TBD Meeting (4748-23)

The investigational anti-body drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd) was associated with both improved progression-free survival and better safety than standard chemotherapy for patients with metastatic HER-2 negative (HR+/HER2–) breast cancer resistant to endocrine therapy, data from the phase 3 TROPION-Breast01 trial showed.

At a median follow-up of 10.8 months, the median progression-free survival (PFS) was 6.9 months for patients randomly assigned to receive Dato-DXd, compared with 4.9 months for the investigator’s choice of chemotherapy with either eribulin mesylate, vinorelbine, capecitabine, or gemcitabine. This difference translated into a 37% reduction in risk of disease progression with the ADC, reported Aditya Bardia, MD, MPH, director of the breast cancer research program at the Mass General Cancer Center in Boston.

Patients who received Dato-DXd had less than half the number of grade 3 or greater toxicities and fewer dose reductions or interruptions than patients who received chemotherapy, he noted in an oral abstract session at the 2023 European Society for Medical Oncology Congress.

“Overall, results support Dato-DXd as a potential new therapeutic option for patients with metastatic hormone receptor–positive breast cancer,” he said.
 

Different ADC, same target

Dr. Bardia noted that there is an unmet need for effective therapies for patients with metastatic HR+/HER2– breast cancer who experience disease progression after endocrine therapy and at least one line of systemic therapy.

Although chemotherapy is widely used in this population, it’s associated with low response rates, poor prognosis, and significant toxicities, including hematologic and neurologic adverse events (AEs).

Dato-DXd is composed of a monoclonal antibody targeting TROP2, a transmembrane glycoprotein overexpressed in cancer cells, linked to the topoisomerase 1 inhibitor deruxtecan as the toxic payload.

Dr. Bardia explained that Dato-DXd has four properties that distinguish it from other TROP2-directed ADCs: an optimized drug to antibody ratio of 4, a stable linker-payload, tumor-selective cleavable linker, both of which reduce off-target toxicities, and a bystander antitumor effect that can target TROP2-expressing cells in the tumor microenvironment.

In the phase I TROPION-PanTumor01 trial, Dato-DXd had promising anti-tumor activity and a manageable safety profile in patients with metastatic HR+/HER2– breast cancer, paving the way for the TROPION-Breast01 study reported here.
 

Efficacy results

In the Breast01 trial, 732 patients with inoperable or metastatic HR+/HER2– breast cancer previously treated with 1 or 2 lines of chemotherapy that had progressed on endocrine therapy were stratified by number of prior chemotherapy lines, geographic region, and prior CDK4/6 inhibitor status, and then randomized to either Dato-DXd 6 mg/kg intravenously on day 1 of each 3-week cycle (365 patients) or to investigator’s choice of chemotherapy (367 patients). According to the protocol, chemotherapy could be eribulin mesylate, vinorelbine, or gemcitabine delivered via IV on days 1 and 8 every 3 weeks, or oral capecitabine on days 1 through 14 of every 3-week cycle.

At the time of data cutoff, 93 patients assigned to the ADC and 39 assigned to chemotherapy were still on treatment.

As noted before, median PFS by blinded independent central review, one of two primary endpoints, was 6.9 months with Dato-DXd, compared with 4.9 months with chemotherapy, translating into a hazard ratio for progression of 0.63 (P < .0001)­­­.

The benefit was seen across nearly all subgroups except among patients who had not previously received a CDK4/6 inhibitor, and patients who had received a prior anthracycline but not a taxane.­

Objective response rates (ORR) were 36.4% with Dato-DXd (99.5% partial and .5% complete response), compared with 22.9% with chemotherapy (all partial responses; P values not reported).

Overall survival data, the other primary endpoint, were not mature at a median OS follow-up of 9.7 months, and will be reported at a later date.
 

­Safety results

“In terms of safety, the rate of grade 3 or higher treatment-related AEs in the Dato-DXd arm was less as compared to investigator choice of chemotherapy. This is a bit different from most of the studies; in general we see that the rate of adverse events is higher in the intervention arm as compared to the control arm,” Dr. Bardia commented.

Rates of dose reductions and dose interruptions due to treatment-related AEs were also lower with the ADC.

There were no patient deaths associated with Dato-DXd. One patient assigned to chemotherapy died from a complication associated with febrile neutropenia.

Most treatment-related AEs occurring in 15% of patients and AEs of special interest were of grade 1 and manageable.

The most common toxicities seen with the ADC were oral mucositis and dry eye. The most common side effects with chemotherapy were neutropenia and anemia, “the usual side effects you would expect with chemotherapy,” Dr. Bardia said, pointing out that the rate of grade 3 neutropenia was 31% with standard chemotherapy, compared with 1% with Dato-DXd.
 

Good, but we can do better

ESMO invited discussant Sarat Chandarlapaty, MD, PhD, a breast oncologist at Memorial Sloan Kettering Cancer Center in New York, commented that while the trial data showed superior efficacy and safety with Dato-DXd, compared with standard chemotherapy, it’s still unclear how it and other ADCs on the market and in the research pipeline may be used in therapy for this patient population.

“Would I rather prescribe Dato-DXd or more chemo after 1 to 2 lines of chemo in unselected HR-positive, HER2-negative breast cancer? The answer is Dato-DXd, but it leaves several unanswered questions for us,” he said.

“First, we have two ADCs approved in HR-positive breast cancer: another TROP2 ADC sacituzumab [govitecan] and a HER2 ADC trastuzumab deruxtecan. Would I rather give Dato over one of these? I don’t have an answer,” he added.

In addition, it’s unknown whether these drugs, which have the same topoisomerase-targeted payload, could be given in sequence, and there are as yet no clear answers as to whether patients might do better with Dato-DXd or with a PIK3ca inhibitor.

“I would say that the elephant in the room is really another question, and that is, ‘Is Dato-DXd in this context delivering on the promise of an ADC?’ ” Dr. Chandarlapaty said.

“I think translational research is urgently needed if we’re ultimately to deliver on the promise of these agents in the clinic,” he concluded.

The TROPION-Breast01 study is sponsored AstraZeneca, which is collaborating with Daiichi-Sankyo on global development and commercialization of Dato-DXd. Dr. Bardia disclosed advisory board activities and institutional research funding from AstraZeneca and Daiichi-Sankyo and others. Dr. Chandarlapaty disclosed research funding from both companies, and advisory board activities for AstraZeneca and others.

The investigational anti-body drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd) was associated with both improved progression-free survival and better safety than standard chemotherapy for patients with metastatic HER-2 negative (HR+/HER2–) breast cancer resistant to endocrine therapy, data from the phase 3 TROPION-Breast01 trial showed.

At a median follow-up of 10.8 months, the median progression-free survival (PFS) was 6.9 months for patients randomly assigned to receive Dato-DXd, compared with 4.9 months for the investigator’s choice of chemotherapy with either eribulin mesylate, vinorelbine, capecitabine, or gemcitabine. This difference translated into a 37% reduction in risk of disease progression with the ADC, reported Aditya Bardia, MD, MPH, director of the breast cancer research program at the Mass General Cancer Center in Boston.

Patients who received Dato-DXd had less than half the number of grade 3 or greater toxicities and fewer dose reductions or interruptions than patients who received chemotherapy, he noted in an oral abstract session at the 2023 European Society for Medical Oncology Congress.

“Overall, results support Dato-DXd as a potential new therapeutic option for patients with metastatic hormone receptor–positive breast cancer,” he said.
 

Different ADC, same target

Dr. Bardia noted that there is an unmet need for effective therapies for patients with metastatic HR+/HER2– breast cancer who experience disease progression after endocrine therapy and at least one line of systemic therapy.

Although chemotherapy is widely used in this population, it’s associated with low response rates, poor prognosis, and significant toxicities, including hematologic and neurologic adverse events (AEs).

Dato-DXd is composed of a monoclonal antibody targeting TROP2, a transmembrane glycoprotein overexpressed in cancer cells, linked to the topoisomerase 1 inhibitor deruxtecan as the toxic payload.

Dr. Bardia explained that Dato-DXd has four properties that distinguish it from other TROP2-directed ADCs: an optimized drug to antibody ratio of 4, a stable linker-payload, tumor-selective cleavable linker, both of which reduce off-target toxicities, and a bystander antitumor effect that can target TROP2-expressing cells in the tumor microenvironment.

In the phase I TROPION-PanTumor01 trial, Dato-DXd had promising anti-tumor activity and a manageable safety profile in patients with metastatic HR+/HER2– breast cancer, paving the way for the TROPION-Breast01 study reported here.
 

Efficacy results

In the Breast01 trial, 732 patients with inoperable or metastatic HR+/HER2– breast cancer previously treated with 1 or 2 lines of chemotherapy that had progressed on endocrine therapy were stratified by number of prior chemotherapy lines, geographic region, and prior CDK4/6 inhibitor status, and then randomized to either Dato-DXd 6 mg/kg intravenously on day 1 of each 3-week cycle (365 patients) or to investigator’s choice of chemotherapy (367 patients). According to the protocol, chemotherapy could be eribulin mesylate, vinorelbine, or gemcitabine delivered via IV on days 1 and 8 every 3 weeks, or oral capecitabine on days 1 through 14 of every 3-week cycle.

At the time of data cutoff, 93 patients assigned to the ADC and 39 assigned to chemotherapy were still on treatment.

As noted before, median PFS by blinded independent central review, one of two primary endpoints, was 6.9 months with Dato-DXd, compared with 4.9 months with chemotherapy, translating into a hazard ratio for progression of 0.63 (P < .0001)­­­.

The benefit was seen across nearly all subgroups except among patients who had not previously received a CDK4/6 inhibitor, and patients who had received a prior anthracycline but not a taxane.­

Objective response rates (ORR) were 36.4% with Dato-DXd (99.5% partial and .5% complete response), compared with 22.9% with chemotherapy (all partial responses; P values not reported).

Overall survival data, the other primary endpoint, were not mature at a median OS follow-up of 9.7 months, and will be reported at a later date.
 

­Safety results

“In terms of safety, the rate of grade 3 or higher treatment-related AEs in the Dato-DXd arm was less as compared to investigator choice of chemotherapy. This is a bit different from most of the studies; in general we see that the rate of adverse events is higher in the intervention arm as compared to the control arm,” Dr. Bardia commented.

Rates of dose reductions and dose interruptions due to treatment-related AEs were also lower with the ADC.

There were no patient deaths associated with Dato-DXd. One patient assigned to chemotherapy died from a complication associated with febrile neutropenia.

Most treatment-related AEs occurring in 15% of patients and AEs of special interest were of grade 1 and manageable.

The most common toxicities seen with the ADC were oral mucositis and dry eye. The most common side effects with chemotherapy were neutropenia and anemia, “the usual side effects you would expect with chemotherapy,” Dr. Bardia said, pointing out that the rate of grade 3 neutropenia was 31% with standard chemotherapy, compared with 1% with Dato-DXd.
 

Good, but we can do better

ESMO invited discussant Sarat Chandarlapaty, MD, PhD, a breast oncologist at Memorial Sloan Kettering Cancer Center in New York, commented that while the trial data showed superior efficacy and safety with Dato-DXd, compared with standard chemotherapy, it’s still unclear how it and other ADCs on the market and in the research pipeline may be used in therapy for this patient population.

“Would I rather prescribe Dato-DXd or more chemo after 1 to 2 lines of chemo in unselected HR-positive, HER2-negative breast cancer? The answer is Dato-DXd, but it leaves several unanswered questions for us,” he said.

“First, we have two ADCs approved in HR-positive breast cancer: another TROP2 ADC sacituzumab [govitecan] and a HER2 ADC trastuzumab deruxtecan. Would I rather give Dato over one of these? I don’t have an answer,” he added.

In addition, it’s unknown whether these drugs, which have the same topoisomerase-targeted payload, could be given in sequence, and there are as yet no clear answers as to whether patients might do better with Dato-DXd or with a PIK3ca inhibitor.

“I would say that the elephant in the room is really another question, and that is, ‘Is Dato-DXd in this context delivering on the promise of an ADC?’ ” Dr. Chandarlapaty said.

“I think translational research is urgently needed if we’re ultimately to deliver on the promise of these agents in the clinic,” he concluded.

The TROPION-Breast01 study is sponsored AstraZeneca, which is collaborating with Daiichi-Sankyo on global development and commercialization of Dato-DXd. Dr. Bardia disclosed advisory board activities and institutional research funding from AstraZeneca and Daiichi-Sankyo and others. Dr. Chandarlapaty disclosed research funding from both companies, and advisory board activities for AstraZeneca and others.

The investigational anti-body drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd) was associated with both improved progression-free survival and better safety than standard chemotherapy for patients with metastatic HER-2 negative (HR+/HER2–) breast cancer resistant to endocrine therapy, data from the phase 3 TROPION-Breast01 trial showed.

At a median follow-up of 10.8 months, the median progression-free survival (PFS) was 6.9 months for patients randomly assigned to receive Dato-DXd, compared with 4.9 months for the investigator’s choice of chemotherapy with either eribulin mesylate, vinorelbine, capecitabine, or gemcitabine. This difference translated into a 37% reduction in risk of disease progression with the ADC, reported Aditya Bardia, MD, MPH, director of the breast cancer research program at the Mass General Cancer Center in Boston.

Patients who received Dato-DXd had less than half the number of grade 3 or greater toxicities and fewer dose reductions or interruptions than patients who received chemotherapy, he noted in an oral abstract session at the 2023 European Society for Medical Oncology Congress.

“Overall, results support Dato-DXd as a potential new therapeutic option for patients with metastatic hormone receptor–positive breast cancer,” he said.
 

Different ADC, same target

Dr. Bardia noted that there is an unmet need for effective therapies for patients with metastatic HR+/HER2– breast cancer who experience disease progression after endocrine therapy and at least one line of systemic therapy.

Although chemotherapy is widely used in this population, it’s associated with low response rates, poor prognosis, and significant toxicities, including hematologic and neurologic adverse events (AEs).

Dato-DXd is composed of a monoclonal antibody targeting TROP2, a transmembrane glycoprotein overexpressed in cancer cells, linked to the topoisomerase 1 inhibitor deruxtecan as the toxic payload.

Dr. Bardia explained that Dato-DXd has four properties that distinguish it from other TROP2-directed ADCs: an optimized drug to antibody ratio of 4, a stable linker-payload, tumor-selective cleavable linker, both of which reduce off-target toxicities, and a bystander antitumor effect that can target TROP2-expressing cells in the tumor microenvironment.

In the phase I TROPION-PanTumor01 trial, Dato-DXd had promising anti-tumor activity and a manageable safety profile in patients with metastatic HR+/HER2– breast cancer, paving the way for the TROPION-Breast01 study reported here.
 

Efficacy results

In the Breast01 trial, 732 patients with inoperable or metastatic HR+/HER2– breast cancer previously treated with 1 or 2 lines of chemotherapy that had progressed on endocrine therapy were stratified by number of prior chemotherapy lines, geographic region, and prior CDK4/6 inhibitor status, and then randomized to either Dato-DXd 6 mg/kg intravenously on day 1 of each 3-week cycle (365 patients) or to investigator’s choice of chemotherapy (367 patients). According to the protocol, chemotherapy could be eribulin mesylate, vinorelbine, or gemcitabine delivered via IV on days 1 and 8 every 3 weeks, or oral capecitabine on days 1 through 14 of every 3-week cycle.

At the time of data cutoff, 93 patients assigned to the ADC and 39 assigned to chemotherapy were still on treatment.

As noted before, median PFS by blinded independent central review, one of two primary endpoints, was 6.9 months with Dato-DXd, compared with 4.9 months with chemotherapy, translating into a hazard ratio for progression of 0.63 (P < .0001)­­­.

The benefit was seen across nearly all subgroups except among patients who had not previously received a CDK4/6 inhibitor, and patients who had received a prior anthracycline but not a taxane.­

Objective response rates (ORR) were 36.4% with Dato-DXd (99.5% partial and .5% complete response), compared with 22.9% with chemotherapy (all partial responses; P values not reported).

Overall survival data, the other primary endpoint, were not mature at a median OS follow-up of 9.7 months, and will be reported at a later date.
 

­Safety results

“In terms of safety, the rate of grade 3 or higher treatment-related AEs in the Dato-DXd arm was less as compared to investigator choice of chemotherapy. This is a bit different from most of the studies; in general we see that the rate of adverse events is higher in the intervention arm as compared to the control arm,” Dr. Bardia commented.

Rates of dose reductions and dose interruptions due to treatment-related AEs were also lower with the ADC.

There were no patient deaths associated with Dato-DXd. One patient assigned to chemotherapy died from a complication associated with febrile neutropenia.

Most treatment-related AEs occurring in 15% of patients and AEs of special interest were of grade 1 and manageable.

The most common toxicities seen with the ADC were oral mucositis and dry eye. The most common side effects with chemotherapy were neutropenia and anemia, “the usual side effects you would expect with chemotherapy,” Dr. Bardia said, pointing out that the rate of grade 3 neutropenia was 31% with standard chemotherapy, compared with 1% with Dato-DXd.
 

Good, but we can do better

ESMO invited discussant Sarat Chandarlapaty, MD, PhD, a breast oncologist at Memorial Sloan Kettering Cancer Center in New York, commented that while the trial data showed superior efficacy and safety with Dato-DXd, compared with standard chemotherapy, it’s still unclear how it and other ADCs on the market and in the research pipeline may be used in therapy for this patient population.

“Would I rather prescribe Dato-DXd or more chemo after 1 to 2 lines of chemo in unselected HR-positive, HER2-negative breast cancer? The answer is Dato-DXd, but it leaves several unanswered questions for us,” he said.

“First, we have two ADCs approved in HR-positive breast cancer: another TROP2 ADC sacituzumab [govitecan] and a HER2 ADC trastuzumab deruxtecan. Would I rather give Dato over one of these? I don’t have an answer,” he added.

In addition, it’s unknown whether these drugs, which have the same topoisomerase-targeted payload, could be given in sequence, and there are as yet no clear answers as to whether patients might do better with Dato-DXd or with a PIK3ca inhibitor.

“I would say that the elephant in the room is really another question, and that is, ‘Is Dato-DXd in this context delivering on the promise of an ADC?’ ” Dr. Chandarlapaty said.

“I think translational research is urgently needed if we’re ultimately to deliver on the promise of these agents in the clinic,” he concluded.

The TROPION-Breast01 study is sponsored AstraZeneca, which is collaborating with Daiichi-Sankyo on global development and commercialization of Dato-DXd. Dr. Bardia disclosed advisory board activities and institutional research funding from AstraZeneca and Daiichi-Sankyo and others. Dr. Chandarlapaty disclosed research funding from both companies, and advisory board activities for AstraZeneca and others.

MADRID – “Why did I choose this?”

That is the core question a Portuguese oncologist posed from the audience during a session at the annual meeting of the European Society for Medical Oncology (ESMO) that was dedicated to building a sustainable oncology workforce.

“Ten, twenty years ago, being a doctor was a dream,” she said, but right now doctors are underpaid, under strain, and have very few resources.

This oncologist is hardly alone.

Rates of burnout among oncologists remain alarmingly high, explained session chair Kok Haw Jonathan Lim, MD, PhD.

A survey from ESMO conducted almost a decade ago found that more than 50% of oncologists across Europe, many of whom were early in their careers, reported being burned out.

This, Dr. Lim said, “was the starting point,” well before the COVID pandemic struck.

More recently, the pandemic has taken its own toll on the well-being of oncologists. A survey presented at ESMO 2020 revealed that 38% of participants, spanning 101 countries, reported experiencing burnout, and 66% said they were not able to perform their job.

Medscape’s 2023 Physician Burnout and Depression Report highlighted similar burnout rates, with 53% of U.S. physicians and 52% of oncologists saying they felt burned out, compared with about 42% in 2018, before the pandemic.

The oncology workforce is in crisis in every country, said Dr. Lim, from the Cancer Dynamics Lab, the Francis Crick Institute, London.

Burnout, characterized by emotional exhaustion, depersonalization or feelings of cynicism, and a low sense of personal accomplishment, can result in a poor work-life balance as well as poor mental and physical health. Factors linked to burnout include social isolation, increased workload, reduced quality of work, lack of control over work, and stressful professional experiences.

Together, these factors can affect patient care and further exacerbate staffing issues, Dr. Lim said.

Staffing shortages are common. Oncologists often work long hours or on weekends to cover gaps caused by staffing shortages. Recent data revealed that in high-income countries, there are on average 0.65 medical oncologists and 0.25 radiation oncologists per 100 patients — a situation made worse by professionals taking early retirement or leaving medicine during the pandemic.

