User login
The Evidence Gap: Immunotherapy Timing in Early-Stage NSCLC?
Since October 2023, the US Food and Drug Administration (FDA) has approved three checkpoint inhibitors — pembrolizumab (Keytruda), durvalumab (Imfinzi), and most recently nivolumab (Opdivo) — alongside platinum-containing chemotherapy before surgery and as monotherapy after surgery to treat resectable NSCLC.
But the trials leading to each approval had a major design flaw. The studies failed to distinguish when patients with resectable NSCLC benefited from immunotherapy — before surgery, after surgery, or at both points.
That missing piece has left oncologists without definitive guidance on how best to treat their patients with resectable disease.
Jamie E. Chaft, MD, a thoracic medical oncologist and attending physician at Memorial Sloan Kettering Cancer Center in New York City, was “surprised” that the FDA had approved the three immunotherapy combination regimens without this clarity. Clinicians are now left with studies that can’t evaluate the contribution of the neoadjuvant and adjuvant phases, she said.
But that may soon change.
In July, an FDA advisory committee met to discuss the pending approval of durvalumab.
During this July meeting, the FDA’s Oncologic Drugs Advisory Committee (ODAC) called out issues with AstraZeneca’s design of the trial, expressing concern that AstraZeneca had not followed the agency’s advice to compare patient outcomes with durvalumab in the neoadjuvant and adjuvant phases.
The ODAC panel ultimately voted unanimously in favor of requiring drug companies to demonstrate that patients need immunotherapy both before and after surgery in resectable NSCLC. Several panelists said this requirement should extend beyond NSCLC to other tumor types.
“We need to understand who needs what therapy when,” Daniel Spratt, MD, chairman of the FDA’s ODAC, told Medscape Medical News.
But even if the FDA does require drug companies to assess the benefit of immunotherapy pre- and post-surgery, will oncologists get the answers they need for their patients with resectable NSCLC? Or will the new costly trial design requirements dead-end progress in this space?
Treating Patients Without Clear Evidence
Despite the ODAC’s strong urging to require — not simply request — that drug companies show patients with resectable NSCLC benefit from immunotherapy in both the neoadjuvant and adjuvant settings, the advisory panel did not think durvalumab’s approval should be delayed until the neoadjuvant vs adjuvant question is answered.
A month later, in August, the FDA approved durvalumab for this indication.
Pembrolizumab (Keytruda, Merck) had already been approved 10 months earlier in the neoadjuvant and adjuvant settings in this setting. And most recently, in October, the FDA added nivolumab (Opdivo, Bristol Myers Squibb) to these approvals.
No trial, however, identified when patients benefited from the drug.
Without this understanding, patients may be taking immunotherapy unnecessarily, at significant expense and toxicity risk.
“Toxicities from immunotherapy can occur at any time after initiation,” said Joshua Eric Reuss, MD, a thoracic medical oncologist at Georgetown University’s Lombardi Comprehensive Cancer Center in Washington, DC. And these “risks definitely continue into the adjuvant period.”
So far, the available evidence does suggest that the neoadjuvant phase of immunotherapy confers the greatest benefit, while adjuvant immunotherapy — which can last a year or longer — may expose patients to more costs and toxicities, with no clear benefit.
A 2024 meta-analysis, which included four trials of neoadjuvant-adjuvant immunotherapy and one trial of neoadjuvant immunotherapy in resectable NSCLC, suggested that the addition of adjuvant immunotherapy did not improve event-free survival (hazard ratio [HR], 0.90; P = .59) or overall survival (HR, 1.18; P = .51) compared with neoadjuvant immunotherapy alone.
According to Spratt, “It’s very clear that the neoadjuvant phase is the more important of the two phases.” Given that, “we’re probably overtreating some patients,” said Spratt, also chairman of Radiation Oncology at University Hospitals Seidman Cancer Center and Case Western Reserve University in Cleveland.
Chaft agreed that “there’s very little data that we need the postoperative phase, and what data we do have is post hoc and limited.”
This evidence gap “has created considerable dilemmas” for oncologists and patients who are faced with “the challenge of deciding which therapeutic options or approach are best suited for each individual,” experts wrote in recent consensus recommendations from the International Association for the Study of Lung Cancer.
Clinicians may ultimately be left to make decisions about prescribing postoperative immunotherapy based on their experience and comfort level.
When Chaft’s patients have a pathologic complete response with immunotherapy and chemotherapy in the neoadjuvant phase, “I’m comfortable stopping because the data would suggest they’re almost certainly cured,” she said.
For patients who have viable disease after neoadjuvant therapy, continuing an immunotherapy postoperatively when it didn’t work preoperatively “is not going to make a difference,” Chaft explained. In these cases, Chaft would look to enroll them in a clinical trial evaluating a different regimen because of the risk for relapse.
With patients who did well preoperatively but still have tumor left at the time of surgery, she would discuss continuing the immunotherapy or participating in a trial, she said.
All the FDA-approved regimens are covered by insurance, said Chaft. Clinicians are most comfortable with pembrolizumab because it is the most widely used immunotherapy in advanced NSCLC, she said. But, she added, “there’s really no strong differentiating data between any of the studies; all the results look very comparable.”
When assessing whether a patient may benefit from immunotherapy after surgery, Reuss looks at a range of factors, including disease stage, histology, gene mutations, and pathologic response. Reuss also weighs patient preferences. A patient coming from another country might only want a neoadjuvant regimen, for instance, he said.
That “isn’t exactly the kind of the level one evidence that one likes to see when making treatment decisions,” said Reuss. “Without prospective data, all we can do is cross-trial comparisons and assessment of subgroups.”
If a new regimen comes along that improves outcomes or decision-making, “I think we would pivot to that in a heartbeat,” he said.
But Will FDA Follow ODAC’s Recommendation?
“ODAC has made their point clear,” said Chaft. “Our patients deserve to know that whatever added risk and cost they’re incurring is merited by a clinical outcome.”
Despite the ODAC’s recommendation, it’s not guaranteed that the FDA will follow it.
An FDA spokesperson did not confirm the agency’s decision on the matter but noted that the FDA is “incorporating the panel’s advice.”
Spratt thinks that, going forward, companies will be held to “a higher bar,” but it’s unclear what that bar will look like.
“Whether this is a mandate or a strong recommendation, I think industry is definitely paying attention,” Spratt said. Companies that do not follow the guidance may risk not having their drug approved, “unless it’s just an absolute huge slam dunk of a major benefit to patients.”
In fact, according to Chaft, drug makers seeking approvals of novel entities in this space “won’t have a choice” but to follow any new trial design requirements from the FDA.
Still, getting answers may be a challenge.
Drug companies with immunotherapies already on the market are unlikely to invest the resources to conduct trials comparing the neoadjuvant and adjuvant settings, said Chaft. “It will take too long and cost too much,” she said.
And it remains unclear whether drug companies will decide to stop pursuing novel agents if approvals will ultimately require more expensive and time-consuming trials.
According to Chaft, oncologists have been discussing protocols that could help fill the knowledge gaps. Such trials will be conducted by the National Cancer Institute’s Cooperative Groups, she noted. But it’s early days.
For the time being, with comparative data from phase 3 trials years away, oncologists will have to work with the limited evidence and individual patients in front of them.
Chaft disclosed ties with AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Genentech/Roche, Guardant Health, Janssen Pharmaceuticals, Eli Lilly, and Merck. Reuss disclosed ties with AstraZeneca, Arcus, AbbVie, Bristol Myers Squibb, CatalYm, Daiichi Sankyo, and Eli Lilly, and that Georgetown has received research funding from Genentech/Roche, Verastem, Nuvalent, LUNGevity Foundation, Exelixis, Arcus, and Revolution Medicines. Spratt disclosed ties with Astellas, AstraZeneca, Bayer, Boston Scientific, Janssen Pharmaceuticals, Novartis, and Pfizer.
A version of this article appeared on Medscape.com.
Since October 2023, the US Food and Drug Administration (FDA) has approved three checkpoint inhibitors — pembrolizumab (Keytruda), durvalumab (Imfinzi), and most recently nivolumab (Opdivo) — alongside platinum-containing chemotherapy before surgery and as monotherapy after surgery to treat resectable NSCLC.
But the trials leading to each approval had a major design flaw. The studies failed to distinguish when patients with resectable NSCLC benefited from immunotherapy — before surgery, after surgery, or at both points.
That missing piece has left oncologists without definitive guidance on how best to treat their patients with resectable disease.
Jamie E. Chaft, MD, a thoracic medical oncologist and attending physician at Memorial Sloan Kettering Cancer Center in New York City, was “surprised” that the FDA had approved the three immunotherapy combination regimens without this clarity. Clinicians are now left with studies that can’t evaluate the contribution of the neoadjuvant and adjuvant phases, she said.
But that may soon change.
In July, an FDA advisory committee met to discuss the pending approval of durvalumab.
During this July meeting, the FDA’s Oncologic Drugs Advisory Committee (ODAC) called out issues with AstraZeneca’s design of the trial, expressing concern that AstraZeneca had not followed the agency’s advice to compare patient outcomes with durvalumab in the neoadjuvant and adjuvant phases.
The ODAC panel ultimately voted unanimously in favor of requiring drug companies to demonstrate that patients need immunotherapy both before and after surgery in resectable NSCLC. Several panelists said this requirement should extend beyond NSCLC to other tumor types.
“We need to understand who needs what therapy when,” Daniel Spratt, MD, chairman of the FDA’s ODAC, told Medscape Medical News.
But even if the FDA does require drug companies to assess the benefit of immunotherapy pre- and post-surgery, will oncologists get the answers they need for their patients with resectable NSCLC? Or will the new costly trial design requirements dead-end progress in this space?
Treating Patients Without Clear Evidence
Despite the ODAC’s strong urging to require — not simply request — that drug companies show patients with resectable NSCLC benefit from immunotherapy in both the neoadjuvant and adjuvant settings, the advisory panel did not think durvalumab’s approval should be delayed until the neoadjuvant vs adjuvant question is answered.
A month later, in August, the FDA approved durvalumab for this indication.
Pembrolizumab (Keytruda, Merck) had already been approved 10 months earlier in the neoadjuvant and adjuvant settings in this setting. And most recently, in October, the FDA added nivolumab (Opdivo, Bristol Myers Squibb) to these approvals.
No trial, however, identified when patients benefited from the drug.
Without this understanding, patients may be taking immunotherapy unnecessarily, at significant expense and toxicity risk.
“Toxicities from immunotherapy can occur at any time after initiation,” said Joshua Eric Reuss, MD, a thoracic medical oncologist at Georgetown University’s Lombardi Comprehensive Cancer Center in Washington, DC. And these “risks definitely continue into the adjuvant period.”
So far, the available evidence does suggest that the neoadjuvant phase of immunotherapy confers the greatest benefit, while adjuvant immunotherapy — which can last a year or longer — may expose patients to more costs and toxicities, with no clear benefit.
A 2024 meta-analysis, which included four trials of neoadjuvant-adjuvant immunotherapy and one trial of neoadjuvant immunotherapy in resectable NSCLC, suggested that the addition of adjuvant immunotherapy did not improve event-free survival (hazard ratio [HR], 0.90; P = .59) or overall survival (HR, 1.18; P = .51) compared with neoadjuvant immunotherapy alone.
According to Spratt, “It’s very clear that the neoadjuvant phase is the more important of the two phases.” Given that, “we’re probably overtreating some patients,” said Spratt, also chairman of Radiation Oncology at University Hospitals Seidman Cancer Center and Case Western Reserve University in Cleveland.
Chaft agreed that “there’s very little data that we need the postoperative phase, and what data we do have is post hoc and limited.”
This evidence gap “has created considerable dilemmas” for oncologists and patients who are faced with “the challenge of deciding which therapeutic options or approach are best suited for each individual,” experts wrote in recent consensus recommendations from the International Association for the Study of Lung Cancer.
Clinicians may ultimately be left to make decisions about prescribing postoperative immunotherapy based on their experience and comfort level.
When Chaft’s patients have a pathologic complete response with immunotherapy and chemotherapy in the neoadjuvant phase, “I’m comfortable stopping because the data would suggest they’re almost certainly cured,” she said.
For patients who have viable disease after neoadjuvant therapy, continuing an immunotherapy postoperatively when it didn’t work preoperatively “is not going to make a difference,” Chaft explained. In these cases, Chaft would look to enroll them in a clinical trial evaluating a different regimen because of the risk for relapse.
With patients who did well preoperatively but still have tumor left at the time of surgery, she would discuss continuing the immunotherapy or participating in a trial, she said.
All the FDA-approved regimens are covered by insurance, said Chaft. Clinicians are most comfortable with pembrolizumab because it is the most widely used immunotherapy in advanced NSCLC, she said. But, she added, “there’s really no strong differentiating data between any of the studies; all the results look very comparable.”
When assessing whether a patient may benefit from immunotherapy after surgery, Reuss looks at a range of factors, including disease stage, histology, gene mutations, and pathologic response. Reuss also weighs patient preferences. A patient coming from another country might only want a neoadjuvant regimen, for instance, he said.
That “isn’t exactly the kind of the level one evidence that one likes to see when making treatment decisions,” said Reuss. “Without prospective data, all we can do is cross-trial comparisons and assessment of subgroups.”
If a new regimen comes along that improves outcomes or decision-making, “I think we would pivot to that in a heartbeat,” he said.
But Will FDA Follow ODAC’s Recommendation?
“ODAC has made their point clear,” said Chaft. “Our patients deserve to know that whatever added risk and cost they’re incurring is merited by a clinical outcome.”
Despite the ODAC’s recommendation, it’s not guaranteed that the FDA will follow it.
An FDA spokesperson did not confirm the agency’s decision on the matter but noted that the FDA is “incorporating the panel’s advice.”
Spratt thinks that, going forward, companies will be held to “a higher bar,” but it’s unclear what that bar will look like.
“Whether this is a mandate or a strong recommendation, I think industry is definitely paying attention,” Spratt said. Companies that do not follow the guidance may risk not having their drug approved, “unless it’s just an absolute huge slam dunk of a major benefit to patients.”
In fact, according to Chaft, drug makers seeking approvals of novel entities in this space “won’t have a choice” but to follow any new trial design requirements from the FDA.
Still, getting answers may be a challenge.
Drug companies with immunotherapies already on the market are unlikely to invest the resources to conduct trials comparing the neoadjuvant and adjuvant settings, said Chaft. “It will take too long and cost too much,” she said.
And it remains unclear whether drug companies will decide to stop pursuing novel agents if approvals will ultimately require more expensive and time-consuming trials.
According to Chaft, oncologists have been discussing protocols that could help fill the knowledge gaps. Such trials will be conducted by the National Cancer Institute’s Cooperative Groups, she noted. But it’s early days.
For the time being, with comparative data from phase 3 trials years away, oncologists will have to work with the limited evidence and individual patients in front of them.
Chaft disclosed ties with AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Genentech/Roche, Guardant Health, Janssen Pharmaceuticals, Eli Lilly, and Merck. Reuss disclosed ties with AstraZeneca, Arcus, AbbVie, Bristol Myers Squibb, CatalYm, Daiichi Sankyo, and Eli Lilly, and that Georgetown has received research funding from Genentech/Roche, Verastem, Nuvalent, LUNGevity Foundation, Exelixis, Arcus, and Revolution Medicines. Spratt disclosed ties with Astellas, AstraZeneca, Bayer, Boston Scientific, Janssen Pharmaceuticals, Novartis, and Pfizer.
A version of this article appeared on Medscape.com.
Since October 2023, the US Food and Drug Administration (FDA) has approved three checkpoint inhibitors — pembrolizumab (Keytruda), durvalumab (Imfinzi), and most recently nivolumab (Opdivo) — alongside platinum-containing chemotherapy before surgery and as monotherapy after surgery to treat resectable NSCLC.
But the trials leading to each approval had a major design flaw. The studies failed to distinguish when patients with resectable NSCLC benefited from immunotherapy — before surgery, after surgery, or at both points.
That missing piece has left oncologists without definitive guidance on how best to treat their patients with resectable disease.
Jamie E. Chaft, MD, a thoracic medical oncologist and attending physician at Memorial Sloan Kettering Cancer Center in New York City, was “surprised” that the FDA had approved the three immunotherapy combination regimens without this clarity. Clinicians are now left with studies that can’t evaluate the contribution of the neoadjuvant and adjuvant phases, she said.
But that may soon change.
In July, an FDA advisory committee met to discuss the pending approval of durvalumab.
During this July meeting, the FDA’s Oncologic Drugs Advisory Committee (ODAC) called out issues with AstraZeneca’s design of the trial, expressing concern that AstraZeneca had not followed the agency’s advice to compare patient outcomes with durvalumab in the neoadjuvant and adjuvant phases.
The ODAC panel ultimately voted unanimously in favor of requiring drug companies to demonstrate that patients need immunotherapy both before and after surgery in resectable NSCLC. Several panelists said this requirement should extend beyond NSCLC to other tumor types.
“We need to understand who needs what therapy when,” Daniel Spratt, MD, chairman of the FDA’s ODAC, told Medscape Medical News.
But even if the FDA does require drug companies to assess the benefit of immunotherapy pre- and post-surgery, will oncologists get the answers they need for their patients with resectable NSCLC? Or will the new costly trial design requirements dead-end progress in this space?
Treating Patients Without Clear Evidence
Despite the ODAC’s strong urging to require — not simply request — that drug companies show patients with resectable NSCLC benefit from immunotherapy in both the neoadjuvant and adjuvant settings, the advisory panel did not think durvalumab’s approval should be delayed until the neoadjuvant vs adjuvant question is answered.
A month later, in August, the FDA approved durvalumab for this indication.
Pembrolizumab (Keytruda, Merck) had already been approved 10 months earlier in the neoadjuvant and adjuvant settings in this setting. And most recently, in October, the FDA added nivolumab (Opdivo, Bristol Myers Squibb) to these approvals.
No trial, however, identified when patients benefited from the drug.
Without this understanding, patients may be taking immunotherapy unnecessarily, at significant expense and toxicity risk.
“Toxicities from immunotherapy can occur at any time after initiation,” said Joshua Eric Reuss, MD, a thoracic medical oncologist at Georgetown University’s Lombardi Comprehensive Cancer Center in Washington, DC. And these “risks definitely continue into the adjuvant period.”
So far, the available evidence does suggest that the neoadjuvant phase of immunotherapy confers the greatest benefit, while adjuvant immunotherapy — which can last a year or longer — may expose patients to more costs and toxicities, with no clear benefit.
A 2024 meta-analysis, which included four trials of neoadjuvant-adjuvant immunotherapy and one trial of neoadjuvant immunotherapy in resectable NSCLC, suggested that the addition of adjuvant immunotherapy did not improve event-free survival (hazard ratio [HR], 0.90; P = .59) or overall survival (HR, 1.18; P = .51) compared with neoadjuvant immunotherapy alone.
According to Spratt, “It’s very clear that the neoadjuvant phase is the more important of the two phases.” Given that, “we’re probably overtreating some patients,” said Spratt, also chairman of Radiation Oncology at University Hospitals Seidman Cancer Center and Case Western Reserve University in Cleveland.
Chaft agreed that “there’s very little data that we need the postoperative phase, and what data we do have is post hoc and limited.”
This evidence gap “has created considerable dilemmas” for oncologists and patients who are faced with “the challenge of deciding which therapeutic options or approach are best suited for each individual,” experts wrote in recent consensus recommendations from the International Association for the Study of Lung Cancer.
Clinicians may ultimately be left to make decisions about prescribing postoperative immunotherapy based on their experience and comfort level.
When Chaft’s patients have a pathologic complete response with immunotherapy and chemotherapy in the neoadjuvant phase, “I’m comfortable stopping because the data would suggest they’re almost certainly cured,” she said.
For patients who have viable disease after neoadjuvant therapy, continuing an immunotherapy postoperatively when it didn’t work preoperatively “is not going to make a difference,” Chaft explained. In these cases, Chaft would look to enroll them in a clinical trial evaluating a different regimen because of the risk for relapse.
With patients who did well preoperatively but still have tumor left at the time of surgery, she would discuss continuing the immunotherapy or participating in a trial, she said.
