real barriers to expanded use of the therapy and that technology should make it easier to deliver at authorized centers.

Limitations to the current study are those common to all phase 1 trials, such as the strict inclusion criteria, Dr. Galal said. As research progresses to phase 2, “I don’t think it will be an obstacle to find patients,” he said. However, patients should be aware of side effects, and clinicians should maintain a culture of education to help them understand the value of the therapy, he added.

The complete data from the preliminary findings are scheduled to be presented at the European Hematology Association (EHA) 2022 Hybrid Congress, Vienna, in June, as abstract P1455, titled “First-in-human trial of CB-010, a CRISPR-edited allogeneic anti-CD19 CAR-T cell therapy with a PD-1 knock out, in patients with relapsed or refractory B cell non-Hodgkin lymphoma (ANTLER study).” The findings are scheduled to be presented by Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center, according to Caribou Biosciences.

Dr. Gauthier had no financial conflicts to disclose. Dr. Galal had no financial conflicts to disclose.

Results of the KEYNOTE-522 clinical trial highlight the importance of neoadjuvant treatment with pembrolizumab for improving survival in patients with early triple negative breast cancer (TNBC).

The findings were presented in Chicago June 4 and 5 at the annual meeting of the American Society of Clinical Oncology by study author Lajos Pusztai, MD, D.Phil, director of Breast Cancer Translational Research at Yale University, New Haven, Conn.

KEYNOTE-522 is the first prospective, randomized, placebo-controlled phase 3 trial of pembrolizumab for early-stage TNBC in the neoadjuvant and adjuvant setting.

The study included 1,174 patients (median age 49 years) with previously untreated stage II or III triple-negative breast cancer. Patients were randomly assigned to receive neoadjuvant therapy with four cycles of pembrolizumab (200 mg) or placebo every 3 weeks plus paclitaxel and carboplatin, followed by four cycles of pembrolizumab or placebo plus doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After surgery, patients received pembrolizumab or placebeo for 9 cycles or until recurrence or unacceptable toxicity. The primary end points were pathological complete response and event-free survival.

A total of 784 patients were treated with pembrolizumab and chemotherapy, and the second group of 390 patients received a placebo and chemotherapy. After surgery, patients received adjuvant pembrolizumab (pembrolizumab-chemotherapy group) or placebo and chemotherapy for every 3 weeks for up to nine cycles.

The estimated event-free survival at 36 months was 84.5% in the pembrolizumab-chemotherapy group, compared with 76.8% in the placebo-chemotherapy group (hazard ratio for event or death, 0.63; 95% confidence interval, 0.48 to 0.82; P <0.001). Adverse events occurred predominantly during the neoadjuvant phase and were consistent with the established safety profiles of pembrolizumab and chemotherapy.

At the first interim analysis, 64.8% achieved pathological complete response in the pembrolizumab group versus 51.2% in the placebo group. At the fourth interim analysis at 36 months, event-free survival was 76.8% in the placebo arm and 84.5% in the pembrolizumab arm. RCB-0 status was achieved by 63.4% and 56.2% of patients in the pembrolizumab and placebo arms, respectively.

Pembrolizumab did contribute immune-related adverse events, mostly grades 1-2, in about 17% of patients with thyroid function abnormalities most common with most occurring 20 weeks prior to surgical treatment.

Treatment with pembrolizumab added to chemotherapy, compared with chemotherapy alone, shifted residual cancer burden to lower categories across the entire spectrum of patients in the trial.

The hazard ratio for event-free survival with RCB-0, which Dr. Pusztai said is equivalent to a pathologic complete response (pCR), was 0.70 (0.38-1.31). For RCB-1 (minimal residual disease) it was 0.92 (0.39-2.20); for RCB-2 (moderate residual disease) it was 0.52 (0.32-0.82); and for RCB-3 (extensive residual disease) it was 1.24 (0.69-2.23).

“The most important finding is that patients in RCB-2, a group with a moderate amount of residual disease, experienced significant improvement with pembrolizumab. This clearly indicates not only that pembrolizumab leads to higher pCR rates but also that the pembrolizumCR/RCB-0 ... extends to patients who do not achieve pCR,” Dr. Pusztai said.

The benefit, he suggested, could be a result of the adjuvant pembrolizumab maintenance phase.

Patients in the RCB-3 category do poorly regardless of treatment (EFS of 34.6 % and 26.2% in the pembrolizumab and placebo arms, respectively).

“The RCB-3 population represents an unmet medical need, and they will need better drugs, and additional postoperative adjuvant therapy,” Dr. Pusztai said. The current standard of care is capecitabine for 6-8 cycles. Emerging new therapies, such as antibody drug conjugates, will be tested, he said.

In terms of limitations, adjuvant capecitabine was not allowed. “It remains uncertain how much better the RCB-2 and -3 patient outcomes would have been if capecitabine were administered,” he said.

The study was funded by Merck Sharp and Dohme, a subsidiary of Merck. Dr. Pusztai has received consulting fees and honoraria from Merck.

Results of the KEYNOTE-522 clinical trial highlight the importance of neoadjuvant treatment with pembrolizumab for improving survival in patients with early triple negative breast cancer (TNBC).

The findings were presented in Chicago June 4 and 5 at the annual meeting of the American Society of Clinical Oncology by study author Lajos Pusztai, MD, D.Phil, director of Breast Cancer Translational Research at Yale University, New Haven, Conn.

KEYNOTE-522 is the first prospective, randomized, placebo-controlled phase 3 trial of pembrolizumab for early-stage TNBC in the neoadjuvant and adjuvant setting.

The study included 1,174 patients (median age 49 years) with previously untreated stage II or III triple-negative breast cancer. Patients were randomly assigned to receive neoadjuvant therapy with four cycles of pembrolizumab (200 mg) or placebo every 3 weeks plus paclitaxel and carboplatin, followed by four cycles of pembrolizumab or placebo plus doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After surgery, patients received pembrolizumab or placebeo for 9 cycles or until recurrence or unacceptable toxicity. The primary end points were pathological complete response and event-free survival.

A total of 784 patients were treated with pembrolizumab and chemotherapy, and the second group of 390 patients received a placebo and chemotherapy. After surgery, patients received adjuvant pembrolizumab (pembrolizumab-chemotherapy group) or placebo and chemotherapy for every 3 weeks for up to nine cycles.

The estimated event-free survival at 36 months was 84.5% in the pembrolizumab-chemotherapy group, compared with 76.8% in the placebo-chemotherapy group (hazard ratio for event or death, 0.63; 95% confidence interval, 0.48 to 0.82; P <0.001). Adverse events occurred predominantly during the neoadjuvant phase and were consistent with the established safety profiles of pembrolizumab and chemotherapy.

At the first interim analysis, 64.8% achieved pathological complete response in the pembrolizumab group versus 51.2% in the placebo group. At the fourth interim analysis at 36 months, event-free survival was 76.8% in the placebo arm and 84.5% in the pembrolizumab arm. RCB-0 status was achieved by 63.4% and 56.2% of patients in the pembrolizumab and placebo arms, respectively.

Pembrolizumab did contribute immune-related adverse events, mostly grades 1-2, in about 17% of patients with thyroid function abnormalities most common with most occurring 20 weeks prior to surgical treatment.

Treatment with pembrolizumab added to chemotherapy, compared with chemotherapy alone, shifted residual cancer burden to lower categories across the entire spectrum of patients in the trial.

The hazard ratio for event-free survival with RCB-0, which Dr. Pusztai said is equivalent to a pathologic complete response (pCR), was 0.70 (0.38-1.31). For RCB-1 (minimal residual disease) it was 0.92 (0.39-2.20); for RCB-2 (moderate residual disease) it was 0.52 (0.32-0.82); and for RCB-3 (extensive residual disease) it was 1.24 (0.69-2.23).

“The most important finding is that patients in RCB-2, a group with a moderate amount of residual disease, experienced significant improvement with pembrolizumab. This clearly indicates not only that pembrolizumab leads to higher pCR rates but also that the pembrolizumCR/RCB-0 ... extends to patients who do not achieve pCR,” Dr. Pusztai said.

The benefit, he suggested, could be a result of the adjuvant pembrolizumab maintenance phase.

Patients in the RCB-3 category do poorly regardless of treatment (EFS of 34.6 % and 26.2% in the pembrolizumab and placebo arms, respectively).

“The RCB-3 population represents an unmet medical need, and they will need better drugs, and additional postoperative adjuvant therapy,” Dr. Pusztai said. The current standard of care is capecitabine for 6-8 cycles. Emerging new therapies, such as antibody drug conjugates, will be tested, he said.

In terms of limitations, adjuvant capecitabine was not allowed. “It remains uncertain how much better the RCB-2 and -3 patient outcomes would have been if capecitabine were administered,” he said.

The study was funded by Merck Sharp and Dohme, a subsidiary of Merck. Dr. Pusztai has received consulting fees and honoraria from Merck.

Results of the KEYNOTE-522 clinical trial highlight the importance of neoadjuvant treatment with pembrolizumab for improving survival in patients with early triple negative breast cancer (TNBC).

The findings were presented in Chicago June 4 and 5 at the annual meeting of the American Society of Clinical Oncology by study author Lajos Pusztai, MD, D.Phil, director of Breast Cancer Translational Research at Yale University, New Haven, Conn.

KEYNOTE-522 is the first prospective, randomized, placebo-controlled phase 3 trial of pembrolizumab for early-stage TNBC in the neoadjuvant and adjuvant setting.

The study included 1,174 patients (median age 49 years) with previously untreated stage II or III triple-negative breast cancer. Patients were randomly assigned to receive neoadjuvant therapy with four cycles of pembrolizumab (200 mg) or placebo every 3 weeks plus paclitaxel and carboplatin, followed by four cycles of pembrolizumab or placebo plus doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After surgery, patients received pembrolizumab or placebeo for 9 cycles or until recurrence or unacceptable toxicity. The primary end points were pathological complete response and event-free survival.

A total of 784 patients were treated with pembrolizumab and chemotherapy, and the second group of 390 patients received a placebo and chemotherapy. After surgery, patients received adjuvant pembrolizumab (pembrolizumab-chemotherapy group) or placebo and chemotherapy for every 3 weeks for up to nine cycles.

The estimated event-free survival at 36 months was 84.5% in the pembrolizumab-chemotherapy group, compared with 76.8% in the placebo-chemotherapy group (hazard ratio for event or death, 0.63; 95% confidence interval, 0.48 to 0.82; P <0.001). Adverse events occurred predominantly during the neoadjuvant phase and were consistent with the established safety profiles of pembrolizumab and chemotherapy.