“We have seen that the shortage of human resources in many countries as well as the increasing workload related to the increasing number of cancers,” as well as patients surviving longer, have increased pressures on the healthcare system, Andrés Cervantes, MD, PhD, president of ESMO, explained in a press conference.

While tackling these oncology workforce problems requires smaller, local changes to a physician’s daily routine, “the real change,” Dr. Lim said, lies at an infrastructure level.

In response to this chronic and growing problem, ESMO launched its Resilience Task Force in 2020 to evaluate burnout and well-being. The task force plans to publish a position paper in which it will propose a set of recommendations regarding the psychosocial risks of burnout as well as flexible work patterns, well-being resources, and targeted support.

A panel of experts at the meeting touched on some of these solutions.

Dealing with staff shortages is a must, said Jean-Yves Blay, MD, PhD, during the session. “It’s a simple mathematical equation,” Dr. Blay said. “We must increase the number of doctors in medical schools and the number of nurses and healthcare professionals in all schools.” Improving staffing would also help reduce chronic workload issues.

Resilience training should also be incorporated into physician training starting in medical school. Teaching oncologists how to deal with bad news and to cope when patients dies is particularly important.

“I was not taught that,” said the oncologist from Portugal. “I had to learn that at my own cost.”

The good news is that it’s possible to develop resiliency skills over time, said Claire Hardy, PhD, from Lancaster University, United Kingdom, who agreed that training programs could be one approach to improve oncologists’ work life.

However, a person’s needs are determined by their institution and personal responsibilities. “No one knows your job better than you,” Dr. Hardy said. “No one knows better than you where the inefficiencies are, where the bureaucracy is that could be taken away, or it could be done by somebody whose role it is to sort all that out.”

But having this understanding is not enough. Physician also need to feel “psychological safety to be able to speak out and say that something isn’t working right now or is too much,” or, “I’m spending too much time doing this.”

In other words, oncologists need to be able to set boundaries and say no.

Dr. Hardy said this concept “has been around a while, but it’s really gaining momentum,” and being able to discuss these issues in a forum such as the ESMO Congress is a promising start.

Dr. Lim has relationships with Janseen and SEOM. No other relevant financial relationships were disclosed.

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

MADRID – “Why did I choose this?”

That is the core question a Portuguese oncologist posed from the audience during a session at the annual meeting of the European Society for Medical Oncology (ESMO) that was dedicated to building a sustainable oncology workforce.

“Ten, twenty years ago, being a doctor was a dream,” she said, but right now doctors are underpaid, under strain, and have very few resources.

This oncologist is hardly alone.

Rates of burnout among oncologists remain alarmingly high, explained session chair Kok Haw Jonathan Lim, MD, PhD.

A survey from ESMO conducted almost a decade ago found that more than 50% of oncologists across Europe, many of whom were early in their careers, reported being burned out.

This, Dr. Lim said, “was the starting point,” well before the COVID pandemic struck.

More recently, the pandemic has taken its own toll on the well-being of oncologists. A survey presented at ESMO 2020 revealed that 38% of participants, spanning 101 countries, reported experiencing burnout, and 66% said they were not able to perform their job.

Medscape’s 2023 Physician Burnout and Depression Report highlighted similar burnout rates, with 53% of U.S. physicians and 52% of oncologists saying they felt burned out, compared with about 42% in 2018, before the pandemic.

The oncology workforce is in crisis in every country, said Dr. Lim, from the Cancer Dynamics Lab, the Francis Crick Institute, London.

Burnout, characterized by emotional exhaustion, depersonalization or feelings of cynicism, and a low sense of personal accomplishment, can result in a poor work-life balance as well as poor mental and physical health. Factors linked to burnout include social isolation, increased workload, reduced quality of work, lack of control over work, and stressful professional experiences.

Together, these factors can affect patient care and further exacerbate staffing issues, Dr. Lim said.

Staffing shortages are common. Oncologists often work long hours or on weekends to cover gaps caused by staffing shortages. Recent data revealed that in high-income countries, there are on average 0.65 medical oncologists and 0.25 radiation oncologists per 100 patients — a situation made worse by professionals taking early retirement or leaving medicine during the pandemic.

“We have seen that the shortage of human resources in many countries as well as the increasing workload related to the increasing number of cancers,” as well as patients surviving longer, have increased pressures on the healthcare system, Andrés Cervantes, MD, PhD, president of ESMO, explained in a press conference.

While tackling these oncology workforce problems requires smaller, local changes to a physician’s daily routine, “the real change,” Dr. Lim said, lies at an infrastructure level.

In response to this chronic and growing problem, ESMO launched its Resilience Task Force in 2020 to evaluate burnout and well-being. The task force plans to publish a position paper in which it will propose a set of recommendations regarding the psychosocial risks of burnout as well as flexible work patterns, well-being resources, and targeted support.

A panel of experts at the meeting touched on some of these solutions.

Dealing with staff shortages is a must, said Jean-Yves Blay, MD, PhD, during the session. “It’s a simple mathematical equation,” Dr. Blay said. “We must increase the number of doctors in medical schools and the number of nurses and healthcare professionals in all schools.” Improving staffing would also help reduce chronic workload issues.

Resilience training should also be incorporated into physician training starting in medical school. Teaching oncologists how to deal with bad news and to cope when patients dies is particularly important.

“I was not taught that,” said the oncologist from Portugal. “I had to learn that at my own cost.”

The good news is that it’s possible to develop resiliency skills over time, said Claire Hardy, PhD, from Lancaster University, United Kingdom, who agreed that training programs could be one approach to improve oncologists’ work life.

However, a person’s needs are determined by their institution and personal responsibilities. “No one knows your job better than you,” Dr. Hardy said. “No one knows better than you where the inefficiencies are, where the bureaucracy is that could be taken away, or it could be done by somebody whose role it is to sort all that out.”

But having this understanding is not enough. Physician also need to feel “psychological safety to be able to speak out and say that something isn’t working right now or is too much,” or, “I’m spending too much time doing this.”

In other words, oncologists need to be able to set boundaries and say no.

Dr. Hardy said this concept “has been around a while, but it’s really gaining momentum,” and being able to discuss these issues in a forum such as the ESMO Congress is a promising start.

Dr. Lim has relationships with Janseen and SEOM. No other relevant financial relationships were disclosed.

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

MADRID – “Why did I choose this?”

That is the core question a Portuguese oncologist posed from the audience during a session at the annual meeting of the European Society for Medical Oncology (ESMO) that was dedicated to building a sustainable oncology workforce.

“Ten, twenty years ago, being a doctor was a dream,” she said, but right now doctors are underpaid, under strain, and have very few resources.

This oncologist is hardly alone.

Rates of burnout among oncologists remain alarmingly high, explained session chair Kok Haw Jonathan Lim, MD, PhD.

A survey from ESMO conducted almost a decade ago found that more than 50% of oncologists across Europe, many of whom were early in their careers, reported being burned out.

This, Dr. Lim said, “was the starting point,” well before the COVID pandemic struck.

More recently, the pandemic has taken its own toll on the well-being of oncologists. A survey presented at ESMO 2020 revealed that 38% of participants, spanning 101 countries, reported experiencing burnout, and 66% said they were not able to perform their job.

Medscape’s 2023 Physician Burnout and Depression Report highlighted similar burnout rates, with 53% of U.S. physicians and 52% of oncologists saying they felt burned out, compared with about 42% in 2018, before the pandemic.

The oncology workforce is in crisis in every country, said Dr. Lim, from the Cancer Dynamics Lab, the Francis Crick Institute, London.

Burnout, characterized by emotional exhaustion, depersonalization or feelings of cynicism, and a low sense of personal accomplishment, can result in a poor work-life balance as well as poor mental and physical health. Factors linked to burnout include social isolation, increased workload, reduced quality of work, lack of control over work, and stressful professional experiences.

Together, these factors can affect patient care and further exacerbate staffing issues, Dr. Lim said.

Staffing shortages are common. Oncologists often work long hours or on weekends to cover gaps caused by staffing shortages. Recent data revealed that in high-income countries, there are on average 0.65 medical oncologists and 0.25 radiation oncologists per 100 patients — a situation made worse by professionals taking early retirement or leaving medicine during the pandemic.

“We have seen that the shortage of human resources in many countries as well as the increasing workload related to the increasing number of cancers,” as well as patients surviving longer, have increased pressures on the healthcare system, Andrés Cervantes, MD, PhD, president of ESMO, explained in a press conference.

While tackling these oncology workforce problems requires smaller, local changes to a physician’s daily routine, “the real change,” Dr. Lim said, lies at an infrastructure level.

In response to this chronic and growing problem, ESMO launched its Resilience Task Force in 2020 to evaluate burnout and well-being. The task force plans to publish a position paper in which it will propose a set of recommendations regarding the psychosocial risks of burnout as well as flexible work patterns, well-being resources, and targeted support.

A panel of experts at the meeting touched on some of these solutions.

Dealing with staff shortages is a must, said Jean-Yves Blay, MD, PhD, during the session. “It’s a simple mathematical equation,” Dr. Blay said. “We must increase the number of doctors in medical schools and the number of nurses and healthcare professionals in all schools.” Improving staffing would also help reduce chronic workload issues.

Resilience training should also be incorporated into physician training starting in medical school. Teaching oncologists how to deal with bad news and to cope when patients dies is particularly important.

“I was not taught that,” said the oncologist from Portugal. “I had to learn that at my own cost.”

The good news is that it’s possible to develop resiliency skills over time, said Claire Hardy, PhD, from Lancaster University, United Kingdom, who agreed that training programs could be one approach to improve oncologists’ work life.

However, a person’s needs are determined by their institution and personal responsibilities. “No one knows your job better than you,” Dr. Hardy said. “No one knows better than you where the inefficiencies are, where the bureaucracy is that could be taken away, or it could be done by somebody whose role it is to sort all that out.”

But having this understanding is not enough. Physician also need to feel “psychological safety to be able to speak out and say that something isn’t working right now or is too much,” or, “I’m spending too much time doing this.”

In other words, oncologists need to be able to set boundaries and say no.

Dr. Hardy said this concept “has been around a while, but it’s really gaining momentum,” and being able to discuss these issues in a forum such as the ESMO Congress is a promising start.

Dr. Lim has relationships with Janseen and SEOM. No other relevant financial relationships were disclosed.

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

Enfortumab vedotin (Padcev) plus pembrolizumab (Keytruda) is being called the new standard of care for the upfront treatment of locally advanced/metastatic urothelial carcinoma following a phase 3 trial presented at the 2023 European Society for Medical Oncology annual meeting.

The combination soundly beat the current standard of care – platinum-based chemotherapy – with a median overall survival of 31.5 months among 442 subjects versus 16.1 months among 444 randomized to gemcitabine with cisplatin or carboplatin, an unprecedented 53% drop in the risk of mortality (P < .00001).

The elimination of chemotherapy also meant that there were substantially fewer grade 3 or higher adverse events with the new combination.

“This is the first time we’ve managed to beat chemotherapy in the first-line setting for overall survival despite multiple previous attempts.” The 30% remission rate with enfortumab vedotin plus pembrolizumab “is not something we’ve seen before,” said lead investigator Thomas Powles, MBBS, MD, a urologic oncologist and researcher at the University of London, who presented the findings.

“We welcome a new standard of care in the management of advanced, metastatic urothelial carcinoma, enfortumab vedotin plus pembrolizumab,” said Andrea Apolo, MD, a urologic oncology researcher at the National Cancer Institute in Bethesda, Md., and discussant on the trial, dubbed EV-302/KEYNOTE-A39.

The news overshadowed a second trial presented immediately after Dr. Powles’ that also showed improvement in overall survival versus standard platinum-based chemotherapy, CheckMate 901.

Instead of replacing chemotherapy, CheckMate 901 added nivolumab. With 304 patients randomized to each arm, nivolumab add-on led to a median overall survival of 21.7 months versus 18.9 months with stand-alone gemcitabine/cisplatin, a 22% drop in the risk of mortality (P = .0171).

It’s the first time that adding immunotherapy to first-line chemotherapy improved survival in metastatic urothelial carcinoma, said lead investigator Michiel van der Heijden, MD, PhD, a urologic oncologist and researcher at the Netherlands Cancer Institute, Amsterdam.

After decades of stagnation, Dr. Apolo said, it’s “monumental for our field” to have two trials that beat chemotherapy in the first-line setting.

However, she said that the much better survival with enfortumab vedotin/pembrolizumab means that the combination now “takes first place as the best first-line regimen in urothelial carcinoma.”
 

Major disruptions in the treatment paradigm

The crowning of a new first-line standard for locally advanced/metastatic urothelial carcinoma means that everything else in the treatment paradigm has to shift, Dr. Apolo said, and there are many new questions that need to be answered.

Among the most pressing, should the previous first-line standard – platinum-based chemotherapy – now move to the second line and be considered the treatment of choice after progression? Also, is there still a role for the previous second-line standards, pembrolizumab and other immunotherapies, if pembrolizumab fails in the first line?

Dr. Apolo said investigators also need to figure out if there is a role for enfortumab vedotin/pembrolizumab in earlier-stage disease, such as muscle-invasive bladder cancer, and if the dose and duration of enfortumab vedotin can be reduced to limit its peculiar ocular and other toxicities.

Finally, “we must discuss cost,” she said. Enfortumab vedotin plus pembrolizumab (EV+P) is expensive. “Will payers be able to afford” it?

Dr. Powles, the lead investigator on EV-302/KEYNOTE-A39, said he doesn’t know how negotiations are going with payers, but that he hopes they move quickly. “We’ve seen transformative results” with the combination for even aggressive cancers in very sick people. “I think it’s going to be a challenge with patients not to talk about these data.”
 

EV-302/KEYNOTE-059 details

Merck, the maker of pembrolizumab, and the makers/marketers of enfortumab vedotin, Astellas and Seagen, said they will use EV-302/KEYNOTE-059 to seek a first-line indication for locally advanced/metastatic urothelial carcinoma from the U.S. Food and Drug Administration and other regulators.

They also said the results serve as the confirmation FDA required when it gave accelerated approval to the combination in April 2023 for cisplatin-ineligible patients based on tumor response rates and response durability, according to press releases from the companies.

Pembrolizumab (P) in the trial was dosed at 200 mg on the first day of 3-week treatment cycles to a maximum of 35 cycles; enfortumab vedotin (EV) was given on the first and eighth day of the cycle with no limit in the number of cycles until progression or unacceptable toxicity.

Cisplatin or carboplatin (C) in the control arm was delivered on the first day and gemcitabine (G) on the first and eighth days for up to six 3-week cycles.

Patients in both arms were split about equally between performance statuses of 0 or 1; less than 4% in each group had statuses of 2.

Echoing the overall survival (OS) results, progression-free survival (PFS) was a median of 12.5 months with EV-P versus 6.3 months with GC, a 55% drop in the risk of progression or death (P < .00001).

The results held regardless of PD-L1 expression, cisplatin eligibility, and the presence or absence of visceral metastases.

Follow-up treatments in the trial begin to address Dr. Apolo’s questions: Almost 60% of GC patients went on to a PD-1/L1 for subsequent maintenance or progression, and almost a quarter of EV+P patients went on to subsequent platinum-based chemotherapy.

Grade 3 or higher adverse events occurred in 55.9% of subjects in the EV+P group versus 69.5% in the GC arm.

The most common in the chemotherapy arm were anemia, neutropenia, thrombocytopenia, fatigue, and nausea. The most common with EV+P were skin reactions, hyperglycemia, neutropenia, peripheral neuropathy, diarrhea, and anemia,
 

CheckMate 901 details

In CheckMate 901, gemcitabine and cisplatin were administered on the first day of 3-week treatment cycles for up to 6 cycles; subjects randomized to nivolumab add-on received 360 mg on day 1 of each cycle, followed by 480 mg every 4 weeks until disease progression or unacceptable toxicity for up to 2 years.

PFS results again mirrored OS, with a median PFS of 7.9 months in the nivolumab arm versus 7.6 months with stand-alone chemotherapy, a 28% drop in the risk of progression or death (P = .0012).

Although OS and PFS benefits were statistically significant overall, they were not significant in subgroup analyses of patients 65 years and older, women, or in patients with liver metastases.

Trends in OS and PFS actually favored chemotherapy in the 40 U.S. subjects (HR OS, 1.92; 95% confidence interval, 0.95-3.88).

The rate of grade 3 or higher adverse events was 61.8% with nivolumab add-on versus 51.7% with chemotherapy alone. Anemia and neutropenia were the most common in both arms, and higher in the nivolumab group.

EV-302/KEYNOTE-A39 was funded by Seagen, Astellas, and Merck. CheckMate 901 was funded by Bristol-Myers Squibb, the maker of nivolumab.

Dr. Powles reported extensive financial ties to pharmaceutical companies, including being an advisor to and receiving research funding from Bristol-Myers Squibb, Merck, SeaGen, and Astellas, as well as travel expenses from Merck. Among other disclosures, Dr. Heijden is an advisor to Seagen and an advisor and researcher for Bristol-Myers Squibb. Dr. Apolo is an unpaid consultant to Merck, Astellas, Seagen, Bristol-Myers Squibb, and other companies.

Enfortumab vedotin (Padcev) plus pembrolizumab (Keytruda) is being called the new standard of care for the upfront treatment of locally advanced/metastatic urothelial carcinoma following a phase 3 trial presented at the 2023 European Society for Medical Oncology annual meeting.

The combination soundly beat the current standard of care – platinum-based chemotherapy – with a median overall survival of 31.5 months among 442 subjects versus 16.1 months among 444 randomized to gemcitabine with cisplatin or carboplatin, an unprecedented 53% drop in the risk of mortality (P < .00001).

The elimination of chemotherapy also meant that there were substantially fewer grade 3 or higher adverse events with the new combination.

“This is the first time we’ve managed to beat chemotherapy in the first-line setting for overall survival despite multiple previous attempts.” The 30% remission rate with enfortumab vedotin plus pembrolizumab “is not something we’ve seen before,” said lead investigator Thomas Powles, MBBS, MD, a urologic oncologist and researcher at the University of London, who presented the findings.

“We welcome a new standard of care in the management of advanced, metastatic urothelial carcinoma, enfortumab vedotin plus pembrolizumab,” said Andrea Apolo, MD, a urologic oncology researcher at the National Cancer Institute in Bethesda, Md., and discussant on the trial, dubbed EV-302/KEYNOTE-A39.

The news overshadowed a second trial presented immediately after Dr. Powles’ that also showed improvement in overall survival versus standard platinum-based chemotherapy, CheckMate 901.

Instead of replacing chemotherapy, CheckMate 901 added nivolumab. With 304 patients randomized to each arm, nivolumab add-on led to a median overall survival of 21.7 months versus 18.9 months with stand-alone gemcitabine/cisplatin, a 22% drop in the risk of mortality (P = .0171).

It’s the first time that adding immunotherapy to first-line chemotherapy improved survival in metastatic urothelial carcinoma, said lead investigator Michiel van der Heijden, MD, PhD, a urologic oncologist and researcher at the Netherlands Cancer Institute, Amsterdam.

After decades of stagnation, Dr. Apolo said, it’s “monumental for our field” to have two trials that beat chemotherapy in the first-line setting.

However, she said that the much better survival with enfortumab vedotin/pembrolizumab means that the combination now “takes first place as the best first-line regimen in urothelial carcinoma.”
 

Major disruptions in the treatment paradigm

The crowning of a new first-line standard for locally advanced/metastatic urothelial carcinoma means that everything else in the treatment paradigm has to shift, Dr. Apolo said, and there are many new questions that need to be answered.

Among the most pressing, should the previous first-line standard – platinum-based chemotherapy – now move to the second line and be considered the treatment of choice after progression? Also, is there still a role for the previous second-line standards, pembrolizumab and other immunotherapies, if pembrolizumab fails in the first line?

Dr. Apolo said investigators also need to figure out if there is a role for enfortumab vedotin/pembrolizumab in earlier-stage disease, such as muscle-invasive bladder cancer, and if the dose and duration of enfortumab vedotin can be reduced to limit its peculiar ocular and other toxicities.

Finally, “we must discuss cost,” she said. Enfortumab vedotin plus pembrolizumab (EV+P) is expensive. “Will payers be able to afford” it?

Dr. Powles, the lead investigator on EV-302/KEYNOTE-A39, said he doesn’t know how negotiations are going with payers, but that he hopes they move quickly. “We’ve seen transformative results” with the combination for even aggressive cancers in very sick people. “I think it’s going to be a challenge with patients not to talk about these data.”
 