All the FDA-approved regimens are covered by insurance, said Chaft. Clinicians are most comfortable with pembrolizumab because it is the most widely used immunotherapy in advanced NSCLC, she said. But, she added, “there’s really no strong differentiating data between any of the studies; all the results look very comparable.”
When assessing whether a patient may benefit from immunotherapy after surgery, Reuss looks at a range of factors, including disease stage, histology, gene mutations, and pathologic response. Reuss also weighs patient preferences. A patient coming from another country might only want a neoadjuvant regimen, for instance, he said.
That “isn’t exactly the kind of the level one evidence that one likes to see when making treatment decisions,” said Reuss. “Without prospective data, all we can do is cross-trial comparisons and assessment of subgroups.”
If a new regimen comes along that improves outcomes or decision-making, “I think we would pivot to that in a heartbeat,” he said.
But Will FDA Follow ODAC’s Recommendation?
“ODAC has made their point clear,” said Chaft. “Our patients deserve to know that whatever added risk and cost they’re incurring is merited by a clinical outcome.”
Despite the ODAC’s recommendation, it’s not guaranteed that the FDA will follow it.
An FDA spokesperson did not confirm the agency’s decision on the matter but noted that the FDA is “incorporating the panel’s advice.”
Spratt thinks that, going forward, companies will be held to “a higher bar,” but it’s unclear what that bar will look like.
“Whether this is a mandate or a strong recommendation, I think industry is definitely paying attention,” Spratt said. Companies that do not follow the guidance may risk not having their drug approved, “unless it’s just an absolute huge slam dunk of a major benefit to patients.”
In fact, according to Chaft, drug makers seeking approvals of novel entities in this space “won’t have a choice” but to follow any new trial design requirements from the FDA.
Still, getting answers may be a challenge.
Drug companies with immunotherapies already on the market are unlikely to invest the resources to conduct trials comparing the neoadjuvant and adjuvant settings, said Chaft. “It will take too long and cost too much,” she said.
And it remains unclear whether drug companies will decide to stop pursuing novel agents if approvals will ultimately require more expensive and time-consuming trials.
According to Chaft, oncologists have been discussing protocols that could help fill the knowledge gaps. Such trials will be conducted by the National Cancer Institute’s Cooperative Groups, she noted. But it’s early days.
For the time being, with comparative data from phase 3 trials years away, oncologists will have to work with the limited evidence and individual patients in front of them.
Chaft disclosed ties with AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Genentech/Roche, Guardant Health, Janssen Pharmaceuticals, Eli Lilly, and Merck. Reuss disclosed ties with AstraZeneca, Arcus, AbbVie, Bristol Myers Squibb, CatalYm, Daiichi Sankyo, and Eli Lilly, and that Georgetown has received research funding from Genentech/Roche, Verastem, Nuvalent, LUNGevity Foundation, Exelixis, Arcus, and Revolution Medicines. Spratt disclosed ties with Astellas, AstraZeneca, Bayer, Boston Scientific, Janssen Pharmaceuticals, Novartis, and Pfizer.
A version of this article appeared on Medscape.com.
Cellular Therapies for Solid Tumors: The Next Big Thing?
The cutting edge of treating solid tumors with cell therapies got notably sharper in 2024.
First came the US Food and Drug Administration (FDA) approval in February 2024 of the tumor-infiltrating lymphocyte (TIL) therapy lifileucel in unresectable or metastatic melanoma that had progressed on prior immunotherapy, the first cellular therapy for any solid tumor. Then came the August FDA approval of afamitresgene autoleucel in unresectable or metastatic synovial sarcoma with failed chemotherapy, the first engineered T-cell therapy for cancers in soft tissue.
“This was a pipe dream just a decade ago,” Alison Betof Warner, MD, PhD, lead author of a lifileucel study (NCT05640193), said in an interview with Medscape Medical News. “At the start of 2024, we had no approvals of these kinds of products in solid cancers. Now we have two.”
As the director of Solid Tumor Cell Therapy and leader of Stanford Medicine’s Melanoma and Cutaneous Oncology Clinical Research Group, Betof Warner has been at the forefront of developing commercial cell therapy using tumor-infiltrating lymphocytes (TILs).
“The approval of lifileucel increases confidence that we can get these therapies across the regulatory finish line and to patients,” Betof Warner said during the interview. She was not involved in the development of afamitresgene autoleucel.
‘Reverse Engineering’
In addition to her contributions to the work that led to lifileucel’s approval, Betof Warner was the lead author on the first consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy.
Betof Warner began studying TILs after doing research with her mentors in immuno-oncology, Jedd D. Wolchok and Michael A. Postow. Their investigations — including one that Betof Warner coauthored — into how monoclonal antibodies and checkpoint inhibitors, such as ipilimumab or nivolumab, might extend the lives of people with advanced unresectable or metastatic melanoma inspired her to push further to find ways to minimize treatment while maximizing outcomes for patients. Betof Warner’s interest overall, she said in the interview, is in capitalizing on what can be learned about how the immune system controls cancer.
“What we know is that the immune system has the ability to kill cancer,” Betof Warner said. “Therefore we need to be thinking about how we can increase immune surveillance. How can we enhance that before a patient develops advanced cancer?
Betof Warner said that although TILs are now standard treatment in melanoma, there is about a 30% response rate compared with about a 50% response rate in immunotherapy, and the latter is easier for the patient to withstand.
“Antibodies on the frontline are better than going through a surgery and then waiting weeks to get your therapy,” Betof Warner said in the interview. “You can come into my clinic and get an antibody therapy in 30 minutes and go straight to work. TILs require patients to be in the hospital for weeks at a time and out of work for months at a time.”
In an effort to combine therapies to maximize best outcomes, a phase 3 trial (NCT05727904) is currently recruiting. The TILVANCE-301 trial will compare immunotherapy plus adoptive cell therapy vs immunotherapy alone in untreated unresectable or metastatic melanoma. Betof Warner is not a part of this study.
Cell Therapies Include CAR T Cells and TCRT
In general, adoptive T-cell therapies such as TILs involve the isolation of autologous immune cells that are removed from the body and either expanded or modified to optimize their efficacy in fighting antigens, before their transfer to the patient as a living drug by infusion.
In addition to TILs, adoptive cell therapies for antitumor therapeutics include chimeric antigen receptor (CAR) T cells and engineered T-cell receptor therapy (TCRT).
In CAR T-cell therapy and TCRT, naive T cells are harvested from the patient’s blood then engineered to target a tumor. In TIL therapy, tumor-specific T cells are taken from the patient’s tumor. Once extracted, the respective cells are expanded billions of times and then delivered back to the patient’s body, said Betof Warner.
“The main promise of this approach is to generate responses in what we know as ‘cold’ tumors, or tumors that do not have a lot of endogenous T-cell infiltration or where the T cells are not working well, to bring in tumor targeting T cells and then trigger an immune response,” Betof Warner told an audience at the American Society of Clinical Oncology (ASCO) 2024 annual meeting.
TIL patients also receive interleukin (IL)-2 infusions to further stimulate the cells. In patients being treated with TCRT, they either receive low or no IL-2, Betof Warner said in her ASCO presentation, “Adopting Cutting-Edge Cell Therapies in Melanoma,” part of the session Beyond the Tip of the Iceberg: Next-Generation Cell-Based Therapies.
Decades in the Making
The National Cancer Institute began investigating TILs in the late 1980s, with the current National Cancer Institute (NCI) surgery chief, Steven Rosenberg, MD, PhD, leading the first-ever trials that showed TILs could shrink tumors in people with advanced melanoma.
Since then, NCI staff and others have also investigated TILs beyond melanoma and additional cell therapies based on CAR T cells and TCRT for antitumor therapeutics.
“TCRs are different from CAR Ts because they go after intracellular antigens instead of extracellular antigens,” said Betof Warner. “That has appeal because many of the tumor antigens we’re looking for will be intracellular.”
Because CAR T cells only target extracellular antigens, their utility is somewhat limited. Although several CAR T-cell therapies exist for blood cancers, there currently are no approved CAR T-cell therapies for solid tumors. However, several trials of CAR T cells in gastrointestinal cancers and melanoma are ongoing, said Betof Warner, who is not a part of these studies.
“We are starting to see early-phase efficacy in pediatric gliomas,” Betof Warner said, mentioning a study conducted by colleagues at Stanford who demonstrated potential for anti-GD2 CAR T-cell therapy in deadly pediatric diffuse midline gliomas, tumors on the spine and brain.
In their study, nine out of 11 participants (median age, 15 years) showed benefit from the cell therapy, with one participant’s tumors resolving completely. The results paved the way for the FDA to grant a Regenerative Medicine Advanced Therapy designation for use of anti-GD2 CAR T cells in H3K27M-positive diffuse midline gliomas.
The investigators are now recruiting for a phase 1 trial (NCT04196413). Results of the initial study were published in Nature last month.
Another lesser-known cell therapy expected to advance at some point in the future for solid tumors is use of the body’s natural killer (NK) cells. “They’ve been known about for a long time, but they are more difficult to regulate, which is one reason why it has taken longer to make NK cell therapies,” said Betof Warner, who is not involved in the study of NK cells. “One of their advantages is that, potentially, there could be an ‘off the shelf’ NK product. They don’t necessarily have to be made with autologous cells.”
Risk-Benefit Profiles Depend on Mechanism of Action
If the corresponding TCR sequence of a tumor antigen is known, said Betof Warner, it is possible to use leukapheresis to generate naive circulating lymphocytes. Once infused, the manufactured TCRTs will activate in the body the same as native cells because the signaling is the same.
An advantage to TCRT compared with CAR T-cell therapy is that it targets intracellular proteins, which are significantly present in the tumor, Betof Warner said in her presentation at ASCO 2024. She clarified that tumors will usually be screened for the presence of this antigen before a patient is selected for treatment with that particular therapy, because not all antigens are highly expressed in every tumor.
“Furthermore, the tumor antigen has to be presented by a major histocompatibility complex, meaning there are human leukocyte antigen restrictions, which impacts patient selection,” she said.
A risk with both TCRT and CAR T-cell therapy, according to Betof Warner, is that because there are often shared antigens between tumor and normal tissues, on-target/off-tumor toxicity is a risk.
“TILs are different because they are nonengineered, at least not for antigen recognition. They are polyclonal and go after multiple targets,” Betof Warner said. “TCRs and CARs are engineered to go after one target. So, TILs have much lower rates of on-tumor/off-target effects, vs when you engineer a very high affinity receptor like a TCR or CAR.”
A good example of how this amplification of TCR affinity can lead to poor outcomes is in metastatic melanoma, said Betof Warner.
In investigations (NCI-07-C-0174 and NCI-07-C-0175) of TCRT in metastatic melanoma, for example, the researchers were targeting MART-1 or gp100, which are expressed in melanocytes.
“The problem was that these antigens are also expressed in the eyes and ears, so it caused eye inflammation and hearing loss in a number of patients because it wasn’t specific enough for the tumor,” said Betof Warner. “So, if that target is highly expressed on normal tissue, then you have a high risk.”
Promise of PRAME
Betof Warner said the most promising TCRT at present is the investigational autologous cell therapy IMA203 (NCT03688124), which targets the preferentially expressed antigen (PRAME). Although PRAME is found in many tumors, this testis antigen does not tend to express in normal, healthy adult tissues. Betof Warner is not affiliated with this study.
“It’s maybe the most exciting TCRT cell in melanoma,” Betof Warner told her audience at the ASCO 2024 meeting. Because the expression rate of PRAME in cutaneous and uveal melanoma is at or above 95% and 90%, respectively, she said “it is a really good target in melanoma.”
Phase 1a results reported in late 2023 from a first-in-human trial of IMA203 involving 13 persons with highly advanced melanoma and a median of 5.5 previous treatments showed a 50% objective response rate in the 12 evaluable results. The duration of response ranged between 2.2 and 14.7 months (median follow-up, 14 months).
The safety profile of the treatment was favorable, with no grade 3 adverse events occurring in more than 10% of the cohort, and no grade 5 adverse events at all.
Phase 1b results published in October by maker Immatics showed that in 28 heavily pretreated metastatic melanoma patients, IMA203 had a confirmed objective response rate of 54% with a median duration of response of 12.1 months, while maintaining a favorable tolerability profile.
Accelerated Approvals, Boxed Warnings
The FDA granted accelerated approvals for both lifileucel, the TIL therapy, and afamitresgene autoleucel, the TCRT.
Both were approved with boxed warnings. Lifileucel’s warning is for treatment-related mortality, prolonged severe cytopenia, severe infection, and cardiopulmonary and renal impairment. Afamitresgene autoleucel’s boxed warning is for serious or fatal cytokine release syndrome, which may be severe or life-threatening.
With these approvals, the bar is now raised on TILs and TCRTs, said Betof Warner.
The lifileucel trial studied 73 patients whose melanoma had continued to metastasize despite treatment with a programmed cell death protein (PD-1)/ programmed death-ligand (PD-L1)–targeted immune checkpoint inhibitor and a BRAF inhibitor (if appropriate based on tumor mutation status), and whose lifileucel dose was at least 7.5 billion cells (the approved dose). The cohort also received a median of six IL-2 (aldesleukin) doses.
The objective response rate was 31.5% (95% CI, 21.1-43.4), and median duration of response was not reached (lower bound of 95% CI, 4.1).
In the afamitresgene autoleucel study, 44 of 52 patients with synovial sarcoma received leukapheresis and a single infusion of afamitresgene autoleucel.
The overall response rate was 43.2% (95% CI, 28.4-59.0). The median time to response was 4.9 weeks (95% CI, 4.4-8), and the median duration of response was 6 months (lower bound of 95% CI, 4.6). Among patients who were responsive to the treatment, 45.6% and 39.0% had a duration of response of 6 months or longer and 12 months or longer, respectively.
New Hope for Patients
Betof Warner and her colleagues are now recruiting for an open-label, phase 1/2 investigation of the safety and efficacy of the TIL therapy OBX-115 in adult advanced solid tumors in melanoma or non–small cell lung cancer. The first-in-human results of a previous trial were presented at the ASCO 2024 meeting, and OBX-115 received FDA fast track designation in July.
“I think the results are really promising,” said Betof Warner. “This is an engineered TIL that does not require administering IL-2 to the patient. There were four out of the nine patients who responded to the treatment and there were no dose-limiting toxicities, no cytokine and no intracranial — all of which is excellent.”
For Betof Warner, the possibility that by using their own immune system, patients with advanced and refractory cancers could soon have a one-time treatment with a cell therapy rather than innumerable bouts of chemotherapy pushes her onward.
“The idea that we can treat cancer one time and have it not recur for years — that’s pushing the start of saying there’s a cure of cancer. That a person could move on from cancer like they move on from an infection. That is the potential of this work. We’re not there yet, but that’s where we need to think and dream big,” she said.
Betof Warner disclosed consulting/advisory roles with BluePath Solutions, Bristol-Myers Squibb/Medarex, Immatics, Instil Bio, Iovance Biotherapeutics, Lyell Immunopharma, Merck, Novartis, and Pfizer and research funding and travel expenses from Iovance Biotherapeutics.
A version of this article appeared on Medscape.com.
The cutting edge of treating solid tumors with cell therapies got notably sharper in 2024.
First came the US Food and Drug Administration (FDA) approval in February 2024 of the tumor-infiltrating lymphocyte (TIL) therapy lifileucel in unresectable or metastatic melanoma that had progressed on prior immunotherapy, the first cellular therapy for any solid tumor. Then came the August FDA approval of afamitresgene autoleucel in unresectable or metastatic synovial sarcoma with failed chemotherapy, the first engineered T-cell therapy for cancers in soft tissue.
“This was a pipe dream just a decade ago,” Alison Betof Warner, MD, PhD, lead author of a lifileucel study (NCT05640193), said in an interview with Medscape Medical News. “At the start of 2024, we had no approvals of these kinds of products in solid cancers. Now we have two.”
As the director of Solid Tumor Cell Therapy and leader of Stanford Medicine’s Melanoma and Cutaneous Oncology Clinical Research Group, Betof Warner has been at the forefront of developing commercial cell therapy using tumor-infiltrating lymphocytes (TILs).
“The approval of lifileucel increases confidence that we can get these therapies across the regulatory finish line and to patients,” Betof Warner said during the interview. She was not involved in the development of afamitresgene autoleucel.
‘Reverse Engineering’
In addition to her contributions to the work that led to lifileucel’s approval, Betof Warner was the lead author on the first consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy.
Betof Warner began studying TILs after doing research with her mentors in immuno-oncology, Jedd D. Wolchok and Michael A. Postow. Their investigations — including one that Betof Warner coauthored — into how monoclonal antibodies and checkpoint inhibitors, such as ipilimumab or nivolumab, might extend the lives of people with advanced unresectable or metastatic melanoma inspired her to push further to find ways to minimize treatment while maximizing outcomes for patients. Betof Warner’s interest overall, she said in the interview, is in capitalizing on what can be learned about how the immune system controls cancer.
“What we know is that the immune system has the ability to kill cancer,” Betof Warner said. “Therefore we need to be thinking about how we can increase immune surveillance. How can we enhance that before a patient develops advanced cancer?
Betof Warner said that although TILs are now standard treatment in melanoma, there is about a 30% response rate compared with about a 50% response rate in immunotherapy, and the latter is easier for the patient to withstand.
“Antibodies on the frontline are better than going through a surgery and then waiting weeks to get your therapy,” Betof Warner said in the interview. “You can come into my clinic and get an antibody therapy in 30 minutes and go straight to work. TILs require patients to be in the hospital for weeks at a time and out of work for months at a time.”
In an effort to combine therapies to maximize best outcomes, a phase 3 trial (NCT05727904) is currently recruiting. The TILVANCE-301 trial will compare immunotherapy plus adoptive cell therapy vs immunotherapy alone in untreated unresectable or metastatic melanoma. Betof Warner is not a part of this study.
Cell Therapies Include CAR T Cells and TCRT
In general, adoptive T-cell therapies such as TILs involve the isolation of autologous immune cells that are removed from the body and either expanded or modified to optimize their efficacy in fighting antigens, before their transfer to the patient as a living drug by infusion.
In addition to TILs, adoptive cell therapies for antitumor therapeutics include chimeric antigen receptor (CAR) T cells and engineered T-cell receptor therapy (TCRT).
In CAR T-cell therapy and TCRT, naive T cells are harvested from the patient’s blood then engineered to target a tumor. In TIL therapy, tumor-specific T cells are taken from the patient’s tumor. Once extracted, the respective cells are expanded billions of times and then delivered back to the patient’s body, said Betof Warner.
“The main promise of this approach is to generate responses in what we know as ‘cold’ tumors, or tumors that do not have a lot of endogenous T-cell infiltration or where the T cells are not working well, to bring in tumor targeting T cells and then trigger an immune response,” Betof Warner told an audience at the American Society of Clinical Oncology (ASCO) 2024 annual meeting.
TIL patients also receive interleukin (IL)-2 infusions to further stimulate the cells. In patients being treated with TCRT, they either receive low or no IL-2, Betof Warner said in her ASCO presentation, “Adopting Cutting-Edge Cell Therapies in Melanoma,” part of the session Beyond the Tip of the Iceberg: Next-Generation Cell-Based Therapies.
Decades in the Making
The National Cancer Institute began investigating TILs in the late 1980s, with the current National Cancer Institute (NCI) surgery chief, Steven Rosenberg, MD, PhD, leading the first-ever trials that showed TILs could shrink tumors in people with advanced melanoma.
Since then, NCI staff and others have also investigated TILs beyond melanoma and additional cell therapies based on CAR T cells and TCRT for antitumor therapeutics.
“TCRs are different from CAR Ts because they go after intracellular antigens instead of extracellular antigens,” said Betof Warner. “That has appeal because many of the tumor antigens we’re looking for will be intracellular.”
Because CAR T cells only target extracellular antigens, their utility is somewhat limited. Although several CAR T-cell therapies exist for blood cancers, there currently are no approved CAR T-cell therapies for solid tumors. However, several trials of CAR T cells in gastrointestinal cancers and melanoma are ongoing, said Betof Warner, who is not a part of these studies.