At the first interim analysis, 64.8% achieved pathological complete response in the pembrolizumab group versus 51.2% in the placebo group. At the fourth interim analysis at 36 months, event-free survival was 76.8% in the placebo arm and 84.5% in the pembrolizumab arm. RCB-0 status was achieved by 63.4% and 56.2% of patients in the pembrolizumab and placebo arms, respectively.

Pembrolizumab did contribute immune-related adverse events, mostly grades 1-2, in about 17% of patients with thyroid function abnormalities most common with most occurring 20 weeks prior to surgical treatment.

Treatment with pembrolizumab added to chemotherapy, compared with chemotherapy alone, shifted residual cancer burden to lower categories across the entire spectrum of patients in the trial.

The hazard ratio for event-free survival with RCB-0, which Dr. Pusztai said is equivalent to a pathologic complete response (pCR), was 0.70 (0.38-1.31). For RCB-1 (minimal residual disease) it was 0.92 (0.39-2.20); for RCB-2 (moderate residual disease) it was 0.52 (0.32-0.82); and for RCB-3 (extensive residual disease) it was 1.24 (0.69-2.23).

“The most important finding is that patients in RCB-2, a group with a moderate amount of residual disease, experienced significant improvement with pembrolizumab. This clearly indicates not only that pembrolizumab leads to higher pCR rates but also that the pembrolizumCR/RCB-0 ... extends to patients who do not achieve pCR,” Dr. Pusztai said.

The benefit, he suggested, could be a result of the adjuvant pembrolizumab maintenance phase.

Patients in the RCB-3 category do poorly regardless of treatment (EFS of 34.6 % and 26.2% in the pembrolizumab and placebo arms, respectively).

“The RCB-3 population represents an unmet medical need, and they will need better drugs, and additional postoperative adjuvant therapy,” Dr. Pusztai said. The current standard of care is capecitabine for 6-8 cycles. Emerging new therapies, such as antibody drug conjugates, will be tested, he said.

In terms of limitations, adjuvant capecitabine was not allowed. “It remains uncertain how much better the RCB-2 and -3 patient outcomes would have been if capecitabine were administered,” he said.

The study was funded by Merck Sharp and Dohme, a subsidiary of Merck. Dr. Pusztai has received consulting fees and honoraria from Merck.

NEW ORLEANS – Treatment of people with obesity but no diabetes with the dual–incretin agonist tirzepatide safely produced “unprecedented” levels of weight loss in the vast majority of patients in SURMOUNT-1, a placebo-controlled trial with more than 2,500 people with obesity or overweight plus at least one weight-related complication.

Although the pivotal trial did not directly compare weekly subcutaneous injection with the twincretin tirzepatide (at 5 mg, 10 mg, or 15 mg) with either bariatric surgery or what has been the reigning champ of weight-loss agents, a 2.4-mg/week injection of semaglutide (Wegovy), the new findings are impressive because they eclipsed semaglutide’s past performance in at least three important ways, said Ania M. Jastreboff, MD, PhD, SURMOUNT-1’s lead investigator, at the annual scientific sessions of the American Diabetes Association.

First, the highest-tested dosage of tirzepatide, 15 mg/week, for 72 weeks, produced a 5% or greater loss in baseline weight in 91%-96% of patients, an effect “not previously seen” in any prior phase 3 trial of a weight-loss agent, noted Dr. Jastreboff, an endocrinologist and director of Weight Management & Obesity Prevention at Yale University in New Haven, Conn.

Second, the average level of weight loss among the 630 people who received 15 mg/week was 22.5% in the on-treatment analysis, and 20.9% in the intention-to-treat analysis, again a magnitude of effect never before seen with any other medical intervention.

And in an exploratory analysis, 40% of people who received the highest-tested tirzepatide dose of 15 mg/week had at least a 25% loss in baseline weight in the on-treatment analysis, another example of unprecedented weight-loss achievement, said Dr. Jastreboff.

Looking at the data another way, the average baseline weight of those in the trial was 104 kg (230 lb) at the start, and the average weight loss was between 35 and 52 lbs by 72 weeks on treatment, Dr. Jastreboff said in a press conference. 

She noted, however, that not everyone will respond to tirzepatide, “but if you do respond to this medicine, you will feel full earlier, you won’t want to go back for seconds, and you may eat smaller amounts more often.”  

Such weight-loss agents will need to be taken chronically, in the same way that medications are for hypertension or dyslipidemia, Dr. Jastreboff stressed. “If you stop the antiobesity medication then the body fat mass set point will go back up so this necessitates long-term treatment.”

A new era: Weight loss ‘in the range of bariatric surgery’

Tirzepatide, developed by Lilly, has recently been approved in the United States for the treatment of type 2 diabetes, under the brand name Mounjaro.

SURMOUNT-1 was designed to examine the effect of the agent in overweight/obesity, and the company will be filing for the additional indication of weight loss in the future. Top-line results of SURMOUNT-1 generated much excitement when Lilly reported them back in April, including a story in The New York Times. 

Semaglutide, a Novo Nordisk drug, is approved in the United States for type 2 diabetes (as Ozempic at doses of either 1 mg or 2 mg per week) and also for weight loss, as Wegovy, at the higher dose of 2.4 mg per week. When Wegovy was given the green light by the Food and Drug Administration a year ago, it too was hailed as a “game changer” for obesity.

The weight-loss results seen in SURMOUNT-1 “put tirzepatide squarely in the range of weight loss achieved with bariatric surgery,” concluded Louis J. Aronne, MD, a coinvestigator on the trial, professor at Weill-Cornell Medicine in New York, and director of the Center for Weight Management and Metabolic Clinical Research of Weill-Cornell.

The results are “amazing,” and propel the weight-loss field into “a new era of obesity treatment,” commented Lee M. Kaplan, MD, who was not involved in the study and served as designated discussant for the trial.

Despite the lack of direct comparison, the findings indicate that “tirzepatide causes more weight loss than semaglutide,” and it provides “an opportunity to meet or exceed” the weight-loss effects of bariatric surgery, added Dr. Kaplan, director of the Obesity, Metabolism and Nutrition Institute at Massachusetts General Hospital in Boston.

Simultaneously with Dr. Jastreboff’s report at the meeting, the results were published online in The New England Journal of Medicine.

An accompanying editorial agrees with Dr. Kaplan: “It is remarkable that the magnitude of weight loss with tirzepatide was similar to that with gastric bypass, which raises the potential for alternative medical approaches to the treatment of obesity.”

“The tides are shifting, and there are now more options for people with obesity to lose weight,” write Clifford J. Rosen, MD, of Tufts University, Boston, and Julie R. Ingelfinger, MD, of Harvard University and Massachusetts General Hospital, Boston.

Dual incretin agonism ‘enhances activity,’ says expert

Tirzepatide is the first agent on the U.S. market from a novel class of dual-incretin agonists, with a molecular structure engineered to activate both the glucagonlike protein-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP), the two predominant incretins in the human gut. This combined activity has led to the twincretin nickname for tirzepatide.

Semaglutide is a single-incretin agonist, with its activity focused exclusively on the GLP-1 receptor.

Dr. Aronne tied the apparently superior efficacy of tirzepatide relative to semaglutide directly to the added incretin activity of tirzepatide. “The dual approach enhances efficacy,” he proposed during his presentation at the meeting.

The impressive efficacy and reassuring safety profile reported from SURMOUNT-1 opens the door to a new approach to treating obesity, which in the past has often taken a back seat to treatments for dyslipidemia, hypertension, and diabetes.

“Now that we can treat obesity safely and effectively, it makes sense to treat obesity first,” Dr. Aronne recommended.

Dr. Jastreboff agreed: “Perhaps we can prevent diabetes by treating obesity head-on,” she remarked. 

Weight-loss agents gain U.S. traction

There have been concerns about patient access to these newer weight-loss drugs in the United States, given that the retail cost of semaglutide for obesity exceeds $1,000/month, but Dr. Aronne reported data that painted a more optimistic picture.

His numbers showed that during the first months that semaglutide was on the U.S. market as a weight-loss agent, the number of U.S. prescriptions written for branded antiobesity medications roughly doubled, a spike that seemed mostly driven by the introduction and growing use of semaglutide.

With tirzepatide, every prespecified cardiometabolic parameter assessed in the trial showed clinically meaningful improvements, reported Dr. Jastreboff, including an average 17% reduction in waist circumference in patients on either of the highest two dosages, a 34% average drop in total fat mass, an average 0.5–percentage point cut in baseline hemoglobin A1c at the highest two dosages, substantial cuts in fasting plasma glucose and fasting insulin levels,  an average 28% drop in triglyceride levels, and an average systolic blood pressure reduction of about 8 mm Hg that occurred within 24 weeks on treatment.

“I think that insurers will sign up” for tirzepatide coverage based on benefits like this, Dr. Aronne predicted.

SURMOUNT-1 randomized 2,539 patients with obesity or with overweight plus at least one weight-related complication at any of 119 sites in nine countries. They had a body mass index of 30 kg/m² or more, or 27 kg/m² or more and at least one weight-related complication, excluding diabetes. They were randomized in a 1:1:1:1 ratio to receive once-weekly, subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 72 weeks, including a 20-week dose-escalation period.

The study’s two primary endpoints were the average percentage change in body weight from entry to 72 weeks, and the percentage of participants reaching at least a 5% reduction in their baseline body weight by 72 weeks.

The most common adverse events with tirzepatide were gastrointestinal, and most were mild to moderate in severity, occurring primarily during dose escalation. Adverse events caused treatment discontinuation in 4.3%, 7.1%, 6.2%, and 2.6% of participants receiving 5-mg, 10-mg, and 15-mg tirzepatide doses and placebo, respectively

The trial ran from December 2019 to April 2022, so during the peak of the COVID-19 pandemic, which Dr. Jastreboff described as an “amazing feat.”

Jamy Ard, MD, who chaired the SURMOUNT-1 session quipped, after hearing the results, “Wow; that’s exciting. If you’re not excited by the results, you’d better check your pulse.”

Dr. Ard is a professor at Wake Forest University, Winston-Salem, N.C., and codirector of the Wake Forest Baptist Health Weight Management Center in Winston-Salem.

