TBD Meeting (4748-22)

PARIS – What do doctors know about their patients’ sexual health? Not a lot. What about oncologists who treat women with breast cancer? Not much more. Yet sexual dysfunction has a significant impact on the quality of life of patients during and after cancer.

To determine the extent of sexual dysfunction among women with breast cancer, Maria Alice Franzoi, MD, an oncologist at Gustave Roussy Hospital, Villejuif, France, analyzed data concerning sexuality from the CANTO cohort study. She showed that sexual dysfunction often predates the cancer diagnosis and doesn’t improve but rather worsens in the following 2 years. She presented her results at the annual meeting of the European Society for Medical Oncology.
 

Present at diagnosis

Dr. Franzoi, whose research projects have focused on patient monitoring post cancer, drew her conclusions from the data provided by CANTO, a longitudinal, prospective cohort study that monitors women being treated for localized breast cancer. Study participants answered the EORTC-QLQ-BR23 quality-of-life questionnaire at the time of diagnosis (T0), 1 year after diagnosis (T1), and 2 years after diagnosis (T2). Four factors were employed to better define women’s sex-related problems: poor body image, poor sexual functioning (activity and desire), lack of sexual pleasure, and a complete lack of sexual activity.

The analysis focused on the responses of 7,895 patients in the CANTO cohort study on sexual activity; 4,523 of those patients answered questions about sexual pleasure. Female respondents who reported engaging in no sexual activity did not have to answer the questions in this second section.

“Seventy-five percent of patients reported at least one of the four concerns during the study,” noted Dr. Franzoi during her presentation. This finding highlights the fact that “sexual problems are already present at the time of diagnosis in a considerable number of patients,” she said. More than a third of participants complained of at least one of the four items.
 

Developments after diagnosis

The proportion of women who reported no arousal or poor sexual function remained stable at around 30% over time, meaning that the sexual problems were reported in similar numbers at T0, T1, and T2. “However, after cancer, more patients are worried about a lack of sexual pleasure (38.7% at T1 and 38.1% at T2, vs. 29.1% at T0) or report having a negative body image (57.8% at T1 and 52.5% at T2, vs. 32.1% at T0),” said Dr. Franzoi.

She identified the following three variables as being associated with sexual dysfunction 2 years after diagnosis: the existence of this problem at the time of diagnosis, the use of adjuvant hormone therapy, and severe depression or a very high stress level after the first year of treatment.
 

Inadequate specific treatment

“Sexual dysfunction is a major unmet need with a significant impact on quality of life,” said Maryam Lustberg, MD, an oncologist at Yale School of Medicine, New Haven, Conn., who was invited to discuss the results at the conference.

Dr. Franzoi observed that most participants with sexual dysfunction that had continued 2 years after diagnosis had not been referred to a doctor for this problem. “In terms of sexual function, it’s better at T2 than at T1, but only 41% of these women have been seen by a gynecologist, and only 15% have received specific treatment,” she reported, emphasizing the need to assess and treat these issues “proactively” at the time of diagnosis and during and after treatment.

“Now we need to work out what the best treatment approach is,” commented Dr. Lustberg. She said that cancers other than breast and gynecologic cancers should also be taken into consideration. She cited the Sexual Health Assessment in Women With Lung Cancer study, which recently revealed that after being diagnosed with lung cancer, female patients experienced a drop in sexual desire (31% vs. 15% before diagnosis) and an increase in vaginal discomfort or dryness (43% vs. 13% before diagnosis). This study, presented in August to the 2022 International Association for the Study of Lung Cancer World Conference on Lung Cancer, also revealed that different parameters affect satisfaction in one’s sex life, including fatigue, sadness, relationship problems with a partner, and even breathing. Dr. Lustberg concluded from this study that a multidisciplinary approach is needed for cancer survivors.

Dr. Franzoi received research funding from Resilience Care. Dr. Lustberg has links with AstraZeneca, Pfizer, Novartis, Sanofi, and Lilly.

This article was translated from the Medscape French edition.

PARIS – What do doctors know about their patients’ sexual health? Not a lot. What about oncologists who treat women with breast cancer? Not much more. Yet sexual dysfunction has a significant impact on the quality of life of patients during and after cancer.

To determine the extent of sexual dysfunction among women with breast cancer, Maria Alice Franzoi, MD, an oncologist at Gustave Roussy Hospital, Villejuif, France, analyzed data concerning sexuality from the CANTO cohort study. She showed that sexual dysfunction often predates the cancer diagnosis and doesn’t improve but rather worsens in the following 2 years. She presented her results at the annual meeting of the European Society for Medical Oncology.
 

Present at diagnosis

Dr. Franzoi, whose research projects have focused on patient monitoring post cancer, drew her conclusions from the data provided by CANTO, a longitudinal, prospective cohort study that monitors women being treated for localized breast cancer. Study participants answered the EORTC-QLQ-BR23 quality-of-life questionnaire at the time of diagnosis (T0), 1 year after diagnosis (T1), and 2 years after diagnosis (T2). Four factors were employed to better define women’s sex-related problems: poor body image, poor sexual functioning (activity and desire), lack of sexual pleasure, and a complete lack of sexual activity.

The analysis focused on the responses of 7,895 patients in the CANTO cohort study on sexual activity; 4,523 of those patients answered questions about sexual pleasure. Female respondents who reported engaging in no sexual activity did not have to answer the questions in this second section.

“Seventy-five percent of patients reported at least one of the four concerns during the study,” noted Dr. Franzoi during her presentation. This finding highlights the fact that “sexual problems are already present at the time of diagnosis in a considerable number of patients,” she said. More than a third of participants complained of at least one of the four items.
 

Developments after diagnosis

The proportion of women who reported no arousal or poor sexual function remained stable at around 30% over time, meaning that the sexual problems were reported in similar numbers at T0, T1, and T2. “However, after cancer, more patients are worried about a lack of sexual pleasure (38.7% at T1 and 38.1% at T2, vs. 29.1% at T0) or report having a negative body image (57.8% at T1 and 52.5% at T2, vs. 32.1% at T0),” said Dr. Franzoi.

She identified the following three variables as being associated with sexual dysfunction 2 years after diagnosis: the existence of this problem at the time of diagnosis, the use of adjuvant hormone therapy, and severe depression or a very high stress level after the first year of treatment.
 

Inadequate specific treatment

“Sexual dysfunction is a major unmet need with a significant impact on quality of life,” said Maryam Lustberg, MD, an oncologist at Yale School of Medicine, New Haven, Conn., who was invited to discuss the results at the conference.

Dr. Franzoi observed that most participants with sexual dysfunction that had continued 2 years after diagnosis had not been referred to a doctor for this problem. “In terms of sexual function, it’s better at T2 than at T1, but only 41% of these women have been seen by a gynecologist, and only 15% have received specific treatment,” she reported, emphasizing the need to assess and treat these issues “proactively” at the time of diagnosis and during and after treatment.

“Now we need to work out what the best treatment approach is,” commented Dr. Lustberg. She said that cancers other than breast and gynecologic cancers should also be taken into consideration. She cited the Sexual Health Assessment in Women With Lung Cancer study, which recently revealed that after being diagnosed with lung cancer, female patients experienced a drop in sexual desire (31% vs. 15% before diagnosis) and an increase in vaginal discomfort or dryness (43% vs. 13% before diagnosis). This study, presented in August to the 2022 International Association for the Study of Lung Cancer World Conference on Lung Cancer, also revealed that different parameters affect satisfaction in one’s sex life, including fatigue, sadness, relationship problems with a partner, and even breathing. Dr. Lustberg concluded from this study that a multidisciplinary approach is needed for cancer survivors.

Dr. Franzoi received research funding from Resilience Care. Dr. Lustberg has links with AstraZeneca, Pfizer, Novartis, Sanofi, and Lilly.

This article was translated from the Medscape French edition.

PARIS – What do doctors know about their patients’ sexual health? Not a lot. What about oncologists who treat women with breast cancer? Not much more. Yet sexual dysfunction has a significant impact on the quality of life of patients during and after cancer.

To determine the extent of sexual dysfunction among women with breast cancer, Maria Alice Franzoi, MD, an oncologist at Gustave Roussy Hospital, Villejuif, France, analyzed data concerning sexuality from the CANTO cohort study. She showed that sexual dysfunction often predates the cancer diagnosis and doesn’t improve but rather worsens in the following 2 years. She presented her results at the annual meeting of the European Society for Medical Oncology.
 

Present at diagnosis

Dr. Franzoi, whose research projects have focused on patient monitoring post cancer, drew her conclusions from the data provided by CANTO, a longitudinal, prospective cohort study that monitors women being treated for localized breast cancer. Study participants answered the EORTC-QLQ-BR23 quality-of-life questionnaire at the time of diagnosis (T0), 1 year after diagnosis (T1), and 2 years after diagnosis (T2). Four factors were employed to better define women’s sex-related problems: poor body image, poor sexual functioning (activity and desire), lack of sexual pleasure, and a complete lack of sexual activity.

The analysis focused on the responses of 7,895 patients in the CANTO cohort study on sexual activity; 4,523 of those patients answered questions about sexual pleasure. Female respondents who reported engaging in no sexual activity did not have to answer the questions in this second section.

“Seventy-five percent of patients reported at least one of the four concerns during the study,” noted Dr. Franzoi during her presentation. This finding highlights the fact that “sexual problems are already present at the time of diagnosis in a considerable number of patients,” she said. More than a third of participants complained of at least one of the four items.
 

Developments after diagnosis

The proportion of women who reported no arousal or poor sexual function remained stable at around 30% over time, meaning that the sexual problems were reported in similar numbers at T0, T1, and T2. “However, after cancer, more patients are worried about a lack of sexual pleasure (38.7% at T1 and 38.1% at T2, vs. 29.1% at T0) or report having a negative body image (57.8% at T1 and 52.5% at T2, vs. 32.1% at T0),” said Dr. Franzoi.

She identified the following three variables as being associated with sexual dysfunction 2 years after diagnosis: the existence of this problem at the time of diagnosis, the use of adjuvant hormone therapy, and severe depression or a very high stress level after the first year of treatment.
 

Inadequate specific treatment

“Sexual dysfunction is a major unmet need with a significant impact on quality of life,” said Maryam Lustberg, MD, an oncologist at Yale School of Medicine, New Haven, Conn., who was invited to discuss the results at the conference.

Dr. Franzoi observed that most participants with sexual dysfunction that had continued 2 years after diagnosis had not been referred to a doctor for this problem. “In terms of sexual function, it’s better at T2 than at T1, but only 41% of these women have been seen by a gynecologist, and only 15% have received specific treatment,” she reported, emphasizing the need to assess and treat these issues “proactively” at the time of diagnosis and during and after treatment.

“Now we need to work out what the best treatment approach is,” commented Dr. Lustberg. She said that cancers other than breast and gynecologic cancers should also be taken into consideration. She cited the Sexual Health Assessment in Women With Lung Cancer study, which recently revealed that after being diagnosed with lung cancer, female patients experienced a drop in sexual desire (31% vs. 15% before diagnosis) and an increase in vaginal discomfort or dryness (43% vs. 13% before diagnosis). This study, presented in August to the 2022 International Association for the Study of Lung Cancer World Conference on Lung Cancer, also revealed that different parameters affect satisfaction in one’s sex life, including fatigue, sadness, relationship problems with a partner, and even breathing. Dr. Lustberg concluded from this study that a multidisciplinary approach is needed for cancer survivors.

Dr. Franzoi received research funding from Resilience Care. Dr. Lustberg has links with AstraZeneca, Pfizer, Novartis, Sanofi, and Lilly.

This article was translated from the Medscape French edition.

This transcript has been edited for clarity.

John Whyte, MD: Welcome, everyone. I’m Dr John Whyte. I’m the chief medical officer at WebMD, and I’m joined today by Fabrice André. He is the chair of the scientific committee at the European Society for Medical Oncology, where we are today in Paris, France. Bonjour, Fabrice.

So, remind our viewers: What is ESMO? What does it do? And why is it so important?

Fabrice André, MD, PhD: First ESMO, is a scientific society – a member-based organization with around 25,000 members.

Dr. Whyte: Equivalent to ASCO (American Society of Clinical Oncology) in the United States, correct?

Dr. André: It has members worldwide, from all over the world. And it aims at disseminating science, educating. The name is European, so it has some roots in Europe; but it is really a global organization for education, dissemination, and also more and more to generate frameworks for the standards of treatment and the common terminology for healthcare professionals to better care for patients.

Dr. Whyte: What are you most excited by at this conference in terms of the innovations that are being discussed?

Dr. André: Today we are at ESMO 2022 in Paris, with 28,000 people registered and the vast majority on site, and what has been the editorial line – the tagline – for the scientific committee is “understand the disease to better treat the patient.” This is extremely important; all of the educational program is built on this tagline, meaning that we need to understand what are the mechanisms of cancer progression? What are the determinants of outcomes if we want to integrate all the wealth of innovation that is coming?

So, then, what are the new things? In the Presidential Symposium, where we usually have the very new things, we will have very important presentations on the role of pollution on cancer and the biological mechanism that induces cancer. Why is it important? First, it has impact on public health. But also, it’s important because, for us, it’s raising the signal that the oncology community must start to invest in this field of prevention.

Dr. Whyte: I was at your booth, by the way, the ESMO booth here, and you have two bicycles, which impressed me. Nobody was on them, I might point out, but the focus was on prevention. But let’s also address how historically, the academic community, the scientific community hasn’t really been focused on prevention. It’s about treatment. So it’s fascinating that you’re talking about prevention, because usually we talk about precision medicine, right? We talk about checkpoint inhibitors; we talk about immunomodulators. And here you’re saying, “Hey, John, we need to understand how we prevent cancer,” which is really a misnomer in a way, because there are many different diseases. Would you agree with that?

Dr. André: I fully agree with you. But what is the premise we are trying to address here? The premise is that prevention has always been very low in the agenda of international conferences. And we think we want to give the signal that it’s really time now that clinical infrastructure, hospitals, invest in this field, create teams dedicated to prevention, new structures for prevention. Why? Because we are discovering step by step that it could be that some drugs we use for patients with cancer could also be developed in the field of prevention. And for this, we need the oncologists. So, more and more, our conviction is that it is the oncology community that will transform the field of prevention, and we need to invest now. Having said that, we have two very important abstracts on this question. The other one is about early cancer detection. But of course, we have our traditional session on immunotherapeutics, precision medicine, and all the wealth of randomized trials. And so in this field, for patients with cancer, what is the new information?

Dr. Whyte: We have this whole continuum. So you talk about prevention – how much cancer is preventable? Eighty percent? Seventy percent? What do you estimate?

Dr. André: You know, I’m also a scientist. So as a scientist, I will say that there is no limit for this question. No, the only limit is the knowledge.

Dr. Whyte: Well, there is some inherited mutation, so we do know that.

Dr. André: We can just go to the current status – what we know now – but I don’t see why we would put some limit on how much we can prevent cancer. But indeed, so far, what are the risk factors? Genetics, hereditary cancer, all habits, and we know them. It’s about tobacco, alcohol, sun, some sexual behavior, etc., that indeed account. In France, we say that around 40% of cancer could be preventable.

Dr. Whyte: More and more, we learn about the issues of gout, other inflammatory diseases; it can have an association, but then we have early screening as well. So, if we’re on this continuum, how excited are you by what’s happening with liquid biopsies, with other testing? Because if we can get a cancer instead of at 500,000 cells at the time of imaging, at 10 or 50 cells, while there are fragments, that’s revolutionary, isn’t it?

Dr. André: I fully agree with you. We will have an important trial presented during ESMO that is the first prospective trial testing the device called Galleri, a tool for early cancer detection based on ctDNA (circulating tumor DNA) analysis by methylation pattern.

Dr. Whyte: General screening of the population or a more tailored population with certain indications? Because right now, most of those have focused on a limited population or are used for patients who already have a cancer, and testing that way – you think it’s going to be broader?

Dr. André: What this trial is investigating is in participants who do not have cancer, 6,000 participants ...

Dr. Whyte: Pas de tout? No cancer at all?

Dr. André: No cancer.

Dr. Whyte: No family history?

Dr. André: They can have family history, but no detectable cancer – can ctDNA analysis detect cancer? And the answer is, indeed, there is around 1% positivity, and around 40% of them, indeed, had cancer. So why is it important? Because it’s really a landmark prospective trial that is telling us that a device based on ctDNA can detect cancer at early stage. Then, how many cancers? What percentage?

Dr. Whyte: Which type of cancer?

Dr. André: And is it going to have an impact on outcome? And for all the questions, we don’t have the answer here. But the answer we have here today is that with this device, done prospectively, you can detect some cancer that would not be detectable without symptoms.

Dr. Whyte: It’s only going to get better, too.

Dr. André: Yeah. So then the next step is improving technology, integrating this technology with other ones we already have, in order to increase the percentage of patients in which we detect cancer at an earlier stage.

Dr. Whyte: What about pancreatic cancer, cancers we can’t detect through screening? People forget that most cancers cannot be detected through screening, so we need better tools. We do know that there are inherited mutations. Those really aren’t preventable in many ways; the goal is to get them early. So then we move to treatments, and you talked about precision medicine. What excites you about what’s going on these days at ESMO right now.

Dr. André: We have many trials on precision medicine. We will have two randomized trials that investigate two new targets; one is gamma secretase inhibitor. So, it’s a first-in-class, first time we even hear about this target at a clinical conference. And the second highly expected trial is a clinical trial in patients with metastatic lung cancer, KRAS mutated, testing sotorasib, which is a KRAS inhibitor, and showing the magnitude of improvement associated with sotorasib. The trial is positive, and it improved PFS [progression-free survival] in these patients. So these are two new targets that are validated at this conference.

Then, if we go on another topic of genomics, there is a question that is extremely important: Can we define patients who present an outlier sensitivity to immunotherapeutics? There will be one trial presented in the Presidential Symposium of immunotherapeutics in patients with colon cancer and microsatellite instability (MSI), showing that a few weeks of immunotherapeutics followed by surgery can cure patients. Why is it important? It’s important because we are all facing a shortage in the healthcare workforce. We have fewer nurses, fewer doctors, and we all have issues of sustainability. So, really now is the time to think about precision medicine, how precision medicine, by identifying outlier responders, can decrease the amount of resources we need to cure a patient. And this trial on immunotherapeutics, guided by genomics, is exactly this point: 8 weeks of treatment to cure a patient.

Dr. Whyte: Do you think there’s going to be a cure for cancer 10 years from now?

Dr. André: What I’m convinced of is that, in the 10 years that are coming, we are going step by step; we’re going to continue to increase the life expectancy of patients with cancer.

Dr. Whyte: And quality of life too, right?

Dr. André: Quality of life is a major issue. We had today a keynote on digital medicine and how ePRO (electronic patient-reported outcomes) can help the patient to really decrease the burden of symptoms. Quality of life is, of course, extremely important because of the very high number of patients who are cured of cancer; we need to decrease the burden of symptom in patients.

Dr. Whyte: And even though cancer rates are going down in most areas of the world, we still globally have millions of deaths from cancer every year. And sometimes people forget that, because they hear about some of the innovations. But I want to end with this: Are we investing enough in cancer care? Because let’s be honest – there are other diseases that we also need to spend time on. Cardiovascular disease is a global burden; infectious disease is a global burden. Are governments, are industries spending enough on cancer research and development?