“We are starting to see early-phase efficacy in pediatric gliomas,” Betof Warner said, mentioning a study conducted by colleagues at Stanford who demonstrated potential for anti-GD2 CAR T-cell therapy in deadly pediatric diffuse midline gliomas, tumors on the spine and brain.
In their study, nine out of 11 participants (median age, 15 years) showed benefit from the cell therapy, with one participant’s tumors resolving completely. The results paved the way for the FDA to grant a Regenerative Medicine Advanced Therapy designation for use of anti-GD2 CAR T cells in H3K27M-positive diffuse midline gliomas.
The investigators are now recruiting for a phase 1 trial (NCT04196413). Results of the initial study were published in Nature last month.
Another lesser-known cell therapy expected to advance at some point in the future for solid tumors is use of the body’s natural killer (NK) cells. “They’ve been known about for a long time, but they are more difficult to regulate, which is one reason why it has taken longer to make NK cell therapies,” said Betof Warner, who is not involved in the study of NK cells. “One of their advantages is that, potentially, there could be an ‘off the shelf’ NK product. They don’t necessarily have to be made with autologous cells.”
Risk-Benefit Profiles Depend on Mechanism of Action
If the corresponding TCR sequence of a tumor antigen is known, said Betof Warner, it is possible to use leukapheresis to generate naive circulating lymphocytes. Once infused, the manufactured TCRTs will activate in the body the same as native cells because the signaling is the same.
An advantage to TCRT compared with CAR T-cell therapy is that it targets intracellular proteins, which are significantly present in the tumor, Betof Warner said in her presentation at ASCO 2024. She clarified that tumors will usually be screened for the presence of this antigen before a patient is selected for treatment with that particular therapy, because not all antigens are highly expressed in every tumor.
“Furthermore, the tumor antigen has to be presented by a major histocompatibility complex, meaning there are human leukocyte antigen restrictions, which impacts patient selection,” she said.
A risk with both TCRT and CAR T-cell therapy, according to Betof Warner, is that because there are often shared antigens between tumor and normal tissues, on-target/off-tumor toxicity is a risk.
“TILs are different because they are nonengineered, at least not for antigen recognition. They are polyclonal and go after multiple targets,” Betof Warner said. “TCRs and CARs are engineered to go after one target. So, TILs have much lower rates of on-tumor/off-target effects, vs when you engineer a very high affinity receptor like a TCR or CAR.”
A good example of how this amplification of TCR affinity can lead to poor outcomes is in metastatic melanoma, said Betof Warner.
In investigations (NCI-07-C-0174 and NCI-07-C-0175) of TCRT in metastatic melanoma, for example, the researchers were targeting MART-1 or gp100, which are expressed in melanocytes.
“The problem was that these antigens are also expressed in the eyes and ears, so it caused eye inflammation and hearing loss in a number of patients because it wasn’t specific enough for the tumor,” said Betof Warner. “So, if that target is highly expressed on normal tissue, then you have a high risk.”
Promise of PRAME
Betof Warner said the most promising TCRT at present is the investigational autologous cell therapy IMA203 (NCT03688124), which targets the preferentially expressed antigen (PRAME). Although PRAME is found in many tumors, this testis antigen does not tend to express in normal, healthy adult tissues. Betof Warner is not affiliated with this study.
“It’s maybe the most exciting TCRT cell in melanoma,” Betof Warner told her audience at the ASCO 2024 meeting. Because the expression rate of PRAME in cutaneous and uveal melanoma is at or above 95% and 90%, respectively, she said “it is a really good target in melanoma.”
Phase 1a results reported in late 2023 from a first-in-human trial of IMA203 involving 13 persons with highly advanced melanoma and a median of 5.5 previous treatments showed a 50% objective response rate in the 12 evaluable results. The duration of response ranged between 2.2 and 14.7 months (median follow-up, 14 months).
The safety profile of the treatment was favorable, with no grade 3 adverse events occurring in more than 10% of the cohort, and no grade 5 adverse events at all.
Phase 1b results published in October by maker Immatics showed that in 28 heavily pretreated metastatic melanoma patients, IMA203 had a confirmed objective response rate of 54% with a median duration of response of 12.1 months, while maintaining a favorable tolerability profile.
Accelerated Approvals, Boxed Warnings
The FDA granted accelerated approvals for both lifileucel, the TIL therapy, and afamitresgene autoleucel, the TCRT.
Both were approved with boxed warnings. Lifileucel’s warning is for treatment-related mortality, prolonged severe cytopenia, severe infection, and cardiopulmonary and renal impairment. Afamitresgene autoleucel’s boxed warning is for serious or fatal cytokine release syndrome, which may be severe or life-threatening.
With these approvals, the bar is now raised on TILs and TCRTs, said Betof Warner.
The lifileucel trial studied 73 patients whose melanoma had continued to metastasize despite treatment with a programmed cell death protein (PD-1)/ programmed death-ligand (PD-L1)–targeted immune checkpoint inhibitor and a BRAF inhibitor (if appropriate based on tumor mutation status), and whose lifileucel dose was at least 7.5 billion cells (the approved dose). The cohort also received a median of six IL-2 (aldesleukin) doses.
The objective response rate was 31.5% (95% CI, 21.1-43.4), and median duration of response was not reached (lower bound of 95% CI, 4.1).
In the afamitresgene autoleucel study, 44 of 52 patients with synovial sarcoma received leukapheresis and a single infusion of afamitresgene autoleucel.
The overall response rate was 43.2% (95% CI, 28.4-59.0). The median time to response was 4.9 weeks (95% CI, 4.4-8), and the median duration of response was 6 months (lower bound of 95% CI, 4.6). Among patients who were responsive to the treatment, 45.6% and 39.0% had a duration of response of 6 months or longer and 12 months or longer, respectively.
New Hope for Patients
Betof Warner and her colleagues are now recruiting for an open-label, phase 1/2 investigation of the safety and efficacy of the TIL therapy OBX-115 in adult advanced solid tumors in melanoma or non–small cell lung cancer. The first-in-human results of a previous trial were presented at the ASCO 2024 meeting, and OBX-115 received FDA fast track designation in July.
“I think the results are really promising,” said Betof Warner. “This is an engineered TIL that does not require administering IL-2 to the patient. There were four out of the nine patients who responded to the treatment and there were no dose-limiting toxicities, no cytokine and no intracranial — all of which is excellent.”
For Betof Warner, the possibility that by using their own immune system, patients with advanced and refractory cancers could soon have a one-time treatment with a cell therapy rather than innumerable bouts of chemotherapy pushes her onward.
“The idea that we can treat cancer one time and have it not recur for years — that’s pushing the start of saying there’s a cure of cancer. That a person could move on from cancer like they move on from an infection. That is the potential of this work. We’re not there yet, but that’s where we need to think and dream big,” she said.
Betof Warner disclosed consulting/advisory roles with BluePath Solutions, Bristol-Myers Squibb/Medarex, Immatics, Instil Bio, Iovance Biotherapeutics, Lyell Immunopharma, Merck, Novartis, and Pfizer and research funding and travel expenses from Iovance Biotherapeutics.
A version of this article appeared on Medscape.com.
The cutting edge of treating solid tumors with cell therapies got notably sharper in 2024.
First came the US Food and Drug Administration (FDA) approval in February 2024 of the tumor-infiltrating lymphocyte (TIL) therapy lifileucel in unresectable or metastatic melanoma that had progressed on prior immunotherapy, the first cellular therapy for any solid tumor. Then came the August FDA approval of afamitresgene autoleucel in unresectable or metastatic synovial sarcoma with failed chemotherapy, the first engineered T-cell therapy for cancers in soft tissue.
“This was a pipe dream just a decade ago,” Alison Betof Warner, MD, PhD, lead author of a lifileucel study (NCT05640193), said in an interview with Medscape Medical News. “At the start of 2024, we had no approvals of these kinds of products in solid cancers. Now we have two.”
As the director of Solid Tumor Cell Therapy and leader of Stanford Medicine’s Melanoma and Cutaneous Oncology Clinical Research Group, Betof Warner has been at the forefront of developing commercial cell therapy using tumor-infiltrating lymphocytes (TILs).
“The approval of lifileucel increases confidence that we can get these therapies across the regulatory finish line and to patients,” Betof Warner said during the interview. She was not involved in the development of afamitresgene autoleucel.
‘Reverse Engineering’
In addition to her contributions to the work that led to lifileucel’s approval, Betof Warner was the lead author on the first consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy.
Betof Warner began studying TILs after doing research with her mentors in immuno-oncology, Jedd D. Wolchok and Michael A. Postow. Their investigations — including one that Betof Warner coauthored — into how monoclonal antibodies and checkpoint inhibitors, such as ipilimumab or nivolumab, might extend the lives of people with advanced unresectable or metastatic melanoma inspired her to push further to find ways to minimize treatment while maximizing outcomes for patients. Betof Warner’s interest overall, she said in the interview, is in capitalizing on what can be learned about how the immune system controls cancer.
“What we know is that the immune system has the ability to kill cancer,” Betof Warner said. “Therefore we need to be thinking about how we can increase immune surveillance. How can we enhance that before a patient develops advanced cancer?
Betof Warner said that although TILs are now standard treatment in melanoma, there is about a 30% response rate compared with about a 50% response rate in immunotherapy, and the latter is easier for the patient to withstand.
“Antibodies on the frontline are better than going through a surgery and then waiting weeks to get your therapy,” Betof Warner said in the interview. “You can come into my clinic and get an antibody therapy in 30 minutes and go straight to work. TILs require patients to be in the hospital for weeks at a time and out of work for months at a time.”
In an effort to combine therapies to maximize best outcomes, a phase 3 trial (NCT05727904) is currently recruiting. The TILVANCE-301 trial will compare immunotherapy plus adoptive cell therapy vs immunotherapy alone in untreated unresectable or metastatic melanoma. Betof Warner is not a part of this study.
Cell Therapies Include CAR T Cells and TCRT
In general, adoptive T-cell therapies such as TILs involve the isolation of autologous immune cells that are removed from the body and either expanded or modified to optimize their efficacy in fighting antigens, before their transfer to the patient as a living drug by infusion.
In addition to TILs, adoptive cell therapies for antitumor therapeutics include chimeric antigen receptor (CAR) T cells and engineered T-cell receptor therapy (TCRT).
In CAR T-cell therapy and TCRT, naive T cells are harvested from the patient’s blood then engineered to target a tumor. In TIL therapy, tumor-specific T cells are taken from the patient’s tumor. Once extracted, the respective cells are expanded billions of times and then delivered back to the patient’s body, said Betof Warner.
“The main promise of this approach is to generate responses in what we know as ‘cold’ tumors, or tumors that do not have a lot of endogenous T-cell infiltration or where the T cells are not working well, to bring in tumor targeting T cells and then trigger an immune response,” Betof Warner told an audience at the American Society of Clinical Oncology (ASCO) 2024 annual meeting.
TIL patients also receive interleukin (IL)-2 infusions to further stimulate the cells. In patients being treated with TCRT, they either receive low or no IL-2, Betof Warner said in her ASCO presentation, “Adopting Cutting-Edge Cell Therapies in Melanoma,” part of the session Beyond the Tip of the Iceberg: Next-Generation Cell-Based Therapies.
Decades in the Making
The National Cancer Institute began investigating TILs in the late 1980s, with the current National Cancer Institute (NCI) surgery chief, Steven Rosenberg, MD, PhD, leading the first-ever trials that showed TILs could shrink tumors in people with advanced melanoma.
Since then, NCI staff and others have also investigated TILs beyond melanoma and additional cell therapies based on CAR T cells and TCRT for antitumor therapeutics.
“TCRs are different from CAR Ts because they go after intracellular antigens instead of extracellular antigens,” said Betof Warner. “That has appeal because many of the tumor antigens we’re looking for will be intracellular.”
Because CAR T cells only target extracellular antigens, their utility is somewhat limited. Although several CAR T-cell therapies exist for blood cancers, there currently are no approved CAR T-cell therapies for solid tumors. However, several trials of CAR T cells in gastrointestinal cancers and melanoma are ongoing, said Betof Warner, who is not a part of these studies.
“We are starting to see early-phase efficacy in pediatric gliomas,” Betof Warner said, mentioning a study conducted by colleagues at Stanford who demonstrated potential for anti-GD2 CAR T-cell therapy in deadly pediatric diffuse midline gliomas, tumors on the spine and brain.
In their study, nine out of 11 participants (median age, 15 years) showed benefit from the cell therapy, with one participant’s tumors resolving completely. The results paved the way for the FDA to grant a Regenerative Medicine Advanced Therapy designation for use of anti-GD2 CAR T cells in H3K27M-positive diffuse midline gliomas.
The investigators are now recruiting for a phase 1 trial (NCT04196413). Results of the initial study were published in Nature last month.
Another lesser-known cell therapy expected to advance at some point in the future for solid tumors is use of the body’s natural killer (NK) cells. “They’ve been known about for a long time, but they are more difficult to regulate, which is one reason why it has taken longer to make NK cell therapies,” said Betof Warner, who is not involved in the study of NK cells. “One of their advantages is that, potentially, there could be an ‘off the shelf’ NK product. They don’t necessarily have to be made with autologous cells.”
Risk-Benefit Profiles Depend on Mechanism of Action
If the corresponding TCR sequence of a tumor antigen is known, said Betof Warner, it is possible to use leukapheresis to generate naive circulating lymphocytes. Once infused, the manufactured TCRTs will activate in the body the same as native cells because the signaling is the same.
An advantage to TCRT compared with CAR T-cell therapy is that it targets intracellular proteins, which are significantly present in the tumor, Betof Warner said in her presentation at ASCO 2024. She clarified that tumors will usually be screened for the presence of this antigen before a patient is selected for treatment with that particular therapy, because not all antigens are highly expressed in every tumor.
“Furthermore, the tumor antigen has to be presented by a major histocompatibility complex, meaning there are human leukocyte antigen restrictions, which impacts patient selection,” she said.
A risk with both TCRT and CAR T-cell therapy, according to Betof Warner, is that because there are often shared antigens between tumor and normal tissues, on-target/off-tumor toxicity is a risk.
“TILs are different because they are nonengineered, at least not for antigen recognition. They are polyclonal and go after multiple targets,” Betof Warner said. “TCRs and CARs are engineered to go after one target. So, TILs have much lower rates of on-tumor/off-target effects, vs when you engineer a very high affinity receptor like a TCR or CAR.”
A good example of how this amplification of TCR affinity can lead to poor outcomes is in metastatic melanoma, said Betof Warner.
In investigations (NCI-07-C-0174 and NCI-07-C-0175) of TCRT in metastatic melanoma, for example, the researchers were targeting MART-1 or gp100, which are expressed in melanocytes.
“The problem was that these antigens are also expressed in the eyes and ears, so it caused eye inflammation and hearing loss in a number of patients because it wasn’t specific enough for the tumor,” said Betof Warner. “So, if that target is highly expressed on normal tissue, then you have a high risk.”
Promise of PRAME
Betof Warner said the most promising TCRT at present is the investigational autologous cell therapy IMA203 (NCT03688124), which targets the preferentially expressed antigen (PRAME). Although PRAME is found in many tumors, this testis antigen does not tend to express in normal, healthy adult tissues. Betof Warner is not affiliated with this study.
“It’s maybe the most exciting TCRT cell in melanoma,” Betof Warner told her audience at the ASCO 2024 meeting. Because the expression rate of PRAME in cutaneous and uveal melanoma is at or above 95% and 90%, respectively, she said “it is a really good target in melanoma.”
Phase 1a results reported in late 2023 from a first-in-human trial of IMA203 involving 13 persons with highly advanced melanoma and a median of 5.5 previous treatments showed a 50% objective response rate in the 12 evaluable results. The duration of response ranged between 2.2 and 14.7 months (median follow-up, 14 months).
The safety profile of the treatment was favorable, with no grade 3 adverse events occurring in more than 10% of the cohort, and no grade 5 adverse events at all.
Phase 1b results published in October by maker Immatics showed that in 28 heavily pretreated metastatic melanoma patients, IMA203 had a confirmed objective response rate of 54% with a median duration of response of 12.1 months, while maintaining a favorable tolerability profile.
Accelerated Approvals, Boxed Warnings
The FDA granted accelerated approvals for both lifileucel, the TIL therapy, and afamitresgene autoleucel, the TCRT.
Both were approved with boxed warnings. Lifileucel’s warning is for treatment-related mortality, prolonged severe cytopenia, severe infection, and cardiopulmonary and renal impairment. Afamitresgene autoleucel’s boxed warning is for serious or fatal cytokine release syndrome, which may be severe or life-threatening.
With these approvals, the bar is now raised on TILs and TCRTs, said Betof Warner.
The lifileucel trial studied 73 patients whose melanoma had continued to metastasize despite treatment with a programmed cell death protein (PD-1)/ programmed death-ligand (PD-L1)–targeted immune checkpoint inhibitor and a BRAF inhibitor (if appropriate based on tumor mutation status), and whose lifileucel dose was at least 7.5 billion cells (the approved dose). The cohort also received a median of six IL-2 (aldesleukin) doses.
The objective response rate was 31.5% (95% CI, 21.1-43.4), and median duration of response was not reached (lower bound of 95% CI, 4.1).
In the afamitresgene autoleucel study, 44 of 52 patients with synovial sarcoma received leukapheresis and a single infusion of afamitresgene autoleucel.
The overall response rate was 43.2% (95% CI, 28.4-59.0). The median time to response was 4.9 weeks (95% CI, 4.4-8), and the median duration of response was 6 months (lower bound of 95% CI, 4.6). Among patients who were responsive to the treatment, 45.6% and 39.0% had a duration of response of 6 months or longer and 12 months or longer, respectively.
New Hope for Patients
Betof Warner and her colleagues are now recruiting for an open-label, phase 1/2 investigation of the safety and efficacy of the TIL therapy OBX-115 in adult advanced solid tumors in melanoma or non–small cell lung cancer. The first-in-human results of a previous trial were presented at the ASCO 2024 meeting, and OBX-115 received FDA fast track designation in July.
“I think the results are really promising,” said Betof Warner. “This is an engineered TIL that does not require administering IL-2 to the patient. There were four out of the nine patients who responded to the treatment and there were no dose-limiting toxicities, no cytokine and no intracranial — all of which is excellent.”
For Betof Warner, the possibility that by using their own immune system, patients with advanced and refractory cancers could soon have a one-time treatment with a cell therapy rather than innumerable bouts of chemotherapy pushes her onward.
“The idea that we can treat cancer one time and have it not recur for years — that’s pushing the start of saying there’s a cure of cancer. That a person could move on from cancer like they move on from an infection. That is the potential of this work. We’re not there yet, but that’s where we need to think and dream big,” she said.
Betof Warner disclosed consulting/advisory roles with BluePath Solutions, Bristol-Myers Squibb/Medarex, Immatics, Instil Bio, Iovance Biotherapeutics, Lyell Immunopharma, Merck, Novartis, and Pfizer and research funding and travel expenses from Iovance Biotherapeutics.
A version of this article appeared on Medscape.com.
Surveillance Instead of Surgery for Low-Risk DCIS?
At 2 years, investigators on the COMET trial found no clinically meaningful difference in the rates of ipsilateral invasive breast cancer among women randomized to active surveillance vs standard upfront surgery with or without radiation.
The 2-year findings suggest that surveillance is safe in the short term.
“While these results are provocative, I don’t think they’re quite practice-changing yet,” said lead investigator Shelley Hwang, MD, a surgical breast oncologist at Duke University in Durham, North Carolina, who presented the findings at the San Antonio Breast Cancer Symposium (SABCS) 2024.
For one thing, it generally takes longer than 2 years for DCIS to convert to invasive cancer, so it will be important to wait for the planned analyses at 5, 7, and 10 years to make sure there isn’t an excess number of invasive breast cancers in the surveillance arm, Hwang said.
If the results prove durable, however, the findings will likely be “practice-changing” for women who were at least 40 years old and had grade 1 or 2 hormone receptor–positive DCIS at low risk for conversion, Hwang said.
The goal of active surveillance is to prevent unnecessary treatment. During surveillance, lesions are monitored for changes that indicate conversion to more advanced disease, at which point guideline-concordant care begins.
Although DCIS can convert to invasive breast cancer, this doesn’t always happen. As a result, upfront surgery and radiation aren’t necessary for some women.
