Interpreting the Outcomes of a Non-Inferiority Phase II Trial: Comparing Lenvatinib Dosages and Their Impact on the Quality of Life in Renal Cell Carcinoma Patients - Cristiane Bergerot
July 7, 2023
Pedro Barata and Cristiane Bergerot discuss the quality of life data from the non-inferiority Phase II trial of lenvatinib/everolimus combination for the treatment of renal cell carcinoma (RCC). The study compares the starting doses of lenvatinib and finds that patients treated with a higher dose of 18mg experience better health-related quality of life and disease burden control. Dr. Bergerot asserts that despite expectations for improved quality of life on lower doses, their research shows that starting treatment with the higher dose is more beneficial for patients. Dr. Bergerot also highlights the importance of developing new measures to assess quality of life in kidney cancer treatments, noting that current methods may not fully capture the impacts of modern therapies. She reveals an ongoing study funded by the Kidney Cancer Association to explore this topic. The conversation underlines the critical need to consider patient experience and quality of life alongside efficacy when analyzing the impact of new treatments.
Biographies:
Cristiane Bergerot, PhD, MS, BS, Head of the Psycho-Oncology Department, Centro de Câncer de Brasília (CETTRO), Brasília, Brasil
Pedro C. Barata, MD, MSc, Leader of the Clinical GU Medical Oncology Research Program, University Hospitals Seidman Cancer Center, Associate Professor of Medicine, Case Western University, Cleveland, OH
Biographies:
Cristiane Bergerot, PhD, MS, BS, Head of the Psycho-Oncology Department, Centro de Câncer de Brasília (CETTRO), Brasília, Brasil
Pedro C. Barata, MD, MSc, Leader of the Clinical GU Medical Oncology Research Program, University Hospitals Seidman Cancer Center, Associate Professor of Medicine, Case Western University, Cleveland, OH
Read the Full Video Transcript
Pedro Barata: Hi there and welcome. I'm Pedro Barata, I'm a GU Medical Oncologist at Seidman Cancer Center. That's Case Western University in Cleveland, Ohio.
I'm really, really happy to be joined today by Cristiane Bergerot. She's a guru in psycho-oncology and quality of life in RCC. She's now actually, the head of psychosocial department of the entire onco clinic organization in Brazil. So it's a big job.
Cris, thank you so much for taking the time to be here with us. By the way, congratulations on your responsibilities.
Cristiane Bergerot: Oh, great. Thank you so much, Pedro. Also thank you to UroToday. It's a great pleasure to be here today. Thank you.
Pedro Barata: Absolutely. Listen, we're going to be chatting a little bit on your great paper, quality of life data, basically, on the non-inferiority Phase II trial of lenvatinib/everolimus combination. I personally find that to be a very important study, because it gives us a lot of insights about the real-world data for two doses, 18 plus five, versus 14 plus five, and multi percent efficacy results. And now, you had a fantastic paper coming out on the quality of life for those two combinations. So maybe I'll let you just summarize for the audience briefly, the design of that trial, if you can.
Cristiane Bergerot: Sure, sure.
This is a Phase II trial comparing to different starting dose of lenvatinib for the treatment of renal cell carcinoma. The main goal for our study was to determine if the treatments provide comparable participant experience with regards to health-related quality of life and disease burden.
Patients with advanced clear-cell carcinoma, and disease progressions on or after VEGF-TKI, were randomly assigned to one of two treatment arms in a 1:1 ratio. Arm one, patient has received lenvatinib 18 milligram as starting dose, and arm two, lenvatinib 14 milligram as a starting dose.
Patients were assessed for FKSI-DRS, EORTC QLQ-C30, and EQ-5D-3L at baseline on day one of each post-treatment cycle after cycle one, and at the end of the treatment visit.
Pedro Barata: Got it. That's fantastic, Cris. And you start mentioning, rightful so, the instruments that you use to measure quality of life. By the way, I should have said, the papers out on The Oncologist, was published not that long ago, actually very fresh and very important data.
