Cutting-Edge Advanced RCC Research Poised to Improve Patient Outcomes

From September 16 to 20, the European Society for Medical Oncology (ESMO) held its annual congress (ESMO Congress 2021) as a virtual experience featuring a robust program of oncology-advancing abstracts. Dozens of posters and presentations focused on advanced renal cell carcinoma (RCC), providing updates on clinical trials, paradigm-shifting data, and real-world research.

Philippe Spiess, MD, genitourinary oncologist and assistant chief of Surgical Services at Moffitt Cancer Center, Tampa, Florida, shares his thoughts on this fascinating — and potentially game-changing — research.

Which of the numerous abstracts on advanced RCC presented at the ESMO Congress 2021 did you find most interesting or clinically impactful?

It was an exceptional meeting. It’s always impressive, as are other major meetings, such as the ASCO® [American Society of Clinical Oncology] Annual Meeting and the ASCO Genitourinary Cancers Symposium. A few of the ESMO Congress 2021 presentations have, in my opinion, the potential to be paradigm-shifting.
 
There was a study on adjuvant pembrolizumab — also presented at the ASCO Annual Meeting and presented here in a different format — from KEYNOTE-564 [ClinicalTrials.gov Identifier: NCT03142334],¹ presented by Toni Choueiri, MD [director of the Lank Center for Genitourinary Oncology and the Kidney Cancer Center at the Dana-Farber Cancer Institute, Boston, and Jerome and Nancy Kohlberg Chair and professor of medicine, Harvard Medical School] and colleagues, that has implications for patients with localized, particularly high-risk kidney cancer and that I think was very impactful. The hazard ratio clearly shows an improvement in disease-free survival with adjuvant pembrolizumab. This is something that we’ve been challenged with in treating kidney cancer; we struggle to offer patients adjuvant therapy that reduces risk over time.

The safety profile of adjuvant pembrolizumab is actually highly acceptable, despite most patients having received as many as 17 treatment cycles. Most clinicians wait until the overall survival endpoint is achieved but, looking at the curves reported in the presentation, I think that’s ultimately just a matter of time.

In a presentation of data from the phase 3 CLEAR trial (ClinicalTrials.gov Identifier: NCT02811861),² researchers shared both subgroup-level outcomes and toxicity updates. Results showed that lenvatinib plus pembrolizumab had an efficacy benefit over sunitinib in patients both with and without adverse prognostic features. Only 15% of patients required high-dose corticosteroid therapy for immune-related adverse events.

Are these data promising, in terms of a potential paradigm shift in treating advanced RCC in patients who have adverse prognostic features?

Yes, it’s an interesting and promising combination of lenvatinib and pembrolizumab. What is reassuring in the analysis of CLEAR is exactly what you mentioned: Survival benefit is seen both in patients who had adverse prognostic factors, such as liver metastases, in patients with or without prior cytoreductive nephrectomy, and across risk groups.

What to offer patients who have adverse features is something that we struggle with. The fact that this study played out with improvement across the CLEAR cohort is promising, and it is something that most clinicians are going to be interested in.

A side note: A concern with the lenvatinib-pembrolizumab combination is the use of corticosteroids, which patients have to take. In this trial, corticosteroids were necessary in only about 15% of patients.

I think that the challenge in advanced RCC is finding which combination is going to be the differentiator, in terms of selecting which subset of patients will benefit from a given systemic treatment combination. Work like this is important because it gives us granular data that we can use clinically; to say, well, in patients with liver metastases, the data still show benefit.

So, I applaud the authors of this presentation. They did a nice job answering a novel study question and conducting a meticulous analysis with meaningful study endpoints.

Researchers shared results of a matching-adjusted indirect comparison of health-related quality of life in patients with previously untreated advanced RCC who were administered either nivolumab plus cabozantinib or pembrolizumab plus axitinib.³ Results were generally positive, showing that nivolumab plus cabozantinib was associated with what they said was “significant improvement” in disease-related symptoms, as well as having overall efficacy and a favorable safety profile.

Will these results change thinking about first-line treatment of advanced RCC, or is further research needed before concrete conclusions can be drawn?

