: For the past year or two and most recently at the Genitourinary Cancers Symposium, we are having an explosion of first-line options in this disease [metastatic renal cell carcinoma]. It is something quite refreshing. The combination of nivolumab and ipilimumab is the only IO [immunotherapy]/IO combination. After multiple cutoffs of the data and follow-up to 4 years, we’re seeing a hazard ratio for survival of 0.6, so stable. This is an option that is illustrated by the NCCN [National Comprehensive Cancer Network] guidelines as a first-line option. Now we are seeing more options coming along. The combination of pembrolizumab and axitinib does have an overall survival after several data cuts, and it is also a preferred regimen, both in [patients with ] favorable and intermediate-poor risk.

The nivolumab and ipilimumab combination is in poor and intermediate only.More recently the option of cabozantinib and nivolumab is also a preferred first-line option in both the favorable and the poor and intermediate, based on the CheckMate 9ER trial. This regimen was approved in January of 2021. There are other recommended regimens, some of them are combinations, some are as a single agent, but these are the most important frontline ones illustrated by the NCCN guidelines.

Frontline Combination Approaches for Metastatic RCC

Until recently, the standard of care for advanced RCC [renal cell carcinoma] consisted of tyrosine kinase inhibitors [TKIs] given as monotherapy. The dominant drugs were sunitinib and pazopanib. More recently it was evident that immunotherapy [IO] was active in RCC, resulting in prolonged survival with nivolumab as a monotherapy, durable responses, and good tolerability. This led to a number of studies that were done in parallel looking at immunotherapy in combination in first-line therapy for renal cell cancer compared to sunitinib monotherapy. The large phase 3 trials were all done in parallel. The regimens were not compared to each other, they were all compared to sunitinib. It makes it difficult to choose one of these drugs or combinations over the other.

The first combination to show a benefit for the intermediate- and poor-risk group was ipilimumab and nivolumab, or IPI/NIVO. That showed a benefit in overall survival [OS] and response rate, primarily in the intermediate- and poor-risk patients. It has the longest duration of follow-up, and it’s become an attractive option for those patients because their responses are sustained. We see about 10% complete responses, and there seems to be a leveling off of progression-free survival without further decline in this important metric. This suggests that response and benefit are sustained for over 4 years now. For the most part, that has been my go-to regimen in first-line therapy for patients who have intermediate- and poor-risk clear cell carcinoma.

More recently there have been 2 randomized phase 3 trials of TKIs plus PD-1 inhibitors, axitinib plus pembrolizumab, and nivolumab plus cabozantinib, that both were compared to sunitinib across the board in all risk groups and showed a benefit in overall survival, response rate, and progression-free survival. These are standouts as options for first-line therapy. Both are FDA approved, and both are now in the NCCN [National Comprehensive Cancer Network] guidelines. They stand above axitinib and avelumab, which didn’t show a survival benefit, because the survival benefit is valued as the gold standard for patient benefit with cancer therapeutics.

It’s difficult to choose one over the other because they haven’t been compared across studies, and either one of them is a good choice. For the most part, they are a good choice for patients who have favorable-risk clear cell carcinoma. They’re also a good choice for patients who have rapidly progressive disease who could run into trouble in a short time, in which you want to guarantee a response. This is because the response rate is so high, about 70%, with these different programs, and also that the response is seen at high levels regardless of risk group. In comparison, the initial response, at least to [ipilimumab, nivolumab], was lower than that of sunitinib in the 214 pivotal trial. Much of it comes down to physician preferences, experience in using these programs, and patient preference in terms of the trade-off for efficacy. There are different toxicity profiles for these different programs and different ways that they’re administered. The risk group can be used to help choose one program after another.

We as investigators are used to presenting the data like they are, and all of these combination treatments occurred at the same time in a way, in the same timeframe. Even if one combination got approved, the trials were still toward the end. What we have is a control arm, which is the same, sunitinib, but none of these combinations were compared against each other. We ended up comparing them in a not-so-scientific, statistically guided way. These were accrued in different years, different timeframe, and their baseline characteristics are different. The performance of the control arm, sunitinib, is different between arms.