Dr. André: Well, we can always claim for more, no? This is how everyone is trying to be, I think. But the reality is that we are living in a world where we have limited resources. I think what is more important for me is to be sure that any euro or dollar invested in cancer research is well used and generates an impact for patients. That is the most important, I think.

Dr. Whyte: And that’s why outcomes are so important in this research.

Dr. André: My conviction is that we have the tools, meaning the knowledge, the biotechnology, to really go the next step in terms of improving outcomes for patients. And for this, we now need clinical trials and translational research, but the tools, meaning basic science, basic knowledge, biotechnology – the basement for progress is here. We need now to transform this into direct impact for the patient. But I would not like to finish by saying we need more money in the field; what we need are people who can transform one euro, one dollar into concrete and measurable advances.

Dr. Whyte: We’re going to need more time on another day because I want to ask you about diversity in clinical trials, how important that is. I want to ask you about pediatric cancers; there are a whole bunch of things that I want to talk to you about. So hopefully we’ll find more time when we’re not at a big international conference such as ESMO. So, Dr Fabrice André, I want to thank you for taking time today.

Dr. André: Thank you and have a nice day.

Dr. Whyte: Stay tuned for a future discussion with Dr André on more about where we’re going in terms of cancer research and development. Thanks for watching, everyone.

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

This transcript has been edited for clarity.

John Whyte, MD: Welcome, everyone. I’m Dr John Whyte. I’m the chief medical officer at WebMD, and I’m joined today by Fabrice André. He is the chair of the scientific committee at the European Society for Medical Oncology, where we are today in Paris, France. Bonjour, Fabrice.

So, remind our viewers: What is ESMO? What does it do? And why is it so important?

Fabrice André, MD, PhD: First ESMO, is a scientific society – a member-based organization with around 25,000 members.

Dr. Whyte: Equivalent to ASCO (American Society of Clinical Oncology) in the United States, correct?

Dr. André: It has members worldwide, from all over the world. And it aims at disseminating science, educating. The name is European, so it has some roots in Europe; but it is really a global organization for education, dissemination, and also more and more to generate frameworks for the standards of treatment and the common terminology for healthcare professionals to better care for patients.

Dr. Whyte: What are you most excited by at this conference in terms of the innovations that are being discussed?

Dr. André: Today we are at ESMO 2022 in Paris, with 28,000 people registered and the vast majority on site, and what has been the editorial line – the tagline – for the scientific committee is “understand the disease to better treat the patient.” This is extremely important; all of the educational program is built on this tagline, meaning that we need to understand what are the mechanisms of cancer progression? What are the determinants of outcomes if we want to integrate all the wealth of innovation that is coming?

So, then, what are the new things? In the Presidential Symposium, where we usually have the very new things, we will have very important presentations on the role of pollution on cancer and the biological mechanism that induces cancer. Why is it important? First, it has impact on public health. But also, it’s important because, for us, it’s raising the signal that the oncology community must start to invest in this field of prevention.

Dr. Whyte: I was at your booth, by the way, the ESMO booth here, and you have two bicycles, which impressed me. Nobody was on them, I might point out, but the focus was on prevention. But let’s also address how historically, the academic community, the scientific community hasn’t really been focused on prevention. It’s about treatment. So it’s fascinating that you’re talking about prevention, because usually we talk about precision medicine, right? We talk about checkpoint inhibitors; we talk about immunomodulators. And here you’re saying, “Hey, John, we need to understand how we prevent cancer,” which is really a misnomer in a way, because there are many different diseases. Would you agree with that?

Dr. André: I fully agree with you. But what is the premise we are trying to address here? The premise is that prevention has always been very low in the agenda of international conferences. And we think we want to give the signal that it’s really time now that clinical infrastructure, hospitals, invest in this field, create teams dedicated to prevention, new structures for prevention. Why? Because we are discovering step by step that it could be that some drugs we use for patients with cancer could also be developed in the field of prevention. And for this, we need the oncologists. So, more and more, our conviction is that it is the oncology community that will transform the field of prevention, and we need to invest now. Having said that, we have two very important abstracts on this question. The other one is about early cancer detection. But of course, we have our traditional session on immunotherapeutics, precision medicine, and all the wealth of randomized trials. And so in this field, for patients with cancer, what is the new information?

Dr. Whyte: We have this whole continuum. So you talk about prevention – how much cancer is preventable? Eighty percent? Seventy percent? What do you estimate?

Dr. André: You know, I’m also a scientist. So as a scientist, I will say that there is no limit for this question. No, the only limit is the knowledge.

Dr. Whyte: Well, there is some inherited mutation, so we do know that.

Dr. André: We can just go to the current status – what we know now – but I don’t see why we would put some limit on how much we can prevent cancer. But indeed, so far, what are the risk factors? Genetics, hereditary cancer, all habits, and we know them. It’s about tobacco, alcohol, sun, some sexual behavior, etc., that indeed account. In France, we say that around 40% of cancer could be preventable.

Dr. Whyte: More and more, we learn about the issues of gout, other inflammatory diseases; it can have an association, but then we have early screening as well. So, if we’re on this continuum, how excited are you by what’s happening with liquid biopsies, with other testing? Because if we can get a cancer instead of at 500,000 cells at the time of imaging, at 10 or 50 cells, while there are fragments, that’s revolutionary, isn’t it?

Dr. André: I fully agree with you. We will have an important trial presented during ESMO that is the first prospective trial testing the device called Galleri, a tool for early cancer detection based on ctDNA (circulating tumor DNA) analysis by methylation pattern.

Dr. Whyte: General screening of the population or a more tailored population with certain indications? Because right now, most of those have focused on a limited population or are used for patients who already have a cancer, and testing that way – you think it’s going to be broader?

Dr. André: What this trial is investigating is in participants who do not have cancer, 6,000 participants ...

Dr. Whyte: Pas de tout? No cancer at all?

Dr. André: No cancer.

Dr. Whyte: No family history?

Dr. André: They can have family history, but no detectable cancer – can ctDNA analysis detect cancer? And the answer is, indeed, there is around 1% positivity, and around 40% of them, indeed, had cancer. So why is it important? Because it’s really a landmark prospective trial that is telling us that a device based on ctDNA can detect cancer at early stage. Then, how many cancers? What percentage?

Dr. Whyte: Which type of cancer?

Dr. André: And is it going to have an impact on outcome? And for all the questions, we don’t have the answer here. But the answer we have here today is that with this device, done prospectively, you can detect some cancer that would not be detectable without symptoms.

Dr. Whyte: It’s only going to get better, too.

Dr. André: Yeah. So then the next step is improving technology, integrating this technology with other ones we already have, in order to increase the percentage of patients in which we detect cancer at an earlier stage.

Dr. Whyte: What about pancreatic cancer, cancers we can’t detect through screening? People forget that most cancers cannot be detected through screening, so we need better tools. We do know that there are inherited mutations. Those really aren’t preventable in many ways; the goal is to get them early. So then we move to treatments, and you talked about precision medicine. What excites you about what’s going on these days at ESMO right now.

Dr. André: We have many trials on precision medicine. We will have two randomized trials that investigate two new targets; one is gamma secretase inhibitor. So, it’s a first-in-class, first time we even hear about this target at a clinical conference. And the second highly expected trial is a clinical trial in patients with metastatic lung cancer, KRAS mutated, testing sotorasib, which is a KRAS inhibitor, and showing the magnitude of improvement associated with sotorasib. The trial is positive, and it improved PFS [progression-free survival] in these patients. So these are two new targets that are validated at this conference.

Then, if we go on another topic of genomics, there is a question that is extremely important: Can we define patients who present an outlier sensitivity to immunotherapeutics? There will be one trial presented in the Presidential Symposium of immunotherapeutics in patients with colon cancer and microsatellite instability (MSI), showing that a few weeks of immunotherapeutics followed by surgery can cure patients. Why is it important? It’s important because we are all facing a shortage in the healthcare workforce. We have fewer nurses, fewer doctors, and we all have issues of sustainability. So, really now is the time to think about precision medicine, how precision medicine, by identifying outlier responders, can decrease the amount of resources we need to cure a patient. And this trial on immunotherapeutics, guided by genomics, is exactly this point: 8 weeks of treatment to cure a patient.

Dr. Whyte: Do you think there’s going to be a cure for cancer 10 years from now?

Dr. André: What I’m convinced of is that, in the 10 years that are coming, we are going step by step; we’re going to continue to increase the life expectancy of patients with cancer.

Dr. Whyte: And quality of life too, right?

Dr. André: Quality of life is a major issue. We had today a keynote on digital medicine and how ePRO (electronic patient-reported outcomes) can help the patient to really decrease the burden of symptoms. Quality of life is, of course, extremely important because of the very high number of patients who are cured of cancer; we need to decrease the burden of symptom in patients.

Dr. Whyte: And even though cancer rates are going down in most areas of the world, we still globally have millions of deaths from cancer every year. And sometimes people forget that, because they hear about some of the innovations. But I want to end with this: Are we investing enough in cancer care? Because let’s be honest – there are other diseases that we also need to spend time on. Cardiovascular disease is a global burden; infectious disease is a global burden. Are governments, are industries spending enough on cancer research and development?

Dr. André: Well, we can always claim for more, no? This is how everyone is trying to be, I think. But the reality is that we are living in a world where we have limited resources. I think what is more important for me is to be sure that any euro or dollar invested in cancer research is well used and generates an impact for patients. That is the most important, I think.

Dr. Whyte: And that’s why outcomes are so important in this research.

Dr. André: My conviction is that we have the tools, meaning the knowledge, the biotechnology, to really go the next step in terms of improving outcomes for patients. And for this, we now need clinical trials and translational research, but the tools, meaning basic science, basic knowledge, biotechnology – the basement for progress is here. We need now to transform this into direct impact for the patient. But I would not like to finish by saying we need more money in the field; what we need are people who can transform one euro, one dollar into concrete and measurable advances.

Dr. Whyte: We’re going to need more time on another day because I want to ask you about diversity in clinical trials, how important that is. I want to ask you about pediatric cancers; there are a whole bunch of things that I want to talk to you about. So hopefully we’ll find more time when we’re not at a big international conference such as ESMO. So, Dr Fabrice André, I want to thank you for taking time today.

Dr. André: Thank you and have a nice day.

Dr. Whyte: Stay tuned for a future discussion with Dr André on more about where we’re going in terms of cancer research and development. Thanks for watching, everyone.

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

This transcript has been edited for clarity.

John Whyte, MD: Welcome, everyone. I’m Dr John Whyte. I’m the chief medical officer at WebMD, and I’m joined today by Fabrice André. He is the chair of the scientific committee at the European Society for Medical Oncology, where we are today in Paris, France. Bonjour, Fabrice.

So, remind our viewers: What is ESMO? What does it do? And why is it so important?

Fabrice André, MD, PhD: First ESMO, is a scientific society – a member-based organization with around 25,000 members.

Dr. Whyte: Equivalent to ASCO (American Society of Clinical Oncology) in the United States, correct?

Dr. André: It has members worldwide, from all over the world. And it aims at disseminating science, educating. The name is European, so it has some roots in Europe; but it is really a global organization for education, dissemination, and also more and more to generate frameworks for the standards of treatment and the common terminology for healthcare professionals to better care for patients.

Dr. Whyte: What are you most excited by at this conference in terms of the innovations that are being discussed?

Dr. André: Today we are at ESMO 2022 in Paris, with 28,000 people registered and the vast majority on site, and what has been the editorial line – the tagline – for the scientific committee is “understand the disease to better treat the patient.” This is extremely important; all of the educational program is built on this tagline, meaning that we need to understand what are the mechanisms of cancer progression? What are the determinants of outcomes if we want to integrate all the wealth of innovation that is coming?

So, then, what are the new things? In the Presidential Symposium, where we usually have the very new things, we will have very important presentations on the role of pollution on cancer and the biological mechanism that induces cancer. Why is it important? First, it has impact on public health. But also, it’s important because, for us, it’s raising the signal that the oncology community must start to invest in this field of prevention.

Dr. Whyte: I was at your booth, by the way, the ESMO booth here, and you have two bicycles, which impressed me. Nobody was on them, I might point out, but the focus was on prevention. But let’s also address how historically, the academic community, the scientific community hasn’t really been focused on prevention. It’s about treatment. So it’s fascinating that you’re talking about prevention, because usually we talk about precision medicine, right? We talk about checkpoint inhibitors; we talk about immunomodulators. And here you’re saying, “Hey, John, we need to understand how we prevent cancer,” which is really a misnomer in a way, because there are many different diseases. Would you agree with that?

Dr. André: I fully agree with you. But what is the premise we are trying to address here? The premise is that prevention has always been very low in the agenda of international conferences. And we think we want to give the signal that it’s really time now that clinical infrastructure, hospitals, invest in this field, create teams dedicated to prevention, new structures for prevention. Why? Because we are discovering step by step that it could be that some drugs we use for patients with cancer could also be developed in the field of prevention. And for this, we need the oncologists. So, more and more, our conviction is that it is the oncology community that will transform the field of prevention, and we need to invest now. Having said that, we have two very important abstracts on this question. The other one is about early cancer detection. But of course, we have our traditional session on immunotherapeutics, precision medicine, and all the wealth of randomized trials. And so in this field, for patients with cancer, what is the new information?

Dr. Whyte: We have this whole continuum. So you talk about prevention – how much cancer is preventable? Eighty percent? Seventy percent? What do you estimate?

Dr. André: You know, I’m also a scientist. So as a scientist, I will say that there is no limit for this question. No, the only limit is the knowledge.

Dr. Whyte: Well, there is some inherited mutation, so we do know that.

Dr. André: We can just go to the current status – what we know now – but I don’t see why we would put some limit on how much we can prevent cancer. But indeed, so far, what are the risk factors? Genetics, hereditary cancer, all habits, and we know them. It’s about tobacco, alcohol, sun, some sexual behavior, etc., that indeed account. In France, we say that around 40% of cancer could be preventable.

Dr. Whyte: More and more, we learn about the issues of gout, other inflammatory diseases; it can have an association, but then we have early screening as well. So, if we’re on this continuum, how excited are you by what’s happening with liquid biopsies, with other testing? Because if we can get a cancer instead of at 500,000 cells at the time of imaging, at 10 or 50 cells, while there are fragments, that’s revolutionary, isn’t it?

Dr. André: I fully agree with you. We will have an important trial presented during ESMO that is the first prospective trial testing the device called Galleri, a tool for early cancer detection based on ctDNA (circulating tumor DNA) analysis by methylation pattern.

Dr. Whyte: General screening of the population or a more tailored population with certain indications? Because right now, most of those have focused on a limited population or are used for patients who already have a cancer, and testing that way – you think it’s going to be broader?

Dr. André: What this trial is investigating is in participants who do not have cancer, 6,000 participants ...

Dr. Whyte: Pas de tout? No cancer at all?

Dr. André: No cancer.

Dr. Whyte: No family history?

Dr. André: They can have family history, but no detectable cancer – can ctDNA analysis detect cancer? And the answer is, indeed, there is around 1% positivity, and around 40% of them, indeed, had cancer. So why is it important? Because it’s really a landmark prospective trial that is telling us that a device based on ctDNA can detect cancer at early stage. Then, how many cancers? What percentage?

Dr. Whyte: Which type of cancer?

Dr. André: And is it going to have an impact on outcome? And for all the questions, we don’t have the answer here. But the answer we have here today is that with this device, done prospectively, you can detect some cancer that would not be detectable without symptoms.

Dr. Whyte: It’s only going to get better, too.

Dr. André: Yeah. So then the next step is improving technology, integrating this technology with other ones we already have, in order to increase the percentage of patients in which we detect cancer at an earlier stage.

Dr. Whyte: What about pancreatic cancer, cancers we can’t detect through screening? People forget that most cancers cannot be detected through screening, so we need better tools. We do know that there are inherited mutations. Those really aren’t preventable in many ways; the goal is to get them early. So then we move to treatments, and you talked about precision medicine. What excites you about what’s going on these days at ESMO right now.

Dr. André: We have many trials on precision medicine. We will have two randomized trials that investigate two new targets; one is gamma secretase inhibitor. So, it’s a first-in-class, first time we even hear about this target at a clinical conference. And the second highly expected trial is a clinical trial in patients with metastatic lung cancer, KRAS mutated, testing sotorasib, which is a KRAS inhibitor, and showing the magnitude of improvement associated with sotorasib. The trial is positive, and it improved PFS [progression-free survival] in these patients. So these are two new targets that are validated at this conference.

Then, if we go on another topic of genomics, there is a question that is extremely important: Can we define patients who present an outlier sensitivity to immunotherapeutics? There will be one trial presented in the Presidential Symposium of immunotherapeutics in patients with colon cancer and microsatellite instability (MSI), showing that a few weeks of immunotherapeutics followed by surgery can cure patients. Why is it important? It’s important because we are all facing a shortage in the healthcare workforce. We have fewer nurses, fewer doctors, and we all have issues of sustainability. So, really now is the time to think about precision medicine, how precision medicine, by identifying outlier responders, can decrease the amount of resources we need to cure a patient. And this trial on immunotherapeutics, guided by genomics, is exactly this point: 8 weeks of treatment to cure a patient.

Dr. Whyte: Do you think there’s going to be a cure for cancer 10 years from now?

Dr. André: What I’m convinced of is that, in the 10 years that are coming, we are going step by step; we’re going to continue to increase the life expectancy of patients with cancer.

Dr. Whyte: And quality of life too, right?

Dr. André: Quality of life is a major issue. We had today a keynote on digital medicine and how ePRO (electronic patient-reported outcomes) can help the patient to really decrease the burden of symptoms. Quality of life is, of course, extremely important because of the very high number of patients who are cured of cancer; we need to decrease the burden of symptom in patients.

Dr. Whyte: And even though cancer rates are going down in most areas of the world, we still globally have millions of deaths from cancer every year. And sometimes people forget that, because they hear about some of the innovations. But I want to end with this: Are we investing enough in cancer care? Because let’s be honest – there are other diseases that we also need to spend time on. Cardiovascular disease is a global burden; infectious disease is a global burden. Are governments, are industries spending enough on cancer research and development?

Dr. André: Well, we can always claim for more, no? This is how everyone is trying to be, I think. But the reality is that we are living in a world where we have limited resources. I think what is more important for me is to be sure that any euro or dollar invested in cancer research is well used and generates an impact for patients. That is the most important, I think.

Dr. Whyte: And that’s why outcomes are so important in this research.

Dr. André: My conviction is that we have the tools, meaning the knowledge, the biotechnology, to really go the next step in terms of improving outcomes for patients. And for this, we now need clinical trials and translational research, but the tools, meaning basic science, basic knowledge, biotechnology – the basement for progress is here. We need now to transform this into direct impact for the patient. But I would not like to finish by saying we need more money in the field; what we need are people who can transform one euro, one dollar into concrete and measurable advances.

Dr. Whyte: We’re going to need more time on another day because I want to ask you about diversity in clinical trials, how important that is. I want to ask you about pediatric cancers; there are a whole bunch of things that I want to talk to you about. So hopefully we’ll find more time when we’re not at a big international conference such as ESMO. So, Dr Fabrice André, I want to thank you for taking time today.

Dr. André: Thank you and have a nice day.

Dr. Whyte: Stay tuned for a future discussion with Dr André on more about where we’re going in terms of cancer research and development. Thanks for watching, everyone.

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

PARIS – “I thought I was as exhausted, and isolated, and neglected as I could get, and then he came home.”

Those were the words of Kate Washington, PhD, from Sacramento as she gave a moving account of the immense burden she felt as caregiver to her husband with cancer.

