VEGF Blockade and Combination Therapeutic Options in Advanced Renal Cell Carcinoma - Andrea Apolo

July 8, 2021

In this conversation, Rana McKay and Andrea Apolo highlight several studies presented during the ASCO 2021 Annual Meeting on combination therapeutic options for advanced renal cell carcinoma (RCC). Dr. Apolo expands on several studies she highlighted in her presentation and where these treatment options fit into the treatment landscape of advanced RCC potentially enhancing the immune effect of immunotherapy. In terms of treatment sequencing Drs. Apolo and McKay discuss the long-awaited CANTATA study and the PDIGREE trial. The CANTATA study evaluated the first-in-class oral selective glutaminase inhibitor telaglenastat, which has demonstrated anti-tumor activity in combination with everolimus and with cabozantinib. Dr. Apolo also highlights results from 42-month follow-up of KEYNOTE-426, pembrolizumab plus axitinib versus sunitinib as first-line therapy, the health-related quality-of-life analysis from the phase 3 CLEAR trial of lenvatinib + pembrolizumab or everolimus versus sunitinib for patients with advanced RCC, first results of a randomized controlled trial of nivolumab and ipilimumab with or without CBM-588, the CheckMate-214, and CheckMate-9ER trials.


Andrea B. Apolo, MD, Investigator Genitourinary Malignancies Branch NIH Lasker Clinical Research Scholar Head, Bladder Cancer Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD

Rana R. McKay, MD, Medical Oncologist, Assistant Professor of Medicine, UC San Diego Health

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Rana McKay: Welcome, today. Thank you for joining us on UroToday. We have our wonderful guest Andrea Apolo giving us a recap of this year's virtual ASCO meeting. Andrea is the head of the Bladder Section of the GU Malignancies Branch of the NCI and we are so excited to have her here with us today. Welcome, Andrea.

Andrea Apolo: Thank you so much for having me. It's a pleasure to be here and talk about the exciting things that happened at ASCO this year.

Rana McKay: Wonderful. So we're going to start with Abstract 4501, the CANTATA trial. I think we've been eagerly awaiting the results of this study of this novel glutaminase inhibitor, telaglenastat, that was paired with cabozantinib versus cabozantinib alone for people with metastatic treatment-refractory renal cell carcinoma. Maybe you can highlight the study results and tell us what your thoughts are about it.

Andrea Apolo: Yeah. So this was a very long-awaited study, the CANTATA study with the agent telaglenastat, which is a first-in-class oral selective glutaminase inhibitor, like you said, which has demonstrated anti-tumor activity in combination with everolimus and with cabozantinib, too. But CANTATA was a randomized phase two study of telaglenastat with cabozantinib daily, versus cabozantinib in patients with metastatic renal cell carcinoma that previously received therapy. They were either second-line or third-line and they could have received one anti-androgenic therapy or they could have received immunotherapy, either monotherapy or nivolumab, and ipilimumab. And the primary endpoint was progression-free survival. 444 patients were randomized and in terms of prior therapy, more than half of the patients, about 60% of the patients had one prior line of therapy and 43% had two lines of prior therapy.

And interesting is that about two-thirds of the patients had prior checkpoint inhibitors of which about half of those, 30%, had nivo-ipi. So that is important because the status gives us a look at cabozantinib in this setting post-checkpoint inhibitor. The outcome was that the combination of telaglenastat with cabozantinib had no PFS, OS, or overall response rate benefit when you added telaglenastat to cabozantinib. Interestingly though, and the authors do point out, that there was a numerical improvement in progression-free survival by about two months in patients that had received prior checkpoint inhibitor and got the combination of telaglenastat and cabozantinib.

And that's interesting as we think about sequencing therapies and I discussed this when I discussed the abstract. When we looked at the METEOR trial where patients were post-TKIs, and they were randomized to receive cabozantinib versus everolimus, the PFS that we have in terms of the outcome for those patients, there was a benefit for cabozantinib over everolimus. But when you compare the data with the CANTATA study, where a lot of patients, two-thirds of them, had prior checkpoint inhibitor, it's interesting to see that the PFS is much greater in the CANTATA study.