Nivolumab and ipilimumab is for intermediate- and poor-risk disease. I don’t use it in favorable risk, knowing that the CR [complete remission] rate is over 10% in favorable risk. If you follow the CR rate as the most important thing, because complete responses tend to be durable, you’re justified to use it. With VEGF/IO, all the approval came in patients with all risk groups: favorable, intermediate, and poor, IMDC [International Metastatic RCC Database Consortium] risk group. On one hand, I follow the evidence of what are the regimens that gave you an overall survival benefit, which remains the gold standard, like it or not, at least when you have it. To that end, you have 3 combinations, 2 with pembrolizumab, which are pembrolizumab/axitinib and pembrolizumab/lenvatinib. The other is nivolumab, VEGF/IO, nivolumab/cabozantinib.

At this time, the pembrolizumab, lenvatinib paper is out, but the regimen is not approved in the US. This makes it a bit easier to compare cabozantinib/nivolumab and axitinib/pembrolizumab. Both do have an OS benefit after more than 1 data update. There are differences between both. Besides the familiarity of the regimen, which investigators, physicians, and health care workers should be familiar with how to use the drug, the baseline characteristics are different.

The cabozantinib plus nivolumab data from CheckMate 9ER had more patients with unfavorable risk categories in terms of the IMDC risk group. They had less favorable and more poor risk than the CLEAR study. They did have more patients without nephrectomy, which the rate of response will decrease with that. They have very strong quality-of-life data. Meanwhile, the CLEAR study was presented, it has the longest progression-free survival and CR to date. More importantly, in that study, it’s hard to put it at the same level yet, because this is the first data cut-off. We did not see quality-of-life data, nor what the OS with hazard ratio is going to be with the next data cut. The most important thing is there are options for patients, and that’s what matters.

Personal Approaches to Frontline Therapy for Metastatic RCC

More recently, at the American Society of Clinical Oncology Genitourinary Cancers Symposium and in 

, the results of the CLEAR trial were presented. This was a very important trial because it was a 3-arm study comparing lenvatinib/pembrolizumab to lenvatinib/everolimus to sunitinib in first-line therapy for patients with clear cell carcinoma. Both of the comparisons of the lenvatinib-containing arms statistically were made to sunitinib and not to each other.

The outcome of the trial showed that there was a powerful effect on progression-free survival [PFS] with lenvatinib/pembrolizumab, with a median PFS of over 23 months, compared to that with sunitinib. There was a high response rate of now over 70%. It’s the first time we’ve crossed that margin, and also notable, a 16% complete response rate by an independent review. Very few, about 5% of patients, had overt progression through that program, and there was a benefit in overall survival as well. The efficacy data looked quite extraordinary with the lenvatinib/[pembrolizumab] combination compared to sunitinib. Now, that is not yet FDA approved. The hope is that it will be soon, so it can be another tool in our medications for advanced RCC [renal cell carcinoma].

Lenvatinib/everolimus, in that study, the outcome was different, and it did show a benefit in progression-free survival, meeting its primary end point, and also a higher response. But the margin wasn’t as high as that with lenvatinib/[pembrolizumab] compared to sunitinib, and it didn’t show an improvement in overall survival. It’s the first of these trials to have more of a contemporary control arm in the study that does not include an immunotherapy [IO] or PD-1 agent. The significance of that study shows a proof of principle about the importance of IO therapy in first-line RCC treatment to achieve that overall survival benefit. A benefit in progression-free survival, and a benefit in response rate was seen as well, but you need that immunotherapy there to push it into a benefit in overall survival for patients. It served as proof of principle for that whole approach of IO in first-line therapy for RCC.

The Phase 3 CLEAR Study in Metastatic RCC

One of the aspects of different therapies is safety. Of course, safety remains always a concern. With all of the approved combinations—axitinib/avelumab, [axitinib/pembrolizumab], [cabozantinib/nivolumab], as of today, and hopefully in the future, [lenvatinib/pembrolizumab], which is the VEGF/IO [immunotherapy]—the initial studies, despite some toxicities, made it to phase 3 and made it to FDA approval, in many situations. While the combinations with nivolumab of sunitinib and pazopanib didn’t make it.