SURMOUNT-1 was sponsored by Eli Lilly, the company that markets tirzepatide (Mounjaro). Dr. Jastreboff has been an advisor or consultant to Eli Lilly, as well as to Boehringer Ingelheim, Intellihealth, Novo Nordisk, Pfizer, Rhythm Pharmaceuticals, Scholar Rock, and Weight Watchers, and she has received research funding from Eli Lilly and Novo Nordisk. Dr. Aronne has been a consultant or advisor to, speaker on behalf of, or received research funding from Eli Lilly as well as from Altimmune, Amgen, Allurion, Intellihealth, Janssen, Novo Nordisk, Pfizer, and United Health group; he has an ownership interest in ERX, Gelesis, and Intellihealth; and he serves on the board of ERX, Jamieson Wellness, and Intellihealth. Dr. Kaplan has been a consultant to Eli Lilly, as well as to Amgen, Boehringer Ingelheim, Gelesis, Gilead, Novo Nordisk, Optum Health, Pfizer, Rhythm Pharmaceuticals, the Obesity and Nutrition Institute, and Xeno Biosciences. Dr. Ard has been a consultant to Eli Lilly, as well as to Nestle Health Sciences and Novo Nordisk, and he has received research funding from Boehringer Ingelheim, Epitomee, Medical, and United Health Group.

A version of this article first appeared on Medscape.com.

NEW ORLEANS – Treatment of people with obesity but no diabetes with the dual–incretin agonist tirzepatide safely produced “unprecedented” levels of weight loss in the vast majority of patients in SURMOUNT-1, a placebo-controlled trial with more than 2,500 people with obesity or overweight plus at least one weight-related complication.

Although the pivotal trial did not directly compare weekly subcutaneous injection with the twincretin tirzepatide (at 5 mg, 10 mg, or 15 mg) with either bariatric surgery or what has been the reigning champ of weight-loss agents, a 2.4-mg/week injection of semaglutide (Wegovy), the new findings are impressive because they eclipsed semaglutide’s past performance in at least three important ways, said Ania M. Jastreboff, MD, PhD, SURMOUNT-1’s lead investigator, at the annual scientific sessions of the American Diabetes Association.

First, the highest-tested dosage of tirzepatide, 15 mg/week, for 72 weeks, produced a 5% or greater loss in baseline weight in 91%-96% of patients, an effect “not previously seen” in any prior phase 3 trial of a weight-loss agent, noted Dr. Jastreboff, an endocrinologist and director of Weight Management & Obesity Prevention at Yale University in New Haven, Conn.

Second, the average level of weight loss among the 630 people who received 15 mg/week was 22.5% in the on-treatment analysis, and 20.9% in the intention-to-treat analysis, again a magnitude of effect never before seen with any other medical intervention.

And in an exploratory analysis, 40% of people who received the highest-tested tirzepatide dose of 15 mg/week had at least a 25% loss in baseline weight in the on-treatment analysis, another example of unprecedented weight-loss achievement, said Dr. Jastreboff.

Looking at the data another way, the average baseline weight of those in the trial was 104 kg (230 lb) at the start, and the average weight loss was between 35 and 52 lbs by 72 weeks on treatment, Dr. Jastreboff said in a press conference. 

She noted, however, that not everyone will respond to tirzepatide, “but if you do respond to this medicine, you will feel full earlier, you won’t want to go back for seconds, and you may eat smaller amounts more often.”  

Such weight-loss agents will need to be taken chronically, in the same way that medications are for hypertension or dyslipidemia, Dr. Jastreboff stressed. “If you stop the antiobesity medication then the body fat mass set point will go back up so this necessitates long-term treatment.”

A new era: Weight loss ‘in the range of bariatric surgery’

Tirzepatide, developed by Lilly, has recently been approved in the United States for the treatment of type 2 diabetes, under the brand name Mounjaro.

SURMOUNT-1 was designed to examine the effect of the agent in overweight/obesity, and the company will be filing for the additional indication of weight loss in the future. Top-line results of SURMOUNT-1 generated much excitement when Lilly reported them back in April, including a story in The New York Times. 

Semaglutide, a Novo Nordisk drug, is approved in the United States for type 2 diabetes (as Ozempic at doses of either 1 mg or 2 mg per week) and also for weight loss, as Wegovy, at the higher dose of 2.4 mg per week. When Wegovy was given the green light by the Food and Drug Administration a year ago, it too was hailed as a “game changer” for obesity.

The weight-loss results seen in SURMOUNT-1 “put tirzepatide squarely in the range of weight loss achieved with bariatric surgery,” concluded Louis J. Aronne, MD, a coinvestigator on the trial, professor at Weill-Cornell Medicine in New York, and director of the Center for Weight Management and Metabolic Clinical Research of Weill-Cornell.

The results are “amazing,” and propel the weight-loss field into “a new era of obesity treatment,” commented Lee M. Kaplan, MD, who was not involved in the study and served as designated discussant for the trial.

Despite the lack of direct comparison, the findings indicate that “tirzepatide causes more weight loss than semaglutide,” and it provides “an opportunity to meet or exceed” the weight-loss effects of bariatric surgery, added Dr. Kaplan, director of the Obesity, Metabolism and Nutrition Institute at Massachusetts General Hospital in Boston.

Simultaneously with Dr. Jastreboff’s report at the meeting, the results were published online in The New England Journal of Medicine.

An accompanying editorial agrees with Dr. Kaplan: “It is remarkable that the magnitude of weight loss with tirzepatide was similar to that with gastric bypass, which raises the potential for alternative medical approaches to the treatment of obesity.”

“The tides are shifting, and there are now more options for people with obesity to lose weight,” write Clifford J. Rosen, MD, of Tufts University, Boston, and Julie R. Ingelfinger, MD, of Harvard University and Massachusetts General Hospital, Boston.

Dual incretin agonism ‘enhances activity,’ says expert

Tirzepatide is the first agent on the U.S. market from a novel class of dual-incretin agonists, with a molecular structure engineered to activate both the glucagonlike protein-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP), the two predominant incretins in the human gut. This combined activity has led to the twincretin nickname for tirzepatide.

Semaglutide is a single-incretin agonist, with its activity focused exclusively on the GLP-1 receptor.

Dr. Aronne tied the apparently superior efficacy of tirzepatide relative to semaglutide directly to the added incretin activity of tirzepatide. “The dual approach enhances efficacy,” he proposed during his presentation at the meeting.

The impressive efficacy and reassuring safety profile reported from SURMOUNT-1 opens the door to a new approach to treating obesity, which in the past has often taken a back seat to treatments for dyslipidemia, hypertension, and diabetes.

“Now that we can treat obesity safely and effectively, it makes sense to treat obesity first,” Dr. Aronne recommended.

Dr. Jastreboff agreed: “Perhaps we can prevent diabetes by treating obesity head-on,” she remarked. 

Weight-loss agents gain U.S. traction

There have been concerns about patient access to these newer weight-loss drugs in the United States, given that the retail cost of semaglutide for obesity exceeds $1,000/month, but Dr. Aronne reported data that painted a more optimistic picture.

His numbers showed that during the first months that semaglutide was on the U.S. market as a weight-loss agent, the number of U.S. prescriptions written for branded antiobesity medications roughly doubled, a spike that seemed mostly driven by the introduction and growing use of semaglutide.

With tirzepatide, every prespecified cardiometabolic parameter assessed in the trial showed clinically meaningful improvements, reported Dr. Jastreboff, including an average 17% reduction in waist circumference in patients on either of the highest two dosages, a 34% average drop in total fat mass, an average 0.5–percentage point cut in baseline hemoglobin A1c at the highest two dosages, substantial cuts in fasting plasma glucose and fasting insulin levels,  an average 28% drop in triglyceride levels, and an average systolic blood pressure reduction of about 8 mm Hg that occurred within 24 weeks on treatment.

“I think that insurers will sign up” for tirzepatide coverage based on benefits like this, Dr. Aronne predicted.

SURMOUNT-1 randomized 2,539 patients with obesity or with overweight plus at least one weight-related complication at any of 119 sites in nine countries. They had a body mass index of 30 kg/m² or more, or 27 kg/m² or more and at least one weight-related complication, excluding diabetes. They were randomized in a 1:1:1:1 ratio to receive once-weekly, subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 72 weeks, including a 20-week dose-escalation period.

The study’s two primary endpoints were the average percentage change in body weight from entry to 72 weeks, and the percentage of participants reaching at least a 5% reduction in their baseline body weight by 72 weeks.

The most common adverse events with tirzepatide were gastrointestinal, and most were mild to moderate in severity, occurring primarily during dose escalation. Adverse events caused treatment discontinuation in 4.3%, 7.1%, 6.2%, and 2.6% of participants receiving 5-mg, 10-mg, and 15-mg tirzepatide doses and placebo, respectively

The trial ran from December 2019 to April 2022, so during the peak of the COVID-19 pandemic, which Dr. Jastreboff described as an “amazing feat.”

Jamy Ard, MD, who chaired the SURMOUNT-1 session quipped, after hearing the results, “Wow; that’s exciting. If you’re not excited by the results, you’d better check your pulse.”

Dr. Ard is a professor at Wake Forest University, Winston-Salem, N.C., and codirector of the Wake Forest Baptist Health Weight Management Center in Winston-Salem.

SURMOUNT-1 was sponsored by Eli Lilly, the company that markets tirzepatide (Mounjaro). Dr. Jastreboff has been an advisor or consultant to Eli Lilly, as well as to Boehringer Ingelheim, Intellihealth, Novo Nordisk, Pfizer, Rhythm Pharmaceuticals, Scholar Rock, and Weight Watchers, and she has received research funding from Eli Lilly and Novo Nordisk. Dr. Aronne has been a consultant or advisor to, speaker on behalf of, or received research funding from Eli Lilly as well as from Altimmune, Amgen, Allurion, Intellihealth, Janssen, Novo Nordisk, Pfizer, and United Health group; he has an ownership interest in ERX, Gelesis, and Intellihealth; and he serves on the board of ERX, Jamieson Wellness, and Intellihealth. Dr. Kaplan has been a consultant to Eli Lilly, as well as to Amgen, Boehringer Ingelheim, Gelesis, Gilead, Novo Nordisk, Optum Health, Pfizer, Rhythm Pharmaceuticals, the Obesity and Nutrition Institute, and Xeno Biosciences. Dr. Ard has been a consultant to Eli Lilly, as well as to Nestle Health Sciences and Novo Nordisk, and he has received research funding from Boehringer Ingelheim, Epitomee, Medical, and United Health Group.

A version of this article first appeared on Medscape.com.

NEW ORLEANS – Treatment of people with obesity but no diabetes with the dual–incretin agonist tirzepatide safely produced “unprecedented” levels of weight loss in the vast majority of patients in SURMOUNT-1, a placebo-controlled trial with more than 2,500 people with obesity or overweight plus at least one weight-related complication.

Although the pivotal trial did not directly compare weekly subcutaneous injection with the twincretin tirzepatide (at 5 mg, 10 mg, or 15 mg) with either bariatric surgery or what has been the reigning champ of weight-loss agents, a 2.4-mg/week injection of semaglutide (Wegovy), the new findings are impressive because they eclipsed semaglutide’s past performance in at least three important ways, said Ania M. Jastreboff, MD, PhD, SURMOUNT-1’s lead investigator, at the annual scientific sessions of the American Diabetes Association.