The COMET trial aimed to determine the short-term safety of an active monitoring approach compared with guideline-concordant care in patients with low-risk DCIS.
The prospective, randomized noninferiority trial included women aged 40 years or older with a new diagnosis of HR–positive grade 1 or grade 2 DCIS without invasive cancer from 100 US Alliance Cancer Cooperative Group clinical trial sites.
In the trial, 484 women with DCIS were randomized to active surveillance — breast mammography and physical exam every 6 months — and 473 were randomized to standard upfront surgery with or without radiation. Overall, 15.7% of participants were Black and 75.0% were White.
Patients in either group could elect to have endocrine therapy, typically over a 5-year period (71% of women in the active monitoring group and 65.5% in the surgery group opted for endocrine therapy).
At 2 years, the cumulative rate of ipsilateral invasive breast cancer was 4.2% in the surveillance group vs 5.9% in the upfront surgery arm.
The study also included a planned per-protocol analysis among 673 patients who strictly followed the study protocol — 246 in the guideline-concordant care group who had received surgery by 6 months and 427 in the surveillance group who initiated the active monitoring protocol at 6 months.
With almost half of patients randomized to surgery declined to have it, which indicates that patients are interested in active monitoring, Hwang said.
At 2 years, the cumulative rate of invasive breast cancer was 3.1% in the active surveillance group vs 8.7% in the upfront surgery arm.
Among patients receiving endocrine therapy, the rate of invasive cancer was 7.15% in the surgery group and 3.21% in the surveillance arm.
Endocrine therapy “may have resulted in a reduced rate of invasive cancer in the active monitoring group,” the study authors noted.
These findings bring up the question of whether endocrine therapy might be just as good as surgery for low-risk DCIS, Hwang added. Given that one third of women undergo mastectomy for DCIS, “I think it’s not an inconsequential question,” Hwang said.
The findings, however, also suggest that surveillance sometimes leaves invasive cancer behind, Hwang explained. Nearly all invasive cancers in the surgery group were found during the initial operation , which may explain the slightly higher rates of invasive cancers in this group. Had the active monitoring group undergone surgery as well, the incidence of invasive cancer may have been the same in both arms, Hwang said.
However, when invasive cancers were removed, there were no significant differences in tumor size, node status, or tumor grade between the two groups, suggesting that there might not be a clinical penalty for delayed intervention with active monitoring, Hwang said.
With more than 10% of patients in the surgery group opting for mastectomy, compared with 1.8% in the active monitoring group, the active monitoring approach may not increase the likelihood of an eventual need for more extensive surgery, the COMET authors explained.
What Strategy Do Patients Prefer?
A companion analysis of patient-reported outcomes in COMET found no meaningful differences in quality of life, symptoms, or anxiety among patients who opted for surveillance over surgery. Results from questionnaires on quality of life, anxiety, depression, and breast cancer concerns were comparable between the two groups, with no evidence of a substantial impact of one approach over the other at 2 years.
“The results of this secondary analysis suggest that the lived experiences of individuals with low-risk DCIS are similar during early follow-up regardless of treatment allocation,” the COMET investigators concluded.
Overall, the findings from COMET provide reassuring short-term data, said Neil Iyengar, MD, a medical breast oncologist at Memorial Sloan Kettering Cancer Center in New York City.
DCIS is not an aggressive cancer, and it’s not going to invade any time soon, so patients have time to consider their options, Iyengar told Medscape Medical News.
The 2-year findings from COMET also help inform patient discussions. “I can tell patients if they decide not to have surgery what the likelihood is that they are going to convert into invasive cancer” after 2 years, he said.
COMET was published in JAMA, and the PRO analysis was published in JAMA Oncology to coincide with the study presentations.
COMET is funded by the Patient-Centered Outcomes Research Institute and others. Hwang is a consultant for Merck and on the advisory board of Clinetic, Exai Bio, and Havah Therapeutics. Iyengar is an advisor and/or researcher for AstraZeneca, Novartis, Pfizer, and other companies.
A version of this article first appeared on Medscape.com.
At 2 years, investigators on the COMET trial found no clinically meaningful difference in the rates of ipsilateral invasive breast cancer among women randomized to active surveillance vs standard upfront surgery with or without radiation.
The 2-year findings suggest that surveillance is safe in the short term.
“While these results are provocative, I don’t think they’re quite practice-changing yet,” said lead investigator Shelley Hwang, MD, a surgical breast oncologist at Duke University in Durham, North Carolina, who presented the findings at the San Antonio Breast Cancer Symposium (SABCS) 2024.
For one thing, it generally takes longer than 2 years for DCIS to convert to invasive cancer, so it will be important to wait for the planned analyses at 5, 7, and 10 years to make sure there isn’t an excess number of invasive breast cancers in the surveillance arm, Hwang said.
If the results prove durable, however, the findings will likely be “practice-changing” for women who were at least 40 years old and had grade 1 or 2 hormone receptor–positive DCIS at low risk for conversion, Hwang said.
The goal of active surveillance is to prevent unnecessary treatment. During surveillance, lesions are monitored for changes that indicate conversion to more advanced disease, at which point guideline-concordant care begins.
Although DCIS can convert to invasive breast cancer, this doesn’t always happen. As a result, upfront surgery and radiation aren’t necessary for some women.
The COMET trial aimed to determine the short-term safety of an active monitoring approach compared with guideline-concordant care in patients with low-risk DCIS.
The prospective, randomized noninferiority trial included women aged 40 years or older with a new diagnosis of HR–positive grade 1 or grade 2 DCIS without invasive cancer from 100 US Alliance Cancer Cooperative Group clinical trial sites.
In the trial, 484 women with DCIS were randomized to active surveillance — breast mammography and physical exam every 6 months — and 473 were randomized to standard upfront surgery with or without radiation. Overall, 15.7% of participants were Black and 75.0% were White.
Patients in either group could elect to have endocrine therapy, typically over a 5-year period (71% of women in the active monitoring group and 65.5% in the surgery group opted for endocrine therapy).
At 2 years, the cumulative rate of ipsilateral invasive breast cancer was 4.2% in the surveillance group vs 5.9% in the upfront surgery arm.
The study also included a planned per-protocol analysis among 673 patients who strictly followed the study protocol — 246 in the guideline-concordant care group who had received surgery by 6 months and 427 in the surveillance group who initiated the active monitoring protocol at 6 months.
With almost half of patients randomized to surgery declined to have it, which indicates that patients are interested in active monitoring, Hwang said.
At 2 years, the cumulative rate of invasive breast cancer was 3.1% in the active surveillance group vs 8.7% in the upfront surgery arm.
Among patients receiving endocrine therapy, the rate of invasive cancer was 7.15% in the surgery group and 3.21% in the surveillance arm.
Endocrine therapy “may have resulted in a reduced rate of invasive cancer in the active monitoring group,” the study authors noted.
These findings bring up the question of whether endocrine therapy might be just as good as surgery for low-risk DCIS, Hwang added. Given that one third of women undergo mastectomy for DCIS, “I think it’s not an inconsequential question,” Hwang said.
The findings, however, also suggest that surveillance sometimes leaves invasive cancer behind, Hwang explained. Nearly all invasive cancers in the surgery group were found during the initial operation , which may explain the slightly higher rates of invasive cancers in this group. Had the active monitoring group undergone surgery as well, the incidence of invasive cancer may have been the same in both arms, Hwang said.
However, when invasive cancers were removed, there were no significant differences in tumor size, node status, or tumor grade between the two groups, suggesting that there might not be a clinical penalty for delayed intervention with active monitoring, Hwang said.
With more than 10% of patients in the surgery group opting for mastectomy, compared with 1.8% in the active monitoring group, the active monitoring approach may not increase the likelihood of an eventual need for more extensive surgery, the COMET authors explained.
What Strategy Do Patients Prefer?
A companion analysis of patient-reported outcomes in COMET found no meaningful differences in quality of life, symptoms, or anxiety among patients who opted for surveillance over surgery. Results from questionnaires on quality of life, anxiety, depression, and breast cancer concerns were comparable between the two groups, with no evidence of a substantial impact of one approach over the other at 2 years.
“The results of this secondary analysis suggest that the lived experiences of individuals with low-risk DCIS are similar during early follow-up regardless of treatment allocation,” the COMET investigators concluded.
Overall, the findings from COMET provide reassuring short-term data, said Neil Iyengar, MD, a medical breast oncologist at Memorial Sloan Kettering Cancer Center in New York City.
DCIS is not an aggressive cancer, and it’s not going to invade any time soon, so patients have time to consider their options, Iyengar told Medscape Medical News.
The 2-year findings from COMET also help inform patient discussions. “I can tell patients if they decide not to have surgery what the likelihood is that they are going to convert into invasive cancer” after 2 years, he said.
COMET was published in JAMA, and the PRO analysis was published in JAMA Oncology to coincide with the study presentations.
COMET is funded by the Patient-Centered Outcomes Research Institute and others. Hwang is a consultant for Merck and on the advisory board of Clinetic, Exai Bio, and Havah Therapeutics. Iyengar is an advisor and/or researcher for AstraZeneca, Novartis, Pfizer, and other companies.
A version of this article first appeared on Medscape.com.
At 2 years, investigators on the COMET trial found no clinically meaningful difference in the rates of ipsilateral invasive breast cancer among women randomized to active surveillance vs standard upfront surgery with or without radiation.
The 2-year findings suggest that surveillance is safe in the short term.
“While these results are provocative, I don’t think they’re quite practice-changing yet,” said lead investigator Shelley Hwang, MD, a surgical breast oncologist at Duke University in Durham, North Carolina, who presented the findings at the San Antonio Breast Cancer Symposium (SABCS) 2024.
For one thing, it generally takes longer than 2 years for DCIS to convert to invasive cancer, so it will be important to wait for the planned analyses at 5, 7, and 10 years to make sure there isn’t an excess number of invasive breast cancers in the surveillance arm, Hwang said.
If the results prove durable, however, the findings will likely be “practice-changing” for women who were at least 40 years old and had grade 1 or 2 hormone receptor–positive DCIS at low risk for conversion, Hwang said.
The goal of active surveillance is to prevent unnecessary treatment. During surveillance, lesions are monitored for changes that indicate conversion to more advanced disease, at which point guideline-concordant care begins.
Although DCIS can convert to invasive breast cancer, this doesn’t always happen. As a result, upfront surgery and radiation aren’t necessary for some women.
The COMET trial aimed to determine the short-term safety of an active monitoring approach compared with guideline-concordant care in patients with low-risk DCIS.
The prospective, randomized noninferiority trial included women aged 40 years or older with a new diagnosis of HR–positive grade 1 or grade 2 DCIS without invasive cancer from 100 US Alliance Cancer Cooperative Group clinical trial sites.
In the trial, 484 women with DCIS were randomized to active surveillance — breast mammography and physical exam every 6 months — and 473 were randomized to standard upfront surgery with or without radiation. Overall, 15.7% of participants were Black and 75.0% were White.
Patients in either group could elect to have endocrine therapy, typically over a 5-year period (71% of women in the active monitoring group and 65.5% in the surgery group opted for endocrine therapy).
At 2 years, the cumulative rate of ipsilateral invasive breast cancer was 4.2% in the surveillance group vs 5.9% in the upfront surgery arm.
The study also included a planned per-protocol analysis among 673 patients who strictly followed the study protocol — 246 in the guideline-concordant care group who had received surgery by 6 months and 427 in the surveillance group who initiated the active monitoring protocol at 6 months.
With almost half of patients randomized to surgery declined to have it, which indicates that patients are interested in active monitoring, Hwang said.
At 2 years, the cumulative rate of invasive breast cancer was 3.1% in the active surveillance group vs 8.7% in the upfront surgery arm.
Among patients receiving endocrine therapy, the rate of invasive cancer was 7.15% in the surgery group and 3.21% in the surveillance arm.
Endocrine therapy “may have resulted in a reduced rate of invasive cancer in the active monitoring group,” the study authors noted.
These findings bring up the question of whether endocrine therapy might be just as good as surgery for low-risk DCIS, Hwang added. Given that one third of women undergo mastectomy for DCIS, “I think it’s not an inconsequential question,” Hwang said.
The findings, however, also suggest that surveillance sometimes leaves invasive cancer behind, Hwang explained. Nearly all invasive cancers in the surgery group were found during the initial operation , which may explain the slightly higher rates of invasive cancers in this group. Had the active monitoring group undergone surgery as well, the incidence of invasive cancer may have been the same in both arms, Hwang said.
However, when invasive cancers were removed, there were no significant differences in tumor size, node status, or tumor grade between the two groups, suggesting that there might not be a clinical penalty for delayed intervention with active monitoring, Hwang said.
With more than 10% of patients in the surgery group opting for mastectomy, compared with 1.8% in the active monitoring group, the active monitoring approach may not increase the likelihood of an eventual need for more extensive surgery, the COMET authors explained.
What Strategy Do Patients Prefer?
A companion analysis of patient-reported outcomes in COMET found no meaningful differences in quality of life, symptoms, or anxiety among patients who opted for surveillance over surgery. Results from questionnaires on quality of life, anxiety, depression, and breast cancer concerns were comparable between the two groups, with no evidence of a substantial impact of one approach over the other at 2 years.
“The results of this secondary analysis suggest that the lived experiences of individuals with low-risk DCIS are similar during early follow-up regardless of treatment allocation,” the COMET investigators concluded.
Overall, the findings from COMET provide reassuring short-term data, said Neil Iyengar, MD, a medical breast oncologist at Memorial Sloan Kettering Cancer Center in New York City.
DCIS is not an aggressive cancer, and it’s not going to invade any time soon, so patients have time to consider their options, Iyengar told Medscape Medical News.
The 2-year findings from COMET also help inform patient discussions. “I can tell patients if they decide not to have surgery what the likelihood is that they are going to convert into invasive cancer” after 2 years, he said.
COMET was published in JAMA, and the PRO analysis was published in JAMA Oncology to coincide with the study presentations.
COMET is funded by the Patient-Centered Outcomes Research Institute and others. Hwang is a consultant for Merck and on the advisory board of Clinetic, Exai Bio, and Havah Therapeutics. Iyengar is an advisor and/or researcher for AstraZeneca, Novartis, Pfizer, and other companies.
A version of this article first appeared on Medscape.com.
FROM SABCS 2024
FDA Approves Cosibelimab for Cutaneous SCC
The programmed death ligand-1 (PD-L1)–blocking antibody is the first and only treatment of its kind approved for advanced CSCC, according to a Checkpoint Therapeutics press release. The FDA approval was based on findings from the multicenter, open-label Study CK-301-101 trial of 109 patients.
In that trial, the objective response rate (ORR) was 47% in 78 patients with metastatic CSCC and 48% in 31 patients with locally advanced CSCC. Median duration of response (DOR) in treated patients was not reached in those with metastatic disease and was 17.7 months in those with locally advanced disease, according to the FDA approval notice.
Adverse reactions occurring in at least 10% of patients included fatigue, musculoskeletal pain, rash, diarrhea, hypothyroidism, constipation, nausea, headache, pruritus, edema, localized infection, and urinary tract infection.
The recommended treatment dose, according to the prescribing information, is 1200 mg given as an intravenous infusion over 60 minutes every 3 weeks until disease progression or unacceptable toxicity.
The agent offers “a differentiated treatment option versus available therapies by binding to PD-L1, rather than programmed death receptor-1 (PD-1), to release the inhibitory effects of PD-L1 on the anti-tumor immune response,” Checkpoint Therapeutics president and chief executive officer James Oliviero stated in the company press release.
The agent has also “demonstrated the ability to induce antibody-dependent cell-mediated cytotoxicity, another potential differentiating feature of the drug compared to existing marketing therapies for CSCC,” Oliviero noted.
“CSCC is the second most common form of skin cancer, and those diagnosed with advanced disease that has recurred or metastasized face a poor prognosis,” stated Emily Ruiz, MD, academic director of the Mohs and Dermatologic Surgery Center at Brigham and Women’s Hospital and director of the High-Risk Skin Cancer Clinic at Dana-Farber Brigham Cancer Center.
“With its dual mechanisms of action and compelling safety profile, this promising drug will provide US oncologists with an important new immunotherapy option for the treatment of CSCC,” she added.
A version of this article appeared on Medscape.com.
The programmed death ligand-1 (PD-L1)–blocking antibody is the first and only treatment of its kind approved for advanced CSCC, according to a Checkpoint Therapeutics press release. The FDA approval was based on findings from the multicenter, open-label Study CK-301-101 trial of 109 patients.
In that trial, the objective response rate (ORR) was 47% in 78 patients with metastatic CSCC and 48% in 31 patients with locally advanced CSCC. Median duration of response (DOR) in treated patients was not reached in those with metastatic disease and was 17.7 months in those with locally advanced disease, according to the FDA approval notice.
Adverse reactions occurring in at least 10% of patients included fatigue, musculoskeletal pain, rash, diarrhea, hypothyroidism, constipation, nausea, headache, pruritus, edema, localized infection, and urinary tract infection.
The recommended treatment dose, according to the prescribing information, is 1200 mg given as an intravenous infusion over 60 minutes every 3 weeks until disease progression or unacceptable toxicity.
The agent offers “a differentiated treatment option versus available therapies by binding to PD-L1, rather than programmed death receptor-1 (PD-1), to release the inhibitory effects of PD-L1 on the anti-tumor immune response,” Checkpoint Therapeutics president and chief executive officer James Oliviero stated in the company press release.
The agent has also “demonstrated the ability to induce antibody-dependent cell-mediated cytotoxicity, another potential differentiating feature of the drug compared to existing marketing therapies for CSCC,” Oliviero noted.
“CSCC is the second most common form of skin cancer, and those diagnosed with advanced disease that has recurred or metastasized face a poor prognosis,” stated Emily Ruiz, MD, academic director of the Mohs and Dermatologic Surgery Center at Brigham and Women’s Hospital and director of the High-Risk Skin Cancer Clinic at Dana-Farber Brigham Cancer Center.
“With its dual mechanisms of action and compelling safety profile, this promising drug will provide US oncologists with an important new immunotherapy option for the treatment of CSCC,” she added.
A version of this article appeared on Medscape.com.
The programmed death ligand-1 (PD-L1)–blocking antibody is the first and only treatment of its kind approved for advanced CSCC, according to a Checkpoint Therapeutics press release. The FDA approval was based on findings from the multicenter, open-label Study CK-301-101 trial of 109 patients.
In that trial, the objective response rate (ORR) was 47% in 78 patients with metastatic CSCC and 48% in 31 patients with locally advanced CSCC. Median duration of response (DOR) in treated patients was not reached in those with metastatic disease and was 17.7 months in those with locally advanced disease, according to the FDA approval notice.
Adverse reactions occurring in at least 10% of patients included fatigue, musculoskeletal pain, rash, diarrhea, hypothyroidism, constipation, nausea, headache, pruritus, edema, localized infection, and urinary tract infection.
The recommended treatment dose, according to the prescribing information, is 1200 mg given as an intravenous infusion over 60 minutes every 3 weeks until disease progression or unacceptable toxicity.
The agent offers “a differentiated treatment option versus available therapies by binding to PD-L1, rather than programmed death receptor-1 (PD-1), to release the inhibitory effects of PD-L1 on the anti-tumor immune response,” Checkpoint Therapeutics president and chief executive officer James Oliviero stated in the company press release.
The agent has also “demonstrated the ability to induce antibody-dependent cell-mediated cytotoxicity, another potential differentiating feature of the drug compared to existing marketing therapies for CSCC,” Oliviero noted.
“CSCC is the second most common form of skin cancer, and those diagnosed with advanced disease that has recurred or metastasized face a poor prognosis,” stated Emily Ruiz, MD, academic director of the Mohs and Dermatologic Surgery Center at Brigham and Women’s Hospital and director of the High-Risk Skin Cancer Clinic at Dana-Farber Brigham Cancer Center.
“With its dual mechanisms of action and compelling safety profile, this promising drug will provide US oncologists with an important new immunotherapy option for the treatment of CSCC,” she added.
A version of this article appeared on Medscape.com.