This is somewhat safe, people have looked at it, but it doesn’t mean that there are no toxicities or that this is going to be something very easy to take. All of these treatments are not taken for a short amount of time. Usually, they’re continued until progression. If you look at [lenvatinib/pembrolizumab] and with everything else, and look at treatment-related AEs [adverse events], how we now report AEs with CTCAE [Common Terminology Criteria for Adverse Events]

 , it makes it hard to tease out what is related, what is not related, what does it mean. The good thing is that the grade 3 or 4 adverse events tend to be low. That’s the one important thing, usually less than 10%. The second thing is if there any toxicities we are not aware of. 

Suddenly, is there a combination that led to an unusual degree of myelitis? And the answer is no. It seems that the toxicity comes from each single agent alone. Sometimes it’s hard to figure out what is causing what because there are some overlapping toxicities with diarrhea and LFTs [liver function test levels] that could be from the TKI [tyrosine kinase inhibitor] or the immune checkpoint inhibitor. What I rely on with this continuous treatment, is the treatment-related adverse event that led to complete treatment discontinuation of 1 or 2 drugs. We can see with all of the combinations, even if you look at [lenvatinib/pembrolizumab], it’s around 10% that lead to both drugs being discontinued because of AEs. Each drug alone is higher, between 18% and 25%. There are dose reductions. There are dose reductions with [pembrolizumab] overall in the [lenvatinib/pembrolizumab] CLEAR study. One of the reasons is we don’t know the dose of the TKI. This is not only lenvatinib, but also [cabozantinib] and others; we do not know.

[Cabozantinib] at 60 mg, once a day approved, 40 mg in combination with [nivolumab]. [Lenvatinib/pembrolizumab], I have seen 20 mg in combination, 20 mg of [lenvatinib]. That is what the phase 3 did. But then, if you look at the combination with everolimus, it’s 18 mg. And if you look at some of the studies with [lenvatinib]/everolimus, it’s between 14 and 18 mg; 18 mg seems to be a bit better, but then you have 20 mg in combination with [pembrolizumab]. The most important message is that it’s fine to start high, but be careful. You may need to dose reduce in the majority of the patients. That’s not a bad thing, as long as you know how to manage toxicities and how to provide the best exposure to patients. Some patients can stay on the lenvatinib at 20 mg, others may need to decrease to 18 mg or 14 mg or even lower, as long as the disease is controlled.

That would be the main message with toxicities, rather than comparing across trial the grade 3/4 [adverse events], it doesn’t help much, and may be confusing. How you would know that is by simply looking at the toxicity of the sunitinib control arm across all studies. There is a difference in toxicities. Look at the LFTs, diarrhea, treatment-related and not related, then say that’s the same arm, that is sunitinib. It was started at 50 mg, 4 weeks on 2 weeks off, how across the studies are there differences in reporting? That is one of the limitations of the toxicity grading we have in oncology.

Metastatic RCC: Frontline TKI/IO Safety Data

We at Memorial Sloan Kettering Cancer Center [MSKCC] are the primary center, and I was the principal investigator for the initial trial of lenvatinib/everolimus compared to lenvatinib monotherapy compared to everolimus, that resulted in regulatory approval for lenvatinib plus everolimus in second-line therapy for RCC [renal cell carcinoma]. I have had considerable experience with that particular regimen, and then certainly when lenvatinib/pembrolizumab was proposed as a trial, we were on board and were one of the initial centers that participated in that. This was a study that was done across different malignancies, including endometrial cancer. Our PI [principal investigator] at the site, Vicky Makker, [MD,] was very much involved in the development of the combination for endometrial cancer as well.