EV-302/KEYNOTE-059 details

Merck, the maker of pembrolizumab, and the makers/marketers of enfortumab vedotin, Astellas and Seagen, said they will use EV-302/KEYNOTE-059 to seek a first-line indication for locally advanced/metastatic urothelial carcinoma from the U.S. Food and Drug Administration and other regulators.

They also said the results serve as the confirmation FDA required when it gave accelerated approval to the combination in April 2023 for cisplatin-ineligible patients based on tumor response rates and response durability, according to press releases from the companies.

Pembrolizumab (P) in the trial was dosed at 200 mg on the first day of 3-week treatment cycles to a maximum of 35 cycles; enfortumab vedotin (EV) was given on the first and eighth day of the cycle with no limit in the number of cycles until progression or unacceptable toxicity.

Cisplatin or carboplatin (C) in the control arm was delivered on the first day and gemcitabine (G) on the first and eighth days for up to six 3-week cycles.

Patients in both arms were split about equally between performance statuses of 0 or 1; less than 4% in each group had statuses of 2.

Echoing the overall survival (OS) results, progression-free survival (PFS) was a median of 12.5 months with EV-P versus 6.3 months with GC, a 55% drop in the risk of progression or death (P < .00001).

The results held regardless of PD-L1 expression, cisplatin eligibility, and the presence or absence of visceral metastases.

Follow-up treatments in the trial begin to address Dr. Apolo’s questions: Almost 60% of GC patients went on to a PD-1/L1 for subsequent maintenance or progression, and almost a quarter of EV+P patients went on to subsequent platinum-based chemotherapy.

Grade 3 or higher adverse events occurred in 55.9% of subjects in the EV+P group versus 69.5% in the GC arm.

The most common in the chemotherapy arm were anemia, neutropenia, thrombocytopenia, fatigue, and nausea. The most common with EV+P were skin reactions, hyperglycemia, neutropenia, peripheral neuropathy, diarrhea, and anemia,
 

CheckMate 901 details

In CheckMate 901, gemcitabine and cisplatin were administered on the first day of 3-week treatment cycles for up to 6 cycles; subjects randomized to nivolumab add-on received 360 mg on day 1 of each cycle, followed by 480 mg every 4 weeks until disease progression or unacceptable toxicity for up to 2 years.

PFS results again mirrored OS, with a median PFS of 7.9 months in the nivolumab arm versus 7.6 months with stand-alone chemotherapy, a 28% drop in the risk of progression or death (P = .0012).

Although OS and PFS benefits were statistically significant overall, they were not significant in subgroup analyses of patients 65 years and older, women, or in patients with liver metastases.

Trends in OS and PFS actually favored chemotherapy in the 40 U.S. subjects (HR OS, 1.92; 95% confidence interval, 0.95-3.88).

The rate of grade 3 or higher adverse events was 61.8% with nivolumab add-on versus 51.7% with chemotherapy alone. Anemia and neutropenia were the most common in both arms, and higher in the nivolumab group.

EV-302/KEYNOTE-A39 was funded by Seagen, Astellas, and Merck. CheckMate 901 was funded by Bristol-Myers Squibb, the maker of nivolumab.

Dr. Powles reported extensive financial ties to pharmaceutical companies, including being an advisor to and receiving research funding from Bristol-Myers Squibb, Merck, SeaGen, and Astellas, as well as travel expenses from Merck. Among other disclosures, Dr. Heijden is an advisor to Seagen and an advisor and researcher for Bristol-Myers Squibb. Dr. Apolo is an unpaid consultant to Merck, Astellas, Seagen, Bristol-Myers Squibb, and other companies.

Enfortumab vedotin (Padcev) plus pembrolizumab (Keytruda) is being called the new standard of care for the upfront treatment of locally advanced/metastatic urothelial carcinoma following a phase 3 trial presented at the 2023 European Society for Medical Oncology annual meeting.

The combination soundly beat the current standard of care – platinum-based chemotherapy – with a median overall survival of 31.5 months among 442 subjects versus 16.1 months among 444 randomized to gemcitabine with cisplatin or carboplatin, an unprecedented 53% drop in the risk of mortality (P < .00001).

The elimination of chemotherapy also meant that there were substantially fewer grade 3 or higher adverse events with the new combination.

“This is the first time we’ve managed to beat chemotherapy in the first-line setting for overall survival despite multiple previous attempts.” The 30% remission rate with enfortumab vedotin plus pembrolizumab “is not something we’ve seen before,” said lead investigator Thomas Powles, MBBS, MD, a urologic oncologist and researcher at the University of London, who presented the findings.

“We welcome a new standard of care in the management of advanced, metastatic urothelial carcinoma, enfortumab vedotin plus pembrolizumab,” said Andrea Apolo, MD, a urologic oncology researcher at the National Cancer Institute in Bethesda, Md., and discussant on the trial, dubbed EV-302/KEYNOTE-A39.

The news overshadowed a second trial presented immediately after Dr. Powles’ that also showed improvement in overall survival versus standard platinum-based chemotherapy, CheckMate 901.

Instead of replacing chemotherapy, CheckMate 901 added nivolumab. With 304 patients randomized to each arm, nivolumab add-on led to a median overall survival of 21.7 months versus 18.9 months with stand-alone gemcitabine/cisplatin, a 22% drop in the risk of mortality (P = .0171).

It’s the first time that adding immunotherapy to first-line chemotherapy improved survival in metastatic urothelial carcinoma, said lead investigator Michiel van der Heijden, MD, PhD, a urologic oncologist and researcher at the Netherlands Cancer Institute, Amsterdam.

After decades of stagnation, Dr. Apolo said, it’s “monumental for our field” to have two trials that beat chemotherapy in the first-line setting.

However, she said that the much better survival with enfortumab vedotin/pembrolizumab means that the combination now “takes first place as the best first-line regimen in urothelial carcinoma.”
 

Major disruptions in the treatment paradigm

The crowning of a new first-line standard for locally advanced/metastatic urothelial carcinoma means that everything else in the treatment paradigm has to shift, Dr. Apolo said, and there are many new questions that need to be answered.

Among the most pressing, should the previous first-line standard – platinum-based chemotherapy – now move to the second line and be considered the treatment of choice after progression? Also, is there still a role for the previous second-line standards, pembrolizumab and other immunotherapies, if pembrolizumab fails in the first line?

Dr. Apolo said investigators also need to figure out if there is a role for enfortumab vedotin/pembrolizumab in earlier-stage disease, such as muscle-invasive bladder cancer, and if the dose and duration of enfortumab vedotin can be reduced to limit its peculiar ocular and other toxicities.

Finally, “we must discuss cost,” she said. Enfortumab vedotin plus pembrolizumab (EV+P) is expensive. “Will payers be able to afford” it?

Dr. Powles, the lead investigator on EV-302/KEYNOTE-A39, said he doesn’t know how negotiations are going with payers, but that he hopes they move quickly. “We’ve seen transformative results” with the combination for even aggressive cancers in very sick people. “I think it’s going to be a challenge with patients not to talk about these data.”
 

EV-302/KEYNOTE-059 details

Merck, the maker of pembrolizumab, and the makers/marketers of enfortumab vedotin, Astellas and Seagen, said they will use EV-302/KEYNOTE-059 to seek a first-line indication for locally advanced/metastatic urothelial carcinoma from the U.S. Food and Drug Administration and other regulators.

They also said the results serve as the confirmation FDA required when it gave accelerated approval to the combination in April 2023 for cisplatin-ineligible patients based on tumor response rates and response durability, according to press releases from the companies.

Pembrolizumab (P) in the trial was dosed at 200 mg on the first day of 3-week treatment cycles to a maximum of 35 cycles; enfortumab vedotin (EV) was given on the first and eighth day of the cycle with no limit in the number of cycles until progression or unacceptable toxicity.

Cisplatin or carboplatin (C) in the control arm was delivered on the first day and gemcitabine (G) on the first and eighth days for up to six 3-week cycles.

Patients in both arms were split about equally between performance statuses of 0 or 1; less than 4% in each group had statuses of 2.

Echoing the overall survival (OS) results, progression-free survival (PFS) was a median of 12.5 months with EV-P versus 6.3 months with GC, a 55% drop in the risk of progression or death (P < .00001).

The results held regardless of PD-L1 expression, cisplatin eligibility, and the presence or absence of visceral metastases.

Follow-up treatments in the trial begin to address Dr. Apolo’s questions: Almost 60% of GC patients went on to a PD-1/L1 for subsequent maintenance or progression, and almost a quarter of EV+P patients went on to subsequent platinum-based chemotherapy.

Grade 3 or higher adverse events occurred in 55.9% of subjects in the EV+P group versus 69.5% in the GC arm.

The most common in the chemotherapy arm were anemia, neutropenia, thrombocytopenia, fatigue, and nausea. The most common with EV+P were skin reactions, hyperglycemia, neutropenia, peripheral neuropathy, diarrhea, and anemia,
 

CheckMate 901 details

In CheckMate 901, gemcitabine and cisplatin were administered on the first day of 3-week treatment cycles for up to 6 cycles; subjects randomized to nivolumab add-on received 360 mg on day 1 of each cycle, followed by 480 mg every 4 weeks until disease progression or unacceptable toxicity for up to 2 years.

PFS results again mirrored OS, with a median PFS of 7.9 months in the nivolumab arm versus 7.6 months with stand-alone chemotherapy, a 28% drop in the risk of progression or death (P = .0012).

Although OS and PFS benefits were statistically significant overall, they were not significant in subgroup analyses of patients 65 years and older, women, or in patients with liver metastases.

Trends in OS and PFS actually favored chemotherapy in the 40 U.S. subjects (HR OS, 1.92; 95% confidence interval, 0.95-3.88).

The rate of grade 3 or higher adverse events was 61.8% with nivolumab add-on versus 51.7% with chemotherapy alone. Anemia and neutropenia were the most common in both arms, and higher in the nivolumab group.

EV-302/KEYNOTE-A39 was funded by Seagen, Astellas, and Merck. CheckMate 901 was funded by Bristol-Myers Squibb, the maker of nivolumab.

Dr. Powles reported extensive financial ties to pharmaceutical companies, including being an advisor to and receiving research funding from Bristol-Myers Squibb, Merck, SeaGen, and Astellas, as well as travel expenses from Merck. Among other disclosures, Dr. Heijden is an advisor to Seagen and an advisor and researcher for Bristol-Myers Squibb. Dr. Apolo is an unpaid consultant to Merck, Astellas, Seagen, Bristol-Myers Squibb, and other companies.

There is an urgent need to raise global awareness about the direct link between alcohol consumption and cancer risk.

That message was delivered by Isabelle Soerjomataram, PhD, with the International Agency for Research on Cancer (IARC), Lyon, France, at a session devoted to alcohol and cancer at the annual meeting of the European Society for Medical Oncology.

“Global awareness about the link between alcohol and cancer continues to be very low,” Dr. Soerjomataram told the audience. “Health professionals – oncologists, nurses, medical doctors, GPs – have an important role in increasing awareness and bringing this knowledge to people, which may lead to reduced consumption.”

Session chair Gilberto Morgan, MD, medical oncologist, Skåne University Hospital, Lund, Sweden, agreed.

Dr. Morgan noted that healthcare professionals tend to downplay their influence over patients’ drinking habits and often don’t address these behaviors.

But that needs to change.

“We have absolutely no problem asking patients if they take supplements or vitamins or if they’re eating [healthy],” Dr. Morgan said. “So, what is the difference? Why not recommend that they cut down their alcohol intake and leave it up to everybody’s personal choice to do it or not?”

In the session, Dr. Soerjomataram highlighted the global statistics on alcohol use. IARC data show, for instance, that nearly half (46%) of the world’s population consumes alcohol, with rates higher in men (54%) than women (38%).

How much are people drinking?

Globally, on average, the amount comes to about six liters of pure ethanol per year per drinker, or about one wine bottle per week. However, consumption patterns vary widely by country. In France, people consume about 12 liters per year or about two wine bottles per week.

Dr. Soerjomataram stressed the link between alcohol consumption and cancer.

According to IARC data, heavy drinking – defined as more than 60 g/day or about six daily drinks – accounts for 47% of the alcohol-attributable cancers. Risky drinking – between 20 and 60 g/day – accounts for 29%, she explained, while moderate drinking – less than 20 g/day or about two daily drinks – accounts for roughly 14% of cases of alcohol-attributable cancers.

Globally, alcohol intake accounted for 4% of all cancers diagnosed in 2020, according to a 2021 analysis by IARC. 

In the United Kingdom alone, “alcohol drinking caused nearly 17,000 cases of cancer in 2020,” Dr. Soerjomataram said, and breast cancer made up almost one in four of those new cases.

In addition to breast cancer, six other cancer types – oral cavity, pharyngeal, laryngeal, esophageal, colorectal, and liver cancer – can be attributed to alcohol consumption, and emerging evidence suggests stomach and pancreatic cancer may be as well.

The good news, said Dr. Soerjomataram, is that long-term trends show declines in alcohol drinking in many countries, including the high wine-producing countries of France and Italy, where large reductions in consumption have been noted since the peak of intake in the 1920s.

“If it’s possible in these countries, I can imagine it’s possible elsewhere,” said Dr. Soerjomataram. 

Dr. Soerjomataram and Dr. Morgan report no relevant financial relationships.

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

There is an urgent need to raise global awareness about the direct link between alcohol consumption and cancer risk.

That message was delivered by Isabelle Soerjomataram, PhD, with the International Agency for Research on Cancer (IARC), Lyon, France, at a session devoted to alcohol and cancer at the annual meeting of the European Society for Medical Oncology.

“Global awareness about the link between alcohol and cancer continues to be very low,” Dr. Soerjomataram told the audience. “Health professionals – oncologists, nurses, medical doctors, GPs – have an important role in increasing awareness and bringing this knowledge to people, which may lead to reduced consumption.”

Session chair Gilberto Morgan, MD, medical oncologist, Skåne University Hospital, Lund, Sweden, agreed.

Dr. Morgan noted that healthcare professionals tend to downplay their influence over patients’ drinking habits and often don’t address these behaviors.

But that needs to change.

“We have absolutely no problem asking patients if they take supplements or vitamins or if they’re eating [healthy],” Dr. Morgan said. “So, what is the difference? Why not recommend that they cut down their alcohol intake and leave it up to everybody’s personal choice to do it or not?”

In the session, Dr. Soerjomataram highlighted the global statistics on alcohol use. IARC data show, for instance, that nearly half (46%) of the world’s population consumes alcohol, with rates higher in men (54%) than women (38%).

How much are people drinking?

Globally, on average, the amount comes to about six liters of pure ethanol per year per drinker, or about one wine bottle per week. However, consumption patterns vary widely by country. In France, people consume about 12 liters per year or about two wine bottles per week.

Dr. Soerjomataram stressed the link between alcohol consumption and cancer.

According to IARC data, heavy drinking – defined as more than 60 g/day or about six daily drinks – accounts for 47% of the alcohol-attributable cancers. Risky drinking – between 20 and 60 g/day – accounts for 29%, she explained, while moderate drinking – less than 20 g/day or about two daily drinks – accounts for roughly 14% of cases of alcohol-attributable cancers.

Globally, alcohol intake accounted for 4% of all cancers diagnosed in 2020, according to a 2021 analysis by IARC. 

In the United Kingdom alone, “alcohol drinking caused nearly 17,000 cases of cancer in 2020,” Dr. Soerjomataram said, and breast cancer made up almost one in four of those new cases.

In addition to breast cancer, six other cancer types – oral cavity, pharyngeal, laryngeal, esophageal, colorectal, and liver cancer – can be attributed to alcohol consumption, and emerging evidence suggests stomach and pancreatic cancer may be as well.

The good news, said Dr. Soerjomataram, is that long-term trends show declines in alcohol drinking in many countries, including the high wine-producing countries of France and Italy, where large reductions in consumption have been noted since the peak of intake in the 1920s.

“If it’s possible in these countries, I can imagine it’s possible elsewhere,” said Dr. Soerjomataram. 

Dr. Soerjomataram and Dr. Morgan report no relevant financial relationships.

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

There is an urgent need to raise global awareness about the direct link between alcohol consumption and cancer risk.

That message was delivered by Isabelle Soerjomataram, PhD, with the International Agency for Research on Cancer (IARC), Lyon, France, at a session devoted to alcohol and cancer at the annual meeting of the European Society for Medical Oncology.

“Global awareness about the link between alcohol and cancer continues to be very low,” Dr. Soerjomataram told the audience. “Health professionals – oncologists, nurses, medical doctors, GPs – have an important role in increasing awareness and bringing this knowledge to people, which may lead to reduced consumption.”

Session chair Gilberto Morgan, MD, medical oncologist, Skåne University Hospital, Lund, Sweden, agreed.

Dr. Morgan noted that healthcare professionals tend to downplay their influence over patients’ drinking habits and often don’t address these behaviors.

But that needs to change.

“We have absolutely no problem asking patients if they take supplements or vitamins or if they’re eating [healthy],” Dr. Morgan said. “So, what is the difference? Why not recommend that they cut down their alcohol intake and leave it up to everybody’s personal choice to do it or not?”

In the session, Dr. Soerjomataram highlighted the global statistics on alcohol use. IARC data show, for instance, that nearly half (46%) of the world’s population consumes alcohol, with rates higher in men (54%) than women (38%).

How much are people drinking?

Globally, on average, the amount comes to about six liters of pure ethanol per year per drinker, or about one wine bottle per week. However, consumption patterns vary widely by country. In France, people consume about 12 liters per year or about two wine bottles per week.

Dr. Soerjomataram stressed the link between alcohol consumption and cancer.

According to IARC data, heavy drinking – defined as more than 60 g/day or about six daily drinks – accounts for 47% of the alcohol-attributable cancers. Risky drinking – between 20 and 60 g/day – accounts for 29%, she explained, while moderate drinking – less than 20 g/day or about two daily drinks – accounts for roughly 14% of cases of alcohol-attributable cancers.

Globally, alcohol intake accounted for 4% of all cancers diagnosed in 2020, according to a 2021 analysis by IARC. 

In the United Kingdom alone, “alcohol drinking caused nearly 17,000 cases of cancer in 2020,” Dr. Soerjomataram said, and breast cancer made up almost one in four of those new cases.

In addition to breast cancer, six other cancer types – oral cavity, pharyngeal, laryngeal, esophageal, colorectal, and liver cancer – can be attributed to alcohol consumption, and emerging evidence suggests stomach and pancreatic cancer may be as well.

The good news, said Dr. Soerjomataram, is that long-term trends show declines in alcohol drinking in many countries, including the high wine-producing countries of France and Italy, where large reductions in consumption have been noted since the peak of intake in the 1920s.

“If it’s possible in these countries, I can imagine it’s possible elsewhere,” said Dr. Soerjomataram. 

Dr. Soerjomataram and Dr. Morgan report no relevant financial relationships.

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

Adding enzalutamide (Xtandi) to androgen deprivation therapy (ADT) can extend metastasis-free survival (MFS) while maintaining quality of life in men with prostate cancer who have a high risk for biochemical recurrence, according to new research presented at the European Society of Medical Oncology meeting in Madrid.

At 5 years, nearly 90% of patients receiving enzalutamide plus the ADT leuprolide (multiple brands) were metastasis-free, while 80% of those receiving only enzalutamide and about 71% of those receiving only leuprolide were metastasis-free.

In a related analysis of patient-reported outcomes, investigators found that patients who received enzalutamide did not appear to have worse quality of life, compared with those treated with leuprolide alone.

“This could be a game-changer for one of the most common disease states in prostate cancer,” lead author Stephen Freedland, MD, director of the Center for Integrated Research in Cancer and Lifestyle at Cedars-Sinai Cancer, Los Angeles, said. The study was published online in the New England Journal of Medicine.

The results “confirm that in this population, as in men with more advanced stages, adding an androgen-receptor inhibitor [enzalutamide] increases the efficacy of androgen deprivation therapy,” Ana Aparicio, MD, from University of Texas MD Anderson Cancer Center, Houston, wrote in an accompanying editorial.

Standard care in this patient population relies on ADT to suppress testosterone, which would otherwise stimulate cancer cell growth. However, Dr. Freedland explained that “when you go on androgen deprivation therapy, the testosterone level in the blood is reduced but not completely eliminated. The concern is that the testosterone that remains may still be enough to stimulate tumor growth.”

Enzalutamide, an oral androgen receptor inhibitor, has already shown benefits in patients with metastases, and the current EMBARK trial explored whether the inhibitor can help men with earlier-stage disease who are at risk for metastases.

The findings from the phase 3 EMBARK trial, also published in NEJM Evidence, included 1,068 patients with prostate cancer at high-risk for biochemical recurrence. Patients, who had a median age of 69 years, spanned 244 sites across 17 countries.