So maybe, I mean, let me ask you, can you summarize for us, what are the main findings on the quality of life piece of the two cohorts of the study?
Cristiane Bergerot: Sure. In our longitudinal analysis, there were significant overall difference in favor of the lenvatinib 18-milligram group. And for time to deteriorations, we saw longer maintenance of health-related quality of life and symptom control within the lenvatinib 18-milligram group, particularly, for definitive deteriorations. And similar effects on gastrointestinal symptoms were found among both groups.
Pedro Barata: That is very interesting, in my opinion. I mean, from the efficacy perspective, I should say as know, when Monty presented those results. So we saw that we cannot say that 14 plus five is equivalent to 18 plus five, because you did not meet the primary endpoint on the efficacy analysis, which means, we cannot say 14/5 is non-inferior to 18/5.
But one would guess, the quality of life might be better on the lower dose, which in essence, that was the reason why the study was mandated, to compare the two doses. Because perhaps, the 18/5 was associated with a little bit more adverse events. We didn't know, so we had to ask that question, and answer it in a prospective manner.
So to me, what was interesting is, to what you're saying as well, that you're publishing to, is actually, not only we don't see a lot of the differences from the different instruments that you use, but actually for instance, if we think of time to the deterioration, it seemed to be longer with the 18/5 group than the 14/5 group; suggesting actually starting at a higher dose preserves quality of life for those patients, compared with the lower dose upfront.
So what are your comments about that? Is that something you guys expected when you did the analysis? What are your insights about that?
Cristiane Bergerot: Yeah. It was really curious, but the result from this exploratory analysis suggests the favorable clinical outcomes within this 18-milligram starting dose of lenvatinib. Considering our study, and the fact that we have noted that this finds impact on health-related quality of life and disease burden, we really consider it important for patients to be treated with this lenvatinib 18 milligrams starting dose, considering that they will have less disease burden and better clinical outcomes. But for sure, if you need to do some dose escalations, I think it will be part of the clinical decision. But it becomes clear that, in this situation, the better overall efficacy was clinically meaningful.
Pedro Barata: Got you. So I think it's a really important point, Cris, because when we talk about in the community and so forth, a lot of us are actually starting patients on a lower dose upfront. And really, this data is so important, because it's such that it tells us that, well, we should be treating patients with the dose that was approved, which is 18 plus five, and then adjust that accordingly, based on the tolerance of the patient, and so forth. I think that's truly important message, and it's a great thing that we have you here.
And maybe I'll take advantage from you, since I have you here, and you are an expert on these instruments we're using to assess quality of life. I mean, no instrument is perfect, right? I have to tell you that, a lot of us clinical practitioners, I think it's challenging sometimes, to understand the differences between the different quality of live instruments.
So let me ask you a more broader, a broad question. What are your comments about the instruments we're using? I mean, do you see limitations with them? Do you see strengths? How would you present that to a treating physician like me, or folks who might be listening to this? Just a general question about pros and cons, and what limitations you see when you use these instruments.
Cristiane Bergerot: Great. So these three measures are cancer specific measures. They were developed to possess sensitivity to change over time, and also to provide insight into disease and treatment related symptoms, and to assess the impact on daily life and overall burden of side effects. However, we know that these instruments were developed in a different era of treatment for renal cell carcinoma. So we are not considering exactly the challenge, or even the symptoms that patients are facing with the immunotherapy and targeted therapy that we have nowadays.
So considering that, we are developing a study funded by the Kidney Cancer Association, to better understand patient's perceptions about these current measures. And also, to guide us on the development of a new measure, that can exactly consider the specificity of each treatment options, and also, difference on disease stage, since nowadays, we have treatment in the adjuvant scenario, and also the metastatic scenario.
Pedro Barata: Got it. And I mean, this is wonderful, and I'm so happy the Kidney Cancer Association is actually funding work in the quality of life piece. I mean, we see that so important. It's been emerging as a very important topic, for example, in prostate cancer. So I'm really happy we are seeing those efforts, and energy being put in the kidney cancer arena as well. So I just have to, kudos to you and the teams that you work with, who are really pushing the envelope to teach us more about the tolerability, the patient's experience, patient reported outcomes, health related quality of life, while we test the efficacy of novel therapies moving forward, including monotherapies, as you said. So that's extremely important.
