Nivolumab/Cabozantinib for Renal Cell Carcinoma: David Braun, MD, PhD, and Wenxin (Vincent) Xu, MD

David Braun, MD, PhD and Wenxin (Vincent) Xu, MD.

Recently, the results of a phase 3 trial on nivolumab/cabozantinib were published in the New England Journal of Medicine. The study (CheckMate 9ER) compared the efficacy and safety of nivolumab/cabozantinib with those of sunitinib in adult patients with previously untreated advanced clear cell renal cell carcinoma (RCC). The trial results demonstrated that nivolumab/cabozantinib has significant benefits over sunitinib in this patient population. In this interview with Oncology Data Advisor, Dr. David Braun and Dr. Wenxin Xu, both of the Dana-Farber Cancer Institute, discuss the significance of these findings.

What are some of the most significant challenges of managing patients with RCC?

Wenxin Xu, MD: There are many challenges that still remain in the management of renal cell carcinoma, although we’ve made a lot of progress. When I look at the kinds of things I struggle with when I see patients today, I think they fit into a few major categories. One is that adjuvant therapy is still an area of major unmet need; even though sunitinib was approved based on the S-TRAC trial, I very rarely use it in my practice due to the toxicity of this medication as well as the lack of survival benefit. Major adjuvant trials are ongoing using checkpoint inhibitor immunotherapies, and some of that data will hopefully read out soon.

I think a second major challenge is selecting the right first-line therapy for the right patient. In the last three or so years, we’ve had the wonderful privilege of having several combination therapies approved in the first-line setting, and choosing the right combination for the right patient is a clinical and scientific challenge. A third challenge is selecting second-line therapy after first-line therapy which, especially with combination therapies, is still very much an evolving field. Fourth, we now have many patients who progress on the best currently available therapies, including tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors, and these patients need access to new salvage agents with novel mechanisms of action. Finally, and I know Dr. Braun and others are working on this, we have less high quality clinical evidence for treating non-clear cell kidney cancers and treating these patients remains difficult. David, what do you think?

David Braun, MD, PhD: I think that’s a beautiful outline of the challenges. I wish I had a lot more to add, but I think you captured it so well. The adjuvant space is such a difficult one. It affects a lot of people, and we just don’t have a successful tool in that domain yet. The second challenge is choosing the first-line therapy, as there are many different options to choose from. Maybe one point I would add here is that I think it’s an incredibly exciting time, where there’s a small fraction of patients who are really getting durable responses. We’re hesitant to say this, but there is probably even a small percentage of patients with advanced clear cell kidney cancer being cured by treating them with current first-line therapy, but that number is very, very low. So, how can we utilize new combinations of available therapies and add novel agents to really improve the depth of response and basically improve that fraction of patients achieving cure? I think that’s a major ongoing challenge.

The last challenge, which Dr. Xu has mentioned and which I completely agree with, is what do we do in the post–programmed cell death protein 1 (PD-1) era? In particular, now that we have combinations of PD-1 blockade with vascular endothelial growth factor (VEGF)-TKIs, we’ve used a lot of our good pillars of therapy in that first line, and so what’s going to come after that? What we really need is new therapeutic developments to target different domains of kidney cancer; whether those are novel immunotherapeutics, or whether those are focused on tumor intrinsic aspects of the disease, that’s going to be really needed now to provide meaningful treatments for our patients who progress past that first line.

Can you comment on the significance of the recent publication on nivolumab and cabozantinib compared with sunitinib?

Dr Braun: I think this is wonderful addition to our therapeutic armamentarium for first-line kidney cancer, specifically clear cell kidney cancer. I think in the past, we’ve had good support for this strategy of a combination of PD-1 blockade with an anti-angiogenic agent from KEYNOTE-426 (pembrolizumab plus axitinib) and from JAVELIN Renal 101 (avelumab plus axitinib). What is this now adding? This is combining an immunotherapy agent with an established track record in RCC (nivolumab), with a therapy that has a really well-established track record in RCC (cabozantinib, a very potent VEGF-TKI), and we think this combination is probably helpful in inhibiting RCC.