Patients had a median prostate-specific antigen (PSA) doubling time of 4.9 months, with a median PSA of 5.2 ng/mL. Those with PSA doubling times of 9 months or less are considered at high-risk for biochemical recurrence and increased risk for death from prostate cancer.

Dr. Freedland and colleagues randomly assigned patients to three groups – enzalutamide 160 mg plus leuprolide every 12 weeks (n = 355), enzalutamide monotherapy (n = 355), and placebo plus leuprolide (n = 358). Patients received treatment for 38.7 months on average. 

At 5-years, 87.3% of men in the combination group were metastasis-free, compared with 80% in the monotherapy group and 71.4% in the leuprolide-only group. Compared with leuprolide alone, combining enzalutamide and leuprolide reduced the risk for metastasis or death by 58% (hazard ratio, 0.42; P < .001). And compared with enzalutamide monotherapy, the combination also significantly reduced the risk for metastasis or death, compared with leuprolide alone (HR, 0.63; P = .005).

The estimated proportion of patients free from PSA progression at 5 years was 97.4% in the combination group, 88.9% in the monotherapy group, and 70% in the leuprolide-only group.

At the time of data cutoff, 33 (9%) patients in the combination group, 42 (12%) in the monotherapy group, and 55 (15%) in the leuprolide-only group had died.

Nearly all (97%) patients experienced adverse events, most of which (86.4%) were treatment-related. Overall, 46.5% of patients in the combination group experienced a grade 3 or higher adverse event, compared with 50% in the enzalutamide monotherapy group and 42.7% in the leuprolide-only group. Clustered adverse effects occurred in 80% or more patients in all three groups, with the most common cluster combining fatigue, falls, fractures, hypertension, and musculoskeletal events.

The most common adverse events in the enzalutamide monotherapy group, occurring in at least 30% of patients, included gynecomastia, joint pain, hot flashes, and fatigue. Nipple pain and breast tenderness were also common side effects in the enzalutamide monotherapy arm – occurring in 15.3% and 14.4% of patients, respectively – compared with the combination (3.1% and 1.1%) or leuprolide-only (1.1% and 1.1%) groups.

However, Dr. Freedland explained, “our quality-of-life data show that you don’t need to sacrifice global quality of life to get these cancer benefits.”

Patient-reported outcomes from EMBARK revealed that both enzalutamide combination and monotherapy versus leuprolide alone preserved high health-related quality of life in patients with a high-risk for biochemical recurrence.

More specifically, Dr. Freedland and colleagues found no differences in the time to first clinically meaningful deterioration based on questionnaires that rated pain and functional status. Functional status measures included physical, social, and emotional well-being as well as symptom severity.

However, some differences emerged. For instance, time to confirmed clinically meaningful deterioration in physical well-being score was significantly shorter among patients receiving enzalutamide, compared with leuprolide monotherapy – 24.8 months in the combination group and 27.6 months in the enzalutamide-only group versus 49.8 months in the leuprolide-only group (HR, 1.41 and 1.35, respectively).

However, sexual activity appeared to be better preserved among patients receiving enzalutamide monotherapy, compared with leuprolide alone. The median time to confirmed clinically meaningful deterioration in sexual activity score was 5.6 months with enzalutamide monotherapy versus 3 months for leuprolide alone (HR, 0.76).

Given the slightly different side-effect profiles in the enzalutamide combination and monotherapy groups, Dr. Freedland noted that “it will be up to patients and care providers to decide which is the right choice for them. I think the important message is that both are a major step forward from the current standard of care, which is androgen deprivation therapy alone.”

Pedro Barata, MD, who was not involved in the research, also noted that “this is the first time we have seen this kind of results with a novel hormonal therapy without castration.”

Overall, “the findings of this trial confirm the benefit of adding a novel hormonal therapy such as enzalutamide earlier in the course of this disease,” said Dr. Barata, a medical oncologist and director of the Clinical Genitourinary Medical Oncology Research Program at University Hospitals Seidman Cancer Center, Cleveland.

However, he explained that many patients with “rising PSA and short doubling time are known to have metastatic disease as detected by PSMA PET and are already being offered a novel hormonal therapy combined with castration. Perhaps it will be an opportunity for men who don’t want to be castrated to be offered an anti–androgen-like enzalutamide by itself without castration in this patient population.”

Research was funded by Pfizer and Astellas Pharma, manufacturers of enzalutamide.

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

Adding enzalutamide (Xtandi) to androgen deprivation therapy (ADT) can extend metastasis-free survival (MFS) while maintaining quality of life in men with prostate cancer who have a high risk for biochemical recurrence, according to new research presented at the European Society of Medical Oncology meeting in Madrid.

At 5 years, nearly 90% of patients receiving enzalutamide plus the ADT leuprolide (multiple brands) were metastasis-free, while 80% of those receiving only enzalutamide and about 71% of those receiving only leuprolide were metastasis-free.

In a related analysis of patient-reported outcomes, investigators found that patients who received enzalutamide did not appear to have worse quality of life, compared with those treated with leuprolide alone.

“This could be a game-changer for one of the most common disease states in prostate cancer,” lead author Stephen Freedland, MD, director of the Center for Integrated Research in Cancer and Lifestyle at Cedars-Sinai Cancer, Los Angeles, said. The study was published online in the New England Journal of Medicine.

The results “confirm that in this population, as in men with more advanced stages, adding an androgen-receptor inhibitor [enzalutamide] increases the efficacy of androgen deprivation therapy,” Ana Aparicio, MD, from University of Texas MD Anderson Cancer Center, Houston, wrote in an accompanying editorial.

Standard care in this patient population relies on ADT to suppress testosterone, which would otherwise stimulate cancer cell growth. However, Dr. Freedland explained that “when you go on androgen deprivation therapy, the testosterone level in the blood is reduced but not completely eliminated. The concern is that the testosterone that remains may still be enough to stimulate tumor growth.”

Enzalutamide, an oral androgen receptor inhibitor, has already shown benefits in patients with metastases, and the current EMBARK trial explored whether the inhibitor can help men with earlier-stage disease who are at risk for metastases.

The findings from the phase 3 EMBARK trial, also published in NEJM Evidence, included 1,068 patients with prostate cancer at high-risk for biochemical recurrence. Patients, who had a median age of 69 years, spanned 244 sites across 17 countries.

Patients had a median prostate-specific antigen (PSA) doubling time of 4.9 months, with a median PSA of 5.2 ng/mL. Those with PSA doubling times of 9 months or less are considered at high-risk for biochemical recurrence and increased risk for death from prostate cancer.

Dr. Freedland and colleagues randomly assigned patients to three groups – enzalutamide 160 mg plus leuprolide every 12 weeks (n = 355), enzalutamide monotherapy (n = 355), and placebo plus leuprolide (n = 358). Patients received treatment for 38.7 months on average. 

At 5-years, 87.3% of men in the combination group were metastasis-free, compared with 80% in the monotherapy group and 71.4% in the leuprolide-only group. Compared with leuprolide alone, combining enzalutamide and leuprolide reduced the risk for metastasis or death by 58% (hazard ratio, 0.42; P < .001). And compared with enzalutamide monotherapy, the combination also significantly reduced the risk for metastasis or death, compared with leuprolide alone (HR, 0.63; P = .005).

The estimated proportion of patients free from PSA progression at 5 years was 97.4% in the combination group, 88.9% in the monotherapy group, and 70% in the leuprolide-only group.

At the time of data cutoff, 33 (9%) patients in the combination group, 42 (12%) in the monotherapy group, and 55 (15%) in the leuprolide-only group had died.

Nearly all (97%) patients experienced adverse events, most of which (86.4%) were treatment-related. Overall, 46.5% of patients in the combination group experienced a grade 3 or higher adverse event, compared with 50% in the enzalutamide monotherapy group and 42.7% in the leuprolide-only group. Clustered adverse effects occurred in 80% or more patients in all three groups, with the most common cluster combining fatigue, falls, fractures, hypertension, and musculoskeletal events.

The most common adverse events in the enzalutamide monotherapy group, occurring in at least 30% of patients, included gynecomastia, joint pain, hot flashes, and fatigue. Nipple pain and breast tenderness were also common side effects in the enzalutamide monotherapy arm – occurring in 15.3% and 14.4% of patients, respectively – compared with the combination (3.1% and 1.1%) or leuprolide-only (1.1% and 1.1%) groups.

However, Dr. Freedland explained, “our quality-of-life data show that you don’t need to sacrifice global quality of life to get these cancer benefits.”

Patient-reported outcomes from EMBARK revealed that both enzalutamide combination and monotherapy versus leuprolide alone preserved high health-related quality of life in patients with a high-risk for biochemical recurrence.

More specifically, Dr. Freedland and colleagues found no differences in the time to first clinically meaningful deterioration based on questionnaires that rated pain and functional status. Functional status measures included physical, social, and emotional well-being as well as symptom severity.

However, some differences emerged. For instance, time to confirmed clinically meaningful deterioration in physical well-being score was significantly shorter among patients receiving enzalutamide, compared with leuprolide monotherapy – 24.8 months in the combination group and 27.6 months in the enzalutamide-only group versus 49.8 months in the leuprolide-only group (HR, 1.41 and 1.35, respectively).

However, sexual activity appeared to be better preserved among patients receiving enzalutamide monotherapy, compared with leuprolide alone. The median time to confirmed clinically meaningful deterioration in sexual activity score was 5.6 months with enzalutamide monotherapy versus 3 months for leuprolide alone (HR, 0.76).

Given the slightly different side-effect profiles in the enzalutamide combination and monotherapy groups, Dr. Freedland noted that “it will be up to patients and care providers to decide which is the right choice for them. I think the important message is that both are a major step forward from the current standard of care, which is androgen deprivation therapy alone.”

Pedro Barata, MD, who was not involved in the research, also noted that “this is the first time we have seen this kind of results with a novel hormonal therapy without castration.”

Overall, “the findings of this trial confirm the benefit of adding a novel hormonal therapy such as enzalutamide earlier in the course of this disease,” said Dr. Barata, a medical oncologist and director of the Clinical Genitourinary Medical Oncology Research Program at University Hospitals Seidman Cancer Center, Cleveland.

However, he explained that many patients with “rising PSA and short doubling time are known to have metastatic disease as detected by PSMA PET and are already being offered a novel hormonal therapy combined with castration. Perhaps it will be an opportunity for men who don’t want to be castrated to be offered an anti–androgen-like enzalutamide by itself without castration in this patient population.”

Research was funded by Pfizer and Astellas Pharma, manufacturers of enzalutamide.

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

Adding enzalutamide (Xtandi) to androgen deprivation therapy (ADT) can extend metastasis-free survival (MFS) while maintaining quality of life in men with prostate cancer who have a high risk for biochemical recurrence, according to new research presented at the European Society of Medical Oncology meeting in Madrid.

At 5 years, nearly 90% of patients receiving enzalutamide plus the ADT leuprolide (multiple brands) were metastasis-free, while 80% of those receiving only enzalutamide and about 71% of those receiving only leuprolide were metastasis-free.

In a related analysis of patient-reported outcomes, investigators found that patients who received enzalutamide did not appear to have worse quality of life, compared with those treated with leuprolide alone.

“This could be a game-changer for one of the most common disease states in prostate cancer,” lead author Stephen Freedland, MD, director of the Center for Integrated Research in Cancer and Lifestyle at Cedars-Sinai Cancer, Los Angeles, said. The study was published online in the New England Journal of Medicine.

The results “confirm that in this population, as in men with more advanced stages, adding an androgen-receptor inhibitor [enzalutamide] increases the efficacy of androgen deprivation therapy,” Ana Aparicio, MD, from University of Texas MD Anderson Cancer Center, Houston, wrote in an accompanying editorial.

Standard care in this patient population relies on ADT to suppress testosterone, which would otherwise stimulate cancer cell growth. However, Dr. Freedland explained that “when you go on androgen deprivation therapy, the testosterone level in the blood is reduced but not completely eliminated. The concern is that the testosterone that remains may still be enough to stimulate tumor growth.”

Enzalutamide, an oral androgen receptor inhibitor, has already shown benefits in patients with metastases, and the current EMBARK trial explored whether the inhibitor can help men with earlier-stage disease who are at risk for metastases.

The findings from the phase 3 EMBARK trial, also published in NEJM Evidence, included 1,068 patients with prostate cancer at high-risk for biochemical recurrence. Patients, who had a median age of 69 years, spanned 244 sites across 17 countries.

Patients had a median prostate-specific antigen (PSA) doubling time of 4.9 months, with a median PSA of 5.2 ng/mL. Those with PSA doubling times of 9 months or less are considered at high-risk for biochemical recurrence and increased risk for death from prostate cancer.

Dr. Freedland and colleagues randomly assigned patients to three groups – enzalutamide 160 mg plus leuprolide every 12 weeks (n = 355), enzalutamide monotherapy (n = 355), and placebo plus leuprolide (n = 358). Patients received treatment for 38.7 months on average. 

At 5-years, 87.3% of men in the combination group were metastasis-free, compared with 80% in the monotherapy group and 71.4% in the leuprolide-only group. Compared with leuprolide alone, combining enzalutamide and leuprolide reduced the risk for metastasis or death by 58% (hazard ratio, 0.42; P < .001). And compared with enzalutamide monotherapy, the combination also significantly reduced the risk for metastasis or death, compared with leuprolide alone (HR, 0.63; P = .005).

The estimated proportion of patients free from PSA progression at 5 years was 97.4% in the combination group, 88.9% in the monotherapy group, and 70% in the leuprolide-only group.

At the time of data cutoff, 33 (9%) patients in the combination group, 42 (12%) in the monotherapy group, and 55 (15%) in the leuprolide-only group had died.

Nearly all (97%) patients experienced adverse events, most of which (86.4%) were treatment-related. Overall, 46.5% of patients in the combination group experienced a grade 3 or higher adverse event, compared with 50% in the enzalutamide monotherapy group and 42.7% in the leuprolide-only group. Clustered adverse effects occurred in 80% or more patients in all three groups, with the most common cluster combining fatigue, falls, fractures, hypertension, and musculoskeletal events.

The most common adverse events in the enzalutamide monotherapy group, occurring in at least 30% of patients, included gynecomastia, joint pain, hot flashes, and fatigue. Nipple pain and breast tenderness were also common side effects in the enzalutamide monotherapy arm – occurring in 15.3% and 14.4% of patients, respectively – compared with the combination (3.1% and 1.1%) or leuprolide-only (1.1% and 1.1%) groups.

However, Dr. Freedland explained, “our quality-of-life data show that you don’t need to sacrifice global quality of life to get these cancer benefits.”

Patient-reported outcomes from EMBARK revealed that both enzalutamide combination and monotherapy versus leuprolide alone preserved high health-related quality of life in patients with a high-risk for biochemical recurrence.

More specifically, Dr. Freedland and colleagues found no differences in the time to first clinically meaningful deterioration based on questionnaires that rated pain and functional status. Functional status measures included physical, social, and emotional well-being as well as symptom severity.

However, some differences emerged. For instance, time to confirmed clinically meaningful deterioration in physical well-being score was significantly shorter among patients receiving enzalutamide, compared with leuprolide monotherapy – 24.8 months in the combination group and 27.6 months in the enzalutamide-only group versus 49.8 months in the leuprolide-only group (HR, 1.41 and 1.35, respectively).

However, sexual activity appeared to be better preserved among patients receiving enzalutamide monotherapy, compared with leuprolide alone. The median time to confirmed clinically meaningful deterioration in sexual activity score was 5.6 months with enzalutamide monotherapy versus 3 months for leuprolide alone (HR, 0.76).

Given the slightly different side-effect profiles in the enzalutamide combination and monotherapy groups, Dr. Freedland noted that “it will be up to patients and care providers to decide which is the right choice for them. I think the important message is that both are a major step forward from the current standard of care, which is androgen deprivation therapy alone.”

Pedro Barata, MD, who was not involved in the research, also noted that “this is the first time we have seen this kind of results with a novel hormonal therapy without castration.”

Overall, “the findings of this trial confirm the benefit of adding a novel hormonal therapy such as enzalutamide earlier in the course of this disease,” said Dr. Barata, a medical oncologist and director of the Clinical Genitourinary Medical Oncology Research Program at University Hospitals Seidman Cancer Center, Cleveland.

However, he explained that many patients with “rising PSA and short doubling time are known to have metastatic disease as detected by PSMA PET and are already being offered a novel hormonal therapy combined with castration. Perhaps it will be an opportunity for men who don’t want to be castrated to be offered an anti–androgen-like enzalutamide by itself without castration in this patient population.”

Research was funded by Pfizer and Astellas Pharma, manufacturers of enzalutamide.

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

MADRID – Research presented at the European Society for Medical Oncology (ESMO) Annual Meeting 2023 underline the benefit of adding immunotherapy to chemotherapy in advanced or recurrent endometrial cancer, and question whether adding the PARP inhibitor olaparib to the chemo-immunotherapy combination could provide further benefit.

In the AtTEnd trial, presented on Oct. 21, more than 550 patients with advanced newly diagnosed or recurrent disease were randomized to the antiprogrammed death–ligand 1 (PD-L1) antibody atezolizumab (Tecentriq) or placebo plus chemotherapy followed by maintenance atezolizumab or placebo.

Adding immunotherapy to chemotherapy improved progression-free survival (PFS) among all-comers – 28.1% vs. 17% at 2 years. The PFS benefit was much more pronounced among patients with mismatch repair-deficient (dMMR) disease – 50.4% vs. 16% at 2 years. Mismatch repair-deficient disease patients receiving atezolizumab also demonstrated an early overall survival benefit, according to findings from the interim analysis.

In the DUO-E trial, presented during the same Oct. 21 session, nearly 720 patients with newly diagnosed advanced or recurrent endometrial cancer were randomized to one of three groups: Chemotherapy alone with maintenance placebo, chemotherapy plus durvalumab (Imfinzi) with maintenance durvalumab, or chemotherapy plus durvalumab with maintenance durvalumab and the PARP inhibitor olaparib.

The results, published simultaneously in the Journal of Clinical Oncology, showed that adding durvalumab to chemotherapy followed by maintenance durvalumab with or without olaparib led to a significant improvement in PFS, compared with chemotherapy alone. As in the AtTEnd trial, this PFS was also more pronounced in dMMR patients.

Overall, Andrés Cervantes, MD, PhD, from the University of Valencia, Spain, and president of ESMO, explained that this research marks “very positive data for women with gynecological cancers,” with immunotherapy now incorporated into the standard of care.

However, an expert questioned whether the DUO-E trial clearly demonstrated the benefit of adding olaparib to immuno- and chemotherapy and whether certain subsets of patients may be more likely to benefit from the PARP inhibitor.
 

Inside AtTEnd

A growing body of research has shown that single agent immunotherapy is effective in treating endometrial cancer, particularly in tumors with dMMR, and that immunotherapy and chemotherapy may have a synergistic effect.

David S. P. Tan, MD, PhD, National University Cancer Institute, Singapore, who was not involved in the studies, commented that “the molecular classification of endometrial cancer is now leading us to areas that we didn’t think before [were] possible.”

The rationale for combining immunotherapy with chemotherapy, Dr. Tan explained, is that “the cytotoxicity you get from chemotherapy is partly dependent on immune activity within the tumor, and so it makes sense” to combine them.

This approach was borne out by recent positive PFS results from the NRG-GY018 trial of pembrolizumab plus chemotherapy in advanced endometrial cancer as well as from the RUBY trial of dostarlimab in primary advanced or recurrent disease.

To further investigate this chemo-immunotherapy strategy, the AtTEnd team enrolled patients with newly diagnosed or recurrent stage III-IV disease who had received no prior systemic chemotherapy for recurrence within the previous 6 months.

Overall, 551 patients from 89 sites across 10 countries were randomized to standard first-line chemotherapy – carboplatin plus paclitaxel – with either atezolizumab or placebo, followed by maintenance atezolizumab or placebo, which continued until confirmed disease progression.

The median age in the intention-to-treat population was 64-67 years. Nearly 23% of patients had dMMR tumors, and 67.2% had recurrent disease.

The baseline characteristics were well balanced and distributed between arms in the dMMR and all-comers population, said Nicoletta Colombo, MD, University of Milan–Bicocca, European Institute of Oncology Istituto di Ricovero e Cura a Carattere Scientifico, Italy, who presented the findings at ESMO.

Over a median follow up of 26.2 months, Dr. Colombo and colleagues observed a statistically significant improvement in PFS in the dMMR arm in favor of atezolizumab (hazard ratio, 0.36; P = .0005). At 2 years, 50.4% of patients receiving the immunotherapy were progression-free, compared with 16.0% in the placebo arm.