First, the highest-tested dosage of tirzepatide, 15 mg/week, for 72 weeks, produced a 5% or greater loss in baseline weight in 91%-96% of patients, an effect “not previously seen” in any prior phase 3 trial of a weight-loss agent, noted Dr. Jastreboff, an endocrinologist and director of Weight Management & Obesity Prevention at Yale University in New Haven, Conn.

Second, the average level of weight loss among the 630 people who received 15 mg/week was 22.5% in the on-treatment analysis, and 20.9% in the intention-to-treat analysis, again a magnitude of effect never before seen with any other medical intervention.

And in an exploratory analysis, 40% of people who received the highest-tested tirzepatide dose of 15 mg/week had at least a 25% loss in baseline weight in the on-treatment analysis, another example of unprecedented weight-loss achievement, said Dr. Jastreboff.

Looking at the data another way, the average baseline weight of those in the trial was 104 kg (230 lb) at the start, and the average weight loss was between 35 and 52 lbs by 72 weeks on treatment, Dr. Jastreboff said in a press conference. 

She noted, however, that not everyone will respond to tirzepatide, “but if you do respond to this medicine, you will feel full earlier, you won’t want to go back for seconds, and you may eat smaller amounts more often.”  

Such weight-loss agents will need to be taken chronically, in the same way that medications are for hypertension or dyslipidemia, Dr. Jastreboff stressed. “If you stop the antiobesity medication then the body fat mass set point will go back up so this necessitates long-term treatment.”

A new era: Weight loss ‘in the range of bariatric surgery’

Tirzepatide, developed by Lilly, has recently been approved in the United States for the treatment of type 2 diabetes, under the brand name Mounjaro.

SURMOUNT-1 was designed to examine the effect of the agent in overweight/obesity, and the company will be filing for the additional indication of weight loss in the future. Top-line results of SURMOUNT-1 generated much excitement when Lilly reported them back in April, including a story in The New York Times. 

Semaglutide, a Novo Nordisk drug, is approved in the United States for type 2 diabetes (as Ozempic at doses of either 1 mg or 2 mg per week) and also for weight loss, as Wegovy, at the higher dose of 2.4 mg per week. When Wegovy was given the green light by the Food and Drug Administration a year ago, it too was hailed as a “game changer” for obesity.

The weight-loss results seen in SURMOUNT-1 “put tirzepatide squarely in the range of weight loss achieved with bariatric surgery,” concluded Louis J. Aronne, MD, a coinvestigator on the trial, professor at Weill-Cornell Medicine in New York, and director of the Center for Weight Management and Metabolic Clinical Research of Weill-Cornell.

The results are “amazing,” and propel the weight-loss field into “a new era of obesity treatment,” commented Lee M. Kaplan, MD, who was not involved in the study and served as designated discussant for the trial.

Despite the lack of direct comparison, the findings indicate that “tirzepatide causes more weight loss than semaglutide,” and it provides “an opportunity to meet or exceed” the weight-loss effects of bariatric surgery, added Dr. Kaplan, director of the Obesity, Metabolism and Nutrition Institute at Massachusetts General Hospital in Boston.

Simultaneously with Dr. Jastreboff’s report at the meeting, the results were published online in The New England Journal of Medicine.

An accompanying editorial agrees with Dr. Kaplan: “It is remarkable that the magnitude of weight loss with tirzepatide was similar to that with gastric bypass, which raises the potential for alternative medical approaches to the treatment of obesity.”

“The tides are shifting, and there are now more options for people with obesity to lose weight,” write Clifford J. Rosen, MD, of Tufts University, Boston, and Julie R. Ingelfinger, MD, of Harvard University and Massachusetts General Hospital, Boston.

Dual incretin agonism ‘enhances activity,’ says expert

Tirzepatide is the first agent on the U.S. market from a novel class of dual-incretin agonists, with a molecular structure engineered to activate both the glucagonlike protein-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP), the two predominant incretins in the human gut. This combined activity has led to the twincretin nickname for tirzepatide.

Semaglutide is a single-incretin agonist, with its activity focused exclusively on the GLP-1 receptor.

Dr. Aronne tied the apparently superior efficacy of tirzepatide relative to semaglutide directly to the added incretin activity of tirzepatide. “The dual approach enhances efficacy,” he proposed during his presentation at the meeting.

The impressive efficacy and reassuring safety profile reported from SURMOUNT-1 opens the door to a new approach to treating obesity, which in the past has often taken a back seat to treatments for dyslipidemia, hypertension, and diabetes.

“Now that we can treat obesity safely and effectively, it makes sense to treat obesity first,” Dr. Aronne recommended.

Dr. Jastreboff agreed: “Perhaps we can prevent diabetes by treating obesity head-on,” she remarked. 

Weight-loss agents gain U.S. traction

There have been concerns about patient access to these newer weight-loss drugs in the United States, given that the retail cost of semaglutide for obesity exceeds $1,000/month, but Dr. Aronne reported data that painted a more optimistic picture.

His numbers showed that during the first months that semaglutide was on the U.S. market as a weight-loss agent, the number of U.S. prescriptions written for branded antiobesity medications roughly doubled, a spike that seemed mostly driven by the introduction and growing use of semaglutide.

With tirzepatide, every prespecified cardiometabolic parameter assessed in the trial showed clinically meaningful improvements, reported Dr. Jastreboff, including an average 17% reduction in waist circumference in patients on either of the highest two dosages, a 34% average drop in total fat mass, an average 0.5–percentage point cut in baseline hemoglobin A1c at the highest two dosages, substantial cuts in fasting plasma glucose and fasting insulin levels,  an average 28% drop in triglyceride levels, and an average systolic blood pressure reduction of about 8 mm Hg that occurred within 24 weeks on treatment.

“I think that insurers will sign up” for tirzepatide coverage based on benefits like this, Dr. Aronne predicted.

SURMOUNT-1 randomized 2,539 patients with obesity or with overweight plus at least one weight-related complication at any of 119 sites in nine countries. They had a body mass index of 30 kg/m² or more, or 27 kg/m² or more and at least one weight-related complication, excluding diabetes. They were randomized in a 1:1:1:1 ratio to receive once-weekly, subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 72 weeks, including a 20-week dose-escalation period.

The study’s two primary endpoints were the average percentage change in body weight from entry to 72 weeks, and the percentage of participants reaching at least a 5% reduction in their baseline body weight by 72 weeks.

The most common adverse events with tirzepatide were gastrointestinal, and most were mild to moderate in severity, occurring primarily during dose escalation. Adverse events caused treatment discontinuation in 4.3%, 7.1%, 6.2%, and 2.6% of participants receiving 5-mg, 10-mg, and 15-mg tirzepatide doses and placebo, respectively

The trial ran from December 2019 to April 2022, so during the peak of the COVID-19 pandemic, which Dr. Jastreboff described as an “amazing feat.”

Jamy Ard, MD, who chaired the SURMOUNT-1 session quipped, after hearing the results, “Wow; that’s exciting. If you’re not excited by the results, you’d better check your pulse.”

Dr. Ard is a professor at Wake Forest University, Winston-Salem, N.C., and codirector of the Wake Forest Baptist Health Weight Management Center in Winston-Salem.

SURMOUNT-1 was sponsored by Eli Lilly, the company that markets tirzepatide (Mounjaro). Dr. Jastreboff has been an advisor or consultant to Eli Lilly, as well as to Boehringer Ingelheim, Intellihealth, Novo Nordisk, Pfizer, Rhythm Pharmaceuticals, Scholar Rock, and Weight Watchers, and she has received research funding from Eli Lilly and Novo Nordisk. Dr. Aronne has been a consultant or advisor to, speaker on behalf of, or received research funding from Eli Lilly as well as from Altimmune, Amgen, Allurion, Intellihealth, Janssen, Novo Nordisk, Pfizer, and United Health group; he has an ownership interest in ERX, Gelesis, and Intellihealth; and he serves on the board of ERX, Jamieson Wellness, and Intellihealth. Dr. Kaplan has been a consultant to Eli Lilly, as well as to Amgen, Boehringer Ingelheim, Gelesis, Gilead, Novo Nordisk, Optum Health, Pfizer, Rhythm Pharmaceuticals, the Obesity and Nutrition Institute, and Xeno Biosciences. Dr. Ard has been a consultant to Eli Lilly, as well as to Nestle Health Sciences and Novo Nordisk, and he has received research funding from Boehringer Ingelheim, Epitomee, Medical, and United Health Group.

A version of this article first appeared on Medscape.com.

CHICAGO -- Breast cancer patients with low levels of HER2 expression, previously considered untreatable with HER2-targeted therapies, benefited from the anti-HER2 antibody drug conjugate trastuzumab deruxtecan. The therapy doubled progression-free survival versus chemotherapy in patients with hormone receptor positive (HR+) and low levels of HER2.

“Overall, these results establish HER2 low metastatic breast cancer as a targetable population of breast cancer with trastuzumab deruxtecan as a new standard of care in this setting,” said Shanu Modi, MD, during a press conference held in Chicago at the annual meeting of the American Society of Clinical Oncology, where she presented the results.

“I think the results of this trial clearly will be practice changing,” said ASCO spokesperson and breast cancer expert Jane Lowe Meisel, MD, during the press conference. “I think what this trial does is really extend the benefits of this agent to a whole new group of patients that traditionally is really quite difficult to treat. I think this will offer a wonderful new option for patients and also will really fundamentally change the way we think about HER2 status and how we classify this in our metastatic patients,” Dr. Meisel added.

The conjugate includes the anti-HER2 antibody trastuzumab and the topoisomerase I inhibitor deruxtecan, which interferes with DNA replication. Trastuzumab has demonstrated efficacy in patients with high levels of HER2 expression, and trastuzumab-deruxtecan received FDA approval in May 2022 for the treatment of HER2-positive breast cancer in patients who had previously received an anti-HER2 regimen.

However, anti-HER2 agents had not been shown to benefit HER2-low patients, defined as immunohistochemistry (IHC) 1+ or 2+. About 60% of breast cancer patients traditionally thought of HER2 negative could be classified as HER2 low, according to Dr. Modi, who is a medical oncologist at Memorial Sloan Kettering Cancer Center, New York.

Asked why she thought trastuzumab deruxtecan succeeded where other anti-HER2 therapies failed in this population, Dr. Modi highlighted the nature of the drug conjugate, including a high drug payload and the use of a topoisomerase inhibitor, which is rarely employed against breast cancer. Once released from the antibody, the drug retains its ability to cross cell membranes and enter the tumor microenvironment. That ‘knock on’ effect might allow it to reach neighboring cells that don’t express HER2. “We know HER2 expression is very heterogeneous. I think that’s why, for the first time, we’re seeing activity for a targeted agent,” Dr. Modi said.