First of all, the response rates for this combination really are outstanding. For patients who have rapidly advancing disease, where they really need a high chance of successful response and tumor shrinkage, this is really a potent therapy. Second, there’s certainly a survival benefit, but we’ll have to see as time moves on how durable these responses are. There’s a hint that some of these responses might be durable, given the survival benefit we’ve seen already, but that’s something that we’ll need to follow up on. Finally, I think a pretty meaningful piece is quality of life. What has been really impressive here is that this combination is not only providing meaningful improvements in terms of response rate, progression-free survival, and overall survival, but it’s also improving quality of life metrics as reported by patients.

Dr. Xu: David, I agree. Again, we have been so blessed in the last few years to have multiple first-line IO-TKI combinations that have shown improvement in progression-free survival and in some cases also overall survival, including CheckMate 9ER with cabozantinib/nivolumab. So while there are now several approved IO-TKI combinations in this setting including axitinib/pembrolizumab, axitinib/avelumab, and also promising data for lenvatinib/pembrolizumab, this particular regimen of cabozantinib/nivolumab is certainly a very important addition to our toolbox because it kind of has it all. When compared to sunitinib you improve progression-free survival, you improve overall survival, there’s a high objective response rate; and one thing I would add is that very few patients, fewer than 10%, have progression of disease as their best response. Also interesting is the quality of life data for cabozantinib/nivolumab. This is the first TKI-IO combination to show an improvement in quality of life, as measured using multiple metrics, compared to sunitinib; so not only are patients getting to live longer, but they’re also living better compared to patients who received sunitinib. So I think this is very, very strong data and will lead to cabozantinib/nivolumab being used in practice.

What adverse events are associated with nivolumab/cabozantinib, and what’s the best way for clinicians to manage them?

Dr. Xu: I’ll take a stab at this one. I think when we look at adverse events in this publication, there was a slightly over 75% rate of grade 3 or higher adverse events, and this is similar to what we’ve seen with other IO-TKI combinations in the first-line setting in clear cell kidney cancer.

The most common grade 3 or higher adverse events were hypertension; palmar-plantar erythrodysesthesia, which consists of rashes generally on the feet and palms; and diarrhea. Overall, the side effects are driven more by the VEGF TKI part of the combination, though of course diarrhea can also be caused by nivolumab. This is similar to what we see also with the other TKI-IO combinations. Generally, these side effects were managed by investigators with dose adjustments and dose delays, and in the case of immune-related adverse events, they’re also managed with systemic steroids which were given to 19.1% of patients. The majority of patients had dose delays of nivolumab (71.9%) and/or cabozantinib (68.1%), but the majority of patients who had sunitinib (51.9%) also had a dose delay, so this rate is not too much different from what we see with TKI monotherapies.

Dr. Braun: I think that’s a really good analysis of the side effect profile and the adverse events. I would say for me, it’s sometimes hard to look at these adverse event tables, because for the majority of these studies, 99% or more will have some grade of toxicity, and the far majority, upwards of 70% or more, will have some sort of grade 3 or higher toxicity. This is true here for both the control arm, sunitinib, and the experimental arm, nivolumab/cabozantinib. That’s why these patient-reported quality of life metrics are so important—because rather than us saying what the physicians and research staff are reporting, the patients are able to say how these therapies are ultimately impacting their quality of life, which I think is so important.

I think an important part of this study is it shows that while there are definitely toxicities associated with nivolumab/cabozantinib, these are not prohibitive. In other words, there are some combinations whose toxicities are additive or even synergistic in such a way that it prohibits the two from being combined, but that’s not the case here. The toxicities are certainly present, and sometimes substantial, but they are manageable.

The final point that might be helpful here is nivolumab/cabozantinib is going to be the third combination of a PD-1 or programmed death-ligand 1 access blocker with an anti-angiogenic agent, and a fourth combination is probably nearing approval as well. There may be minor efficacy differences, but these aren’t going to be compared head to head, so how does one choose between these? I think this is where the oncologist’s comfort level with using the specific agents and with managing toxicities of the different therapies is going to play such a big role.

Dr. Xu: I think safety of the patients is paramount, and part of that is having a provider who knows their own preferred regimen inside and out, knows the dosage and is able to adjust safely, knows the common side effects, and knows the idiosyncrasies of the drugs. We use the phrase “IO-TKI combination” as an umbrella term to refer to not only cabozantinib/nivolumab, but also the other regimens that Dr. Braun alluded to including axitinib/nivolumab, axitinib/pembrolizumab, and now with the recent publication of the CLEAR trial, lenvatinib/pembrolizumab. However, these drugs are probably not exactly equivalent, but have slightly different mechanisms of activity in ways that I think we are just starting to understand in clinical practice. With ongoing work in this this area, including your ongoing work, David, hopefully these regimens are going to be thought of as not just directly interchangeable, but we may learn that some subsets of patients may be better suited to certain combinations.