In all-comers, the PFS improvement with atezolizumab was less pronounced but remained significant (HR, 0.74; P = .0219).

A secondary analysis revealed, among dMMR patients, atezolizumab was associated with an overall survival advantage over placebo (HR, 0.41), with 75% of patients still alive at 2 years vs. 54.2% in the placebo arm. Dr. Colombo also noted a “clear trend” for improved overall survival with atezolizumab as well (HR, 0.82; P = .0483), but no PFS or overall survival benefit was seen with atezolizumab in MMR proficient (pMMR) patients.

Dr. Colombo said the safety profile of atezolizumab plus chemotherapy was “manageable,” with no differences in the rates of “major side effects,” although there was an increase in the rate of treatment-related grade ≥ 3 adverse events in the atezolizumab group (25.8% vs. 14.1%).

Dr. Tan noted that the AtTEnd trial revealed comparable results to earlier trials in this space but underlined that the survival curves in the interim analysis revealed a “red zone” of dMMR patients who do not respond to the combination and in whom immunotherapy is “not sufficient.”

Alongside this, Dr. Tan flagged a “blue zone” of dMMR patients who plateaued in both PFS and overall survival after 2 years. The question for these patients at this point is whether they need to continue immunotherapy beyond 24 months, he said.

But overall, Dr. Tan noted, the AtTEnd data “continue to validate practice-changing therapy for dMMR endometrial cancer patients” with immunotherapy plus chemotherapy, with the lack of benefit in pMMR disease underscoring an “unmet medical need.”
 

Inside DUO-E

The burning question, however, was whether adding a PARP inhibitor to immunotherapy and chemotherapy would boost the survival outcomes further.

The DUO-E trial involved patients with newly diagnosed stage III/IV or recurrent endometrial cancer who had not received systematic therapy for advanced disease and were naive to both PARP inhibitors and immune-mediated therapy.

Overall, 718 patients were randomized to one of three arms: Chemotherapy alone followed by maintenance placebo, chemotherapy plus durvalumab with maintenance durvalumab, or chemotherapy plus durvalumab with maintenance durvalumab plus olaparib.

Maintenance was continued until disease progression or unacceptable toxicity, or the patients met another discontinuation criteria.

About half of patients were newly diagnosed, half had recurrent disease, and approximately one-fifth had dMMR disease, said Shannon Westin, MD, from the University of Texas MD Anderson Cancer Center, Houston, who presented the findings.

Compared with placebo plus chemotherapy, patients in both the durvalumab alone and durvalumab plus olaparib arms experienced a significant improvement in PFS (HR, 0.71; P = .003; and HR, 0.55; P < .0001, respectively).

This effect was amplified in dMMR patients with durvalumab (HR, 0.42) as well as with durvalumab plus olaparib (HR, 0.41).

In pMMR patients, PFS benefit was stronger in the durvalumab-olaparib arm vs. durvalumab (HR, 0.57 vs. 0.77).

Although the overall survival analysis remains exploratory, Dr. Westin noted a trend toward better overall survival in the two treatment arms vs. placebo (HR, 0.77 with durvalumab, and HR, 0.59 with durvalumab plus olaparib).

However, adding olaparib to the equation increased the rate of grade ≥ 3 adverse events – 67.2% vs. 54.9% with durvalumab and 56.4% with chemotherapy alone in the overall analysis. The addition of olaparib also led to treatment discontinuation in 24.4% of patients vs. 20.9% in the durvalumab arm and 18.6% in the chemotherapy alone arm.

Domenica Lorusso, MD, PhD, who was not involved in the study, commented that the marginal PFS benefit of adding olaparib in DUO-E is “not surprising” because the bar set by immunotherapy is “so high in this population that it’s very difficult” to go any higher.

But the results in pMMR patients reveal “a clear additional benefit” to olaparib, said Dr. Lorusso, from Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.

“The main limitation of the trial,” she continued, “is that it was not powered to make a formal comparison between the two experimental arms.”

So, what then is the added benefit of olaparib? “Unfortunately, that remains an unanswered question,” Dr. Lorusso said.

AtTEnd was sponsored by the Mario Negri Institute for Pharmacological Research.

DUO-E was funded by AstraZeneca.

Dr. Colombo declares relationships with AstraZeneca, Clovis Oncology, Esai, GSK, Immunogen, Mersana, MSD/Merck, Nuvation Bio, OncXerna, Pieris, Roche, and Novocure.

Dr. Tan declares relationships with AstraZeneca, Karyopharm Therapeutics, Bayer, Roche, MSD, Genmab, Esai, PMV, BioNTech, Ellipses Pharma, Boehringer Ingelheim, Merck Serono, Takeda, and Clovis.

Dr. Westin declares relationships with AstraZeneca, Avenge Bio, Bayer, Bio-Path, Clovis, Genentech/Roche, GSK, Jazz Pharmaceuticals, Mereo, Novartis, Nuvectis, and Zentalis; and consulting and advisory roles for AstraZeneca, Caris, Clovis, Eisai, EQRx, Genentech/Roche, Gilead, GSK, Immunocore, ImmunoGen, Lilly, Merck, Mersana, Mereo, NGM Bio, Nuvectis, Seagen, Verastem, Vincerx, Zentalis, and ZielBio.

Dr. Lorusso declares relationships with PharmaMar, Merck Serono, Novartis, AstraZeneca, Clovis, Tesaro/GSK, Genmab, Immunogen, and Roche.

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

MADRID – Research presented at the European Society for Medical Oncology (ESMO) Annual Meeting 2023 underline the benefit of adding immunotherapy to chemotherapy in advanced or recurrent endometrial cancer, and question whether adding the PARP inhibitor olaparib to the chemo-immunotherapy combination could provide further benefit.

In the AtTEnd trial, presented on Oct. 21, more than 550 patients with advanced newly diagnosed or recurrent disease were randomized to the antiprogrammed death–ligand 1 (PD-L1) antibody atezolizumab (Tecentriq) or placebo plus chemotherapy followed by maintenance atezolizumab or placebo.

Adding immunotherapy to chemotherapy improved progression-free survival (PFS) among all-comers – 28.1% vs. 17% at 2 years. The PFS benefit was much more pronounced among patients with mismatch repair-deficient (dMMR) disease – 50.4% vs. 16% at 2 years. Mismatch repair-deficient disease patients receiving atezolizumab also demonstrated an early overall survival benefit, according to findings from the interim analysis.

In the DUO-E trial, presented during the same Oct. 21 session, nearly 720 patients with newly diagnosed advanced or recurrent endometrial cancer were randomized to one of three groups: Chemotherapy alone with maintenance placebo, chemotherapy plus durvalumab (Imfinzi) with maintenance durvalumab, or chemotherapy plus durvalumab with maintenance durvalumab and the PARP inhibitor olaparib.

The results, published simultaneously in the Journal of Clinical Oncology, showed that adding durvalumab to chemotherapy followed by maintenance durvalumab with or without olaparib led to a significant improvement in PFS, compared with chemotherapy alone. As in the AtTEnd trial, this PFS was also more pronounced in dMMR patients.

Overall, Andrés Cervantes, MD, PhD, from the University of Valencia, Spain, and president of ESMO, explained that this research marks “very positive data for women with gynecological cancers,” with immunotherapy now incorporated into the standard of care.

However, an expert questioned whether the DUO-E trial clearly demonstrated the benefit of adding olaparib to immuno- and chemotherapy and whether certain subsets of patients may be more likely to benefit from the PARP inhibitor.
 

Inside AtTEnd

A growing body of research has shown that single agent immunotherapy is effective in treating endometrial cancer, particularly in tumors with dMMR, and that immunotherapy and chemotherapy may have a synergistic effect.

David S. P. Tan, MD, PhD, National University Cancer Institute, Singapore, who was not involved in the studies, commented that “the molecular classification of endometrial cancer is now leading us to areas that we didn’t think before [were] possible.”

The rationale for combining immunotherapy with chemotherapy, Dr. Tan explained, is that “the cytotoxicity you get from chemotherapy is partly dependent on immune activity within the tumor, and so it makes sense” to combine them.

This approach was borne out by recent positive PFS results from the NRG-GY018 trial of pembrolizumab plus chemotherapy in advanced endometrial cancer as well as from the RUBY trial of dostarlimab in primary advanced or recurrent disease.

To further investigate this chemo-immunotherapy strategy, the AtTEnd team enrolled patients with newly diagnosed or recurrent stage III-IV disease who had received no prior systemic chemotherapy for recurrence within the previous 6 months.

Overall, 551 patients from 89 sites across 10 countries were randomized to standard first-line chemotherapy – carboplatin plus paclitaxel – with either atezolizumab or placebo, followed by maintenance atezolizumab or placebo, which continued until confirmed disease progression.

The median age in the intention-to-treat population was 64-67 years. Nearly 23% of patients had dMMR tumors, and 67.2% had recurrent disease.

The baseline characteristics were well balanced and distributed between arms in the dMMR and all-comers population, said Nicoletta Colombo, MD, University of Milan–Bicocca, European Institute of Oncology Istituto di Ricovero e Cura a Carattere Scientifico, Italy, who presented the findings at ESMO.

Over a median follow up of 26.2 months, Dr. Colombo and colleagues observed a statistically significant improvement in PFS in the dMMR arm in favor of atezolizumab (hazard ratio, 0.36; P = .0005). At 2 years, 50.4% of patients receiving the immunotherapy were progression-free, compared with 16.0% in the placebo arm.

In all-comers, the PFS improvement with atezolizumab was less pronounced but remained significant (HR, 0.74; P = .0219).

A secondary analysis revealed, among dMMR patients, atezolizumab was associated with an overall survival advantage over placebo (HR, 0.41), with 75% of patients still alive at 2 years vs. 54.2% in the placebo arm. Dr. Colombo also noted a “clear trend” for improved overall survival with atezolizumab as well (HR, 0.82; P = .0483), but no PFS or overall survival benefit was seen with atezolizumab in MMR proficient (pMMR) patients.

Dr. Colombo said the safety profile of atezolizumab plus chemotherapy was “manageable,” with no differences in the rates of “major side effects,” although there was an increase in the rate of treatment-related grade ≥ 3 adverse events in the atezolizumab group (25.8% vs. 14.1%).

Dr. Tan noted that the AtTEnd trial revealed comparable results to earlier trials in this space but underlined that the survival curves in the interim analysis revealed a “red zone” of dMMR patients who do not respond to the combination and in whom immunotherapy is “not sufficient.”

Alongside this, Dr. Tan flagged a “blue zone” of dMMR patients who plateaued in both PFS and overall survival after 2 years. The question for these patients at this point is whether they need to continue immunotherapy beyond 24 months, he said.

But overall, Dr. Tan noted, the AtTEnd data “continue to validate practice-changing therapy for dMMR endometrial cancer patients” with immunotherapy plus chemotherapy, with the lack of benefit in pMMR disease underscoring an “unmet medical need.”
 

Inside DUO-E

The burning question, however, was whether adding a PARP inhibitor to immunotherapy and chemotherapy would boost the survival outcomes further.

The DUO-E trial involved patients with newly diagnosed stage III/IV or recurrent endometrial cancer who had not received systematic therapy for advanced disease and were naive to both PARP inhibitors and immune-mediated therapy.

Overall, 718 patients were randomized to one of three arms: Chemotherapy alone followed by maintenance placebo, chemotherapy plus durvalumab with maintenance durvalumab, or chemotherapy plus durvalumab with maintenance durvalumab plus olaparib.

Maintenance was continued until disease progression or unacceptable toxicity, or the patients met another discontinuation criteria.

About half of patients were newly diagnosed, half had recurrent disease, and approximately one-fifth had dMMR disease, said Shannon Westin, MD, from the University of Texas MD Anderson Cancer Center, Houston, who presented the findings.

Compared with placebo plus chemotherapy, patients in both the durvalumab alone and durvalumab plus olaparib arms experienced a significant improvement in PFS (HR, 0.71; P = .003; and HR, 0.55; P < .0001, respectively).

This effect was amplified in dMMR patients with durvalumab (HR, 0.42) as well as with durvalumab plus olaparib (HR, 0.41).

In pMMR patients, PFS benefit was stronger in the durvalumab-olaparib arm vs. durvalumab (HR, 0.57 vs. 0.77).

Although the overall survival analysis remains exploratory, Dr. Westin noted a trend toward better overall survival in the two treatment arms vs. placebo (HR, 0.77 with durvalumab, and HR, 0.59 with durvalumab plus olaparib).

However, adding olaparib to the equation increased the rate of grade ≥ 3 adverse events – 67.2% vs. 54.9% with durvalumab and 56.4% with chemotherapy alone in the overall analysis. The addition of olaparib also led to treatment discontinuation in 24.4% of patients vs. 20.9% in the durvalumab arm and 18.6% in the chemotherapy alone arm.

Domenica Lorusso, MD, PhD, who was not involved in the study, commented that the marginal PFS benefit of adding olaparib in DUO-E is “not surprising” because the bar set by immunotherapy is “so high in this population that it’s very difficult” to go any higher.

But the results in pMMR patients reveal “a clear additional benefit” to olaparib, said Dr. Lorusso, from Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.

“The main limitation of the trial,” she continued, “is that it was not powered to make a formal comparison between the two experimental arms.”

So, what then is the added benefit of olaparib? “Unfortunately, that remains an unanswered question,” Dr. Lorusso said.

AtTEnd was sponsored by the Mario Negri Institute for Pharmacological Research.

DUO-E was funded by AstraZeneca.

Dr. Colombo declares relationships with AstraZeneca, Clovis Oncology, Esai, GSK, Immunogen, Mersana, MSD/Merck, Nuvation Bio, OncXerna, Pieris, Roche, and Novocure.

Dr. Tan declares relationships with AstraZeneca, Karyopharm Therapeutics, Bayer, Roche, MSD, Genmab, Esai, PMV, BioNTech, Ellipses Pharma, Boehringer Ingelheim, Merck Serono, Takeda, and Clovis.

Dr. Westin declares relationships with AstraZeneca, Avenge Bio, Bayer, Bio-Path, Clovis, Genentech/Roche, GSK, Jazz Pharmaceuticals, Mereo, Novartis, Nuvectis, and Zentalis; and consulting and advisory roles for AstraZeneca, Caris, Clovis, Eisai, EQRx, Genentech/Roche, Gilead, GSK, Immunocore, ImmunoGen, Lilly, Merck, Mersana, Mereo, NGM Bio, Nuvectis, Seagen, Verastem, Vincerx, Zentalis, and ZielBio.

Dr. Lorusso declares relationships with PharmaMar, Merck Serono, Novartis, AstraZeneca, Clovis, Tesaro/GSK, Genmab, Immunogen, and Roche.

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

MADRID – Research presented at the European Society for Medical Oncology (ESMO) Annual Meeting 2023 underline the benefit of adding immunotherapy to chemotherapy in advanced or recurrent endometrial cancer, and question whether adding the PARP inhibitor olaparib to the chemo-immunotherapy combination could provide further benefit.

In the AtTEnd trial, presented on Oct. 21, more than 550 patients with advanced newly diagnosed or recurrent disease were randomized to the antiprogrammed death–ligand 1 (PD-L1) antibody atezolizumab (Tecentriq) or placebo plus chemotherapy followed by maintenance atezolizumab or placebo.

Adding immunotherapy to chemotherapy improved progression-free survival (PFS) among all-comers – 28.1% vs. 17% at 2 years. The PFS benefit was much more pronounced among patients with mismatch repair-deficient (dMMR) disease – 50.4% vs. 16% at 2 years. Mismatch repair-deficient disease patients receiving atezolizumab also demonstrated an early overall survival benefit, according to findings from the interim analysis.

In the DUO-E trial, presented during the same Oct. 21 session, nearly 720 patients with newly diagnosed advanced or recurrent endometrial cancer were randomized to one of three groups: Chemotherapy alone with maintenance placebo, chemotherapy plus durvalumab (Imfinzi) with maintenance durvalumab, or chemotherapy plus durvalumab with maintenance durvalumab and the PARP inhibitor olaparib.

The results, published simultaneously in the Journal of Clinical Oncology, showed that adding durvalumab to chemotherapy followed by maintenance durvalumab with or without olaparib led to a significant improvement in PFS, compared with chemotherapy alone. As in the AtTEnd trial, this PFS was also more pronounced in dMMR patients.

Overall, Andrés Cervantes, MD, PhD, from the University of Valencia, Spain, and president of ESMO, explained that this research marks “very positive data for women with gynecological cancers,” with immunotherapy now incorporated into the standard of care.

However, an expert questioned whether the DUO-E trial clearly demonstrated the benefit of adding olaparib to immuno- and chemotherapy and whether certain subsets of patients may be more likely to benefit from the PARP inhibitor.
 

Inside AtTEnd

A growing body of research has shown that single agent immunotherapy is effective in treating endometrial cancer, particularly in tumors with dMMR, and that immunotherapy and chemotherapy may have a synergistic effect.

David S. P. Tan, MD, PhD, National University Cancer Institute, Singapore, who was not involved in the studies, commented that “the molecular classification of endometrial cancer is now leading us to areas that we didn’t think before [were] possible.”

The rationale for combining immunotherapy with chemotherapy, Dr. Tan explained, is that “the cytotoxicity you get from chemotherapy is partly dependent on immune activity within the tumor, and so it makes sense” to combine them.

This approach was borne out by recent positive PFS results from the NRG-GY018 trial of pembrolizumab plus chemotherapy in advanced endometrial cancer as well as from the RUBY trial of dostarlimab in primary advanced or recurrent disease.

To further investigate this chemo-immunotherapy strategy, the AtTEnd team enrolled patients with newly diagnosed or recurrent stage III-IV disease who had received no prior systemic chemotherapy for recurrence within the previous 6 months.

Overall, 551 patients from 89 sites across 10 countries were randomized to standard first-line chemotherapy – carboplatin plus paclitaxel – with either atezolizumab or placebo, followed by maintenance atezolizumab or placebo, which continued until confirmed disease progression.

The median age in the intention-to-treat population was 64-67 years. Nearly 23% of patients had dMMR tumors, and 67.2% had recurrent disease.

The baseline characteristics were well balanced and distributed between arms in the dMMR and all-comers population, said Nicoletta Colombo, MD, University of Milan–Bicocca, European Institute of Oncology Istituto di Ricovero e Cura a Carattere Scientifico, Italy, who presented the findings at ESMO.

Over a median follow up of 26.2 months, Dr. Colombo and colleagues observed a statistically significant improvement in PFS in the dMMR arm in favor of atezolizumab (hazard ratio, 0.36; P = .0005). At 2 years, 50.4% of patients receiving the immunotherapy were progression-free, compared with 16.0% in the placebo arm.

In all-comers, the PFS improvement with atezolizumab was less pronounced but remained significant (HR, 0.74; P = .0219).

A secondary analysis revealed, among dMMR patients, atezolizumab was associated with an overall survival advantage over placebo (HR, 0.41), with 75% of patients still alive at 2 years vs. 54.2% in the placebo arm. Dr. Colombo also noted a “clear trend” for improved overall survival with atezolizumab as well (HR, 0.82; P = .0483), but no PFS or overall survival benefit was seen with atezolizumab in MMR proficient (pMMR) patients.

Dr. Colombo said the safety profile of atezolizumab plus chemotherapy was “manageable,” with no differences in the rates of “major side effects,” although there was an increase in the rate of treatment-related grade ≥ 3 adverse events in the atezolizumab group (25.8% vs. 14.1%).

Dr. Tan noted that the AtTEnd trial revealed comparable results to earlier trials in this space but underlined that the survival curves in the interim analysis revealed a “red zone” of dMMR patients who do not respond to the combination and in whom immunotherapy is “not sufficient.”

Alongside this, Dr. Tan flagged a “blue zone” of dMMR patients who plateaued in both PFS and overall survival after 2 years. The question for these patients at this point is whether they need to continue immunotherapy beyond 24 months, he said.

But overall, Dr. Tan noted, the AtTEnd data “continue to validate practice-changing therapy for dMMR endometrial cancer patients” with immunotherapy plus chemotherapy, with the lack of benefit in pMMR disease underscoring an “unmet medical need.”
 

Inside DUO-E

The burning question, however, was whether adding a PARP inhibitor to immunotherapy and chemotherapy would boost the survival outcomes further.

The DUO-E trial involved patients with newly diagnosed stage III/IV or recurrent endometrial cancer who had not received systematic therapy for advanced disease and were naive to both PARP inhibitors and immune-mediated therapy.

Overall, 718 patients were randomized to one of three arms: Chemotherapy alone followed by maintenance placebo, chemotherapy plus durvalumab with maintenance durvalumab, or chemotherapy plus durvalumab with maintenance durvalumab plus olaparib.