The DESTINY-Breast04 study included 557 patients in Asia, Europe, and North America with HR-negative or HR-positive, HER2-low, unresectable, and/or metastatic breast cancer. Patients were randomized to trastuzumab deruxtecan or physician’s choice of several standard chemotherapy drugs. After a median follow-up of 18.4 months, compared with the chemotherapy group, patients in the trastuzumab deruxtecan arm had a 49% reduction in risk of progression and a 36% reduction in mortality. The group also had longer progression-free survival (10.1 months vs. 5.4 months) and overall survival (23.9 months vs. 17.5 months).

Although adverse events were similar between the two groups (52.6% in trastuzumab deruxtecan, 67.4% in chemotherapy), lung toxicity occurred in 12% of the group, and there were 3 fatalities as a result (0.8%). Interstitial lung disease/pneumonitis has been linked to trastuzumab treatment in the past, with one meta-analysis finding a frequency of 2.4% and fatality rate of 0.2%.

Additional studies are in progress to determine the minimum threshold of HER2 expression needed to gain a benefit from trastuzumab deruxtecan treatment.

The study was funded by Daiichi Sankyo, and AstraZeneca. Dr. Modi has advised, consulted for, or received honoraria from Daiichi Sankyo, and AstraZeneca. Dr. Meisel has advised or consulted for Medscape and AstraZeneca.

CHICAGO -- Breast cancer patients with low levels of HER2 expression, previously considered untreatable with HER2-targeted therapies, benefited from the anti-HER2 antibody drug conjugate trastuzumab deruxtecan. The therapy doubled progression-free survival versus chemotherapy in patients with hormone receptor positive (HR+) and low levels of HER2.

“Overall, these results establish HER2 low metastatic breast cancer as a targetable population of breast cancer with trastuzumab deruxtecan as a new standard of care in this setting,” said Shanu Modi, MD, during a press conference held in Chicago at the annual meeting of the American Society of Clinical Oncology, where she presented the results.

“I think the results of this trial clearly will be practice changing,” said ASCO spokesperson and breast cancer expert Jane Lowe Meisel, MD, during the press conference. “I think what this trial does is really extend the benefits of this agent to a whole new group of patients that traditionally is really quite difficult to treat. I think this will offer a wonderful new option for patients and also will really fundamentally change the way we think about HER2 status and how we classify this in our metastatic patients,” Dr. Meisel added.

The conjugate includes the anti-HER2 antibody trastuzumab and the topoisomerase I inhibitor deruxtecan, which interferes with DNA replication. Trastuzumab has demonstrated efficacy in patients with high levels of HER2 expression, and trastuzumab-deruxtecan received FDA approval in May 2022 for the treatment of HER2-positive breast cancer in patients who had previously received an anti-HER2 regimen.

However, anti-HER2 agents had not been shown to benefit HER2-low patients, defined as immunohistochemistry (IHC) 1+ or 2+. About 60% of breast cancer patients traditionally thought of HER2 negative could be classified as HER2 low, according to Dr. Modi, who is a medical oncologist at Memorial Sloan Kettering Cancer Center, New York.

Asked why she thought trastuzumab deruxtecan succeeded where other anti-HER2 therapies failed in this population, Dr. Modi highlighted the nature of the drug conjugate, including a high drug payload and the use of a topoisomerase inhibitor, which is rarely employed against breast cancer. Once released from the antibody, the drug retains its ability to cross cell membranes and enter the tumor microenvironment. That ‘knock on’ effect might allow it to reach neighboring cells that don’t express HER2. “We know HER2 expression is very heterogeneous. I think that’s why, for the first time, we’re seeing activity for a targeted agent,” Dr. Modi said.

The DESTINY-Breast04 study included 557 patients in Asia, Europe, and North America with HR-negative or HR-positive, HER2-low, unresectable, and/or metastatic breast cancer. Patients were randomized to trastuzumab deruxtecan or physician’s choice of several standard chemotherapy drugs. After a median follow-up of 18.4 months, compared with the chemotherapy group, patients in the trastuzumab deruxtecan arm had a 49% reduction in risk of progression and a 36% reduction in mortality. The group also had longer progression-free survival (10.1 months vs. 5.4 months) and overall survival (23.9 months vs. 17.5 months).

Although adverse events were similar between the two groups (52.6% in trastuzumab deruxtecan, 67.4% in chemotherapy), lung toxicity occurred in 12% of the group, and there were 3 fatalities as a result (0.8%). Interstitial lung disease/pneumonitis has been linked to trastuzumab treatment in the past, with one meta-analysis finding a frequency of 2.4% and fatality rate of 0.2%.

Additional studies are in progress to determine the minimum threshold of HER2 expression needed to gain a benefit from trastuzumab deruxtecan treatment.

The study was funded by Daiichi Sankyo, and AstraZeneca. Dr. Modi has advised, consulted for, or received honoraria from Daiichi Sankyo, and AstraZeneca. Dr. Meisel has advised or consulted for Medscape and AstraZeneca.

CHICAGO -- Breast cancer patients with low levels of HER2 expression, previously considered untreatable with HER2-targeted therapies, benefited from the anti-HER2 antibody drug conjugate trastuzumab deruxtecan. The therapy doubled progression-free survival versus chemotherapy in patients with hormone receptor positive (HR+) and low levels of HER2.

“Overall, these results establish HER2 low metastatic breast cancer as a targetable population of breast cancer with trastuzumab deruxtecan as a new standard of care in this setting,” said Shanu Modi, MD, during a press conference held in Chicago at the annual meeting of the American Society of Clinical Oncology, where she presented the results.

“I think the results of this trial clearly will be practice changing,” said ASCO spokesperson and breast cancer expert Jane Lowe Meisel, MD, during the press conference. “I think what this trial does is really extend the benefits of this agent to a whole new group of patients that traditionally is really quite difficult to treat. I think this will offer a wonderful new option for patients and also will really fundamentally change the way we think about HER2 status and how we classify this in our metastatic patients,” Dr. Meisel added.

The conjugate includes the anti-HER2 antibody trastuzumab and the topoisomerase I inhibitor deruxtecan, which interferes with DNA replication. Trastuzumab has demonstrated efficacy in patients with high levels of HER2 expression, and trastuzumab-deruxtecan received FDA approval in May 2022 for the treatment of HER2-positive breast cancer in patients who had previously received an anti-HER2 regimen.

However, anti-HER2 agents had not been shown to benefit HER2-low patients, defined as immunohistochemistry (IHC) 1+ or 2+. About 60% of breast cancer patients traditionally thought of HER2 negative could be classified as HER2 low, according to Dr. Modi, who is a medical oncologist at Memorial Sloan Kettering Cancer Center, New York.

Asked why she thought trastuzumab deruxtecan succeeded where other anti-HER2 therapies failed in this population, Dr. Modi highlighted the nature of the drug conjugate, including a high drug payload and the use of a topoisomerase inhibitor, which is rarely employed against breast cancer. Once released from the antibody, the drug retains its ability to cross cell membranes and enter the tumor microenvironment. That ‘knock on’ effect might allow it to reach neighboring cells that don’t express HER2. “We know HER2 expression is very heterogeneous. I think that’s why, for the first time, we’re seeing activity for a targeted agent,” Dr. Modi said.

The DESTINY-Breast04 study included 557 patients in Asia, Europe, and North America with HR-negative or HR-positive, HER2-low, unresectable, and/or metastatic breast cancer. Patients were randomized to trastuzumab deruxtecan or physician’s choice of several standard chemotherapy drugs. After a median follow-up of 18.4 months, compared with the chemotherapy group, patients in the trastuzumab deruxtecan arm had a 49% reduction in risk of progression and a 36% reduction in mortality. The group also had longer progression-free survival (10.1 months vs. 5.4 months) and overall survival (23.9 months vs. 17.5 months).

Although adverse events were similar between the two groups (52.6% in trastuzumab deruxtecan, 67.4% in chemotherapy), lung toxicity occurred in 12% of the group, and there were 3 fatalities as a result (0.8%). Interstitial lung disease/pneumonitis has been linked to trastuzumab treatment in the past, with one meta-analysis finding a frequency of 2.4% and fatality rate of 0.2%.

Additional studies are in progress to determine the minimum threshold of HER2 expression needed to gain a benefit from trastuzumab deruxtecan treatment.

The study was funded by Daiichi Sankyo, and AstraZeneca. Dr. Modi has advised, consulted for, or received honoraria from Daiichi Sankyo, and AstraZeneca. Dr. Meisel has advised or consulted for Medscape and AstraZeneca.

The number of general internists choosing a career in hospital medicine jumped from 25% to 40% over 10 years, according to data from the American Board of Internal Medicine.

In a new study, published in Annals of Internal Medicine, researchers from ABIM reviewed certification data from 67,902 general internists, accounting for 80% of all general internists certified in the United States from 1990 to 2017.

The researchers also used data from Medicare fee-for-service claims from 2008-2018 to measure and categorize practice setting types. The claims were from patients aged 65 years or older with at least 20 evaluation and management visits each year. Practice settings were categorized as hospitalist, outpatient, or mixed.

“ABIM is always working to understand the real-life experience of physicians, and this project grew out of that sort of analysis,” lead author Bradley M. Gray, PhD, a health services researcher at ABIM in Philadelphia, said in an interview. “We wanted to better understand practice setting, because that relates to the kinds of questions that we ask on our certifying exams. When we did this, we noticed a trend toward hospital medicine.”

Overall, the percentages of general internists in hospitalist practice and outpatient-only practice increased during the study period, from 25% to 40% and from 23% to 38%, respectively. By contrast, the percentage of general internists in a mixed-practice setting decreased from 52% to 23%, a 56% decline. Most of the physicians who left the mixed practice setting switched to outpatient-only practices.

Among the internists certified in 2017, 71% practiced as hospitalists, compared with 8% practicing as outpatient-only physicians. Most physicians remained in their original choice of practice setting. For physicians certified in 1999 and 2012, 86% and 85%, respectively, of those who chose hospitalist medicine remained in the hospital setting 5 years later, as did 95% of outpatient physicians, but only 57% of mixed-practice physicians.

The shift to outpatient practice among senior physicians offset the potential decline in outpatient primary care resulting from the increased choice of hospitalist medicine by new internists, the researchers noted.

The study findings were limited by several factors, including the reliance on Medicare fee-for-service claims, the researchers noted.

“We were surprised by both the dramatic shift toward hospital medicine by new physicians and the shift to outpatient only (an extreme category) for more senior physicians,” Dr. Gray said in an interview.