How do you see treatment of RCC evolving based on all of these data?

Dr. Braun: I think we’re in this exciting but also somewhat confusing time period where we have so many different options to choose from for first-line treatment of clear cell RCC. So how do we choose optimal therapy for patients moving forward? Provider comfort is going to be a major thing; as Dr. Xu mentioned, oncologists will consider what regimens they’re familiar with in terms of dosing, side effects, toxicities, and managing those adverse events. I think that’s going to be a really important component.

The second consideration will be individual histologies. We talk about clear cell kidney cancer as if it’s one entity, but some histologies have more aggressive features, such as sarcomatoid or rhabdoid features. In those specific cases, we know that a regimen of pure immunotherapy has a really high, complete response rate. That’s something that might aid in selection as well.

Then the last thing that I think is going to play a big role in selecting a regimen is the urgency of getting a response. With regimens like nivolumab/cabozantinib and pembrolizumab/lenvatinib, the rate of primary progressive disease as best response is very low. For those patients who have rapidly progressing disease, who have extensive visceral metastasis, and who are at risk for impending visceral crisis, these regimens that have incredibly high response rates and could play a very important role here.

Dr. Xu: Absolutely, and data is going to be coming down the line for new combinations, which hopefully will have even higher response rates than the already impressive ones we’re seeing in trials like CheckMate-9ER. For example, there’s the ongoing trial COSMIC-313, which is looking at cabozantinib and nivolumab but also ipilimumab, all in the upfront setting. While that trial is still ongoing, there’s a strong rationale that these advanced combination therapies may allow even more patients to have an excellent response in the first-line setting. Even farther down the road, there are other novel therapies that are in the investigational stage. These include HIF-2α inhibitors, such as MK-6482 which has promising early data, and there are other novel therapies including some of the cancer vaccines which Dr. Braun works on.

Hopefully, we’ll have more and more combinations that will give patients a higher and higher chance of response and deeper responses, and hopefully, as we understand biology better and better, we’ll know which patients don’t need the upfront combinations and can have more personalized, specific treatment strategies that can minimize toxicity without compromising response rate.

Is there anything else that either of you would like to add today?

Dr. Braun: Where we are in kidney cancer right now is an incredibly promising time, but also a time that demonstrates that more work needs to be done. More and more patients are getting benefit from RCC therapies, and some are getting these incredible durable responses, but they are still the minority. We still have a lot of work to go, both in terms of optimizing combinations of drugs that we already know about, with trials like COSMIC-313 as Dr. Xu mentioned, and other upcoming trials, but also in terms of novel therapeutic development. We need new targets so that the majority of patients, instead of just a few, are receiving long-term durable benefit.

Dr. Xu: I agree completely. I think what drives us to do this work in kidney cancer is that we all know patients whom we’ve treated, who had terrible disease that responded spectacularly and have very durable long-term remissions. Now, unfortunately, even though we remember these patients very well, they’re not yet the majority of patients, and the hope is that all this work moves things in that direction.

About Dr. Braun

David Braun, MD, PhD, is a medical oncologist who treats patients with kidney cancer at Dana-Farber Cancer Institute in Boston, MA. He is also a scientist, an author of numerous publications, and an Instructor in Medicine at Harvard Medical School. Dr. Braun’s interests include using immunogenomic approaches to understand and improve immune therapies in kidney cancer, and he has presented his findings on RCC at American Society of Clinical Oncology meetings.

About Dr. Xu

Wenxin Xu, MD, is a medical oncologist who treats patients with genitourinary cancers at Dana-Farber Cancer Institute in Boston, MA, and Newton, MA. He is a clinical investigator and an Instructor in Medicine at Harvard Medical School. Dr. Xu’s interests include clinical and translational biomarkers for early detection and prediction of treatment outcomes in kidney cancer, and he has presented his findings at American Society of Clinical Oncology meetings.

For More Information

Choueiri TK, Powles T, Burotto M, et al (2021). Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med, 384(9):829-841. DOI:10.1056/NEJMoa2026982

Transcript edited for clarity. Any views expressed above are the speaker’s own and do not necessarily reflect those of Oncology Data Advisor.

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