Maintenance was continued until disease progression or unacceptable toxicity, or the patients met another discontinuation criteria.

About half of patients were newly diagnosed, half had recurrent disease, and approximately one-fifth had dMMR disease, said Shannon Westin, MD, from the University of Texas MD Anderson Cancer Center, Houston, who presented the findings.

Compared with placebo plus chemotherapy, patients in both the durvalumab alone and durvalumab plus olaparib arms experienced a significant improvement in PFS (HR, 0.71; P = .003; and HR, 0.55; P < .0001, respectively).

This effect was amplified in dMMR patients with durvalumab (HR, 0.42) as well as with durvalumab plus olaparib (HR, 0.41).

In pMMR patients, PFS benefit was stronger in the durvalumab-olaparib arm vs. durvalumab (HR, 0.57 vs. 0.77).

Although the overall survival analysis remains exploratory, Dr. Westin noted a trend toward better overall survival in the two treatment arms vs. placebo (HR, 0.77 with durvalumab, and HR, 0.59 with durvalumab plus olaparib).

However, adding olaparib to the equation increased the rate of grade ≥ 3 adverse events – 67.2% vs. 54.9% with durvalumab and 56.4% with chemotherapy alone in the overall analysis. The addition of olaparib also led to treatment discontinuation in 24.4% of patients vs. 20.9% in the durvalumab arm and 18.6% in the chemotherapy alone arm.

Domenica Lorusso, MD, PhD, who was not involved in the study, commented that the marginal PFS benefit of adding olaparib in DUO-E is “not surprising” because the bar set by immunotherapy is “so high in this population that it’s very difficult” to go any higher.

But the results in pMMR patients reveal “a clear additional benefit” to olaparib, said Dr. Lorusso, from Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.

“The main limitation of the trial,” she continued, “is that it was not powered to make a formal comparison between the two experimental arms.”

So, what then is the added benefit of olaparib? “Unfortunately, that remains an unanswered question,” Dr. Lorusso said.

AtTEnd was sponsored by the Mario Negri Institute for Pharmacological Research.

DUO-E was funded by AstraZeneca.

Dr. Colombo declares relationships with AstraZeneca, Clovis Oncology, Esai, GSK, Immunogen, Mersana, MSD/Merck, Nuvation Bio, OncXerna, Pieris, Roche, and Novocure.

Dr. Tan declares relationships with AstraZeneca, Karyopharm Therapeutics, Bayer, Roche, MSD, Genmab, Esai, PMV, BioNTech, Ellipses Pharma, Boehringer Ingelheim, Merck Serono, Takeda, and Clovis.

Dr. Westin declares relationships with AstraZeneca, Avenge Bio, Bayer, Bio-Path, Clovis, Genentech/Roche, GSK, Jazz Pharmaceuticals, Mereo, Novartis, Nuvectis, and Zentalis; and consulting and advisory roles for AstraZeneca, Caris, Clovis, Eisai, EQRx, Genentech/Roche, Gilead, GSK, Immunocore, ImmunoGen, Lilly, Merck, Mersana, Mereo, NGM Bio, Nuvectis, Seagen, Verastem, Vincerx, Zentalis, and ZielBio.

Dr. Lorusso declares relationships with PharmaMar, Merck Serono, Novartis, AstraZeneca, Clovis, Tesaro/GSK, Genmab, Immunogen, and Roche.

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

Alectinib, a potent anaplastic lymphoma kinase (ALK) inhibitor, significantly improved disease-free survival (DFS) at 2 years, compared with chemotherapy, in patients with completely resected ALK+ non–small cell lung cancer (NSCLC), according to interim findings from the open-label phase 3 ALINA trial.

The results suggest that alectinib, which is currently the first-line treatment choice in more advanced NSCLC, also provides an effective new treatment strategy for patients with resected ALK+ NSCLC, said Ben Solomon, MBBS, PhD, who presented late-breaking data from the trial at the annual meeting of the European Society for Medical Oncology.

ALINA is the first phase 3 trial of an ALK inhibitor to show a DFS benefit in completely resected stage IB-IIIA disease, said Dr. Solomon, professor and medical oncologist at Peter MacCallum Cancer Centre, Melbourne.

The current treatment recommendation for after surgery in this patient population is platinum-based chemotherapy, which is associated with modest improvements in overall survival. But multiple trials looking at alectinib in stage I-III NSCLC are underway given the unmet need for treatment in the 4%-5% of NSCLC patients with ALK rearrangements, Dr. Solomon explained.

The ALINA trial enrolled adults with good performance status and completely resected stage IB-IIIA ALK+ NSCLC. Patients were randomized 1:1 to 600 mg of oral alectinib twice daily for up to 24 months or until disease recurrence, or up to four 21-day cycles of intravenous platinum-based chemotherapy.

At median follow-up of 27.8 months, Dr. Solomon and colleagues observed an overall DFS benefit in 130 patients with stage II-IIIA disease randomized to receive alectinib, compared with the 127 patients who received chemotherapy (median DFS not reached vs. 44.4 months; hazard ratio, 0.24). The benefit was observed in the overall intention-to-treat (ITT) population of patients with stage IB-IIIA disease (median DFS not reached vs. 41.3 months; HR, 0.24).

Two-year DFS was also improved with alectinib vs. chemotherapy for stage IB (HR, 0.21), stage II (HR, 0.24), and stage IIIA disease (HR, 0.25).

The investigators observed a clinically meaningful central nervous system DFS benefit in the ITT population as well (HR, 0.22). This finding is important, given that patients with ALK+ disease have a high risk of brain metastases, which occurs in 50%-60% of patients over the course of disease, Dr. Solomon noted.

Over the treatment duration in each arm, 23.4% of patients in the alectinib arm and 25.8% in the chemotherapy arm experienced grade 3 or 4 adverse events; 5 patients in the alectinib arm and 13 in the chemotherapy arm had adverse events that led to treatment discontinuation.

“Adjuvant alectinib was tolerable and in line with the known safety profile of alectinib,” Dr. Solomon concluded, but noted that the overall survival data were not yet mature.

Invited discussant Marina Garassino, MBBS, however, cautioned against rushing to judgment, calling the DFS findings “interesting, but early.”

“Are 2 years of alectinib enough to impact overall survival? We don’t know yet,” said Dr. Garassino, professor of medicine and director of the thoracic oncology program at the University of Chicago.

Chemotherapy, conversely, has been shown to improve overall survival, she noted.

Toxicity of alectinib in the adjuvant setting may be a concern as well, she said, explaining that patients have reported numerous side effects that can affect quality of life, such as sun sensitivity, difficulty focusing, neuropathy, lower back muscle soreness, and constipation.

“So, I think we should still wait for more results from this trial,” she said.

In the meantime, she said she will ask patients “if they want this kind of toxicity in the absence of a clear overall survival benefit.”

The ALINA trial is funded by F. Hoffmann-La Roche. Dr. Solomon and Dr. Garassino each reported numerous relationships with pharmaceutical companies and other entities.

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

Alectinib, a potent anaplastic lymphoma kinase (ALK) inhibitor, significantly improved disease-free survival (DFS) at 2 years, compared with chemotherapy, in patients with completely resected ALK+ non–small cell lung cancer (NSCLC), according to interim findings from the open-label phase 3 ALINA trial.

The results suggest that alectinib, which is currently the first-line treatment choice in more advanced NSCLC, also provides an effective new treatment strategy for patients with resected ALK+ NSCLC, said Ben Solomon, MBBS, PhD, who presented late-breaking data from the trial at the annual meeting of the European Society for Medical Oncology.

ALINA is the first phase 3 trial of an ALK inhibitor to show a DFS benefit in completely resected stage IB-IIIA disease, said Dr. Solomon, professor and medical oncologist at Peter MacCallum Cancer Centre, Melbourne.

The current treatment recommendation for after surgery in this patient population is platinum-based chemotherapy, which is associated with modest improvements in overall survival. But multiple trials looking at alectinib in stage I-III NSCLC are underway given the unmet need for treatment in the 4%-5% of NSCLC patients with ALK rearrangements, Dr. Solomon explained.

The ALINA trial enrolled adults with good performance status and completely resected stage IB-IIIA ALK+ NSCLC. Patients were randomized 1:1 to 600 mg of oral alectinib twice daily for up to 24 months or until disease recurrence, or up to four 21-day cycles of intravenous platinum-based chemotherapy.

At median follow-up of 27.8 months, Dr. Solomon and colleagues observed an overall DFS benefit in 130 patients with stage II-IIIA disease randomized to receive alectinib, compared with the 127 patients who received chemotherapy (median DFS not reached vs. 44.4 months; hazard ratio, 0.24). The benefit was observed in the overall intention-to-treat (ITT) population of patients with stage IB-IIIA disease (median DFS not reached vs. 41.3 months; HR, 0.24).

Two-year DFS was also improved with alectinib vs. chemotherapy for stage IB (HR, 0.21), stage II (HR, 0.24), and stage IIIA disease (HR, 0.25).

The investigators observed a clinically meaningful central nervous system DFS benefit in the ITT population as well (HR, 0.22). This finding is important, given that patients with ALK+ disease have a high risk of brain metastases, which occurs in 50%-60% of patients over the course of disease, Dr. Solomon noted.

Over the treatment duration in each arm, 23.4% of patients in the alectinib arm and 25.8% in the chemotherapy arm experienced grade 3 or 4 adverse events; 5 patients in the alectinib arm and 13 in the chemotherapy arm had adverse events that led to treatment discontinuation.

“Adjuvant alectinib was tolerable and in line with the known safety profile of alectinib,” Dr. Solomon concluded, but noted that the overall survival data were not yet mature.

Invited discussant Marina Garassino, MBBS, however, cautioned against rushing to judgment, calling the DFS findings “interesting, but early.”

“Are 2 years of alectinib enough to impact overall survival? We don’t know yet,” said Dr. Garassino, professor of medicine and director of the thoracic oncology program at the University of Chicago.

Chemotherapy, conversely, has been shown to improve overall survival, she noted.

Toxicity of alectinib in the adjuvant setting may be a concern as well, she said, explaining that patients have reported numerous side effects that can affect quality of life, such as sun sensitivity, difficulty focusing, neuropathy, lower back muscle soreness, and constipation.

“So, I think we should still wait for more results from this trial,” she said.

In the meantime, she said she will ask patients “if they want this kind of toxicity in the absence of a clear overall survival benefit.”

The ALINA trial is funded by F. Hoffmann-La Roche. Dr. Solomon and Dr. Garassino each reported numerous relationships with pharmaceutical companies and other entities.

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

Alectinib, a potent anaplastic lymphoma kinase (ALK) inhibitor, significantly improved disease-free survival (DFS) at 2 years, compared with chemotherapy, in patients with completely resected ALK+ non–small cell lung cancer (NSCLC), according to interim findings from the open-label phase 3 ALINA trial.

The results suggest that alectinib, which is currently the first-line treatment choice in more advanced NSCLC, also provides an effective new treatment strategy for patients with resected ALK+ NSCLC, said Ben Solomon, MBBS, PhD, who presented late-breaking data from the trial at the annual meeting of the European Society for Medical Oncology.

ALINA is the first phase 3 trial of an ALK inhibitor to show a DFS benefit in completely resected stage IB-IIIA disease, said Dr. Solomon, professor and medical oncologist at Peter MacCallum Cancer Centre, Melbourne.

The current treatment recommendation for after surgery in this patient population is platinum-based chemotherapy, which is associated with modest improvements in overall survival. But multiple trials looking at alectinib in stage I-III NSCLC are underway given the unmet need for treatment in the 4%-5% of NSCLC patients with ALK rearrangements, Dr. Solomon explained.

The ALINA trial enrolled adults with good performance status and completely resected stage IB-IIIA ALK+ NSCLC. Patients were randomized 1:1 to 600 mg of oral alectinib twice daily for up to 24 months or until disease recurrence, or up to four 21-day cycles of intravenous platinum-based chemotherapy.

At median follow-up of 27.8 months, Dr. Solomon and colleagues observed an overall DFS benefit in 130 patients with stage II-IIIA disease randomized to receive alectinib, compared with the 127 patients who received chemotherapy (median DFS not reached vs. 44.4 months; hazard ratio, 0.24). The benefit was observed in the overall intention-to-treat (ITT) population of patients with stage IB-IIIA disease (median DFS not reached vs. 41.3 months; HR, 0.24).

Two-year DFS was also improved with alectinib vs. chemotherapy for stage IB (HR, 0.21), stage II (HR, 0.24), and stage IIIA disease (HR, 0.25).

The investigators observed a clinically meaningful central nervous system DFS benefit in the ITT population as well (HR, 0.22). This finding is important, given that patients with ALK+ disease have a high risk of brain metastases, which occurs in 50%-60% of patients over the course of disease, Dr. Solomon noted.

Over the treatment duration in each arm, 23.4% of patients in the alectinib arm and 25.8% in the chemotherapy arm experienced grade 3 or 4 adverse events; 5 patients in the alectinib arm and 13 in the chemotherapy arm had adverse events that led to treatment discontinuation.

“Adjuvant alectinib was tolerable and in line with the known safety profile of alectinib,” Dr. Solomon concluded, but noted that the overall survival data were not yet mature.

Invited discussant Marina Garassino, MBBS, however, cautioned against rushing to judgment, calling the DFS findings “interesting, but early.”

“Are 2 years of alectinib enough to impact overall survival? We don’t know yet,” said Dr. Garassino, professor of medicine and director of the thoracic oncology program at the University of Chicago.

Chemotherapy, conversely, has been shown to improve overall survival, she noted.

Toxicity of alectinib in the adjuvant setting may be a concern as well, she said, explaining that patients have reported numerous side effects that can affect quality of life, such as sun sensitivity, difficulty focusing, neuropathy, lower back muscle soreness, and constipation.

“So, I think we should still wait for more results from this trial,” she said.

In the meantime, she said she will ask patients “if they want this kind of toxicity in the absence of a clear overall survival benefit.”

The ALINA trial is funded by F. Hoffmann-La Roche. Dr. Solomon and Dr. Garassino each reported numerous relationships with pharmaceutical companies and other entities.

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

Neoadjuvant nivolumab (Opdivo) plus chemotherapy followed by adjuvant nivolumab led to a statistically significant and clinically meaningful improvement in event-free survival (EFS) in patients with resectable non–small cell lung cancer (NSCLC), according to interim findings from the phase 3 CheckMate 77T trial.

In the interim analysis, median EFS was not reached in 229 patients randomly assigned to the adjuvant nivolumab treatment group vs. 18.4 months in 232 patients randomly assigned to a placebo group over a minimum follow-up of 15.7 months (hazard ratio, 0.58), first author Tina Cascone, MD, reported at the annual meeting of the European Society for Medical Oncology.

“CheckMate 77T is the first phase 3 perioperative study to build on the standard of care neoadjuvant nivolumab plus chemotherapy and supports perioperative nivolumab as a potential new treatment option for patients with resectable non–small cell lung cancer,” said Dr. Cascone, associate professor in the division of cancer medicine at University of Texas MD Anderson Cancer Center, Houston.

Invited discussant Marina Garassino, MBBS, professor of medicine and director of the thoracic oncology program at the University of Chicago, noted that the “practice-changing” CheckMate 77T findings – including the “highly statistically significant impressive hazard ratio of 0.58” – add to the increasing evidence supporting perioperative immunochemotherapy in the resectable NSCLC space.

This trial is the fourth to show an EFS benefit in this setting with a perioperative approach. Most recently, Merck’s pembrolizumab (Keytruda) demonstrated improvements in both EFS and overall survival when used in the perioperative setting for patients with resectable NSCLC, according to data from the pivotal KEYNOTE-671 trial. Those findings, also presented at the ESMO congress, led to the approval this past week of pembrolizumab in that population.

The CheckMate 77T included 461 adults with untreated resectable stage IIA-IIIB NSCLC, 77% of whom underwent definitive surgery. The median age of participants was 66 years. Patients were randomly assigned to active treatment with nivolumab plus platinum-doublet chemotherapy followed by surgery and adjuvant nivolumab or placebo. The neoadjuvant nivolumab dose was 360 mg every 3 weeks for four cycles, and the adjuvant dose was 480 mg every 4 weeks for 1 year.

Overall, adding adjuvant nivolumab led to a significant improvement in EFS over a follow-up spanning 15.7-44.2 months (not reached vs. 18.4 months; HR, 0.58; P = .00025).

The EFS benefits were observed across most key subgroups but was lower in patients with stage II vs. stage III disease (HR, 0.81 vs. 0.51), and in those with programmed death-ligand 1 (PD-L1) expression of less than 1% vs. 1% or greater (HR, 0.73 vs. 0.52).

Neoadjuvant/adjuvant nivolumab also led to a significant improvement in pathological complete response (25.3% vs. 4.7%; odds ratio, 6.64) and major pathological response (35.4% vs. 12.1%; OR, 4.01) – the trial’s secondary endpoints.

In an exploratory analysis, perioperative nivolumab showed a trend toward improved EFS in patients without a pathological complete response, Dr. Cascone added.

No new safety signals were observed. Grade 3-4 treatment-related adverse events occurred in 32% of patients in the treatment arm and 25% in the placebo arm. Surgery-related adverse events occurred in 12% in each arm.

Despite the promising findings, some questions remain, said Dr. Garassino.

First, should PD-L1–negative patients and those with stage II NSCLC receive perioperative treatment? Pooled data from recent perioperative trials indicated EFS benefits in the perioperative setting for both PD-L1-negative disease (HR, 0.72) and stage II disease (HR, 0.68), she said.

So, “the answer is yes, we should treat” these patients, she said.

But a big question is whether patients who don’t achieve a pathological complete response need adjuvant therapy. “We really don’t know,” she continued. “What we know is that those patients who achieve pathological complete response do very, very well, and I think for those patients who don’t achieve pathological complete response, we have to work with new biomarkers, [circulating tumor] DNA, new drugs, and we have to run proper trials to increase the power of these patients, that unfortunately is still very low.”

CheckMate 77T is funded by Bristol-Myers Squibb. Dr. Cascone and Dr. Garassino each reported relationships (personal and institutional) with numerous pharmaceutical companies and other entities.

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

Neoadjuvant nivolumab (Opdivo) plus chemotherapy followed by adjuvant nivolumab led to a statistically significant and clinically meaningful improvement in event-free survival (EFS) in patients with resectable non–small cell lung cancer (NSCLC), according to interim findings from the phase 3 CheckMate 77T trial.

In the interim analysis, median EFS was not reached in 229 patients randomly assigned to the adjuvant nivolumab treatment group vs. 18.4 months in 232 patients randomly assigned to a placebo group over a minimum follow-up of 15.7 months (hazard ratio, 0.58), first author Tina Cascone, MD, reported at the annual meeting of the European Society for Medical Oncology.

“CheckMate 77T is the first phase 3 perioperative study to build on the standard of care neoadjuvant nivolumab plus chemotherapy and supports perioperative nivolumab as a potential new treatment option for patients with resectable non–small cell lung cancer,” said Dr. Cascone, associate professor in the division of cancer medicine at University of Texas MD Anderson Cancer Center, Houston.

Invited discussant Marina Garassino, MBBS, professor of medicine and director of the thoracic oncology program at the University of Chicago, noted that the “practice-changing” CheckMate 77T findings – including the “highly statistically significant impressive hazard ratio of 0.58” – add to the increasing evidence supporting perioperative immunochemotherapy in the resectable NSCLC space.

This trial is the fourth to show an EFS benefit in this setting with a perioperative approach. Most recently, Merck’s pembrolizumab (Keytruda) demonstrated improvements in both EFS and overall survival when used in the perioperative setting for patients with resectable NSCLC, according to data from the pivotal KEYNOTE-671 trial. Those findings, also presented at the ESMO congress, led to the approval this past week of pembrolizumab in that population.

The CheckMate 77T included 461 adults with untreated resectable stage IIA-IIIB NSCLC, 77% of whom underwent definitive surgery. The median age of participants was 66 years. Patients were randomly assigned to active treatment with nivolumab plus platinum-doublet chemotherapy followed by surgery and adjuvant nivolumab or placebo. The neoadjuvant nivolumab dose was 360 mg every 3 weeks for four cycles, and the adjuvant dose was 480 mg every 4 weeks for 1 year.

Overall, adding adjuvant nivolumab led to a significant improvement in EFS over a follow-up spanning 15.7-44.2 months (not reached vs. 18.4 months; HR, 0.58; P = .00025).

The EFS benefits were observed across most key subgroups but was lower in patients with stage II vs. stage III disease (HR, 0.81 vs. 0.51), and in those with programmed death-ligand 1 (PD-L1) expression of less than 1% vs. 1% or greater (HR, 0.73 vs. 0.52).

Neoadjuvant/adjuvant nivolumab also led to a significant improvement in pathological complete response (25.3% vs. 4.7%; odds ratio, 6.64) and major pathological response (35.4% vs. 12.1%; OR, 4.01) – the trial’s secondary endpoints.

In an exploratory analysis, perioperative nivolumab showed a trend toward improved EFS in patients without a pathological complete response, Dr. Cascone added.

No new safety signals were observed. Grade 3-4 treatment-related adverse events occurred in 32% of patients in the treatment arm and 25% in the placebo arm. Surgery-related adverse events occurred in 12% in each arm.

Despite the promising findings, some questions remain, said Dr. Garassino.

First, should PD-L1–negative patients and those with stage II NSCLC receive perioperative treatment? Pooled data from recent perioperative trials indicated EFS benefits in the perioperative setting for both PD-L1-negative disease (HR, 0.72) and stage II disease (HR, 0.68), she said.

So, “the answer is yes, we should treat” these patients, she said.

But a big question is whether patients who don’t achieve a pathological complete response need adjuvant therapy. “We really don’t know,” she continued. “What we know is that those patients who achieve pathological complete response do very, very well, and I think for those patients who don’t achieve pathological complete response, we have to work with new biomarkers, [circulating tumor] DNA, new drugs, and we have to run proper trials to increase the power of these patients, that unfortunately is still very low.”

CheckMate 77T is funded by Bristol-Myers Squibb. Dr. Cascone and Dr. Garassino each reported relationships (personal and institutional) with numerous pharmaceutical companies and other entities.

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

Neoadjuvant nivolumab (Opdivo) plus chemotherapy followed by adjuvant nivolumab led to a statistically significant and clinically meaningful improvement in event-free survival (EFS) in patients with resectable non–small cell lung cancer (NSCLC), according to interim findings from the phase 3 CheckMate 77T trial.

In the interim analysis, median EFS was not reached in 229 patients randomly assigned to the adjuvant nivolumab treatment group vs. 18.4 months in 232 patients randomly assigned to a placebo group over a minimum follow-up of 15.7 months (hazard ratio, 0.58), first author Tina Cascone, MD, reported at the annual meeting of the European Society for Medical Oncology.

“CheckMate 77T is the first phase 3 perioperative study to build on the standard of care neoadjuvant nivolumab plus chemotherapy and supports perioperative nivolumab as a potential new treatment option for patients with resectable non–small cell lung cancer,” said Dr. Cascone, associate professor in the division of cancer medicine at University of Texas MD Anderson Cancer Center, Houston.

Invited discussant Marina Garassino, MBBS, professor of medicine and director of the thoracic oncology program at the University of Chicago, noted that the “practice-changing” CheckMate 77T findings – including the “highly statistically significant impressive hazard ratio of 0.58” – add to the increasing evidence supporting perioperative immunochemotherapy in the resectable NSCLC space.

This trial is the fourth to show an EFS benefit in this setting with a perioperative approach. Most recently, Merck’s pembrolizumab (Keytruda) demonstrated improvements in both EFS and overall survival when used in the perioperative setting for patients with resectable NSCLC, according to data from the pivotal KEYNOTE-671 trial. Those findings, also presented at the ESMO congress, led to the approval this past week of pembrolizumab in that population.

The CheckMate 77T included 461 adults with untreated resectable stage IIA-IIIB NSCLC, 77% of whom underwent definitive surgery. The median age of participants was 66 years. Patients were randomly assigned to active treatment with nivolumab plus platinum-doublet chemotherapy followed by surgery and adjuvant nivolumab or placebo. The neoadjuvant nivolumab dose was 360 mg every 3 weeks for four cycles, and the adjuvant dose was 480 mg every 4 weeks for 1 year.

Overall, adding adjuvant nivolumab led to a significant improvement in EFS over a follow-up spanning 15.7-44.2 months (not reached vs. 18.4 months; HR, 0.58; P = .00025).

The EFS benefits were observed across most key subgroups but was lower in patients with stage II vs. stage III disease (HR, 0.81 vs. 0.51), and in those with programmed death-ligand 1 (PD-L1) expression of less than 1% vs. 1% or greater (HR, 0.73 vs. 0.52).

Neoadjuvant/adjuvant nivolumab also led to a significant improvement in pathological complete response (25.3% vs. 4.7%; odds ratio, 6.64) and major pathological response (35.4% vs. 12.1%; OR, 4.01) – the trial’s secondary endpoints.

In an exploratory analysis, perioperative nivolumab showed a trend toward improved EFS in patients without a pathological complete response, Dr. Cascone added.

No new safety signals were observed. Grade 3-4 treatment-related adverse events occurred in 32% of patients in the treatment arm and 25% in the placebo arm. Surgery-related adverse events occurred in 12% in each arm.

Despite the promising findings, some questions remain, said Dr. Garassino.

First, should PD-L1–negative patients and those with stage II NSCLC receive perioperative treatment? Pooled data from recent perioperative trials indicated EFS benefits in the perioperative setting for both PD-L1-negative disease (HR, 0.72) and stage II disease (HR, 0.68), she said.

So, “the answer is yes, we should treat” these patients, she said.

But a big question is whether patients who don’t achieve a pathological complete response need adjuvant therapy. “We really don’t know,” she continued. “What we know is that those patients who achieve pathological complete response do very, very well, and I think for those patients who don’t achieve pathological complete response, we have to work with new biomarkers, [circulating tumor] DNA, new drugs, and we have to run proper trials to increase the power of these patients, that unfortunately is still very low.”

CheckMate 77T is funded by Bristol-Myers Squibb. Dr. Cascone and Dr. Garassino each reported relationships (personal and institutional) with numerous pharmaceutical companies and other entities.

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

Further evidence for the benefit of adding immune checkpoint inhibitors to neoadjuvant chemotherapy in patients with early high-risk estrogen receptor–positive, HER2-negative (HR+/HER2–) breast cancer comes from results of two randomized trials presented at the annual meeting of the European Society for Medical Oncology.

In the KEYNOTE-756 trial, adding pembrolizumab (Keytruda) to neoadjuvant chemotherapy resulted in an 8.5% increase in pathologic complete response (pCR) rates, compared with chemotherapy alone, regardless of the patients’ programmed death ligand-1 (PD-L1) status, reported Fatima Cardoso, MD, director of the breast unit at the Champalimaud Clinical Center in Lisbon.

In the Checkmate 7FL trial, a study bedeviled by unexpected circumstances, the addition of nivolumab (Opdivo) to neoadjuvant chemotherapy resulted in a 10.5% absolute increase in pCR rates, compared with chemotherapy alone, reported Sherene Loi, MBBS, PhD, from the Peter MacCallum Cancer Centre in Melbourne.

A new paradigm?

Taken together, the trials suggest that neoadjuvant immunotherapy has the potential to be “a new paradigm,” said ESMO invited discussant Steven RD Johnston, MD, PhD, professor of breast cancer medicine at the Royal Marsden Hospital and Institute of Cancer Research in London.

“Is the management of ER-positive breast cancer going to change with immunotherapy? Can we improve pCR rates? Yes, we can. We’ve seen a significant improvement in two separate studies, albeit the rates are only at 24%, and at this point, it’s unclear if this will translate into a better event-free survival [EFS] because we have to wait and follow the data,” he said.

The data from the two studies suggest that the patients who are likely to benefit most would be those with higher-grade tumors, luminal B subtype tumors, and, possibly, those whose tumors express higher levels of PD-L1, although the definition of PD-L1 positive depends on the assay used, he said

“I think we have to make better efforts to evaluate whether genomic or immune signatures can further define those who have most to gain, and I would urge investigators in both studies to do more digging into understanding this, because you might really enrich the patients who have the most to gain from the is approach,” Dr. Johnston said.

Checkmate 7FL details

In this prospective, randomized multicenter trial patients received four cycles of neoadjuvant paclitaxel followed by four cycles of doxorubicin and cyclophosphamide (AC) and surgery with adjuvant endocrine therapy. In arm A, 257 patients received neoadjuvant and adjuvant nivolumab. In arm B 253, patients received a nivolumab placebo in both the neoadjuvant and adjuvant settings.

Eligible patients had newly diagnosed ER+/HER2– breast cancer centrally confirmed. Patients with T1c or T2 tumors who were clinically node positive on histology and those with T3 or T4 tumors of any nodal status were eligible. Patients were required to have grade 3 histology as determined by the local pathologist, or grade 2 with low ER expression.

Patients were stratified by PD-L1 status, tumor grade, axillary nodal status and frequency of AC delivery (every 2 or 3 weeks) and were then randomized into one of the two treatment arms.

Destiny takes a hand

The protocol was changed following the approval in October 2021 of adjuvant abemaciclib in patients with high-risk ER+/HER2– disease.

“This was expected to result in a high rate of withdrawals due to safety concerns when combining a CDK4/6 inhibitor with an anti-PD-1, and this put the co-primary endpoint of EFS at risk,” Dr. Loi explained.

Therefore, the investigators amended the trial protocol to establish pCR as the sole primary endpoint and ceased accrual after 521 patients were randomized.

In addition, the primary efficacy population was modified to include 510 patients across 221 sites in 31 countries after Russian sites with a total of 11 patients closed due to Russia’s war on Ukraine.

And another hurdle, trial recruitment occurred from November 2019 through April 2022, during the COVID-19 pandemic.

Checkmate 7FL results

The pCR rate in the modified intention-to-treat (ITT) population was 24.5% for patients who received nivolumab, compared with 13.8% for patients who did not, translating in an odds ratio for benefit with the ICI of 2.05 (P = .0021),

In patients with PD-L1 expression in at least 1% of cells, a secondary endpoint, the respective pCR rates were 44.3% and 20.2%, with OR of 3.11, and a confidence interval indicating statistical significance.

Residual cancer burden (RCB) rates of 0 or 1 were also higher in the nivolumab-containing arm in both the modified ITT population (30.7% vs. 21.3%), and in the PD-L1–enriched population (54.5% vs. 26.2%).

In the safety population, which included 517 patients who received at least one dose of nivolumab or placebo, rates of overall adverse events and treatment-related adverse events were similar between the two arms, with the exception of two deaths from drug toxicity in Arm A (from pneumonitis in a patient 61 days after the last neoadjuvant cycles and hepatitis in a patient 51 days after) vs. no drug toxicity deaths reported in Arm B.

Safety of the nivolumab and neoadjuvant chemotherapy combinations was consistent with known safety profiles, with no new safety signals seen, Dr. Loi said.

KEYNOTE-756 details

The KEYNOTE-756 investigators had an easier time of it than Dr. Loi and colleagues. In fact, the trial “is the first fully accrued phase 3 immunotherapy study in high-risk, early-stage ER-positive, HER2-negative breast cancer, and it met one of its primary endpoints, pCR,” Dr. Cardoso said.

She noted that in the adaptive I-SPY2 trial, the addition of pembrolizumab to neoadjuvant chemotherapy resulted in a nearly threefold improvement in estimated pCR rates in patients with ER+/HER2– tumors, indicating that the role of immunotherapy in this population warranted further exploration.

In the placebo-controlled KEYNOTE-756 trial, treatment-naive patients with locally confirmed invasive ductal breast carcinoma with stage T1c or T2 tumors 2 cm or larger with nodal status CN1 or 2, or T3 and T4 tumors with nodal status CN0-2 were enrolled.

In most centers (Eastern Europe and China being the exceptions) patients were stratified by PD-L1 status, nodal status, anthracycline regimen chosen (AC or epirubicin-cyclophosphamide [EC]) and by degree of ER-positivity. Patients, 1,278 in total, were then randomly assigned to pembrolizumab for four cycles plus paclitaxel for 12 weeks, followed by AC or EC for four cycles plus pembrolizumab, or to the same regimen without pembrolizumab.

Following surgery, patients went on to endocrine therapy for up to 10 years, with or without 6 months of additional pembrolizumab every 6 months.

KEYNOTE-756 results

For the ITT analysis, 635 patients assigned to pembrolizumab and 643 assigned to placebo were evaluable.

At the first interim assessment, conducted at a median follow-up of 33.2 months, with the longest follow-up out to 51.8 months, the co-primary endpoint of an improvement in pCR with immunotherapy was met. The pCR rate with pembrolizumab was 24.3%, compared with 15.6% with placebo, an absolute difference of 8.5% (P = .00005).

Data for the other co-primary endpoint, EFS, were not mature at the time of data cutoff, and will be reported at a future date, Dr. Cardoso said.

An analysis of pCR rates in subgroups showed that pembrolizumab benefited most patients, with the exception of those 65 years and older, patients with Eastern Cooperative Oncology Group performance status of 1 (vs. 0), patients who received their anthracycline regimen every 2 weeks rather than every 3, and node-negative patients.

The benefit was particular pronounced among patients with less than 10% ER positivity, she pointed out.

Adverse events in the neoadjuvant phase were primarily related to chemotherapy, with no major differences between the arms, although grade 3 or greater events were slightly more frequent with pembrolizumab (52.5% vs. 46.4%), and two patients in the pembrolizumab arm died (one death was from acute myocardial infarction considered related to the long QT syndrome; cause of the other patient’s death was not specified).

Adverse events leading to discontinuation were also more common with pembrolizumab (19.1% vs. 10.1%, respectively).

Immune-mediated adverse events of any grade were also higher in the immunotherapy arm, occurring in 32.8% of patients vs. 7% of patients in the placebo arm.

There were no deaths from immune-related adverse events.

Eye on safety

In his discussion, Dr. Johnston emphasized that “it’s important in a curative population that we don’t harm patients in a setting where we have a variety of other therapies available.”

Recalling the deaths of patients in the immunotherapy arm of each trial, he commented that “deaths in early breast cancer in a treatment setting are always a disaster, and we have to make sure that we manage these adverse events as we can best, and we know how to do that now.”

Checkmate 7FL was supported by Bristol Myers Squibb. Dr. Loi reported financial and nonfinancial interests with BMS and with other companies. KEYNOTE-756 was supported by Merck Sharp & Dohme. Dr. Cardoso disclosed consulting and institutional research support from Merck and others. Dr. Johnston reported consulting or advisory roles, honoraria, and research funding from several companies, not including either BMS or Merck.

Further evidence for the benefit of adding immune checkpoint inhibitors to neoadjuvant chemotherapy in patients with early high-risk estrogen receptor–positive, HER2-negative (HR+/HER2–) breast cancer comes from results of two randomized trials presented at the annual meeting of the European Society for Medical Oncology.

In the KEYNOTE-756 trial, adding pembrolizumab (Keytruda) to neoadjuvant chemotherapy resulted in an 8.5% increase in pathologic complete response (pCR) rates, compared with chemotherapy alone, regardless of the patients’ programmed death ligand-1 (PD-L1) status, reported Fatima Cardoso, MD, director of the breast unit at the Champalimaud Clinical Center in Lisbon.

In the Checkmate 7FL trial, a study bedeviled by unexpected circumstances, the addition of nivolumab (Opdivo) to neoadjuvant chemotherapy resulted in a 10.5% absolute increase in pCR rates, compared with chemotherapy alone, reported Sherene Loi, MBBS, PhD, from the Peter MacCallum Cancer Centre in Melbourne.

A new paradigm?

Taken together, the trials suggest that neoadjuvant immunotherapy has the potential to be “a new paradigm,” said ESMO invited discussant Steven RD Johnston, MD, PhD, professor of breast cancer medicine at the Royal Marsden Hospital and Institute of Cancer Research in London.

“Is the management of ER-positive breast cancer going to change with immunotherapy? Can we improve pCR rates? Yes, we can. We’ve seen a significant improvement in two separate studies, albeit the rates are only at 24%, and at this point, it’s unclear if this will translate into a better event-free survival [EFS] because we have to wait and follow the data,” he said.

The data from the two studies suggest that the patients who are likely to benefit most would be those with higher-grade tumors, luminal B subtype tumors, and, possibly, those whose tumors express higher levels of PD-L1, although the definition of PD-L1 positive depends on the assay used, he said

“I think we have to make better efforts to evaluate whether genomic or immune signatures can further define those who have most to gain, and I would urge investigators in both studies to do more digging into understanding this, because you might really enrich the patients who have the most to gain from the is approach,” Dr. Johnston said.

Checkmate 7FL details

In this prospective, randomized multicenter trial patients received four cycles of neoadjuvant paclitaxel followed by four cycles of doxorubicin and cyclophosphamide (AC) and surgery with adjuvant endocrine therapy. In arm A, 257 patients received neoadjuvant and adjuvant nivolumab. In arm B 253, patients received a nivolumab placebo in both the neoadjuvant and adjuvant settings.

Eligible patients had newly diagnosed ER+/HER2– breast cancer centrally confirmed. Patients with T1c or T2 tumors who were clinically node positive on histology and those with T3 or T4 tumors of any nodal status were eligible. Patients were required to have grade 3 histology as determined by the local pathologist, or grade 2 with low ER expression.

Patients were stratified by PD-L1 status, tumor grade, axillary nodal status and frequency of AC delivery (every 2 or 3 weeks) and were then randomized into one of the two treatment arms.

Destiny takes a hand

The protocol was changed following the approval in October 2021 of adjuvant abemaciclib in patients with high-risk ER+/HER2– disease.

“This was expected to result in a high rate of withdrawals due to safety concerns when combining a CDK4/6 inhibitor with an anti-PD-1, and this put the co-primary endpoint of EFS at risk,” Dr. Loi explained.

Therefore, the investigators amended the trial protocol to establish pCR as the sole primary endpoint and ceased accrual after 521 patients were randomized.

In addition, the primary efficacy population was modified to include 510 patients across 221 sites in 31 countries after Russian sites with a total of 11 patients closed due to Russia’s war on Ukraine.

And another hurdle, trial recruitment occurred from November 2019 through April 2022, during the COVID-19 pandemic.

Checkmate 7FL results

The pCR rate in the modified intention-to-treat (ITT) population was 24.5% for patients who received nivolumab, compared with 13.8% for patients who did not, translating in an odds ratio for benefit with the ICI of 2.05 (P = .0021),

In patients with PD-L1 expression in at least 1% of cells, a secondary endpoint, the respective pCR rates were 44.3% and 20.2%, with OR of 3.11, and a confidence interval indicating statistical significance.

Residual cancer burden (RCB) rates of 0 or 1 were also higher in the nivolumab-containing arm in both the modified ITT population (30.7% vs. 21.3%), and in the PD-L1–enriched population (54.5% vs. 26.2%).

In the safety population, which included 517 patients who received at least one dose of nivolumab or placebo, rates of overall adverse events and treatment-related adverse events were similar between the two arms, with the exception of two deaths from drug toxicity in Arm A (from pneumonitis in a patient 61 days after the last neoadjuvant cycles and hepatitis in a patient 51 days after) vs. no drug toxicity deaths reported in Arm B.

Safety of the nivolumab and neoadjuvant chemotherapy combinations was consistent with known safety profiles, with no new safety signals seen, Dr. Loi said.

KEYNOTE-756 details

The KEYNOTE-756 investigators had an easier time of it than Dr. Loi and colleagues. In fact, the trial “is the first fully accrued phase 3 immunotherapy study in high-risk, early-stage ER-positive, HER2-negative breast cancer, and it met one of its primary endpoints, pCR,” Dr. Cardoso said.

She noted that in the adaptive I-SPY2 trial, the addition of pembrolizumab to neoadjuvant chemotherapy resulted in a nearly threefold improvement in estimated pCR rates in patients with ER+/HER2– tumors, indicating that the role of immunotherapy in this population warranted further exploration.

In the placebo-controlled KEYNOTE-756 trial, treatment-naive patients with locally confirmed invasive ductal breast carcinoma with stage T1c or T2 tumors 2 cm or larger with nodal status CN1 or 2, or T3 and T4 tumors with nodal status CN0-2 were enrolled.

In most centers (Eastern Europe and China being the exceptions) patients were stratified by PD-L1 status, nodal status, anthracycline regimen chosen (AC or epirubicin-cyclophosphamide [EC]) and by degree of ER-positivity. Patients, 1,278 in total, were then randomly assigned to pembrolizumab for four cycles plus paclitaxel for 12 weeks, followed by AC or EC for four cycles plus pembrolizumab, or to the same regimen without pembrolizumab.

Following surgery, patients went on to endocrine therapy for up to 10 years, with or without 6 months of additional pembrolizumab every 6 months.

KEYNOTE-756 results

For the ITT analysis, 635 patients assigned to pembrolizumab and 643 assigned to placebo were evaluable.