The shift toward outpatient practice among older physicians may be driven by convenience, said Dr. Gray. “I suspect that it is more efficient to specialize in terms of practice setting. Only seeing patients in the outpatient setting means that you don’t have to travel to the hospital, which can be time consuming.

“Also, with fewer new physicians going into primary care, older physicians need to focus on outpatient visits. This could be problematic in the future as more senior physicians retire and are replaced by new physicians who focus on hospital care,” which could lead to more shortages in primary care physicians, he explained.

The trend toward hospital medicine as a career has been going on since before the pandemic, said Dr. Gray. “I don’t think the pandemic will ultimately impact this trend. That said, at least in the short run, there may have been a decreased demand for primary care, but that is just my speculation. As more data flow in we will be able to answer this question more directly.”

Next steps for research included digging deeper into the data to understand the nature of conditions facing hospitalists, Dr. Gray said.
 

Implications for primary care

“This study provides an updated snapshot of the popularity of hospital medicine,” said Bradley A. Sharpe, MD, of the division of hospital medicine at the University of California, San Francisco. “It is also important to conduct this study now as health systems think about the challenge of providing high-quality primary care with a rapidly decreasing number of internists choosing to practice outpatient medicine.” Dr. Sharpe was not involved in the study.

“The most surprising finding to me was not the increase in general internists focusing on hospital medicine, but the amount of the increase; it is remarkable that nearly three quarters of general internists are choosing to practice as hospitalists,” Dr. Sharpe noted.

“I think there are a number of key factors at play,” he said. “First, as hospital medicine as a field is now more than 25 years old, hospitals and health systems have evolved to create hospital medicine jobs that are interesting, engaging, rewarding (financially and otherwise), doable, and sustainable. Second, being an outpatient internist is incredibly challenging; multiple studies have shown that it is essentially impossible to complete the evidence-based preventive care for a panel of patients on top of everything else. We know burnout rates are often higher among primary care and family medicine providers. On top of that, the expansion of electronic health records and patient access has led to a massive increase in messages to providers; this has been shown to be associated with burnout.”

The potential impact of the pandemic on physicians’ choices and the trend toward hospital medicine is an interested question, Dr. Sharpe said. The current study showed only trends through 2017.

“To be honest, I think it is difficult to predict,” he said. “Hospitalists shouldered much of the burden of COVID care nationally and burnout rates are high. One could imagine the extra work (as well as concern for personal safety) could lead to fewer providers choosing hospital medicine.

“At the same time, the pandemic has driven many of us to reflect on life and our values and what is important and, through that lens, providers might choose hospital medicine as a more sustainable, do-able, rewarding, and enjoyable career choice,” Dr. Sharpe emphasized.

“Additional research could explore the drivers of this clear trend toward hospital medicine. Determining what is motivating this trend could help hospitals and health systems ensure they have the right workforce for the future and, in particular, how to create outpatient positions that are attractive and rewarding,” he said.

The study received no outside funding. The researchers and Dr. Sharpe disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The number of general internists choosing a career in hospital medicine jumped from 25% to 40% over 10 years, according to data from the American Board of Internal Medicine.

In a new study, published in Annals of Internal Medicine, researchers from ABIM reviewed certification data from 67,902 general internists, accounting for 80% of all general internists certified in the United States from 1990 to 2017.

The researchers also used data from Medicare fee-for-service claims from 2008-2018 to measure and categorize practice setting types. The claims were from patients aged 65 years or older with at least 20 evaluation and management visits each year. Practice settings were categorized as hospitalist, outpatient, or mixed.

“ABIM is always working to understand the real-life experience of physicians, and this project grew out of that sort of analysis,” lead author Bradley M. Gray, PhD, a health services researcher at ABIM in Philadelphia, said in an interview. “We wanted to better understand practice setting, because that relates to the kinds of questions that we ask on our certifying exams. When we did this, we noticed a trend toward hospital medicine.”

Overall, the percentages of general internists in hospitalist practice and outpatient-only practice increased during the study period, from 25% to 40% and from 23% to 38%, respectively. By contrast, the percentage of general internists in a mixed-practice setting decreased from 52% to 23%, a 56% decline. Most of the physicians who left the mixed practice setting switched to outpatient-only practices.

Among the internists certified in 2017, 71% practiced as hospitalists, compared with 8% practicing as outpatient-only physicians. Most physicians remained in their original choice of practice setting. For physicians certified in 1999 and 2012, 86% and 85%, respectively, of those who chose hospitalist medicine remained in the hospital setting 5 years later, as did 95% of outpatient physicians, but only 57% of mixed-practice physicians.

The shift to outpatient practice among senior physicians offset the potential decline in outpatient primary care resulting from the increased choice of hospitalist medicine by new internists, the researchers noted.

The study findings were limited by several factors, including the reliance on Medicare fee-for-service claims, the researchers noted.

“We were surprised by both the dramatic shift toward hospital medicine by new physicians and the shift to outpatient only (an extreme category) for more senior physicians,” Dr. Gray said in an interview.

The shift toward outpatient practice among older physicians may be driven by convenience, said Dr. Gray. “I suspect that it is more efficient to specialize in terms of practice setting. Only seeing patients in the outpatient setting means that you don’t have to travel to the hospital, which can be time consuming.

“Also, with fewer new physicians going into primary care, older physicians need to focus on outpatient visits. This could be problematic in the future as more senior physicians retire and are replaced by new physicians who focus on hospital care,” which could lead to more shortages in primary care physicians, he explained.

The trend toward hospital medicine as a career has been going on since before the pandemic, said Dr. Gray. “I don’t think the pandemic will ultimately impact this trend. That said, at least in the short run, there may have been a decreased demand for primary care, but that is just my speculation. As more data flow in we will be able to answer this question more directly.”

Next steps for research included digging deeper into the data to understand the nature of conditions facing hospitalists, Dr. Gray said.
 

Implications for primary care

“This study provides an updated snapshot of the popularity of hospital medicine,” said Bradley A. Sharpe, MD, of the division of hospital medicine at the University of California, San Francisco. “It is also important to conduct this study now as health systems think about the challenge of providing high-quality primary care with a rapidly decreasing number of internists choosing to practice outpatient medicine.” Dr. Sharpe was not involved in the study.

“The most surprising finding to me was not the increase in general internists focusing on hospital medicine, but the amount of the increase; it is remarkable that nearly three quarters of general internists are choosing to practice as hospitalists,” Dr. Sharpe noted.

“I think there are a number of key factors at play,” he said. “First, as hospital medicine as a field is now more than 25 years old, hospitals and health systems have evolved to create hospital medicine jobs that are interesting, engaging, rewarding (financially and otherwise), doable, and sustainable. Second, being an outpatient internist is incredibly challenging; multiple studies have shown that it is essentially impossible to complete the evidence-based preventive care for a panel of patients on top of everything else. We know burnout rates are often higher among primary care and family medicine providers. On top of that, the expansion of electronic health records and patient access has led to a massive increase in messages to providers; this has been shown to be associated with burnout.”

The potential impact of the pandemic on physicians’ choices and the trend toward hospital medicine is an interested question, Dr. Sharpe said. The current study showed only trends through 2017.

“To be honest, I think it is difficult to predict,” he said. “Hospitalists shouldered much of the burden of COVID care nationally and burnout rates are high. One could imagine the extra work (as well as concern for personal safety) could lead to fewer providers choosing hospital medicine.

“At the same time, the pandemic has driven many of us to reflect on life and our values and what is important and, through that lens, providers might choose hospital medicine as a more sustainable, do-able, rewarding, and enjoyable career choice,” Dr. Sharpe emphasized.

“Additional research could explore the drivers of this clear trend toward hospital medicine. Determining what is motivating this trend could help hospitals and health systems ensure they have the right workforce for the future and, in particular, how to create outpatient positions that are attractive and rewarding,” he said.

The study received no outside funding. The researchers and Dr. Sharpe disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The number of general internists choosing a career in hospital medicine jumped from 25% to 40% over 10 years, according to data from the American Board of Internal Medicine.

In a new study, published in Annals of Internal Medicine, researchers from ABIM reviewed certification data from 67,902 general internists, accounting for 80% of all general internists certified in the United States from 1990 to 2017.

The researchers also used data from Medicare fee-for-service claims from 2008-2018 to measure and categorize practice setting types. The claims were from patients aged 65 years or older with at least 20 evaluation and management visits each year. Practice settings were categorized as hospitalist, outpatient, or mixed.

“ABIM is always working to understand the real-life experience of physicians, and this project grew out of that sort of analysis,” lead author Bradley M. Gray, PhD, a health services researcher at ABIM in Philadelphia, said in an interview. “We wanted to better understand practice setting, because that relates to the kinds of questions that we ask on our certifying exams. When we did this, we noticed a trend toward hospital medicine.”

Overall, the percentages of general internists in hospitalist practice and outpatient-only practice increased during the study period, from 25% to 40% and from 23% to 38%, respectively. By contrast, the percentage of general internists in a mixed-practice setting decreased from 52% to 23%, a 56% decline. Most of the physicians who left the mixed practice setting switched to outpatient-only practices.

Among the internists certified in 2017, 71% practiced as hospitalists, compared with 8% practicing as outpatient-only physicians. Most physicians remained in their original choice of practice setting. For physicians certified in 1999 and 2012, 86% and 85%, respectively, of those who chose hospitalist medicine remained in the hospital setting 5 years later, as did 95% of outpatient physicians, but only 57% of mixed-practice physicians.

The shift to outpatient practice among senior physicians offset the potential decline in outpatient primary care resulting from the increased choice of hospitalist medicine by new internists, the researchers noted.

The study findings were limited by several factors, including the reliance on Medicare fee-for-service claims, the researchers noted.

“We were surprised by both the dramatic shift toward hospital medicine by new physicians and the shift to outpatient only (an extreme category) for more senior physicians,” Dr. Gray said in an interview.

The shift toward outpatient practice among older physicians may be driven by convenience, said Dr. Gray. “I suspect that it is more efficient to specialize in terms of practice setting. Only seeing patients in the outpatient setting means that you don’t have to travel to the hospital, which can be time consuming.

“Also, with fewer new physicians going into primary care, older physicians need to focus on outpatient visits. This could be problematic in the future as more senior physicians retire and are replaced by new physicians who focus on hospital care,” which could lead to more shortages in primary care physicians, he explained.

The trend toward hospital medicine as a career has been going on since before the pandemic, said Dr. Gray. “I don’t think the pandemic will ultimately impact this trend. That said, at least in the short run, there may have been a decreased demand for primary care, but that is just my speculation. As more data flow in we will be able to answer this question more directly.”

Next steps for research included digging deeper into the data to understand the nature of conditions facing hospitalists, Dr. Gray said.
 

