Feature

Durvalumab (Imfinzi, AstraZeneca) is now approved for adults with limited-stage small cell lung cancer (LS-SCLC) whose disease has not progressed after treatment with concurrent platinum-based chemotherapy and radiation therapy.

The Food and Drug Administration approval makes the monoclonal antibody — which is already approved for multiple tumor types — the first immunotherapy regimen approved in this setting, AstraZeneca noted in a press release.

“Durvalumab is the first and only systemic treatment following curative-intent, platinum-based chemoradiotherapy to show improved survival for patients with this aggressive form of lung cancer,” international coordinating investigator on the trial, Suresh Senan, PhD, stated in the press release. “This finding represents the first advance for this disease in 4 decades.”

Approval, which followed Priority Review and Breakthrough Therapy Designation, was based on findings from the phase 3 ADRIATIC trial showing a 27% reduction in the risk for death with durvalumab vs placebo.

Findings from the trial were reported during a plenary session at the 2024 American Society of Clinical Oncology conference, and subsequently published in The New England Journal of Medicine.

In 730 patients with LS-SCLC who were randomized 1:1:1 to receive single-agent durvalumab, durvalumab in combination with tremelimumab, or placebo, overall survival (OS) and progression-free survival (PFS) were significantly improved with durvalumab alone vs placebo (hazard ratio, 0.73 and 0.76, for OS and PFS, respectively). Median OS was 55.9 months vs 33.4 months with durvalumab vs placebo, and PFS was 16.6 vs 9.2 months, respectively.

Senan, a professor of clinical experimental radiotherapy at the Amsterdam University Medical Center in the Netherlands, noted in the press release that 57% of patients were still alive at 3 years after being treated with durvalumab, which underscores the practice-changing potential of this medicine in this setting.

“This new treatment option is a game changer for patients with limited-stage small cell lung cancer, a disease known for its high rate of recurrence,” Dusty Donaldson, founder and executive director of the nonprofit advocacy organization LiveLung, stated in the release. “Historically, more often than not, clinical trials to identify new treatment options for this type of cancer have failed to show benefit. We are therefore so excited that many more people will now have the opportunity to access this immunotherapy treatment that holds the potential to significantly improve outcomes.”

Adverse reactions occurring in at least 20% of patients in the ADRIATIC trial included pneumonitis or radiation pneumonitis and fatigue.

The recommended durvalumab dose, according to prescribing information, is 1500 mg every 4 weeks for patients weighing at least 30 kg and 20 mg/kg every 4 weeks for those weighing less than 30 kg, until disease progression or unacceptable toxicity or a maximum of 24 months.

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

Durvalumab (Imfinzi, AstraZeneca) is now approved for adults with limited-stage small cell lung cancer (LS-SCLC) whose disease has not progressed after treatment with concurrent platinum-based chemotherapy and radiation therapy.

The Food and Drug Administration approval makes the monoclonal antibody — which is already approved for multiple tumor types — the first immunotherapy regimen approved in this setting, AstraZeneca noted in a press release.

“Durvalumab is the first and only systemic treatment following curative-intent, platinum-based chemoradiotherapy to show improved survival for patients with this aggressive form of lung cancer,” international coordinating investigator on the trial, Suresh Senan, PhD, stated in the press release. “This finding represents the first advance for this disease in 4 decades.”

Approval, which followed Priority Review and Breakthrough Therapy Designation, was based on findings from the phase 3 ADRIATIC trial showing a 27% reduction in the risk for death with durvalumab vs placebo.

Findings from the trial were reported during a plenary session at the 2024 American Society of Clinical Oncology conference, and subsequently published in The New England Journal of Medicine.

In 730 patients with LS-SCLC who were randomized 1:1:1 to receive single-agent durvalumab, durvalumab in combination with tremelimumab, or placebo, overall survival (OS) and progression-free survival (PFS) were significantly improved with durvalumab alone vs placebo (hazard ratio, 0.73 and 0.76, for OS and PFS, respectively). Median OS was 55.9 months vs 33.4 months with durvalumab vs placebo, and PFS was 16.6 vs 9.2 months, respectively.

Senan, a professor of clinical experimental radiotherapy at the Amsterdam University Medical Center in the Netherlands, noted in the press release that 57% of patients were still alive at 3 years after being treated with durvalumab, which underscores the practice-changing potential of this medicine in this setting.

“This new treatment option is a game changer for patients with limited-stage small cell lung cancer, a disease known for its high rate of recurrence,” Dusty Donaldson, founder and executive director of the nonprofit advocacy organization LiveLung, stated in the release. “Historically, more often than not, clinical trials to identify new treatment options for this type of cancer have failed to show benefit. We are therefore so excited that many more people will now have the opportunity to access this immunotherapy treatment that holds the potential to significantly improve outcomes.”

Adverse reactions occurring in at least 20% of patients in the ADRIATIC trial included pneumonitis or radiation pneumonitis and fatigue.

The recommended durvalumab dose, according to prescribing information, is 1500 mg every 4 weeks for patients weighing at least 30 kg and 20 mg/kg every 4 weeks for those weighing less than 30 kg, until disease progression or unacceptable toxicity or a maximum of 24 months.

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

Durvalumab (Imfinzi, AstraZeneca) is now approved for adults with limited-stage small cell lung cancer (LS-SCLC) whose disease has not progressed after treatment with concurrent platinum-based chemotherapy and radiation therapy.

The Food and Drug Administration approval makes the monoclonal antibody — which is already approved for multiple tumor types — the first immunotherapy regimen approved in this setting, AstraZeneca noted in a press release.

“Durvalumab is the first and only systemic treatment following curative-intent, platinum-based chemoradiotherapy to show improved survival for patients with this aggressive form of lung cancer,” international coordinating investigator on the trial, Suresh Senan, PhD, stated in the press release. “This finding represents the first advance for this disease in 4 decades.”

Approval, which followed Priority Review and Breakthrough Therapy Designation, was based on findings from the phase 3 ADRIATIC trial showing a 27% reduction in the risk for death with durvalumab vs placebo.

Findings from the trial were reported during a plenary session at the 2024 American Society of Clinical Oncology conference, and subsequently published in The New England Journal of Medicine.

In 730 patients with LS-SCLC who were randomized 1:1:1 to receive single-agent durvalumab, durvalumab in combination with tremelimumab, or placebo, overall survival (OS) and progression-free survival (PFS) were significantly improved with durvalumab alone vs placebo (hazard ratio, 0.73 and 0.76, for OS and PFS, respectively). Median OS was 55.9 months vs 33.4 months with durvalumab vs placebo, and PFS was 16.6 vs 9.2 months, respectively.

Senan, a professor of clinical experimental radiotherapy at the Amsterdam University Medical Center in the Netherlands, noted in the press release that 57% of patients were still alive at 3 years after being treated with durvalumab, which underscores the practice-changing potential of this medicine in this setting.

“This new treatment option is a game changer for patients with limited-stage small cell lung cancer, a disease known for its high rate of recurrence,” Dusty Donaldson, founder and executive director of the nonprofit advocacy organization LiveLung, stated in the release. “Historically, more often than not, clinical trials to identify new treatment options for this type of cancer have failed to show benefit. We are therefore so excited that many more people will now have the opportunity to access this immunotherapy treatment that holds the potential to significantly improve outcomes.”

Adverse reactions occurring in at least 20% of patients in the ADRIATIC trial included pneumonitis or radiation pneumonitis and fatigue.

The recommended durvalumab dose, according to prescribing information, is 1500 mg every 4 weeks for patients weighing at least 30 kg and 20 mg/kg every 4 weeks for those weighing less than 30 kg, until disease progression or unacceptable toxicity or a maximum of 24 months.

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

Vaccines for treating and preventing cancer have long been considered a holy grail in oncology.

But aside from a few notable exceptions — including the human papillomavirus (HPV) vaccine, which has dramatically reduced the incidence of HPV-related cancers, and a Bacillus Calmette-Guerin vaccine, which helps prevent early-stage bladder cancer recurrence — most have failed to deliver.

Following a string of disappointments over the past decade, recent advances in the immunotherapy space are bringing renewed hope for progress.

In an American Association for Cancer Research (AACR) series earlier in 2024, Catherine J. Wu, MD, predicted big strides for cancer vaccines, especially for personalized vaccines that target patient-specific neoantigens — the proteins that form on cancer cells — as well as vaccines that can treat diverse tumor types.

“A focus on neoantigens that arise from driver mutations in different tumor types could allow us to make progress in creating off-the-shelf vaccines,” said Wu, the Lavine Family Chair of Preventative Cancer Therapies at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

A prime example is a personalized, messenger RNA (mRNA)–based vaccine designed to prevent melanoma recurrence. The mRNA-4157 vaccine encodes up to 34 different patient-specific neoantigens.

“This is one of the most exciting developments in modern cancer therapy,” said Lawrence Young, a virologist and professor of molecular oncology at the University of Warwick, Coventry, England, who commented on the investigational vaccine via the UK-based Science Media Centre.

Other promising options are on the horizon as well. In August, BioNTech announced a phase 1 global trial to study BNT116 — a vaccine to treat non–small cell lung cancer (NSCLC). BNT116, like mRNA-4157, targets specific antigens in the lung cancer cells.

“This technology is the next big phase of cancer treatment,” Siow Ming Lee, MD, a consultant medical oncologist at University College London Hospitals in England, which is leading the UK trial for the lung cancer and melanoma vaccines, told The Guardian. “We are now entering this very exciting new era of mRNA-based immunotherapy clinical trials to investigate the treatment of lung cancer.”

Still, these predictions have a familiar ring. While the prospects are exciting, delivering on them is another story. There are simply no guarantees these strategies will work as hoped.

 

Then: Where We Were

Cancer vaccine research began to ramp up in the 2000s, and in 2006, the first-generation HPV vaccine, Gardasil, was approved. Gardasil prevents infection from four strains of HPV that cause about 80% of cervical cancer cases.

In 2010, the Food and Drug Administration approved sipuleucel-T, the first therapeutic cancer vaccine, which improved overall survival in patients with hormone-refractory prostate cancer.

Researchers predicted this approval would “pave the way for developing innovative, next generation of vaccines with enhanced antitumor potency.”

In a 2015 AACR research forecast report, Drew Pardoll, MD, PhD, co-director of the Cancer Immunology and Hematopoiesis Program at Johns Hopkins University, Baltimore, Maryland, said that “we can expect to see encouraging results from studies using cancer vaccines.”

Despite the excitement surrounding cancer vaccines alongside a few successes, the next decade brought a longer string of late-phase disappointments.

In 2016, the phase 3 ACT IV trial of a therapeutic vaccine to treat glioblastoma multiforme (CDX-110) was terminated after it failed to demonstrate improved survival.

In 2017, a phase 3 trial of the therapeutic pancreatic cancer vaccine, GVAX, was stopped early for lack of efficacy.

That year, an attenuated Listeria monocytogenes vaccine to treat pancreatic cancer and mesothelioma also failed to come to fruition. In late 2017, concerns over listeria infections prompted Aduro Biotech to cancel its listeria-based cancer treatment program.

In 2018, a phase 3 trial of belagenpumatucel-L, a therapeutic NSCLC vaccine, failed to demonstrate a significant improvement in survival and further study was discontinued.

And in 2019, a vaccine targeting MAGE-A3, a cancer-testis antigen present in multiple tumor types, failed to meet endpoints for improved survival in a phase 3 trial, leading to discontinuation of the vaccine program.

But these disappointments and failures are normal parts of medical research and drug development and have allowed for incremental advances that helped fuel renewed interest and hope for cancer vaccines, when the timing was right, explained vaccine pioneer Larry W. Kwak, MD, PhD, deputy director of the Comprehensive Cancer Center at City of Hope, Duarte, California.

When it comes to vaccine progress, timing makes a difference. In 2011, Kwak and colleagues published promising phase 3 trial results on a personalized vaccine. The vaccine was a patient-specific tumor-derived antigen for patients with follicular lymphoma in their first remission following chemotherapy. Patients who received the vaccine demonstrated significantly longer disease-free survival.

But, at the time, personalized vaccines faced strong headwinds due, largely, to high costs, and commercial interest failed to materialize. “That’s been the major hurdle for a long time,” said Kwak.

Now, however, interest has returned alongside advances in technology and research. The big shift has been the emergence of lower-cost rapid-production mRNA and DNA platforms and a better understanding of how vaccines and potent immune stimulants, like checkpoint inhibitors, can work together to improve outcomes, he explained.

“The timing wasn’t right” back then, Kwak noted. “Now, it’s a different environment and a different time.”

 

A Turning Point?

Indeed, a decade later, cancer vaccine development appears to be headed in a more promising direction.

Among key cancer vaccines to watch is the mRNA-4157 vaccine, developed by Merck and Moderna, designed to prevent melanoma recurrence. In a recent phase 2 study, patients receiving the mRNA-4157 vaccine alongside pembrolizumab had nearly half the risk for melanoma recurrence or death at 3 years compared with those receiving pembrolizumab alone. Investigators are now evaluating the vaccine in a global phase 3 study in patients with high-risk, stage IIB to IV melanoma following surgery.

Another one to watch is the BNT116 NSCLC vaccine from BioNTech. This vaccine presents the immune system with NSCLC tumor markers to encourage the body to fight cancer cells expressing those markers while ignoring healthy cells. BioNTech also launched a global clinical trial for its vaccine this year.

Other notables include a pancreatic cancer mRNA vaccine, which has shown promising early results in a small trial of 16 patients. Of 16 patients who received the vaccine alongside chemotherapy and after surgery and immunotherapy, 8 responded. Of these eight, six remained recurrence free at 3 years. Investigators noted that the vaccine appeared to stimulate a durable T-cell response in patients who responded.

Kwak has also continued his work on lymphoma vaccines. In August, his team published promising first-in-human data on the use of personalized neoantigen vaccines as an early intervention in untreated patients with lymphoplasmacytic lymphoma. Among nine asymptomatic patients who received the vaccine, all achieved stable disease or better, with no dose-limiting toxicities. One patient had a minor response, and the median time to progression was greater than 72 months.

“The current setting is more for advanced disease,” Kwak explained. “It’s a tougher task, but combined with checkpoint blockade, it may be potent enough to work.” 

Still, caution is important. Despite early promise, it’s too soon to tell which, if any, of these investigational vaccines will pan out in the long run. Like investigational drugs, cancer vaccines may show big promising initially but then fail in larger trials.

One key to success, according to Kwak, is to design trials so that even negative results will inform next steps.

But, he noted, failures in large clinical trials will “put a chilling effect on cancer vaccine research again.”

“That’s what keeps me up at night,” he said. “We know the science is fundamentally sound and we have seen glimpses over decades of research that cancer vaccines can work, so it’s really just a matter of tweaking things to optimize trial design.”

Companies tend to design trials to test if a vaccine works or not, without trying to understand why, he said.

“What we need to do is design those so that we can learn from negative results,” he said. That’s what he and his colleagues attempted to do in their recent trial. “We didn’t just look at clinical results; we’re interrogating the actual tumor environment to understand what worked and didn’t and how to tweak that for the next trial.”

Kwak and his colleagues found, for instance, that the vaccine had a greater effect on B cell–derived tumor cells than on cells of plasma origin, so “the most rational design for the next iteration is to combine the vaccine with agents that work directly against plasma cells,” he explained.

As for what’s next, Kwak said: “We’re just focused on trying to do good science and understand. We’ve seen glimpses of success. That’s where we are.”

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

Vaccines for treating and preventing cancer have long been considered a holy grail in oncology.

But aside from a few notable exceptions — including the human papillomavirus (HPV) vaccine, which has dramatically reduced the incidence of HPV-related cancers, and a Bacillus Calmette-Guerin vaccine, which helps prevent early-stage bladder cancer recurrence — most have failed to deliver.

Following a string of disappointments over the past decade, recent advances in the immunotherapy space are bringing renewed hope for progress.

In an American Association for Cancer Research (AACR) series earlier in 2024, Catherine J. Wu, MD, predicted big strides for cancer vaccines, especially for personalized vaccines that target patient-specific neoantigens — the proteins that form on cancer cells — as well as vaccines that can treat diverse tumor types.

“A focus on neoantigens that arise from driver mutations in different tumor types could allow us to make progress in creating off-the-shelf vaccines,” said Wu, the Lavine Family Chair of Preventative Cancer Therapies at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

A prime example is a personalized, messenger RNA (mRNA)–based vaccine designed to prevent melanoma recurrence. The mRNA-4157 vaccine encodes up to 34 different patient-specific neoantigens.

“This is one of the most exciting developments in modern cancer therapy,” said Lawrence Young, a virologist and professor of molecular oncology at the University of Warwick, Coventry, England, who commented on the investigational vaccine via the UK-based Science Media Centre.

Other promising options are on the horizon as well. In August, BioNTech announced a phase 1 global trial to study BNT116 — a vaccine to treat non–small cell lung cancer (NSCLC). BNT116, like mRNA-4157, targets specific antigens in the lung cancer cells.

“This technology is the next big phase of cancer treatment,” Siow Ming Lee, MD, a consultant medical oncologist at University College London Hospitals in England, which is leading the UK trial for the lung cancer and melanoma vaccines, told The Guardian. “We are now entering this very exciting new era of mRNA-based immunotherapy clinical trials to investigate the treatment of lung cancer.”

Still, these predictions have a familiar ring. While the prospects are exciting, delivering on them is another story. There are simply no guarantees these strategies will work as hoped.

 

Then: Where We Were

Cancer vaccine research began to ramp up in the 2000s, and in 2006, the first-generation HPV vaccine, Gardasil, was approved. Gardasil prevents infection from four strains of HPV that cause about 80% of cervical cancer cases.

In 2010, the Food and Drug Administration approved sipuleucel-T, the first therapeutic cancer vaccine, which improved overall survival in patients with hormone-refractory prostate cancer.

Researchers predicted this approval would “pave the way for developing innovative, next generation of vaccines with enhanced antitumor potency.”

In a 2015 AACR research forecast report, Drew Pardoll, MD, PhD, co-director of the Cancer Immunology and Hematopoiesis Program at Johns Hopkins University, Baltimore, Maryland, said that “we can expect to see encouraging results from studies using cancer vaccines.”

Despite the excitement surrounding cancer vaccines alongside a few successes, the next decade brought a longer string of late-phase disappointments.

In 2016, the phase 3 ACT IV trial of a therapeutic vaccine to treat glioblastoma multiforme (CDX-110) was terminated after it failed to demonstrate improved survival.

In 2017, a phase 3 trial of the therapeutic pancreatic cancer vaccine, GVAX, was stopped early for lack of efficacy.

That year, an attenuated Listeria monocytogenes vaccine to treat pancreatic cancer and mesothelioma also failed to come to fruition. In late 2017, concerns over listeria infections prompted Aduro Biotech to cancel its listeria-based cancer treatment program.

In 2018, a phase 3 trial of belagenpumatucel-L, a therapeutic NSCLC vaccine, failed to demonstrate a significant improvement in survival and further study was discontinued.

And in 2019, a vaccine targeting MAGE-A3, a cancer-testis antigen present in multiple tumor types, failed to meet endpoints for improved survival in a phase 3 trial, leading to discontinuation of the vaccine program.

But these disappointments and failures are normal parts of medical research and drug development and have allowed for incremental advances that helped fuel renewed interest and hope for cancer vaccines, when the timing was right, explained vaccine pioneer Larry W. Kwak, MD, PhD, deputy director of the Comprehensive Cancer Center at City of Hope, Duarte, California.

When it comes to vaccine progress, timing makes a difference. In 2011, Kwak and colleagues published promising phase 3 trial results on a personalized vaccine. The vaccine was a patient-specific tumor-derived antigen for patients with follicular lymphoma in their first remission following chemotherapy. Patients who received the vaccine demonstrated significantly longer disease-free survival.

But, at the time, personalized vaccines faced strong headwinds due, largely, to high costs, and commercial interest failed to materialize. “That’s been the major hurdle for a long time,” said Kwak.

Now, however, interest has returned alongside advances in technology and research. The big shift has been the emergence of lower-cost rapid-production mRNA and DNA platforms and a better understanding of how vaccines and potent immune stimulants, like checkpoint inhibitors, can work together to improve outcomes, he explained.

“The timing wasn’t right” back then, Kwak noted. “Now, it’s a different environment and a different time.”

 

A Turning Point?

Indeed, a decade later, cancer vaccine development appears to be headed in a more promising direction.

Among key cancer vaccines to watch is the mRNA-4157 vaccine, developed by Merck and Moderna, designed to prevent melanoma recurrence. In a recent phase 2 study, patients receiving the mRNA-4157 vaccine alongside pembrolizumab had nearly half the risk for melanoma recurrence or death at 3 years compared with those receiving pembrolizumab alone. Investigators are now evaluating the vaccine in a global phase 3 study in patients with high-risk, stage IIB to IV melanoma following surgery.

Another one to watch is the BNT116 NSCLC vaccine from BioNTech. This vaccine presents the immune system with NSCLC tumor markers to encourage the body to fight cancer cells expressing those markers while ignoring healthy cells. BioNTech also launched a global clinical trial for its vaccine this year.

Other notables include a pancreatic cancer mRNA vaccine, which has shown promising early results in a small trial of 16 patients. Of 16 patients who received the vaccine alongside chemotherapy and after surgery and immunotherapy, 8 responded. Of these eight, six remained recurrence free at 3 years. Investigators noted that the vaccine appeared to stimulate a durable T-cell response in patients who responded.

Kwak has also continued his work on lymphoma vaccines. In August, his team published promising first-in-human data on the use of personalized neoantigen vaccines as an early intervention in untreated patients with lymphoplasmacytic lymphoma. Among nine asymptomatic patients who received the vaccine, all achieved stable disease or better, with no dose-limiting toxicities. One patient had a minor response, and the median time to progression was greater than 72 months.

“The current setting is more for advanced disease,” Kwak explained. “It’s a tougher task, but combined with checkpoint blockade, it may be potent enough to work.” 

Still, caution is important. Despite early promise, it’s too soon to tell which, if any, of these investigational vaccines will pan out in the long run. Like investigational drugs, cancer vaccines may show big promising initially but then fail in larger trials.

One key to success, according to Kwak, is to design trials so that even negative results will inform next steps.

But, he noted, failures in large clinical trials will “put a chilling effect on cancer vaccine research again.”

“That’s what keeps me up at night,” he said. “We know the science is fundamentally sound and we have seen glimpses over decades of research that cancer vaccines can work, so it’s really just a matter of tweaking things to optimize trial design.”

Companies tend to design trials to test if a vaccine works or not, without trying to understand why, he said.

“What we need to do is design those so that we can learn from negative results,” he said. That’s what he and his colleagues attempted to do in their recent trial. “We didn’t just look at clinical results; we’re interrogating the actual tumor environment to understand what worked and didn’t and how to tweak that for the next trial.”

Kwak and his colleagues found, for instance, that the vaccine had a greater effect on B cell–derived tumor cells than on cells of plasma origin, so “the most rational design for the next iteration is to combine the vaccine with agents that work directly against plasma cells,” he explained.

As for what’s next, Kwak said: “We’re just focused on trying to do good science and understand. We’ve seen glimpses of success. That’s where we are.”

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

Vaccines for treating and preventing cancer have long been considered a holy grail in oncology.

But aside from a few notable exceptions — including the human papillomavirus (HPV) vaccine, which has dramatically reduced the incidence of HPV-related cancers, and a Bacillus Calmette-Guerin vaccine, which helps prevent early-stage bladder cancer recurrence — most have failed to deliver.

Following a string of disappointments over the past decade, recent advances in the immunotherapy space are bringing renewed hope for progress.

In an American Association for Cancer Research (AACR) series earlier in 2024, Catherine J. Wu, MD, predicted big strides for cancer vaccines, especially for personalized vaccines that target patient-specific neoantigens — the proteins that form on cancer cells — as well as vaccines that can treat diverse tumor types.

“A focus on neoantigens that arise from driver mutations in different tumor types could allow us to make progress in creating off-the-shelf vaccines,” said Wu, the Lavine Family Chair of Preventative Cancer Therapies at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

A prime example is a personalized, messenger RNA (mRNA)–based vaccine designed to prevent melanoma recurrence. The mRNA-4157 vaccine encodes up to 34 different patient-specific neoantigens.

“This is one of the most exciting developments in modern cancer therapy,” said Lawrence Young, a virologist and professor of molecular oncology at the University of Warwick, Coventry, England, who commented on the investigational vaccine via the UK-based Science Media Centre.

Other promising options are on the horizon as well. In August, BioNTech announced a phase 1 global trial to study BNT116 — a vaccine to treat non–small cell lung cancer (NSCLC). BNT116, like mRNA-4157, targets specific antigens in the lung cancer cells.

“This technology is the next big phase of cancer treatment,” Siow Ming Lee, MD, a consultant medical oncologist at University College London Hospitals in England, which is leading the UK trial for the lung cancer and melanoma vaccines, told The Guardian. “We are now entering this very exciting new era of mRNA-based immunotherapy clinical trials to investigate the treatment of lung cancer.”

Still, these predictions have a familiar ring. While the prospects are exciting, delivering on them is another story. There are simply no guarantees these strategies will work as hoped.

 

Then: Where We Were

Cancer vaccine research began to ramp up in the 2000s, and in 2006, the first-generation HPV vaccine, Gardasil, was approved. Gardasil prevents infection from four strains of HPV that cause about 80% of cervical cancer cases.

In 2010, the Food and Drug Administration approved sipuleucel-T, the first therapeutic cancer vaccine, which improved overall survival in patients with hormone-refractory prostate cancer.

Researchers predicted this approval would “pave the way for developing innovative, next generation of vaccines with enhanced antitumor potency.”

In a 2015 AACR research forecast report, Drew Pardoll, MD, PhD, co-director of the Cancer Immunology and Hematopoiesis Program at Johns Hopkins University, Baltimore, Maryland, said that “we can expect to see encouraging results from studies using cancer vaccines.”

Despite the excitement surrounding cancer vaccines alongside a few successes, the next decade brought a longer string of late-phase disappointments.

In 2016, the phase 3 ACT IV trial of a therapeutic vaccine to treat glioblastoma multiforme (CDX-110) was terminated after it failed to demonstrate improved survival.

In 2017, a phase 3 trial of the therapeutic pancreatic cancer vaccine, GVAX, was stopped early for lack of efficacy.

That year, an attenuated Listeria monocytogenes vaccine to treat pancreatic cancer and mesothelioma also failed to come to fruition. In late 2017, concerns over listeria infections prompted Aduro Biotech to cancel its listeria-based cancer treatment program.

In 2018, a phase 3 trial of belagenpumatucel-L, a therapeutic NSCLC vaccine, failed to demonstrate a significant improvement in survival and further study was discontinued.

And in 2019, a vaccine targeting MAGE-A3, a cancer-testis antigen present in multiple tumor types, failed to meet endpoints for improved survival in a phase 3 trial, leading to discontinuation of the vaccine program.

But these disappointments and failures are normal parts of medical research and drug development and have allowed for incremental advances that helped fuel renewed interest and hope for cancer vaccines, when the timing was right, explained vaccine pioneer Larry W. Kwak, MD, PhD, deputy director of the Comprehensive Cancer Center at City of Hope, Duarte, California.

When it comes to vaccine progress, timing makes a difference. In 2011, Kwak and colleagues published promising phase 3 trial results on a personalized vaccine. The vaccine was a patient-specific tumor-derived antigen for patients with follicular lymphoma in their first remission following chemotherapy. Patients who received the vaccine demonstrated significantly longer disease-free survival.

But, at the time, personalized vaccines faced strong headwinds due, largely, to high costs, and commercial interest failed to materialize. “That’s been the major hurdle for a long time,” said Kwak.

Now, however, interest has returned alongside advances in technology and research. The big shift has been the emergence of lower-cost rapid-production mRNA and DNA platforms and a better understanding of how vaccines and potent immune stimulants, like checkpoint inhibitors, can work together to improve outcomes, he explained.

“The timing wasn’t right” back then, Kwak noted. “Now, it’s a different environment and a different time.”

 

A Turning Point?

Indeed, a decade later, cancer vaccine development appears to be headed in a more promising direction.

Among key cancer vaccines to watch is the mRNA-4157 vaccine, developed by Merck and Moderna, designed to prevent melanoma recurrence. In a recent phase 2 study, patients receiving the mRNA-4157 vaccine alongside pembrolizumab had nearly half the risk for melanoma recurrence or death at 3 years compared with those receiving pembrolizumab alone. Investigators are now evaluating the vaccine in a global phase 3 study in patients with high-risk, stage IIB to IV melanoma following surgery.

Another one to watch is the BNT116 NSCLC vaccine from BioNTech. This vaccine presents the immune system with NSCLC tumor markers to encourage the body to fight cancer cells expressing those markers while ignoring healthy cells. BioNTech also launched a global clinical trial for its vaccine this year.

Other notables include a pancreatic cancer mRNA vaccine, which has shown promising early results in a small trial of 16 patients. Of 16 patients who received the vaccine alongside chemotherapy and after surgery and immunotherapy, 8 responded. Of these eight, six remained recurrence free at 3 years. Investigators noted that the vaccine appeared to stimulate a durable T-cell response in patients who responded.

Kwak has also continued his work on lymphoma vaccines. In August, his team published promising first-in-human data on the use of personalized neoantigen vaccines as an early intervention in untreated patients with lymphoplasmacytic lymphoma. Among nine asymptomatic patients who received the vaccine, all achieved stable disease or better, with no dose-limiting toxicities. One patient had a minor response, and the median time to progression was greater than 72 months.

“The current setting is more for advanced disease,” Kwak explained. “It’s a tougher task, but combined with checkpoint blockade, it may be potent enough to work.” 

Still, caution is important. Despite early promise, it’s too soon to tell which, if any, of these investigational vaccines will pan out in the long run. Like investigational drugs, cancer vaccines may show big promising initially but then fail in larger trials.

One key to success, according to Kwak, is to design trials so that even negative results will inform next steps.

But, he noted, failures in large clinical trials will “put a chilling effect on cancer vaccine research again.”

“That’s what keeps me up at night,” he said. “We know the science is fundamentally sound and we have seen glimpses over decades of research that cancer vaccines can work, so it’s really just a matter of tweaking things to optimize trial design.”

Companies tend to design trials to test if a vaccine works or not, without trying to understand why, he said.

“What we need to do is design those so that we can learn from negative results,” he said. That’s what he and his colleagues attempted to do in their recent trial. “We didn’t just look at clinical results; we’re interrogating the actual tumor environment to understand what worked and didn’t and how to tweak that for the next trial.”

Kwak and his colleagues found, for instance, that the vaccine had a greater effect on B cell–derived tumor cells than on cells of plasma origin, so “the most rational design for the next iteration is to combine the vaccine with agents that work directly against plasma cells,” he explained.

As for what’s next, Kwak said: “We’re just focused on trying to do good science and understand. We’ve seen glimpses of success. That’s where we are.”

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

The Food and Drug Administration (FDA) has granted accelerated approval to zenocutuzumab-zbco (Bizengri, Merus) as an intravenous infusion for the treatment of certain adults with non–small cell lung cancer (NSCLC) or pancreatic adenocarcinoma.

Specifically, the systemic agent was approved for those with advanced, unresectable, or metastatic NSCLC or pancreatic adenocarcinoma harboring a neuregulin 1 (NRG1) gene fusion who progress on or after prior systemic therapy, according to the FDA.

The approval, based on findings from the multicenter, open-label eNRGy study, is the first from the FDA for a systemic therapy in this setting. In the multicohort study, treatment was associated with an overall response rate of 33% and 40% in 64 patients with NSCLC and 40 patients with pancreatic adenocarcinoma, respectively. Median duration of response was 7.4 months in the NSCLC patients and ranged from 3.7 to 16.6 months in those with pancreatic adenocarcinoma.

Adverse reactions occurring in at least 10% of patients included diarrhea, musculoskeletal pain, fatigue, nausea, infusion-related reactions, dyspnea, rash, constipation, vomiting, abdominal pain, and edema. Grade 3 or 4 laboratory abnormalities occurring in at least 10% of patients included increased gamma-glutamyl transferase and decreased hemoglobin, sodium, and platelets.

“The Personalized Medicine Coalition applauds the approval of BIZENGRI®,” Edward Abrahams, president of the Personalized Medicine Coalition, a Washington-based education and advocacy organization, stated in a press release from Merus. “In keeping with the growing number of personalized medicines on the market today, BIZENGRI® offers the only approved NRG1+ therapy for patients with these difficult-to-treat cancers.”

The agent is expected to be available for use in the “coming weeks,” according to Merus.

“The FDA approval of BIZENGRI® marks an important milestone for patients with pancreatic adenocarcinoma or NSCLC that is advanced unresectable or metastatic and harbors the NRG1 gene fusion,” noted Alison Schram, MD, an attending medical oncologist in the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, New York City, and a principal investigator for the ongoing eNRGy trial. “I have seen firsthand how treatment with BIZENGRI® can deliver clinically meaningful outcomes for patients.”

Prescribing information for zenocutuzumab-zbco includes a Boxed Warning for embryo-fetal toxicity. The recommended treatment dose is 750 mg every 2 weeks until disease progression or unacceptable toxicity.

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

The Food and Drug Administration (FDA) has granted accelerated approval to zenocutuzumab-zbco (Bizengri, Merus) as an intravenous infusion for the treatment of certain adults with non–small cell lung cancer (NSCLC) or pancreatic adenocarcinoma.

Specifically, the systemic agent was approved for those with advanced, unresectable, or metastatic NSCLC or pancreatic adenocarcinoma harboring a neuregulin 1 (NRG1) gene fusion who progress on or after prior systemic therapy, according to the FDA.

The approval, based on findings from the multicenter, open-label eNRGy study, is the first from the FDA for a systemic therapy in this setting. In the multicohort study, treatment was associated with an overall response rate of 33% and 40% in 64 patients with NSCLC and 40 patients with pancreatic adenocarcinoma, respectively. Median duration of response was 7.4 months in the NSCLC patients and ranged from 3.7 to 16.6 months in those with pancreatic adenocarcinoma.

Adverse reactions occurring in at least 10% of patients included diarrhea, musculoskeletal pain, fatigue, nausea, infusion-related reactions, dyspnea, rash, constipation, vomiting, abdominal pain, and edema. Grade 3 or 4 laboratory abnormalities occurring in at least 10% of patients included increased gamma-glutamyl transferase and decreased hemoglobin, sodium, and platelets.

“The Personalized Medicine Coalition applauds the approval of BIZENGRI®,” Edward Abrahams, president of the Personalized Medicine Coalition, a Washington-based education and advocacy organization, stated in a press release from Merus. “In keeping with the growing number of personalized medicines on the market today, BIZENGRI® offers the only approved NRG1+ therapy for patients with these difficult-to-treat cancers.”

The agent is expected to be available for use in the “coming weeks,” according to Merus.

“The FDA approval of BIZENGRI® marks an important milestone for patients with pancreatic adenocarcinoma or NSCLC that is advanced unresectable or metastatic and harbors the NRG1 gene fusion,” noted Alison Schram, MD, an attending medical oncologist in the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, New York City, and a principal investigator for the ongoing eNRGy trial. “I have seen firsthand how treatment with BIZENGRI® can deliver clinically meaningful outcomes for patients.”

Prescribing information for zenocutuzumab-zbco includes a Boxed Warning for embryo-fetal toxicity. The recommended treatment dose is 750 mg every 2 weeks until disease progression or unacceptable toxicity.

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

The Food and Drug Administration (FDA) has granted accelerated approval to zenocutuzumab-zbco (Bizengri, Merus) as an intravenous infusion for the treatment of certain adults with non–small cell lung cancer (NSCLC) or pancreatic adenocarcinoma.

Specifically, the systemic agent was approved for those with advanced, unresectable, or metastatic NSCLC or pancreatic adenocarcinoma harboring a neuregulin 1 (NRG1) gene fusion who progress on or after prior systemic therapy, according to the FDA.

The approval, based on findings from the multicenter, open-label eNRGy study, is the first from the FDA for a systemic therapy in this setting. In the multicohort study, treatment was associated with an overall response rate of 33% and 40% in 64 patients with NSCLC and 40 patients with pancreatic adenocarcinoma, respectively. Median duration of response was 7.4 months in the NSCLC patients and ranged from 3.7 to 16.6 months in those with pancreatic adenocarcinoma.

Adverse reactions occurring in at least 10% of patients included diarrhea, musculoskeletal pain, fatigue, nausea, infusion-related reactions, dyspnea, rash, constipation, vomiting, abdominal pain, and edema. Grade 3 or 4 laboratory abnormalities occurring in at least 10% of patients included increased gamma-glutamyl transferase and decreased hemoglobin, sodium, and platelets.

“The Personalized Medicine Coalition applauds the approval of BIZENGRI®,” Edward Abrahams, president of the Personalized Medicine Coalition, a Washington-based education and advocacy organization, stated in a press release from Merus. “In keeping with the growing number of personalized medicines on the market today, BIZENGRI® offers the only approved NRG1+ therapy for patients with these difficult-to-treat cancers.”

The agent is expected to be available for use in the “coming weeks,” according to Merus.

“The FDA approval of BIZENGRI® marks an important milestone for patients with pancreatic adenocarcinoma or NSCLC that is advanced unresectable or metastatic and harbors the NRG1 gene fusion,” noted Alison Schram, MD, an attending medical oncologist in the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, New York City, and a principal investigator for the ongoing eNRGy trial. “I have seen firsthand how treatment with BIZENGRI® can deliver clinically meaningful outcomes for patients.”

Prescribing information for zenocutuzumab-zbco includes a Boxed Warning for embryo-fetal toxicity. The recommended treatment dose is 750 mg every 2 weeks until disease progression or unacceptable toxicity.

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

The results of the SUMMIT trial of the long-acting agonist of glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors, tirzepatide, in patients with heart failure with preserved ejection fraction (HFpEF) and obesity are positive. But the trial design leaves clinicians and regulators with big doses of uncertainty.

Known Facts About HFpEF

HFpEF has exceeded heart failure with reduced ejection fraction (HFrEF) as the most common form of heart failure. HFpEF differs from HFrEF in that patients with preserved ejection fraction often present later in life with more comorbidities.

Some of these comorbidities are on the causal pathway of heart failure. Obesity, for instance, both associates with HFpEF and surely causes the diastolic dysfunction central to the condition. This may be a direct effect via high excess adipose tissue or an indirect effect via pro-inflammatory pathways.

GLP-1 agonists and the dual-acting GIP/GLP1 agonist tirzepatide have proven efficacy for weight loss. Semaglutide has previously been shown to improve quality of life and physical functioning in two small trials of patients with HFpEF and obesity. Semaglutide also reduced hard clinical outcomes in patients with obesity and these other conditions: chronic kidney disease, diabetes, and established atherosclerotic vascular disease.

This class of drugs is costly. The combination of both high drug costs and highly prevalent conditions such as obesity and HFpEF forces clinicians to make both value and clinical judgments when translating evidence.

 

The SUMMIT Trial

The SUMMIT trial aimed to evaluate tirzepatide’s effect on typical heart failure events, health status and functional capacity in patients with obesity and HFpEF. A total of 731 patients were randomly assigned to receive to tirzepatide or placebo.

Investigators chose two co-primary endpoints. The first was a composite of cardiovascular (CV) death and worsening heart failure events—the latter could be a hospitalization for heart failure, a visit for intravenous diuretics, or intensification of oral diuretics. The idea behind this rather unique composite was to capture all heart failure events. The second co-primary endpoint was a change in baseline Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) at 1 year.

Characteristics of the patients included an average age of 65 years, 55% were female, the average body mass index was 38, and the mean left ventricular ejection fraction was 61% (the minimum for trial entry was 50%). Just under half had been hospitalized for heart failure in the year before trial entry.

 

Tirzepatide Results

The primary outcome of CV death and first heart failure event occurred in 36 patients (9.9%) in the tirzepatide group and 56 patients (15.3%) in the placebo group, for a hazard ratio of 0.62 (95% CI, 0.41-0.95; P =.026).

The 5.4% absolute risk reduction in the primary endpoint was completely driven by lower rates of heart failure events (8% vs 14.2%). CV death was actually higher in the tirzepatide arm, but the number of deaths was low in both arms (8 vs 5).

The rate of hospitalizations due to heart failure was lower with tirzepatide (3.3% vs 7.1%), as was intensification of oral diuretics (4.7% vs 5.7%).

The second co-primary endpoint of change from baseline in KCCQ-CSS favored tirzepatide.

Other secondary endpoints also favored tirzepatide: longer 6-minute walk distance, greater change in body weight (-11.6%), and lower high-sensitivity C-reactive protein levels and systolic blood pressure (-4.7 mm Hg).

 

Authors’ Conclusions and Expert Comments

At the American Heart Association Scientific Sessions, the primary investigator Milton Packer, MD, said SUMMIT was the first trial of patients with obesity and HFpEF that had major heart failure outcomes as the primary endpoint. And that tirzepatide changed the clinical trajectory of the disease.

Jennifer Ho, MD, associate professor of medicine at Harvard Medical School, Boston, Massachusetts, said, “This really is a practice-changing trial and cements this type of therapy as one of the cornerstones of obesity and HFpEF treatment.”

Other experts cited a recently published pooled analysis of semaglutide trials looking specifically at patients with HFpEF and found lower rates of HF events with the GLP-1 agonist.

The SUMMIT trial results were covered in 53 news outlets— nearly all with glowing headlines.

 

My Six Concerns With SUMMIT

The trial delivered statistically positive findings. What’s more, patients lost weight, and a greater than 11% weight loss difference is meaningful. Patients with a baseline weight of more than 100 kg who lose this much weight are bound to feel and function better.

The first problem comes when we ask whether the results are disease-modifying. There was no difference in CV death. And the number of hospitalizations for heart failure — the more standard endpoint — was low, at only 12 and 26, respectively. Contrast this with the DELIVER trial of the sodium-glucose cotransporter 2 inhibitor dapagliflozin in HFpEF where there were nearly 750 hospitalizations for heart failure and PARAGON-HF of sacubitril-valsartan vs valsartan in HFpEF, where there were nearly 1500. SUMMIT simply had too few events to make conclusions — a point Packer has made regarding AF ablation trials in patients with heart failure.

I have previously called GLP-1 drugs disease-modifying in patients with obesity and atherosclerotic disease. This is because the SELECT trial of semaglutide randomized more than 17,000 patients and recorded a 20% reduction in hard outcomes. And there were more than 1200 primary outcome events. SUMMIT does not come close to this measure.

The second issue is short follow-up. These were 65-year-old patients and with only 2 years of follow-up, it is hard to make conclusions regarding whether or not these drugs can provide long-term benefit.

The third issue is that SUMMIT authors don’t tell us the number of all-cause hospitalizations. I was part of a recently published meta-analysis of more than 100 heart failure trials that raised questions regarding the value of hospitalizations for heart failure as a surrogate for heart failure outcomes.

For instance, we found that in large trials there was great variability in the ability of a reduction in HF hospitalizations to predict a reduction in all-cause hospitalization. In small trials, such as SUMMIT, it would likely be impossible to predict how the reduction in HF hospitalization would predict all-cause hospitalization. I believe all-cause hospitalization is a more inclusive endpoint because it is bias free; it captures benefits and potential harms of the therapy; and it is patient-centered, because patients probably do not care what type of hospitalization they avoid.

The fourth issue with SUMMIT is the difficulty in maintaining blinding, which reduces confidence in outcomes that require clinical decisions or patient judgments. Owing to gastrointestinal symptoms, decreased appetite, and weight loss, patients on this class of drugs are very likely to know their treatment assignment. This is a criticism of not only SUMMIT but all GLP-1 agonist trials. The fact that blinding is difficult to maintain argues for choosing endpoints less susceptible to bias, such as CV death or all-cause hospitalization.

Proponents of tirzepatide for this indication might argue that unblinding is less of an issue because of objective endpoints such as biomarkers. And they have a point, but nearly all other endpoints, especially the co-primary endpoint of KCCQ-CSS, are largely susceptible to bias.

The fifth and main problem comes in translating this evidence in the clinic. Should doctors give up on nondrug means of weight loss? All of the positive outcome trials in this class of drugs have also shown weight loss. I believe we should take these data and use them to re-invigorate our advocacy for weight loss without medication. I know the standard answer to this proposal is nihilism: It just will not work. And I cannot deny that we have failed previously in our efforts to help patients lose weight. But perhaps now, with the vast amount of data, we can be more persuasive. Imagine a world where key opinion leaders made weight loss the message rather than prescription of a drug.

Finally, if you approach SUMMIT from the view of a regulator, with its small numbers of outcome events and bias-susceptible endpoints, you cannot allow a disease-modifying claim. For that we would need a properly powered trial that shows that the drug reduces both CV death and all-cause hospitalization.

In the end, SUMMIT is not close to changing treatment norms in patients with HFpEF. As evidence-based clinicians, we should demand more from our partners in industry and academia.

Dr. Mandrola practices cardiac electrophysiology in Baptist Medical Associates, Louisville, Kentucky, and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. He has disclosed no relevant financial relationships.

 

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

The results of the SUMMIT trial of the long-acting agonist of glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors, tirzepatide, in patients with heart failure with preserved ejection fraction (HFpEF) and obesity are positive. But the trial design leaves clinicians and regulators with big doses of uncertainty.

Known Facts About HFpEF

HFpEF has exceeded heart failure with reduced ejection fraction (HFrEF) as the most common form of heart failure. HFpEF differs from HFrEF in that patients with preserved ejection fraction often present later in life with more comorbidities.

Some of these comorbidities are on the causal pathway of heart failure. Obesity, for instance, both associates with HFpEF and surely causes the diastolic dysfunction central to the condition. This may be a direct effect via high excess adipose tissue or an indirect effect via pro-inflammatory pathways.

GLP-1 agonists and the dual-acting GIP/GLP1 agonist tirzepatide have proven efficacy for weight loss. Semaglutide has previously been shown to improve quality of life and physical functioning in two small trials of patients with HFpEF and obesity. Semaglutide also reduced hard clinical outcomes in patients with obesity and these other conditions: chronic kidney disease, diabetes, and established atherosclerotic vascular disease.

This class of drugs is costly. The combination of both high drug costs and highly prevalent conditions such as obesity and HFpEF forces clinicians to make both value and clinical judgments when translating evidence.

 

The SUMMIT Trial

The SUMMIT trial aimed to evaluate tirzepatide’s effect on typical heart failure events, health status and functional capacity in patients with obesity and HFpEF. A total of 731 patients were randomly assigned to receive to tirzepatide or placebo.

Investigators chose two co-primary endpoints. The first was a composite of cardiovascular (CV) death and worsening heart failure events—the latter could be a hospitalization for heart failure, a visit for intravenous diuretics, or intensification of oral diuretics. The idea behind this rather unique composite was to capture all heart failure events. The second co-primary endpoint was a change in baseline Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) at 1 year.

Characteristics of the patients included an average age of 65 years, 55% were female, the average body mass index was 38, and the mean left ventricular ejection fraction was 61% (the minimum for trial entry was 50%). Just under half had been hospitalized for heart failure in the year before trial entry.

 

Tirzepatide Results

The primary outcome of CV death and first heart failure event occurred in 36 patients (9.9%) in the tirzepatide group and 56 patients (15.3%) in the placebo group, for a hazard ratio of 0.62 (95% CI, 0.41-0.95; P =.026).

The 5.4% absolute risk reduction in the primary endpoint was completely driven by lower rates of heart failure events (8% vs 14.2%). CV death was actually higher in the tirzepatide arm, but the number of deaths was low in both arms (8 vs 5).

The rate of hospitalizations due to heart failure was lower with tirzepatide (3.3% vs 7.1%), as was intensification of oral diuretics (4.7% vs 5.7%).

The second co-primary endpoint of change from baseline in KCCQ-CSS favored tirzepatide.

Other secondary endpoints also favored tirzepatide: longer 6-minute walk distance, greater change in body weight (-11.6%), and lower high-sensitivity C-reactive protein levels and systolic blood pressure (-4.7 mm Hg).

 

Authors’ Conclusions and Expert Comments

At the American Heart Association Scientific Sessions, the primary investigator Milton Packer, MD, said SUMMIT was the first trial of patients with obesity and HFpEF that had major heart failure outcomes as the primary endpoint. And that tirzepatide changed the clinical trajectory of the disease.

Jennifer Ho, MD, associate professor of medicine at Harvard Medical School, Boston, Massachusetts, said, “This really is a practice-changing trial and cements this type of therapy as one of the cornerstones of obesity and HFpEF treatment.”

Other experts cited a recently published pooled analysis of semaglutide trials looking specifically at patients with HFpEF and found lower rates of HF events with the GLP-1 agonist.

The SUMMIT trial results were covered in 53 news outlets— nearly all with glowing headlines.

 

My Six Concerns With SUMMIT

The trial delivered statistically positive findings. What’s more, patients lost weight, and a greater than 11% weight loss difference is meaningful. Patients with a baseline weight of more than 100 kg who lose this much weight are bound to feel and function better.

The first problem comes when we ask whether the results are disease-modifying. There was no difference in CV death. And the number of hospitalizations for heart failure — the more standard endpoint — was low, at only 12 and 26, respectively. Contrast this with the DELIVER trial of the sodium-glucose cotransporter 2 inhibitor dapagliflozin in HFpEF where there were nearly 750 hospitalizations for heart failure and PARAGON-HF of sacubitril-valsartan vs valsartan in HFpEF, where there were nearly 1500. SUMMIT simply had too few events to make conclusions — a point Packer has made regarding AF ablation trials in patients with heart failure.

I have previously called GLP-1 drugs disease-modifying in patients with obesity and atherosclerotic disease. This is because the SELECT trial of semaglutide randomized more than 17,000 patients and recorded a 20% reduction in hard outcomes. And there were more than 1200 primary outcome events. SUMMIT does not come close to this measure.

The second issue is short follow-up. These were 65-year-old patients and with only 2 years of follow-up, it is hard to make conclusions regarding whether or not these drugs can provide long-term benefit.

The third issue is that SUMMIT authors don’t tell us the number of all-cause hospitalizations. I was part of a recently published meta-analysis of more than 100 heart failure trials that raised questions regarding the value of hospitalizations for heart failure as a surrogate for heart failure outcomes.

For instance, we found that in large trials there was great variability in the ability of a reduction in HF hospitalizations to predict a reduction in all-cause hospitalization. In small trials, such as SUMMIT, it would likely be impossible to predict how the reduction in HF hospitalization would predict all-cause hospitalization. I believe all-cause hospitalization is a more inclusive endpoint because it is bias free; it captures benefits and potential harms of the therapy; and it is patient-centered, because patients probably do not care what type of hospitalization they avoid.

The fourth issue with SUMMIT is the difficulty in maintaining blinding, which reduces confidence in outcomes that require clinical decisions or patient judgments. Owing to gastrointestinal symptoms, decreased appetite, and weight loss, patients on this class of drugs are very likely to know their treatment assignment. This is a criticism of not only SUMMIT but all GLP-1 agonist trials. The fact that blinding is difficult to maintain argues for choosing endpoints less susceptible to bias, such as CV death or all-cause hospitalization.

Proponents of tirzepatide for this indication might argue that unblinding is less of an issue because of objective endpoints such as biomarkers. And they have a point, but nearly all other endpoints, especially the co-primary endpoint of KCCQ-CSS, are largely susceptible to bias.

The fifth and main problem comes in translating this evidence in the clinic. Should doctors give up on nondrug means of weight loss? All of the positive outcome trials in this class of drugs have also shown weight loss. I believe we should take these data and use them to re-invigorate our advocacy for weight loss without medication. I know the standard answer to this proposal is nihilism: It just will not work. And I cannot deny that we have failed previously in our efforts to help patients lose weight. But perhaps now, with the vast amount of data, we can be more persuasive. Imagine a world where key opinion leaders made weight loss the message rather than prescription of a drug.

Finally, if you approach SUMMIT from the view of a regulator, with its small numbers of outcome events and bias-susceptible endpoints, you cannot allow a disease-modifying claim. For that we would need a properly powered trial that shows that the drug reduces both CV death and all-cause hospitalization.

In the end, SUMMIT is not close to changing treatment norms in patients with HFpEF. As evidence-based clinicians, we should demand more from our partners in industry and academia.

Dr. Mandrola practices cardiac electrophysiology in Baptist Medical Associates, Louisville, Kentucky, and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. He has disclosed no relevant financial relationships.

 

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

The results of the SUMMIT trial of the long-acting agonist of glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors, tirzepatide, in patients with heart failure with preserved ejection fraction (HFpEF) and obesity are positive. But the trial design leaves clinicians and regulators with big doses of uncertainty.

Known Facts About HFpEF

HFpEF has exceeded heart failure with reduced ejection fraction (HFrEF) as the most common form of heart failure. HFpEF differs from HFrEF in that patients with preserved ejection fraction often present later in life with more comorbidities.

Some of these comorbidities are on the causal pathway of heart failure. Obesity, for instance, both associates with HFpEF and surely causes the diastolic dysfunction central to the condition. This may be a direct effect via high excess adipose tissue or an indirect effect via pro-inflammatory pathways.

GLP-1 agonists and the dual-acting GIP/GLP1 agonist tirzepatide have proven efficacy for weight loss. Semaglutide has previously been shown to improve quality of life and physical functioning in two small trials of patients with HFpEF and obesity. Semaglutide also reduced hard clinical outcomes in patients with obesity and these other conditions: chronic kidney disease, diabetes, and established atherosclerotic vascular disease.

This class of drugs is costly. The combination of both high drug costs and highly prevalent conditions such as obesity and HFpEF forces clinicians to make both value and clinical judgments when translating evidence.

 

The SUMMIT Trial

The SUMMIT trial aimed to evaluate tirzepatide’s effect on typical heart failure events, health status and functional capacity in patients with obesity and HFpEF. A total of 731 patients were randomly assigned to receive to tirzepatide or placebo.

Investigators chose two co-primary endpoints. The first was a composite of cardiovascular (CV) death and worsening heart failure events—the latter could be a hospitalization for heart failure, a visit for intravenous diuretics, or intensification of oral diuretics. The idea behind this rather unique composite was to capture all heart failure events. The second co-primary endpoint was a change in baseline Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) at 1 year.

Characteristics of the patients included an average age of 65 years, 55% were female, the average body mass index was 38, and the mean left ventricular ejection fraction was 61% (the minimum for trial entry was 50%). Just under half had been hospitalized for heart failure in the year before trial entry.

 

Tirzepatide Results

The primary outcome of CV death and first heart failure event occurred in 36 patients (9.9%) in the tirzepatide group and 56 patients (15.3%) in the placebo group, for a hazard ratio of 0.62 (95% CI, 0.41-0.95; P =.026).

The 5.4% absolute risk reduction in the primary endpoint was completely driven by lower rates of heart failure events (8% vs 14.2%). CV death was actually higher in the tirzepatide arm, but the number of deaths was low in both arms (8 vs 5).

The rate of hospitalizations due to heart failure was lower with tirzepatide (3.3% vs 7.1%), as was intensification of oral diuretics (4.7% vs 5.7%).

The second co-primary endpoint of change from baseline in KCCQ-CSS favored tirzepatide.

Other secondary endpoints also favored tirzepatide: longer 6-minute walk distance, greater change in body weight (-11.6%), and lower high-sensitivity C-reactive protein levels and systolic blood pressure (-4.7 mm Hg).

 

Authors’ Conclusions and Expert Comments

At the American Heart Association Scientific Sessions, the primary investigator Milton Packer, MD, said SUMMIT was the first trial of patients with obesity and HFpEF that had major heart failure outcomes as the primary endpoint. And that tirzepatide changed the clinical trajectory of the disease.

Jennifer Ho, MD, associate professor of medicine at Harvard Medical School, Boston, Massachusetts, said, “This really is a practice-changing trial and cements this type of therapy as one of the cornerstones of obesity and HFpEF treatment.”

Other experts cited a recently published pooled analysis of semaglutide trials looking specifically at patients with HFpEF and found lower rates of HF events with the GLP-1 agonist.

The SUMMIT trial results were covered in 53 news outlets— nearly all with glowing headlines.

 

My Six Concerns With SUMMIT

The trial delivered statistically positive findings. What’s more, patients lost weight, and a greater than 11% weight loss difference is meaningful. Patients with a baseline weight of more than 100 kg who lose this much weight are bound to feel and function better.

The first problem comes when we ask whether the results are disease-modifying. There was no difference in CV death. And the number of hospitalizations for heart failure — the more standard endpoint — was low, at only 12 and 26, respectively. Contrast this with the DELIVER trial of the sodium-glucose cotransporter 2 inhibitor dapagliflozin in HFpEF where there were nearly 750 hospitalizations for heart failure and PARAGON-HF of sacubitril-valsartan vs valsartan in HFpEF, where there were nearly 1500. SUMMIT simply had too few events to make conclusions — a point Packer has made regarding AF ablation trials in patients with heart failure.

I have previously called GLP-1 drugs disease-modifying in patients with obesity and atherosclerotic disease. This is because the SELECT trial of semaglutide randomized more than 17,000 patients and recorded a 20% reduction in hard outcomes. And there were more than 1200 primary outcome events. SUMMIT does not come close to this measure.

The second issue is short follow-up. These were 65-year-old patients and with only 2 years of follow-up, it is hard to make conclusions regarding whether or not these drugs can provide long-term benefit.

The third issue is that SUMMIT authors don’t tell us the number of all-cause hospitalizations. I was part of a recently published meta-analysis of more than 100 heart failure trials that raised questions regarding the value of hospitalizations for heart failure as a surrogate for heart failure outcomes.

For instance, we found that in large trials there was great variability in the ability of a reduction in HF hospitalizations to predict a reduction in all-cause hospitalization. In small trials, such as SUMMIT, it would likely be impossible to predict how the reduction in HF hospitalization would predict all-cause hospitalization. I believe all-cause hospitalization is a more inclusive endpoint because it is bias free; it captures benefits and potential harms of the therapy; and it is patient-centered, because patients probably do not care what type of hospitalization they avoid.

The fourth issue with SUMMIT is the difficulty in maintaining blinding, which reduces confidence in outcomes that require clinical decisions or patient judgments. Owing to gastrointestinal symptoms, decreased appetite, and weight loss, patients on this class of drugs are very likely to know their treatment assignment. This is a criticism of not only SUMMIT but all GLP-1 agonist trials. The fact that blinding is difficult to maintain argues for choosing endpoints less susceptible to bias, such as CV death or all-cause hospitalization.

Proponents of tirzepatide for this indication might argue that unblinding is less of an issue because of objective endpoints such as biomarkers. And they have a point, but nearly all other endpoints, especially the co-primary endpoint of KCCQ-CSS, are largely susceptible to bias.

The fifth and main problem comes in translating this evidence in the clinic. Should doctors give up on nondrug means of weight loss? All of the positive outcome trials in this class of drugs have also shown weight loss. I believe we should take these data and use them to re-invigorate our advocacy for weight loss without medication. I know the standard answer to this proposal is nihilism: It just will not work. And I cannot deny that we have failed previously in our efforts to help patients lose weight. But perhaps now, with the vast amount of data, we can be more persuasive. Imagine a world where key opinion leaders made weight loss the message rather than prescription of a drug.

Finally, if you approach SUMMIT from the view of a regulator, with its small numbers of outcome events and bias-susceptible endpoints, you cannot allow a disease-modifying claim. For that we would need a properly powered trial that shows that the drug reduces both CV death and all-cause hospitalization.

In the end, SUMMIT is not close to changing treatment norms in patients with HFpEF. As evidence-based clinicians, we should demand more from our partners in industry and academia.

Dr. Mandrola practices cardiac electrophysiology in Baptist Medical Associates, Louisville, Kentucky, and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. He has disclosed no relevant financial relationships.

 

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

Glucagon-like peptide 1 receptor agonist (GLP-1) prescriptions for diabetes and obesity treatment are soaring, as is the interest in their potential for treating an array of other conditions. One area in particular is addiction, which, like obesity and diabetes, has been increasing, both in terms of case numbers and deaths from drug overdose, excessive alcohol use, and tobacco/e-cigarettes.

So far, data supporting GLP-1 use in addiction are limited to preclinical studies, anecdotal evidence, a few cohort analyses, and randomized clinical trials. But the chatter among researchers and clinicians, not to mention patients, portends its promise. 

 

“The evidence is very preliminary and very exciting,” said Nora D. Volkow, MD, director of the National Institute on Drug Abuse (NIDA). “The studies have been going on for more than a decade looking at the effects of GLP medications, mostly first generation and predominantly in rodents,” she said.

GLP “drugs like exenatide and liraglutide all reduced consumption of nicotine, of alcohol, of cocaine, and response to opioids,” Volkow said.

 

Clinical, Real-World Data Promising

Second-generation agents like semaglutide appear to hold greater promise than their first-generation counterparts. Volkow noted that not only is semaglutide a “much more potent drug,” but pointed to recent findings that saw significant declines in heavy drinking days among patients with alcohol use disorder (AUD).

At the Research Society on Alcohol’s annual meeting in June, researchers from the University of North Carolina at Chapel Hill presented findings of a 2-month, phase 2, randomized clinical trial comparing two low doses (0.25 mg/wk, 0.5 mg/wk) of semaglutide with placebo in 48 participants reporting symptoms of AUD. Though preliminary and unpublished, the data showed a reduction in drinking quantity and heavy drinking in the semaglutide vs placebo groups.

Real-world evidence from electronic health records has also underscored the potential benefit of semaglutide in AUD. In a 12-month retrospective cohort analysis of the records of patients with obesity and no prior AUD diagnosis prescribed semaglutide (n = 45,797) or non-GLP-1 anti-obesity medications (naltrexone, topiramate, n = 38,028), semaglutide was associated with a 50% lower risk for a recurrent AUD diagnosis and a 56% significantly lower risk for incidence AUD diagnosis across gender, age group, and race, and in patients with/without type 2 diabetes.

Likewise, findings from another cohort analysis assigned 1306 treatment-naive patients with type 2 diabetes and no prior AUD diagnosis to semaglutide or non-GLP-1 anti-diabetes medications and followed them for 12 months. Compared with people prescribed non-GLP-1 diabetes medications, those who took semaglutide had a 42% lower risk for recurrent alcohol use diagnosis, consistent across gender, age group, and race, whether the person had been diagnosed with obesity.

However, AUD is not the only addiction where semaglutide appears to have potential benefit. Cohort studies conducted by Volkow and her colleagues have suggested as much as a 78% reduced risk or opioid overdose in patients with comorbid obesity and type 2 diabetes) and a 44% reduction in cannabis use disorder in type 2 diabetes patients without a prior cannabis use disorder history.

 

Unclear Mechanisms, Multiple Theories

It’s not entirely clear how semaglutide provides a path for addicts to reduce their cravings or which patients might benefit most.

Preclinical studies have suggested that GLP-1 receptors are expressed throughout the mesolimbic dopamine system and transmit dopamine directly to reward centers in the forebrain, for example, the nucleus accumbens. The drugs appear to reduce dopamine release and transmission to these reward centers, as well as to areas that are responsible for impulse control.

“What we’re seeing is counteracting mechanisms that allow you to self-regulate are also involved in addiction, but I don’t know to what extent these medications could help strengthen that,” said Volkow.

Henry Kranzler, MD, professor of psychiatry and director of the Center for Studies of Addiction at the University of Pennsylvania’s Perelman School of Medicine in Philadelphia, has a paper in press looking at genetic correlation between body mass index (BMI) and AUD. “Genetic analysis showed that many of the same genes are working in both disorders but in opposite directions,” he said.

The bottom line is that “they share genetics, but by no means are they the same; this gives us reason to believe that the GLP-1s could be beneficial in obesity but not nearly as beneficial for treating addiction,” said Kranzler.

 

Behind Closed Doors

Like many people with overweight or obesity who are on semaglutide, Bridget Pilloud, a writer who divides her time between Washington State and Arizona, no longer has any desire to drink.

“I used to really enjoy sitting and slowly sipping an Old Fashioned. I used to really enjoy specific whiskeys. Now, I don’t even like the flavor; the pleasure of drinking is gone,” she said.

Inexplicably, Pilloud said that she’s also given up compulsive shopping; “The hunt and acquisition of it was always really delicious to me,” she said.

Pilloud’s experience is not unique. Angela Fitch, MD, an obesity medicine specialist, co-founder and CMO of knownwell health, and former president of the Obesity Medicine Association, has had patients on semaglutide tell her that they’re not shopping as much.

But self-reports about alcohol consumption are far more common.

A 2023 analysis of social media posts reinforced that the experience is quite common, albeit self-reported.

Researchers used machine learning attribution mapping of 68,250 posts related to GLP-1 or GLP-1/glucose-dependent insulinotropic polypeptide agonists on the Reddit platform. Among the 1580 alcohol-related posts, 71% (1134/1580) of users of either drug said they had reduced cravings and decreased desire to drink. In a remote companion study of 153 people with obesity taking semaglutide (n = 56), tirzepatide (n = 50), or neither (n = 47), there appeared to be a reduced suppression of the desire to consume alcohol, with users reporting fewer drinks and binge episodes than control individuals.

Self-reports also underscored the association between either of the medications and less stimulating/sedative effects of alcohol compared with before starting the medications and to controls.

Behind closed doors, there appears to be as much chatter about the potential of these agents for AUD and other addiction disorders as there are questions about factors like treatment duration, safety of long-term, chronic use, and dosage.

“We don’t have data around people with normal weight and how much risk that is to them if they start taking these medications for addiction and reduce their BMI as low as 18,” said Fitch.

There’s also the question of when and how to wean patients off the medications, a consideration that is quite important for patients with addiction problems, said Volkow.

“What happens when you become addicted to drugs is that you start to degrade social support systems needed for well-being,” she explained. “The big difference with drugs versus foods is that you can live happily with no drugs at all, whereas you die if you don’t eat. So, there are greater challenges in the ability to change the environment (eg, help stabilize everyday life so people have alternative reinforcers) when you remove the reward.” 

Additional considerations range from overuse and the development of treatment-resistant obesity to the need to ensure that patients on these drugs receive ongoing management and, of course, access, noted Fitch.

Still, the NIDA coffers are open. “We’re waiting for proposals,” said Volkow.

Fitch is cofounder and CMO of knownwell health. Volkow reported no relevant financial relationships. Kranzler is a member of advisory boards for Altimmune, Clearmind Medicine, Dicerna Pharmaceuticals, Enthion Pharmaceuticals, Eli Lilly and Company, and Sophrosyne Pharmaceuticals; a consultant to Sobrera Pharma and Altimmune; the recipient of research funding and medication supplies for an investigator-initiated study from Alkermes; a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which was supported in the past 3 years by Alkermes, Dicerna Pharmaceuticals, Ethypharm, Imbrium, Indivior, Kinnov, Eli Lilly, Otsuka, and Pear; and a holder of US patent 10,900,082 titled: “Genotype-guided dosing of opioid agonists,” issued on January 26, 2021.

A version of this article appeared on Medscape.com.

Glucagon-like peptide 1 receptor agonist (GLP-1) prescriptions for diabetes and obesity treatment are soaring, as is the interest in their potential for treating an array of other conditions. One area in particular is addiction, which, like obesity and diabetes, has been increasing, both in terms of case numbers and deaths from drug overdose, excessive alcohol use, and tobacco/e-cigarettes.

So far, data supporting GLP-1 use in addiction are limited to preclinical studies, anecdotal evidence, a few cohort analyses, and randomized clinical trials. But the chatter among researchers and clinicians, not to mention patients, portends its promise. 

 

“The evidence is very preliminary and very exciting,” said Nora D. Volkow, MD, director of the National Institute on Drug Abuse (NIDA). “The studies have been going on for more than a decade looking at the effects of GLP medications, mostly first generation and predominantly in rodents,” she said.

GLP “drugs like exenatide and liraglutide all reduced consumption of nicotine, of alcohol, of cocaine, and response to opioids,” Volkow said.

 

Clinical, Real-World Data Promising

Second-generation agents like semaglutide appear to hold greater promise than their first-generation counterparts. Volkow noted that not only is semaglutide a “much more potent drug,” but pointed to recent findings that saw significant declines in heavy drinking days among patients with alcohol use disorder (AUD).

At the Research Society on Alcohol’s annual meeting in June, researchers from the University of North Carolina at Chapel Hill presented findings of a 2-month, phase 2, randomized clinical trial comparing two low doses (0.25 mg/wk, 0.5 mg/wk) of semaglutide with placebo in 48 participants reporting symptoms of AUD. Though preliminary and unpublished, the data showed a reduction in drinking quantity and heavy drinking in the semaglutide vs placebo groups.

Real-world evidence from electronic health records has also underscored the potential benefit of semaglutide in AUD. In a 12-month retrospective cohort analysis of the records of patients with obesity and no prior AUD diagnosis prescribed semaglutide (n = 45,797) or non-GLP-1 anti-obesity medications (naltrexone, topiramate, n = 38,028), semaglutide was associated with a 50% lower risk for a recurrent AUD diagnosis and a 56% significantly lower risk for incidence AUD diagnosis across gender, age group, and race, and in patients with/without type 2 diabetes.

Likewise, findings from another cohort analysis assigned 1306 treatment-naive patients with type 2 diabetes and no prior AUD diagnosis to semaglutide or non-GLP-1 anti-diabetes medications and followed them for 12 months. Compared with people prescribed non-GLP-1 diabetes medications, those who took semaglutide had a 42% lower risk for recurrent alcohol use diagnosis, consistent across gender, age group, and race, whether the person had been diagnosed with obesity.

However, AUD is not the only addiction where semaglutide appears to have potential benefit. Cohort studies conducted by Volkow and her colleagues have suggested as much as a 78% reduced risk or opioid overdose in patients with comorbid obesity and type 2 diabetes) and a 44% reduction in cannabis use disorder in type 2 diabetes patients without a prior cannabis use disorder history.

 

Unclear Mechanisms, Multiple Theories

It’s not entirely clear how semaglutide provides a path for addicts to reduce their cravings or which patients might benefit most.

Preclinical studies have suggested that GLP-1 receptors are expressed throughout the mesolimbic dopamine system and transmit dopamine directly to reward centers in the forebrain, for example, the nucleus accumbens. The drugs appear to reduce dopamine release and transmission to these reward centers, as well as to areas that are responsible for impulse control.

“What we’re seeing is counteracting mechanisms that allow you to self-regulate are also involved in addiction, but I don’t know to what extent these medications could help strengthen that,” said Volkow.

Henry Kranzler, MD, professor of psychiatry and director of the Center for Studies of Addiction at the University of Pennsylvania’s Perelman School of Medicine in Philadelphia, has a paper in press looking at genetic correlation between body mass index (BMI) and AUD. “Genetic analysis showed that many of the same genes are working in both disorders but in opposite directions,” he said.

The bottom line is that “they share genetics, but by no means are they the same; this gives us reason to believe that the GLP-1s could be beneficial in obesity but not nearly as beneficial for treating addiction,” said Kranzler.

 

Behind Closed Doors

Like many people with overweight or obesity who are on semaglutide, Bridget Pilloud, a writer who divides her time between Washington State and Arizona, no longer has any desire to drink.

“I used to really enjoy sitting and slowly sipping an Old Fashioned. I used to really enjoy specific whiskeys. Now, I don’t even like the flavor; the pleasure of drinking is gone,” she said.

Inexplicably, Pilloud said that she’s also given up compulsive shopping; “The hunt and acquisition of it was always really delicious to me,” she said.

Pilloud’s experience is not unique. Angela Fitch, MD, an obesity medicine specialist, co-founder and CMO of knownwell health, and former president of the Obesity Medicine Association, has had patients on semaglutide tell her that they’re not shopping as much.

But self-reports about alcohol consumption are far more common.

A 2023 analysis of social media posts reinforced that the experience is quite common, albeit self-reported.

Researchers used machine learning attribution mapping of 68,250 posts related to GLP-1 or GLP-1/glucose-dependent insulinotropic polypeptide agonists on the Reddit platform. Among the 1580 alcohol-related posts, 71% (1134/1580) of users of either drug said they had reduced cravings and decreased desire to drink. In a remote companion study of 153 people with obesity taking semaglutide (n = 56), tirzepatide (n = 50), or neither (n = 47), there appeared to be a reduced suppression of the desire to consume alcohol, with users reporting fewer drinks and binge episodes than control individuals.

Self-reports also underscored the association between either of the medications and less stimulating/sedative effects of alcohol compared with before starting the medications and to controls.

Behind closed doors, there appears to be as much chatter about the potential of these agents for AUD and other addiction disorders as there are questions about factors like treatment duration, safety of long-term, chronic use, and dosage.

“We don’t have data around people with normal weight and how much risk that is to them if they start taking these medications for addiction and reduce their BMI as low as 18,” said Fitch.

There’s also the question of when and how to wean patients off the medications, a consideration that is quite important for patients with addiction problems, said Volkow.

“What happens when you become addicted to drugs is that you start to degrade social support systems needed for well-being,” she explained. “The big difference with drugs versus foods is that you can live happily with no drugs at all, whereas you die if you don’t eat. So, there are greater challenges in the ability to change the environment (eg, help stabilize everyday life so people have alternative reinforcers) when you remove the reward.” 

Additional considerations range from overuse and the development of treatment-resistant obesity to the need to ensure that patients on these drugs receive ongoing management and, of course, access, noted Fitch.

Still, the NIDA coffers are open. “We’re waiting for proposals,” said Volkow.

Fitch is cofounder and CMO of knownwell health. Volkow reported no relevant financial relationships. Kranzler is a member of advisory boards for Altimmune, Clearmind Medicine, Dicerna Pharmaceuticals, Enthion Pharmaceuticals, Eli Lilly and Company, and Sophrosyne Pharmaceuticals; a consultant to Sobrera Pharma and Altimmune; the recipient of research funding and medication supplies for an investigator-initiated study from Alkermes; a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which was supported in the past 3 years by Alkermes, Dicerna Pharmaceuticals, Ethypharm, Imbrium, Indivior, Kinnov, Eli Lilly, Otsuka, and Pear; and a holder of US patent 10,900,082 titled: “Genotype-guided dosing of opioid agonists,” issued on January 26, 2021.

A version of this article appeared on Medscape.com.

Glucagon-like peptide 1 receptor agonist (GLP-1) prescriptions for diabetes and obesity treatment are soaring, as is the interest in their potential for treating an array of other conditions. One area in particular is addiction, which, like obesity and diabetes, has been increasing, both in terms of case numbers and deaths from drug overdose, excessive alcohol use, and tobacco/e-cigarettes.

So far, data supporting GLP-1 use in addiction are limited to preclinical studies, anecdotal evidence, a few cohort analyses, and randomized clinical trials. But the chatter among researchers and clinicians, not to mention patients, portends its promise. 

 

“The evidence is very preliminary and very exciting,” said Nora D. Volkow, MD, director of the National Institute on Drug Abuse (NIDA). “The studies have been going on for more than a decade looking at the effects of GLP medications, mostly first generation and predominantly in rodents,” she said.

GLP “drugs like exenatide and liraglutide all reduced consumption of nicotine, of alcohol, of cocaine, and response to opioids,” Volkow said.

 

Clinical, Real-World Data Promising

Second-generation agents like semaglutide appear to hold greater promise than their first-generation counterparts. Volkow noted that not only is semaglutide a “much more potent drug,” but pointed to recent findings that saw significant declines in heavy drinking days among patients with alcohol use disorder (AUD).

At the Research Society on Alcohol’s annual meeting in June, researchers from the University of North Carolina at Chapel Hill presented findings of a 2-month, phase 2, randomized clinical trial comparing two low doses (0.25 mg/wk, 0.5 mg/wk) of semaglutide with placebo in 48 participants reporting symptoms of AUD. Though preliminary and unpublished, the data showed a reduction in drinking quantity and heavy drinking in the semaglutide vs placebo groups.

Real-world evidence from electronic health records has also underscored the potential benefit of semaglutide in AUD. In a 12-month retrospective cohort analysis of the records of patients with obesity and no prior AUD diagnosis prescribed semaglutide (n = 45,797) or non-GLP-1 anti-obesity medications (naltrexone, topiramate, n = 38,028), semaglutide was associated with a 50% lower risk for a recurrent AUD diagnosis and a 56% significantly lower risk for incidence AUD diagnosis across gender, age group, and race, and in patients with/without type 2 diabetes.

Likewise, findings from another cohort analysis assigned 1306 treatment-naive patients with type 2 diabetes and no prior AUD diagnosis to semaglutide or non-GLP-1 anti-diabetes medications and followed them for 12 months. Compared with people prescribed non-GLP-1 diabetes medications, those who took semaglutide had a 42% lower risk for recurrent alcohol use diagnosis, consistent across gender, age group, and race, whether the person had been diagnosed with obesity.

However, AUD is not the only addiction where semaglutide appears to have potential benefit. Cohort studies conducted by Volkow and her colleagues have suggested as much as a 78% reduced risk or opioid overdose in patients with comorbid obesity and type 2 diabetes) and a 44% reduction in cannabis use disorder in type 2 diabetes patients without a prior cannabis use disorder history.

 

Unclear Mechanisms, Multiple Theories

It’s not entirely clear how semaglutide provides a path for addicts to reduce their cravings or which patients might benefit most.

Preclinical studies have suggested that GLP-1 receptors are expressed throughout the mesolimbic dopamine system and transmit dopamine directly to reward centers in the forebrain, for example, the nucleus accumbens. The drugs appear to reduce dopamine release and transmission to these reward centers, as well as to areas that are responsible for impulse control.

“What we’re seeing is counteracting mechanisms that allow you to self-regulate are also involved in addiction, but I don’t know to what extent these medications could help strengthen that,” said Volkow.

Henry Kranzler, MD, professor of psychiatry and director of the Center for Studies of Addiction at the University of Pennsylvania’s Perelman School of Medicine in Philadelphia, has a paper in press looking at genetic correlation between body mass index (BMI) and AUD. “Genetic analysis showed that many of the same genes are working in both disorders but in opposite directions,” he said.

The bottom line is that “they share genetics, but by no means are they the same; this gives us reason to believe that the GLP-1s could be beneficial in obesity but not nearly as beneficial for treating addiction,” said Kranzler.