She was taking part in the session, “I am FINE: Frustrated * Isolated * Neglected * Emotional,” at the annual meeting of the European Society for Medical Oncology. In that session, speakers assessed the toll of cancer on patients, caregivers, nurses, and doctors.

Dr. Washington, author of “Already Toast: Caregiving and Burnout in America” (Boston: Beacon Press, 2021), explained that she cared for her husband and young family while he was “suffering through two different kinds of lymphoma and really devastating stem cell transplants.”

When her husband was first diagnosed with a rare form of lymphoma in 2015, he was placed on a watch-and-wait protocol. At that point, he seemed fine, Dr. Washington said.

A few months later, he started coughing up blood. After being rushed to the emergency department, doctors found that a slow-growing lung tumor had ruptured.

Three weeks later, he came out of the hospital with a collapsed lung – an effect of his chemotherapy, Dr. Washington said.

But that was hardly the last word. He soon experienced relapse with a “very aggressive” form of his disease, and in 2016, he underwent a stem cell transplant.

“He spent 1½ months in the hospital ... in isolation, not seeing our daughters,” Dr. Washington said. He lost his vision and developed grade 4 graft-versus-host disease, among other problems.

He was alive, just barely, Dr. Washington said.

“As you might imagine, I was pulled between the hospital and the home, taking care of our daughters, who were not seeing him during that time,” she recalled.

But every time someone asked her whether she was okay, she replied: “I am fine.”

“A total lie,” she admitted.

Dr. Washington felt frustrated, not only from the financial strain of out-of-pocket health care costs and lost earnings but also from fast evolving relationships and a feeling of being “unseen and underappreciated.”

Another jarring change: When her husband was discharged from the hospital, Dr. Washington was suddenly thrust into the role of full-time caretaker.

Her husband could not be left alone, his doctor had said. And with two young children, Dr. Washington did not know how she would manage.

The demands of being a full-time caregiver are intense. Caregivers, Dr. Washington explained, can spend 32 hours a week looking after a loved one with cancer.

Like Dr. Washington, most caregivers feel they have no choice but to take on this intense role – one for which they have little or no training or preparation. The nonstop demands leave little time for self-care and can lead to high rates of caregiver injury and illness.

Isolation often creeps in because it can be “hard to ask for help,” she said. About 30% of caregivers report having depression or anxiety, and 21% feel lonely.

“When he was very ill, I found it really difficult to connect with other people and my friends,” Dr. Washington recalled. “I didn’t feel like I could really adequately explain the kind of strain that I was under.”
 

Are patients fine?

Like caregivers, patients often say they are fine when they are not.

The toll cancer takes on patients is immense. Natacha Bolanos Fernandez, from the Lymphoma Coalition Europe, highlighted the physical, mental, and social strain that can affect patients with cancer.

The physical aspects can encompass a host of problems – fatigue, night sweats, weight loss, and the vomiting that accompanies many cancer treatments. Patients may face changes in their mobility and independence as well. The mental side of cancer can include anxiety, depression, and psychological distress, while the social aspects span changing, perhaps strained, relationships with family and friends.

Fatigue, in particular, is an underreported, underdiagnosed, and undertreated problem, Ms. Fernandez noted. According to recent survey data from the Lymphoma Coalition’s Global Patient Survey, 72% of patients reported fatigue. This problem worsened over time, with 59% reporting fatigue after their diagnosis and up to 82% among patients who experienced relapse two or more times.

Fatigue “may be getting worse rather than better over time,” Ms. Fernandez said, and many patients felt that their life had changed completely because of cancer-related fatigue.

To help patients manage, the Lymphoma Coalition has published a report on the impact of cancer-related fatigue and how to improve outcomes. Methods include greater awareness, regular screening, and interventions such as yoga or mindfulness-based cognitive therapy.
 

Are clinicians fine?

Nurses and physicians face challenges caring for patients with cancer.

Although “nurses love their jobs and are extremely committed,” the impact cancer has on a nursing career is often undervalued or “neglected,” said Lena Sharp, RN, PhD, of the Regional Cancer Centre, Stockholm-Gotland.

Burnout, in particular, remains a problem among oncologists and nurses, and it was made worse during the COVID-19 pandemic.

Fatima Cardoso, MD, explained that burnout has an impact on doctors as well as patients because it affects communication with patients and performance. Physicians can, for instance, appear detached, emotional, or tired.

Patients may then feel less inclined to tell their oncologist how they’re feeling, said Dr. Cardoso, director of the breast unit at Champalimaud Clinical Center, Lisbon.

It is important to remember to not just focus on the patient’s disease or treatment but to also ask how they are doing and what is going on in their lives.

Above all, “show that you care,” said Dr. Cardoso.

The Lymphoma Coalition Europe has relationships with Bristol-Myers Squibb, Establishment Labs, Kyowa Kirin, Novartis, Roche, Takeda. Dr. Cardoso has relationships with Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, and other companies. No other relevant financial relationships were reported.

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

PARIS – “I thought I was as exhausted, and isolated, and neglected as I could get, and then he came home.”

Those were the words of Kate Washington, PhD, from Sacramento as she gave a moving account of the immense burden she felt as caregiver to her husband with cancer.

She was taking part in the session, “I am FINE: Frustrated * Isolated * Neglected * Emotional,” at the annual meeting of the European Society for Medical Oncology. In that session, speakers assessed the toll of cancer on patients, caregivers, nurses, and doctors.

Dr. Washington, author of “Already Toast: Caregiving and Burnout in America” (Boston: Beacon Press, 2021), explained that she cared for her husband and young family while he was “suffering through two different kinds of lymphoma and really devastating stem cell transplants.”

When her husband was first diagnosed with a rare form of lymphoma in 2015, he was placed on a watch-and-wait protocol. At that point, he seemed fine, Dr. Washington said.

A few months later, he started coughing up blood. After being rushed to the emergency department, doctors found that a slow-growing lung tumor had ruptured.

Three weeks later, he came out of the hospital with a collapsed lung – an effect of his chemotherapy, Dr. Washington said.

But that was hardly the last word. He soon experienced relapse with a “very aggressive” form of his disease, and in 2016, he underwent a stem cell transplant.

“He spent 1½ months in the hospital ... in isolation, not seeing our daughters,” Dr. Washington said. He lost his vision and developed grade 4 graft-versus-host disease, among other problems.

He was alive, just barely, Dr. Washington said.

“As you might imagine, I was pulled between the hospital and the home, taking care of our daughters, who were not seeing him during that time,” she recalled.

But every time someone asked her whether she was okay, she replied: “I am fine.”

“A total lie,” she admitted.

Dr. Washington felt frustrated, not only from the financial strain of out-of-pocket health care costs and lost earnings but also from fast evolving relationships and a feeling of being “unseen and underappreciated.”

Another jarring change: When her husband was discharged from the hospital, Dr. Washington was suddenly thrust into the role of full-time caretaker.

Her husband could not be left alone, his doctor had said. And with two young children, Dr. Washington did not know how she would manage.

The demands of being a full-time caregiver are intense. Caregivers, Dr. Washington explained, can spend 32 hours a week looking after a loved one with cancer.

Like Dr. Washington, most caregivers feel they have no choice but to take on this intense role – one for which they have little or no training or preparation. The nonstop demands leave little time for self-care and can lead to high rates of caregiver injury and illness.

Isolation often creeps in because it can be “hard to ask for help,” she said. About 30% of caregivers report having depression or anxiety, and 21% feel lonely.

“When he was very ill, I found it really difficult to connect with other people and my friends,” Dr. Washington recalled. “I didn’t feel like I could really adequately explain the kind of strain that I was under.”
 

Are patients fine?

Like caregivers, patients often say they are fine when they are not.

The toll cancer takes on patients is immense. Natacha Bolanos Fernandez, from the Lymphoma Coalition Europe, highlighted the physical, mental, and social strain that can affect patients with cancer.

The physical aspects can encompass a host of problems – fatigue, night sweats, weight loss, and the vomiting that accompanies many cancer treatments. Patients may face changes in their mobility and independence as well. The mental side of cancer can include anxiety, depression, and psychological distress, while the social aspects span changing, perhaps strained, relationships with family and friends.

Fatigue, in particular, is an underreported, underdiagnosed, and undertreated problem, Ms. Fernandez noted. According to recent survey data from the Lymphoma Coalition’s Global Patient Survey, 72% of patients reported fatigue. This problem worsened over time, with 59% reporting fatigue after their diagnosis and up to 82% among patients who experienced relapse two or more times.

Fatigue “may be getting worse rather than better over time,” Ms. Fernandez said, and many patients felt that their life had changed completely because of cancer-related fatigue.

To help patients manage, the Lymphoma Coalition has published a report on the impact of cancer-related fatigue and how to improve outcomes. Methods include greater awareness, regular screening, and interventions such as yoga or mindfulness-based cognitive therapy.
 

Are clinicians fine?

Nurses and physicians face challenges caring for patients with cancer.

Although “nurses love their jobs and are extremely committed,” the impact cancer has on a nursing career is often undervalued or “neglected,” said Lena Sharp, RN, PhD, of the Regional Cancer Centre, Stockholm-Gotland.

Burnout, in particular, remains a problem among oncologists and nurses, and it was made worse during the COVID-19 pandemic.

Fatima Cardoso, MD, explained that burnout has an impact on doctors as well as patients because it affects communication with patients and performance. Physicians can, for instance, appear detached, emotional, or tired.

Patients may then feel less inclined to tell their oncologist how they’re feeling, said Dr. Cardoso, director of the breast unit at Champalimaud Clinical Center, Lisbon.

It is important to remember to not just focus on the patient’s disease or treatment but to also ask how they are doing and what is going on in their lives.

Above all, “show that you care,” said Dr. Cardoso.

The Lymphoma Coalition Europe has relationships with Bristol-Myers Squibb, Establishment Labs, Kyowa Kirin, Novartis, Roche, Takeda. Dr. Cardoso has relationships with Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, and other companies. No other relevant financial relationships were reported.

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

PARIS – “I thought I was as exhausted, and isolated, and neglected as I could get, and then he came home.”

Those were the words of Kate Washington, PhD, from Sacramento as she gave a moving account of the immense burden she felt as caregiver to her husband with cancer.

She was taking part in the session, “I am FINE: Frustrated * Isolated * Neglected * Emotional,” at the annual meeting of the European Society for Medical Oncology. In that session, speakers assessed the toll of cancer on patients, caregivers, nurses, and doctors.

Dr. Washington, author of “Already Toast: Caregiving and Burnout in America” (Boston: Beacon Press, 2021), explained that she cared for her husband and young family while he was “suffering through two different kinds of lymphoma and really devastating stem cell transplants.”

When her husband was first diagnosed with a rare form of lymphoma in 2015, he was placed on a watch-and-wait protocol. At that point, he seemed fine, Dr. Washington said.

A few months later, he started coughing up blood. After being rushed to the emergency department, doctors found that a slow-growing lung tumor had ruptured.

Three weeks later, he came out of the hospital with a collapsed lung – an effect of his chemotherapy, Dr. Washington said.

But that was hardly the last word. He soon experienced relapse with a “very aggressive” form of his disease, and in 2016, he underwent a stem cell transplant.

“He spent 1½ months in the hospital ... in isolation, not seeing our daughters,” Dr. Washington said. He lost his vision and developed grade 4 graft-versus-host disease, among other problems.

He was alive, just barely, Dr. Washington said.

“As you might imagine, I was pulled between the hospital and the home, taking care of our daughters, who were not seeing him during that time,” she recalled.

But every time someone asked her whether she was okay, she replied: “I am fine.”

“A total lie,” she admitted.

Dr. Washington felt frustrated, not only from the financial strain of out-of-pocket health care costs and lost earnings but also from fast evolving relationships and a feeling of being “unseen and underappreciated.”

Another jarring change: When her husband was discharged from the hospital, Dr. Washington was suddenly thrust into the role of full-time caretaker.

Her husband could not be left alone, his doctor had said. And with two young children, Dr. Washington did not know how she would manage.

The demands of being a full-time caregiver are intense. Caregivers, Dr. Washington explained, can spend 32 hours a week looking after a loved one with cancer.

Like Dr. Washington, most caregivers feel they have no choice but to take on this intense role – one for which they have little or no training or preparation. The nonstop demands leave little time for self-care and can lead to high rates of caregiver injury and illness.

Isolation often creeps in because it can be “hard to ask for help,” she said. About 30% of caregivers report having depression or anxiety, and 21% feel lonely.

“When he was very ill, I found it really difficult to connect with other people and my friends,” Dr. Washington recalled. “I didn’t feel like I could really adequately explain the kind of strain that I was under.”
 

Are patients fine?

Like caregivers, patients often say they are fine when they are not.

The toll cancer takes on patients is immense. Natacha Bolanos Fernandez, from the Lymphoma Coalition Europe, highlighted the physical, mental, and social strain that can affect patients with cancer.

The physical aspects can encompass a host of problems – fatigue, night sweats, weight loss, and the vomiting that accompanies many cancer treatments. Patients may face changes in their mobility and independence as well. The mental side of cancer can include anxiety, depression, and psychological distress, while the social aspects span changing, perhaps strained, relationships with family and friends.

Fatigue, in particular, is an underreported, underdiagnosed, and undertreated problem, Ms. Fernandez noted. According to recent survey data from the Lymphoma Coalition’s Global Patient Survey, 72% of patients reported fatigue. This problem worsened over time, with 59% reporting fatigue after their diagnosis and up to 82% among patients who experienced relapse two or more times.

Fatigue “may be getting worse rather than better over time,” Ms. Fernandez said, and many patients felt that their life had changed completely because of cancer-related fatigue.

To help patients manage, the Lymphoma Coalition has published a report on the impact of cancer-related fatigue and how to improve outcomes. Methods include greater awareness, regular screening, and interventions such as yoga or mindfulness-based cognitive therapy.
 

Are clinicians fine?

Nurses and physicians face challenges caring for patients with cancer.

Although “nurses love their jobs and are extremely committed,” the impact cancer has on a nursing career is often undervalued or “neglected,” said Lena Sharp, RN, PhD, of the Regional Cancer Centre, Stockholm-Gotland.

Burnout, in particular, remains a problem among oncologists and nurses, and it was made worse during the COVID-19 pandemic.

Fatima Cardoso, MD, explained that burnout has an impact on doctors as well as patients because it affects communication with patients and performance. Physicians can, for instance, appear detached, emotional, or tired.

Patients may then feel less inclined to tell their oncologist how they’re feeling, said Dr. Cardoso, director of the breast unit at Champalimaud Clinical Center, Lisbon.

It is important to remember to not just focus on the patient’s disease or treatment but to also ask how they are doing and what is going on in their lives.

Above all, “show that you care,” said Dr. Cardoso.

The Lymphoma Coalition Europe has relationships with Bristol-Myers Squibb, Establishment Labs, Kyowa Kirin, Novartis, Roche, Takeda. Dr. Cardoso has relationships with Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, and other companies. No other relevant financial relationships were reported.

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

PARIS – New disappointing results from a trial of adjuvant immunotherapy for patients with renal cell carcinoma who underwent nephrectomy contrast with those from a previous trial that showed benefit with another agent.

The new results, from CheckMate 914, show that adjuvant treatment with the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) did not improve disease-free survival (DFS), compared with placebo.

The finding was presented at the annual meeting of the European Society for Medical Oncology.

CheckMate 914 “did not meet the primary endpoint,” study presenter Robert J. Motzer, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York, said at a press conference.

The results contrast with those seen with pembrolizumab (Keytruda) in the same setting, where the drug achieved a 32% reduction in risk of recurrence or death over placebo in KEYNOTE-564. This led to the U.S. Food and Drug Administration granting approval for the drug as adjuvant treatment following surgery in patients with renal cell carcinoma at intermediate or high risk for recurrence after nephrectomy or after nephrectomy and resection of metastatic lesions.

Another trial of adjuvant immunotherapy in renal cell carcinoma, also presented at ESMO 2022, the IMmotion010 trial with adjuvant atezolizumab (Tecentriq), also did not show any clinical benefit over placebo.

However, Dr. Motzer said that despite both of these new trials showing no benefit, “I don’t think it takes away from standard of care pembrolizumab” in this setting.

There is a great need for adjuvant therapy for patients who undergo surgery, Dr. Motzer commented. The standard treatment for stage I-III localized nonmetastatic renal cell carcinoma is radical or partial nephrectomy, but there remains a “substantial risk” of relapse after surgery, occurring in up to 50% of patients.

In the past, the standard of care for these patients would be watching and waiting and “hoping that the patient doesn’t relapse,” he said, and if they did, then “we would treat accordingly for metastatic disease.”
 

Differences between trials

When asked about the contrast between the latest trial with the adjuvant nivolumab-ipilimumab combination and the earlier trial with adjuvant pembrolizumab, Dr. Motzer told this news organization that there are differences in the designs of the two studies. “Although they are both global phase 2 trials ... [there are] some differences in the patient population.”

However, the “main differences” are the duration, intensity, and tolerability of the treatment regimens. “I suspect that’s impacted on the outcome of our trial,” he said, as “many of our patients didn’t complete even that 6 months of the more toxic immunotherapy [nivolumab-ipilimumab combination].”

Dr. Motzer also noted that, compared with the metastatic setting, patients “do not tolerate therapy as well” in the adjuvant setting. Consequently, the risk-benefit of a drug is “slightly different ... as we have to be much more concerned about toxicity.”

In addition, he said, “our trial also used these kind-of gross clinical features that were developed years ago” to select patients, but now “there’s other much more refined techniques” that look at the underlying biological signatures “to identify who responds to immunotherapy.”

“So I think we have to do a deep dive into the biology in this trial and in the Merck trial [of pembrolizumab] to see if we can better define who is going to relapse and who is going to benefit,” he said.

Commenting on the new results, Dominik Berthold, MD, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, also wondered whether differences in trial design and study populations could explain the divergent results between the CheckMate and KEYNOTE trials.

“Investigators will need to look in detail at subpopulations and biomarkers to guide treatment decisions and trial design for current and future patients,” he added.

Dr. Berthold said he agrees that pembrolizumab remains standard of care, but “I’m not really sure that we have really to offer all patients” the drug.

He explained that, on the one hand, there is the risk of over-treating many patients, depending on their stage, and on the other hand, “many patients who get pembrolizumab actually do progress.”

In addition, there is the question of the treatment sequence in patients who are already exposed to immunotherapy and when to start tyrosine kinase inhibitors, as well as the much broader issue of the lack of long-term overall survival data with pembrolizumab.

Dr. Berthold noted the issue of whether the high treatment discontinuation rate in CheckMate 914 affected the efficacy of nivolumab plus ipilimumab raises the question of whether, from an immunological point of view, 1 year of pembrolizumab is more effective than 3 months of the combination therapy.

“I think it might be one of the explanations,” he said, adding, however, that these are just “hypotheses” at this stage.
 

Details of the new results

Previous results with the nivolumab-ipilimumab combination, from the CheckMate 214 trial in patients with advanced renal cell carcinoma, had demonstrated that upfront nivolumab plus ipilimumab offered significantly longer treatment-free survival than the VEGF inhibitor sunitinib. The “striking results” from that trial indicated the combination was not only associated with a survival benefit, but also “high response rates, durable responses, complete responses, and even treatment responses that continue after treatment is discontinued,” Dr. Motzer commented.

So his team set out to test the combination in the adjuvant setting in the CheckMate 914 trial, designed in two parts: Part A, comparing nivolumab plus ipilimumab with placebo, and Part B, adding nivolumab monotherapy as another comparator.

Reporting on Part A of the trial, Dr. Motzer explained that they included 816 patients with renal cell carcinoma who had undergone radical or partial nephrectomy with negative surgical margins and had a predominantly clear cell histology.

They also selected patients based on their pathologic TNM staging, choosing “high-risk” individuals, Dr. Motzer explained, but who nevertheless had no evidence of residual disease or distant metastases following nephrectomy.

Between 4 and 12 weeks after surgery, patients were randomized to receive 12 doses of nivolumab plus four doses of ipilimumab or matched placebos for an expected treatment duration of 24 weeks.

The median age of patients was 58-59 years, and approximately 71% were men. By far the most common type of surgery was radical nephrectomy, with 93%, and Dr. Motzer noted that most patients (77%-78%) had pT3 disease without nodal involvement.

After a median follow-up of 37.0 months, there was no significant difference between groups in the primary endpoint of DFS, as assessed by blinded independent central review.

Median DFS was not reached for nivolumab plus ipilimumab versus 50.7 months for placebo, at a hazard ratio of 0.92 (P = .5347). At 24 months, DFS was 76.4% with the combination therapy versus 74.0% for placebo.

Subgroup analysis did not reveal any patient groups that significantly benefitted from the combination therapy, although there was a signal of greater benefit in those with other than pT3 disease.

While tumors with sarcomatoid features appeared to have a significant benefit from nivolumab plus ipilimumab therapy, they represented only 5% of the study population.

During his presentation, Dr. Motzer showed the median duration of therapy was 5.1 months in both groups, but only 57% of nivolumab plus ipilimumab patients completed all doses versus 89% of those assigned to placebo.

In addition, 33% of patients given nivolumab plus ipilimumab discontinued due to study drug toxicity and 29% had a treatment-related adverse event that led to treatment discontinuation. This compared with only 1% of patients for both outcomes with placebo.

The most common treatment-related adverse events in the combination therapy group were pruritus (27%), fatigue (25%), diarrhea (20%), rash (19%), hyperthyroidism (16%), and hypothyroidism (16%), and the vast majority of events were grade 1-2.

Dr. Motzer said that, following these negative results, they are “certainly digging deeper into the details to see which particular groups may have benefited and when toxicity occurred.

Then, more importantly, the team will look out for the results of Part B of the trial to assess the impact of nivolumab monotherapy. “I’m hoping it’s better tolerated,” he said.

Discussant James Larkin, MD, PhD, a consultant medical oncologist at The Royal Marsden, London, said the results from CheckMate 914 came “as a bit of a surprise.”

As did Dr. Motzer, Dr. Larkin singled out the high number of patients who could not complete the full dosing schedule and discontinued treatment.

He added that, while one has to be “cautious” when comparing trials, KEYNOTE-564 was “relatively similar” in design, and it’s “unlikely there’s any significant difference in activity” between the two drugs.

Dr. Larkin also believes data from Part B of CheckMate 914 will be “illuminating.”

There are nevertheless a number of outstanding questions about the results from Part A, he said, the main one being how to better select patients who might respond to the combination, which currently is not possible due to the lack of clinically relevant biomarkers.

The study was funded by Bristol Myers Squibb. Dr. Motzer has disclosed relationships with AstraZeneca, Aveo Pharmaceuticals, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly Oncology, Merck, Novartis, and Pfizer.

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

PARIS – New disappointing results from a trial of adjuvant immunotherapy for patients with renal cell carcinoma who underwent nephrectomy contrast with those from a previous trial that showed benefit with another agent.

The new results, from CheckMate 914, show that adjuvant treatment with the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) did not improve disease-free survival (DFS), compared with placebo.

The finding was presented at the annual meeting of the European Society for Medical Oncology.

CheckMate 914 “did not meet the primary endpoint,” study presenter Robert J. Motzer, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York, said at a press conference.

The results contrast with those seen with pembrolizumab (Keytruda) in the same setting, where the drug achieved a 32% reduction in risk of recurrence or death over placebo in KEYNOTE-564. This led to the U.S. Food and Drug Administration granting approval for the drug as adjuvant treatment following surgery in patients with renal cell carcinoma at intermediate or high risk for recurrence after nephrectomy or after nephrectomy and resection of metastatic lesions.

Another trial of adjuvant immunotherapy in renal cell carcinoma, also presented at ESMO 2022, the IMmotion010 trial with adjuvant atezolizumab (Tecentriq), also did not show any clinical benefit over placebo.

However, Dr. Motzer said that despite both of these new trials showing no benefit, “I don’t think it takes away from standard of care pembrolizumab” in this setting.

There is a great need for adjuvant therapy for patients who undergo surgery, Dr. Motzer commented. The standard treatment for stage I-III localized nonmetastatic renal cell carcinoma is radical or partial nephrectomy, but there remains a “substantial risk” of relapse after surgery, occurring in up to 50% of patients.

In the past, the standard of care for these patients would be watching and waiting and “hoping that the patient doesn’t relapse,” he said, and if they did, then “we would treat accordingly for metastatic disease.”
 

Differences between trials

When asked about the contrast between the latest trial with the adjuvant nivolumab-ipilimumab combination and the earlier trial with adjuvant pembrolizumab, Dr. Motzer told this news organization that there are differences in the designs of the two studies. “Although they are both global phase 2 trials ... [there are] some differences in the patient population.”

However, the “main differences” are the duration, intensity, and tolerability of the treatment regimens. “I suspect that’s impacted on the outcome of our trial,” he said, as “many of our patients didn’t complete even that 6 months of the more toxic immunotherapy [nivolumab-ipilimumab combination].”

Dr. Motzer also noted that, compared with the metastatic setting, patients “do not tolerate therapy as well” in the adjuvant setting. Consequently, the risk-benefit of a drug is “slightly different ... as we have to be much more concerned about toxicity.”

In addition, he said, “our trial also used these kind-of gross clinical features that were developed years ago” to select patients, but now “there’s other much more refined techniques” that look at the underlying biological signatures “to identify who responds to immunotherapy.”

“So I think we have to do a deep dive into the biology in this trial and in the Merck trial [of pembrolizumab] to see if we can better define who is going to relapse and who is going to benefit,” he said.

Commenting on the new results, Dominik Berthold, MD, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, also wondered whether differences in trial design and study populations could explain the divergent results between the CheckMate and KEYNOTE trials.

“Investigators will need to look in detail at subpopulations and biomarkers to guide treatment decisions and trial design for current and future patients,” he added.

Dr. Berthold said he agrees that pembrolizumab remains standard of care, but “I’m not really sure that we have really to offer all patients” the drug.

He explained that, on the one hand, there is the risk of over-treating many patients, depending on their stage, and on the other hand, “many patients who get pembrolizumab actually do progress.”

In addition, there is the question of the treatment sequence in patients who are already exposed to immunotherapy and when to start tyrosine kinase inhibitors, as well as the much broader issue of the lack of long-term overall survival data with pembrolizumab.

Dr. Berthold noted the issue of whether the high treatment discontinuation rate in CheckMate 914 affected the efficacy of nivolumab plus ipilimumab raises the question of whether, from an immunological point of view, 1 year of pembrolizumab is more effective than 3 months of the combination therapy.

“I think it might be one of the explanations,” he said, adding, however, that these are just “hypotheses” at this stage.
 

Details of the new results

Previous results with the nivolumab-ipilimumab combination, from the CheckMate 214 trial in patients with advanced renal cell carcinoma, had demonstrated that upfront nivolumab plus ipilimumab offered significantly longer treatment-free survival than the VEGF inhibitor sunitinib. The “striking results” from that trial indicated the combination was not only associated with a survival benefit, but also “high response rates, durable responses, complete responses, and even treatment responses that continue after treatment is discontinued,” Dr. Motzer commented.

So his team set out to test the combination in the adjuvant setting in the CheckMate 914 trial, designed in two parts: Part A, comparing nivolumab plus ipilimumab with placebo, and Part B, adding nivolumab monotherapy as another comparator.

Reporting on Part A of the trial, Dr. Motzer explained that they included 816 patients with renal cell carcinoma who had undergone radical or partial nephrectomy with negative surgical margins and had a predominantly clear cell histology.

They also selected patients based on their pathologic TNM staging, choosing “high-risk” individuals, Dr. Motzer explained, but who nevertheless had no evidence of residual disease or distant metastases following nephrectomy.

Between 4 and 12 weeks after surgery, patients were randomized to receive 12 doses of nivolumab plus four doses of ipilimumab or matched placebos for an expected treatment duration of 24 weeks.

The median age of patients was 58-59 years, and approximately 71% were men. By far the most common type of surgery was radical nephrectomy, with 93%, and Dr. Motzer noted that most patients (77%-78%) had pT3 disease without nodal involvement.

After a median follow-up of 37.0 months, there was no significant difference between groups in the primary endpoint of DFS, as assessed by blinded independent central review.

Median DFS was not reached for nivolumab plus ipilimumab versus 50.7 months for placebo, at a hazard ratio of 0.92 (P = .5347). At 24 months, DFS was 76.4% with the combination therapy versus 74.0% for placebo.

Subgroup analysis did not reveal any patient groups that significantly benefitted from the combination therapy, although there was a signal of greater benefit in those with other than pT3 disease.

While tumors with sarcomatoid features appeared to have a significant benefit from nivolumab plus ipilimumab therapy, they represented only 5% of the study population.

During his presentation, Dr. Motzer showed the median duration of therapy was 5.1 months in both groups, but only 57% of nivolumab plus ipilimumab patients completed all doses versus 89% of those assigned to placebo.

In addition, 33% of patients given nivolumab plus ipilimumab discontinued due to study drug toxicity and 29% had a treatment-related adverse event that led to treatment discontinuation. This compared with only 1% of patients for both outcomes with placebo.

The most common treatment-related adverse events in the combination therapy group were pruritus (27%), fatigue (25%), diarrhea (20%), rash (19%), hyperthyroidism (16%), and hypothyroidism (16%), and the vast majority of events were grade 1-2.

Dr. Motzer said that, following these negative results, they are “certainly digging deeper into the details to see which particular groups may have benefited and when toxicity occurred.

Then, more importantly, the team will look out for the results of Part B of the trial to assess the impact of nivolumab monotherapy. “I’m hoping it’s better tolerated,” he said.

Discussant James Larkin, MD, PhD, a consultant medical oncologist at The Royal Marsden, London, said the results from CheckMate 914 came “as a bit of a surprise.”

As did Dr. Motzer, Dr. Larkin singled out the high number of patients who could not complete the full dosing schedule and discontinued treatment.

He added that, while one has to be “cautious” when comparing trials, KEYNOTE-564 was “relatively similar” in design, and it’s “unlikely there’s any significant difference in activity” between the two drugs.

Dr. Larkin also believes data from Part B of CheckMate 914 will be “illuminating.”

There are nevertheless a number of outstanding questions about the results from Part A, he said, the main one being how to better select patients who might respond to the combination, which currently is not possible due to the lack of clinically relevant biomarkers.

The study was funded by Bristol Myers Squibb. Dr. Motzer has disclosed relationships with AstraZeneca, Aveo Pharmaceuticals, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly Oncology, Merck, Novartis, and Pfizer.

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

PARIS – New disappointing results from a trial of adjuvant immunotherapy for patients with renal cell carcinoma who underwent nephrectomy contrast with those from a previous trial that showed benefit with another agent.

The new results, from CheckMate 914, show that adjuvant treatment with the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) did not improve disease-free survival (DFS), compared with placebo.

The finding was presented at the annual meeting of the European Society for Medical Oncology.

CheckMate 914 “did not meet the primary endpoint,” study presenter Robert J. Motzer, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York, said at a press conference.

The results contrast with those seen with pembrolizumab (Keytruda) in the same setting, where the drug achieved a 32% reduction in risk of recurrence or death over placebo in KEYNOTE-564. This led to the U.S. Food and Drug Administration granting approval for the drug as adjuvant treatment following surgery in patients with renal cell carcinoma at intermediate or high risk for recurrence after nephrectomy or after nephrectomy and resection of metastatic lesions.

Another trial of adjuvant immunotherapy in renal cell carcinoma, also presented at ESMO 2022, the IMmotion010 trial with adjuvant atezolizumab (Tecentriq), also did not show any clinical benefit over placebo.

However, Dr. Motzer said that despite both of these new trials showing no benefit, “I don’t think it takes away from standard of care pembrolizumab” in this setting.

There is a great need for adjuvant therapy for patients who undergo surgery, Dr. Motzer commented. The standard treatment for stage I-III localized nonmetastatic renal cell carcinoma is radical or partial nephrectomy, but there remains a “substantial risk” of relapse after surgery, occurring in up to 50% of patients.

In the past, the standard of care for these patients would be watching and waiting and “hoping that the patient doesn’t relapse,” he said, and if they did, then “we would treat accordingly for metastatic disease.”
 

Differences between trials

When asked about the contrast between the latest trial with the adjuvant nivolumab-ipilimumab combination and the earlier trial with adjuvant pembrolizumab, Dr. Motzer told this news organization that there are differences in the designs of the two studies. “Although they are both global phase 2 trials ... [there are] some differences in the patient population.”

However, the “main differences” are the duration, intensity, and tolerability of the treatment regimens. “I suspect that’s impacted on the outcome of our trial,” he said, as “many of our patients didn’t complete even that 6 months of the more toxic immunotherapy [nivolumab-ipilimumab combination].”

Dr. Motzer also noted that, compared with the metastatic setting, patients “do not tolerate therapy as well” in the adjuvant setting. Consequently, the risk-benefit of a drug is “slightly different ... as we have to be much more concerned about toxicity.”

In addition, he said, “our trial also used these kind-of gross clinical features that were developed years ago” to select patients, but now “there’s other much more refined techniques” that look at the underlying biological signatures “to identify who responds to immunotherapy.”

“So I think we have to do a deep dive into the biology in this trial and in the Merck trial [of pembrolizumab] to see if we can better define who is going to relapse and who is going to benefit,” he said.

Commenting on the new results, Dominik Berthold, MD, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, also wondered whether differences in trial design and study populations could explain the divergent results between the CheckMate and KEYNOTE trials.

“Investigators will need to look in detail at subpopulations and biomarkers to guide treatment decisions and trial design for current and future patients,” he added.

Dr. Berthold said he agrees that pembrolizumab remains standard of care, but “I’m not really sure that we have really to offer all patients” the drug.

He explained that, on the one hand, there is the risk of over-treating many patients, depending on their stage, and on the other hand, “many patients who get pembrolizumab actually do progress.”

In addition, there is the question of the treatment sequence in patients who are already exposed to immunotherapy and when to start tyrosine kinase inhibitors, as well as the much broader issue of the lack of long-term overall survival data with pembrolizumab.

Dr. Berthold noted the issue of whether the high treatment discontinuation rate in CheckMate 914 affected the efficacy of nivolumab plus ipilimumab raises the question of whether, from an immunological point of view, 1 year of pembrolizumab is more effective than 3 months of the combination therapy.

“I think it might be one of the explanations,” he said, adding, however, that these are just “hypotheses” at this stage.
 

Details of the new results

Previous results with the nivolumab-ipilimumab combination, from the CheckMate 214 trial in patients with advanced renal cell carcinoma, had demonstrated that upfront nivolumab plus ipilimumab offered significantly longer treatment-free survival than the VEGF inhibitor sunitinib. The “striking results” from that trial indicated the combination was not only associated with a survival benefit, but also “high response rates, durable responses, complete responses, and even treatment responses that continue after treatment is discontinued,” Dr. Motzer commented.

So his team set out to test the combination in the adjuvant setting in the CheckMate 914 trial, designed in two parts: Part A, comparing nivolumab plus ipilimumab with placebo, and Part B, adding nivolumab monotherapy as another comparator.

Reporting on Part A of the trial, Dr. Motzer explained that they included 816 patients with renal cell carcinoma who had undergone radical or partial nephrectomy with negative surgical margins and had a predominantly clear cell histology.

They also selected patients based on their pathologic TNM staging, choosing “high-risk” individuals, Dr. Motzer explained, but who nevertheless had no evidence of residual disease or distant metastases following nephrectomy.

Between 4 and 12 weeks after surgery, patients were randomized to receive 12 doses of nivolumab plus four doses of ipilimumab or matched placebos for an expected treatment duration of 24 weeks.

The median age of patients was 58-59 years, and approximately 71% were men. By far the most common type of surgery was radical nephrectomy, with 93%, and Dr. Motzer noted that most patients (77%-78%) had pT3 disease without nodal involvement.

After a median follow-up of 37.0 months, there was no significant difference between groups in the primary endpoint of DFS, as assessed by blinded independent central review.

Median DFS was not reached for nivolumab plus ipilimumab versus 50.7 months for placebo, at a hazard ratio of 0.92 (P = .5347). At 24 months, DFS was 76.4% with the combination therapy versus 74.0% for placebo.

Subgroup analysis did not reveal any patient groups that significantly benefitted from the combination therapy, although there was a signal of greater benefit in those with other than pT3 disease.

While tumors with sarcomatoid features appeared to have a significant benefit from nivolumab plus ipilimumab therapy, they represented only 5% of the study population.

During his presentation, Dr. Motzer showed the median duration of therapy was 5.1 months in both groups, but only 57% of nivolumab plus ipilimumab patients completed all doses versus 89% of those assigned to placebo.

In addition, 33% of patients given nivolumab plus ipilimumab discontinued due to study drug toxicity and 29% had a treatment-related adverse event that led to treatment discontinuation. This compared with only 1% of patients for both outcomes with placebo.

The most common treatment-related adverse events in the combination therapy group were pruritus (27%), fatigue (25%), diarrhea (20%), rash (19%), hyperthyroidism (16%), and hypothyroidism (16%), and the vast majority of events were grade 1-2.

Dr. Motzer said that, following these negative results, they are “certainly digging deeper into the details to see which particular groups may have benefited and when toxicity occurred.

Then, more importantly, the team will look out for the results of Part B of the trial to assess the impact of nivolumab monotherapy. “I’m hoping it’s better tolerated,” he said.

Discussant James Larkin, MD, PhD, a consultant medical oncologist at The Royal Marsden, London, said the results from CheckMate 914 came “as a bit of a surprise.”

As did Dr. Motzer, Dr. Larkin singled out the high number of patients who could not complete the full dosing schedule and discontinued treatment.

He added that, while one has to be “cautious” when comparing trials, KEYNOTE-564 was “relatively similar” in design, and it’s “unlikely there’s any significant difference in activity” between the two drugs.

Dr. Larkin also believes data from Part B of CheckMate 914 will be “illuminating.”

There are nevertheless a number of outstanding questions about the results from Part A, he said, the main one being how to better select patients who might respond to the combination, which currently is not possible due to the lack of clinically relevant biomarkers.

The study was funded by Bristol Myers Squibb. Dr. Motzer has disclosed relationships with AstraZeneca, Aveo Pharmaceuticals, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly Oncology, Merck, Novartis, and Pfizer.

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

Neoadjuvant immunotherapy for stage II-IV cutaneous squamous cell carcinoma (CSCC) led to a strong pathological complete response rate, according to results from a stage 2 clinical trial.

CSCC hasn’t received much attention from pharmaceutical companies, in part because it so often responds well to surgery or local therapy. Still, some patients develop more advanced cancer that requires surgery, often on exposed surfaces like the scalp, face, or neck. That can lead to cosmetic and functional impairment.

“Having witnessed the toxicity of treatments over time has really kind of kind of pushed me for a long time to seek better ways to treat this,” lead author Neil Gross, MD, said in an interview. Dr. Gross is director of clinical research in the department of head and neck surgery at the University of Texas MD Anderson Cancer Center, Houston. The study was presented at the annual meeting of the European Society for Medical Oncology and published simultaneously in the New England Journal of Medicine.

Dr. Gross and colleagues conducted a pilot study that examined neoadjuvant immunotherapy with cemiplimab (Libtayo, Regeneron). It received Food and Drug Administration approval in 2018 for metastatic cutaneous squamous cell carcinoma. The aim of the study was to determine how cells responded to the therapy and learn more about the biology, but the results turned heads. “We were surprised to learn just how well the patients responded, Over half of the patients had a complete pathologic response to treatment, and another 4 patients out of 20 had a near-complete pathological response. It prompted a multicenter trial to confirm whether or not what we’re seeing was real,” Dr. Gross said.

The new phase 2 study, conducted in 79 patients at centers in Australia, Germany, and the United States, was encouraging. “The results were very, very similar. About 63% overall had this really impressive pathologic response to treatment. And, it may even be an underestimation of the responses because there were several patients in the trial who responded so well that they refused surgery. Those patients were counted as nonresponders just to be most conservative,” Dr. Gross said.

“I think it will change practice. The results are just so dramatic that it’s hard to imagine it’s not going to influence how patients are treated,” he said.
 

Dramatic results and an attractive option

Among 79 patients in the new trial, the median age was 73 years, 85% were male, and 87% were White. About 91% of primary tumors were head and neck; 6% were stage II, 48% stage III, and 46% stage IV. All patients received four doses of 350 mg cemiplimab at 3-week intervals.

After a median follow-up of 9.7 months (range, 1.3-19.6 months), 51% achieved a pathological complete response (95% confidence interval, 39%-62%). The null hypothesis was that 25% would achieve a pathologic response. An additional 13% had a pathological major response (95% CI, 6%-22%). 25% did not achieve a pathological complete or pathological major response, which was defined as viable tumor cells representing at least 10% of the surgical specimen.

72% of patients experienced an adverse event considered by the investigator to be related to treatment, most commonly fatigue (28%), maculopapular rash (14%), and diarrhea (11%). 15% of patients experienced immune-related adverse events. 4% experienced a grade 3 immune-related adverse event.

Despite the encouraging results, more research needs to be done. One key question is the optimal number of treatments prior to surgery. The pilot study used two doses while the phase 2 study used four doses. Another is whether the surgical excision can be safely reduced after treatment to reduce morbidity, and still another is whether some patients can avoid radiation. “There are lots of unanswered questions that are really important to how this gets rolled out into clinical practice, but I do think that there’s no turning back. The results are so dramatic that it’s a very attractive option to patients and providers. We will have to figure out how to learn the best way to use this in practice while it’s being used,” Dr. Gross said.

Additional studies are in the planning phase, though the results are so encouraging that they might hinder future research. “Will patients be willing in the future to be randomized to the current standard of care, which would be upfront surgery and radiation for advanced disease? I don’t know. There’s a lot of thought being put into the best way to design these studies moving forward that are really advantageous to patients, but still answer these some of these fundamental questions,” Dr. Gross said.

He also noted that these studies looked at pathological responses, not overall survival or clinical outcomes. “We believe that these responses will be durable, but this has to be borne out as the data matures.”

The study was funded by Regeneron. Dr. Gross has consulted for DragonFly Therapeutics, Intuitive Surgical, Regeneron, and Sanofi/Genzyme. He has been on scientific advisory boards for PDS Biotechnology and Shattuck Labs.

Neoadjuvant immunotherapy for stage II-IV cutaneous squamous cell carcinoma (CSCC) led to a strong pathological complete response rate, according to results from a stage 2 clinical trial.

CSCC hasn’t received much attention from pharmaceutical companies, in part because it so often responds well to surgery or local therapy. Still, some patients develop more advanced cancer that requires surgery, often on exposed surfaces like the scalp, face, or neck. That can lead to cosmetic and functional impairment.

“Having witnessed the toxicity of treatments over time has really kind of kind of pushed me for a long time to seek better ways to treat this,” lead author Neil Gross, MD, said in an interview. Dr. Gross is director of clinical research in the department of head and neck surgery at the University of Texas MD Anderson Cancer Center, Houston. The study was presented at the annual meeting of the European Society for Medical Oncology and published simultaneously in the New England Journal of Medicine.

Dr. Gross and colleagues conducted a pilot study that examined neoadjuvant immunotherapy with cemiplimab (Libtayo, Regeneron). It received Food and Drug Administration approval in 2018 for metastatic cutaneous squamous cell carcinoma. The aim of the study was to determine how cells responded to the therapy and learn more about the biology, but the results turned heads. “We were surprised to learn just how well the patients responded, Over half of the patients had a complete pathologic response to treatment, and another 4 patients out of 20 had a near-complete pathological response. It prompted a multicenter trial to confirm whether or not what we’re seeing was real,” Dr. Gross said.

The new phase 2 study, conducted in 79 patients at centers in Australia, Germany, and the United States, was encouraging. “The results were very, very similar. About 63% overall had this really impressive pathologic response to treatment. And, it may even be an underestimation of the responses because there were several patients in the trial who responded so well that they refused surgery. Those patients were counted as nonresponders just to be most conservative,” Dr. Gross said.

“I think it will change practice. The results are just so dramatic that it’s hard to imagine it’s not going to influence how patients are treated,” he said.
 

Dramatic results and an attractive option

Among 79 patients in the new trial, the median age was 73 years, 85% were male, and 87% were White. About 91% of primary tumors were head and neck; 6% were stage II, 48% stage III, and 46% stage IV. All patients received four doses of 350 mg cemiplimab at 3-week intervals.

After a median follow-up of 9.7 months (range, 1.3-19.6 months), 51% achieved a pathological complete response (95% confidence interval, 39%-62%). The null hypothesis was that 25% would achieve a pathologic response. An additional 13% had a pathological major response (95% CI, 6%-22%). 25% did not achieve a pathological complete or pathological major response, which was defined as viable tumor cells representing at least 10% of the surgical specimen.

72% of patients experienced an adverse event considered by the investigator to be related to treatment, most commonly fatigue (28%), maculopapular rash (14%), and diarrhea (11%). 15% of patients experienced immune-related adverse events. 4% experienced a grade 3 immune-related adverse event.

Despite the encouraging results, more research needs to be done. One key question is the optimal number of treatments prior to surgery. The pilot study used two doses while the phase 2 study used four doses. Another is whether the surgical excision can be safely reduced after treatment to reduce morbidity, and still another is whether some patients can avoid radiation. “There are lots of unanswered questions that are really important to how this gets rolled out into clinical practice, but I do think that there’s no turning back. The results are so dramatic that it’s a very attractive option to patients and providers. We will have to figure out how to learn the best way to use this in practice while it’s being used,” Dr. Gross said.

Additional studies are in the planning phase, though the results are so encouraging that they might hinder future research. “Will patients be willing in the future to be randomized to the current standard of care, which would be upfront surgery and radiation for advanced disease? I don’t know. There’s a lot of thought being put into the best way to design these studies moving forward that are really advantageous to patients, but still answer these some of these fundamental questions,” Dr. Gross said.

He also noted that these studies looked at pathological responses, not overall survival or clinical outcomes. “We believe that these responses will be durable, but this has to be borne out as the data matures.”

The study was funded by Regeneron. Dr. Gross has consulted for DragonFly Therapeutics, Intuitive Surgical, Regeneron, and Sanofi/Genzyme. He has been on scientific advisory boards for PDS Biotechnology and Shattuck Labs.

Neoadjuvant immunotherapy for stage II-IV cutaneous squamous cell carcinoma (CSCC) led to a strong pathological complete response rate, according to results from a stage 2 clinical trial.

CSCC hasn’t received much attention from pharmaceutical companies, in part because it so often responds well to surgery or local therapy. Still, some patients develop more advanced cancer that requires surgery, often on exposed surfaces like the scalp, face, or neck. That can lead to cosmetic and functional impairment.

“Having witnessed the toxicity of treatments over time has really kind of kind of pushed me for a long time to seek better ways to treat this,” lead author Neil Gross, MD, said in an interview. Dr. Gross is director of clinical research in the department of head and neck surgery at the University of Texas MD Anderson Cancer Center, Houston. The study was presented at the annual meeting of the European Society for Medical Oncology and published simultaneously in the New England Journal of Medicine.

Dr. Gross and colleagues conducted a pilot study that examined neoadjuvant immunotherapy with cemiplimab (Libtayo, Regeneron). It received Food and Drug Administration approval in 2018 for metastatic cutaneous squamous cell carcinoma. The aim of the study was to determine how cells responded to the therapy and learn more about the biology, but the results turned heads. “We were surprised to learn just how well the patients responded, Over half of the patients had a complete pathologic response to treatment, and another 4 patients out of 20 had a near-complete pathological response. It prompted a multicenter trial to confirm whether or not what we’re seeing was real,” Dr. Gross said.

The new phase 2 study, conducted in 79 patients at centers in Australia, Germany, and the United States, was encouraging. “The results were very, very similar. About 63% overall had this really impressive pathologic response to treatment. And, it may even be an underestimation of the responses because there were several patients in the trial who responded so well that they refused surgery. Those patients were counted as nonresponders just to be most conservative,” Dr. Gross said.

“I think it will change practice. The results are just so dramatic that it’s hard to imagine it’s not going to influence how patients are treated,” he said.
 

Dramatic results and an attractive option

Among 79 patients in the new trial, the median age was 73 years, 85% were male, and 87% were White. About 91% of primary tumors were head and neck; 6% were stage II, 48% stage III, and 46% stage IV. All patients received four doses of 350 mg cemiplimab at 3-week intervals.

After a median follow-up of 9.7 months (range, 1.3-19.6 months), 51% achieved a pathological complete response (95% confidence interval, 39%-62%). The null hypothesis was that 25% would achieve a pathologic response. An additional 13% had a pathological major response (95% CI, 6%-22%). 25% did not achieve a pathological complete or pathological major response, which was defined as viable tumor cells representing at least 10% of the surgical specimen.

72% of patients experienced an adverse event considered by the investigator to be related to treatment, most commonly fatigue (28%), maculopapular rash (14%), and diarrhea (11%). 15% of patients experienced immune-related adverse events. 4% experienced a grade 3 immune-related adverse event.

Despite the encouraging results, more research needs to be done. One key question is the optimal number of treatments prior to surgery. The pilot study used two doses while the phase 2 study used four doses. Another is whether the surgical excision can be safely reduced after treatment to reduce morbidity, and still another is whether some patients can avoid radiation. “There are lots of unanswered questions that are really important to how this gets rolled out into clinical practice, but I do think that there’s no turning back. The results are so dramatic that it’s a very attractive option to patients and providers. We will have to figure out how to learn the best way to use this in practice while it’s being used,” Dr. Gross said.

Additional studies are in the planning phase, though the results are so encouraging that they might hinder future research. “Will patients be willing in the future to be randomized to the current standard of care, which would be upfront surgery and radiation for advanced disease? I don’t know. There’s a lot of thought being put into the best way to design these studies moving forward that are really advantageous to patients, but still answer these some of these fundamental questions,” Dr. Gross said.

He also noted that these studies looked at pathological responses, not overall survival or clinical outcomes. “We believe that these responses will be durable, but this has to be borne out as the data matures.”

The study was funded by Regeneron. Dr. Gross has consulted for DragonFly Therapeutics, Intuitive Surgical, Regeneron, and Sanofi/Genzyme. He has been on scientific advisory boards for PDS Biotechnology and Shattuck Labs.

Cancer cachexia is a syndrome of weight loss that frequently occurs during cancer treatment. Consequences can include skeletal muscle loss, fatigue, functional impairment, worse quality of life, and worse survival. On the other hand, weight gain during cancer treatment has been tied to better survival.

A new study shows that, among patients with non–small cell lung cancer (NSCLC), weight gain over the course of treatment with standard of care chemotherapy was associated with improved survival in both men and women. Few studies have examined the relationship between weight gain and outcomes by sex.

“The finding that weight gain occurred in subsets of males and females is a new observation. The fact that weight gain occurs in cancer patients during anticancer treatment could confound results of clinical [trials] evaluating novel anticachexia treatments. Simultaneously studying longitudinal body weights and serum and cellular biomarkers in cancer patients might provide insights into mechanisms involved in cachexia. Increased understanding of mechanisms driving cachexia could lead to new therapeutic strategies,” said study coauthor Philip Bonomi, MD, who is an oncologist at Rush Medical College, Chicago.

“This data, although it appears to be very basic, is critically important, especially as we consider our novel interventions in the treatment of cancer cachexia,” said Eric Roeland, MD, during his presentation of the study at the annual meeting of European Society for Medical Oncology. Dr. Roeland is a medical oncologist at Oregon Health & Science University, Portland.

Dr. Roeland is also the lead author of cancer cachexia guidelines published by the American Society of Clinical Oncology in 2020. The guidelines suggest that dietary counseling can be offered to patients, but warns against routine use of enteral feeding tubes and parenteral nutrition. Although no specific drug can be recommended for cancer cachexia, progesterone analogs and corticosteroids used over the short term (weeks) can be used on a trial base to improve appetite and weight gain. While not approved in the United States, anamorelin was approved in 2020 in Japan for cancer cachexia in NSCLC, gastric cancer, pancreatic cancer, and colorectal cancer.

The new study should raise awareness of the importance of adverse effects of cancer treatments, said Karin Jordan, MD, University Hospital Heidelberg (Germany). She served as a discussant following the presentation. “As a medical oncologist, we focus a bit too much on the benefits of antineoplastic therapy, both on cure and on the survival benefit. But what is also very, very important to do is a balanced oncology treatment to focus on the risks of oncology therapies,” she said.

The study is limited by its retrospective nature and potential for bias. “The hypothesis that weight gain leads to improved survival is not really proven as it likewise may be the other way around,” Dr. Jordan said.

However, in oncology research, a phenomenon called the “obesity paradox” is increasingly catching the interest of investigators. Observational studies have shown that overweight patients with certain cancers (specifically, colorectal, endometrial and lung cancer). actually have improved overall survival as compared with normal-weight patients.
 

Details from the new study

The researchers pooled data 1,030 patients who participated in three phase 3 clinical trials conducted between 2005 and 2011. The patients all received platinum-based chemotherapy as part of control arms. 304 were female and 726 were male. The median age was 62. 16.7% were Asian, the mean body mass index was 24.6 kg/m², 88.5% had stage 4 disease, 36.9% had adenocarcinoma, and 86.3% were current or former smokers.

Males and females had similar magnitudes and rate of weight gain over the course of treatment. Any weight gain was associated with improved overall survival in both males (12.7 vs. 8.0 months; hazard ratio, 0.60; P < .001) and females (16.2 vs. 10.1 months; HR, 0.65; P = .0028). Patients who had a weight gain of 2.5% of body weight or more saw an improvement in overall survival in both males (14.0 vs. 8.2 months; HR, 0.57; P < .001) and females (16.7 vs. 11.3 months; HR, 0.61; P = .0041).

Patients with a weight gain of 5% or more was associated with improved survival in males (13.6 vs. 8.9 months; HR, 0.62; P = .0001), but there was no statistically significant association in females (16.7 vs. 12.6 months; HR, 0.69; P = .1107).

Regardless of weight-gain status, males had lower survival rates than females. All of the associations were independent of smoking status.

The study was funded by Pfizer. Dr. Bonomi has received honoraria from Pfizer and Helsinn for participation in scientific advisory boards. Dr. Jordan has consulted for Amgen, Hexal, Riemser, Helsinn, Voluntis, Pfizer, and BD Solution. She has received research funding from Deutsche Krebshilfe. She has received honoraria from MSD, Merck, Amgen, Hexal, Riemser, Helsinn, Voluntis, Pfizer, Pomme-med, PharmaMar, arttemoi, OnkoUpdate, Stemline, and Roche.

Cancer cachexia is a syndrome of weight loss that frequently occurs during cancer treatment. Consequences can include skeletal muscle loss, fatigue, functional impairment, worse quality of life, and worse survival. On the other hand, weight gain during cancer treatment has been tied to better survival.

A new study shows that, among patients with non–small cell lung cancer (NSCLC), weight gain over the course of treatment with standard of care chemotherapy was associated with improved survival in both men and women. Few studies have examined the relationship between weight gain and outcomes by sex.

“The finding that weight gain occurred in subsets of males and females is a new observation. The fact that weight gain occurs in cancer patients during anticancer treatment could confound results of clinical [trials] evaluating novel anticachexia treatments. Simultaneously studying longitudinal body weights and serum and cellular biomarkers in cancer patients might provide insights into mechanisms involved in cachexia. Increased understanding of mechanisms driving cachexia could lead to new therapeutic strategies,” said study coauthor Philip Bonomi, MD, who is an oncologist at Rush Medical College, Chicago.

“This data, although it appears to be very basic, is critically important, especially as we consider our novel interventions in the treatment of cancer cachexia,” said Eric Roeland, MD, during his presentation of the study at the annual meeting of European Society for Medical Oncology. Dr. Roeland is a medical oncologist at Oregon Health & Science University, Portland.

Dr. Roeland is also the lead author of cancer cachexia guidelines published by the American Society of Clinical Oncology in 2020. The guidelines suggest that dietary counseling can be offered to patients, but warns against routine use of enteral feeding tubes and parenteral nutrition. Although no specific drug can be recommended for cancer cachexia, progesterone analogs and corticosteroids used over the short term (weeks) can be used on a trial base to improve appetite and weight gain. While not approved in the United States, anamorelin was approved in 2020 in Japan for cancer cachexia in NSCLC, gastric cancer, pancreatic cancer, and colorectal cancer.

The new study should raise awareness of the importance of adverse effects of cancer treatments, said Karin Jordan, MD, University Hospital Heidelberg (Germany). She served as a discussant following the presentation. “As a medical oncologist, we focus a bit too much on the benefits of antineoplastic therapy, both on cure and on the survival benefit. But what is also very, very important to do is a balanced oncology treatment to focus on the risks of oncology therapies,” she said.

The study is limited by its retrospective nature and potential for bias. “The hypothesis that weight gain leads to improved survival is not really proven as it likewise may be the other way around,” Dr. Jordan said.

However, in oncology research, a phenomenon called the “obesity paradox” is increasingly catching the interest of investigators. Observational studies have shown that overweight patients with certain cancers (specifically, colorectal, endometrial and lung cancer). actually have improved overall survival as compared with normal-weight patients.
 

Details from the new study

The researchers pooled data 1,030 patients who participated in three phase 3 clinical trials conducted between 2005 and 2011. The patients all received platinum-based chemotherapy as part of control arms. 304 were female and 726 were male. The median age was 62. 16.7% were Asian, the mean body mass index was 24.6 kg/m², 88.5% had stage 4 disease, 36.9% had adenocarcinoma, and 86.3% were current or former smokers.

Males and females had similar magnitudes and rate of weight gain over the course of treatment. Any weight gain was associated with improved overall survival in both males (12.7 vs. 8.0 months; hazard ratio, 0.60; P < .001) and females (16.2 vs. 10.1 months; HR, 0.65; P = .0028). Patients who had a weight gain of 2.5% of body weight or more saw an improvement in overall survival in both males (14.0 vs. 8.2 months; HR, 0.57; P < .001) and females (16.7 vs. 11.3 months; HR, 0.61; P = .0041).

Patients with a weight gain of 5% or more was associated with improved survival in males (13.6 vs. 8.9 months; HR, 0.62; P = .0001), but there was no statistically significant association in females (16.7 vs. 12.6 months; HR, 0.69; P = .1107).

Regardless of weight-gain status, males had lower survival rates than females. All of the associations were independent of smoking status.

The study was funded by Pfizer. Dr. Bonomi has received honoraria from Pfizer and Helsinn for participation in scientific advisory boards. Dr. Jordan has consulted for Amgen, Hexal, Riemser, Helsinn, Voluntis, Pfizer, and BD Solution. She has received research funding from Deutsche Krebshilfe. She has received honoraria from MSD, Merck, Amgen, Hexal, Riemser, Helsinn, Voluntis, Pfizer, Pomme-med, PharmaMar, arttemoi, OnkoUpdate, Stemline, and Roche.

Cancer cachexia is a syndrome of weight loss that frequently occurs during cancer treatment. Consequences can include skeletal muscle loss, fatigue, functional impairment, worse quality of life, and worse survival. On the other hand, weight gain during cancer treatment has been tied to better survival.

A new study shows that, among patients with non–small cell lung cancer (NSCLC), weight gain over the course of treatment with standard of care chemotherapy was associated with improved survival in both men and women. Few studies have examined the relationship between weight gain and outcomes by sex.

“The finding that weight gain occurred in subsets of males and females is a new observation. The fact that weight gain occurs in cancer patients during anticancer treatment could confound results of clinical [trials] evaluating novel anticachexia treatments. Simultaneously studying longitudinal body weights and serum and cellular biomarkers in cancer patients might provide insights into mechanisms involved in cachexia. Increased understanding of mechanisms driving cachexia could lead to new therapeutic strategies,” said study coauthor Philip Bonomi, MD, who is an oncologist at Rush Medical College, Chicago.

“This data, although it appears to be very basic, is critically important, especially as we consider our novel interventions in the treatment of cancer cachexia,” said Eric Roeland, MD, during his presentation of the study at the annual meeting of European Society for Medical Oncology. Dr. Roeland is a medical oncologist at Oregon Health & Science University, Portland.

Dr. Roeland is also the lead author of cancer cachexia guidelines published by the American Society of Clinical Oncology in 2020. The guidelines suggest that dietary counseling can be offered to patients, but warns against routine use of enteral feeding tubes and parenteral nutrition. Although no specific drug can be recommended for cancer cachexia, progesterone analogs and corticosteroids used over the short term (weeks) can be used on a trial base to improve appetite and weight gain. While not approved in the United States, anamorelin was approved in 2020 in Japan for cancer cachexia in NSCLC, gastric cancer, pancreatic cancer, and colorectal cancer.

The new study should raise awareness of the importance of adverse effects of cancer treatments, said Karin Jordan, MD, University Hospital Heidelberg (Germany). She served as a discussant following the presentation. “As a medical oncologist, we focus a bit too much on the benefits of antineoplastic therapy, both on cure and on the survival benefit. But what is also very, very important to do is a balanced oncology treatment to focus on the risks of oncology therapies,” she said.

The study is limited by its retrospective nature and potential for bias. “The hypothesis that weight gain leads to improved survival is not really proven as it likewise may be the other way around,” Dr. Jordan said.

However, in oncology research, a phenomenon called the “obesity paradox” is increasingly catching the interest of investigators. Observational studies have shown that overweight patients with certain cancers (specifically, colorectal, endometrial and lung cancer). actually have improved overall survival as compared with normal-weight patients.
 

Details from the new study

The researchers pooled data 1,030 patients who participated in three phase 3 clinical trials conducted between 2005 and 2011. The patients all received platinum-based chemotherapy as part of control arms. 304 were female and 726 were male. The median age was 62. 16.7% were Asian, the mean body mass index was 24.6 kg/m², 88.5% had stage 4 disease, 36.9% had adenocarcinoma, and 86.3% were current or former smokers.

Males and females had similar magnitudes and rate of weight gain over the course of treatment. Any weight gain was associated with improved overall survival in both males (12.7 vs. 8.0 months; hazard ratio, 0.60; P < .001) and females (16.2 vs. 10.1 months; HR, 0.65; P = .0028). Patients who had a weight gain of 2.5% of body weight or more saw an improvement in overall survival in both males (14.0 vs. 8.2 months; HR, 0.57; P < .001) and females (16.7 vs. 11.3 months; HR, 0.61; P = .0041).

Patients with a weight gain of 5% or more was associated with improved survival in males (13.6 vs. 8.9 months; HR, 0.62; P = .0001), but there was no statistically significant association in females (16.7 vs. 12.6 months; HR, 0.69; P = .1107).

Regardless of weight-gain status, males had lower survival rates than females. All of the associations were independent of smoking status.

The study was funded by Pfizer. Dr. Bonomi has received honoraria from Pfizer and Helsinn for participation in scientific advisory boards. Dr. Jordan has consulted for Amgen, Hexal, Riemser, Helsinn, Voluntis, Pfizer, and BD Solution. She has received research funding from Deutsche Krebshilfe. She has received honoraria from MSD, Merck, Amgen, Hexal, Riemser, Helsinn, Voluntis, Pfizer, Pomme-med, PharmaMar, arttemoi, OnkoUpdate, Stemline, and Roche.

High body mass index (BMI) values are associated with higher survival among metastatic cancer patients treated with first- and second-line immune checkpoint inhibitors (ICIs), but the relationship was only present in males.

That is the conclusion of a new retrospective analysis presented during a poster session given at the annual meeting of the European Society for Medical Oncology. The study sought to better understand ICI outcomes. “These are complex new treatments and, because they harness the immune system, no two patients are likely to respond in the same way. BMI has previously been associated with improved survival in patients with advanced lung cancer treated with immunotherapy. However, the reasons behind this observation, and the implications for treatment are unknown, as is whether this observation is specific for patients with only certain types of cancers,” study author Dwight Owen, MD, said in an email.

He pointed out that the retrospective nature of the findings means that they have no immediate clinical implications. “The reason for the discrepancy in males remains unclear. Although our study included a relatively large number of patients, it is a heterogenous cohort and there may be confounding factors that we haven’t recognized, so these findings need to be replicated in larger cohorts,” said Dr. Owen, a medical oncologist with The Ohio State University Comprehensive Cancer Center, Columbus.

Asked if there is a potential biological explanation for a difference between males and females, Dr. Owen said that this is an area of intense research. One recent study examined whether androgen could help explain why men are more likely than women to both develop and have more aggressive nonreproductive cancers. They concluded that androgen receptor signaling may be leading to loss of effector and proliferative potential of CD8+ T cells in the tumor microenvironment. Once exhausted, these cells do not respond well to stimulation that can occur after ICI treatment.

On the opposite end of the spectrum, cancer cachexia is also a key subject of study. It is characterized by weight loss and is associated with worse clinical outcomes. A cachexia mouse model found that weight loss can lead to more clearance of immune checkpoint antibodies.

Still, much more work needs to be done. “For now, how BMI, obesity, and cachexia relate to other factors, for instance the microbiome and tumor immunogenicity, are still not fully understood,” Dr. Owen said.
 

The study data

The researchers analyzed data from 688 patients with metastatic cancer treated at their center between 2011 and 2017. 94% were White and 5% were Black. 41% were female and the mean age was 61.9 years. The mean BMI was 28.8 kg/m²; 40% of patients had melanoma, 23% had non–small cell lung cancer, 10% had renal cancer, and 27% had another form of cancer.

For every unit decrease in BMI, the researchers observed a 1.8% decrease in mortality (hazard ratio, 0.982; P = .007). Patients with a BMI of 40 or above had better survival than all other patients grouped by 5 BMI increments (that is, 35-40, 30-35, etc.). When separated by sex, males had a significant decrease in mortality for every increase in BMI unit (HR, 0.964; P = .004), but there was no significant difference among women (HR, 1.003; P = .706). The relationship in men held up after adjustment for Eastern Cooperative Oncology Group score, line of therapy, and cancer type (HR, 0.979; P = .0308). The researchers also looked at a separate cohort of 185 normal weight and 15 obese (BMI ≥ 40) NSCLC patients. Median survival was 27.5 months in the obese group and 9.1 months in the normal weight group (HR, 0.474; 95% CI, 0.232-0.969).

Dr. Owen has received research funding through his institution from Bristol-Myers Squibb, Genentech, Pfizer, Palobiofarma, and Onc.AI.

High body mass index (BMI) values are associated with higher survival among metastatic cancer patients treated with first- and second-line immune checkpoint inhibitors (ICIs), but the relationship was only present in males.

That is the conclusion of a new retrospective analysis presented during a poster session given at the annual meeting of the European Society for Medical Oncology. The study sought to better understand ICI outcomes. “These are complex new treatments and, because they harness the immune system, no two patients are likely to respond in the same way. BMI has previously been associated with improved survival in patients with advanced lung cancer treated with immunotherapy. However, the reasons behind this observation, and the implications for treatment are unknown, as is whether this observation is specific for patients with only certain types of cancers,” study author Dwight Owen, MD, said in an email.

He pointed out that the retrospective nature of the findings means that they have no immediate clinical implications. “The reason for the discrepancy in males remains unclear. Although our study included a relatively large number of patients, it is a heterogenous cohort and there may be confounding factors that we haven’t recognized, so these findings need to be replicated in larger cohorts,” said Dr. Owen, a medical oncologist with The Ohio State University Comprehensive Cancer Center, Columbus.

Asked if there is a potential biological explanation for a difference between males and females, Dr. Owen said that this is an area of intense research. One recent study examined whether androgen could help explain why men are more likely than women to both develop and have more aggressive nonreproductive cancers. They concluded that androgen receptor signaling may be leading to loss of effector and proliferative potential of CD8+ T cells in the tumor microenvironment. Once exhausted, these cells do not respond well to stimulation that can occur after ICI treatment.

On the opposite end of the spectrum, cancer cachexia is also a key subject of study. It is characterized by weight loss and is associated with worse clinical outcomes. A cachexia mouse model found that weight loss can lead to more clearance of immune checkpoint antibodies.

Still, much more work needs to be done. “For now, how BMI, obesity, and cachexia relate to other factors, for instance the microbiome and tumor immunogenicity, are still not fully understood,” Dr. Owen said.
 

The study data

The researchers analyzed data from 688 patients with metastatic cancer treated at their center between 2011 and 2017. 94% were White and 5% were Black. 41% were female and the mean age was 61.9 years. The mean BMI was 28.8 kg/m²; 40% of patients had melanoma, 23% had non–small cell lung cancer, 10% had renal cancer, and 27% had another form of cancer.

For every unit decrease in BMI, the researchers observed a 1.8% decrease in mortality (hazard ratio, 0.982; P = .007). Patients with a BMI of 40 or above had better survival than all other patients grouped by 5 BMI increments (that is, 35-40, 30-35, etc.). When separated by sex, males had a significant decrease in mortality for every increase in BMI unit (HR, 0.964; P = .004), but there was no significant difference among women (HR, 1.003; P = .706). The relationship in men held up after adjustment for Eastern Cooperative Oncology Group score, line of therapy, and cancer type (HR, 0.979; P = .0308). The researchers also looked at a separate cohort of 185 normal weight and 15 obese (BMI ≥ 40) NSCLC patients. Median survival was 27.5 months in the obese group and 9.1 months in the normal weight group (HR, 0.474; 95% CI, 0.232-0.969).

Dr. Owen has received research funding through his institution from Bristol-Myers Squibb, Genentech, Pfizer, Palobiofarma, and Onc.AI.

High body mass index (BMI) values are associated with higher survival among metastatic cancer patients treated with first- and second-line immune checkpoint inhibitors (ICIs), but the relationship was only present in males.

That is the conclusion of a new retrospective analysis presented during a poster session given at the annual meeting of the European Society for Medical Oncology. The study sought to better understand ICI outcomes. “These are complex new treatments and, because they harness the immune system, no two patients are likely to respond in the same way. BMI has previously been associated with improved survival in patients with advanced lung cancer treated with immunotherapy. However, the reasons behind this observation, and the implications for treatment are unknown, as is whether this observation is specific for patients with only certain types of cancers,” study author Dwight Owen, MD, said in an email.

He pointed out that the retrospective nature of the findings means that they have no immediate clinical implications. “The reason for the discrepancy in males remains unclear. Although our study included a relatively large number of patients, it is a heterogenous cohort and there may be confounding factors that we haven’t recognized, so these findings need to be replicated in larger cohorts,” said Dr. Owen, a medical oncologist with The Ohio State University Comprehensive Cancer Center, Columbus.

Asked if there is a potential biological explanation for a difference between males and females, Dr. Owen said that this is an area of intense research. One recent study examined whether androgen could help explain why men are more likely than women to both develop and have more aggressive nonreproductive cancers. They concluded that androgen receptor signaling may be leading to loss of effector and proliferative potential of CD8+ T cells in the tumor microenvironment. Once exhausted, these cells do not respond well to stimulation that can occur after ICI treatment.

On the opposite end of the spectrum, cancer cachexia is also a key subject of study. It is characterized by weight loss and is associated with worse clinical outcomes. A cachexia mouse model found that weight loss can lead to more clearance of immune checkpoint antibodies.

Still, much more work needs to be done. “For now, how BMI, obesity, and cachexia relate to other factors, for instance the microbiome and tumor immunogenicity, are still not fully understood,” Dr. Owen said.
 

The study data

The researchers analyzed data from 688 patients with metastatic cancer treated at their center between 2011 and 2017. 94% were White and 5% were Black. 41% were female and the mean age was 61.9 years. The mean BMI was 28.8 kg/m²; 40% of patients had melanoma, 23% had non–small cell lung cancer, 10% had renal cancer, and 27% had another form of cancer.

For every unit decrease in BMI, the researchers observed a 1.8% decrease in mortality (hazard ratio, 0.982; P = .007). Patients with a BMI of 40 or above had better survival than all other patients grouped by 5 BMI increments (that is, 35-40, 30-35, etc.). When separated by sex, males had a significant decrease in mortality for every increase in BMI unit (HR, 0.964; P = .004), but there was no significant difference among women (HR, 1.003; P = .706). The relationship in men held up after adjustment for Eastern Cooperative Oncology Group score, line of therapy, and cancer type (HR, 0.979; P = .0308). The researchers also looked at a separate cohort of 185 normal weight and 15 obese (BMI ≥ 40) NSCLC patients. Median survival was 27.5 months in the obese group and 9.1 months in the normal weight group (HR, 0.474; 95% CI, 0.232-0.969).

Dr. Owen has received research funding through his institution from Bristol-Myers Squibb, Genentech, Pfizer, Palobiofarma, and Onc.AI.

PARIS – For patients with non–small cell lung cancers (NSCLC) bearing the KRAS G12C mutation that have progressed on prior therapies, the first-in-class KRAS G12C inhibitor sotorasib (Lumykras) was associated with better progression-free survival (PFS) and objective response rates than docetaxel in the randomized, phase 3 CodeBreaK 200 trial.

­Among 345 patients who had experienced disease progression after prior platinum-based chemotherapy and an immune checkpoint inhibitor, 1-year PFS rates at a median follow-up of 17.7 months were 24.8% for patients randomized to receive sotorasib versus 10.1% for patients assigned to docetaxel, reported Melissa L, Johnson, MD, from the Sarah Cannon Research Institute at Tennessee Oncology in Nashville.

“In my opinion, this supports sotorasib as a new second-line standard for patients with KRAS G12C non–small cell lung cancer,” she said in a media briefing prior to her presentation of the data in an oral abstract session at the annual meeting of the European Society for Medical Oncology.
 

First phase 3, randomized, controlled trial

The trial is the first head-to-head, randomized comparison pitting a KRAS G12C inhibitor against the standard of care in patients with NSCLC.

Approximately 30% of patients with NSCLC have KRAS driver mutations, and KRAS G12C–mutant NSCLC comprises an estimated 13% of all NSCLC cases, Dr. Johnson said.

Sotorasib was hailed as “a triumph of drug discovery” when early results of the trial were reported at the 2020 ESMO annual meeting. It is a small-molecule, specific, and irreversible inhibitor of KRAS that interacts with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drug inhibits oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form.
 

CodeBreaK 200 details

A total of 345 patients from sites in the United States, Europe, Asia and Australia were enrolled and randomly assigned to receive either oral sotorasib 960 mg daily, or intravenous docetaxel 75 mg/m² every 3 weeks.

As noted before, the trial met its primary endpoint of a statistically significant improvement in PFS with sotorasib as measured by independent central reviewers blinded to study assignment, with a hazard ratio of 0.66 (P = .002). Median PFS with sotorasib was 5.6 months, compared with 4.5 months for docetaxel.

The objective response rate was significantly improved for sotorasib versus docetaxel (28.1% vs. 13.2%, P < .001), as was the disease control rate at 82.5% for sotorasib versus 60.3% for docetaxel. Overall survival was not significantly different between treatment arms, though the study was not powered for this endpoint.

Sotorasib was also superior to docetaxel at forestalling deterioration of patients’ global health status, physical functioning, and cancer-related symptoms such as dyspnea and cough. There was no significant difference between the study arms in reported chest pain, however.

Grade 3 or greater treatment-related adverse events occurred in 33.1% of patients with sotorasib, compared with 40.4% of patients on docetaxel.
 

‘Tremendous advance’

“I think the conduct of this study is impressive, it’s well designed, it was well run, any imbalances really favored the control arm, and I think that this advance is relevant not just for performance status 0 and 1 KRAS G12C–mutant patients, but even beyond, to performance status 2 and perhaps even performance status 3,” commented Natasha Leighl, MD, MMSc, from the Princess Margaret Cancer Center, Toronto, the invited discussant.

Comparing the drug performance of the respective arms, Dr. Leighl said that “I don’t think I’ve ever seen such good outcomes in a randomized trial with the chemotherapy, but unfortunately sotorasib performed a little bit less well than we had hoped.”

Nonetheless, “I think CodeBreaK 200 is a tremendous advance for patients. It is a confirmatory positive trial, and I think sotorasib is the new standard of care in patients who have received chemo and immunotherapy for KRAS G12C–mutant lung cancer,” she said.

CodeBreaK 200 was supported by Amgen. Dr. Johnson disclosed a consulting and advisory role with payments to her institution from Amgen and others. Dr. Leighl disclosed institutional grant funding and personal honoraria from Amgen and others.

PARIS – For patients with non–small cell lung cancers (NSCLC) bearing the KRAS G12C mutation that have progressed on prior therapies, the first-in-class KRAS G12C inhibitor sotorasib (Lumykras) was associated with better progression-free survival (PFS) and objective response rates than docetaxel in the randomized, phase 3 CodeBreaK 200 trial.

­Among 345 patients who had experienced disease progression after prior platinum-based chemotherapy and an immune checkpoint inhibitor, 1-year PFS rates at a median follow-up of 17.7 months were 24.8% for patients randomized to receive sotorasib versus 10.1% for patients assigned to docetaxel, reported Melissa L, Johnson, MD, from the Sarah Cannon Research Institute at Tennessee Oncology in Nashville.

“In my opinion, this supports sotorasib as a new second-line standard for patients with KRAS G12C non–small cell lung cancer,” she said in a media briefing prior to her presentation of the data in an oral abstract session at the annual meeting of the European Society for Medical Oncology.
 

First phase 3, randomized, controlled trial

The trial is the first head-to-head, randomized comparison pitting a KRAS G12C inhibitor against the standard of care in patients with NSCLC.

Approximately 30% of patients with NSCLC have KRAS driver mutations, and KRAS G12C–mutant NSCLC comprises an estimated 13% of all NSCLC cases, Dr. Johnson said.

Sotorasib was hailed as “a triumph of drug discovery” when early results of the trial were reported at the 2020 ESMO annual meeting. It is a small-molecule, specific, and irreversible inhibitor of KRAS that interacts with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drug inhibits oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form.
 

CodeBreaK 200 details

A total of 345 patients from sites in the United States, Europe, Asia and Australia were enrolled and randomly assigned to receive either oral sotorasib 960 mg daily, or intravenous docetaxel 75 mg/m² every 3 weeks.

As noted before, the trial met its primary endpoint of a statistically significant improvement in PFS with sotorasib as measured by independent central reviewers blinded to study assignment, with a hazard ratio of 0.66 (P = .002). Median PFS with sotorasib was 5.6 months, compared with 4.5 months for docetaxel.

The objective response rate was significantly improved for sotorasib versus docetaxel (28.1% vs. 13.2%, P < .001), as was the disease control rate at 82.5% for sotorasib versus 60.3% for docetaxel. Overall survival was not significantly different between treatment arms, though the study was not powered for this endpoint.

Sotorasib was also superior to docetaxel at forestalling deterioration of patients’ global health status, physical functioning, and cancer-related symptoms such as dyspnea and cough. There was no significant difference between the study arms in reported chest pain, however.

Grade 3 or greater treatment-related adverse events occurred in 33.1% of patients with sotorasib, compared with 40.4% of patients on docetaxel.
 

‘Tremendous advance’

“I think the conduct of this study is impressive, it’s well designed, it was well run, any imbalances really favored the control arm, and I think that this advance is relevant not just for performance status 0 and 1 KRAS G12C–mutant patients, but even beyond, to performance status 2 and perhaps even performance status 3,” commented Natasha Leighl, MD, MMSc, from the Princess Margaret Cancer Center, Toronto, the invited discussant.

Comparing the drug performance of the respective arms, Dr. Leighl said that “I don’t think I’ve ever seen such good outcomes in a randomized trial with the chemotherapy, but unfortunately sotorasib performed a little bit less well than we had hoped.”

Nonetheless, “I think CodeBreaK 200 is a tremendous advance for patients. It is a confirmatory positive trial, and I think sotorasib is the new standard of care in patients who have received chemo and immunotherapy for KRAS G12C–mutant lung cancer,” she said.

CodeBreaK 200 was supported by Amgen. Dr. Johnson disclosed a consulting and advisory role with payments to her institution from Amgen and others. Dr. Leighl disclosed institutional grant funding and personal honoraria from Amgen and others.

PARIS – For patients with non–small cell lung cancers (NSCLC) bearing the KRAS G12C mutation that have progressed on prior therapies, the first-in-class KRAS G12C inhibitor sotorasib (Lumykras) was associated with better progression-free survival (PFS) and objective response rates than docetaxel in the randomized, phase 3 CodeBreaK 200 trial.

­Among 345 patients who had experienced disease progression after prior platinum-based chemotherapy and an immune checkpoint inhibitor, 1-year PFS rates at a median follow-up of 17.7 months were 24.8% for patients randomized to receive sotorasib versus 10.1% for patients assigned to docetaxel, reported Melissa L, Johnson, MD, from the Sarah Cannon Research Institute at Tennessee Oncology in Nashville.

“In my opinion, this supports sotorasib as a new second-line standard for patients with KRAS G12C non–small cell lung cancer,” she said in a media briefing prior to her presentation of the data in an oral abstract session at the annual meeting of the European Society for Medical Oncology.
 

First phase 3, randomized, controlled trial

The trial is the first head-to-head, randomized comparison pitting a KRAS G12C inhibitor against the standard of care in patients with NSCLC.

Approximately 30% of patients with NSCLC have KRAS driver mutations, and KRAS G12C–mutant NSCLC comprises an estimated 13% of all NSCLC cases, Dr. Johnson said.

Sotorasib was hailed as “a triumph of drug discovery” when early results of the trial were reported at the 2020 ESMO annual meeting. It is a small-molecule, specific, and irreversible inhibitor of KRAS that interacts with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drug inhibits oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form.
 

CodeBreaK 200 details

A total of 345 patients from sites in the United States, Europe, Asia and Australia were enrolled and randomly assigned to receive either oral sotorasib 960 mg daily, or intravenous docetaxel 75 mg/m² every 3 weeks.

As noted before, the trial met its primary endpoint of a statistically significant improvement in PFS with sotorasib as measured by independent central reviewers blinded to study assignment, with a hazard ratio of 0.66 (P = .002). Median PFS with sotorasib was 5.6 months, compared with 4.5 months for docetaxel.

The objective response rate was significantly improved for sotorasib versus docetaxel (28.1% vs. 13.2%, P < .001), as was the disease control rate at 82.5% for sotorasib versus 60.3% for docetaxel. Overall survival was not significantly different between treatment arms, though the study was not powered for this endpoint.

Sotorasib was also superior to docetaxel at forestalling deterioration of patients’ global health status, physical functioning, and cancer-related symptoms such as dyspnea and cough. There was no significant difference between the study arms in reported chest pain, however.

Grade 3 or greater treatment-related adverse events occurred in 33.1% of patients with sotorasib, compared with 40.4% of patients on docetaxel.
 

‘Tremendous advance’

“I think the conduct of this study is impressive, it’s well designed, it was well run, any imbalances really favored the control arm, and I think that this advance is relevant not just for performance status 0 and 1 KRAS G12C–mutant patients, but even beyond, to performance status 2 and perhaps even performance status 3,” commented Natasha Leighl, MD, MMSc, from the Princess Margaret Cancer Center, Toronto, the invited discussant.

Comparing the drug performance of the respective arms, Dr. Leighl said that “I don’t think I’ve ever seen such good outcomes in a randomized trial with the chemotherapy, but unfortunately sotorasib performed a little bit less well than we had hoped.”

Nonetheless, “I think CodeBreaK 200 is a tremendous advance for patients. It is a confirmatory positive trial, and I think sotorasib is the new standard of care in patients who have received chemo and immunotherapy for KRAS G12C–mutant lung cancer,” she said.

CodeBreaK 200 was supported by Amgen. Dr. Johnson disclosed a consulting and advisory role with payments to her institution from Amgen and others. Dr. Leighl disclosed institutional grant funding and personal honoraria from Amgen and others.

PARIS – Patients with untreated non–small cell lung cancer (NSCLC) who could not withstand the rigors of platinum-based chemotherapy regimens had significantly better overall survival when treated with the immune checkpoint inhibitor atezolizumab (Tecentriq), compared with their counterparts treated with either vinorelbine or gemcitabine in a phase 3 randomized trial.

Among 353 patients with treatment-naive stage 3B to 4 NSCLC who were not candidates for platinum-based chemotherapy because of poor performance status (PS), advanced age, or significant comorbidities, the median overall survival (OS) was 10.3 months for patients treated with atezolizumab vs. 9.2 months for patients assigned to receive the investigator’s choice of single-agent chemotherapy.

This difference translated into a hazard ratio for death with atezolizumab of 0.78 (P = .028), Siow Ming Lee, MD, PhD, of University College London, reported at the ESMO Congress.

The 2-year OS rate with atezolizumab was 24.3%, compared with 12.4% for single-agent chemotherapy.

“When I saw the data, I was amazed. One of four patients survived for 2 years!” he said in an interview.

Neil Osterweil/MDedge News

Excluded from clinical trials

“Cancer chemotherapy has changed the treatment landscape for the metastatic NSCLC population, but these treatments are mainly recommended for fit patients,” Dr. Lee said during his presentation of the data in a presidential symposium.

First-line pivotal trials for lung cancer patients comparing either single-agent immunotherapy or an immunotherapy/chemotherapy combination have all been conducted in fit patients, with ECOG PS of 0 or 1, he noted.

“In reality, we still have a large population of unfit NSCLC patients, of at least 40%, many of which we cannot treat with standard platinum chemotherapy. There are many elderly patients with poor performance status, and the elderly with many comorbidities, and they are frequently on many drug medications, which we see frequently in our clinic,” he said.
 

Study details

To see whether immunotherapy could improve outcomes for unfit patients, investigators designed the IPSOS trial, a phase 3 multicenter open-label study of efficacy, safety, and patient-reported outcomes with atezolizumab compared with single-agent chemotherapy.

Patients from 23 centers in North America, South America, Europe, and Asia who were ineligible for platinum-based chemotherapy because of ECOG performance status of 2 or 3, or who were aged 70 or older with performance status 0 or 1 but with multiple comorbidities or other contraindications to platinum were stratified by histology, programmed death-ligand-1 (PD-L1) expression, and brain metastases, and were then randomly assigned to receive either atezolizumab 1,200 mg intravenously every 3 weeks (302 patients), or to investigator’s choice of either vinorelbine delivered orally or intravenously, according to local practice, or intravenous gemcitabine given intravenously per local practice (151 patients).

As noted before, overall survival, the primary endpoint, was significantly better with atezolizumab, translating into a 22% reduction in risk of death compared with chemotherapy.

The 1-year OS rates were 43.7% with atezolizumab vs. 36.6% with chemotherapy, and the 2-year rates were 24.3% vs. 12.4%, respectively.

­­A subgroup analysis showed trends toward better benefit for immunotherapy regardless of age, sex, race, performance status, history of tobacco use, tumor histology, stage, presence of liver metastases, number of metastatic sites, or PD-L1 expression levels. The benefit of atezolizumab was also significantly better among patients without brain metastases.

The median duration of response was 14 months with ateziluzmab vs. 7.8 months with chemotherapy. Respective objective response rates were 16.9% vs. 15.5%. Median progression-free survival, a secondary endpoint, was 4.2 months with atezolizumab and 4 months with chemotherapy, a difference that was not statistically significant. Median treatment duration was 3.5 months with atezolizumab, 2.3 months with gemcitabine, and 1.8 months with vinorelbine. Treatment-related adverse events of any grade occurred in 57% of patients on immunotherapy vs. 80.3% of those on chemotherapy. Grade 3 or 4 adverse events related to therapy occurred in 16.3% vs. 33.3%, respectively. About 13% of patients in each arm had an adverse event leading to drug discontinuation. There were three treatment-related deaths among patients on atezolizumab, and four among patients on chemotherapy. Compared with chemotherapy, atezolizumab was associated with stabilizing of health-related quality-of-life domains of functioning, and significant improvement in delaying the time to deterioration of chest pain.
 

Age is not prognostic

“I think it’s important though to remember that in this study there are very distinct populations of patients. Poor performance status and comorbidities are prognostic, but age is not,” Dr. Leighl said in her discussion.

“In terms of current standards, performance status 3 patients are currently recommended to have best supportive care unless a targeted therapy is available for them, and while PS 2 patients have been excluded from checkpoint inhibitor trials, we treat most of these patients the same way. In this study in particular, patients had to be ineligible for platinum doublet therapy, but of course this definition was subjective,” she said.

She also commented that “if we’re now going to treat everyone with atezolizumab, I think the budget impact of this is going to be huge.”

It will be important to identify more clearly those patients aged 80 and older who might benefit from atezolizumab in this setting by better incorporating biomarkers such as PD-L1 levels to determine who can benefit from therapy and who might be spared the necessity of coming into the hospital or clinic for regular intravenous infusions, she added.

The study was supported by F. Hoffman-La Roche. Dr. Lee disclosed research funding from the company to his institution. Dr. Leighl disclosed institutional grant funding and personal fees from Roche and others.

PARIS – Patients with untreated non–small cell lung cancer (NSCLC) who could not withstand the rigors of platinum-based chemotherapy regimens had significantly better overall survival when treated with the immune checkpoint inhibitor atezolizumab (Tecentriq), compared with their counterparts treated with either vinorelbine or gemcitabine in a phase 3 randomized trial.

Among 353 patients with treatment-naive stage 3B to 4 NSCLC who were not candidates for platinum-based chemotherapy because of poor performance status (PS), advanced age, or significant comorbidities, the median overall survival (OS) was 10.3 months for patients treated with atezolizumab vs. 9.2 months for patients assigned to receive the investigator’s choice of single-agent chemotherapy.

This difference translated into a hazard ratio for death with atezolizumab of 0.78 (P = .028), Siow Ming Lee, MD, PhD, of University College London, reported at the ESMO Congress.

The 2-year OS rate with atezolizumab was 24.3%, compared with 12.4% for single-agent chemotherapy.

“When I saw the data, I was amazed. One of four patients survived for 2 years!” he said in an interview.

Neil Osterweil/MDedge News

Excluded from clinical trials

“Cancer chemotherapy has changed the treatment landscape for the metastatic NSCLC population, but these treatments are mainly recommended for fit patients,” Dr. Lee said during his presentation of the data in a presidential symposium.

First-line pivotal trials for lung cancer patients comparing either single-agent immunotherapy or an immunotherapy/chemotherapy combination have all been conducted in fit patients, with ECOG PS of 0 or 1, he noted.

“In reality, we still have a large population of unfit NSCLC patients, of at least 40%, many of which we cannot treat with standard platinum chemotherapy. There are many elderly patients with poor performance status, and the elderly with many comorbidities, and they are frequently on many drug medications, which we see frequently in our clinic,” he said.
 

Study details

To see whether immunotherapy could improve outcomes for unfit patients, investigators designed the IPSOS trial, a phase 3 multicenter open-label study of efficacy, safety, and patient-reported outcomes with atezolizumab compared with single-agent chemotherapy.

Patients from 23 centers in North America, South America, Europe, and Asia who were ineligible for platinum-based chemotherapy because of ECOG performance status of 2 or 3, or who were aged 70 or older with performance status 0 or 1 but with multiple comorbidities or other contraindications to platinum were stratified by histology, programmed death-ligand-1 (PD-L1) expression, and brain metastases, and were then randomly assigned to receive either atezolizumab 1,200 mg intravenously every 3 weeks (302 patients), or to investigator’s choice of either vinorelbine delivered orally or intravenously, according to local practice, or intravenous gemcitabine given intravenously per local practice (151 patients).

As noted before, overall survival, the primary endpoint, was significantly better with atezolizumab, translating into a 22% reduction in risk of death compared with chemotherapy.

The 1-year OS rates were 43.7% with atezolizumab vs. 36.6% with chemotherapy, and the 2-year rates were 24.3% vs. 12.4%, respectively.

­­A subgroup analysis showed trends toward better benefit for immunotherapy regardless of age, sex, race, performance status, history of tobacco use, tumor histology, stage, presence of liver metastases, number of metastatic sites, or PD-L1 expression levels. The benefit of atezolizumab was also significantly better among patients without brain metastases.

The median duration of response was 14 months with ateziluzmab vs. 7.8 months with chemotherapy. Respective objective response rates were 16.9% vs. 15.5%. Median progression-free survival, a secondary endpoint, was 4.2 months with atezolizumab and 4 months with chemotherapy, a difference that was not statistically significant. Median treatment duration was 3.5 months with atezolizumab, 2.3 months with gemcitabine, and 1.8 months with vinorelbine. Treatment-related adverse events of any grade occurred in 57% of patients on immunotherapy vs. 80.3% of those on chemotherapy. Grade 3 or 4 adverse events related to therapy occurred in 16.3% vs. 33.3%, respectively. About 13% of patients in each arm had an adverse event leading to drug discontinuation. There were three treatment-related deaths among patients on atezolizumab, and four among patients on chemotherapy. Compared with chemotherapy, atezolizumab was associated with stabilizing of health-related quality-of-life domains of functioning, and significant improvement in delaying the time to deterioration of chest pain.
 

Age is not prognostic

“I think it’s important though to remember that in this study there are very distinct populations of patients. Poor performance status and comorbidities are prognostic, but age is not,” Dr. Leighl said in her discussion.

“In terms of current standards, performance status 3 patients are currently recommended to have best supportive care unless a targeted therapy is available for them, and while PS 2 patients have been excluded from checkpoint inhibitor trials, we treat most of these patients the same way. In this study in particular, patients had to be ineligible for platinum doublet therapy, but of course this definition was subjective,” she said.

She also commented that “if we’re now going to treat everyone with atezolizumab, I think the budget impact of this is going to be huge.”

It will be important to identify more clearly those patients aged 80 and older who might benefit from atezolizumab in this setting by better incorporating biomarkers such as PD-L1 levels to determine who can benefit from therapy and who might be spared the necessity of coming into the hospital or clinic for regular intravenous infusions, she added.

The study was supported by F. Hoffman-La Roche. Dr. Lee disclosed research funding from the company to his institution. Dr. Leighl disclosed institutional grant funding and personal fees from Roche and others.

PARIS – Patients with untreated non–small cell lung cancer (NSCLC) who could not withstand the rigors of platinum-based chemotherapy regimens had significantly better overall survival when treated with the immune checkpoint inhibitor atezolizumab (Tecentriq), compared with their counterparts treated with either vinorelbine or gemcitabine in a phase 3 randomized trial.

Among 353 patients with treatment-naive stage 3B to 4 NSCLC who were not candidates for platinum-based chemotherapy because of poor performance status (PS), advanced age, or significant comorbidities, the median overall survival (OS) was 10.3 months for patients treated with atezolizumab vs. 9.2 months for patients assigned to receive the investigator’s choice of single-agent chemotherapy.

This difference translated into a hazard ratio for death with atezolizumab of 0.78 (P = .028), Siow Ming Lee, MD, PhD, of University College London, reported at the ESMO Congress.

The 2-year OS rate with atezolizumab was 24.3%, compared with 12.4% for single-agent chemotherapy.

“When I saw the data, I was amazed. One of four patients survived for 2 years!” he said in an interview.

Neil Osterweil/MDedge News

Excluded from clinical trials

“Cancer chemotherapy has changed the treatment landscape for the metastatic NSCLC population, but these treatments are mainly recommended for fit patients,” Dr. Lee said during his presentation of the data in a presidential symposium.

First-line pivotal trials for lung cancer patients comparing either single-agent immunotherapy or an immunotherapy/chemotherapy combination have all been conducted in fit patients, with ECOG PS of 0 or 1, he noted.

“In reality, we still have a large population of unfit NSCLC patients, of at least 40%, many of which we cannot treat with standard platinum chemotherapy. There are many elderly patients with poor performance status, and the elderly with many comorbidities, and they are frequently on many drug medications, which we see frequently in our clinic,” he said.
 

Study details

To see whether immunotherapy could improve outcomes for unfit patients, investigators designed the IPSOS trial, a phase 3 multicenter open-label study of efficacy, safety, and patient-reported outcomes with atezolizumab compared with single-agent chemotherapy.

Patients from 23 centers in North America, South America, Europe, and Asia who were ineligible for platinum-based chemotherapy because of ECOG performance status of 2 or 3, or who were aged 70 or older with performance status 0 or 1 but with multiple comorbidities or other contraindications to platinum were stratified by histology, programmed death-ligand-1 (PD-L1) expression, and brain metastases, and were then randomly assigned to receive either atezolizumab 1,200 mg intravenously every 3 weeks (302 patients), or to investigator’s choice of either vinorelbine delivered orally or intravenously, according to local practice, or intravenous gemcitabine given intravenously per local practice (151 patients).

As noted before, overall survival, the primary endpoint, was significantly better with atezolizumab, translating into a 22% reduction in risk of death compared with chemotherapy.