So there seems to be a benefit in sequencing the therapies, and I think that this data set is going to be really important because of that. And I wanted to mention that there is a trial right now, the PDIGREE Trial, run by Dr. Tian Zhang through the Alliance where they are really asking sequencing therapies, and they start off with nivo-ipi, and then patients are randomized depending on their response to receive either nivo alone if they have a CR. If they have a PR stable disease, then they are randomized to receive cabo-nivo. And then if they have progressive disease, they get cab-1. I think sequencing is going to be really important as we have all these therapies available now for patients with metastatic renal cell carcinoma.

Rana McKay: That's really excellent. I think a great overview of the trial. I do agree with you that I think the CANTATA trial does provide a contemporary dataset of the performance of cabo in kind of the modern era and the subset of patients that got nivo-ipi and looking at the activity of cabo post-modern-day regimens, I think is going to be important for the future. And I want to say that, I don't know if there are plans to potentially look at a combination telaglenastat with IO or in a biomarker selected patient population. What are your thoughts on that? Do you think that there is still potential for this agent? I think we were really all enthusiastic about it being a successful trial. Do you think that other combinations should be explored or a biomarker-specific cohort should be looked at?

Andrea Apolo: They didn't report on a biomarker in the abstract, but I think that would be very important. In combination with immunotherapy would also be very interesting. They did say that they would look into additional combinations, so I think that they are planning to do additional studies with the agents. I don't think that we are done with it, even though it didn't show a benefit in this particular study.

Rana McKay: That's great. And then anything else, kind of new agents kind of on the horizon or new targets on the horizon that we should be on the lookout for in the coming months to years?

Andrea Apolo: Yeah, I think that's a great question. There's a couple of abstracts and that were presented looking at novel TKIs, and I'm also looking at potentially enhancing the immune effect of immunotherapy. There was one that was very interesting, presented by Dr. Meza with CBM-588, which is a probiotic that may increase the effects of immunotherapy. And that was in combination with nivo-ipi in patients with metastatic renal cell carcinoma. Vorolanib plus everolimus in the CONCEPT study were also presented in patients with renal cell carcinoma. That's another VEGF-targeted agent. So I think these agents are not all similar, although we have a lot of TKIs that we work with and that have activity in renal cell carcinoma, they are all a little bit different, and really understanding their targets is going to be important and especially how we combine them.

Rana McKay: That's excellent. It was really exciting to see that randomized trial with a probiotic. I have not seen data like that, looking at interrogating an agent that impacts the microbiome with some elegant correlative work really done, in really lots of solid tumors. I think there's not a lot of randomized trials like this in people with advanced disease with a probiotic with an immunologic agent. So kudos to the team at City of Hope and Dr. Pal for that trial. So thank you for that.

We are going to kind of shift gears a little bit now, kind of going into the data regarding the CLEAR trial, abstract 4502. As we know, the efficacy data were presented at the genital urinary cancer symposium in 2021,  and certainly yet another efficacious regimen. Dr. Motzer presented the health-related quality of life data, which I think is something that's been becoming increasingly more important as patients are living longer, making sure that they are truly living better. So maybe you can give us a summary of the data that Dr. Motzer presented and then think about placing it in context with the other IO VEGF combos.

Andrea Apolo: Yeah, this is such an important study. And I think in general, looking at the quality of life in our patients is really important, but the tools that we use are still in development. And I think that it does need to be noted that although in some regimens, in some studies, the same tools were used, not always are the same tools used. So Dr. Motzer presented abstract 4502, looking at the health-related quality of life in the CLEAR study. The CLEAR study is a randomized first-line study in metastatic renal cell carcinoma patients. It has three arms: lenvatinib and pembrolizumab, lenvatinib, and everolimus versus sunitinib, and in the study, he used three quality of life instruments: the FKSI-DRS, the EORTC QLQ-C30, and the EQ-5D-3L.

And it's a mouthful to say these, but these have been really developed specifically for patients with cancer and some of them specifically for kidney cancer patients. And I thought it was important to go through the questionnaire so when I discuss the abstract, I actually put the questionnaire up just so people can see the questions. The FKSI-DRS includes nine questions focusing on symptoms, such as lack of energy, pain, weight loss, and fevers, among other things. And the EORTC QLQ-C30 includes 30 questions that focus on the activity level that the patient has, whether they are depressed, anxious, overall how they feel, and the EQ-5D-3L assesses the activity of the patient, self-care, pain, depression, and also includes sort of a visual skill where the patient says, "This is how I feel." And you can just kind of look at a scale.

