Within the last few years, treatment of renal cell carcinoma has improved dramatically, with FDA approvals of several agents and numerous others in development. In this interview, Bradley McGregor, MD, Clinical Director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and an Instructor in Medicine at Harvard Medical School, highlights these exciting developments and sheds light on the additional progress that is underway for the treatment of renal cell carcinoma.
Oncology Data Advisor: How has the treatment landscape of renal cell carcinoma changed within the last few years, and what challenges remain in managing patients with this disease?
Bradley McGregor, MD: Therapy for renal carcinoma has certainly changed dramatically in the past five years, starting with the CheckMate 214 trial showing improvement in overall survival with nivolumab/ipilimumab versus sunitinib in patients with intermediate- and poor-risk disease. Subsequently, we've had four different vascular endothelial growth factor (VEGF)/immuno-oncology (IO) combinations that have improved progression-free survival across risk groups. Three of them have shown improved overall survival across risk groups as well: pembrolizumab/axitinib, nivolumab/cabozantinib, and lenvatinib/pembrolizumab, which are all intriguing options.
While we now have this variety of options, I think it's very clear that particularly in patients with intermediate- and poor-risk disease, combination therapies remain the standard of care. Now, it's an issue of having multiple great regimens and deciding which regimen makes the most sense for a given patient at a given point in time.Of the VEGF/IO combinations, those that have a sure improvement in overall survival are preferred. Compared with IO/IO combinations, VEGF/IO combinations are associated with higher overall response rates exceeding 70% in some studies, with progressive disease less than 10%. In a situation in which a response is needed, this is the preferred approach.
However, nivolumab/ipilimumab still has a role. What we've seen with extended follow-up is that there does seem to be a tail to the curve with nivolumab/ipilimumab—we saw that at the European Society for Medical Oncology (ESMO) meeting this year: with a five-year follow-up in the intent-to-treat analysis, the median survival was 56 months with nivolumab/ipilimumab versus just under 40 months with sunitinib. The survival that we've seen with the pembrolizumab/axitinib combination was impressive but not to the same magnitude as we saw with the IO/IO combination.
With nivolumab/ipilimumab, data on conditional survival is intriguing. If you have a response two years into therapy, 80% to 90% of patients maintain that response at two years. We're not sure if we get that with VEGF/IO, although we do know that responses with VEGF/IO are much higher. Lenvatinib/pembrolizumab produces a response rate of around 70%, which is quite remarkable as opposed to nivolumab/ipilimumab, which has a response rate of only around 40%. I think there is this caveat that nivolumab/ipilimumab can certainly lead to a marked response, but the chance of response is certainly much higher with the tyrosine kinase inhibitor (TKI)/IO combination. If I have a patient with very aggressive disease—liver metastases, symptomatic—and they don't respond, I'm going to go with something that has a higher response rate, and that's when the TKI/IO combination comes in.
For favorable-risk disease, IO/TKI combinations have shown to improve OS across risk groups. While subgroup analysis suggests there may be less benefit in favorable risk disease, the numbers are small. Furthermore, while nivolumab/ipilimumab is not approved for favorable-risk disease, with extended follow-up, overall survival is numerically higher with nivolumab/ipilimumab versus sunitinib, with still impressive rates of complete response and durable response.
Oncology Data Advisor: Do you have any advice for balancing the toxicities of treatment against the benefits of these new agents?
Dr. McGregor: What we've seen overall is that these regimens are safe and have grade 3/4 toxicities that are comparable with sunitinib. Nivolumab/ipilimumab is fairly straightforward; if there's a toxicity, you're going to hold medications and use steroids as needed. With TKI/IO combinations, there are overlapping toxicities, such as diarrhea and hepatotoxicity. It requires an individual nuanced approach for each situation. For severe cases, you're going to hold the TKI, monitor to see if things get better, and then start steroids if it continues to worsen and it is felt to be due to IO. To that end, we have so many different TKI combinations that are available, and they're all fantastic. I would say to pick one and become familiar with it, so that as you do approach these toxicity conundrums, you can feel comfortable with management.
There has been discussion that pembrolizumab/axitinib is the best TKI/IO combination, due to the fact that it has a short half-life. I would say that in my experience, yes, axitinib has a shorter half-life compared with cabozantinib or lenvatinib, but with cabozantinib and lenvatinib, even though the drug is not going to be gone completely in one or two days, you will notice a difference within two to three days of stopping if that toxicity is from the TKI.
Oncology Data Advisor: How do you anticipate the treatment landscape for renal cell carcinoma to continue to evolve in the coming years?