 

Behind Closed Doors

Like many people with overweight or obesity who are on semaglutide, Bridget Pilloud, a writer who divides her time between Washington State and Arizona, no longer has any desire to drink.

“I used to really enjoy sitting and slowly sipping an Old Fashioned. I used to really enjoy specific whiskeys. Now, I don’t even like the flavor; the pleasure of drinking is gone,” she said.

Inexplicably, Pilloud said that she’s also given up compulsive shopping; “The hunt and acquisition of it was always really delicious to me,” she said.

Pilloud’s experience is not unique. Angela Fitch, MD, an obesity medicine specialist, co-founder and CMO of knownwell health, and former president of the Obesity Medicine Association, has had patients on semaglutide tell her that they’re not shopping as much.

But self-reports about alcohol consumption are far more common.

A 2023 analysis of social media posts reinforced that the experience is quite common, albeit self-reported.

Researchers used machine learning attribution mapping of 68,250 posts related to GLP-1 or GLP-1/glucose-dependent insulinotropic polypeptide agonists on the Reddit platform. Among the 1580 alcohol-related posts, 71% (1134/1580) of users of either drug said they had reduced cravings and decreased desire to drink. In a remote companion study of 153 people with obesity taking semaglutide (n = 56), tirzepatide (n = 50), or neither (n = 47), there appeared to be a reduced suppression of the desire to consume alcohol, with users reporting fewer drinks and binge episodes than control individuals.

Self-reports also underscored the association between either of the medications and less stimulating/sedative effects of alcohol compared with before starting the medications and to controls.

Behind closed doors, there appears to be as much chatter about the potential of these agents for AUD and other addiction disorders as there are questions about factors like treatment duration, safety of long-term, chronic use, and dosage.

“We don’t have data around people with normal weight and how much risk that is to them if they start taking these medications for addiction and reduce their BMI as low as 18,” said Fitch.

There’s also the question of when and how to wean patients off the medications, a consideration that is quite important for patients with addiction problems, said Volkow.

“What happens when you become addicted to drugs is that you start to degrade social support systems needed for well-being,” she explained. “The big difference with drugs versus foods is that you can live happily with no drugs at all, whereas you die if you don’t eat. So, there are greater challenges in the ability to change the environment (eg, help stabilize everyday life so people have alternative reinforcers) when you remove the reward.” 

Additional considerations range from overuse and the development of treatment-resistant obesity to the need to ensure that patients on these drugs receive ongoing management and, of course, access, noted Fitch.

Still, the NIDA coffers are open. “We’re waiting for proposals,” said Volkow.

Fitch is cofounder and CMO of knownwell health. Volkow reported no relevant financial relationships. Kranzler is a member of advisory boards for Altimmune, Clearmind Medicine, Dicerna Pharmaceuticals, Enthion Pharmaceuticals, Eli Lilly and Company, and Sophrosyne Pharmaceuticals; a consultant to Sobrera Pharma and Altimmune; the recipient of research funding and medication supplies for an investigator-initiated study from Alkermes; a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which was supported in the past 3 years by Alkermes, Dicerna Pharmaceuticals, Ethypharm, Imbrium, Indivior, Kinnov, Eli Lilly, Otsuka, and Pear; and a holder of US patent 10,900,082 titled: “Genotype-guided dosing of opioid agonists,” issued on January 26, 2021.

A version of this article appeared on Medscape.com.

Three basic truths about ultraprocessed foods: Junk food, available pretty much everywhere, tastes great. Advertising works. And most of us don’t crave green leafy salads when we’re hungry.

Of those three truths, the one that tends to get more public health attention is advertising. More specifically, advertising junk food to kids. 

Back in the days when cable television was king of all free time, study after study tried to quantify junk- and fast-food advertising to kids and speculated about its impact on childhood obesity rates. But as broadcast television use began fading, advertisers — and, of course, studies about advertising — turned their attention first to gaming and now to social media.

The social media numbers are quite staggering. According to a study published — probably not coincidentally — on Halloween, looking at the 40 top brands of junk- and fast food sold in Canada, those 40 brands alone were mentioned over 16 million times by social media users, reaching an estimated 42 billion total users within a 1-year period. 

And unique to the challenge of junk- and fast-food advertising on social media is that it also includes “earned” advertising, the kind not paid for by manufacturers but rather the kind where friends, family, and influencers post about junk food. Occasionally, though, these lines are blurred by initiatives from fast-food manufacturers explicitly encouraging social sharing. Consequently, even were there a desire, there isn’t likely to be a regulatory mechanism to markedly reduce it. 

For years, here in North America, excepting Quebec, the desire has been mainly to just talk about how concerned we are about junk-food advertising to kids. Elsewhere, however, some countries tried to do more, including both Mexico and Chile, which put kid-targeted TV food advertising bans in place in 2014 and 2016, respectively. 

Did they work? It depends on what outcome you’re considering. If the question is, did they work in regard to obesity? — which is how everyone tends to frame the question — by themselves, probably not. No one sandbag stops a flood, and though junk-food advertising is certainly a sandbag, we’re still facing a torrential downpour of obesity contributors. No doubt they did work to reduce kids’ exposure to junk-food advertising on television, but what remains to be seen is whether there is a means to now tackle social media’s generous servings of the same. Moreover, the obesity lens is the wrong one. Ultraprocessed food consumption isn’t good for anyone, regardless of weight, and its reduced marketing and consumption is a worthy goal of its own.

But Chile and Mexico are filling more than single sandbags, as both countries have rolled out a suite of interventions they are hoping will help improve nutrition: from front-of–package labeling reforms and warnings, to the banning of advertising geared specifically to appeal to children (like sugary cereal cartoon mascots), to implementing sugar-sweetened-beverage taxes, to having blanket overall bans on food advertising during the daytime.

Mexico is even taking first steps to start addressing junk food’s ubiquity by banning its sale in schools altogether. Schools found to be selling common Mexican junk food fare, such as sugary fruit drinks; chips; artificial pork rinds; and soy-encased, salty peanuts with chili, will see their administrators facing heavy fines. 

Because therein lies the biggest rub. Going back to those three simple truths, junk food is hyperpalatable and consequently tends to be what we crave when we’re hungry. So even if we miraculously one day do more than just talk about advertising reforms, and especially given that we won’t be able to do anything about social media’s earned product placements, junk food’s ubiquitous availability within arms’ reach or on our Uber Eats apps will see us be likely to continue its excessive consumption. 

That’s not to say we shouldn’t emulate Mexico and Chile’s initiatives, nor that they shouldn’t continue to build upon them, but one thing is certain: Human nature and inconvenient truths around food are incredibly powerful forces that we haven’t yet figured out how to tame.

Dr. Freedhoff, Associate Professor, Department of Family Medicine, University of Ottawa; Medical Director, Bariatric Medical Institute, Ottawa, Ontario, Canada, has disclosed relevant financial relationships with Bariatric Medical Institute, Constant Health, Novo Nordisk, and Weighty Matters.

A version of this article appeared on Medscape.com.

Three basic truths about ultraprocessed foods: Junk food, available pretty much everywhere, tastes great. Advertising works. And most of us don’t crave green leafy salads when we’re hungry.

Of those three truths, the one that tends to get more public health attention is advertising. More specifically, advertising junk food to kids. 

Back in the days when cable television was king of all free time, study after study tried to quantify junk- and fast-food advertising to kids and speculated about its impact on childhood obesity rates. But as broadcast television use began fading, advertisers — and, of course, studies about advertising — turned their attention first to gaming and now to social media.

The social media numbers are quite staggering. According to a study published — probably not coincidentally — on Halloween, looking at the 40 top brands of junk- and fast food sold in Canada, those 40 brands alone were mentioned over 16 million times by social media users, reaching an estimated 42 billion total users within a 1-year period. 

And unique to the challenge of junk- and fast-food advertising on social media is that it also includes “earned” advertising, the kind not paid for by manufacturers but rather the kind where friends, family, and influencers post about junk food. Occasionally, though, these lines are blurred by initiatives from fast-food manufacturers explicitly encouraging social sharing. Consequently, even were there a desire, there isn’t likely to be a regulatory mechanism to markedly reduce it. 

For years, here in North America, excepting Quebec, the desire has been mainly to just talk about how concerned we are about junk-food advertising to kids. Elsewhere, however, some countries tried to do more, including both Mexico and Chile, which put kid-targeted TV food advertising bans in place in 2014 and 2016, respectively. 

Did they work? It depends on what outcome you’re considering. If the question is, did they work in regard to obesity? — which is how everyone tends to frame the question — by themselves, probably not. No one sandbag stops a flood, and though junk-food advertising is certainly a sandbag, we’re still facing a torrential downpour of obesity contributors. No doubt they did work to reduce kids’ exposure to junk-food advertising on television, but what remains to be seen is whether there is a means to now tackle social media’s generous servings of the same. Moreover, the obesity lens is the wrong one. Ultraprocessed food consumption isn’t good for anyone, regardless of weight, and its reduced marketing and consumption is a worthy goal of its own.

But Chile and Mexico are filling more than single sandbags, as both countries have rolled out a suite of interventions they are hoping will help improve nutrition: from front-of–package labeling reforms and warnings, to the banning of advertising geared specifically to appeal to children (like sugary cereal cartoon mascots), to implementing sugar-sweetened-beverage taxes, to having blanket overall bans on food advertising during the daytime.

Mexico is even taking first steps to start addressing junk food’s ubiquity by banning its sale in schools altogether. Schools found to be selling common Mexican junk food fare, such as sugary fruit drinks; chips; artificial pork rinds; and soy-encased, salty peanuts with chili, will see their administrators facing heavy fines. 

Because therein lies the biggest rub. Going back to those three simple truths, junk food is hyperpalatable and consequently tends to be what we crave when we’re hungry. So even if we miraculously one day do more than just talk about advertising reforms, and especially given that we won’t be able to do anything about social media’s earned product placements, junk food’s ubiquitous availability within arms’ reach or on our Uber Eats apps will see us be likely to continue its excessive consumption. 

That’s not to say we shouldn’t emulate Mexico and Chile’s initiatives, nor that they shouldn’t continue to build upon them, but one thing is certain: Human nature and inconvenient truths around food are incredibly powerful forces that we haven’t yet figured out how to tame.

Dr. Freedhoff, Associate Professor, Department of Family Medicine, University of Ottawa; Medical Director, Bariatric Medical Institute, Ottawa, Ontario, Canada, has disclosed relevant financial relationships with Bariatric Medical Institute, Constant Health, Novo Nordisk, and Weighty Matters.

A version of this article appeared on Medscape.com.

Three basic truths about ultraprocessed foods: Junk food, available pretty much everywhere, tastes great. Advertising works. And most of us don’t crave green leafy salads when we’re hungry.

Of those three truths, the one that tends to get more public health attention is advertising. More specifically, advertising junk food to kids. 

Back in the days when cable television was king of all free time, study after study tried to quantify junk- and fast-food advertising to kids and speculated about its impact on childhood obesity rates. But as broadcast television use began fading, advertisers — and, of course, studies about advertising — turned their attention first to gaming and now to social media.

The social media numbers are quite staggering. According to a study published — probably not coincidentally — on Halloween, looking at the 40 top brands of junk- and fast food sold in Canada, those 40 brands alone were mentioned over 16 million times by social media users, reaching an estimated 42 billion total users within a 1-year period. 

And unique to the challenge of junk- and fast-food advertising on social media is that it also includes “earned” advertising, the kind not paid for by manufacturers but rather the kind where friends, family, and influencers post about junk food. Occasionally, though, these lines are blurred by initiatives from fast-food manufacturers explicitly encouraging social sharing. Consequently, even were there a desire, there isn’t likely to be a regulatory mechanism to markedly reduce it. 

For years, here in North America, excepting Quebec, the desire has been mainly to just talk about how concerned we are about junk-food advertising to kids. Elsewhere, however, some countries tried to do more, including both Mexico and Chile, which put kid-targeted TV food advertising bans in place in 2014 and 2016, respectively. 

Did they work? It depends on what outcome you’re considering. If the question is, did they work in regard to obesity? — which is how everyone tends to frame the question — by themselves, probably not. No one sandbag stops a flood, and though junk-food advertising is certainly a sandbag, we’re still facing a torrential downpour of obesity contributors. No doubt they did work to reduce kids’ exposure to junk-food advertising on television, but what remains to be seen is whether there is a means to now tackle social media’s generous servings of the same. Moreover, the obesity lens is the wrong one. Ultraprocessed food consumption isn’t good for anyone, regardless of weight, and its reduced marketing and consumption is a worthy goal of its own.

But Chile and Mexico are filling more than single sandbags, as both countries have rolled out a suite of interventions they are hoping will help improve nutrition: from front-of–package labeling reforms and warnings, to the banning of advertising geared specifically to appeal to children (like sugary cereal cartoon mascots), to implementing sugar-sweetened-beverage taxes, to having blanket overall bans on food advertising during the daytime.

Mexico is even taking first steps to start addressing junk food’s ubiquity by banning its sale in schools altogether. Schools found to be selling common Mexican junk food fare, such as sugary fruit drinks; chips; artificial pork rinds; and soy-encased, salty peanuts with chili, will see their administrators facing heavy fines. 

Because therein lies the biggest rub. Going back to those three simple truths, junk food is hyperpalatable and consequently tends to be what we crave when we’re hungry. So even if we miraculously one day do more than just talk about advertising reforms, and especially given that we won’t be able to do anything about social media’s earned product placements, junk food’s ubiquitous availability within arms’ reach or on our Uber Eats apps will see us be likely to continue its excessive consumption. 

That’s not to say we shouldn’t emulate Mexico and Chile’s initiatives, nor that they shouldn’t continue to build upon them, but one thing is certain: Human nature and inconvenient truths around food are incredibly powerful forces that we haven’t yet figured out how to tame.

Dr. Freedhoff, Associate Professor, Department of Family Medicine, University of Ottawa; Medical Director, Bariatric Medical Institute, Ottawa, Ontario, Canada, has disclosed relevant financial relationships with Bariatric Medical Institute, Constant Health, Novo Nordisk, and Weighty Matters.

A version of this article appeared on Medscape.com.

In a new statement, the American Diabetes Association (ADA) has advised against the use of compounded glucagon-like peptide 1 receptor agonist (GLP-1 RA) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RA medication classes.

The ADA recommends GLP-1 RA and GIP/GLP-1 RA medications approved by the Food and Drug Administration (FDA) for the treatment of type 2 diabetes, cardiovascular and kidney disease risk reduction, and weight management. The new ADA statement pertains to the unapproved, unregulated versions that have emerged as the demand for these medications for weight loss increases. These are often marketed directly to consumers.

“Compounded GLP-1 RA and dual GIP/GLP-1 RA products have been associated with clinically important dosing errors and adverse events. More concerning to individuals’ safety are counterfeit products that have made their way into the US drug supply chain and those advertised online and by unregulated sources,” the ADA said in the statement, published online on December 2, 2024, in Diabetes Care.

The statement, authored by Joshua J. Neumiller, PharmD, CDCES, of the Department of Pharmacotherapy, Washington State University, Spokane, and colleagues, states the following:

• Non–FDA-approved compounded incretin products are not recommended for use due to uncertainty about their content and resulting concerns about safety, quality, and effectiveness.
• If an incretin medication is unavailable (eg, in shortage), switching to a different FDA-approved medication is recommended as clinically appropriate to achieve and maintain individualized glucose-lowering, weight management, and/or cardiovascular and kidney risk reduction goals.
• Upon resolution of incretin product unavailability, reassess the appropriateness of resuming the original FDA-approved incretin medication.

The document points out that compounded products are not identical to the FDA-approved versions, may be distributed in nonstandard dosing devices, and may not provide sufficient user instructions.

However, “the ADA also recognizes that individuals and clinicians may still elect to use or recommend compounded products for financial or other reasons,” and therefore offers additional advice for the public, including the following:

• Discuss product use with their usual healthcare providers.
• Only use products that include dosing guidance.
• Verify that the compounding pharmacy is registered with FDA.

In addition, report any adverse events or medication errors to the FDA’s Medwatch.

A version of this article appeared on Medscape.com.

In a new statement, the American Diabetes Association (ADA) has advised against the use of compounded glucagon-like peptide 1 receptor agonist (GLP-1 RA) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RA medication classes.

The ADA recommends GLP-1 RA and GIP/GLP-1 RA medications approved by the Food and Drug Administration (FDA) for the treatment of type 2 diabetes, cardiovascular and kidney disease risk reduction, and weight management. The new ADA statement pertains to the unapproved, unregulated versions that have emerged as the demand for these medications for weight loss increases. These are often marketed directly to consumers.

“Compounded GLP-1 RA and dual GIP/GLP-1 RA products have been associated with clinically important dosing errors and adverse events. More concerning to individuals’ safety are counterfeit products that have made their way into the US drug supply chain and those advertised online and by unregulated sources,” the ADA said in the statement, published online on December 2, 2024, in Diabetes Care.

The statement, authored by Joshua J. Neumiller, PharmD, CDCES, of the Department of Pharmacotherapy, Washington State University, Spokane, and colleagues, states the following:

• Non–FDA-approved compounded incretin products are not recommended for use due to uncertainty about their content and resulting concerns about safety, quality, and effectiveness.
• If an incretin medication is unavailable (eg, in shortage), switching to a different FDA-approved medication is recommended as clinically appropriate to achieve and maintain individualized glucose-lowering, weight management, and/or cardiovascular and kidney risk reduction goals.
• Upon resolution of incretin product unavailability, reassess the appropriateness of resuming the original FDA-approved incretin medication.

The document points out that compounded products are not identical to the FDA-approved versions, may be distributed in nonstandard dosing devices, and may not provide sufficient user instructions.

However, “the ADA also recognizes that individuals and clinicians may still elect to use or recommend compounded products for financial or other reasons,” and therefore offers additional advice for the public, including the following:

• Discuss product use with their usual healthcare providers.
• Only use products that include dosing guidance.
• Verify that the compounding pharmacy is registered with FDA.

In addition, report any adverse events or medication errors to the FDA’s Medwatch.

A version of this article appeared on Medscape.com.

In a new statement, the American Diabetes Association (ADA) has advised against the use of compounded glucagon-like peptide 1 receptor agonist (GLP-1 RA) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RA medication classes.

The ADA recommends GLP-1 RA and GIP/GLP-1 RA medications approved by the Food and Drug Administration (FDA) for the treatment of type 2 diabetes, cardiovascular and kidney disease risk reduction, and weight management. The new ADA statement pertains to the unapproved, unregulated versions that have emerged as the demand for these medications for weight loss increases. These are often marketed directly to consumers.

“Compounded GLP-1 RA and dual GIP/GLP-1 RA products have been associated with clinically important dosing errors and adverse events. More concerning to individuals’ safety are counterfeit products that have made their way into the US drug supply chain and those advertised online and by unregulated sources,” the ADA said in the statement, published online on December 2, 2024, in Diabetes Care.

The statement, authored by Joshua J. Neumiller, PharmD, CDCES, of the Department of Pharmacotherapy, Washington State University, Spokane, and colleagues, states the following:

• Non–FDA-approved compounded incretin products are not recommended for use due to uncertainty about their content and resulting concerns about safety, quality, and effectiveness.
• If an incretin medication is unavailable (eg, in shortage), switching to a different FDA-approved medication is recommended as clinically appropriate to achieve and maintain individualized glucose-lowering, weight management, and/or cardiovascular and kidney risk reduction goals.
• Upon resolution of incretin product unavailability, reassess the appropriateness of resuming the original FDA-approved incretin medication.

The document points out that compounded products are not identical to the FDA-approved versions, may be distributed in nonstandard dosing devices, and may not provide sufficient user instructions.