At the first interim assessment, conducted at a median follow-up of 33.2 months, with the longest follow-up out to 51.8 months, the co-primary endpoint of an improvement in pCR with immunotherapy was met. The pCR rate with pembrolizumab was 24.3%, compared with 15.6% with placebo, an absolute difference of 8.5% (P = .00005).

Data for the other co-primary endpoint, EFS, were not mature at the time of data cutoff, and will be reported at a future date, Dr. Cardoso said.

An analysis of pCR rates in subgroups showed that pembrolizumab benefited most patients, with the exception of those 65 years and older, patients with Eastern Cooperative Oncology Group performance status of 1 (vs. 0), patients who received their anthracycline regimen every 2 weeks rather than every 3, and node-negative patients.

The benefit was particular pronounced among patients with less than 10% ER positivity, she pointed out.

Adverse events in the neoadjuvant phase were primarily related to chemotherapy, with no major differences between the arms, although grade 3 or greater events were slightly more frequent with pembrolizumab (52.5% vs. 46.4%), and two patients in the pembrolizumab arm died (one death was from acute myocardial infarction considered related to the long QT syndrome; cause of the other patient’s death was not specified).

Adverse events leading to discontinuation were also more common with pembrolizumab (19.1% vs. 10.1%, respectively).

Immune-mediated adverse events of any grade were also higher in the immunotherapy arm, occurring in 32.8% of patients vs. 7% of patients in the placebo arm.

There were no deaths from immune-related adverse events.

Eye on safety

In his discussion, Dr. Johnston emphasized that “it’s important in a curative population that we don’t harm patients in a setting where we have a variety of other therapies available.”

Recalling the deaths of patients in the immunotherapy arm of each trial, he commented that “deaths in early breast cancer in a treatment setting are always a disaster, and we have to make sure that we manage these adverse events as we can best, and we know how to do that now.”

Checkmate 7FL was supported by Bristol Myers Squibb. Dr. Loi reported financial and nonfinancial interests with BMS and with other companies. KEYNOTE-756 was supported by Merck Sharp & Dohme. Dr. Cardoso disclosed consulting and institutional research support from Merck and others. Dr. Johnston reported consulting or advisory roles, honoraria, and research funding from several companies, not including either BMS or Merck.

Further evidence for the benefit of adding immune checkpoint inhibitors to neoadjuvant chemotherapy in patients with early high-risk estrogen receptor–positive, HER2-negative (HR+/HER2–) breast cancer comes from results of two randomized trials presented at the annual meeting of the European Society for Medical Oncology.

In the KEYNOTE-756 trial, adding pembrolizumab (Keytruda) to neoadjuvant chemotherapy resulted in an 8.5% increase in pathologic complete response (pCR) rates, compared with chemotherapy alone, regardless of the patients’ programmed death ligand-1 (PD-L1) status, reported Fatima Cardoso, MD, director of the breast unit at the Champalimaud Clinical Center in Lisbon.

In the Checkmate 7FL trial, a study bedeviled by unexpected circumstances, the addition of nivolumab (Opdivo) to neoadjuvant chemotherapy resulted in a 10.5% absolute increase in pCR rates, compared with chemotherapy alone, reported Sherene Loi, MBBS, PhD, from the Peter MacCallum Cancer Centre in Melbourne.

A new paradigm?

Taken together, the trials suggest that neoadjuvant immunotherapy has the potential to be “a new paradigm,” said ESMO invited discussant Steven RD Johnston, MD, PhD, professor of breast cancer medicine at the Royal Marsden Hospital and Institute of Cancer Research in London.

“Is the management of ER-positive breast cancer going to change with immunotherapy? Can we improve pCR rates? Yes, we can. We’ve seen a significant improvement in two separate studies, albeit the rates are only at 24%, and at this point, it’s unclear if this will translate into a better event-free survival [EFS] because we have to wait and follow the data,” he said.

The data from the two studies suggest that the patients who are likely to benefit most would be those with higher-grade tumors, luminal B subtype tumors, and, possibly, those whose tumors express higher levels of PD-L1, although the definition of PD-L1 positive depends on the assay used, he said

“I think we have to make better efforts to evaluate whether genomic or immune signatures can further define those who have most to gain, and I would urge investigators in both studies to do more digging into understanding this, because you might really enrich the patients who have the most to gain from the is approach,” Dr. Johnston said.

Checkmate 7FL details

In this prospective, randomized multicenter trial patients received four cycles of neoadjuvant paclitaxel followed by four cycles of doxorubicin and cyclophosphamide (AC) and surgery with adjuvant endocrine therapy. In arm A, 257 patients received neoadjuvant and adjuvant nivolumab. In arm B 253, patients received a nivolumab placebo in both the neoadjuvant and adjuvant settings.

Eligible patients had newly diagnosed ER+/HER2– breast cancer centrally confirmed. Patients with T1c or T2 tumors who were clinically node positive on histology and those with T3 or T4 tumors of any nodal status were eligible. Patients were required to have grade 3 histology as determined by the local pathologist, or grade 2 with low ER expression.

Patients were stratified by PD-L1 status, tumor grade, axillary nodal status and frequency of AC delivery (every 2 or 3 weeks) and were then randomized into one of the two treatment arms.

Destiny takes a hand

The protocol was changed following the approval in October 2021 of adjuvant abemaciclib in patients with high-risk ER+/HER2– disease.

“This was expected to result in a high rate of withdrawals due to safety concerns when combining a CDK4/6 inhibitor with an anti-PD-1, and this put the co-primary endpoint of EFS at risk,” Dr. Loi explained.

Therefore, the investigators amended the trial protocol to establish pCR as the sole primary endpoint and ceased accrual after 521 patients were randomized.

In addition, the primary efficacy population was modified to include 510 patients across 221 sites in 31 countries after Russian sites with a total of 11 patients closed due to Russia’s war on Ukraine.

And another hurdle, trial recruitment occurred from November 2019 through April 2022, during the COVID-19 pandemic.

Checkmate 7FL results

The pCR rate in the modified intention-to-treat (ITT) population was 24.5% for patients who received nivolumab, compared with 13.8% for patients who did not, translating in an odds ratio for benefit with the ICI of 2.05 (P = .0021),

In patients with PD-L1 expression in at least 1% of cells, a secondary endpoint, the respective pCR rates were 44.3% and 20.2%, with OR of 3.11, and a confidence interval indicating statistical significance.

Residual cancer burden (RCB) rates of 0 or 1 were also higher in the nivolumab-containing arm in both the modified ITT population (30.7% vs. 21.3%), and in the PD-L1–enriched population (54.5% vs. 26.2%).

In the safety population, which included 517 patients who received at least one dose of nivolumab or placebo, rates of overall adverse events and treatment-related adverse events were similar between the two arms, with the exception of two deaths from drug toxicity in Arm A (from pneumonitis in a patient 61 days after the last neoadjuvant cycles and hepatitis in a patient 51 days after) vs. no drug toxicity deaths reported in Arm B.

Safety of the nivolumab and neoadjuvant chemotherapy combinations was consistent with known safety profiles, with no new safety signals seen, Dr. Loi said.

KEYNOTE-756 details

The KEYNOTE-756 investigators had an easier time of it than Dr. Loi and colleagues. In fact, the trial “is the first fully accrued phase 3 immunotherapy study in high-risk, early-stage ER-positive, HER2-negative breast cancer, and it met one of its primary endpoints, pCR,” Dr. Cardoso said.

She noted that in the adaptive I-SPY2 trial, the addition of pembrolizumab to neoadjuvant chemotherapy resulted in a nearly threefold improvement in estimated pCR rates in patients with ER+/HER2– tumors, indicating that the role of immunotherapy in this population warranted further exploration.

In the placebo-controlled KEYNOTE-756 trial, treatment-naive patients with locally confirmed invasive ductal breast carcinoma with stage T1c or T2 tumors 2 cm or larger with nodal status CN1 or 2, or T3 and T4 tumors with nodal status CN0-2 were enrolled.

In most centers (Eastern Europe and China being the exceptions) patients were stratified by PD-L1 status, nodal status, anthracycline regimen chosen (AC or epirubicin-cyclophosphamide [EC]) and by degree of ER-positivity. Patients, 1,278 in total, were then randomly assigned to pembrolizumab for four cycles plus paclitaxel for 12 weeks, followed by AC or EC for four cycles plus pembrolizumab, or to the same regimen without pembrolizumab.

Following surgery, patients went on to endocrine therapy for up to 10 years, with or without 6 months of additional pembrolizumab every 6 months.

KEYNOTE-756 results

For the ITT analysis, 635 patients assigned to pembrolizumab and 643 assigned to placebo were evaluable.

At the first interim assessment, conducted at a median follow-up of 33.2 months, with the longest follow-up out to 51.8 months, the co-primary endpoint of an improvement in pCR with immunotherapy was met. The pCR rate with pembrolizumab was 24.3%, compared with 15.6% with placebo, an absolute difference of 8.5% (P = .00005).

Data for the other co-primary endpoint, EFS, were not mature at the time of data cutoff, and will be reported at a future date, Dr. Cardoso said.

An analysis of pCR rates in subgroups showed that pembrolizumab benefited most patients, with the exception of those 65 years and older, patients with Eastern Cooperative Oncology Group performance status of 1 (vs. 0), patients who received their anthracycline regimen every 2 weeks rather than every 3, and node-negative patients.

The benefit was particular pronounced among patients with less than 10% ER positivity, she pointed out.

Adverse events in the neoadjuvant phase were primarily related to chemotherapy, with no major differences between the arms, although grade 3 or greater events were slightly more frequent with pembrolizumab (52.5% vs. 46.4%), and two patients in the pembrolizumab arm died (one death was from acute myocardial infarction considered related to the long QT syndrome; cause of the other patient’s death was not specified).

Adverse events leading to discontinuation were also more common with pembrolizumab (19.1% vs. 10.1%, respectively).

Immune-mediated adverse events of any grade were also higher in the immunotherapy arm, occurring in 32.8% of patients vs. 7% of patients in the placebo arm.

There were no deaths from immune-related adverse events.

Eye on safety

In his discussion, Dr. Johnston emphasized that “it’s important in a curative population that we don’t harm patients in a setting where we have a variety of other therapies available.”

Recalling the deaths of patients in the immunotherapy arm of each trial, he commented that “deaths in early breast cancer in a treatment setting are always a disaster, and we have to make sure that we manage these adverse events as we can best, and we know how to do that now.”

Checkmate 7FL was supported by Bristol Myers Squibb. Dr. Loi reported financial and nonfinancial interests with BMS and with other companies. KEYNOTE-756 was supported by Merck Sharp & Dohme. Dr. Cardoso disclosed consulting and institutional research support from Merck and others. Dr. Johnston reported consulting or advisory roles, honoraria, and research funding from several companies, not including either BMS or Merck.

Adjuvant radiotherapy after radical prostatectomy provided no meaningful benefit in patients with prostate cancer but increased the risk for urinary and bowel morbidity, compared with men followed with observation alone, according to the latest results from the phase 3 RADICALS-RT trial.

The new findings showed no difference in the rate of 10-year freedom from distant metastases or overall survival in patients who received adjuvant radiotherapy vs. those who underwent observation with salvage radiotherapy if their disease progressed and provided further confirmation of earlier results reported in The Lancet in 2020.

Observation with early salvage radiotherapy in cases of biochemical failure should be the standard of care, concluded study coauthor Noel Clarke, MBBS, who presented the results at the annual meeting of the European Society for Medical Oncology.

Invited discussant and session cochair Shahneed Sandhu, MBBS, said that the findings definitively confirm the value of observation with salvage radiotherapy over adjuvant radiotherapy in this patient population.

“The approach of early salvage radiotherapy spared morbidity [from] radiation in the vast majority of patients, and further bowel and bladder toxicity is reduced in the setting of salvage radiotherapy,” said Dr. Sandhu, an associate professor and consultant medical oncologist at Peter MacCallum Cancer Centre, Victoria, Australia.

The aim of the RADICALS-RT study was to clarify the optimal timing for radiotherapy after radical prostatectomy in men with prostate cancer, which previously had been uncertain.

In the study, 697 patients were randomly assigned to adjuvant radiotherapy and 699 to observation with salvage radiotherapy. Participants had undergone radical prostatectomy; had a postoperative prostate-specific antigen (PSA) level ≤ 0.2 ng/mL; and at least one risk factor for cancer relapse, including pathologic T-stage III or IV, Gleason score of 7-10, positive margins, or preoperative PSA ≥ 10 ng/mL.

Patients in the observation arm received salvage radiotherapy if they experienced two consecutive PSA increases ≥ 0.1 ng/mL or three consecutive rises.

Overall, the investigators found similar rates of 10-year freedom from distant metastases in both arms: 93% in the adjuvant radiotherapy group vs. 90% in the observation group (hazard ratio, 0.68; P = .095). The 10-year overall survival rates were similar as well: 88% in the adjuvant radiotherapy group and 87% in the observation group (HR, 0.98; P = .92).

However, self-reported urinary and fecal incontinence rates at 1 year were significantly higher in the adjuvant radiotherapy group vs. the observation group, 60% of whom had not received salvage radiotherapy at that time.

Secondary outcome measures, including biochemical progression-free survival and time to further hormone therapy, were also similar in the treatment and observation arms.

Overall, the trial results “support the use of early salvage radiotherapy for PSA failure after radical prostatectomy rather than early adjuvant intervention, “ concluded Dr. Clarke, a professor and consultant urologist at the Christie Hospital and Salford Royal Hospital, Manchester, England.

And when biochemical recurrence does occur, Dr. Sandhu noted that prostate-specific membrane antigen PET is increasingly used in practice to help “define the extent of disease” and “tailor radiation fields.”

Dr. Clarke reported serving on advisory boards for Janssen, Astellas, and Bayer. Dr. Sandhu reported receiving research grant support and/or serving as a consultant or adviser for Advanced Accelerator Application (a Novartis company), AstraZeneca, Merck Sharp and Dohme, Roche/Genentech, Amgen, Pfizer, Merck Serono, Bristol-Myers Squibb, Novartis, Janssen, and Sehnwa.

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

Adjuvant radiotherapy after radical prostatectomy provided no meaningful benefit in patients with prostate cancer but increased the risk for urinary and bowel morbidity, compared with men followed with observation alone, according to the latest results from the phase 3 RADICALS-RT trial.

The new findings showed no difference in the rate of 10-year freedom from distant metastases or overall survival in patients who received adjuvant radiotherapy vs. those who underwent observation with salvage radiotherapy if their disease progressed and provided further confirmation of earlier results reported in The Lancet in 2020.

Observation with early salvage radiotherapy in cases of biochemical failure should be the standard of care, concluded study coauthor Noel Clarke, MBBS, who presented the results at the annual meeting of the European Society for Medical Oncology.

Invited discussant and session cochair Shahneed Sandhu, MBBS, said that the findings definitively confirm the value of observation with salvage radiotherapy over adjuvant radiotherapy in this patient population.

“The approach of early salvage radiotherapy spared morbidity [from] radiation in the vast majority of patients, and further bowel and bladder toxicity is reduced in the setting of salvage radiotherapy,” said Dr. Sandhu, an associate professor and consultant medical oncologist at Peter MacCallum Cancer Centre, Victoria, Australia.

The aim of the RADICALS-RT study was to clarify the optimal timing for radiotherapy after radical prostatectomy in men with prostate cancer, which previously had been uncertain.

In the study, 697 patients were randomly assigned to adjuvant radiotherapy and 699 to observation with salvage radiotherapy. Participants had undergone radical prostatectomy; had a postoperative prostate-specific antigen (PSA) level ≤ 0.2 ng/mL; and at least one risk factor for cancer relapse, including pathologic T-stage III or IV, Gleason score of 7-10, positive margins, or preoperative PSA ≥ 10 ng/mL.

Patients in the observation arm received salvage radiotherapy if they experienced two consecutive PSA increases ≥ 0.1 ng/mL or three consecutive rises.

Overall, the investigators found similar rates of 10-year freedom from distant metastases in both arms: 93% in the adjuvant radiotherapy group vs. 90% in the observation group (hazard ratio, 0.68; P = .095). The 10-year overall survival rates were similar as well: 88% in the adjuvant radiotherapy group and 87% in the observation group (HR, 0.98; P = .92).

However, self-reported urinary and fecal incontinence rates at 1 year were significantly higher in the adjuvant radiotherapy group vs. the observation group, 60% of whom had not received salvage radiotherapy at that time.

Secondary outcome measures, including biochemical progression-free survival and time to further hormone therapy, were also similar in the treatment and observation arms.

Overall, the trial results “support the use of early salvage radiotherapy for PSA failure after radical prostatectomy rather than early adjuvant intervention, “ concluded Dr. Clarke, a professor and consultant urologist at the Christie Hospital and Salford Royal Hospital, Manchester, England.

And when biochemical recurrence does occur, Dr. Sandhu noted that prostate-specific membrane antigen PET is increasingly used in practice to help “define the extent of disease” and “tailor radiation fields.”

Dr. Clarke reported serving on advisory boards for Janssen, Astellas, and Bayer. Dr. Sandhu reported receiving research grant support and/or serving as a consultant or adviser for Advanced Accelerator Application (a Novartis company), AstraZeneca, Merck Sharp and Dohme, Roche/Genentech, Amgen, Pfizer, Merck Serono, Bristol-Myers Squibb, Novartis, Janssen, and Sehnwa.

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

Adjuvant radiotherapy after radical prostatectomy provided no meaningful benefit in patients with prostate cancer but increased the risk for urinary and bowel morbidity, compared with men followed with observation alone, according to the latest results from the phase 3 RADICALS-RT trial.

The new findings showed no difference in the rate of 10-year freedom from distant metastases or overall survival in patients who received adjuvant radiotherapy vs. those who underwent observation with salvage radiotherapy if their disease progressed and provided further confirmation of earlier results reported in The Lancet in 2020.

Observation with early salvage radiotherapy in cases of biochemical failure should be the standard of care, concluded study coauthor Noel Clarke, MBBS, who presented the results at the annual meeting of the European Society for Medical Oncology.

Invited discussant and session cochair Shahneed Sandhu, MBBS, said that the findings definitively confirm the value of observation with salvage radiotherapy over adjuvant radiotherapy in this patient population.

“The approach of early salvage radiotherapy spared morbidity [from] radiation in the vast majority of patients, and further bowel and bladder toxicity is reduced in the setting of salvage radiotherapy,” said Dr. Sandhu, an associate professor and consultant medical oncologist at Peter MacCallum Cancer Centre, Victoria, Australia.

The aim of the RADICALS-RT study was to clarify the optimal timing for radiotherapy after radical prostatectomy in men with prostate cancer, which previously had been uncertain.

In the study, 697 patients were randomly assigned to adjuvant radiotherapy and 699 to observation with salvage radiotherapy. Participants had undergone radical prostatectomy; had a postoperative prostate-specific antigen (PSA) level ≤ 0.2 ng/mL; and at least one risk factor for cancer relapse, including pathologic T-stage III or IV, Gleason score of 7-10, positive margins, or preoperative PSA ≥ 10 ng/mL.

Patients in the observation arm received salvage radiotherapy if they experienced two consecutive PSA increases ≥ 0.1 ng/mL or three consecutive rises.

Overall, the investigators found similar rates of 10-year freedom from distant metastases in both arms: 93% in the adjuvant radiotherapy group vs. 90% in the observation group (hazard ratio, 0.68; P = .095). The 10-year overall survival rates were similar as well: 88% in the adjuvant radiotherapy group and 87% in the observation group (HR, 0.98; P = .92).

However, self-reported urinary and fecal incontinence rates at 1 year were significantly higher in the adjuvant radiotherapy group vs. the observation group, 60% of whom had not received salvage radiotherapy at that time.

Secondary outcome measures, including biochemical progression-free survival and time to further hormone therapy, were also similar in the treatment and observation arms.

Overall, the trial results “support the use of early salvage radiotherapy for PSA failure after radical prostatectomy rather than early adjuvant intervention, “ concluded Dr. Clarke, a professor and consultant urologist at the Christie Hospital and Salford Royal Hospital, Manchester, England.

And when biochemical recurrence does occur, Dr. Sandhu noted that prostate-specific membrane antigen PET is increasingly used in practice to help “define the extent of disease” and “tailor radiation fields.”

Dr. Clarke reported serving on advisory boards for Janssen, Astellas, and Bayer. Dr. Sandhu reported receiving research grant support and/or serving as a consultant or adviser for Advanced Accelerator Application (a Novartis company), AstraZeneca, Merck Sharp and Dohme, Roche/Genentech, Amgen, Pfizer, Merck Serono, Bristol-Myers Squibb, Novartis, Janssen, and Sehnwa.

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