It basically goes up from zero to a hundred and they can kind of say, "This is how I feel today." And then those answers are then added, and they are divided by the number of answers that the patient answers at baseline and at each time point while they are getting treatment, and then they are compared. And this works really great in randomized trials. And the wonderful thing is that these quality of life tools are being incorporated in large trials, and several of the large trials have incorporated these and reported these. But we do have to remember that a lot of these are exploratory, in that they do not predefine what is going to be a meaningful score. And they present p-values, but these are not predefined and they are not adjusted for multiple comparisons, so there is a lot of issues with the quality of life forms.

That being said, I think that they are a great step in really kind of us understanding how patients do with the therapies that they are receiving because a lot of these therapies can be toxic and can potentially decrease the quality of life that the patients have. So, for Dr. Mozart's abstract, he presented the quality of life for the three arms. For the lenvatinib and everolimus arm, when they compared to sunitinib, the quality of life scores were very similar to sunitinib. Maybe statistically, a little bit worse in the lenvatinib and everolimus in terms of pain, appetite, loss, diarrhea, and just the global health and quality of life score was favored actually to sunitinib, which makes sense because a combination can be a little bit harder to tolerate for some patients. And then looking at the three quality of life instruments with lenvatinib and pembrolizumab versus sunitinib, basically there was statistically no difference.

They looked at 18 factors and statistically four out of the 18 were a little bit better with the lenvatinib and pembrolizumab and over the sunitinib arm, and this included fatigue, dyspnea, constipation, and the physical function scale. So overall, looking at the quality of life data for the CLEAR study, there was no difference in the quality of life scores between lenvatinib and pembrolizumab compared to sunitinib, or lenvatinib and everolimus compared to sunitinib. Now let's put this into context with the other studies that have been reported there. The KEYNOTE-426 actually reported some preliminary data in a EUA abstract 2020 using the same quality of life instruments that the CLEAR study used. And similarly, there was no difference in the quality of life of the combination of axitinib and pembrolizumab compared to sunitinib, similar to lenvatinib/pembrolizumab versus sunitinib. So, there was no difference.

Looking at the CheckMate 214 study of nivolumab and ipilimumab and the CheckMate 9ER study of nivolumab and cabozantinib in terms of the quality of life instruments, they use the same quality of life instruments. So it's easier to compare between those two studies, between the two CheckMate studies. And there was actually a benefit in terms of the combinations versus sunitinib. So nivo-ipi patients had a better quality of life than sunitinib patients and the same thing for the cabo-nivo. The cabo-nivo patients had a better quality of life than the sunitinib. So, that is kind of putting it into context. And I kind of discussed this a little bit in my discussion, that it can be difficult to interpret, but if you have the same tools, then it can be a little bit easier to kind of understand what the findings and the quality of life studies mean in terms of our patient care and how they are doing overall.

Rana McKay: Wonderful summary, thank you so much for that. I think the quality of life data has probably been some of the hardest data to interpret because I think the instruments are all unique. They're all different across the studies. Understanding what is statistically significant versus what is actually clinically meaningful is also variable. So I think going through that, I think is really important. I think as patients are living longer, they are staying on the TKI therapy combinations for a longer period of time. I do think it's important to pay attention to the quality of life. Other things, like who's filling out the surveys, what's the drop-off and the compliance rate with the surveys, and how many questions are actually getting completed at every time. If people are feeling not great, are they going to want to complete a survey or are you kind of biasing towards people that are doing better, especially later on? So I think these are all important things to think about. You really hit the nail on the head kind of in reviewing sort of all that data. What are your thoughts about coming up with very standardized metrics for integration into trials, as should we just be using these three tools for kidney cancer standardization?  What are your thoughts on a sort of standardization?

Andrea Apolo: I think that we need to do that, and I think that is the goal of the investigators within the trials is to be able to interpret these and compare them across trials. So I think those efforts are ongoing, but once they are developed, if they are any different than what we already have, they do need to be validated. And that means they need to be correlated with outcomes in a trial in order to really see how closely your questions or these questions correlate with kind of how the patient is doing.