However, “the ADA also recognizes that individuals and clinicians may still elect to use or recommend compounded products for financial or other reasons,” and therefore offers additional advice for the public, including the following:

• Discuss product use with their usual healthcare providers.
• Only use products that include dosing guidance.
• Verify that the compounding pharmacy is registered with FDA.

In addition, report any adverse events or medication errors to the FDA’s Medwatch.

A version of this article appeared on Medscape.com.

VANCOUVER, BRITISH COLUMBIA — Canadian women aged 40-49 years at no or moderate risk for breast cancer who participated in organized mammography screening programs had a significantly greater breast cancer 10-year net survival than that of similar women who did not participate in such programs, according to data presented here at the Family Medicine Forum 2024. 

The data call into question draft guidelines from the Canadian Task Force on Preventive Health Care, which suggest not systematically screening women in this age group with mammography.

 

Overdiagnosis Challenged

Given that some jurisdictions in Canada have organized screening programs and some do not, there was an opportunity to compare breast cancer 10-year net survival of women who lived in jurisdictions with and without such programs, explained family physician Anna N. Wilkinson, MD, Ottawa regional cancer primary care lead and associate professor at the University of Ottawa in Ontario, Canada.

“The question was [whether] we could use big cancer data to figure out what’s going on,” she told this news organization. 

To investigate, Wilkinson and co-investigators reviewed data from the Canadian Cancer Registry linked to mortality information and assessed outcomes for women aged 40-49 and 50-59 years diagnosed with breast cancer from 2002 to 2007. They compared 10-year net survival estimates in jurisdictions with organized screening programs for those aged 40-49 years with the jurisdictions without them. 

“Net survival is important because it’s a survival measure that looks at only the cancer in question,” Wilkinson explained.

Investigators determined breast cancer to be the primary cause of 10-year mortality in women aged 40-49 years diagnosed with the disease (90.7% of deaths). 

Furthermore, the 10-year net survival in jurisdictions that screened these women (84.8%) was 1.9 percentage points higher than for jurisdictions that did not (82.9%). 

The difference in 10-year net survival favoring jurisdictions that offered screening was significant for women aged 45-49 years (2.6 percentage points) but not for those aged 40-44 years (0.9 percentage points).

Given that 90% of the deaths in women in their 40s who had a breast cancer diagnosis were due to breast cancer, Wilkinson challenged the concept of women in their 40s being overdiagnosed with breast cancer, meaning that the cancers detected were indolent and did not require treatment nor result in death.

Earlier detection would generally mean finding disease at an earlier stage and the need for less invasive treatment, she noted. “And one of the biggest benefits [of screening women in their 40s] is that you have diagnosis at earlier stage disease, which means fewer intensive therapies, less time off work, less long-term morbidity, and less cost to our healthcare system.”

 

Modeling Shows Little Screening Benefit

The task force’s draft guidelines, released earlier this year, were based on evidence from 165 studies including randomized, controlled trials, observational studies, time-trend studies and modeling. They suggest not systematically screening women 40-49 with mammography who are not high risk.

Family physician Guylène Thériault, MD, chair of the task force and its breast cancer working group, and director of the Pedagogy Center at the Outaouais Campus, McGill University, Montreal, Quebec, Canada, explained that to come to that conclusion, the task force had assessed the impact of organized screening for women in Canada aged 40-49 years and calculated the impact of mammography for every 1000 women over 10 years.

The model suggested that screening would yield 368 false positives, leading to 55 biopsies, and then to a breast cancer diagnosis in 19 women. Of those 19, the task force estimated 17 or 18 would not die of breast cancer over 10 years, two would be treated for breast cancer that would not have caused problems, ie, overdiagnosis, and one to two would die of breast cancer.

Without screening, on the other hand, the model suggested that 983 of 1000 women aged 40-49 years would not be diagnosed with breast cancer, and 17 would be, 15 of whom would not die from breast cancer over 10 years (no overdiagnosis, no deaths prevented) and two would die.

It is important that family physicians provide their patients with this information to assist in shared decision making about screening, Thériault said.

Wilkinson concluded that screening programs that included women in their 40s were associated with a significantly higher breast cancer 10-year survival, without an increased rate of diagnosis. She suggested that the study findings can inform the screening guidelines for women aged 40-49 years. 

The study was supported by the University of Ottawa’s department of family medicine. 

Wilkinson, MD, is a consultant for Thrive Health. Thériault, MD, disclosed no relevant financial relationships.

 

A version of this article appeared on Medscape.com.

VANCOUVER, BRITISH COLUMBIA — Canadian women aged 40-49 years at no or moderate risk for breast cancer who participated in organized mammography screening programs had a significantly greater breast cancer 10-year net survival than that of similar women who did not participate in such programs, according to data presented here at the Family Medicine Forum 2024. 

The data call into question draft guidelines from the Canadian Task Force on Preventive Health Care, which suggest not systematically screening women in this age group with mammography.

 

Overdiagnosis Challenged

Given that some jurisdictions in Canada have organized screening programs and some do not, there was an opportunity to compare breast cancer 10-year net survival of women who lived in jurisdictions with and without such programs, explained family physician Anna N. Wilkinson, MD, Ottawa regional cancer primary care lead and associate professor at the University of Ottawa in Ontario, Canada.

“The question was [whether] we could use big cancer data to figure out what’s going on,” she told this news organization. 

To investigate, Wilkinson and co-investigators reviewed data from the Canadian Cancer Registry linked to mortality information and assessed outcomes for women aged 40-49 and 50-59 years diagnosed with breast cancer from 2002 to 2007. They compared 10-year net survival estimates in jurisdictions with organized screening programs for those aged 40-49 years with the jurisdictions without them. 

“Net survival is important because it’s a survival measure that looks at only the cancer in question,” Wilkinson explained.

Investigators determined breast cancer to be the primary cause of 10-year mortality in women aged 40-49 years diagnosed with the disease (90.7% of deaths). 

Furthermore, the 10-year net survival in jurisdictions that screened these women (84.8%) was 1.9 percentage points higher than for jurisdictions that did not (82.9%). 

The difference in 10-year net survival favoring jurisdictions that offered screening was significant for women aged 45-49 years (2.6 percentage points) but not for those aged 40-44 years (0.9 percentage points).

Given that 90% of the deaths in women in their 40s who had a breast cancer diagnosis were due to breast cancer, Wilkinson challenged the concept of women in their 40s being overdiagnosed with breast cancer, meaning that the cancers detected were indolent and did not require treatment nor result in death.

Earlier detection would generally mean finding disease at an earlier stage and the need for less invasive treatment, she noted. “And one of the biggest benefits [of screening women in their 40s] is that you have diagnosis at earlier stage disease, which means fewer intensive therapies, less time off work, less long-term morbidity, and less cost to our healthcare system.”

 

Modeling Shows Little Screening Benefit

The task force’s draft guidelines, released earlier this year, were based on evidence from 165 studies including randomized, controlled trials, observational studies, time-trend studies and modeling. They suggest not systematically screening women 40-49 with mammography who are not high risk.

Family physician Guylène Thériault, MD, chair of the task force and its breast cancer working group, and director of the Pedagogy Center at the Outaouais Campus, McGill University, Montreal, Quebec, Canada, explained that to come to that conclusion, the task force had assessed the impact of organized screening for women in Canada aged 40-49 years and calculated the impact of mammography for every 1000 women over 10 years.

The model suggested that screening would yield 368 false positives, leading to 55 biopsies, and then to a breast cancer diagnosis in 19 women. Of those 19, the task force estimated 17 or 18 would not die of breast cancer over 10 years, two would be treated for breast cancer that would not have caused problems, ie, overdiagnosis, and one to two would die of breast cancer.

Without screening, on the other hand, the model suggested that 983 of 1000 women aged 40-49 years would not be diagnosed with breast cancer, and 17 would be, 15 of whom would not die from breast cancer over 10 years (no overdiagnosis, no deaths prevented) and two would die.

It is important that family physicians provide their patients with this information to assist in shared decision making about screening, Thériault said.

Wilkinson concluded that screening programs that included women in their 40s were associated with a significantly higher breast cancer 10-year survival, without an increased rate of diagnosis. She suggested that the study findings can inform the screening guidelines for women aged 40-49 years. 

The study was supported by the University of Ottawa’s department of family medicine. 

Wilkinson, MD, is a consultant for Thrive Health. Thériault, MD, disclosed no relevant financial relationships.

 

A version of this article appeared on Medscape.com.

VANCOUVER, BRITISH COLUMBIA — Canadian women aged 40-49 years at no or moderate risk for breast cancer who participated in organized mammography screening programs had a significantly greater breast cancer 10-year net survival than that of similar women who did not participate in such programs, according to data presented here at the Family Medicine Forum 2024. 

The data call into question draft guidelines from the Canadian Task Force on Preventive Health Care, which suggest not systematically screening women in this age group with mammography.

 

Overdiagnosis Challenged

Given that some jurisdictions in Canada have organized screening programs and some do not, there was an opportunity to compare breast cancer 10-year net survival of women who lived in jurisdictions with and without such programs, explained family physician Anna N. Wilkinson, MD, Ottawa regional cancer primary care lead and associate professor at the University of Ottawa in Ontario, Canada.

“The question was [whether] we could use big cancer data to figure out what’s going on,” she told this news organization. 

To investigate, Wilkinson and co-investigators reviewed data from the Canadian Cancer Registry linked to mortality information and assessed outcomes for women aged 40-49 and 50-59 years diagnosed with breast cancer from 2002 to 2007. They compared 10-year net survival estimates in jurisdictions with organized screening programs for those aged 40-49 years with the jurisdictions without them. 

“Net survival is important because it’s a survival measure that looks at only the cancer in question,” Wilkinson explained.

Investigators determined breast cancer to be the primary cause of 10-year mortality in women aged 40-49 years diagnosed with the disease (90.7% of deaths). 

Furthermore, the 10-year net survival in jurisdictions that screened these women (84.8%) was 1.9 percentage points higher than for jurisdictions that did not (82.9%). 

The difference in 10-year net survival favoring jurisdictions that offered screening was significant for women aged 45-49 years (2.6 percentage points) but not for those aged 40-44 years (0.9 percentage points).

Given that 90% of the deaths in women in their 40s who had a breast cancer diagnosis were due to breast cancer, Wilkinson challenged the concept of women in their 40s being overdiagnosed with breast cancer, meaning that the cancers detected were indolent and did not require treatment nor result in death.

Earlier detection would generally mean finding disease at an earlier stage and the need for less invasive treatment, she noted. “And one of the biggest benefits [of screening women in their 40s] is that you have diagnosis at earlier stage disease, which means fewer intensive therapies, less time off work, less long-term morbidity, and less cost to our healthcare system.”

 

Modeling Shows Little Screening Benefit

The task force’s draft guidelines, released earlier this year, were based on evidence from 165 studies including randomized, controlled trials, observational studies, time-trend studies and modeling. They suggest not systematically screening women 40-49 with mammography who are not high risk.

Family physician Guylène Thériault, MD, chair of the task force and its breast cancer working group, and director of the Pedagogy Center at the Outaouais Campus, McGill University, Montreal, Quebec, Canada, explained that to come to that conclusion, the task force had assessed the impact of organized screening for women in Canada aged 40-49 years and calculated the impact of mammography for every 1000 women over 10 years.

The model suggested that screening would yield 368 false positives, leading to 55 biopsies, and then to a breast cancer diagnosis in 19 women. Of those 19, the task force estimated 17 or 18 would not die of breast cancer over 10 years, two would be treated for breast cancer that would not have caused problems, ie, overdiagnosis, and one to two would die of breast cancer.

Without screening, on the other hand, the model suggested that 983 of 1000 women aged 40-49 years would not be diagnosed with breast cancer, and 17 would be, 15 of whom would not die from breast cancer over 10 years (no overdiagnosis, no deaths prevented) and two would die.

It is important that family physicians provide their patients with this information to assist in shared decision making about screening, Thériault said.

Wilkinson concluded that screening programs that included women in their 40s were associated with a significantly higher breast cancer 10-year survival, without an increased rate of diagnosis. She suggested that the study findings can inform the screening guidelines for women aged 40-49 years. 

The study was supported by the University of Ottawa’s department of family medicine. 

Wilkinson, MD, is a consultant for Thrive Health. Thériault, MD, disclosed no relevant financial relationships.

 

A version of this article appeared on Medscape.com.

The emergence of vorasidenib, the first targeted therapy for certain gliomas with IDH mutations, has ignited a wave of excitement in both patient and physician spaces.

After years with limited treatment options, experts hailed vorasidenib “a promising breakthrough,” “a paradigm shift,” a “new hope,” and “probably the most important advance in the treatment of low-grade gliomas in the last decade.”

Promising results from vorasidenib’s pivotal INDIGO trial fueled petitions and patient advocacy circles to push for the drug’s approval. And, in August 2024, the Food and Drug Administration (FDA) approved vorasidenib for grade 2 astrocytomas or oligodendrogliomas with an IDH1 or IDH2 mutation.

But following the approval, some experts expressed concerns and doubts about the drug and the INDIGO trial, bringing a host of unanswered questions into sharper focus.

In an editorial, Stanislav Lazarev, MD, and Kunal K. Sindhu, MD, both radiation oncologists from Icahn School of Medicine at Mount Sinai, New York City, suggest that the FDA approval “might be premature given the high cost of this drug and lack of clear benefit over standard treatments.”

Another recent critique also pointed to the lack of clear evidence that vorasidenib is superior to the prevailing standard of care, despite the drug’s high cost. These authors noted that “patients want to live longer, and if not, at least live better,” but “based on the INDIGO study, it is impossible to say whether vorasidenib can provide either.”

Vorasidenib is now one of the most expensive cancer therapies, with an annual cost of nearly $500,000, but the INDIGO trial did not explore whether the drug led to improved overall survival or better quality of life. Among the trial’s design flaws, experts called out the use of progression-free survival as the primary outcome, instead of overall survival, and the use of an inappropriate comparator group.

INDIGO was a phase 3 trial that included 331 adult patients (median age, 40.5 years) with grade-2 IDH-mutant recurrent or residual glioma after surgery. To be eligible, patients had to be followed for at least 1 year, and up to 5 years, post surgery and had to be considered appropriate candidates for a watch-and-wait approach.

Participants were randomly assigned to receive either 40 mg of vorasidenib or a matching placebo orally, once daily, in continuous 28-day cycles until imaging-confirmed tumor disease progression or unacceptable toxicity, at which point crossover to vorasidenib from placebo was permitted. Over one third (n = 58) of patients in the placebo group crossed over and 90% of them (n = 52) received vorasidenib.

Median progression-free survival was significantly better in the vorasidenib group at 27.7 months vs 11.1 months in the placebo group (hazard ratio [HR], 0.39).

A key secondary endpoint — time to next intervention — was also significant; the likelihood of being alive and not receiving further treatment at 18 months was 85.6% in the vorasidenib group and 47.4% in the placebo group (HR, 0.26). This finding indicates that most patients receiving vorasidenib could delay chemoradiation for 18 months or longer.

Despite these impressive outcomes, some experts noted that using progression-free survival as the primary endpoint was a major flaw of the INDIGO trial because, currently, there is no evidence that progression-free survival is a reliable surrogate endpoint for overall survival in this setting.

The high rate of crossover to vorasidenib is another issue because it may limit a longer-term analysis of overall survival. If, for instance, overall survival is the same between the groups, it could signal that the drug is effective in both groups or, alternatively, that the drug has no effect on survival in either group.

“That is a legitimate concern,” Seema Nagpal, MD, a neuro-oncologist at Stanford University in California, and a site principal investigator for the INDIGO trial, said in an interview. “We don’t know that this drug changes overall survival, and I think we’re not going to get a super clean answer on that.”

Another major issue centers on the standard of care assigned to control patients in the INDIGO trial.

In the trial, vorasidenib was compared with placebo — an appropriate standard-of-care comparison for patients with low-risk gliomas. These patients often initially undergo watch-and-wait to delay chemoradiation. But Lazarev and Sindhu argue that the patients in INDIGO were really high risk, which means the control group should have received the standard of care for these patients: Chemoradiation following surgery.

This question about the appropriate standard of care stems from ongoing uncertainty about the distinction between high- and low-risk gliomas.

The classification for gliomas falls into either low risk or high risk for early disease progression. The RTOG 9802 criteria, often used for glioma risk stratification, defines low-risk patients as those younger than 40 years with gross total resection and high-risk patients as those aged 40 years or older with any extent of resection or those younger than 40 years with subtotal or biopsy resection.

But an evolving understanding of genetic anomalies that affect prognoses in this tumor type has muddied the current high- and low-risk distinctions.

“People haven’t totally figured out what high and low risk means,” Nagpal acknowledged.

This uncertainty has spilled over into the INDIGO trial.

While the trial excluded patients who had any features indicating high risk, such as brain stem involvement or neurocognitive deficits, the researchers also did not explicitly define patients as low risk. However, the inclusion criteria specified that patients had to be observed for at least 1 year after surgery and be considered appropriate for a watch-and-wait protocol, which does suggest patients were considered low risk, said Nagpal.

Still, some experts argue that the patients in INDIGO were not low risk.

Patients had residual or recurrent disease so “wouldn’t be classified as low risk,” said Sindhu in an interview. The standard of care for these patients is chemoradiation, Lazarev added.

“The definition of a phase 3 clinical trial is that you compare the novel intervention to the standard of care,” said Lazarev. “Level 1 evidence clearly shows that omitting chemoradiation leads to worse outcomes, with patients literally dying sooner. For the investigators to knowingly exclude this proven treatment raises serious ethical and methodological questions about the study’s design.” 

In a recent opinion piece, Nagpal agreed that most patients selected for INDIGO would not have been considered low risk by many providers. All patients selected for INDIGO had postoperative residual/recurrent disease and many were older than 40 years.

But, Nagpal explained, the risk stratification of the INDIGO patients was still lower than what is commonly considered high risk. The patients had all been observed for a year or more already, “so by definition, the clinician treating them already decided they were not high risk,” she said.

In another recent opinion piece, oncologists suggested that, because patients in the INDIGO trial do not squarely fall into either category, instead representing a “grey area,” it’s time to create a new risk category.

“Perhaps the time has come to abandon the old binary risk stratification (“low risk” vs “high risk”), which still contains arbitrary elements (such as the age cutoff), proving impractical in real-world clinical decision-making, and to adopt a new one, also taking into account many emerging prognostic biomarkers,” the authors wrote.

Despite the uncertainty surrounding risk categories, the INDIGO authors justified their study design.

A watch-and-wait period for patients in the trial, which “represents the earliest clinical phase in tumorigenesis of IDH-mutant WHO grade 2 glioma,” is “an opportunity to detect a clear signal of antitumor activity for new therapies in placebo-controlled trials” and “postpone the use of radiation therapy and chemotherapy,” the authors explained.

Lazarev, however, questioned the premise that chemoradiation should be delayed.

Oncologists’ desire to delay chemoradiation for their patients reflects “a limited understanding of modern irradiation therapy,” Lazarev said. “Modern technology has improved dramatically. We’re more precise, our understanding about late side effects is better. So, the big picture is that the absolute risk of late neurocognitive affects that actually will affect patients’ quality of life, their ability to work, go to school, succeed on a personal or professional level is exceedingly low.”

Nagpal strongly disagreed.

“Please come to my clinic and ask an actual patient,” said Nagpal. “Once a radiation oncologist has irradiated the patient, they almost never seen them again. People who are on the medical side, who follow these patients from beginning to end, recognize that delaying radiation is a huge deal.”

Although vorasidenib isn’t a cure, Nagpal said, it is a less toxic way to delay radiation “because that is a real and disabling thing” for patients and is why neuro-oncologists are excited about alternative treatment options.

Another issue surrounding the vorasidenib approval lies in the FDA’s vague prescribing information. The prescribing information does not specify that patients should be followed for at least 1 year post surgery or that patients need to be lower risk. Prescribing physicians may, therefore, think vorasidenib is appropriate for any patient with a grade-2 IDH mutant glioma at any time and defer or not offer chemoradiation to high-risk patients.

Amid lingering questions about the INDIGO trial design and ongoing uncertainties about how to define and treat this patient population, experts remain divided on whether vorasidenib is worth it.

“If vorasidenib is truly transformative, it should be feasible to demonstrate its superiority over chemoradiotherapy,” Lazarev and Sindhu wrote. “For a drug with such a staggering price tag, an imperative should be placed on the investigators and manufacturer to provide clear evidence of efficacy, whether in terms of improved [overall survival] or quality of life, before vorasidenib is recommended for the treatment of IDH-mutant low-grade gliomas.”

The INDIGO trial was supported by Servier, the manufacturer of vorasidenib. Many of the study authors reported employment or support from the company. Nagpal reported consulting fees from Servier and AnHeart Therapeutics. Lazarev and Sindhu reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

The emergence of vorasidenib, the first targeted therapy for certain gliomas with IDH mutations, has ignited a wave of excitement in both patient and physician spaces.

After years with limited treatment options, experts hailed vorasidenib “a promising breakthrough,” “a paradigm shift,” a “new hope,” and “probably the most important advance in the treatment of low-grade gliomas in the last decade.”

Promising results from vorasidenib’s pivotal INDIGO trial fueled petitions and patient advocacy circles to push for the drug’s approval. And, in August 2024, the Food and Drug Administration (FDA) approved vorasidenib for grade 2 astrocytomas or oligodendrogliomas with an IDH1 or IDH2 mutation.

But following the approval, some experts expressed concerns and doubts about the drug and the INDIGO trial, bringing a host of unanswered questions into sharper focus.

In an editorial, Stanislav Lazarev, MD, and Kunal K. Sindhu, MD, both radiation oncologists from Icahn School of Medicine at Mount Sinai, New York City, suggest that the FDA approval “might be premature given the high cost of this drug and lack of clear benefit over standard treatments.”

Another recent critique also pointed to the lack of clear evidence that vorasidenib is superior to the prevailing standard of care, despite the drug’s high cost. These authors noted that “patients want to live longer, and if not, at least live better,” but “based on the INDIGO study, it is impossible to say whether vorasidenib can provide either.”

Vorasidenib is now one of the most expensive cancer therapies, with an annual cost of nearly $500,000, but the INDIGO trial did not explore whether the drug led to improved overall survival or better quality of life. Among the trial’s design flaws, experts called out the use of progression-free survival as the primary outcome, instead of overall survival, and the use of an inappropriate comparator group.

INDIGO was a phase 3 trial that included 331 adult patients (median age, 40.5 years) with grade-2 IDH-mutant recurrent or residual glioma after surgery. To be eligible, patients had to be followed for at least 1 year, and up to 5 years, post surgery and had to be considered appropriate candidates for a watch-and-wait approach.

Participants were randomly assigned to receive either 40 mg of vorasidenib or a matching placebo orally, once daily, in continuous 28-day cycles until imaging-confirmed tumor disease progression or unacceptable toxicity, at which point crossover to vorasidenib from placebo was permitted. Over one third (n = 58) of patients in the placebo group crossed over and 90% of them (n = 52) received vorasidenib.

Median progression-free survival was significantly better in the vorasidenib group at 27.7 months vs 11.1 months in the placebo group (hazard ratio [HR], 0.39).

A key secondary endpoint — time to next intervention — was also significant; the likelihood of being alive and not receiving further treatment at 18 months was 85.6% in the vorasidenib group and 47.4% in the placebo group (HR, 0.26). This finding indicates that most patients receiving vorasidenib could delay chemoradiation for 18 months or longer.

Despite these impressive outcomes, some experts noted that using progression-free survival as the primary endpoint was a major flaw of the INDIGO trial because, currently, there is no evidence that progression-free survival is a reliable surrogate endpoint for overall survival in this setting.

The high rate of crossover to vorasidenib is another issue because it may limit a longer-term analysis of overall survival. If, for instance, overall survival is the same between the groups, it could signal that the drug is effective in both groups or, alternatively, that the drug has no effect on survival in either group.

“That is a legitimate concern,” Seema Nagpal, MD, a neuro-oncologist at Stanford University in California, and a site principal investigator for the INDIGO trial, said in an interview. “We don’t know that this drug changes overall survival, and I think we’re not going to get a super clean answer on that.”

Another major issue centers on the standard of care assigned to control patients in the INDIGO trial.

In the trial, vorasidenib was compared with placebo — an appropriate standard-of-care comparison for patients with low-risk gliomas. These patients often initially undergo watch-and-wait to delay chemoradiation. But Lazarev and Sindhu argue that the patients in INDIGO were really high risk, which means the control group should have received the standard of care for these patients: Chemoradiation following surgery.

This question about the appropriate standard of care stems from ongoing uncertainty about the distinction between high- and low-risk gliomas.

The classification for gliomas falls into either low risk or high risk for early disease progression. The RTOG 9802 criteria, often used for glioma risk stratification, defines low-risk patients as those younger than 40 years with gross total resection and high-risk patients as those aged 40 years or older with any extent of resection or those younger than 40 years with subtotal or biopsy resection.

But an evolving understanding of genetic anomalies that affect prognoses in this tumor type has muddied the current high- and low-risk distinctions.

“People haven’t totally figured out what high and low risk means,” Nagpal acknowledged.

This uncertainty has spilled over into the INDIGO trial.

While the trial excluded patients who had any features indicating high risk, such as brain stem involvement or neurocognitive deficits, the researchers also did not explicitly define patients as low risk. However, the inclusion criteria specified that patients had to be observed for at least 1 year after surgery and be considered appropriate for a watch-and-wait protocol, which does suggest patients were considered low risk, said Nagpal.

Still, some experts argue that the patients in INDIGO were not low risk.

Patients had residual or recurrent disease so “wouldn’t be classified as low risk,” said Sindhu in an interview. The standard of care for these patients is chemoradiation, Lazarev added.

“The definition of a phase 3 clinical trial is that you compare the novel intervention to the standard of care,” said Lazarev. “Level 1 evidence clearly shows that omitting chemoradiation leads to worse outcomes, with patients literally dying sooner. For the investigators to knowingly exclude this proven treatment raises serious ethical and methodological questions about the study’s design.” 

In a recent opinion piece, Nagpal agreed that most patients selected for INDIGO would not have been considered low risk by many providers. All patients selected for INDIGO had postoperative residual/recurrent disease and many were older than 40 years.

But, Nagpal explained, the risk stratification of the INDIGO patients was still lower than what is commonly considered high risk. The patients had all been observed for a year or more already, “so by definition, the clinician treating them already decided they were not high risk,” she said.

In another recent opinion piece, oncologists suggested that, because patients in the INDIGO trial do not squarely fall into either category, instead representing a “grey area,” it’s time to create a new risk category.

“Perhaps the time has come to abandon the old binary risk stratification (“low risk” vs “high risk”), which still contains arbitrary elements (such as the age cutoff), proving impractical in real-world clinical decision-making, and to adopt a new one, also taking into account many emerging prognostic biomarkers,” the authors wrote.

Despite the uncertainty surrounding risk categories, the INDIGO authors justified their study design.

A watch-and-wait period for patients in the trial, which “represents the earliest clinical phase in tumorigenesis of IDH-mutant WHO grade 2 glioma,” is “an opportunity to detect a clear signal of antitumor activity for new therapies in placebo-controlled trials” and “postpone the use of radiation therapy and chemotherapy,” the authors explained.

Lazarev, however, questioned the premise that chemoradiation should be delayed.

Oncologists’ desire to delay chemoradiation for their patients reflects “a limited understanding of modern irradiation therapy,” Lazarev said. “Modern technology has improved dramatically. We’re more precise, our understanding about late side effects is better. So, the big picture is that the absolute risk of late neurocognitive affects that actually will affect patients’ quality of life, their ability to work, go to school, succeed on a personal or professional level is exceedingly low.”

Nagpal strongly disagreed.

“Please come to my clinic and ask an actual patient,” said Nagpal. “Once a radiation oncologist has irradiated the patient, they almost never seen them again. People who are on the medical side, who follow these patients from beginning to end, recognize that delaying radiation is a huge deal.”

Although vorasidenib isn’t a cure, Nagpal said, it is a less toxic way to delay radiation “because that is a real and disabling thing” for patients and is why neuro-oncologists are excited about alternative treatment options.

Another issue surrounding the vorasidenib approval lies in the FDA’s vague prescribing information. The prescribing information does not specify that patients should be followed for at least 1 year post surgery or that patients need to be lower risk. Prescribing physicians may, therefore, think vorasidenib is appropriate for any patient with a grade-2 IDH mutant glioma at any time and defer or not offer chemoradiation to high-risk patients.

Amid lingering questions about the INDIGO trial design and ongoing uncertainties about how to define and treat this patient population, experts remain divided on whether vorasidenib is worth it.

“If vorasidenib is truly transformative, it should be feasible to demonstrate its superiority over chemoradiotherapy,” Lazarev and Sindhu wrote. “For a drug with such a staggering price tag, an imperative should be placed on the investigators and manufacturer to provide clear evidence of efficacy, whether in terms of improved [overall survival] or quality of life, before vorasidenib is recommended for the treatment of IDH-mutant low-grade gliomas.”

The INDIGO trial was supported by Servier, the manufacturer of vorasidenib. Many of the study authors reported employment or support from the company. Nagpal reported consulting fees from Servier and AnHeart Therapeutics. Lazarev and Sindhu reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

The emergence of vorasidenib, the first targeted therapy for certain gliomas with IDH mutations, has ignited a wave of excitement in both patient and physician spaces.

After years with limited treatment options, experts hailed vorasidenib “a promising breakthrough,” “a paradigm shift,” a “new hope,” and “probably the most important advance in the treatment of low-grade gliomas in the last decade.”

Promising results from vorasidenib’s pivotal INDIGO trial fueled petitions and patient advocacy circles to push for the drug’s approval. And, in August 2024, the Food and Drug Administration (FDA) approved vorasidenib for grade 2 astrocytomas or oligodendrogliomas with an IDH1 or IDH2 mutation.

But following the approval, some experts expressed concerns and doubts about the drug and the INDIGO trial, bringing a host of unanswered questions into sharper focus.

In an editorial, Stanislav Lazarev, MD, and Kunal K. Sindhu, MD, both radiation oncologists from Icahn School of Medicine at Mount Sinai, New York City, suggest that the FDA approval “might be premature given the high cost of this drug and lack of clear benefit over standard treatments.”

Another recent critique also pointed to the lack of clear evidence that vorasidenib is superior to the prevailing standard of care, despite the drug’s high cost. These authors noted that “patients want to live longer, and if not, at least live better,” but “based on the INDIGO study, it is impossible to say whether vorasidenib can provide either.”

Vorasidenib is now one of the most expensive cancer therapies, with an annual cost of nearly $500,000, but the INDIGO trial did not explore whether the drug led to improved overall survival or better quality of life. Among the trial’s design flaws, experts called out the use of progression-free survival as the primary outcome, instead of overall survival, and the use of an inappropriate comparator group.

INDIGO was a phase 3 trial that included 331 adult patients (median age, 40.5 years) with grade-2 IDH-mutant recurrent or residual glioma after surgery. To be eligible, patients had to be followed for at least 1 year, and up to 5 years, post surgery and had to be considered appropriate candidates for a watch-and-wait approach.

Participants were randomly assigned to receive either 40 mg of vorasidenib or a matching placebo orally, once daily, in continuous 28-day cycles until imaging-confirmed tumor disease progression or unacceptable toxicity, at which point crossover to vorasidenib from placebo was permitted. Over one third (n = 58) of patients in the placebo group crossed over and 90% of them (n = 52) received vorasidenib.

Median progression-free survival was significantly better in the vorasidenib group at 27.7 months vs 11.1 months in the placebo group (hazard ratio [HR], 0.39).

A key secondary endpoint — time to next intervention — was also significant; the likelihood of being alive and not receiving further treatment at 18 months was 85.6% in the vorasidenib group and 47.4% in the placebo group (HR, 0.26). This finding indicates that most patients receiving vorasidenib could delay chemoradiation for 18 months or longer.

Despite these impressive outcomes, some experts noted that using progression-free survival as the primary endpoint was a major flaw of the INDIGO trial because, currently, there is no evidence that progression-free survival is a reliable surrogate endpoint for overall survival in this setting.

The high rate of crossover to vorasidenib is another issue because it may limit a longer-term analysis of overall survival. If, for instance, overall survival is the same between the groups, it could signal that the drug is effective in both groups or, alternatively, that the drug has no effect on survival in either group.

“That is a legitimate concern,” Seema Nagpal, MD, a neuro-oncologist at Stanford University in California, and a site principal investigator for the INDIGO trial, said in an interview. “We don’t know that this drug changes overall survival, and I think we’re not going to get a super clean answer on that.”

Another major issue centers on the standard of care assigned to control patients in the INDIGO trial.

In the trial, vorasidenib was compared with placebo — an appropriate standard-of-care comparison for patients with low-risk gliomas. These patients often initially undergo watch-and-wait to delay chemoradiation. But Lazarev and Sindhu argue that the patients in INDIGO were really high risk, which means the control group should have received the standard of care for these patients: Chemoradiation following surgery.

This question about the appropriate standard of care stems from ongoing uncertainty about the distinction between high- and low-risk gliomas.

The classification for gliomas falls into either low risk or high risk for early disease progression. The RTOG 9802 criteria, often used for glioma risk stratification, defines low-risk patients as those younger than 40 years with gross total resection and high-risk patients as those aged 40 years or older with any extent of resection or those younger than 40 years with subtotal or biopsy resection.

But an evolving understanding of genetic anomalies that affect prognoses in this tumor type has muddied the current high- and low-risk distinctions.

“People haven’t totally figured out what high and low risk means,” Nagpal acknowledged.

This uncertainty has spilled over into the INDIGO trial.

While the trial excluded patients who had any features indicating high risk, such as brain stem involvement or neurocognitive deficits, the researchers also did not explicitly define patients as low risk. However, the inclusion criteria specified that patients had to be observed for at least 1 year after surgery and be considered appropriate for a watch-and-wait protocol, which does suggest patients were considered low risk, said Nagpal.

Still, some experts argue that the patients in INDIGO were not low risk.

Patients had residual or recurrent disease so “wouldn’t be classified as low risk,” said Sindhu in an interview. The standard of care for these patients is chemoradiation, Lazarev added.

“The definition of a phase 3 clinical trial is that you compare the novel intervention to the standard of care,” said Lazarev. “Level 1 evidence clearly shows that omitting chemoradiation leads to worse outcomes, with patients literally dying sooner. For the investigators to knowingly exclude this proven treatment raises serious ethical and methodological questions about the study’s design.” 

In a recent opinion piece, Nagpal agreed that most patients selected for INDIGO would not have been considered low risk by many providers. All patients selected for INDIGO had postoperative residual/recurrent disease and many were older than 40 years.

But, Nagpal explained, the risk stratification of the INDIGO patients was still lower than what is commonly considered high risk. The patients had all been observed for a year or more already, “so by definition, the clinician treating them already decided they were not high risk,” she said.

In another recent opinion piece, oncologists suggested that, because patients in the INDIGO trial do not squarely fall into either category, instead representing a “grey area,” it’s time to create a new risk category.

“Perhaps the time has come to abandon the old binary risk stratification (“low risk” vs “high risk”), which still contains arbitrary elements (such as the age cutoff), proving impractical in real-world clinical decision-making, and to adopt a new one, also taking into account many emerging prognostic biomarkers,” the authors wrote.

Despite the uncertainty surrounding risk categories, the INDIGO authors justified their study design.

A watch-and-wait period for patients in the trial, which “represents the earliest clinical phase in tumorigenesis of IDH-mutant WHO grade 2 glioma,” is “an opportunity to detect a clear signal of antitumor activity for new therapies in placebo-controlled trials” and “postpone the use of radiation therapy and chemotherapy,” the authors explained.

Lazarev, however, questioned the premise that chemoradiation should be delayed.

Oncologists’ desire to delay chemoradiation for their patients reflects “a limited understanding of modern irradiation therapy,” Lazarev said. “Modern technology has improved dramatically. We’re more precise, our understanding about late side effects is better. So, the big picture is that the absolute risk of late neurocognitive affects that actually will affect patients’ quality of life, their ability to work, go to school, succeed on a personal or professional level is exceedingly low.”

Nagpal strongly disagreed.

“Please come to my clinic and ask an actual patient,” said Nagpal. “Once a radiation oncologist has irradiated the patient, they almost never seen them again. People who are on the medical side, who follow these patients from beginning to end, recognize that delaying radiation is a huge deal.”

Although vorasidenib isn’t a cure, Nagpal said, it is a less toxic way to delay radiation “because that is a real and disabling thing” for patients and is why neuro-oncologists are excited about alternative treatment options.

Another issue surrounding the vorasidenib approval lies in the FDA’s vague prescribing information. The prescribing information does not specify that patients should be followed for at least 1 year post surgery or that patients need to be lower risk. Prescribing physicians may, therefore, think vorasidenib is appropriate for any patient with a grade-2 IDH mutant glioma at any time and defer or not offer chemoradiation to high-risk patients.

Amid lingering questions about the INDIGO trial design and ongoing uncertainties about how to define and treat this patient population, experts remain divided on whether vorasidenib is worth it.

“If vorasidenib is truly transformative, it should be feasible to demonstrate its superiority over chemoradiotherapy,” Lazarev and Sindhu wrote. “For a drug with such a staggering price tag, an imperative should be placed on the investigators and manufacturer to provide clear evidence of efficacy, whether in terms of improved [overall survival] or quality of life, before vorasidenib is recommended for the treatment of IDH-mutant low-grade gliomas.”

The INDIGO trial was supported by Servier, the manufacturer of vorasidenib. Many of the study authors reported employment or support from the company. Nagpal reported consulting fees from Servier and AnHeart Therapeutics. Lazarev and Sindhu reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

US regulators’ use of a speedy clearance pathway for a new frontline indication for asciminib for chronic myeloid leukemia (CML) has raised questions due to the number of medications already available for this condition.

In October, the US Food and Drug Administration (FDA) granted accelerated approval to asciminib (Scemblix, Novartis AG) for adult patients with newly diagnosed Philadelphia chromosome–positive CML in chronic phase.

Asciminib is one of the six tyrosine kinase inhibitor (TKI) drugs used for CML, a class that began with the introduction of imatinib (Gleevec) in 2001. By 2016, researchers reported that TKIs had helped make life expectancy in patients with CML approach that of the general population. Physicians and patients now have several options of second-generation TKI drugs that also can be used in newly diagnosed patients, along with the option to begin with the more affordable option of imatinib.

The FDA in 1992 instituted the accelerated approval pathway to try to speed market drugs for serious conditions that fill unmet medical needs.

The agency and companies essentially make bets on promising study results, often using surrogate markers, to allow sales of medicines while waiting for evidence from confirmatory studies. For example, the FDA in August used the accelerated approval process to clear the first T-cell receptor gene therapy for certain advanced forms of sarcoma, a form of cancer with limited treatment options.

The next accelerated approval of a cancer drug was the indication for asciminib as a frontline therapy. The FDA also used accelerated approval for the initial clearance of asciminib in 2021 for use in CML previously treated with two or more TKIs. By 2022, Novartis presented sufficient evidence of the drug’s merit to win full approval for the drug in this use.