That’s a good question. First, the authors did a nice job matching cohorts from 2 studies (CheckMate 9ER [ClinicalTrials.gov Identifier: NCT03141177] and KEYNOTE-426 [ClinicalTrials.gov Identifier: NCT02853331]). Ultimately, those 2 drug combinations are fairly comparable in terms of their oncologic benefit. Second, what ends up being important is, what is the patient’s quality of life? And, third, what are the disease-related oncologic endpoints, in terms of events that are impactful to these patients?

I think the authors were able to show that the combination of nivolumab and cabozantinib improved quality of life overall using several validated questionnaires.
 
But, as you asked, is this going to be a paradigm-shifter? I don’t think so. The analysis wasn’t done in the setting of a single clinical trial. I do think it’s thought-provoking and lends itself to the notion that nivolumab plus cabozantinib is probably a more favorable combination when quality of life is an important consideration — which it is, for many patients. I don’t think of this work as inherently changing the clinical paradigm. Both combinations are definitely highly effective as first-line therapy; this study probably leans in the direction of favoring nivolumab plus cabozantinib, if one had to choose.

An abstract⁴ reviewed the way in which functional adaptive responses might contribute to targeted treatment resistance in RCC. Results indicated that functional changes induced by cabozantinib aided investigators in selecting targets for combination therapy. How might this type of profiling be used when treating patients with advanced RCC?

This is a nice study but a fairly preliminary, not clinically validated, patient cohort-type one; it was done in a cell line. But it is biologically important because it gives us better understanding of changes in the tumor microenvironment and the profile of a specific agent, cabozantinib, and what genes are upregulated and, ultimately, are potentially targetable.

I congratulate the researchers for a thought-provoking, innovative study. I think this is probably a platform that can be used to look at various other systemic agents or, potentially, to help scientists develop hypotheses about which treatment combinations are worth considering, in terms of designing future clinical trials.

Let’s discuss results of the study that you and your colleagues conducted of methylthioadenosine phosphorylase (MTAP) deletion in sarcomatoid RCC.⁵ In the conclusion of the ESMO abstract, you mention that studies of antiprotein arginine methyltransferase 5 (anti-PRMT5) drugs might be warranted. What might these studies look like, and are there relevant drugs in the pipeline?

This was a large, multi-institution collaboration with international colleagues and Foundation Medicine, Inc. (we weren’t compensated for participating). We compared comprehensive genomic profiling of a small subset of 66 cases of sarcomatoid RCC with more than 800 cases of conventional clear-cell kidney cancer. Ultimately, we looked at differences in expression and — to your point — saw a significantly (2-and-a-half times) higher incidence of MTAP deletion in sarcomatoid RCC; there was a 50% incidence of MTAP deletion compared with only 6% in conventional clear-cell RCC.

What we found is clinically interesting and offers an opportunity to look at novel compounds, such as anti-PRMT5 drugs that target MTAP inhibition. Potentially, there is clinical value to this work in terms of future design and development of agents. In fact, there are such agents readily available in the form of specific polyclonal and monoclonal antibodies that have been developed to target the underlying biologic pathway.

The big question is: How might the findings of this research fit the therapeutic paradigm? Most immunotherapy combinations — nivolumab, ipilimumab, and other agents — definitely have some efficacy against sarcomatoid-specific variants. So, potentially, anti-PRMT5 agents can be used to treat tumors that are refractory to second-line or third-line agents, or combinations of agents, and some can be considered in patients with sarcomatoid RCC.

Is there anything else that you’d like to add?

Worth mentioning is a study that was presented in an ESMO Congress 2021 abstract⁶ by Lisa Derosa, MD, [of the Medical Oncology Department at Institut de Cancérologie Gustave Roussy, in Paris, France] and colleagues, who looked at data from the NIVOREN trial (ClinicalTrials.gov Identifier: NCT0301335).
 
This study shows that patients who received antibiotics either 2 months before or 1 month after immune checkpoint inhibitor therapy saw lower efficacy from their immunotherapy. This finding is interesting because it raises the question: By giving our patients antibiotics, are we affecting how efficacious our treatments are? The researchers looked at data from more than 730 patients in this NIVOREN dataset and found that there were significant differences in efficacy and, ultimately, higher risk of progression in those who received antibiotic therapy within that timeline.

This is something we have to look at more. It’s possible simply that patients who received antibiotics were sicker, and that’s why they had worse outcomes. But the oncology community should follow this because if the findings hold true, we need to be aware of this clinical outcome.