Cris, before I let you go, anything else you'd like to bring up for the group today?
Cristiane Bergerot: Yes, I think it was a great conversation, and we are really looking forward to present our data on these new measures for CARTITUDE-5. I think it will be useful for our patients, and also in these clinical trial scenarios. And hoping we can improve this data, and also, to have more information about our patients' experience during this type of treatment.
Pedro Barata: Yeah, no, that's great. We're definitely going to stay tuned for that, and we'll get you to sit here with us again to present that to the audience. So Cris, thank you so much for taking the time. Very generous of you. Congratulations for the fantastic work, and we'll see you soon. Thank you.
Cristiane Bergerot: Thank you so much. See you soon.
Pedro Barata: Hi there and welcome. I'm Pedro Barata, I'm a GU Medical Oncologist at Seidman Cancer Center. That's Case Western University in Cleveland, Ohio.
I'm really, really happy to be joined today by Cristiane Bergerot. She's a guru in psycho-oncology and quality of life in RCC. She's now actually, the head of psychosocial department of the entire onco clinic organization in Brazil. So it's a big job.
Cris, thank you so much for taking the time to be here with us. By the way, congratulations on your responsibilities.
Cristiane Bergerot: Oh, great. Thank you so much, Pedro. Also thank you to UroToday. It's a great pleasure to be here today. Thank you.
Pedro Barata: Absolutely. Listen, we're going to be chatting a little bit on your great paper, quality of life data, basically, on the non-inferiority Phase II trial of lenvatinib/everolimus combination. I personally find that to be a very important study, because it gives us a lot of insights about the real-world data for two doses, 18 plus five, versus 14 plus five, and multi percent efficacy results. And now, you had a fantastic paper coming out on the quality of life for those two combinations. So maybe I'll let you just summarize for the audience briefly, the design of that trial, if you can.
Cristiane Bergerot: Sure, sure.
This is a Phase II trial comparing to different starting dose of lenvatinib for the treatment of renal cell carcinoma. The main goal for our study was to determine if the treatments provide comparable participant experience with regards to health-related quality of life and disease burden.
Patients with advanced clear-cell carcinoma, and disease progressions on or after VEGF-TKI, were randomly assigned to one of two treatment arms in a 1:1 ratio. Arm one, patient has received lenvatinib 18 milligram as starting dose, and arm two, lenvatinib 14 milligram as a starting dose.
Patients were assessed for FKSI-DRS, EORTC QLQ-C30, and EQ-5D-3L at baseline on day one of each post-treatment cycle after cycle one, and at the end of the treatment visit.
Pedro Barata: Got it. That's fantastic, Cris. And you start mentioning, rightful so, the instruments that you use to measure quality of life. By the way, I should have said, the papers out on The Oncologist, was published not that long ago, actually very fresh and very important data.
So maybe, I mean, let me ask you, can you summarize for us, what are the main findings on the quality of life piece of the two cohorts of the study?
Cristiane Bergerot: Sure. In our longitudinal analysis, there were significant overall difference in favor of the lenvatinib 18-milligram group. And for time to deteriorations, we saw longer maintenance of health-related quality of life and symptom control within the lenvatinib 18-milligram group, particularly, for definitive deteriorations. And similar effects on gastrointestinal symptoms were found among both groups.
Pedro Barata: That is very interesting, in my opinion. I mean, from the efficacy perspective, I should say as know, when Monty presented those results. So we saw that we cannot say that 14 plus five is equivalent to 18 plus five, because you did not meet the primary endpoint on the efficacy analysis, which means, we cannot say 14/5 is non-inferior to 18/5.
But one would guess, the quality of life might be better on the lower dose, which in essence, that was the reason why the study was mandated, to compare the two doses. Because perhaps, the 18/5 was associated with a little bit more adverse events. We didn't know, so we had to ask that question, and answer it in a prospective manner.
So to me, what was interesting is, to what you're saying as well, that you're publishing to, is actually, not only we don't see a lot of the differences from the different instruments that you use, but actually for instance, if we think of time to the deterioration, it seemed to be longer with the 18/5 group than the 14/5 group; suggesting actually starting at a higher dose preserves quality of life for those patients, compared with the lower dose upfront.
So what are your comments about that? Is that something you guys expected when you did the analysis? What are your insights about that?
Cristiane Bergerot: Yeah. It was really curious, but the result from this exploratory analysis suggests the favorable clinical outcomes within this 18-milligram starting dose of lenvatinib. Considering our study, and the fact that we have noted that this finds impact on health-related quality of life and disease burden, we really consider it important for patients to be treated with this lenvatinib 18 milligrams starting dose, considering that they will have less disease burden and better clinical outcomes. But for sure, if you need to do some dose escalations, I think it will be part of the clinical decision. But it becomes clear that, in this situation, the better overall efficacy was clinically meaningful.
Pedro Barata: Got you. So I think it's a really important point, Cris, because when we talk about in the community and so forth, a lot of us are actually starting patients on a lower dose upfront. And really, this data is so important, because it's such that it tells us that, well, we should be treating patients with the dose that was approved, which is 18 plus five, and then adjust that accordingly, based on the tolerance of the patient, and so forth. I think that's truly important message, and it's a great thing that we have you here.
And maybe I'll take advantage from you, since I have you here, and you are an expert on these instruments we're using to assess quality of life. I mean, no instrument is perfect, right? I have to tell you that, a lot of us clinical practitioners, I think it's challenging sometimes, to understand the differences between the different quality of live instruments.
So let me ask you a more broader, a broad question. What are your comments about the instruments we're using? I mean, do you see limitations with them? Do you see strengths? How would you present that to a treating physician like me, or folks who might be listening to this? Just a general question about pros and cons, and what limitations you see when you use these instruments.
Cristiane Bergerot: Great. So these three measures are cancer specific measures. They were developed to possess sensitivity to change over time, and also to provide insight into disease and treatment related symptoms, and to assess the impact on daily life and overall burden of side effects. However, we know that these instruments were developed in a different era of treatment for renal cell carcinoma. So we are not considering exactly the challenge, or even the symptoms that patients are facing with the immunotherapy and targeted therapy that we have nowadays.
So considering that, we are developing a study funded by the Kidney Cancer Association, to better understand patient's perceptions about these current measures. And also, to guide us on the development of a new measure, that can exactly consider the specificity of each treatment options, and also, difference on disease stage, since nowadays, we have treatment in the adjuvant scenario, and also the metastatic scenario.
Pedro Barata: Got it. And I mean, this is wonderful, and I'm so happy the Kidney Cancer Association is actually funding work in the quality of life piece. I mean, we see that so important. It's been emerging as a very important topic, for example, in prostate cancer. So I'm really happy we are seeing those efforts, and energy being put in the kidney cancer arena as well. So I just have to, kudos to you and the teams that you work with, who are really pushing the envelope to teach us more about the tolerability, the patient's experience, patient reported outcomes, health related quality of life, while we test the efficacy of novel therapies moving forward, including monotherapies, as you said. So that's extremely important.
Cris, before I let you go, anything else you'd like to bring up for the group today?
Cristiane Bergerot: Yes, I think it was a great conversation, and we are really looking forward to present our data on these new measures for CARTITUDE-5. I think it will be useful for our patients, and also in these clinical trial scenarios. And hoping we can improve this data, and also, to have more information about our patients' experience during this type of treatment.
Pedro Barata: Yeah, no, that's great. We're definitely going to stay tuned for that, and we'll get you to sit here with us again to present that to the audience. So Cris, thank you so much for taking the time. Very generous of you. Congratulations for the fantastic work, and we'll see you soon. Thank you.
Cristiane Bergerot: Thank you so much. See you soon.