Implications for primary care

“This study provides an updated snapshot of the popularity of hospital medicine,” said Bradley A. Sharpe, MD, of the division of hospital medicine at the University of California, San Francisco. “It is also important to conduct this study now as health systems think about the challenge of providing high-quality primary care with a rapidly decreasing number of internists choosing to practice outpatient medicine.” Dr. Sharpe was not involved in the study.

“The most surprising finding to me was not the increase in general internists focusing on hospital medicine, but the amount of the increase; it is remarkable that nearly three quarters of general internists are choosing to practice as hospitalists,” Dr. Sharpe noted.

“I think there are a number of key factors at play,” he said. “First, as hospital medicine as a field is now more than 25 years old, hospitals and health systems have evolved to create hospital medicine jobs that are interesting, engaging, rewarding (financially and otherwise), doable, and sustainable. Second, being an outpatient internist is incredibly challenging; multiple studies have shown that it is essentially impossible to complete the evidence-based preventive care for a panel of patients on top of everything else. We know burnout rates are often higher among primary care and family medicine providers. On top of that, the expansion of electronic health records and patient access has led to a massive increase in messages to providers; this has been shown to be associated with burnout.”

The potential impact of the pandemic on physicians’ choices and the trend toward hospital medicine is an interested question, Dr. Sharpe said. The current study showed only trends through 2017.

“To be honest, I think it is difficult to predict,” he said. “Hospitalists shouldered much of the burden of COVID care nationally and burnout rates are high. One could imagine the extra work (as well as concern for personal safety) could lead to fewer providers choosing hospital medicine.

“At the same time, the pandemic has driven many of us to reflect on life and our values and what is important and, through that lens, providers might choose hospital medicine as a more sustainable, do-able, rewarding, and enjoyable career choice,” Dr. Sharpe emphasized.

“Additional research could explore the drivers of this clear trend toward hospital medicine. Determining what is motivating this trend could help hospitals and health systems ensure they have the right workforce for the future and, in particular, how to create outpatient positions that are attractive and rewarding,” he said.

The study received no outside funding. The researchers and Dr. Sharpe disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

MAR DEL PLATA, ARGENTINA – Psychiatrists should prescribe metformin early to patients who experience rapid weight gain after they begin taking antipsychotic drugs, according to a new evidence-based Irish guideline for the management of this common complication in adults with psychoses who are taking medications.

The document was discussed during one of the sessions of the XXXV Argentine Congress of Psychiatry of the Association of Argentine Psychiatrists. The document also was presented by one of its authors at the European Congress on Obesity 2022.

The guideline encourages psychiatrists not to underestimate the adverse metabolic effects of their treatments and encourages them to contemplate and carry out this prevention and management strategy, commented María Delia Michat, PhD, professor of clinical psychiatry and psychopharmacology at the APSA Postgraduate Training Institute, Buenos Aires.

“Although it is always good to work as a team, it is usually we psychiatrists who coordinate the pharmacological treatment of our patients, and we have to know how to manage drugs that can prevent cardiovascular disease,” Dr. Michat said in an interview.

“The new guideline is helpful because it protocolizes the use of metformin, which is the cheapest drug and has the most evidence for antipsychotic-induced weight gain,” she added.
 

Avoiding metabolic syndrome

In patients with schizophrenia, obesity rates are 40% higher than in the general population, and 80% of patients develop weight gain after their first treatment, noted Dr. Michat. “Right away, weight gain is seen in the first month. And it is a serious problem, because patients with schizophrenia, major depression, or bipolar disorder already have an increased risk of premature mortality, especially from cardiovascular diseases, and they have an increased risk of metabolic syndrome. And we sometimes give drugs that further increase that risk,” she said.

Being overweight is a major criterion for defining metabolic syndrome. Dr. Michat noted that, among the antipsychotic drugs that increase weight the most are clozapine, olanzapine, chlorpromazine, quetiapine, and risperidone, in addition to other psychoactive drugs, such as valproic acid, lithium, mirtazapine, and tricyclic antidepressants.

Several clinical trials, such as a pioneering Chinese study from 2008, have shown the potential of metformin to mitigate the weight gain induced by this type of drug.

However, Dr. Michat noted that so far the major guidelines (for example, the Canadian Network for Mood and Anxiety Treatments [CANMAT]/International Society for Bipolar Disorders [ISBD] for bipolar disorder and the American Psychiatric Association [APA] for schizophrenia) “say very little” on how to address this complication. They propose what she defined as a “problematic” order of action in which the initial emphasis is on promoting lifestyle changes, which are difficult for these patients to carry out, as well as general proposals for changing medication (which is not simple to implement when the patient’s condition is stabilized) and eventual consultation with a clinician to start therapy with metformin or other drugs, such as liraglutide, semaglutide, and topiramate.

The new clinical practice guideline, which was published in Evidence-Based Mental Health (of the BMJ journal group), was written by a multidisciplinary team of pharmacists, psychiatrists, and mental health nurses from Ireland. It aims to fill that gap. The investigators reviewed 1,270 scientific articles and analyzed 26 of them in depth, including seven randomized clinical trials and a 2016 systematic review and meta-analysis. The authors made a “strong” recommendation, for which there was moderate-quality evidence, that for patients for whom a lifestyle intervention is unacceptable or inappropriate the use of metformin is an “alternative first-line intervention” for antipsychotic drug–induced weight gain.

Likewise, as a strong recommendation with moderate-quality evidence, the guidance encourages the use of metformin when nonpharmacologic intervention does not seem to be effective.

The guideline also says it is preferable to start metformin early for patients who gain more than 7% of their baseline weight within the first month of antipsychotic treatment. It also endorses metformin when weight gain is established.

Other recommendations include evaluating baseline kidney function before starting metformin treatment and suggest a dose adjustment when the estimated glomerular filtration rate (eGFR) is < 60 mL/min/1.73 m². The guidance says the use of metformin is contraindicated for patients in whom eGFR is <30 mL/min per 1.73 m². The proposed starting dosage is 500 mg twice per day with meals, with increments of 500 mg every 1-2 weeks until reaching a target dose of 2,000 mg/day. The guidance recommends that consideration always be given to individual tolerability and efficacy.

Treatment goals should be personalized and agreed upon with patients. In the case of early intervention, the guideline proposes initially stabilizing the weight gained or, if possible, reverse excess weight. When weight gain is established, the goal would be to lose at least 5% of the weight within the next 6 months.

The authors also recommend monitoring kidney function annually, as well as vitamin B₁₂ levels and individual tolerability and compliance. Gastrointestinal adverse effects can be managed by dose reduction or slower dose titration. The risk of lactic acidosis, which affects 4.3 per 100,000 person-years among those taking metformin, can be attenuated by adjusting the dose according to kidney function or avoiding prescribing it to patients who have a history of alcohol abuse or who are receiving treatment that may interact with the drug.
 

Validating pharmacologic management

The lead author of the new guideline, Ita Fitzgerald, a teacher in clinical pharmacy and senior pharmacist at St. Patrick’s Mental Health Services in Dublin, pointed out that there is a bias toward not using drugs for weight management and shifting the responsibility onto the patients themselves, something that is very often out of their control.

“The purpose of the guideline was to decide on a range of criteria to maximize the use of metformin, to recognize that for many people, pharmacological management is a valid and important option that could and should be more widely used and to provide precise and practical guidance to physicians to facilitate a more widespread use,” Ms. Fitzgerald said in an interview.

According to Fitzgerald, who is pursuing her doctorate at University College Cork (Ireland), one of the most outstanding results of the work is that it highlights that the main benefit of metformin is to flatten rather than reverse antipsychotic-induced weight gain and that indicating it late can nullify that effect.

“In all the recommendations, we try very hard to shift the focus from metformin’s role as a weight reversal agent to one as a weight management agent that should be used early in treatment, which is when most weight gain occurs. If metformin succeeds in flattening that increase, that’s a huge potential benefit for an inexpensive and easily accessible drug. When people have already established weight gain, metformin may not be enough and alternative treatments should be used,” she said.

In addition to its effects on weight, metformin has many other potential health benefits. Of particular importance is that it reduces hyperphagia-mediated antipsychotic-induced weight gain, Ms. Fitzgerald pointed out.

“This is subjectively very important for patients and provides a more positive experience when taking antipsychotics. Antipsychotic-induced weight gain is one of the main reasons for premature discontinuation or incomplete adherence to these drugs and therefore needs to be addressed proactively,” she concluded.

Ms. Fitzgerald and Dr. Michat have disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com. This article was translated from the Medscape Spanish edition.

MAR DEL PLATA, ARGENTINA – Psychiatrists should prescribe metformin early to patients who experience rapid weight gain after they begin taking antipsychotic drugs, according to a new evidence-based Irish guideline for the management of this common complication in adults with psychoses who are taking medications.

The document was discussed during one of the sessions of the XXXV Argentine Congress of Psychiatry of the Association of Argentine Psychiatrists. The document also was presented by one of its authors at the European Congress on Obesity 2022.

The guideline encourages psychiatrists not to underestimate the adverse metabolic effects of their treatments and encourages them to contemplate and carry out this prevention and management strategy, commented María Delia Michat, PhD, professor of clinical psychiatry and psychopharmacology at the APSA Postgraduate Training Institute, Buenos Aires.

“Although it is always good to work as a team, it is usually we psychiatrists who coordinate the pharmacological treatment of our patients, and we have to know how to manage drugs that can prevent cardiovascular disease,” Dr. Michat said in an interview.

“The new guideline is helpful because it protocolizes the use of metformin, which is the cheapest drug and has the most evidence for antipsychotic-induced weight gain,” she added.
 

Avoiding metabolic syndrome

In patients with schizophrenia, obesity rates are 40% higher than in the general population, and 80% of patients develop weight gain after their first treatment, noted Dr. Michat. “Right away, weight gain is seen in the first month. And it is a serious problem, because patients with schizophrenia, major depression, or bipolar disorder already have an increased risk of premature mortality, especially from cardiovascular diseases, and they have an increased risk of metabolic syndrome. And we sometimes give drugs that further increase that risk,” she said.

Being overweight is a major criterion for defining metabolic syndrome. Dr. Michat noted that, among the antipsychotic drugs that increase weight the most are clozapine, olanzapine, chlorpromazine, quetiapine, and risperidone, in addition to other psychoactive drugs, such as valproic acid, lithium, mirtazapine, and tricyclic antidepressants.

Several clinical trials, such as a pioneering Chinese study from 2008, have shown the potential of metformin to mitigate the weight gain induced by this type of drug.