The 1-year OS rates were 43.7% with atezolizumab vs. 36.6% with chemotherapy, and the 2-year rates were 24.3% vs. 12.4%, respectively.

­­A subgroup analysis showed trends toward better benefit for immunotherapy regardless of age, sex, race, performance status, history of tobacco use, tumor histology, stage, presence of liver metastases, number of metastatic sites, or PD-L1 expression levels. The benefit of atezolizumab was also significantly better among patients without brain metastases.

The median duration of response was 14 months with ateziluzmab vs. 7.8 months with chemotherapy. Respective objective response rates were 16.9% vs. 15.5%. Median progression-free survival, a secondary endpoint, was 4.2 months with atezolizumab and 4 months with chemotherapy, a difference that was not statistically significant. Median treatment duration was 3.5 months with atezolizumab, 2.3 months with gemcitabine, and 1.8 months with vinorelbine. Treatment-related adverse events of any grade occurred in 57% of patients on immunotherapy vs. 80.3% of those on chemotherapy. Grade 3 or 4 adverse events related to therapy occurred in 16.3% vs. 33.3%, respectively. About 13% of patients in each arm had an adverse event leading to drug discontinuation. There were three treatment-related deaths among patients on atezolizumab, and four among patients on chemotherapy. Compared with chemotherapy, atezolizumab was associated with stabilizing of health-related quality-of-life domains of functioning, and significant improvement in delaying the time to deterioration of chest pain.
 

Age is not prognostic

“I think it’s important though to remember that in this study there are very distinct populations of patients. Poor performance status and comorbidities are prognostic, but age is not,” Dr. Leighl said in her discussion.

“In terms of current standards, performance status 3 patients are currently recommended to have best supportive care unless a targeted therapy is available for them, and while PS 2 patients have been excluded from checkpoint inhibitor trials, we treat most of these patients the same way. In this study in particular, patients had to be ineligible for platinum doublet therapy, but of course this definition was subjective,” she said.

She also commented that “if we’re now going to treat everyone with atezolizumab, I think the budget impact of this is going to be huge.”

It will be important to identify more clearly those patients aged 80 and older who might benefit from atezolizumab in this setting by better incorporating biomarkers such as PD-L1 levels to determine who can benefit from therapy and who might be spared the necessity of coming into the hospital or clinic for regular intravenous infusions, she added.

The study was supported by F. Hoffman-La Roche. Dr. Lee disclosed research funding from the company to his institution. Dr. Leighl disclosed institutional grant funding and personal fees from Roche and others.

PARIS – If results of phase 3, randomized clinical trials are the gold standard for cancer drug approvals, then single-arm trials are at best a bronze or even brass standard, with results that should only be used, under certain conditions, for accelerated approvals that should then be followed by confirmatory studies.

In fact, many drugs approved over the last decade based solely on data from single-arm trials have been subsequently withdrawn when put through the rigors of a head-to-head randomized controlled trial, according to Bishal Gyawali, MD, PhD, from the department of oncology at Queen’s University, Kingston, Ont.

“Single-arm trials are not meant to provide confirmatory evidence sufficient for approval; However, that ship has sailed, and we have several drugs that are approved on the basis of single-arm trials, but we need to make sure that those approvals are accelerated or conditional approvals, not regular approval,” he said in a presentation included in a special session on drug approvals at the European Society for Medical Oncology Congress.

“We should not allow premature regular approval based on single-arm trials, because once a drug gets conditional approval, access is not an issue. Patients will have access to the drug anyway, but we should ensure that robust evidence follows, and long-term follow-up data are needed to develop confidence in the efficacy outcomes that are seen in single-arm trials,” he said.

In many cases, single-arm trials are large enough or of long enough duration that investigators could have reasonably performed a randomized controlled trial (RCT) in the first place, Dr. Gyawali added.
 

Why do single-arm trials?

The term “single-arm registration trial” is something of an oxymoron, he said, noting that the purpose of such trials should be whether to take the drug to a phase 3, randomized trial. But as authors of a 2019 study in JAMA Network Open showed, of a sample of phase 3 RCTs, 42% did not have a prior phase 2 trial, and 28% had a negative phase 2 trial. Single-arm trials may be acceptable for conditional drug approvals if all of the following conditions are met:

• A RCT is not possible because the disease is rare or randomization would be unethical.
• The safety of the drug is established and its potential benefits outweigh its risks.
• The drug is associated with a high and durable overall or objective response rate.
• The mechanism of action is supported by a strong scientific rationale, and if the drug may meet an unmet medical need.

Survival endpoints won’t do

Efficacy endpoints typically used in RCTs, such as progression-free survival (PFS) and overall survival (OS) can be misleading because they may be a result of the natural history of the disease and not the drug being tested, whereas ORRs are almost certainly reflective of the action of the drug itself, because spontaneous tumor regression is a rare phenomenon, Dr. Gyawali said.

He cautioned, however, that the ORR of placebo is not zero percent. For example in a 2018 study of sorafenib (Nexavar) versus placebo for advanced or refractory desmoid tumors, the ORR with the active drug was 33%, and the ORR for placebo was 20%.

It’s also open to question, he said, what constitutes an acceptably high ORR and duration of response, pointing to Food and Drug Administration accelerated approval of an indication for nivolumab (Opdivo) for treatment of patients with hepatocellular carcinoma (HCC) that had progressed on sorafenib. In the single-arm trial used as the basis for approval, the ORRs as assessed by an independent central review committee blinded to the results was 14.3%.

“So, nivolumab in hepatocellular cancer was approved on the basis of a response rate lower than that of placebo, albeit in a different tumor. But the point I’m trying to show here is we don’t have a good definition of what is a good response rate,” he said.

In July 2021, Bristol-Myers Squibb voluntarily withdrew the HCC indication for nivolumab, following negative results of the CheckMate 459 trial and a 5-4 vote against continuing the accelerated approval.
 

On second thought ...

Citing data compiled by Nathan I. Cherny, MD, from Shaare Zedek Medical Center, Jerusalem, Dr. Gyawali noted that 58 of 161 FDA approvals from 2017 to 2021 of drugs for adult solid tumors were based on single-arm trials. Of the 58 drugs, 39 received accelerated approvals, and 19 received regular approvals; of the 39 that received accelerated approvals, 4 were subsequently withdrawn, 8 were converted to regular approvals, and the remainder continued as accelerated approvals.

Interestingly, the median response rate among all the drugs was 40%, and did not differ between the type of approval received, suggesting that response rates are not predictive of whether a drug will receive a conditional or full-fledged go-ahead.
 

What’s rare and safe?

The definition of a rare disease in the United States is one that affects fewer than 40,000 per year, and in Europe it’s an incidence rate of less than 6 per 100,000 population, Dr. Gyawali noted. But he argued that even non–small cell lung cancer, the most common form of cancer in the world, could be considered rare if it is broken down into subtypes that are treated according to specific mutations that may occur in a relatively small number of patients.

He also noted that a specific drug’s safety, one of the most important criteria for granting approval to a drug based on a single-arm trial, can be difficult to judge without adequate controls for comparison.
 

Cherry-picking patients

Winette van der Graaf, MD, president of the European Organization for the Research and Treatment of Cancer, who attended the session where Dr. Gyawali’s presentation was played, said in an interview that clinicians should cast a critical eye on how trials are designed and conducted, including patient selection and choice of endpoints.

“One of the most obvious things to be concerned about is that we’re still having patients with good performance status enrolled, mostly PS 0 or 1, so how representative are these clinical trials for the patients we see in front of us on a daily basis?” she said.

“The other question is radiological endpoints, which we focus on with OS and PFS are most important for patients, especially if you consider that if patients may have asymptomatic disease, and we are only treating them with potentially toxic medication, what are we doing for them? Median overall survival when you look at all of these trials is only 4 months, so we really need to take into account how we affect patients in clinical trials,” she added.

Dr. van der Graaf emphasized that clinical trial investigators need to more routinely incorporate quality of life measures and other patient-reported outcomes in clinical trial results to help regulators and clinicians in practice get a better sense of the true clinical benefit of a new drug.

Dr. Gyawali did not disclose a funding source for his presentation. He reported consulting fees from Vivio Health and research grants from the American Society of Clinical Oncology. Dr. van der Graaf reported no conflicts of interest.

PARIS – If results of phase 3, randomized clinical trials are the gold standard for cancer drug approvals, then single-arm trials are at best a bronze or even brass standard, with results that should only be used, under certain conditions, for accelerated approvals that should then be followed by confirmatory studies.

In fact, many drugs approved over the last decade based solely on data from single-arm trials have been subsequently withdrawn when put through the rigors of a head-to-head randomized controlled trial, according to Bishal Gyawali, MD, PhD, from the department of oncology at Queen’s University, Kingston, Ont.

“Single-arm trials are not meant to provide confirmatory evidence sufficient for approval; However, that ship has sailed, and we have several drugs that are approved on the basis of single-arm trials, but we need to make sure that those approvals are accelerated or conditional approvals, not regular approval,” he said in a presentation included in a special session on drug approvals at the European Society for Medical Oncology Congress.

“We should not allow premature regular approval based on single-arm trials, because once a drug gets conditional approval, access is not an issue. Patients will have access to the drug anyway, but we should ensure that robust evidence follows, and long-term follow-up data are needed to develop confidence in the efficacy outcomes that are seen in single-arm trials,” he said.

In many cases, single-arm trials are large enough or of long enough duration that investigators could have reasonably performed a randomized controlled trial (RCT) in the first place, Dr. Gyawali added.
 

Why do single-arm trials?

The term “single-arm registration trial” is something of an oxymoron, he said, noting that the purpose of such trials should be whether to take the drug to a phase 3, randomized trial. But as authors of a 2019 study in JAMA Network Open showed, of a sample of phase 3 RCTs, 42% did not have a prior phase 2 trial, and 28% had a negative phase 2 trial. Single-arm trials may be acceptable for conditional drug approvals if all of the following conditions are met:

• A RCT is not possible because the disease is rare or randomization would be unethical.
• The safety of the drug is established and its potential benefits outweigh its risks.
• The drug is associated with a high and durable overall or objective response rate.
• The mechanism of action is supported by a strong scientific rationale, and if the drug may meet an unmet medical need.

Survival endpoints won’t do

Efficacy endpoints typically used in RCTs, such as progression-free survival (PFS) and overall survival (OS) can be misleading because they may be a result of the natural history of the disease and not the drug being tested, whereas ORRs are almost certainly reflective of the action of the drug itself, because spontaneous tumor regression is a rare phenomenon, Dr. Gyawali said.

He cautioned, however, that the ORR of placebo is not zero percent. For example in a 2018 study of sorafenib (Nexavar) versus placebo for advanced or refractory desmoid tumors, the ORR with the active drug was 33%, and the ORR for placebo was 20%.

It’s also open to question, he said, what constitutes an acceptably high ORR and duration of response, pointing to Food and Drug Administration accelerated approval of an indication for nivolumab (Opdivo) for treatment of patients with hepatocellular carcinoma (HCC) that had progressed on sorafenib. In the single-arm trial used as the basis for approval, the ORRs as assessed by an independent central review committee blinded to the results was 14.3%.

“So, nivolumab in hepatocellular cancer was approved on the basis of a response rate lower than that of placebo, albeit in a different tumor. But the point I’m trying to show here is we don’t have a good definition of what is a good response rate,” he said.

In July 2021, Bristol-Myers Squibb voluntarily withdrew the HCC indication for nivolumab, following negative results of the CheckMate 459 trial and a 5-4 vote against continuing the accelerated approval.
 

On second thought ...

Citing data compiled by Nathan I. Cherny, MD, from Shaare Zedek Medical Center, Jerusalem, Dr. Gyawali noted that 58 of 161 FDA approvals from 2017 to 2021 of drugs for adult solid tumors were based on single-arm trials. Of the 58 drugs, 39 received accelerated approvals, and 19 received regular approvals; of the 39 that received accelerated approvals, 4 were subsequently withdrawn, 8 were converted to regular approvals, and the remainder continued as accelerated approvals.

Interestingly, the median response rate among all the drugs was 40%, and did not differ between the type of approval received, suggesting that response rates are not predictive of whether a drug will receive a conditional or full-fledged go-ahead.
 

What’s rare and safe?

The definition of a rare disease in the United States is one that affects fewer than 40,000 per year, and in Europe it’s an incidence rate of less than 6 per 100,000 population, Dr. Gyawali noted. But he argued that even non–small cell lung cancer, the most common form of cancer in the world, could be considered rare if it is broken down into subtypes that are treated according to specific mutations that may occur in a relatively small number of patients.

He also noted that a specific drug’s safety, one of the most important criteria for granting approval to a drug based on a single-arm trial, can be difficult to judge without adequate controls for comparison.
 

Cherry-picking patients

Winette van der Graaf, MD, president of the European Organization for the Research and Treatment of Cancer, who attended the session where Dr. Gyawali’s presentation was played, said in an interview that clinicians should cast a critical eye on how trials are designed and conducted, including patient selection and choice of endpoints.

“One of the most obvious things to be concerned about is that we’re still having patients with good performance status enrolled, mostly PS 0 or 1, so how representative are these clinical trials for the patients we see in front of us on a daily basis?” she said.

“The other question is radiological endpoints, which we focus on with OS and PFS are most important for patients, especially if you consider that if patients may have asymptomatic disease, and we are only treating them with potentially toxic medication, what are we doing for them? Median overall survival when you look at all of these trials is only 4 months, so we really need to take into account how we affect patients in clinical trials,” she added.

Dr. van der Graaf emphasized that clinical trial investigators need to more routinely incorporate quality of life measures and other patient-reported outcomes in clinical trial results to help regulators and clinicians in practice get a better sense of the true clinical benefit of a new drug.

Dr. Gyawali did not disclose a funding source for his presentation. He reported consulting fees from Vivio Health and research grants from the American Society of Clinical Oncology. Dr. van der Graaf reported no conflicts of interest.

PARIS – If results of phase 3, randomized clinical trials are the gold standard for cancer drug approvals, then single-arm trials are at best a bronze or even brass standard, with results that should only be used, under certain conditions, for accelerated approvals that should then be followed by confirmatory studies.

In fact, many drugs approved over the last decade based solely on data from single-arm trials have been subsequently withdrawn when put through the rigors of a head-to-head randomized controlled trial, according to Bishal Gyawali, MD, PhD, from the department of oncology at Queen’s University, Kingston, Ont.

“Single-arm trials are not meant to provide confirmatory evidence sufficient for approval; However, that ship has sailed, and we have several drugs that are approved on the basis of single-arm trials, but we need to make sure that those approvals are accelerated or conditional approvals, not regular approval,” he said in a presentation included in a special session on drug approvals at the European Society for Medical Oncology Congress.

“We should not allow premature regular approval based on single-arm trials, because once a drug gets conditional approval, access is not an issue. Patients will have access to the drug anyway, but we should ensure that robust evidence follows, and long-term follow-up data are needed to develop confidence in the efficacy outcomes that are seen in single-arm trials,” he said.

In many cases, single-arm trials are large enough or of long enough duration that investigators could have reasonably performed a randomized controlled trial (RCT) in the first place, Dr. Gyawali added.
 

Why do single-arm trials?

The term “single-arm registration trial” is something of an oxymoron, he said, noting that the purpose of such trials should be whether to take the drug to a phase 3, randomized trial. But as authors of a 2019 study in JAMA Network Open showed, of a sample of phase 3 RCTs, 42% did not have a prior phase 2 trial, and 28% had a negative phase 2 trial. Single-arm trials may be acceptable for conditional drug approvals if all of the following conditions are met:

• A RCT is not possible because the disease is rare or randomization would be unethical.
• The safety of the drug is established and its potential benefits outweigh its risks.
• The drug is associated with a high and durable overall or objective response rate.
• The mechanism of action is supported by a strong scientific rationale, and if the drug may meet an unmet medical need.

Survival endpoints won’t do

Efficacy endpoints typically used in RCTs, such as progression-free survival (PFS) and overall survival (OS) can be misleading because they may be a result of the natural history of the disease and not the drug being tested, whereas ORRs are almost certainly reflective of the action of the drug itself, because spontaneous tumor regression is a rare phenomenon, Dr. Gyawali said.

He cautioned, however, that the ORR of placebo is not zero percent. For example in a 2018 study of sorafenib (Nexavar) versus placebo for advanced or refractory desmoid tumors, the ORR with the active drug was 33%, and the ORR for placebo was 20%.

It’s also open to question, he said, what constitutes an acceptably high ORR and duration of response, pointing to Food and Drug Administration accelerated approval of an indication for nivolumab (Opdivo) for treatment of patients with hepatocellular carcinoma (HCC) that had progressed on sorafenib. In the single-arm trial used as the basis for approval, the ORRs as assessed by an independent central review committee blinded to the results was 14.3%.

“So, nivolumab in hepatocellular cancer was approved on the basis of a response rate lower than that of placebo, albeit in a different tumor. But the point I’m trying to show here is we don’t have a good definition of what is a good response rate,” he said.

In July 2021, Bristol-Myers Squibb voluntarily withdrew the HCC indication for nivolumab, following negative results of the CheckMate 459 trial and a 5-4 vote against continuing the accelerated approval.
 

On second thought ...

Citing data compiled by Nathan I. Cherny, MD, from Shaare Zedek Medical Center, Jerusalem, Dr. Gyawali noted that 58 of 161 FDA approvals from 2017 to 2021 of drugs for adult solid tumors were based on single-arm trials. Of the 58 drugs, 39 received accelerated approvals, and 19 received regular approvals; of the 39 that received accelerated approvals, 4 were subsequently withdrawn, 8 were converted to regular approvals, and the remainder continued as accelerated approvals.

Interestingly, the median response rate among all the drugs was 40%, and did not differ between the type of approval received, suggesting that response rates are not predictive of whether a drug will receive a conditional or full-fledged go-ahead.
 

What’s rare and safe?

The definition of a rare disease in the United States is one that affects fewer than 40,000 per year, and in Europe it’s an incidence rate of less than 6 per 100,000 population, Dr. Gyawali noted. But he argued that even non–small cell lung cancer, the most common form of cancer in the world, could be considered rare if it is broken down into subtypes that are treated according to specific mutations that may occur in a relatively small number of patients.

He also noted that a specific drug’s safety, one of the most important criteria for granting approval to a drug based on a single-arm trial, can be difficult to judge without adequate controls for comparison.
 

Cherry-picking patients

Winette van der Graaf, MD, president of the European Organization for the Research and Treatment of Cancer, who attended the session where Dr. Gyawali’s presentation was played, said in an interview that clinicians should cast a critical eye on how trials are designed and conducted, including patient selection and choice of endpoints.

“One of the most obvious things to be concerned about is that we’re still having patients with good performance status enrolled, mostly PS 0 or 1, so how representative are these clinical trials for the patients we see in front of us on a daily basis?” she said.

“The other question is radiological endpoints, which we focus on with OS and PFS are most important for patients, especially if you consider that if patients may have asymptomatic disease, and we are only treating them with potentially toxic medication, what are we doing for them? Median overall survival when you look at all of these trials is only 4 months, so we really need to take into account how we affect patients in clinical trials,” she added.

Dr. van der Graaf emphasized that clinical trial investigators need to more routinely incorporate quality of life measures and other patient-reported outcomes in clinical trial results to help regulators and clinicians in practice get a better sense of the true clinical benefit of a new drug.

Dr. Gyawali did not disclose a funding source for his presentation. He reported consulting fees from Vivio Health and research grants from the American Society of Clinical Oncology. Dr. van der Graaf reported no conflicts of interest.