Rana McKay: Awesome. Well, thank you so much. That brings us right into our last abstract we'll discuss and also actually CheckMate 9ER as well. So abstract 4500 was the updated data from KEYNOTE-426 with pembro-axi. I think this is the final analysis at 42 months, and it would be great to kind of give an overview summary of the data that Dr. Rini presented. And I know that your very elegant work that... I mean, you were the champion of nivo-cabo. I think phase three would have never gotten done if you didn't have the thought. You developed the phase one study, basically, that led to the development of phase three. And so as we talk about KEYNOTE-426 and this efficacious regimen, kind of thinking about the 9ER data, too. So if you want to maybe give a summary of what Dr. Rini presented and then we will talk about it in context.

Andrea Apolo: Yeah. So, we were really looking forward to the results of the KEYNOTE-426 updated data. And just to summarize, KEYNOTE-426 is a phase three trial for patients also for the first-line treatment of metastatic clear-cell renal cell carcinoma. And the patients were randomized to pembrolizumab and axitinib versus sunitinib with the primary endpoint being PFS and OS, and these data have been reported, and we know this is very active. Axitinib and pembrolizumab were FDA approved in April 2019 so we know that this regimen is very active. What was being updated at ASCO was the 42-month follow-up because it is important to make sure that the OS and the PFS data continue to be robust, and in the report, it did. The overall survival data continued to be robust.

The hazard ratio was 0.73. The PFS data also continued to be robust. The hazard ratio was 0.68. The overall response rate, 60% for the axitinib pembrolizumab versus 40% for the sunitinib, and the complete response rate was 10% for axitinib and pembrolizumab versus 4% for the sunitinib. So, the data continues to be strong and continues to support the combination of pembrolizumab and axitinib as a standard of care in the first-line setting. What I did when I discussed the abstract, I put it into the context of other major studies that have been reported, including the CheckMate 9ER. I included the CheckMate 214 study, which now we have a 42-month follow-up in, so I think it's a fair comparison. I did include the intent to treat population, but really the CheckMate 214 data really focused their primary outcome on the patients with intermediate and poor risk, as opposed to just including the patients with favorable risk.

And I also included the CheckMate 9ER data, which has a 24 month follow up and the CLEAR study that has a 27-month follow-up. And looking at the PFS, at the OS, at the responses, all of the four trials that I just mentioned really have great efficacy in the frontline setting. And I did caution against comparing against trials just because there are different eligibility criteria, but there are also differences in the patients that end up enrolling and how they kind of are distributed in terms of the IMDC risk scores. So I included kind of how they broke down for each study and how this can really change the outcomes in terms of survival for each of these studies. But looking at the PFS and the OS, I'll mention the 9ER data from the 24-month follow-up.

I mean, the data looks great in terms of PFS, the hazard ratio is 0.524, OS is 0.66, so this is updated from the prior report. We updated this at GU ASCO, and we also updated, and I'll talk a little bit later about, we did a subgroup analysis of the CheckMate 9ER, but in terms of the OS and the PFS, comparing it to the KEYNOTE-426, these regimens are all active. So that's nivo-ipi, pembrolizumab/axitinib, cabozantinib and nivolumab, and lenvatinib and pembrolizumab. So just to remind everybody that the CLEAR Cell study had three arms: lenvatinib and pembrolizumab, lenvatinib and everolimus and sunitinib, and for the lenvatinib/pembrolizumab versus sunitinib, there was an improvement in PFS and an improvement in OS, but for the lenvatinib/everolimus, it was only an improvement in PFS, not in OS. So that is important, and it's important to kind of think about in terms of the context of first-line therapies.

Other factors that I think are important when we talk about these combinations are the treatment-free intervals. And this is something that I discuss in my discussion, is can we possibly discontinue these therapies and continue to benefit from the therapeutic effects? And we saw that in the KEYNOTE-426 study. They stopped at two years, and all this data that I'm reporting is with pembrolizumab given for a maximum of two years, however, axitinib could be continued. And I challenged that I think axitinib could possibly be discontinued. And we did that in my phase one cabo-nivo and cabo-nivo-ipi study. If the patients achieved a CR or a PR, we stopped both drugs after two years, and the patients that we did those in continued to have a benefit. There was one kidney cancer patient that did end up progressing at about a year and we challenged them and we were able to salvage that patient.