However, Dr. Michat noted that so far the major guidelines (for example, the Canadian Network for Mood and Anxiety Treatments [CANMAT]/International Society for Bipolar Disorders [ISBD] for bipolar disorder and the American Psychiatric Association [APA] for schizophrenia) “say very little” on how to address this complication. They propose what she defined as a “problematic” order of action in which the initial emphasis is on promoting lifestyle changes, which are difficult for these patients to carry out, as well as general proposals for changing medication (which is not simple to implement when the patient’s condition is stabilized) and eventual consultation with a clinician to start therapy with metformin or other drugs, such as liraglutide, semaglutide, and topiramate.

The new clinical practice guideline, which was published in Evidence-Based Mental Health (of the BMJ journal group), was written by a multidisciplinary team of pharmacists, psychiatrists, and mental health nurses from Ireland. It aims to fill that gap. The investigators reviewed 1,270 scientific articles and analyzed 26 of them in depth, including seven randomized clinical trials and a 2016 systematic review and meta-analysis. The authors made a “strong” recommendation, for which there was moderate-quality evidence, that for patients for whom a lifestyle intervention is unacceptable or inappropriate the use of metformin is an “alternative first-line intervention” for antipsychotic drug–induced weight gain.

Likewise, as a strong recommendation with moderate-quality evidence, the guidance encourages the use of metformin when nonpharmacologic intervention does not seem to be effective.

The guideline also says it is preferable to start metformin early for patients who gain more than 7% of their baseline weight within the first month of antipsychotic treatment. It also endorses metformin when weight gain is established.

Other recommendations include evaluating baseline kidney function before starting metformin treatment and suggest a dose adjustment when the estimated glomerular filtration rate (eGFR) is < 60 mL/min/1.73 m². The guidance says the use of metformin is contraindicated for patients in whom eGFR is <30 mL/min per 1.73 m². The proposed starting dosage is 500 mg twice per day with meals, with increments of 500 mg every 1-2 weeks until reaching a target dose of 2,000 mg/day. The guidance recommends that consideration always be given to individual tolerability and efficacy.

Treatment goals should be personalized and agreed upon with patients. In the case of early intervention, the guideline proposes initially stabilizing the weight gained or, if possible, reverse excess weight. When weight gain is established, the goal would be to lose at least 5% of the weight within the next 6 months.

The authors also recommend monitoring kidney function annually, as well as vitamin B₁₂ levels and individual tolerability and compliance. Gastrointestinal adverse effects can be managed by dose reduction or slower dose titration. The risk of lactic acidosis, which affects 4.3 per 100,000 person-years among those taking metformin, can be attenuated by adjusting the dose according to kidney function or avoiding prescribing it to patients who have a history of alcohol abuse or who are receiving treatment that may interact with the drug.
 

Validating pharmacologic management

The lead author of the new guideline, Ita Fitzgerald, a teacher in clinical pharmacy and senior pharmacist at St. Patrick’s Mental Health Services in Dublin, pointed out that there is a bias toward not using drugs for weight management and shifting the responsibility onto the patients themselves, something that is very often out of their control.

“The purpose of the guideline was to decide on a range of criteria to maximize the use of metformin, to recognize that for many people, pharmacological management is a valid and important option that could and should be more widely used and to provide precise and practical guidance to physicians to facilitate a more widespread use,” Ms. Fitzgerald said in an interview.

According to Fitzgerald, who is pursuing her doctorate at University College Cork (Ireland), one of the most outstanding results of the work is that it highlights that the main benefit of metformin is to flatten rather than reverse antipsychotic-induced weight gain and that indicating it late can nullify that effect.

“In all the recommendations, we try very hard to shift the focus from metformin’s role as a weight reversal agent to one as a weight management agent that should be used early in treatment, which is when most weight gain occurs. If metformin succeeds in flattening that increase, that’s a huge potential benefit for an inexpensive and easily accessible drug. When people have already established weight gain, metformin may not be enough and alternative treatments should be used,” she said.

In addition to its effects on weight, metformin has many other potential health benefits. Of particular importance is that it reduces hyperphagia-mediated antipsychotic-induced weight gain, Ms. Fitzgerald pointed out.

“This is subjectively very important for patients and provides a more positive experience when taking antipsychotics. Antipsychotic-induced weight gain is one of the main reasons for premature discontinuation or incomplete adherence to these drugs and therefore needs to be addressed proactively,” she concluded.

Ms. Fitzgerald and Dr. Michat have disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com. This article was translated from the Medscape Spanish edition.

MAR DEL PLATA, ARGENTINA – Psychiatrists should prescribe metformin early to patients who experience rapid weight gain after they begin taking antipsychotic drugs, according to a new evidence-based Irish guideline for the management of this common complication in adults with psychoses who are taking medications.

The document was discussed during one of the sessions of the XXXV Argentine Congress of Psychiatry of the Association of Argentine Psychiatrists. The document also was presented by one of its authors at the European Congress on Obesity 2022.

The guideline encourages psychiatrists not to underestimate the adverse metabolic effects of their treatments and encourages them to contemplate and carry out this prevention and management strategy, commented María Delia Michat, PhD, professor of clinical psychiatry and psychopharmacology at the APSA Postgraduate Training Institute, Buenos Aires.

“Although it is always good to work as a team, it is usually we psychiatrists who coordinate the pharmacological treatment of our patients, and we have to know how to manage drugs that can prevent cardiovascular disease,” Dr. Michat said in an interview.

“The new guideline is helpful because it protocolizes the use of metformin, which is the cheapest drug and has the most evidence for antipsychotic-induced weight gain,” she added.
 

Avoiding metabolic syndrome

In patients with schizophrenia, obesity rates are 40% higher than in the general population, and 80% of patients develop weight gain after their first treatment, noted Dr. Michat. “Right away, weight gain is seen in the first month. And it is a serious problem, because patients with schizophrenia, major depression, or bipolar disorder already have an increased risk of premature mortality, especially from cardiovascular diseases, and they have an increased risk of metabolic syndrome. And we sometimes give drugs that further increase that risk,” she said.

Being overweight is a major criterion for defining metabolic syndrome. Dr. Michat noted that, among the antipsychotic drugs that increase weight the most are clozapine, olanzapine, chlorpromazine, quetiapine, and risperidone, in addition to other psychoactive drugs, such as valproic acid, lithium, mirtazapine, and tricyclic antidepressants.

Several clinical trials, such as a pioneering Chinese study from 2008, have shown the potential of metformin to mitigate the weight gain induced by this type of drug.

However, Dr. Michat noted that so far the major guidelines (for example, the Canadian Network for Mood and Anxiety Treatments [CANMAT]/International Society for Bipolar Disorders [ISBD] for bipolar disorder and the American Psychiatric Association [APA] for schizophrenia) “say very little” on how to address this complication. They propose what she defined as a “problematic” order of action in which the initial emphasis is on promoting lifestyle changes, which are difficult for these patients to carry out, as well as general proposals for changing medication (which is not simple to implement when the patient’s condition is stabilized) and eventual consultation with a clinician to start therapy with metformin or other drugs, such as liraglutide, semaglutide, and topiramate.

The new clinical practice guideline, which was published in Evidence-Based Mental Health (of the BMJ journal group), was written by a multidisciplinary team of pharmacists, psychiatrists, and mental health nurses from Ireland. It aims to fill that gap. The investigators reviewed 1,270 scientific articles and analyzed 26 of them in depth, including seven randomized clinical trials and a 2016 systematic review and meta-analysis. The authors made a “strong” recommendation, for which there was moderate-quality evidence, that for patients for whom a lifestyle intervention is unacceptable or inappropriate the use of metformin is an “alternative first-line intervention” for antipsychotic drug–induced weight gain.

Likewise, as a strong recommendation with moderate-quality evidence, the guidance encourages the use of metformin when nonpharmacologic intervention does not seem to be effective.

The guideline also says it is preferable to start metformin early for patients who gain more than 7% of their baseline weight within the first month of antipsychotic treatment. It also endorses metformin when weight gain is established.

Other recommendations include evaluating baseline kidney function before starting metformin treatment and suggest a dose adjustment when the estimated glomerular filtration rate (eGFR) is < 60 mL/min/1.73 m². The guidance says the use of metformin is contraindicated for patients in whom eGFR is <30 mL/min per 1.73 m². The proposed starting dosage is 500 mg twice per day with meals, with increments of 500 mg every 1-2 weeks until reaching a target dose of 2,000 mg/day. The guidance recommends that consideration always be given to individual tolerability and efficacy.

Treatment goals should be personalized and agreed upon with patients. In the case of early intervention, the guideline proposes initially stabilizing the weight gained or, if possible, reverse excess weight. When weight gain is established, the goal would be to lose at least 5% of the weight within the next 6 months.

The authors also recommend monitoring kidney function annually, as well as vitamin B₁₂ levels and individual tolerability and compliance. Gastrointestinal adverse effects can be managed by dose reduction or slower dose titration. The risk of lactic acidosis, which affects 4.3 per 100,000 person-years among those taking metformin, can be attenuated by adjusting the dose according to kidney function or avoiding prescribing it to patients who have a history of alcohol abuse or who are receiving treatment that may interact with the drug.
 

Validating pharmacologic management

The lead author of the new guideline, Ita Fitzgerald, a teacher in clinical pharmacy and senior pharmacist at St. Patrick’s Mental Health Services in Dublin, pointed out that there is a bias toward not using drugs for weight management and shifting the responsibility onto the patients themselves, something that is very often out of their control.

“The purpose of the guideline was to decide on a range of criteria to maximize the use of metformin, to recognize that for many people, pharmacological management is a valid and important option that could and should be more widely used and to provide precise and practical guidance to physicians to facilitate a more widespread use,” Ms. Fitzgerald said in an interview.

According to Fitzgerald, who is pursuing her doctorate at University College Cork (Ireland), one of the most outstanding results of the work is that it highlights that the main benefit of metformin is to flatten rather than reverse antipsychotic-induced weight gain and that indicating it late can nullify that effect.

“In all the recommendations, we try very hard to shift the focus from metformin’s role as a weight reversal agent to one as a weight management agent that should be used early in treatment, which is when most weight gain occurs. If metformin succeeds in flattening that increase, that’s a huge potential benefit for an inexpensive and easily accessible drug. When people have already established weight gain, metformin may not be enough and alternative treatments should be used,” she said.

In addition to its effects on weight, metformin has many other potential health benefits. Of particular importance is that it reduces hyperphagia-mediated antipsychotic-induced weight gain, Ms. Fitzgerald pointed out.

“This is subjectively very important for patients and provides a more positive experience when taking antipsychotics. Antipsychotic-induced weight gain is one of the main reasons for premature discontinuation or incomplete adherence to these drugs and therefore needs to be addressed proactively,” she concluded.

Ms. Fitzgerald and Dr. Michat have disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com. This article was translated from the Medscape Spanish edition.