In RCC we led the accrual for that particular regimen. It’s a single-arm regimen. It was initially dose-finding and then expanded in different cohorts. The total number of patients treated on that was over 140, and I treated 20 or 30 patients on that program. MSKCC was also the lead center for the CLEAR phase 3 trial. In that study, we accrued close to 40 patients. I’ve had considerable experience with the lenvatinib/pembrolizumab regimen, and I have been impressed with that regimen with regard to its efficacy.

I do think overall it’s a generally well-tolerated regimen, and the key is to start out high with the lenvatinib, and then as toxicities or adverse events are seen, individualize treatment to that patient by dose reduction of the lenvatinib. More than half of the patients do get dose reductions of lenvatinib, and when looking at the long term with that program, many of the patients are being maintained on a dose of lenvatinib at 10 mg. That’s a very comfortable dose for long-term treatment. The high dose early on may be important for the extreme efficacy that’s been seen with the regimen. It’s an exceptionally good regimen. The efficacy is quite remarkable. I’m hoping that soon it will be a treatment program we can offer our patients.

We are blessed now with 4 combinations that have an OS [overall survival] benefit: [nivolumab/ipilimumab], [pembrolizumab/axitinib], [pembrolizumab/lenvatinib], and [cabozantinib/nivolumab]. [Pembrolizumab/lenvatinib] is not approved at this time, but this regimen is likely to be approved at some point. They all have an overall survival benefit. It’s going to be a bit hard, and it is going to be personal preference. You’ll have to follow the label, [nivolumab/ipilimumab] is for intermediate- and poor-risk disease.

The one advantage is once you’re done with the 3-month combination and you’re on [nivolumab] maintenance, there are no TKI [tyrosine kinase inhibitor] [adverse] effects, and you have a data set that has been updated up to 4 years showing a hazard ratio 0.6. Now the PD 

 rate is around 20%, and the response rate is 40%. If you need an immediate response, if you have a significant disease burden, you could respond very well, this is lower than all the VEGF/IO [immunotherapy] combinations that posted anywhere between 55% and 70% response rate with a low rate of PD. The second thing to look at with the VEGF/TKI combos that have an OS benefit—[cabozantinib/nivolumab, pembrolizumab/lenvatinib and pembrolizumab/axitinib]—are the quality-of-life data. 

The patient-reported outcome is the patient’s voice. And with what I mentioned about how the CTCAE [Common Terminology Criteria for Adverse Events] grading and toxicity reporting has many problems now, these were not devised for immunotherapy and TKIs. We have to dig more into the patient-reported outcomes to guide ours. To that extent, we have seen patient-reported outcomes with [cabozantinib/nivolumab], extensively so far, presented [at the Genitourinary Cancers Symposium 2021], that showed superiority over sunitinib. We have not seen that with the [pembrolizumab/axitinib] combination. It was not inferior to sunitinib, but there isn’t any metric that was superior, knowing the timing of that questionnaire was usually the same.

We haven’t seen any with [pembrolizumab/lenvatinib]. The other thing is not to forget, despite having combinations, that clinical trials are ongoing with 3 drugs versus 2 drugs. If we want to increase those responses and make them durable, one strategy is what is the 1 drug for this 1 patient, that concept of the biomarker. We haven’t had complete luck now, so perhaps we should revert back to many years ago and give the appropriate patients, say the intermediate and poor risk, a triple combination. These trials are ongoing.

I have experience with [pembrolizumab/axitinib], having co-led the phase 1 study with [Michael] Atkins, [MD]. I have experience with [pembrolizumab/lenvatinib] from the phase 3. I also have experience with [cabozantinib/nivolumab] from CheckMate 9ER. What we have done with our nursing staff and colleagues, is to be able to know the day-to-day management of these TKIs. That’s very important. The team here, at Dana-Farber [Cancer Institute], has done a great job, our nursing team and our research team, to manage the right dosage of the TKI to achieve the maximal exposure tolerated by the patient.

Implications for Treating Metastatic RCC With TKI/I-O Regimens Upfront

Many people are saying they want to get rid of the IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] risk groups…I get a lot of comments that they are a relic. They will say they want to do biomarkers, they want to sound smarter than they are. That is fine too, but there is no doubt that the IMDC and the MSKCC [Memorial Sloan Kettering Cancer Center risk stratification model] and all of these risk groups, do capture the natural biology of metastatic RCC [renal cell carcinoma]. We started to know why now for a few years because we are integrating DNA and RNA and the protein markers. We are seeing that the good-risk patients have more of an angiogenic signature. The poor-risk patients have an aggressive biology dictated by EMT [epithelial-mesenchymal transition], and may also have some infiltrated immune signals.

In probably less than 5 seconds, you could still guess the natural biology of this disease. They [the risk criteria] are important today, they remain important, and they should be used. Now, in the future, once we combine these drugs and we have more options and more CRs [complete remissions], perhaps there are not any more options with IMDC and it shouldn’t be used, except to de-escalate. We’ve already seen signals of this. If you look at the IMDC favorable risk, the OS [overall survival] benefit, not the PFS [progression-free survival], nor the response rate, the hazard ratio crosses 1 with most of these studies, or close to 1. It could mean that maybe for survival, if that’s what you are thinking about always, you don’t need 2 drugs, you need 1 drug. But which drug? I can’t tell you.

Do you need the TKI [tyrosine kinase inhibitor], or do you need the PD-1? There are more data with the TKI. On the other hand, with favorable risk, there aren’t studies that are powered enough for favorable risk only. These patients have more of an indolent course. So it’s possible that this hazard ratio close to 1 for OS is simply because we don’t have a thousand patients with favorable risk who are having enough events. That is also a possibility, which makes them [risk criteria] even more relevant today. But hopefully, tomorrow when we have 3, 4, or 5 drugs in the right patient, knowing we have to be very careful with the toxicity. But if we are achieving a CR suddenly of 50% or 60%, irrespective of the IMDC risk group, then you know we can say goodbye to them.

Risk Scoring Systems for Metastatic RCC

We need to get rid of COVID-19, and we need to get back together. We are embarking, at the Dana-Farber Cancer Institute, on a study of COVID-19 from a clinical perspective, looking into what the risk factors are in patients with cancer who get COVID-19. We integrated that into our research. Once we are done controlling COVID-19 by whatever way you want to, then we can talk more about the future of renal cell carcinoma [RCC]. There are combinations, and there are new targets.

Combination-wise, I am excited about integrating TKIs [tyrosine kinase inhibitors] with NIVO/IPI [nivolumab, ipilimumab], with CTLA-4, PD-1. COSMIC-313 is a study that adds cabozantinib with a modern control, nivolumab and [ipilimumab]; it’s accruing very well. I am one of the leaders of this study. PEDIGREE is another important study that starts with [nivolumab, ipilimumab] and then based on the response, it adds cabozantinib. There are triplets emerging with other combinations as the control arm, where the control arm is not sunitinib single-agent TKI. So the triplets concept is important.

The second is novel targets, and there are many novel targets here and I divide them into immunotherapy and not immunotherapy. The not immunotherapy is the HIF-2 [hypoxia-inducible factor-2] inhibitor, you have seen that at [the Genitourinary Cancers Symposium 2021]. There were 2 oral presentations out of 4 on the HIF-2 inhibitor. That led to an ongoing study, post–PD-1, post-VEGF, with the HIF-2 inhibitor belzutifan. In the initial study with clear cell RCC, the response rate in a highly refractory population was 25%, a first-in-class agent. The HIF-2 target was elusive for a long time, it’s a transcription factor, it does lack those pockets where a small molecule can go in. But people smarter than I am were able through eloquent crystallographic work to find molecules that go there. We use them in first-generation HIF-2 inhibitors, now second generation. We saw with the second generation a response rate of 25%, with a favorable [adverse] effect profile. We see anemia and hypoxia, which are both on target.

We don’t see the bothersome immune-related AEs [adverse effects]. We don’t see the bothersome VEGF-targeted therapy [adverse] effects of fatigue, diarrhea, and hypertension. We combined it with cabozantinib, there were some dose reductions, but we’ve seen activity. HIF-2 [inhibitors] are drugs that work on tumor metabolism, which is a big thing. Unfortunately, we had a setback with a negative study with the glutaminase inhibitor in combination with the VEGF/TKI from Calithera [Biosciences, Inc]. We have to continue here, continue the fight for new targets. Moving to immunotherapy, besides novel immune checkpoints, like TIGIT [T-cell immunoreceptor with immunoglobulin and ITIM domain], and others that are being used, CAR [chimeric antigen receptor] T cells are making an entry into solid tumors, including renal cell. A pegylated form of IL-2 [interleukin-2] showed activity with nivolumab, and showed efficacy.

There is a study by the name PIVOT-09, with nivolumab plus pegylated IL-2, NKTR-214, versus TKI, which is ongoing. We always need a new target. We need this despite, this is a bit naive to say, going for the cure. That’s actually what the patients want at the end of the day. There are other cancers where this [a cure] was possible: testicular cancer, leukemias, and lymphoma. We always have to think about that while we are remaining realistic. Sometimes progress comes in incremental steps.

Adjuvant studies and adjuvant drugs in renal cell cancer remain a bit elusive, unlike bladder [cancer], for example, another tumor where you could discuss chemotherapy. Here you have 1 FDA-approved drug, sunitinib, which is not much use because of the absence of an OS [overall survival] benefit, the decrease in quality of life, and because other trials with VEGF and TKIs did not show the benefit in disease-free survival. We and others have launched studies in the adjuvant high-risk patient with an immune checkpoint inhibitor. Two studies, one was atezolizumab and pembrolizumab, finished accrual, and 2 or maybe 3 others are accruing. Two finished accrual. If these studies are going to show a benefit that we accept, disease-free survival and/or OS, it’s going to make us look again and say how do we apply this frontline trial? This is a patient who was on an adjuvant study with [pembrolizumab], or this is a patient who received adjuvant [pembrolizumab or atezolizumab].

Let’s say the studies are positive for a year and a half and now their tumor progressed, should we give them [nivolumab/ipilimumab], [pembrolizumab/lenalidomide], or the triplet? Most of these studies did not allow adjuvant IO [immunotherapy], what’s the response of IO post-IO? There are studies addressing this, one I’m leading with [Thomas] Powles, [MD,] with cabozantinib/atezolizumab versus cabozantinib only. That also might take the field by storm, just because we’re not ready. We didn’t have the particular setting, it’s going to create confusion in the first line, and we need to accumulate data.

In first-line therapy, the priority trial that I see that’s being conducted right now is the COSMIC-313 trial. That is a randomized trial that looks at [ipilimumab/nivolumab] plus cabozantinib versus [ipilimumab/nivolumab] plus placebo. It’s a trial that’s looking at whether there’s a benefit for combining an IO combination with a very potent TKI, cabozantinib, in a first-line therapy for RCC. To date, the studies that have shown that IO/TKI combinations are very effective, and [ipilimumab/nivolumab] as an IO/IO combination is very effective. That is going one step further to look to see whether the triplet adds benefit and is a tolerable regimen, and I see it as the priority phase 3 trial to watch that will hopefully gain us a step further in terms of efficacy and benefit to our patients.

Future Use of Novel Combinations for Metastatic RCC Treatment

Refining Combination Strategies in Metastatic RCC

Drs Toni Choueiri and Robert J. Motzer reflect on recent data supporting the use of TKI/I-O combination regimens for frontline treatment of metastatic renal cell carcinoma.

Refining Combination Strategies in Metastatic RCC

EP. 1: Frontline Combination Approaches for Metastatic RCC

EP. 2: Personal Approaches to Frontline Therapy for Metastatic RCC

EP. 3: The Phase 3 CLEAR Study in Metastatic RCC

EP. 4: Metastatic RCC: Frontline TKI/IO Safety Data

EP. 5: Implications for Treating Metastatic RCC With TKI/I-O Regimens Upfront

EP. 6: Risk Scoring Systems for Metastatic RCC

EP. 7: Future Use of Novel Combinations for Metastatic RCC Treatment