So, and the patient, he's still on therapy. But these are small numbers, and I think it's important to really do additional studies where we discontinue therapy because no one feels as good as they feel when they are off therapy. And we don't know when to discontinue these therapies, so I think it needs to be done in the setting of a clinical trial where we do this in a structured fashion and then we have the chance to retreat patients, especially now that we know that these therapies are active. I think that would be the next step, is when can we stop these therapies? And other things to consider as we had just talked about is of course the quality of life outcomes. But in general, the KEYNOTE-426 data just continues to show robust outcomes and continues to show activity after the long-term follow-up.

Rana McKay: That's really excellent to hear that I think we are in a world of riches here with regards to first-line options for patients with advanced RCC. I think one of the beauties about the long-term follow-up data is I think one of the biggest questions that have been on people's minds is, what's the durability associated with IOIO regimens versus IO VEGF regimens. And again, hard to compare between the trials, but you look at those PFS curves and you look at that nivo-ipi PFS curve, and it starts to plateau around 30 months or 32 months, somewhere in there. And it kind of holds steady. And I think this is probably the last update that we will see from KEYNOTE-426, but what are your thoughts around the durability of response, or is it just that it's hard to tell because the trial wasn't really designed to do that, so we can't really do that? I'd love to hear your thoughts.

Andrea Apolo: No, I think the durability of response is important. And I think that should be an outcome, that now that we do have these effective agents, that should be an outcome that should really be looked at closer and with more statistical rigor. But I do think that how long a patient can hold these responses is really critical, I mean, this is really critical. And we don't know what the best thing to look at is. Do we look at complete responses? Do we look at PRs? Honestly, I think that PRs a lot of times are almost as good as complete responses. It's just sometimes it can be very subjective as to what you're measuring. Are you measuring the scar? Are you really measuring a residual lesion there in responders? So I think that can be a little bit tricky, but really looking at the responses and the durability of the responses, I completely agree. I think that's going to be really important in looking at these trials and looking at the outcomes.

Rana McKay: Awesome. That's excellent. And then the last thing we'll end on is I know you presented some updated subgroup analysis from CheckMate 9ER of the combination of nivo-cabo versus sunitinib. I'd love to have you share that with us as I really think the only reason this regimen is out there has really been a lot of your hard work conducting phase one, showing the safety, showing the signal of efficacy that really spawned the generation of this phase three.

Andrea Apolo: Thank you. And we're actually excited about this data. I think the data is really important as we are trying to figure out what are the baseline characteristics of the patients that respond to cabo-nivo? So, this is an update of the CheckMate 9ER study, looking at the baseline characteristics of the patients and looking at how the patients did if they had certain characteristics. So we looked at the IMDC risk scores, we looked at favorable, we looked at intermediate, poor risk. We looked at organ sites of disease. Did the patient have disease in the liver? Did they have disease in the bone? Did they have disease in the lung? We looked at the size of the tumors, specifically of the target and of the non-target lesions. Did the number of organ sites that were affected actually change outcomes in terms of the responses? We looked at the size. We measured target lesions and we looked at what is the sum of the diameters of the target lesions?

And then we found the median, and then we found if you are above the median versus if you are below the median, really trying to assess the burden of disease. How do you do and which drug do you do best with? And looking at PFS and OS and overall response rate, in every single category, patients did better if they received cabo-nivo versus sunitinib. So it's really fun to kind of dive into the data and to kind of just really look at these parameters as we tried to identify the patients that may do best with the combination versus with a monotherapy like sunitinib, and really in all of these aspects, the patients that received the combination of cabozantinib and nivolumab did better.

Rana McKay: That's really amazing. It's really great to see those subgroup analyses kind of and really tease apart the data. I think it's excellent that we have now four regimens that improve OS for people with advanced disease.

Andrea, I want to thank you so much for joining us today on UroToday, and really summarizing these key abstracts from this year's virtual ASCO meeting. Hopefully, we will be able to reconvene in person at some time, but you really are a champion for patients in the field, so thank you so much for joining us today.

Andrea Apolo: Thank you so much for having me. It's been fun to chat and talk about all the data.

Rana McKay: Great.