The timeline is longer for the expected confirmatory research for asciminib as a frontline therapy, with a 2028 deadline set for this work. The data presented to date on asciminib have not persuaded some oncologists on the need for the speedy approval of frontline use.

“This boils down to a drug that looks as if it’s just as good as other second-generation TKIs,” Mikkael A. Sekeres, MD, MS, chief of the Division of Hematology at the Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami. “I don’t know how they could use the accelerated approval mechanism to get this through.”

Sekeres, a former chair of the Oncologic Drugs Advisory Committee, explored concerns and challenges involved with the use of the accelerated approval process in his 2022 book, Drugs and the FDA: Safety, Efficacy, and the Public’s Trust.

“The intent of the accelerated approval mechanism is that you’re bringing a new therapy to treat a serious disease in a way that others haven’t previously, where there aren’t existing options,” Sekeres said.

This is a markedly different situation that exists for CML, where medicines have improved dramatically in the 21st century, unlike many other forms of cancer treated by hematologists.

“As someone who specializes in treating people with leukemia, I’d be happy every clinic day of my life if all of my patients came in with chronic phase, chronic myeloid leukemia,” instead of other cancers lacking these robust treatment options, he said.

With CML, physicians select among TKIs considering side effects and other health conditions patients have, including weighing the impact of financial toxicity in some cases, he said.

“If I have a patient with lower risk chronic phase, chronic myeloid leukemia, I’m treating them with imatinib,” Sekeres said.

 

Questions About Surrogate Endpoints

Sekeres is not alone in questioning the use of the speedier FDA pathway for a new indication for a TKI in CML.

“Where is the ‘unmet need’ justifying an accelerated approval in this setting?” Timothée Olivier, MD, who is affiliated with both the Hôpitaux universitaires de Genève and the VK Prasad Laboratory funded by Vinay Prasad, MD, MPH, wrote in a November 3 post on X.

Olivier, Prasad, and coauthors in a September correspondence to the American Journal of Hematology raised questions about the study design for a key asciminib study, ASC4FIRST. They noted what they consider a weakness with the endpoints used.

“Molecular milestones like the 48-week MMR [major molecular response] are often used in clinical trials due to their convenience and shorter timeline for assessment,” they wrote. “However, these milestones are not definitive indicators of long-term survival or overall clinical benefit.”

There has been rising concern in recent years about the evidence gap between initial accelerated approvals and the completion of studies that show whether these promising therapies actually help patients live longer or better. Researchers including Bishal Gyawali, MD, PhD, a Medscape Medical News contributor, also have questioned the degree of reliance on surrogate endpoints in accelerated approvals.

In response, the FDA’s Cancer Division and the US Congress have taken steps to try to force drugmakers to more quickly answer the key question in accelerated approvals: Does this medicine produce the expected benefits? For example, the FDA in March appears to have turned down a bid for accelerated approval of a lymphoma drug due to concerns about the timing of completion of confirmatory research.

The use of accelerated approval will continue to be a balancing act, due in part to demand for newer agents, Ravi Bhatia, MD, of the O’Neal Comprehensive Cancer Center at The University of Alabama at Birmingham, told this news organization.

“Accelerated approval of agents for up-front treatment of CML does not appear well justified, given the high degree of efficacy of existing agents,” said Bhatia, vice chair of the National Comprehensive Cancer Network’s Clinical Practice Guidelines in Oncology Panel for Chronic Myeloid Leukemia.

“On the other hand, there is greater urgency for developing agents for patients who have failed existing agents and patients with advanced phase disease, and the use of accelerated approval may be justified in this setting,” Bhatia said.

In an interview with this news organization, Richard A. Larson, MD, a professor in the Department of Hematology/Oncology at The University of Chicago, who is an ASC4FIRST investigator, noted the 96-week follow-up data from the trial will be presented at the annual meeting of the American Society of Hematology in December in San Diego.

Larson said data from this trial will show continued benefit with the frontline use of asciminib. Larson also is an author of a New England Journal of Medicine article in May about the ASC4FIRST trial.

“The data speak for themselves, that asciminib is at least as effective or more so and at least as well tolerated as what’s already on the market,” Larson said. “So their argument, at the end of the day, really boils down to the cost of a new drug and whether we need a new drug.”

From the point of view of patients with cancer, the answer to that is clear, he said.

“If you talk to cancer patients, they’d like to see new drugs become available as quickly as possible. And I think that was the original rationale for the accelerated approval pathway, that a drug that has been shown to be safe and effective in a prospective clinical trial could get accelerated approval based on a surrogate endpoint.”

The remarkable success seen in developing TKI drugs for CML creates difficulties in testing later entrants in this class due to their prolonged survival, Larson said.

“If you look on a population basis, the overall survival of newly diagnosed CML patients with all of these therapeutic options available to them now approximate that of the non-CML population.”

“For most anticancer drugs, the FDA would like to see an overall survival benefit, but patients with newly diagnosed CML are surviving 20 or 30 years, and they’re not dying at an accelerated rate the way they were. So it’d be impractical to require a clinical trial to show a survival benefit, a randomized trial.”

“That’s where the use of a surrogate endpoint, which is the major molecular response at 1 year, has been so valuable, gets the drugs approved, gets them into patients far earlier than if there was a survival end point requirement,” he said.

Larson reported ties with AbbVie, Amgen, Astellas, Celgene, Cellectis, Curis, CVS Caremark, Daiichi Sankyo, ImmunoGen, Jazz, MorphoSys, Rigel, Servier, Forty Seven/Gilead, Novartis, and Rafael Pharmaceuticals. Sekeres disclosed relationships with BMS, Kurome, and Novartis Advisory Boards. Bhatia reported no relevant disclosures.

 

A version of this article appeared on Medscape.com.

US regulators’ use of a speedy clearance pathway for a new frontline indication for asciminib for chronic myeloid leukemia (CML) has raised questions due to the number of medications already available for this condition.

In October, the US Food and Drug Administration (FDA) granted accelerated approval to asciminib (Scemblix, Novartis AG) for adult patients with newly diagnosed Philadelphia chromosome–positive CML in chronic phase.

Asciminib is one of the six tyrosine kinase inhibitor (TKI) drugs used for CML, a class that began with the introduction of imatinib (Gleevec) in 2001. By 2016, researchers reported that TKIs had helped make life expectancy in patients with CML approach that of the general population. Physicians and patients now have several options of second-generation TKI drugs that also can be used in newly diagnosed patients, along with the option to begin with the more affordable option of imatinib.

The FDA in 1992 instituted the accelerated approval pathway to try to speed market drugs for serious conditions that fill unmet medical needs.

The agency and companies essentially make bets on promising study results, often using surrogate markers, to allow sales of medicines while waiting for evidence from confirmatory studies. For example, the FDA in August used the accelerated approval process to clear the first T-cell receptor gene therapy for certain advanced forms of sarcoma, a form of cancer with limited treatment options.

The next accelerated approval of a cancer drug was the indication for asciminib as a frontline therapy. The FDA also used accelerated approval for the initial clearance of asciminib in 2021 for use in CML previously treated with two or more TKIs. By 2022, Novartis presented sufficient evidence of the drug’s merit to win full approval for the drug in this use.

The timeline is longer for the expected confirmatory research for asciminib as a frontline therapy, with a 2028 deadline set for this work. The data presented to date on asciminib have not persuaded some oncologists on the need for the speedy approval of frontline use.

“This boils down to a drug that looks as if it’s just as good as other second-generation TKIs,” Mikkael A. Sekeres, MD, MS, chief of the Division of Hematology at the Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami. “I don’t know how they could use the accelerated approval mechanism to get this through.”

Sekeres, a former chair of the Oncologic Drugs Advisory Committee, explored concerns and challenges involved with the use of the accelerated approval process in his 2022 book, Drugs and the FDA: Safety, Efficacy, and the Public’s Trust.

“The intent of the accelerated approval mechanism is that you’re bringing a new therapy to treat a serious disease in a way that others haven’t previously, where there aren’t existing options,” Sekeres said.

This is a markedly different situation that exists for CML, where medicines have improved dramatically in the 21st century, unlike many other forms of cancer treated by hematologists.

“As someone who specializes in treating people with leukemia, I’d be happy every clinic day of my life if all of my patients came in with chronic phase, chronic myeloid leukemia,” instead of other cancers lacking these robust treatment options, he said.

With CML, physicians select among TKIs considering side effects and other health conditions patients have, including weighing the impact of financial toxicity in some cases, he said.

“If I have a patient with lower risk chronic phase, chronic myeloid leukemia, I’m treating them with imatinib,” Sekeres said.

 

Questions About Surrogate Endpoints

Sekeres is not alone in questioning the use of the speedier FDA pathway for a new indication for a TKI in CML.

“Where is the ‘unmet need’ justifying an accelerated approval in this setting?” Timothée Olivier, MD, who is affiliated with both the Hôpitaux universitaires de Genève and the VK Prasad Laboratory funded by Vinay Prasad, MD, MPH, wrote in a November 3 post on X.

Olivier, Prasad, and coauthors in a September correspondence to the American Journal of Hematology raised questions about the study design for a key asciminib study, ASC4FIRST. They noted what they consider a weakness with the endpoints used.

“Molecular milestones like the 48-week MMR [major molecular response] are often used in clinical trials due to their convenience and shorter timeline for assessment,” they wrote. “However, these milestones are not definitive indicators of long-term survival or overall clinical benefit.”

There has been rising concern in recent years about the evidence gap between initial accelerated approvals and the completion of studies that show whether these promising therapies actually help patients live longer or better. Researchers including Bishal Gyawali, MD, PhD, a Medscape Medical News contributor, also have questioned the degree of reliance on surrogate endpoints in accelerated approvals.

In response, the FDA’s Cancer Division and the US Congress have taken steps to try to force drugmakers to more quickly answer the key question in accelerated approvals: Does this medicine produce the expected benefits? For example, the FDA in March appears to have turned down a bid for accelerated approval of a lymphoma drug due to concerns about the timing of completion of confirmatory research.

The use of accelerated approval will continue to be a balancing act, due in part to demand for newer agents, Ravi Bhatia, MD, of the O’Neal Comprehensive Cancer Center at The University of Alabama at Birmingham, told this news organization.

“Accelerated approval of agents for up-front treatment of CML does not appear well justified, given the high degree of efficacy of existing agents,” said Bhatia, vice chair of the National Comprehensive Cancer Network’s Clinical Practice Guidelines in Oncology Panel for Chronic Myeloid Leukemia.

“On the other hand, there is greater urgency for developing agents for patients who have failed existing agents and patients with advanced phase disease, and the use of accelerated approval may be justified in this setting,” Bhatia said.

In an interview with this news organization, Richard A. Larson, MD, a professor in the Department of Hematology/Oncology at The University of Chicago, who is an ASC4FIRST investigator, noted the 96-week follow-up data from the trial will be presented at the annual meeting of the American Society of Hematology in December in San Diego.

Larson said data from this trial will show continued benefit with the frontline use of asciminib. Larson also is an author of a New England Journal of Medicine article in May about the ASC4FIRST trial.

“The data speak for themselves, that asciminib is at least as effective or more so and at least as well tolerated as what’s already on the market,” Larson said. “So their argument, at the end of the day, really boils down to the cost of a new drug and whether we need a new drug.”

From the point of view of patients with cancer, the answer to that is clear, he said.

“If you talk to cancer patients, they’d like to see new drugs become available as quickly as possible. And I think that was the original rationale for the accelerated approval pathway, that a drug that has been shown to be safe and effective in a prospective clinical trial could get accelerated approval based on a surrogate endpoint.”

The remarkable success seen in developing TKI drugs for CML creates difficulties in testing later entrants in this class due to their prolonged survival, Larson said.

“If you look on a population basis, the overall survival of newly diagnosed CML patients with all of these therapeutic options available to them now approximate that of the non-CML population.”

“For most anticancer drugs, the FDA would like to see an overall survival benefit, but patients with newly diagnosed CML are surviving 20 or 30 years, and they’re not dying at an accelerated rate the way they were. So it’d be impractical to require a clinical trial to show a survival benefit, a randomized trial.”

“That’s where the use of a surrogate endpoint, which is the major molecular response at 1 year, has been so valuable, gets the drugs approved, gets them into patients far earlier than if there was a survival end point requirement,” he said.

Larson reported ties with AbbVie, Amgen, Astellas, Celgene, Cellectis, Curis, CVS Caremark, Daiichi Sankyo, ImmunoGen, Jazz, MorphoSys, Rigel, Servier, Forty Seven/Gilead, Novartis, and Rafael Pharmaceuticals. Sekeres disclosed relationships with BMS, Kurome, and Novartis Advisory Boards. Bhatia reported no relevant disclosures.

 

A version of this article appeared on Medscape.com.

US regulators’ use of a speedy clearance pathway for a new frontline indication for asciminib for chronic myeloid leukemia (CML) has raised questions due to the number of medications already available for this condition.

In October, the US Food and Drug Administration (FDA) granted accelerated approval to asciminib (Scemblix, Novartis AG) for adult patients with newly diagnosed Philadelphia chromosome–positive CML in chronic phase.

Asciminib is one of the six tyrosine kinase inhibitor (TKI) drugs used for CML, a class that began with the introduction of imatinib (Gleevec) in 2001. By 2016, researchers reported that TKIs had helped make life expectancy in patients with CML approach that of the general population. Physicians and patients now have several options of second-generation TKI drugs that also can be used in newly diagnosed patients, along with the option to begin with the more affordable option of imatinib.

The FDA in 1992 instituted the accelerated approval pathway to try to speed market drugs for serious conditions that fill unmet medical needs.

The agency and companies essentially make bets on promising study results, often using surrogate markers, to allow sales of medicines while waiting for evidence from confirmatory studies. For example, the FDA in August used the accelerated approval process to clear the first T-cell receptor gene therapy for certain advanced forms of sarcoma, a form of cancer with limited treatment options.

The next accelerated approval of a cancer drug was the indication for asciminib as a frontline therapy. The FDA also used accelerated approval for the initial clearance of asciminib in 2021 for use in CML previously treated with two or more TKIs. By 2022, Novartis presented sufficient evidence of the drug’s merit to win full approval for the drug in this use.

The timeline is longer for the expected confirmatory research for asciminib as a frontline therapy, with a 2028 deadline set for this work. The data presented to date on asciminib have not persuaded some oncologists on the need for the speedy approval of frontline use.

“This boils down to a drug that looks as if it’s just as good as other second-generation TKIs,” Mikkael A. Sekeres, MD, MS, chief of the Division of Hematology at the Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami. “I don’t know how they could use the accelerated approval mechanism to get this through.”

Sekeres, a former chair of the Oncologic Drugs Advisory Committee, explored concerns and challenges involved with the use of the accelerated approval process in his 2022 book, Drugs and the FDA: Safety, Efficacy, and the Public’s Trust.

“The intent of the accelerated approval mechanism is that you’re bringing a new therapy to treat a serious disease in a way that others haven’t previously, where there aren’t existing options,” Sekeres said.

This is a markedly different situation that exists for CML, where medicines have improved dramatically in the 21st century, unlike many other forms of cancer treated by hematologists.

“As someone who specializes in treating people with leukemia, I’d be happy every clinic day of my life if all of my patients came in with chronic phase, chronic myeloid leukemia,” instead of other cancers lacking these robust treatment options, he said.

With CML, physicians select among TKIs considering side effects and other health conditions patients have, including weighing the impact of financial toxicity in some cases, he said.

“If I have a patient with lower risk chronic phase, chronic myeloid leukemia, I’m treating them with imatinib,” Sekeres said.

 

Questions About Surrogate Endpoints

Sekeres is not alone in questioning the use of the speedier FDA pathway for a new indication for a TKI in CML.

“Where is the ‘unmet need’ justifying an accelerated approval in this setting?” Timothée Olivier, MD, who is affiliated with both the Hôpitaux universitaires de Genève and the VK Prasad Laboratory funded by Vinay Prasad, MD, MPH, wrote in a November 3 post on X.

Olivier, Prasad, and coauthors in a September correspondence to the American Journal of Hematology raised questions about the study design for a key asciminib study, ASC4FIRST. They noted what they consider a weakness with the endpoints used.

“Molecular milestones like the 48-week MMR [major molecular response] are often used in clinical trials due to their convenience and shorter timeline for assessment,” they wrote. “However, these milestones are not definitive indicators of long-term survival or overall clinical benefit.”

There has been rising concern in recent years about the evidence gap between initial accelerated approvals and the completion of studies that show whether these promising therapies actually help patients live longer or better. Researchers including Bishal Gyawali, MD, PhD, a Medscape Medical News contributor, also have questioned the degree of reliance on surrogate endpoints in accelerated approvals.

In response, the FDA’s Cancer Division and the US Congress have taken steps to try to force drugmakers to more quickly answer the key question in accelerated approvals: Does this medicine produce the expected benefits? For example, the FDA in March appears to have turned down a bid for accelerated approval of a lymphoma drug due to concerns about the timing of completion of confirmatory research.

The use of accelerated approval will continue to be a balancing act, due in part to demand for newer agents, Ravi Bhatia, MD, of the O’Neal Comprehensive Cancer Center at The University of Alabama at Birmingham, told this news organization.

“Accelerated approval of agents for up-front treatment of CML does not appear well justified, given the high degree of efficacy of existing agents,” said Bhatia, vice chair of the National Comprehensive Cancer Network’s Clinical Practice Guidelines in Oncology Panel for Chronic Myeloid Leukemia.

“On the other hand, there is greater urgency for developing agents for patients who have failed existing agents and patients with advanced phase disease, and the use of accelerated approval may be justified in this setting,” Bhatia said.

In an interview with this news organization, Richard A. Larson, MD, a professor in the Department of Hematology/Oncology at The University of Chicago, who is an ASC4FIRST investigator, noted the 96-week follow-up data from the trial will be presented at the annual meeting of the American Society of Hematology in December in San Diego.

Larson said data from this trial will show continued benefit with the frontline use of asciminib. Larson also is an author of a New England Journal of Medicine article in May about the ASC4FIRST trial.

“The data speak for themselves, that asciminib is at least as effective or more so and at least as well tolerated as what’s already on the market,” Larson said. “So their argument, at the end of the day, really boils down to the cost of a new drug and whether we need a new drug.”

From the point of view of patients with cancer, the answer to that is clear, he said.

“If you talk to cancer patients, they’d like to see new drugs become available as quickly as possible. And I think that was the original rationale for the accelerated approval pathway, that a drug that has been shown to be safe and effective in a prospective clinical trial could get accelerated approval based on a surrogate endpoint.”

The remarkable success seen in developing TKI drugs for CML creates difficulties in testing later entrants in this class due to their prolonged survival, Larson said.

“If you look on a population basis, the overall survival of newly diagnosed CML patients with all of these therapeutic options available to them now approximate that of the non-CML population.”

“For most anticancer drugs, the FDA would like to see an overall survival benefit, but patients with newly diagnosed CML are surviving 20 or 30 years, and they’re not dying at an accelerated rate the way they were. So it’d be impractical to require a clinical trial to show a survival benefit, a randomized trial.”

“That’s where the use of a surrogate endpoint, which is the major molecular response at 1 year, has been so valuable, gets the drugs approved, gets them into patients far earlier than if there was a survival end point requirement,” he said.

Larson reported ties with AbbVie, Amgen, Astellas, Celgene, Cellectis, Curis, CVS Caremark, Daiichi Sankyo, ImmunoGen, Jazz, MorphoSys, Rigel, Servier, Forty Seven/Gilead, Novartis, and Rafael Pharmaceuticals. Sekeres disclosed relationships with BMS, Kurome, and Novartis Advisory Boards. Bhatia reported no relevant disclosures.

 

A version of this article appeared on Medscape.com.