Dr. McGregor: I think there are a lot of things that are going to change. There are several ongoing trials looking at triplets: we have IO/IO and IO/VEGF, but what about IO/IO/VEGF? There's the COSMIC-313 trial evaluating nivolumab/ipilimumab/cabozantinib versus nivolumab/ipilimumab. This trial has completed accrual, and we look forward to seeing those results, which will hopefully demonstrate some durability of response. We'll see how that turns out. There's an ongoing trial looking at pembrolizumab/lenvatinib/belzutifan versus pembrolizumab/quavonlimab/lenvatinib versus pembrolizumab/lenvatinib. Looking at triplet therapy, I think that's really exciting, with hopes to get durability from the addition of cytotoxic T lymphocyte–associated antigen-4 (CTLA-4), but also increased upfront responses with TKI. We haven't yet found biomarkers to use to develop therapies, so in this situation giving more therapy may enhance the chance for more durable responses.
We also saw very promising data for pembrolizumab in the adjuvant space, with an improvement in disease-free survival at two years by investigator-assessed imaging. Given what we've seen in the past, I imagine this will lead to approval and it will be an option to discuss with patients. Another key question is the role of maintenance immunotherapy. There's the CONTACT-03 trial looking at cabozantinib/atezolizumab versus cabozantinib and the upcoming tivozanib/nivolumab trial exploring tivozanib/nivolumab versus tivozanib, which will certainly be important and will answer some of these difficult questions.
Finally, we need novel targets; we were excited about the trial of telaglenastat with everolimus or cabozantinib, but unfortunately neither trial showed an improved progression-free survival with the addition of telaglenastat. However, there remains a lot of excitement surrounding belzutifan, which has been approved for patients with von Hippel-Lindau–associated renal cell carcinoma. Given impressive data in heavily treated patients in the phase 1 setting, we look forward to results from the ongoing phase 3 trial of belzutifan versus everolimus.
For more expert perspectives from Dr. McGregor, check out his free CME/NCPD-approved activity on renal cell carcinoma.
For More Information
Albiges L, Tannir NM, Burotto M, et al (2020). Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open, 5(6):e001079. DOI:10.1136/esmoopen-2020-001079
Motzer RJ, Tannir NM, McDermott DF, et al (2021). Conditional survival and 5-year follow-up in CheckMate 214: first-line nivolumab + ipilimumab (N+I) versus sunitinib (S) in advanced renal cell carcinoma (aRCC). Ann Oncol, 32 (suppl_5): S678-S724. Abstract 661P. DOI:10.1016/annonc/annonc675
Powles T, Plimack ER, Soulières D, et al (2020). Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomized, open-label, phase 3 trial. Lancet Oncol, 21(12):1563-1573. DOI:10.1016/S1470-2045(20)30436-8
Choueiri TK, Albiges L, Powles T, et al (2020). A phase III study (COSMIC-313) of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in patients (pts) with previously untreated advanced renal cell carcinoma (aRCC) of intermediate or poor risk. J Clin Oncol, 38(suppl_6). Abstract TPS767. DOI:10.1200/JCO.2020.38.6_suppl.TPS767
Rini BI, Plimack ER, Powles TB, et al (2021). Randomized, open-label, 3-arm phase III study comparing MK-1308A + lenvatinib and pembrolizumab (pembro) + belzutifan + lenvatinib versus pembro + lenvatinib as first-line (1L) treatment for advanced clear cell renal cell carcinoma (ccRCC). Ann Oncol, 32 (suppl_5): S678-S724. Abstract 717TiP. DOI:10.1016/annonc/annonc675
Pal SK, Albiges L, Rodriguez CS, et al (2021). CONTACT-03: Randomized, open-label phase III study of atezolizumab plus cabozantinib versus cabozantinib monotherapy following progression on/after immune checkpoint inhibitor (ICI) treatment in patients with advanced/metastatic renal cell carcinoma. J Clin Oncol, 39(suppl_6). Abstract TPS370. DOI:10.1200/JCO.2021.39.6_suppl.TPS370
Wood A, George S, Adra N, et al (2019). Phase I study of the mTOR inhibitor everolimus in combination with the histone deacetylase inhibitor panobinostat in patients with advanced clear cell renal cell carcinoma. Invest New Drugs, 38(4):1108-1116. DOI:10.1007/s10637-019-00864-7
About Dr. McGregor
Bradley McGregor, MD, is the Clinical Director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and an Instructor in Medicine at Harvard Medical School. His medical oncology practice covers all genitourinary malignancies, including kidney tumors. Dr. McGregor is active in clinical trial research, exploring the role of combination immunotherapy in rare genitourinary cancers and leading clinical trials evaluating novel combinations of immunotherapies.
Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor.