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FAQ: Tx for Metastatic RCC
Experts Answer HCP Questions on Therapy for Metastatic Renal Cell Carcinoma

Released: April 13, 2022

Expiration: April 12, 2023

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In this second of 2 commentaries adapted from a live webinar, experts Brian A. Costello, MD, MS; Eric Jonasch, MD; and Elizabeth R. Plimack, MD, MS, answer questions from healthcare professionals on the latest developments in the management of metastatic renal cell carcinoma (RCC). Please click here to read the first commentary answering questions on nonmetastatic RCC.

Is the CARMENA trial relevant to current clinical practice?

Elizabeth R. Plimack, MD, MS:
Yes. Recall that the phase III CARMENA trial is a noninferiority study comparing nephrectomy followed by sunitinib vs sunitinib alone in patients with metastatic clear-cell RCC who had received no prior systemic therapy. This trial showed that prompt initiation of sunitinib was noninferior to upfront cytoreductive surgery. These results were not surprising given that sunitinib is an effective VEGF-directed therapy, whereas upfront cytoreductive surgery is not curative and delays initiation of therapy.

Now that we have combination therapies that are more effective than sunitinib, we hypothesize that there is an even stronger rationale to start with systemic therapy and use consolidative surgery to achieve complete response or palliative endpoints later.

Brian A. Costello, MD, MS:
This is an excellent question. I agree that the CARMENA trial is not as informative for current clinical practice. Sunitinib and other tyrosine kinase inhibitors (TKIs) are largely not being used as a single agent for first-line therapy. That said, we might consider using a single-agent TKI in the first‑line metastatic setting for a patient who is frail or older and thus might not be able to handle combination treatment.

How do you decide between a TKI alone vs immunotherapy plus a TKI for patients with favorable-risk RCC?

Elizabeth R. Plimack, MD, MS:
I consider a TKI alone only in patients who are averse to additive toxicity or who have both a relative contraindication to immunotherapy and indolent disease that I might otherwise observe. A single-agent TKI can be the gentlest and most convenient treatment for some patients, and combination therapies have not yet demonstrated improved overall survival (OS) in patients with favorable-risk RCC. When selecting a single-agent TKI, I use pazopanib because of its favorable safety profile.

Is there any evidence of efficacy in patients with central nervous system metastases who receive immunotherapy combinations?

Elizabeth R. Plimack, MD, MS:
Efficacy against central nervous system metastases has not yet been shown.

Is the response rate with immunotherapy the same between bone metastases vs pulmonary or soft-tissue metastases?

Elizabeth R. Plimack, MD, MS:
Bone metastases are not measurable by definition, so assessing response is challenging. We typically consider bone metastases to be controlled and/or responding if there is no progression in the bone. There is no evidence clinically that bone metastases have innate differences in their response to treatment.

At what point might you consider pausing treatment for a patient who had resected kidney disease and complete radiographic response of pulmonary metastases after ipilimumab plus nivolumab followed by maintenance nivolumab and who has remained NED (no evidence of disease) on imaging?

Elizabeth R. Plimack, MD, MS:
We usually begin discussing cessation of therapy at 1 year, and by 2 years in this situation, I would encourage therapy cessation. If a patient experiences immune-related toxicity before that 2-year mark in the setting of a complete response, we usually stop therapy. Unfortunately, there are no data to answer this question because in the randomized phase III CheckMate 214 trial evaluating ipilimumab plus nivolumab, maintenance nivolumab was continued until progressive disease (PD) per protocol.

Is the first-line treatment landscape moving toward triplet combinations (eg, COSMIC-313)?

Elizabeth R. Plimack, MD, MS:
We will need to see the data to know whether practice will be changed by the phase III COSMIC-313 trial, which is comparing first-line cabozantinib vs placebo in combination with ipilimumab plus nivolumab in patients with intermediate-/poor-risk advanced RCC (NCT03937219). The bar will be high for triplets. A triplet regimen would need to exceed the long-term durable outcomes that we can currently achieve with sequential therapy, as sequential therapy is almost always less toxic, is more cost effective, and may offer comparable efficacy and therefore a better approach if efficacy is the same.

What guides your choice of first-line therapy with immunotherapy combinations? What are the next steps for a patient who does not respond to first-line immunotherapy?

Elizabeth R. Plimack, MD, MS:
Short-term efficacy endpoints are best met with immunotherapy combined with TKI therapy. These combinations have higher response rates, lower primary PD rates, and, in patients with favorable risk, better progression-free survival (PFS) than data with nivolumab/ipilimumab. Although the length of follow-up in the CheckMate 214 trial with nivolumab/ipilimumab is longer than comparable trials with immunotherapy plus TKI combinations, all OS and PFS landmark analyses have been met or exceeded by immunotherapy plus TKI combinations, so we have yet to learn whether durable long-term OS is similar with immunotherapy plus TKI combinations compared with nivolumab/ipilimumab. I am personally optimistic that it will be.

Because the CheckMate 214 trial demonstrated that 20% of patients had PD as best response on nivolumab/ipilimumab, the question of what therapy to consider next is an important one. Data from the phase Ib/II KEYNOTE-146/Study 111 trial support use of lenvatinib plus pembrolizumab in this setting. Alternatively, the patient could switch to TKI-based therapy, such as cabozantinib, at that point.

What percentage of patients progress after first-line therapy?

Eric Jonasch, MD:
A notable majority of patients progress after first-line therapy, as shown by the Kaplan-Meier curves for PFS in contemporary phase III trials. Precise numbers are difficult to obtain, but 40% to 60% of patients go on to receive second-line therapy.

How do you choose between cabozantinib vs lenvatinib plus everolimus in the later-line setting?

Eric Jonasch, MD:
Both are excellent choices. Cabozantinib provides the practical advantage of requiring only 1 agent. Lenvatinib plus everolimus is associated with a long PFS. However, it is impossible to reach any comparative conclusions, as these regimens have not been studied in a head-to-head comparison trial.

In a patient with persistent hypoxia at each dose level of belzutifan, should the dose schedule be modified to be similar to that of sunitinib?

Eric Jonasch, MD:
If hypoxia persists at a given dose level, belzutifan should be held until oxygen saturation approaches baseline levels. A further dose reduction should be considered.

You presented the case of a 48-year-old man with metastatic clear-cell RCC who received ipilimumab plus nivolumab and developed high-grade, immunotherapy-induced gastroenteritis refractory to methylprednisolone and vedolizumab. The patient had resolution of his diarrhea after receiving 2 fecal matter transplants (FMTs). Could the diarrhea have been due to colitis caused by Clostridioides difficile?

Eric Jonasch, MD:
Infectious etiology was ruled out in this case. It was determined through colonoscopy and biopsy, as well as through laboratory parameters (stool lactoferrin), that the patient had refractory immunotherapy-induced colitis. Based on prior experience, FMT was administered to this patient and resulted in improvement of his immunotherapy-induced colitis. All FMT donor material is screened for potential bacterial and viral pathogens—including COVID-19—to prevent potential transmission to recipients.

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