Tamoxifen Reduces Risk for Invasive Recurrence of Ductal Carcinoma
These findings come from an exploratory analysis of combined data from two clinical trials. They suggest that, for this select group of patients, the choice to forgo radiation following definitive surgery may be an acceptable option, assuming that they follow a full course of endocrine therapy.
“In the absence of survival impact for adjuvant therapy, the decision to recommend radiation therapy or endocrine therapy should be part of a shared decision process, and I think that this data helps us provide clearer data points to our patients to help them make choices between endocrine therapy and radiation therapy in the setting of good-risk [ductal carcinoma in situ],” said Jean L. Wright, MD, from the University of North Carolina at Chapel Hill.
She presented the findings in an oral abstract session and media briefing at San Antonio Breast Cancer Symposium (SABCS) 2024.
Trial Results Combined
Wright and colleagues looked at pooled data from two clinical trials that enrolled patients with low- or intermediate-grade DCIS with tumor size no larger than 2.5 cm, grade 1 or 2 lesions, and with surgical margins ≥ 3 mm.
The trials included NRG/RTOG 9804, with 317 patients who fit the “good-risk category,” and ECOG-ACRIN E5194, which included a cohort of 561 patients that met the good-risk definition used for the exploratory analysis.
In each trial, tamoxifen use was optional, and choices were tracked. In the NRG/RTOG trial, 66% of patients used tamoxifen and 34% did not. The respective percentages in the ECOG/ACRIN trial were 30% and 70%.
The majority of patients were adherent to the 5-year prescribed course of tamoxifen, Wright said.
Analysis Details
In the combined data, the median age of patients who used tamoxifen vs who did not use tamoxifen was 58 vs 61 years.
In all, 23% of women in both the tamoxifen yes or no groups were premenopausal, with the remainder either postmenopausal or of unknown menopausal status.
After a median follow-up of 14.85 years, the rate of 15-year ipsilateral breast recurrence (IBR) was 19% for patients who did not receive tamoxifen vs 11.4% for those who did. This translated into a hazard ratio for IBR on tamoxifen of 0.52 (P = .001).
Tamoxifen also reduced the risk for invasive recurrence in the same breast, with a 15-year invasive IBR rate of 11.5% in the no tamoxifen group vs 6% in the yes tamoxifen group.
However, as noted before, tamoxifen use was not associated with significant reduction in the risk for noninvasive DCIS recurrence in the same breast, as evidenced by a 15-year DCIS IBR rate of 8.1% without tamoxifen and 5.5% with tamoxifen, a difference that did not reach statistical significance.
A Surprising Result
One finding from the data that seemed to defy clinical wisdom was that tamoxifen use did not appear to significantly reduce the risk for events in the other breast. The 15-year rate of contralateral breast events was 8.8% in the no-tamoxifen group vs 5.6% in the yes tamoxifen group, a difference that was not statically significant.
“It was surprising that there was so little effect on contralateral disease,” commented Elinor Sawyer, MBBS, PhD, the invited discussant.
“But I think it’s really important, this decrease in ipsilateral invasive recurrence [with tamoxifen] because there are studies such as the Sloane study from the United Kingdom that show that if you develop an invasive recurrence after DCIS, you have a worse survival than those who develop a pure DCIS recurrence,” she said.
At the media briefing held prior to Wright’s presentation, moderator Virginia Kaklamani, MD, leader of the breast cancer program at UT Health San Antonio in Texas, also said that she found it surprising that tamoxifen did not reduce risk for contralateral breast cancer “since every study that we’ve done has shown that.”
“I also found that result a little bit surprising,” Wright agreed.
“I think the main feature that we want to focus on is that this was a group of patients with a very clear inclusion criteria of this good-risk DCIS, and even though the definition of good-risk DCIS included patients with [tumors] up to 2.5 cm in DCIS, we saw that, in reality, the patients enrolled had very small DCIS. So I’m wondering if it’s perhaps that it’s related to the fact that patients that were enrolled in these studies had really low-risk features and perhaps just had a lower risk of contralateral breast events as compared to a broader population of patients with DCIS,” she said.
The analysis by Wright and colleagues was supported by grants from the National Cancer Institute. Wright reported receiving honoraria from ASTRO and PER. Sawyer disclosed receiving grants/research support from Pfizer, Seagen, and IQIVIA. Kaklamani disclosed serving as a speaker and/or consultant for AstraZeneca, Celldex Therapeutics, Daiichi Sankyo, Genentech, Gilead, Lilly, Menarini, and Novartis and receiving research support from Eisai.
A version of this article first appeared on Medscape.com.
These findings come from an exploratory analysis of combined data from two clinical trials. They suggest that, for this select group of patients, the choice to forgo radiation following definitive surgery may be an acceptable option, assuming that they follow a full course of endocrine therapy.
“In the absence of survival impact for adjuvant therapy, the decision to recommend radiation therapy or endocrine therapy should be part of a shared decision process, and I think that this data helps us provide clearer data points to our patients to help them make choices between endocrine therapy and radiation therapy in the setting of good-risk [ductal carcinoma in situ],” said Jean L. Wright, MD, from the University of North Carolina at Chapel Hill.
She presented the findings in an oral abstract session and media briefing at San Antonio Breast Cancer Symposium (SABCS) 2024.
Trial Results Combined
Wright and colleagues looked at pooled data from two clinical trials that enrolled patients with low- or intermediate-grade DCIS with tumor size no larger than 2.5 cm, grade 1 or 2 lesions, and with surgical margins ≥ 3 mm.
The trials included NRG/RTOG 9804, with 317 patients who fit the “good-risk category,” and ECOG-ACRIN E5194, which included a cohort of 561 patients that met the good-risk definition used for the exploratory analysis.
In each trial, tamoxifen use was optional, and choices were tracked. In the NRG/RTOG trial, 66% of patients used tamoxifen and 34% did not. The respective percentages in the ECOG/ACRIN trial were 30% and 70%.
The majority of patients were adherent to the 5-year prescribed course of tamoxifen, Wright said.
Analysis Details
In the combined data, the median age of patients who used tamoxifen vs who did not use tamoxifen was 58 vs 61 years.
In all, 23% of women in both the tamoxifen yes or no groups were premenopausal, with the remainder either postmenopausal or of unknown menopausal status.
After a median follow-up of 14.85 years, the rate of 15-year ipsilateral breast recurrence (IBR) was 19% for patients who did not receive tamoxifen vs 11.4% for those who did. This translated into a hazard ratio for IBR on tamoxifen of 0.52 (P = .001).
Tamoxifen also reduced the risk for invasive recurrence in the same breast, with a 15-year invasive IBR rate of 11.5% in the no tamoxifen group vs 6% in the yes tamoxifen group.
However, as noted before, tamoxifen use was not associated with significant reduction in the risk for noninvasive DCIS recurrence in the same breast, as evidenced by a 15-year DCIS IBR rate of 8.1% without tamoxifen and 5.5% with tamoxifen, a difference that did not reach statistical significance.
A Surprising Result
One finding from the data that seemed to defy clinical wisdom was that tamoxifen use did not appear to significantly reduce the risk for events in the other breast. The 15-year rate of contralateral breast events was 8.8% in the no-tamoxifen group vs 5.6% in the yes tamoxifen group, a difference that was not statically significant.
“It was surprising that there was so little effect on contralateral disease,” commented Elinor Sawyer, MBBS, PhD, the invited discussant.
“But I think it’s really important, this decrease in ipsilateral invasive recurrence [with tamoxifen] because there are studies such as the Sloane study from the United Kingdom that show that if you develop an invasive recurrence after DCIS, you have a worse survival than those who develop a pure DCIS recurrence,” she said.
At the media briefing held prior to Wright’s presentation, moderator Virginia Kaklamani, MD, leader of the breast cancer program at UT Health San Antonio in Texas, also said that she found it surprising that tamoxifen did not reduce risk for contralateral breast cancer “since every study that we’ve done has shown that.”
“I also found that result a little bit surprising,” Wright agreed.
“I think the main feature that we want to focus on is that this was a group of patients with a very clear inclusion criteria of this good-risk DCIS, and even though the definition of good-risk DCIS included patients with [tumors] up to 2.5 cm in DCIS, we saw that, in reality, the patients enrolled had very small DCIS. So I’m wondering if it’s perhaps that it’s related to the fact that patients that were enrolled in these studies had really low-risk features and perhaps just had a lower risk of contralateral breast events as compared to a broader population of patients with DCIS,” she said.
The analysis by Wright and colleagues was supported by grants from the National Cancer Institute. Wright reported receiving honoraria from ASTRO and PER. Sawyer disclosed receiving grants/research support from Pfizer, Seagen, and IQIVIA. Kaklamani disclosed serving as a speaker and/or consultant for AstraZeneca, Celldex Therapeutics, Daiichi Sankyo, Genentech, Gilead, Lilly, Menarini, and Novartis and receiving research support from Eisai.
A version of this article first appeared on Medscape.com.
These findings come from an exploratory analysis of combined data from two clinical trials. They suggest that, for this select group of patients, the choice to forgo radiation following definitive surgery may be an acceptable option, assuming that they follow a full course of endocrine therapy.
“In the absence of survival impact for adjuvant therapy, the decision to recommend radiation therapy or endocrine therapy should be part of a shared decision process, and I think that this data helps us provide clearer data points to our patients to help them make choices between endocrine therapy and radiation therapy in the setting of good-risk [ductal carcinoma in situ],” said Jean L. Wright, MD, from the University of North Carolina at Chapel Hill.
She presented the findings in an oral abstract session and media briefing at San Antonio Breast Cancer Symposium (SABCS) 2024.
Trial Results Combined
Wright and colleagues looked at pooled data from two clinical trials that enrolled patients with low- or intermediate-grade DCIS with tumor size no larger than 2.5 cm, grade 1 or 2 lesions, and with surgical margins ≥ 3 mm.
The trials included NRG/RTOG 9804, with 317 patients who fit the “good-risk category,” and ECOG-ACRIN E5194, which included a cohort of 561 patients that met the good-risk definition used for the exploratory analysis.
In each trial, tamoxifen use was optional, and choices were tracked. In the NRG/RTOG trial, 66% of patients used tamoxifen and 34% did not. The respective percentages in the ECOG/ACRIN trial were 30% and 70%.
The majority of patients were adherent to the 5-year prescribed course of tamoxifen, Wright said.
Analysis Details
In the combined data, the median age of patients who used tamoxifen vs who did not use tamoxifen was 58 vs 61 years.
In all, 23% of women in both the tamoxifen yes or no groups were premenopausal, with the remainder either postmenopausal or of unknown menopausal status.
After a median follow-up of 14.85 years, the rate of 15-year ipsilateral breast recurrence (IBR) was 19% for patients who did not receive tamoxifen vs 11.4% for those who did. This translated into a hazard ratio for IBR on tamoxifen of 0.52 (P = .001).
Tamoxifen also reduced the risk for invasive recurrence in the same breast, with a 15-year invasive IBR rate of 11.5% in the no tamoxifen group vs 6% in the yes tamoxifen group.
However, as noted before, tamoxifen use was not associated with significant reduction in the risk for noninvasive DCIS recurrence in the same breast, as evidenced by a 15-year DCIS IBR rate of 8.1% without tamoxifen and 5.5% with tamoxifen, a difference that did not reach statistical significance.
A Surprising Result
One finding from the data that seemed to defy clinical wisdom was that tamoxifen use did not appear to significantly reduce the risk for events in the other breast. The 15-year rate of contralateral breast events was 8.8% in the no-tamoxifen group vs 5.6% in the yes tamoxifen group, a difference that was not statically significant.
“It was surprising that there was so little effect on contralateral disease,” commented Elinor Sawyer, MBBS, PhD, the invited discussant.
“But I think it’s really important, this decrease in ipsilateral invasive recurrence [with tamoxifen] because there are studies such as the Sloane study from the United Kingdom that show that if you develop an invasive recurrence after DCIS, you have a worse survival than those who develop a pure DCIS recurrence,” she said.
At the media briefing held prior to Wright’s presentation, moderator Virginia Kaklamani, MD, leader of the breast cancer program at UT Health San Antonio in Texas, also said that she found it surprising that tamoxifen did not reduce risk for contralateral breast cancer “since every study that we’ve done has shown that.”
“I also found that result a little bit surprising,” Wright agreed.
“I think the main feature that we want to focus on is that this was a group of patients with a very clear inclusion criteria of this good-risk DCIS, and even though the definition of good-risk DCIS included patients with [tumors] up to 2.5 cm in DCIS, we saw that, in reality, the patients enrolled had very small DCIS. So I’m wondering if it’s perhaps that it’s related to the fact that patients that were enrolled in these studies had really low-risk features and perhaps just had a lower risk of contralateral breast events as compared to a broader population of patients with DCIS,” she said.
The analysis by Wright and colleagues was supported by grants from the National Cancer Institute. Wright reported receiving honoraria from ASTRO and PER. Sawyer disclosed receiving grants/research support from Pfizer, Seagen, and IQIVIA. Kaklamani disclosed serving as a speaker and/or consultant for AstraZeneca, Celldex Therapeutics, Daiichi Sankyo, Genentech, Gilead, Lilly, Menarini, and Novartis and receiving research support from Eisai.
A version of this article first appeared on Medscape.com.
FROM SABCS 2024
Imlunestrant Shows PFS Benefit in Advanced Breast Cancer
according to recent findings from the EMBER-3 trial.
This progression-free survival benefit with imlunestrant did not extend to the overall population, but a combination of imlunestrant plus abemaciclib did lead to a significant improvement in progression-free survival compared with imlunestrant alone, regardless of patients’ ESR1 mutation status.
Lead author Komal Jhaveri, MD, a breast oncologist at Memorial Sloan Kettering Cancer Center in New York City, called the findings “encouraging.”
The phase 3 results raise the possibility of a second-line all-oral targeted therapy option for patients with ER–positive, HER2–negative advanced breast cancer, said Jhaveri, who presented the findings at the San Antonio Breast Cancer Symposium (SABCS) 2024, which were published simultaneously in The New England Journal of Medicine.
However, outside experts provided a note of caution that the trial design may limit how relevant the findings are to clinical practice.
First-line treatment for advanced ER–positive, HER2–negative breast cancer includes an aromatase inhibitor, such as exemestane, and a CDK4/6 inhibitor, such as abemaciclib. However, an ESR1 mutation may develop, which can undermine the effectiveness of the aromatase inhibitor. These patients may swap in a selective estrogen receptor degrader (SERD) — typically, the injectable fulvestrant — in place of the aromatase inhibitor.
Over the past several years, researchers have searched for a better agent than fulvestrant because this injectable drug has limited efficacy in patients with ESR1 mutations, and the monthly intramuscular shots are painful and inconvenient for patients.
The oral SERD imlunestrant is one such candidate.
The EMBER-3 trial initially randomized 661 patients after progression/recurrence evenly to either imlunestrant monotherapy (400 mg once daily) or a standard treatment arm that included either exemestane or fulvestrant, with 90% of these patients receiving fulvestrant. Investigators added a third combination arm shortly after the trial started, which included 213 patients who received imlunestrant plus abemaciclib.
About 60% of the overall population had received prior CDK4/6 inhibitors, primarily palbociclib and ribociclib. About 37% of the study population had ESR1 mutations.
Among patients with ESR1 mutations, imlunestrant monotherapy led to a significant improvement in median progression-free survival of 5.5 months vs 3.8 months in the standard care arm (P < .001). Among all patients, however, progression-free survival was no different between the two arms — 5.6 months in the imlunestrant group vs 5.5 months in the standard care group.
When comparing the two treatment arms in the overall population, the median progression-free survival was significantly better in patients who received imlunestrant plus abemaciclib — 9.4 months vs 5.5 months in the imlunestrant group (hazard ratio [HR] for progression or death, 0.57; P < .001). The progression-free survival benefit held across most patient subgroups, regardless of ESR1 mutation status, as well as among patients who had received a CDK4/6 inhibitor previously.
Data from other studies presented at SABCS indicate that another SERD, elacestrant, in combination with abemaciclib, may provide a similar progression-free survival benefit in this patient population. Elacestrant was approved by the US Food and Drug Administration (FDA) in January 2023 for second-line treatment of patients with advanced breast cancer and ESR1 mutations.
The EMBER trial also reported early overall survival findings. Although immature, overall survival trends favored imlunestrant over the standard treatment. The estimated overall survival at 18 months was 77% in the imlunestrant group and 58.6% in the standard therapy group among patients with ESR1 mutations (HR, 0.55), and 78.6% in the imlunestrant group vs 71.8% in the standard-therapy group for all patients (HR, 0.69).
Common all-grade adverse events with imlunestrant vs standard therapy included fatigue (22.6% vs 13.3%), diarrhea (21.4% vs 11.7%), and nausea (17% vs 13%). Grade 3 or higher anemia and neutropenia were low and similar in both arms.
All-grade diarrhea (86%) and nausea (49%) were more common with the combination of imlunestrant and abemaciclib.
The incidence of grade 3 or higher events was 17% with imlunestrant monotherapy, 21% for standard treatment, and 49% for imlunestrant plus abemaciclib.
EMBER-3 discussant Harold Burstein, MD, PhD, a breast oncologist at the Dana-Farber Cancer Institute, Boston, said that, overall, oral SERDs are starting to “break out from the ESR1 mutation box,” perhaps reflecting the idea that an agent more active than fulvestrant in combination with a non-cross–resistant CDK4/6 inhibitor like abemaciclib might lead to a better long-term outcome, regardless of ESR1 status.
A major limit of EMBER-3, however, is that it did not compare imlunestrant/abemaciclib with fulvestrant/abemaciclib, which would have been a true standard-of-care control, said Burstein.
Kathy Miller, MD, a breast oncologist at Indiana University, Indianapolis, agreed.
She was also concerned about the use of monotherapy in the standard care arm.
“Monotherapy hormone therapy is not what people would be treated with,” Miller said. Patients would typically get fulvestrant with either a targeted therapy or everolimus.
Without appropriate controls, “the data are impossible to interpret” in the context of current practice, Miller told Medscape Medical News.
Eli Lilly, maker of imlunestrant, funded, designed, and largely conducted the trial. Jhaveri is a consultant and researcher for the company. Burstein and Miller had no disclosures. Miller is an editorial advisor for Medscape Oncology.
A version of this article appeared on Medscape.com.
according to recent findings from the EMBER-3 trial.
This progression-free survival benefit with imlunestrant did not extend to the overall population, but a combination of imlunestrant plus abemaciclib did lead to a significant improvement in progression-free survival compared with imlunestrant alone, regardless of patients’ ESR1 mutation status.
Lead author Komal Jhaveri, MD, a breast oncologist at Memorial Sloan Kettering Cancer Center in New York City, called the findings “encouraging.”
The phase 3 results raise the possibility of a second-line all-oral targeted therapy option for patients with ER–positive, HER2–negative advanced breast cancer, said Jhaveri, who presented the findings at the San Antonio Breast Cancer Symposium (SABCS) 2024, which were published simultaneously in The New England Journal of Medicine.
However, outside experts provided a note of caution that the trial design may limit how relevant the findings are to clinical practice.
First-line treatment for advanced ER–positive, HER2–negative breast cancer includes an aromatase inhibitor, such as exemestane, and a CDK4/6 inhibitor, such as abemaciclib. However, an ESR1 mutation may develop, which can undermine the effectiveness of the aromatase inhibitor. These patients may swap in a selective estrogen receptor degrader (SERD) — typically, the injectable fulvestrant — in place of the aromatase inhibitor.
Over the past several years, researchers have searched for a better agent than fulvestrant because this injectable drug has limited efficacy in patients with ESR1 mutations, and the monthly intramuscular shots are painful and inconvenient for patients.
The oral SERD imlunestrant is one such candidate.
The EMBER-3 trial initially randomized 661 patients after progression/recurrence evenly to either imlunestrant monotherapy (400 mg once daily) or a standard treatment arm that included either exemestane or fulvestrant, with 90% of these patients receiving fulvestrant. Investigators added a third combination arm shortly after the trial started, which included 213 patients who received imlunestrant plus abemaciclib.
About 60% of the overall population had received prior CDK4/6 inhibitors, primarily palbociclib and ribociclib. About 37% of the study population had ESR1 mutations.
Among patients with ESR1 mutations, imlunestrant monotherapy led to a significant improvement in median progression-free survival of 5.5 months vs 3.8 months in the standard care arm (P < .001). Among all patients, however, progression-free survival was no different between the two arms — 5.6 months in the imlunestrant group vs 5.5 months in the standard care group.
When comparing the two treatment arms in the overall population, the median progression-free survival was significantly better in patients who received imlunestrant plus abemaciclib — 9.4 months vs 5.5 months in the imlunestrant group (hazard ratio [HR] for progression or death, 0.57; P < .001). The progression-free survival benefit held across most patient subgroups, regardless of ESR1 mutation status, as well as among patients who had received a CDK4/6 inhibitor previously.
Data from other studies presented at SABCS indicate that another SERD, elacestrant, in combination with abemaciclib, may provide a similar progression-free survival benefit in this patient population. Elacestrant was approved by the US Food and Drug Administration (FDA) in January 2023 for second-line treatment of patients with advanced breast cancer and ESR1 mutations.
The EMBER trial also reported early overall survival findings. Although immature, overall survival trends favored imlunestrant over the standard treatment. The estimated overall survival at 18 months was 77% in the imlunestrant group and 58.6% in the standard therapy group among patients with ESR1 mutations (HR, 0.55), and 78.6% in the imlunestrant group vs 71.8% in the standard-therapy group for all patients (HR, 0.69).
Common all-grade adverse events with imlunestrant vs standard therapy included fatigue (22.6% vs 13.3%), diarrhea (21.4% vs 11.7%), and nausea (17% vs 13%). Grade 3 or higher anemia and neutropenia were low and similar in both arms.
All-grade diarrhea (86%) and nausea (49%) were more common with the combination of imlunestrant and abemaciclib.
The incidence of grade 3 or higher events was 17% with imlunestrant monotherapy, 21% for standard treatment, and 49% for imlunestrant plus abemaciclib.
EMBER-3 discussant Harold Burstein, MD, PhD, a breast oncologist at the Dana-Farber Cancer Institute, Boston, said that, overall, oral SERDs are starting to “break out from the ESR1 mutation box,” perhaps reflecting the idea that an agent more active than fulvestrant in combination with a non-cross–resistant CDK4/6 inhibitor like abemaciclib might lead to a better long-term outcome, regardless of ESR1 status.
A major limit of EMBER-3, however, is that it did not compare imlunestrant/abemaciclib with fulvestrant/abemaciclib, which would have been a true standard-of-care control, said Burstein.
Kathy Miller, MD, a breast oncologist at Indiana University, Indianapolis, agreed.
She was also concerned about the use of monotherapy in the standard care arm.
“Monotherapy hormone therapy is not what people would be treated with,” Miller said. Patients would typically get fulvestrant with either a targeted therapy or everolimus.
Without appropriate controls, “the data are impossible to interpret” in the context of current practice, Miller told Medscape Medical News.
Eli Lilly, maker of imlunestrant, funded, designed, and largely conducted the trial. Jhaveri is a consultant and researcher for the company. Burstein and Miller had no disclosures. Miller is an editorial advisor for Medscape Oncology.
A version of this article appeared on Medscape.com.
according to recent findings from the EMBER-3 trial.
This progression-free survival benefit with imlunestrant did not extend to the overall population, but a combination of imlunestrant plus abemaciclib did lead to a significant improvement in progression-free survival compared with imlunestrant alone, regardless of patients’ ESR1 mutation status.
Lead author Komal Jhaveri, MD, a breast oncologist at Memorial Sloan Kettering Cancer Center in New York City, called the findings “encouraging.”
The phase 3 results raise the possibility of a second-line all-oral targeted therapy option for patients with ER–positive, HER2–negative advanced breast cancer, said Jhaveri, who presented the findings at the San Antonio Breast Cancer Symposium (SABCS) 2024, which were published simultaneously in The New England Journal of Medicine.
However, outside experts provided a note of caution that the trial design may limit how relevant the findings are to clinical practice.
First-line treatment for advanced ER–positive, HER2–negative breast cancer includes an aromatase inhibitor, such as exemestane, and a CDK4/6 inhibitor, such as abemaciclib. However, an ESR1 mutation may develop, which can undermine the effectiveness of the aromatase inhibitor. These patients may swap in a selective estrogen receptor degrader (SERD) — typically, the injectable fulvestrant — in place of the aromatase inhibitor.
Over the past several years, researchers have searched for a better agent than fulvestrant because this injectable drug has limited efficacy in patients with ESR1 mutations, and the monthly intramuscular shots are painful and inconvenient for patients.
The oral SERD imlunestrant is one such candidate.
The EMBER-3 trial initially randomized 661 patients after progression/recurrence evenly to either imlunestrant monotherapy (400 mg once daily) or a standard treatment arm that included either exemestane or fulvestrant, with 90% of these patients receiving fulvestrant. Investigators added a third combination arm shortly after the trial started, which included 213 patients who received imlunestrant plus abemaciclib.
About 60% of the overall population had received prior CDK4/6 inhibitors, primarily palbociclib and ribociclib. About 37% of the study population had ESR1 mutations.
Among patients with ESR1 mutations, imlunestrant monotherapy led to a significant improvement in median progression-free survival of 5.5 months vs 3.8 months in the standard care arm (P < .001). Among all patients, however, progression-free survival was no different between the two arms — 5.6 months in the imlunestrant group vs 5.5 months in the standard care group.
When comparing the two treatment arms in the overall population, the median progression-free survival was significantly better in patients who received imlunestrant plus abemaciclib — 9.4 months vs 5.5 months in the imlunestrant group (hazard ratio [HR] for progression or death, 0.57; P < .001). The progression-free survival benefit held across most patient subgroups, regardless of ESR1 mutation status, as well as among patients who had received a CDK4/6 inhibitor previously.
Data from other studies presented at SABCS indicate that another SERD, elacestrant, in combination with abemaciclib, may provide a similar progression-free survival benefit in this patient population. Elacestrant was approved by the US Food and Drug Administration (FDA) in January 2023 for second-line treatment of patients with advanced breast cancer and ESR1 mutations.
The EMBER trial also reported early overall survival findings. Although immature, overall survival trends favored imlunestrant over the standard treatment. The estimated overall survival at 18 months was 77% in the imlunestrant group and 58.6% in the standard therapy group among patients with ESR1 mutations (HR, 0.55), and 78.6% in the imlunestrant group vs 71.8% in the standard-therapy group for all patients (HR, 0.69).
Common all-grade adverse events with imlunestrant vs standard therapy included fatigue (22.6% vs 13.3%), diarrhea (21.4% vs 11.7%), and nausea (17% vs 13%). Grade 3 or higher anemia and neutropenia were low and similar in both arms.
All-grade diarrhea (86%) and nausea (49%) were more common with the combination of imlunestrant and abemaciclib.
The incidence of grade 3 or higher events was 17% with imlunestrant monotherapy, 21% for standard treatment, and 49% for imlunestrant plus abemaciclib.
EMBER-3 discussant Harold Burstein, MD, PhD, a breast oncologist at the Dana-Farber Cancer Institute, Boston, said that, overall, oral SERDs are starting to “break out from the ESR1 mutation box,” perhaps reflecting the idea that an agent more active than fulvestrant in combination with a non-cross–resistant CDK4/6 inhibitor like abemaciclib might lead to a better long-term outcome, regardless of ESR1 status.
A major limit of EMBER-3, however, is that it did not compare imlunestrant/abemaciclib with fulvestrant/abemaciclib, which would have been a true standard-of-care control, said Burstein.
Kathy Miller, MD, a breast oncologist at Indiana University, Indianapolis, agreed.
She was also concerned about the use of monotherapy in the standard care arm.
“Monotherapy hormone therapy is not what people would be treated with,” Miller said. Patients would typically get fulvestrant with either a targeted therapy or everolimus.
Without appropriate controls, “the data are impossible to interpret” in the context of current practice, Miller told Medscape Medical News.
Eli Lilly, maker of imlunestrant, funded, designed, and largely conducted the trial. Jhaveri is a consultant and researcher for the company. Burstein and Miller had no disclosures. Miller is an editorial advisor for Medscape Oncology.
A version of this article appeared on Medscape.com.
FROM SABCS 2024
Multiple Myeloma: Dexamethasone-Sparing Approach Benefits Frail Older Adults
The study “is the first randomized phase 3 study dedicated to frail patients,” said first author Salomon Manier, MD, PhD, an associate professor of hematology at Lille University Hospital, Lille, France. He presented the findings this week at the American Society of Hematology (ASH) 2024 Annual Meeting in San Diego.
“It shows that daratumumab-lenalidomide [with limited dexamethasone] led to a significant reduced risk of progression or death by 49% in frail patients, with a favorable safety profile and an improved health-related quality of life,” Manier said.
Older adult patients who are newly diagnosed with MM have varying levels of fitness or frailty and have been shown to have shorter survival, with higher rates of nonhematologic adverse events and treatment discontinuation.
While the regimen of daratumumab, lenalidomide, and dexamethasone has become a standard of care, with efficacy and tolerance, including for patients with frailty, the infection and pneumonia rates with the approach can be high, particularly for patients with frailty.
To evaluate if an alternative, dexamethasone-sparing approach could improve outcomes while limiting toxicity for older adults, Manier and his colleagues conducted the prospective, open-label phase 3 IFM2017-03 trial, involving 295 patients (age, 65 years) with newly diagnosed MM at 90 centers in France.
The patients had a median age of 81, with 84% older than 75 years and 61% older than 80 years. All had an Eastern Cooperative Oncology Group proxy frailty score ≥ 2.
The patients were randomized 1:2 to treatment either with the Rd regimen of 28-day cycles of lenalidomide (25 mg/d, 21/28) and dexamethasone (20 mg once weekly) or with the dexamethasone-sparing regimen (DR) of daratumumab (1800 mg subcutaneous once weekly for 8 weeks, once every 2 weeks for 16 weeks, and once every 4 weeks thereafter), lenalidomide (25 mg/d, 21/28), and two cycles of dexamethasone (20 mg once weekly for 8 weeks then stopping).
The randomization included stratification based on age and cancer stage. Baseline characteristics were well balanced in the two groups.
Both regimens were administered until disease progression or unacceptable toxicity.
As of the data cut-off in November 2024, with a median follow-up of 46.3 months, 81 of the original 200 patients in the DR arm remained on treatment, and 11 of 95 continued in the Rd arm.
The overall median treatment duration among the 200 original patients in the DR arm was 31.6 months and 14.3 months in the Rd arm.
The study met its primary endpoint of progression-free survival (PFS), with a median rate of 53.4 months in the DR arm vs 22.5 months in the Rd arm (hazard ratio [HR], 0.51; P < .0001).
The improved PFS in the DR arm was observed across all subgroups based on age, Charlson comorbidity index, cancer stage, cytogenetics, and creatinine clearance; however, those with lower frailty scores had better outcomes in both groups.
A median overall survival was not reached in the DR arm vs 47.2 months in the Rd arm (HR, 0.52; P = .0001).
The DR arm also showed a higher overall best response rate of 94% vs 86% (P = .005), respectively, with deeper responses in the DR arm at all time points, including the earliest points at 4 months.
In terms of adverse events (AEs), at least one AE of grade ≥ 3 occurred in 89% in the DR arm and 79% in the Rd arm.
Those in the DR arm had significantly more grade 3 or higher hematologic AEs with neutropenia (62% vs 34%); however, grade ≥ 3 infections were similar, with 19% in the DR arm and 21% in the Rd arm. Infections involving pneumonia occurred in 6% and 8%, respectively.
There were no significant differences between the two arms in discontinuations due to AEs (30% in the DR arm and 34% in the Rd arm).
While health-related quality of life measures at baseline were well balanced between the two groups, those in the DR arm reported significantly shorter times to clinically meaningful improvement in all domains of the EORTC Core Quality of Life questionnaire (EORTC QLQ-C30).
“The safety profile was significantly improved and was favorable, without increased infection or pneumonia rates, with similar rates of treatment discontinuation,” Manier said.
Based on the findings, “we believe that the dexamethasone-sparing strategy is effective and safe for treating these frail patients with multiple myeloma,” he added.
Commenting on the study, Manni Mohyuddin, MD, an assistant professor in the multiple myeloma program at the Huntsman Cancer Institute, University of Utah, Salt Lake City, noted that, with the popularity of triplet regimens such as daratumumab, lenalidomide, and dexamethasone, the Rd regimen in the study is not as commonly used.
“But what this trial tells us is that efficacy outcomes in such a group of patients are encouraging despite getting rid of dexamethasone so quickly,” he said in an interview.
However, “while the tide is changing, dexamethasone is still given long-term, week after week after week in most myeloma protocols and in the community,” he noted. “Hopefully, this trial, and some of the other work, will lead to a change in this space.”
Mohyuddin suggests one approach can involve starting off with just daratumumab and a low dose of dexamethasone, then adding lenalidomide at a lower dose later in a sequential/graded approach.
“Other approaches that should be studied should be bispecific antibodies used sparingly, with less frequent dosing, or finite period,” he added. “There is lot to refine.”
Mohyuddin added a critique that the study’s endpoint of PFS may not have been ideal for the population of elderly and frail patients.
“Older people generally prioritize functional independence and quality of life, and perhaps a more patient-centered endpoint could have led to an even more informative study,” he said.
Manier’s disclosures included consultancy with Takeda Pharmaceuticals, Sanofi, Novartis, Janssen, GlaxoSmithKline, Celgene/BMS, Amgen, Adaptive Biotechnologies, Roche, Regeneron, and AbbVie. Mohyuddin had no disclosures.
A version of this article appeared on Medscape.com.
The study “is the first randomized phase 3 study dedicated to frail patients,” said first author Salomon Manier, MD, PhD, an associate professor of hematology at Lille University Hospital, Lille, France. He presented the findings this week at the American Society of Hematology (ASH) 2024 Annual Meeting in San Diego.
“It shows that daratumumab-lenalidomide [with limited dexamethasone] led to a significant reduced risk of progression or death by 49% in frail patients, with a favorable safety profile and an improved health-related quality of life,” Manier said.
Older adult patients who are newly diagnosed with MM have varying levels of fitness or frailty and have been shown to have shorter survival, with higher rates of nonhematologic adverse events and treatment discontinuation.
While the regimen of daratumumab, lenalidomide, and dexamethasone has become a standard of care, with efficacy and tolerance, including for patients with frailty, the infection and pneumonia rates with the approach can be high, particularly for patients with frailty.
To evaluate if an alternative, dexamethasone-sparing approach could improve outcomes while limiting toxicity for older adults, Manier and his colleagues conducted the prospective, open-label phase 3 IFM2017-03 trial, involving 295 patients (age, 65 years) with newly diagnosed MM at 90 centers in France.
The patients had a median age of 81, with 84% older than 75 years and 61% older than 80 years. All had an Eastern Cooperative Oncology Group proxy frailty score ≥ 2.
The patients were randomized 1:2 to treatment either with the Rd regimen of 28-day cycles of lenalidomide (25 mg/d, 21/28) and dexamethasone (20 mg once weekly) or with the dexamethasone-sparing regimen (DR) of daratumumab (1800 mg subcutaneous once weekly for 8 weeks, once every 2 weeks for 16 weeks, and once every 4 weeks thereafter), lenalidomide (25 mg/d, 21/28), and two cycles of dexamethasone (20 mg once weekly for 8 weeks then stopping).
The randomization included stratification based on age and cancer stage. Baseline characteristics were well balanced in the two groups.
Both regimens were administered until disease progression or unacceptable toxicity.
As of the data cut-off in November 2024, with a median follow-up of 46.3 months, 81 of the original 200 patients in the DR arm remained on treatment, and 11 of 95 continued in the Rd arm.
The overall median treatment duration among the 200 original patients in the DR arm was 31.6 months and 14.3 months in the Rd arm.
The study met its primary endpoint of progression-free survival (PFS), with a median rate of 53.4 months in the DR arm vs 22.5 months in the Rd arm (hazard ratio [HR], 0.51; P < .0001).
The improved PFS in the DR arm was observed across all subgroups based on age, Charlson comorbidity index, cancer stage, cytogenetics, and creatinine clearance; however, those with lower frailty scores had better outcomes in both groups.
A median overall survival was not reached in the DR arm vs 47.2 months in the Rd arm (HR, 0.52; P = .0001).
The DR arm also showed a higher overall best response rate of 94% vs 86% (P = .005), respectively, with deeper responses in the DR arm at all time points, including the earliest points at 4 months.
In terms of adverse events (AEs), at least one AE of grade ≥ 3 occurred in 89% in the DR arm and 79% in the Rd arm.
Those in the DR arm had significantly more grade 3 or higher hematologic AEs with neutropenia (62% vs 34%); however, grade ≥ 3 infections were similar, with 19% in the DR arm and 21% in the Rd arm. Infections involving pneumonia occurred in 6% and 8%, respectively.
There were no significant differences between the two arms in discontinuations due to AEs (30% in the DR arm and 34% in the Rd arm).
While health-related quality of life measures at baseline were well balanced between the two groups, those in the DR arm reported significantly shorter times to clinically meaningful improvement in all domains of the EORTC Core Quality of Life questionnaire (EORTC QLQ-C30).
“The safety profile was significantly improved and was favorable, without increased infection or pneumonia rates, with similar rates of treatment discontinuation,” Manier said.
Based on the findings, “we believe that the dexamethasone-sparing strategy is effective and safe for treating these frail patients with multiple myeloma,” he added.
Commenting on the study, Manni Mohyuddin, MD, an assistant professor in the multiple myeloma program at the Huntsman Cancer Institute, University of Utah, Salt Lake City, noted that, with the popularity of triplet regimens such as daratumumab, lenalidomide, and dexamethasone, the Rd regimen in the study is not as commonly used.
“But what this trial tells us is that efficacy outcomes in such a group of patients are encouraging despite getting rid of dexamethasone so quickly,” he said in an interview.
However, “while the tide is changing, dexamethasone is still given long-term, week after week after week in most myeloma protocols and in the community,” he noted. “Hopefully, this trial, and some of the other work, will lead to a change in this space.”
Mohyuddin suggests one approach can involve starting off with just daratumumab and a low dose of dexamethasone, then adding lenalidomide at a lower dose later in a sequential/graded approach.
“Other approaches that should be studied should be bispecific antibodies used sparingly, with less frequent dosing, or finite period,” he added. “There is lot to refine.”
Mohyuddin added a critique that the study’s endpoint of PFS may not have been ideal for the population of elderly and frail patients.
“Older people generally prioritize functional independence and quality of life, and perhaps a more patient-centered endpoint could have led to an even more informative study,” he said.
Manier’s disclosures included consultancy with Takeda Pharmaceuticals, Sanofi, Novartis, Janssen, GlaxoSmithKline, Celgene/BMS, Amgen, Adaptive Biotechnologies, Roche, Regeneron, and AbbVie. Mohyuddin had no disclosures.
A version of this article appeared on Medscape.com.
The study “is the first randomized phase 3 study dedicated to frail patients,” said first author Salomon Manier, MD, PhD, an associate professor of hematology at Lille University Hospital, Lille, France. He presented the findings this week at the American Society of Hematology (ASH) 2024 Annual Meeting in San Diego.
“It shows that daratumumab-lenalidomide [with limited dexamethasone] led to a significant reduced risk of progression or death by 49% in frail patients, with a favorable safety profile and an improved health-related quality of life,” Manier said.
Older adult patients who are newly diagnosed with MM have varying levels of fitness or frailty and have been shown to have shorter survival, with higher rates of nonhematologic adverse events and treatment discontinuation.
While the regimen of daratumumab, lenalidomide, and dexamethasone has become a standard of care, with efficacy and tolerance, including for patients with frailty, the infection and pneumonia rates with the approach can be high, particularly for patients with frailty.
To evaluate if an alternative, dexamethasone-sparing approach could improve outcomes while limiting toxicity for older adults, Manier and his colleagues conducted the prospective, open-label phase 3 IFM2017-03 trial, involving 295 patients (age, 65 years) with newly diagnosed MM at 90 centers in France.
The patients had a median age of 81, with 84% older than 75 years and 61% older than 80 years. All had an Eastern Cooperative Oncology Group proxy frailty score ≥ 2.
The patients were randomized 1:2 to treatment either with the Rd regimen of 28-day cycles of lenalidomide (25 mg/d, 21/28) and dexamethasone (20 mg once weekly) or with the dexamethasone-sparing regimen (DR) of daratumumab (1800 mg subcutaneous once weekly for 8 weeks, once every 2 weeks for 16 weeks, and once every 4 weeks thereafter), lenalidomide (25 mg/d, 21/28), and two cycles of dexamethasone (20 mg once weekly for 8 weeks then stopping).
The randomization included stratification based on age and cancer stage. Baseline characteristics were well balanced in the two groups.
Both regimens were administered until disease progression or unacceptable toxicity.
As of the data cut-off in November 2024, with a median follow-up of 46.3 months, 81 of the original 200 patients in the DR arm remained on treatment, and 11 of 95 continued in the Rd arm.
The overall median treatment duration among the 200 original patients in the DR arm was 31.6 months and 14.3 months in the Rd arm.
The study met its primary endpoint of progression-free survival (PFS), with a median rate of 53.4 months in the DR arm vs 22.5 months in the Rd arm (hazard ratio [HR], 0.51; P < .0001).
The improved PFS in the DR arm was observed across all subgroups based on age, Charlson comorbidity index, cancer stage, cytogenetics, and creatinine clearance; however, those with lower frailty scores had better outcomes in both groups.
A median overall survival was not reached in the DR arm vs 47.2 months in the Rd arm (HR, 0.52; P = .0001).
The DR arm also showed a higher overall best response rate of 94% vs 86% (P = .005), respectively, with deeper responses in the DR arm at all time points, including the earliest points at 4 months.
In terms of adverse events (AEs), at least one AE of grade ≥ 3 occurred in 89% in the DR arm and 79% in the Rd arm.
Those in the DR arm had significantly more grade 3 or higher hematologic AEs with neutropenia (62% vs 34%); however, grade ≥ 3 infections were similar, with 19% in the DR arm and 21% in the Rd arm. Infections involving pneumonia occurred in 6% and 8%, respectively.
There were no significant differences between the two arms in discontinuations due to AEs (30% in the DR arm and 34% in the Rd arm).
While health-related quality of life measures at baseline were well balanced between the two groups, those in the DR arm reported significantly shorter times to clinically meaningful improvement in all domains of the EORTC Core Quality of Life questionnaire (EORTC QLQ-C30).
“The safety profile was significantly improved and was favorable, without increased infection or pneumonia rates, with similar rates of treatment discontinuation,” Manier said.
Based on the findings, “we believe that the dexamethasone-sparing strategy is effective and safe for treating these frail patients with multiple myeloma,” he added.
Commenting on the study, Manni Mohyuddin, MD, an assistant professor in the multiple myeloma program at the Huntsman Cancer Institute, University of Utah, Salt Lake City, noted that, with the popularity of triplet regimens such as daratumumab, lenalidomide, and dexamethasone, the Rd regimen in the study is not as commonly used.
“But what this trial tells us is that efficacy outcomes in such a group of patients are encouraging despite getting rid of dexamethasone so quickly,” he said in an interview.
However, “while the tide is changing, dexamethasone is still given long-term, week after week after week in most myeloma protocols and in the community,” he noted. “Hopefully, this trial, and some of the other work, will lead to a change in this space.”
Mohyuddin suggests one approach can involve starting off with just daratumumab and a low dose of dexamethasone, then adding lenalidomide at a lower dose later in a sequential/graded approach.
“Other approaches that should be studied should be bispecific antibodies used sparingly, with less frequent dosing, or finite period,” he added. “There is lot to refine.”
Mohyuddin added a critique that the study’s endpoint of PFS may not have been ideal for the population of elderly and frail patients.
“Older people generally prioritize functional independence and quality of life, and perhaps a more patient-centered endpoint could have led to an even more informative study,” he said.
Manier’s disclosures included consultancy with Takeda Pharmaceuticals, Sanofi, Novartis, Janssen, GlaxoSmithKline, Celgene/BMS, Amgen, Adaptive Biotechnologies, Roche, Regeneron, and AbbVie. Mohyuddin had no disclosures.
A version of this article appeared on Medscape.com.
FROM ASH 2024
Do Risk-Reducing Surgeries Benefit BRCA Carriers With Early-Onset Breast Cancer History?
according to new data presented at the San Antonio Breast Cancer Symposium (SABCS) 2024.
Having a risk-reducing mastectomy or salpingo-oophorectomy was associated with significantly improved overall survival and disease-free survival in BRCA-mutation carriers who had been diagnosed with a first breast cancer at age ≤ 40 years.
“This global study provides the first evidence that risk-reducing surgeries improve survival outcomes among young BRCA-mutation carriers with a prior history of early-onset breast cancer,” study investigator Matteo Lambertini, MD, PhD, oncologist with the University of Genova–IRCCS Policlinico San Martino Hospital in Genoa, Italy, said in a statement from the SABCS, where he presented the findings. “Considering the unique traits and needs of this younger population, and their high risk for secondary malignancies, it is critical to understand how risk-reducing surgeries affect patient outcomes, so that the risks and benefits of these procedures can be carefully weighed.”
“We hope these findings may help to improve the counseling on cancer-risk management strategies for BRCA carriers with young-onset of breast cancer below the age of 40 years,” Lambertini added during a press briefing.
Various risk-reducing strategies, including risk-reducing surgeries, are recommended for BRCA-mutation carriers without a prior history of cancer, but the impact of these surgeries among younger populations with a history of early-onset breast cancer has been less clear.
The new findings come from the BRCA BCY Collaboration, an international, multicenter, retrospective cohort study of 5290 patients with likely pathogenic/pathogenic germline BRCA1 and/or BRCA2 mutations who were diagnosed with stages I-III breast cancer at ≤ 40 years. The risk-reducing mastectomy analysis included 2910 patients (55%) who underwent the surgery less than 1 year from diagnosis and 2380 who opted not to have the surgery.
Primary endpoint was overall survival, and disease-free survival and breast cancer-free interval were secondary endpoints. Overall survival models were adjusted for the development of distant recurrences or second primary malignancies.
During median follow-up of 5.1 years, patients who underwent risk-reducing mastectomy had a 35% lower risk of dying (adjusted hazard ratio [aHR], 0.65) as well as a significant improvement in both disease-free survival (aHR, 0.58) and breast cancer-free interval (aHR, 0.55). The improved outcomes were seen in both BRCA1 and BRCA2 carriers, Lambertini reported.
The risk-reducing salpingo-oophorectomy analysis included 2782 patients who underwent this surgery a median of 3 years from diagnosis and 2508 who did not.
During median follow up of 4.9 years, risk-reducing salpingo-oophorectomy was associated with a 42% lower risk for death (aHR, 0.58) as well as an improvement in both disease-free survival (aHR, 0.68) and breast cancer-free interval (aHR, 0.65).
For risk-reducing salpingo-oophorectomy, there was an interaction based on breast cancer subtype and BRCA mutation.
“Specifically, the benefit of risk-reducing salpingo-oophorectomy was greater for patients with BRCA1 pathogenic variants and for those with triple-negative disease, as compared to those with BRCA2 pathogenic variants or luminal disease,” Lambertini reported.
Overall survival results were similar in patients who underwent one or both surgeries.
Briefing moderator Kate Lathrop, MD, with the University of Texas Health Science Center at San Antonio, noted that this study provides valuable information for counseling younger patients. Having datasets like this helps us give patients “potentially our best estimate of the amount of reduction of risk you could have by having the surgery now.”
In an interview, Freya Schnabel, MD, director of breast surgery at NYU Langone Health’s Perlmutter Cancer Center, New York City, emphasized the importance of early, well-informed decision-making upfront at the time of diagnosis in this patient population.
The benefit of “risk-reducing oophorectomy cannot be overemphasized, even in the presence of a known breast cancer because, as my colleagues and I say — we don’t want to cure their breast cancer and then have them die of ovarian cancer,” said Schnabel, who was not involved in the study.
In terms of prophylactic contralateral mastectomy, Schnabel noted that BRCA-mutation carriers have a “very high” risk for a second primary breast cancer. In her experience, “that’s what drives patients frequently at the time of diagnosis to have bilateral mastectomy because who wants to go through this more than once?”
This is especially true for BRCA1 carriers who have a higher risk for triple-negative breast cancer, which is associated with a worse prognosis and is harder to treat, Schnabel said.
“For these patients, having surgery prevents the patient from getting into a situation where their second primary tumor winds up being biologically more aggressive and then affects their survival,” Schnabel said.
The study was supported by the Italian Association for Cancer Research and the European Society for Medical Oncology. Lambertini reported advisory roles for Roche, Lilly, Novartis, AstraZeneca, Pfizer, Seagen, Gilead, MSD, Exact Sciences, Pierre Fabre, and Menarini. Lathrop consults for TeraSera Pharmaceuticals. Schnabel had no relevant disclosures.
A version of this article first appeared on Medscape.com.
according to new data presented at the San Antonio Breast Cancer Symposium (SABCS) 2024.
Having a risk-reducing mastectomy or salpingo-oophorectomy was associated with significantly improved overall survival and disease-free survival in BRCA-mutation carriers who had been diagnosed with a first breast cancer at age ≤ 40 years.
“This global study provides the first evidence that risk-reducing surgeries improve survival outcomes among young BRCA-mutation carriers with a prior history of early-onset breast cancer,” study investigator Matteo Lambertini, MD, PhD, oncologist with the University of Genova–IRCCS Policlinico San Martino Hospital in Genoa, Italy, said in a statement from the SABCS, where he presented the findings. “Considering the unique traits and needs of this younger population, and their high risk for secondary malignancies, it is critical to understand how risk-reducing surgeries affect patient outcomes, so that the risks and benefits of these procedures can be carefully weighed.”
“We hope these findings may help to improve the counseling on cancer-risk management strategies for BRCA carriers with young-onset of breast cancer below the age of 40 years,” Lambertini added during a press briefing.
Various risk-reducing strategies, including risk-reducing surgeries, are recommended for BRCA-mutation carriers without a prior history of cancer, but the impact of these surgeries among younger populations with a history of early-onset breast cancer has been less clear.
The new findings come from the BRCA BCY Collaboration, an international, multicenter, retrospective cohort study of 5290 patients with likely pathogenic/pathogenic germline BRCA1 and/or BRCA2 mutations who were diagnosed with stages I-III breast cancer at ≤ 40 years. The risk-reducing mastectomy analysis included 2910 patients (55%) who underwent the surgery less than 1 year from diagnosis and 2380 who opted not to have the surgery.
Primary endpoint was overall survival, and disease-free survival and breast cancer-free interval were secondary endpoints. Overall survival models were adjusted for the development of distant recurrences or second primary malignancies.
During median follow-up of 5.1 years, patients who underwent risk-reducing mastectomy had a 35% lower risk of dying (adjusted hazard ratio [aHR], 0.65) as well as a significant improvement in both disease-free survival (aHR, 0.58) and breast cancer-free interval (aHR, 0.55). The improved outcomes were seen in both BRCA1 and BRCA2 carriers, Lambertini reported.
The risk-reducing salpingo-oophorectomy analysis included 2782 patients who underwent this surgery a median of 3 years from diagnosis and 2508 who did not.
During median follow up of 4.9 years, risk-reducing salpingo-oophorectomy was associated with a 42% lower risk for death (aHR, 0.58) as well as an improvement in both disease-free survival (aHR, 0.68) and breast cancer-free interval (aHR, 0.65).
For risk-reducing salpingo-oophorectomy, there was an interaction based on breast cancer subtype and BRCA mutation.
“Specifically, the benefit of risk-reducing salpingo-oophorectomy was greater for patients with BRCA1 pathogenic variants and for those with triple-negative disease, as compared to those with BRCA2 pathogenic variants or luminal disease,” Lambertini reported.
Overall survival results were similar in patients who underwent one or both surgeries.
Briefing moderator Kate Lathrop, MD, with the University of Texas Health Science Center at San Antonio, noted that this study provides valuable information for counseling younger patients. Having datasets like this helps us give patients “potentially our best estimate of the amount of reduction of risk you could have by having the surgery now.”
In an interview, Freya Schnabel, MD, director of breast surgery at NYU Langone Health’s Perlmutter Cancer Center, New York City, emphasized the importance of early, well-informed decision-making upfront at the time of diagnosis in this patient population.
The benefit of “risk-reducing oophorectomy cannot be overemphasized, even in the presence of a known breast cancer because, as my colleagues and I say — we don’t want to cure their breast cancer and then have them die of ovarian cancer,” said Schnabel, who was not involved in the study.
In terms of prophylactic contralateral mastectomy, Schnabel noted that BRCA-mutation carriers have a “very high” risk for a second primary breast cancer. In her experience, “that’s what drives patients frequently at the time of diagnosis to have bilateral mastectomy because who wants to go through this more than once?”
This is especially true for BRCA1 carriers who have a higher risk for triple-negative breast cancer, which is associated with a worse prognosis and is harder to treat, Schnabel said.
“For these patients, having surgery prevents the patient from getting into a situation where their second primary tumor winds up being biologically more aggressive and then affects their survival,” Schnabel said.
The study was supported by the Italian Association for Cancer Research and the European Society for Medical Oncology. Lambertini reported advisory roles for Roche, Lilly, Novartis, AstraZeneca, Pfizer, Seagen, Gilead, MSD, Exact Sciences, Pierre Fabre, and Menarini. Lathrop consults for TeraSera Pharmaceuticals. Schnabel had no relevant disclosures.
A version of this article first appeared on Medscape.com.
according to new data presented at the San Antonio Breast Cancer Symposium (SABCS) 2024.
Having a risk-reducing mastectomy or salpingo-oophorectomy was associated with significantly improved overall survival and disease-free survival in BRCA-mutation carriers who had been diagnosed with a first breast cancer at age ≤ 40 years.
“This global study provides the first evidence that risk-reducing surgeries improve survival outcomes among young BRCA-mutation carriers with a prior history of early-onset breast cancer,” study investigator Matteo Lambertini, MD, PhD, oncologist with the University of Genova–IRCCS Policlinico San Martino Hospital in Genoa, Italy, said in a statement from the SABCS, where he presented the findings. “Considering the unique traits and needs of this younger population, and their high risk for secondary malignancies, it is critical to understand how risk-reducing surgeries affect patient outcomes, so that the risks and benefits of these procedures can be carefully weighed.”
“We hope these findings may help to improve the counseling on cancer-risk management strategies for BRCA carriers with young-onset of breast cancer below the age of 40 years,” Lambertini added during a press briefing.
Various risk-reducing strategies, including risk-reducing surgeries, are recommended for BRCA-mutation carriers without a prior history of cancer, but the impact of these surgeries among younger populations with a history of early-onset breast cancer has been less clear.
The new findings come from the BRCA BCY Collaboration, an international, multicenter, retrospective cohort study of 5290 patients with likely pathogenic/pathogenic germline BRCA1 and/or BRCA2 mutations who were diagnosed with stages I-III breast cancer at ≤ 40 years. The risk-reducing mastectomy analysis included 2910 patients (55%) who underwent the surgery less than 1 year from diagnosis and 2380 who opted not to have the surgery.
Primary endpoint was overall survival, and disease-free survival and breast cancer-free interval were secondary endpoints. Overall survival models were adjusted for the development of distant recurrences or second primary malignancies.
During median follow-up of 5.1 years, patients who underwent risk-reducing mastectomy had a 35% lower risk of dying (adjusted hazard ratio [aHR], 0.65) as well as a significant improvement in both disease-free survival (aHR, 0.58) and breast cancer-free interval (aHR, 0.55). The improved outcomes were seen in both BRCA1 and BRCA2 carriers, Lambertini reported.
The risk-reducing salpingo-oophorectomy analysis included 2782 patients who underwent this surgery a median of 3 years from diagnosis and 2508 who did not.
During median follow up of 4.9 years, risk-reducing salpingo-oophorectomy was associated with a 42% lower risk for death (aHR, 0.58) as well as an improvement in both disease-free survival (aHR, 0.68) and breast cancer-free interval (aHR, 0.65).
For risk-reducing salpingo-oophorectomy, there was an interaction based on breast cancer subtype and BRCA mutation.
“Specifically, the benefit of risk-reducing salpingo-oophorectomy was greater for patients with BRCA1 pathogenic variants and for those with triple-negative disease, as compared to those with BRCA2 pathogenic variants or luminal disease,” Lambertini reported.
Overall survival results were similar in patients who underwent one or both surgeries.
Briefing moderator Kate Lathrop, MD, with the University of Texas Health Science Center at San Antonio, noted that this study provides valuable information for counseling younger patients. Having datasets like this helps us give patients “potentially our best estimate of the amount of reduction of risk you could have by having the surgery now.”
In an interview, Freya Schnabel, MD, director of breast surgery at NYU Langone Health’s Perlmutter Cancer Center, New York City, emphasized the importance of early, well-informed decision-making upfront at the time of diagnosis in this patient population.
The benefit of “risk-reducing oophorectomy cannot be overemphasized, even in the presence of a known breast cancer because, as my colleagues and I say — we don’t want to cure their breast cancer and then have them die of ovarian cancer,” said Schnabel, who was not involved in the study.
In terms of prophylactic contralateral mastectomy, Schnabel noted that BRCA-mutation carriers have a “very high” risk for a second primary breast cancer. In her experience, “that’s what drives patients frequently at the time of diagnosis to have bilateral mastectomy because who wants to go through this more than once?”
This is especially true for BRCA1 carriers who have a higher risk for triple-negative breast cancer, which is associated with a worse prognosis and is harder to treat, Schnabel said.
“For these patients, having surgery prevents the patient from getting into a situation where their second primary tumor winds up being biologically more aggressive and then affects their survival,” Schnabel said.
The study was supported by the Italian Association for Cancer Research and the European Society for Medical Oncology. Lambertini reported advisory roles for Roche, Lilly, Novartis, AstraZeneca, Pfizer, Seagen, Gilead, MSD, Exact Sciences, Pierre Fabre, and Menarini. Lathrop consults for TeraSera Pharmaceuticals. Schnabel had no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM SABCS 2024
How Are Patients Managing Intermediate-Risk Prostate Cancer?
TOPLINE:
METHODOLOGY:
- Current guidelines support active surveillance or watchful waiting for select patients with intermediate-risk prostate cancer. These observation strategies may help reduce the adverse effects associated with immediate radical treatment.
- To understand the trends over time in the use of active surveillance and watchful waiting, researchers looked at data of 147,205 individuals with intermediate-risk prostate cancer from the Surveillance, Epidemiology, and End Results prostate cancer database between 2010 and 2020 in the United States.
- Criteria for intermediate-risk included Gleason grade group 2 or 3, prostate-specific antigen (PSA) levels of 10-20 ng/mL, or stage cT2b of the disease. Researchers also included trends for patients with Gleason grade group 1, as a reference group.
- Researchers assessed the temporal trends and factors associated with the selection of active surveillance and watchful waiting in this population.
TAKEAWAY:
- Overall, the rate of active surveillance and watchful waiting more than doubled among intermediate-risk patients from 5% to 12.3% between 2010 and 2020.
- Between 2010 and 2020, the use of active surveillance and watchful waiting increased significantly among patients in Gleason grade group 1 (13.2% to 53.8%) and Gleason grade group 2 (4.0% to 11.6%) but remained stable for those in Gleason grade group 3 (2.5% to 2.8%; P = .85). For those with PSA levels < 10 ng/mL, adoption increased from 3.4% in 2010 to 9.2% in 2020 and more than doubled (9.3% to 20.7%) for those with PSA levels of 10-20 ng/mL.
- Higher Gleason grade groups had a significantly lower likelihood of adopting active surveillance or watchful waiting (Gleason grade group 2 vs 1: odds ratio [OR], 0.83; Gleason grade group 3 vs 1: OR, 0.79).
- Hispanic or Latino individuals (OR, 0.98) and non-Hispanic Black individuals (OR, 0.99) were slightly less likely to adopt these strategies than non-Hispanic White individuals.
IN PRACTICE:
“This study found a significant increase in initial active surveillance and watchful waiting for intermediate-risk prostate cancer between 2010 and 2020,” the authors wrote. “Research priorities should include reducing upfront overdiagnosis and better defining criteria for starting and stopping active surveillance and watchful waiting beyond conventional clinical measures such as GGs [Gleason grade groups] or PSA levels alone.”
SOURCE:
This study, led by Ismail Ajjawi, Yale School of Medicine, New Haven, Connecticut, was published online in JAMA.
LIMITATIONS:
This study relied on observational data and therefore could not capture various factors influencing clinical decision-making processes. Additionally, the absence of information on patient outcomes restricted the ability to assess the long-term implications of different management strategies.
DISCLOSURES:
This study received financial support from the Urological Research Foundation. Several authors reported having various ties with various sources.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Current guidelines support active surveillance or watchful waiting for select patients with intermediate-risk prostate cancer. These observation strategies may help reduce the adverse effects associated with immediate radical treatment.
- To understand the trends over time in the use of active surveillance and watchful waiting, researchers looked at data of 147,205 individuals with intermediate-risk prostate cancer from the Surveillance, Epidemiology, and End Results prostate cancer database between 2010 and 2020 in the United States.
- Criteria for intermediate-risk included Gleason grade group 2 or 3, prostate-specific antigen (PSA) levels of 10-20 ng/mL, or stage cT2b of the disease. Researchers also included trends for patients with Gleason grade group 1, as a reference group.
- Researchers assessed the temporal trends and factors associated with the selection of active surveillance and watchful waiting in this population.
TAKEAWAY:
- Overall, the rate of active surveillance and watchful waiting more than doubled among intermediate-risk patients from 5% to 12.3% between 2010 and 2020.
- Between 2010 and 2020, the use of active surveillance and watchful waiting increased significantly among patients in Gleason grade group 1 (13.2% to 53.8%) and Gleason grade group 2 (4.0% to 11.6%) but remained stable for those in Gleason grade group 3 (2.5% to 2.8%; P = .85). For those with PSA levels < 10 ng/mL, adoption increased from 3.4% in 2010 to 9.2% in 2020 and more than doubled (9.3% to 20.7%) for those with PSA levels of 10-20 ng/mL.
- Higher Gleason grade groups had a significantly lower likelihood of adopting active surveillance or watchful waiting (Gleason grade group 2 vs 1: odds ratio [OR], 0.83; Gleason grade group 3 vs 1: OR, 0.79).
- Hispanic or Latino individuals (OR, 0.98) and non-Hispanic Black individuals (OR, 0.99) were slightly less likely to adopt these strategies than non-Hispanic White individuals.
IN PRACTICE:
“This study found a significant increase in initial active surveillance and watchful waiting for intermediate-risk prostate cancer between 2010 and 2020,” the authors wrote. “Research priorities should include reducing upfront overdiagnosis and better defining criteria for starting and stopping active surveillance and watchful waiting beyond conventional clinical measures such as GGs [Gleason grade groups] or PSA levels alone.”
SOURCE:
This study, led by Ismail Ajjawi, Yale School of Medicine, New Haven, Connecticut, was published online in JAMA.
LIMITATIONS:
This study relied on observational data and therefore could not capture various factors influencing clinical decision-making processes. Additionally, the absence of information on patient outcomes restricted the ability to assess the long-term implications of different management strategies.
DISCLOSURES:
This study received financial support from the Urological Research Foundation. Several authors reported having various ties with various sources.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Current guidelines support active surveillance or watchful waiting for select patients with intermediate-risk prostate cancer. These observation strategies may help reduce the adverse effects associated with immediate radical treatment.
- To understand the trends over time in the use of active surveillance and watchful waiting, researchers looked at data of 147,205 individuals with intermediate-risk prostate cancer from the Surveillance, Epidemiology, and End Results prostate cancer database between 2010 and 2020 in the United States.
- Criteria for intermediate-risk included Gleason grade group 2 or 3, prostate-specific antigen (PSA) levels of 10-20 ng/mL, or stage cT2b of the disease. Researchers also included trends for patients with Gleason grade group 1, as a reference group.
- Researchers assessed the temporal trends and factors associated with the selection of active surveillance and watchful waiting in this population.
TAKEAWAY:
- Overall, the rate of active surveillance and watchful waiting more than doubled among intermediate-risk patients from 5% to 12.3% between 2010 and 2020.
- Between 2010 and 2020, the use of active surveillance and watchful waiting increased significantly among patients in Gleason grade group 1 (13.2% to 53.8%) and Gleason grade group 2 (4.0% to 11.6%) but remained stable for those in Gleason grade group 3 (2.5% to 2.8%; P = .85). For those with PSA levels < 10 ng/mL, adoption increased from 3.4% in 2010 to 9.2% in 2020 and more than doubled (9.3% to 20.7%) for those with PSA levels of 10-20 ng/mL.
- Higher Gleason grade groups had a significantly lower likelihood of adopting active surveillance or watchful waiting (Gleason grade group 2 vs 1: odds ratio [OR], 0.83; Gleason grade group 3 vs 1: OR, 0.79).
- Hispanic or Latino individuals (OR, 0.98) and non-Hispanic Black individuals (OR, 0.99) were slightly less likely to adopt these strategies than non-Hispanic White individuals.
IN PRACTICE:
“This study found a significant increase in initial active surveillance and watchful waiting for intermediate-risk prostate cancer between 2010 and 2020,” the authors wrote. “Research priorities should include reducing upfront overdiagnosis and better defining criteria for starting and stopping active surveillance and watchful waiting beyond conventional clinical measures such as GGs [Gleason grade groups] or PSA levels alone.”
SOURCE:
This study, led by Ismail Ajjawi, Yale School of Medicine, New Haven, Connecticut, was published online in JAMA.
LIMITATIONS:
This study relied on observational data and therefore could not capture various factors influencing clinical decision-making processes. Additionally, the absence of information on patient outcomes restricted the ability to assess the long-term implications of different management strategies.
DISCLOSURES:
This study received financial support from the Urological Research Foundation. Several authors reported having various ties with various sources.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
New Cancer Drugs: Do Patients Prefer Faster Access or Clinical Benefit?
When the Food and Drug Administration (FDA) grants cancer drugs accelerated approval, a key aim is to provide patients faster access to therapies that can benefit them.
The downside of a speedier approval timeline, however, is that it’s often not yet clear whether the new drugs will actually allow a patient to live longer or better. Information on overall survival and quality of life typically comes years later, after drugs undergo confirmatory trials, or sometimes not at all, if companies fail to conduct these trials.
During this waiting period, patients may be receiving a cancer drug that provides no real clinical benefit but comes with a host of toxicities.
In fact, the odds are about as good as a coin flip. For cancer drugs that have confirmatory trial data, more than half don’t ultimately provide an overall survival or quality of life benefit.
Inherent to the accelerated approval process is the assumption that patients are willing to accept this uncertainty in exchange for faster access.
But is that really the case?
The researchers asked about 870 adults with experience of cancer challenges — either their own cancer diagnosis or that of family or a close friend — whether they valued faster access or certainty that a drug really works.
In the study, participants imagined they had been diagnosed with cancer and could choose between two cancer drugs under investigation in clinical trials but with uncertain effectiveness, and a current standard treatment. Participants had to make a series of choices based on five scenarios.
The first two scenarios were based on the impact of the current standard treatment: A patient’s life expectancy on the standard treatment (6 months up to 3 years), and a patient’s physical health on the standard treatment (functional status restricted only during strenuous activities up to completely disabled).
The remaining three scenarios dealt with the two new drugs: The effect of the new drugs on a surrogate endpoint, progression-free survival (whether the drugs slowed tumor growth for an extra month or 5 additional months compared with the standard treatment), certainty that slowing tumor growth will improve survival (very low to high), and the wait time to access the drugs (immediately to as long as 2 years).
The researchers assessed the relative importance of survival benefit certainty vs wait time and how that balance shifted depending on the different scenarios.
Overall, the researchers found that, if there was no evidence linking the surrogate endpoint (progression-free survival) to overall survival, patients were willing to wait about 8 months for weak evidence of an overall survival benefit (ie, low certainty the drug will extend survival by 1-5 months), about 16 months for moderate certainty, and almost 22 months for high certainty.
Despite a willingness to wait for greater certainty, participants did value speed as well. Overall, respondents showed a strong preference against a 1-year delay in FDA approval time. People who were aged 55 years or more and were non-White individuals made less than $40,000 year as well as those with the lowest life expectancy on a current standard treatment were most sensitive to wait times while those with better functional status and longer life expectancies on a current treatment were less sensitive to longer wait times.
“Our results indicate that some patients (except those with the poorest prognoses) would find the additional time required to generate evidence on the survival benefit of new cancer drugs an acceptable tradeoff,” the study authors concluded.
Although people do place high value on timely access to new cancer drugs, especially if there are limited treatment options, many are willing to wait for greater certainty that a new drug provides an overall survival benefit, lead author Robin Forrest, MSc, with the Department of Health Policy, London School of Economics in England, said in an interview.
In the study, respondents also did not place significant value on whether the drug substantially slowed cancer growth. “In other words, substantial progression-free survival benefit of a drug did not compensate for lack of certainty about a drug’s benefit on survival in respondents’ drug choices,” the authors explained.
“In an effort to move quickly, we have accepted progression-free survival [as a surrogate endpoint],” Jyoti D. Patel, MD, oncologist with Northwestern Memorial Hospital, Chicago, Illinois, who wasn’t involved in the study. But a growing body of evidence indicates that progression-free survival is often a poor surrogate for overall survival. And what this study suggests is that “patients uniformly care about improvements in overall survival and the quality of that survival,” Patel said.
Bishal Gyawali, MD, PhD, was not surprised by the findings.
“I always thought this was the real-world scenario, but the problem is the voices of ordinary patients are not heard,” Gyawali, with Queen’s University, Kingston, Ontario, Canada, who also wasn’t involved in the study, said in an interview.
“What is heard is the loud noise of ‘we need access now, today, yesterday’ — ‘we don’t care if the drug doesn’t improve overall survival, we just need a drug, any drug’ — ‘we don’t care how much it costs, we need access today,’ ” Gyawali said. “Not saying this is wrong, but this is not the representation of all patients.”
However, the voices of patients who are more cautious and want evidence of benefit before accepting toxicities don’t make headlines, he added.
What this survey means from a policy perspective, said Gyawali, is that accelerated approvals that do not mandate survival endpoint in confirmatory trials are ignoring the need of many patients who prioritize certainty of benefit over speed of access.
The study was funded by the London School of Economics and Political Science Phelan United States Centre. Forrest had no relevant disclosures. Gyawali has received consulting fees from Vivio Health. Patel has various relationships with AbbVie, Anheart, AstraZeneca, Bristol-Myers Squibb, Guardant, Tempus, Sanofi, BluePrint, Takeda, and Gilead.
A version of this article first appeared on Medscape.com.
When the Food and Drug Administration (FDA) grants cancer drugs accelerated approval, a key aim is to provide patients faster access to therapies that can benefit them.
The downside of a speedier approval timeline, however, is that it’s often not yet clear whether the new drugs will actually allow a patient to live longer or better. Information on overall survival and quality of life typically comes years later, after drugs undergo confirmatory trials, or sometimes not at all, if companies fail to conduct these trials.
During this waiting period, patients may be receiving a cancer drug that provides no real clinical benefit but comes with a host of toxicities.
In fact, the odds are about as good as a coin flip. For cancer drugs that have confirmatory trial data, more than half don’t ultimately provide an overall survival or quality of life benefit.
Inherent to the accelerated approval process is the assumption that patients are willing to accept this uncertainty in exchange for faster access.
But is that really the case?
The researchers asked about 870 adults with experience of cancer challenges — either their own cancer diagnosis or that of family or a close friend — whether they valued faster access or certainty that a drug really works.
In the study, participants imagined they had been diagnosed with cancer and could choose between two cancer drugs under investigation in clinical trials but with uncertain effectiveness, and a current standard treatment. Participants had to make a series of choices based on five scenarios.
The first two scenarios were based on the impact of the current standard treatment: A patient’s life expectancy on the standard treatment (6 months up to 3 years), and a patient’s physical health on the standard treatment (functional status restricted only during strenuous activities up to completely disabled).
The remaining three scenarios dealt with the two new drugs: The effect of the new drugs on a surrogate endpoint, progression-free survival (whether the drugs slowed tumor growth for an extra month or 5 additional months compared with the standard treatment), certainty that slowing tumor growth will improve survival (very low to high), and the wait time to access the drugs (immediately to as long as 2 years).
The researchers assessed the relative importance of survival benefit certainty vs wait time and how that balance shifted depending on the different scenarios.
Overall, the researchers found that, if there was no evidence linking the surrogate endpoint (progression-free survival) to overall survival, patients were willing to wait about 8 months for weak evidence of an overall survival benefit (ie, low certainty the drug will extend survival by 1-5 months), about 16 months for moderate certainty, and almost 22 months for high certainty.
Despite a willingness to wait for greater certainty, participants did value speed as well. Overall, respondents showed a strong preference against a 1-year delay in FDA approval time. People who were aged 55 years or more and were non-White individuals made less than $40,000 year as well as those with the lowest life expectancy on a current standard treatment were most sensitive to wait times while those with better functional status and longer life expectancies on a current treatment were less sensitive to longer wait times.
“Our results indicate that some patients (except those with the poorest prognoses) would find the additional time required to generate evidence on the survival benefit of new cancer drugs an acceptable tradeoff,” the study authors concluded.
Although people do place high value on timely access to new cancer drugs, especially if there are limited treatment options, many are willing to wait for greater certainty that a new drug provides an overall survival benefit, lead author Robin Forrest, MSc, with the Department of Health Policy, London School of Economics in England, said in an interview.
In the study, respondents also did not place significant value on whether the drug substantially slowed cancer growth. “In other words, substantial progression-free survival benefit of a drug did not compensate for lack of certainty about a drug’s benefit on survival in respondents’ drug choices,” the authors explained.
“In an effort to move quickly, we have accepted progression-free survival [as a surrogate endpoint],” Jyoti D. Patel, MD, oncologist with Northwestern Memorial Hospital, Chicago, Illinois, who wasn’t involved in the study. But a growing body of evidence indicates that progression-free survival is often a poor surrogate for overall survival. And what this study suggests is that “patients uniformly care about improvements in overall survival and the quality of that survival,” Patel said.
Bishal Gyawali, MD, PhD, was not surprised by the findings.
“I always thought this was the real-world scenario, but the problem is the voices of ordinary patients are not heard,” Gyawali, with Queen’s University, Kingston, Ontario, Canada, who also wasn’t involved in the study, said in an interview.
“What is heard is the loud noise of ‘we need access now, today, yesterday’ — ‘we don’t care if the drug doesn’t improve overall survival, we just need a drug, any drug’ — ‘we don’t care how much it costs, we need access today,’ ” Gyawali said. “Not saying this is wrong, but this is not the representation of all patients.”
However, the voices of patients who are more cautious and want evidence of benefit before accepting toxicities don’t make headlines, he added.
What this survey means from a policy perspective, said Gyawali, is that accelerated approvals that do not mandate survival endpoint in confirmatory trials are ignoring the need of many patients who prioritize certainty of benefit over speed of access.
The study was funded by the London School of Economics and Political Science Phelan United States Centre. Forrest had no relevant disclosures. Gyawali has received consulting fees from Vivio Health. Patel has various relationships with AbbVie, Anheart, AstraZeneca, Bristol-Myers Squibb, Guardant, Tempus, Sanofi, BluePrint, Takeda, and Gilead.
A version of this article first appeared on Medscape.com.
When the Food and Drug Administration (FDA) grants cancer drugs accelerated approval, a key aim is to provide patients faster access to therapies that can benefit them.
The downside of a speedier approval timeline, however, is that it’s often not yet clear whether the new drugs will actually allow a patient to live longer or better. Information on overall survival and quality of life typically comes years later, after drugs undergo confirmatory trials, or sometimes not at all, if companies fail to conduct these trials.
During this waiting period, patients may be receiving a cancer drug that provides no real clinical benefit but comes with a host of toxicities.
In fact, the odds are about as good as a coin flip. For cancer drugs that have confirmatory trial data, more than half don’t ultimately provide an overall survival or quality of life benefit.
Inherent to the accelerated approval process is the assumption that patients are willing to accept this uncertainty in exchange for faster access.
But is that really the case?
The researchers asked about 870 adults with experience of cancer challenges — either their own cancer diagnosis or that of family or a close friend — whether they valued faster access or certainty that a drug really works.
In the study, participants imagined they had been diagnosed with cancer and could choose between two cancer drugs under investigation in clinical trials but with uncertain effectiveness, and a current standard treatment. Participants had to make a series of choices based on five scenarios.
The first two scenarios were based on the impact of the current standard treatment: A patient’s life expectancy on the standard treatment (6 months up to 3 years), and a patient’s physical health on the standard treatment (functional status restricted only during strenuous activities up to completely disabled).
The remaining three scenarios dealt with the two new drugs: The effect of the new drugs on a surrogate endpoint, progression-free survival (whether the drugs slowed tumor growth for an extra month or 5 additional months compared with the standard treatment), certainty that slowing tumor growth will improve survival (very low to high), and the wait time to access the drugs (immediately to as long as 2 years).
The researchers assessed the relative importance of survival benefit certainty vs wait time and how that balance shifted depending on the different scenarios.
Overall, the researchers found that, if there was no evidence linking the surrogate endpoint (progression-free survival) to overall survival, patients were willing to wait about 8 months for weak evidence of an overall survival benefit (ie, low certainty the drug will extend survival by 1-5 months), about 16 months for moderate certainty, and almost 22 months for high certainty.
Despite a willingness to wait for greater certainty, participants did value speed as well. Overall, respondents showed a strong preference against a 1-year delay in FDA approval time. People who were aged 55 years or more and were non-White individuals made less than $40,000 year as well as those with the lowest life expectancy on a current standard treatment were most sensitive to wait times while those with better functional status and longer life expectancies on a current treatment were less sensitive to longer wait times.
“Our results indicate that some patients (except those with the poorest prognoses) would find the additional time required to generate evidence on the survival benefit of new cancer drugs an acceptable tradeoff,” the study authors concluded.
Although people do place high value on timely access to new cancer drugs, especially if there are limited treatment options, many are willing to wait for greater certainty that a new drug provides an overall survival benefit, lead author Robin Forrest, MSc, with the Department of Health Policy, London School of Economics in England, said in an interview.
In the study, respondents also did not place significant value on whether the drug substantially slowed cancer growth. “In other words, substantial progression-free survival benefit of a drug did not compensate for lack of certainty about a drug’s benefit on survival in respondents’ drug choices,” the authors explained.
“In an effort to move quickly, we have accepted progression-free survival [as a surrogate endpoint],” Jyoti D. Patel, MD, oncologist with Northwestern Memorial Hospital, Chicago, Illinois, who wasn’t involved in the study. But a growing body of evidence indicates that progression-free survival is often a poor surrogate for overall survival. And what this study suggests is that “patients uniformly care about improvements in overall survival and the quality of that survival,” Patel said.
Bishal Gyawali, MD, PhD, was not surprised by the findings.
“I always thought this was the real-world scenario, but the problem is the voices of ordinary patients are not heard,” Gyawali, with Queen’s University, Kingston, Ontario, Canada, who also wasn’t involved in the study, said in an interview.
“What is heard is the loud noise of ‘we need access now, today, yesterday’ — ‘we don’t care if the drug doesn’t improve overall survival, we just need a drug, any drug’ — ‘we don’t care how much it costs, we need access today,’ ” Gyawali said. “Not saying this is wrong, but this is not the representation of all patients.”
However, the voices of patients who are more cautious and want evidence of benefit before accepting toxicities don’t make headlines, he added.
What this survey means from a policy perspective, said Gyawali, is that accelerated approvals that do not mandate survival endpoint in confirmatory trials are ignoring the need of many patients who prioritize certainty of benefit over speed of access.
The study was funded by the London School of Economics and Political Science Phelan United States Centre. Forrest had no relevant disclosures. Gyawali has received consulting fees from Vivio Health. Patel has various relationships with AbbVie, Anheart, AstraZeneca, Bristol-Myers Squibb, Guardant, Tempus, Sanofi, BluePrint, Takeda, and Gilead.
A version of this article first appeared on Medscape.com.
FROM THE LANCET ONCOLOGY