Establishing Biomarkers Is Key to Driving Personalized Systemic Treatment Choices in Advanced RCC

The FDA approval of belzutifan (Welireg) for the treatment of patients with advanced renal cell carcinoma who received prior treatment with a PD-1/PD-L1 inhibitor and a VEGF TKI added another option to the treatment paradigm, and as the list of systemic therapies for the RCC patient population grows, identifying biomarkers will be key to better inform individualized treatment approaches, according to Wenxin (Vincent) Xu, MD.

“Systemic therapy for RCC has changed very quickly. Every year, it's exciting to see that we're getting new developments, new drug approvals, and changes in the standard of care,” Xu reported in an interview with OncLive^® during the 17th Annual Interdisciplinary Prostate Cancer Congress^® and Other Genitourinary Malignancies.

In the interview, Xu highlighted the rapidly evolving landscape of systemic therapy for RCC, expanded on ongoing trials exploring combination therapies for advanced RCC, and addressed the need for biomarkers to help drive treatment decisions for this patient population.

Xu is a physician at the Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

OncLive: Could you walk through some of the main points that you hoped to relay to the audience during your presentation at NY GU?

Xu: In the past year, we saw several highlights including a new FDA drug approval for belzutifan in refractory clear cell kidney cancer, which is the first medication we have that's in the HIF2α inhibitor drug class for this disease. [This is] a very exciting new class of medications, [which currently approved only] for patients with refractory [disease].

Additionally, we saw the first overall survival benefit demonstrated in the adjuvant setting for [patients with clear cell RCC treated with] pembrolizumab [in the phase 3 KEYNOTE-564 trial (NCT03142334)], which has also changed the standard of care.

How have more mature data with combination approaches affected clinical practice?

For patients with first-line metastatic [disease], we have [seen] ongoing data developments for recent doublet trials, with new data being released showing a continued benefit [for these combination regimens] over a single agent TKI.

The key problem is [that] we need biomarkers [to guide treatment selection]. The field has made a lot of progress by just combining highly active agents together. What we have started to see is that we're hitting the plateau for what we can achieve by simply combining agents. For example, we saw this from the phase 3 COSMIC-313 trial [NCT03937219], where the combination of cabozantinib [Cabometyx], ipilimumab [Yervoy], and nivolumab [Opdivo]—all 3 of which are individually active drugs—resulted in improved PFS with the cost of significant toxicity.

Moving forward, we need [biomarkers] to know how to better combine these medications, as well as to de-escalate in patients [when appropriate].

Are there any specific trials or approaches that are attempting to identify biomarkers?

There are several. [For example, the phase 2 OPTIC RCC trial (NCT05361720)] is looking at using mRNA gene expression signatures. These are bulk RNA signatures that were derived from multiple prior phase 3 trials, including IMmotion151 [NCT02420821] and JAVELIN Renal 101 [NCT02684006]. [OPTIC RCC] is looking to identify which patients are more likely to respond to VEGF-targeted therapy [with the combination of cabozantinib and nivolumab] vs immunotherapy [with the combination of nivolumab and ipilimumab]. It's a small trial, but it'll be exciting to see where that leads.

Other biomarkers are investigational. There are several groups around the country working on, for example, circulating biomarkers that may one day result in blood tests that could predict response to therapy.

Until established biomarkers are available, what drives your decision-making in the first-line setting for patients with RCC?

Right now, it is a personalized decision that's driven by the individual characteristics of the patient in front of us. There is no one-size-fits-all approach. We have several good approaches; however, for example, patients who have symptoms of rapidly progressive disease or are feeling sick from their disease may benefit from an immuno-oncology [IO]/TKI combination because of a fast onset of response and high response rate to get them feeling better.

On the other hand, patients who need treatment for metastatic disease but have fewer symptoms, and who want a chance at a durable response and even treatment-free survival, are good candidates for ipilimumab plus nivolumab, which has the longest durability of data thus far.

How do you typically approach treatment after progression?

It depends on the situation. Every patient is different, and one of the key differences between patients is the toxicities they experience during first-line treatment. For example, many of my patients who were on a first-line IO/TKI regimen are worn down from the TKI toxicities, especially if they've been on the TKI for 3 years or longer. In those situations, belzutifan is a great choice because it lets the patient take a break from all their TKI toxicities. We see that in the quality-of-life [QOL] data [from the phase 3 LITESPARK-005 trial (NCT04195750)], where belzutifan had much better QOL and better time to symptom deterioration compared with everolimus [Afinitor] in the control arm.

On the other hand, for patients who are not too sick from their TKI toxicity, are robust, and can get more treatment, I sometimes like to use a second- or third-line, aggressive TKI regimen, such as cabozantinib or lenvatinib [Lenvima] plus everolimus; these are still highly active regimens. Tivozanib [Fotivda] is the other TKI [approved] in [the third-line] setting, especially for patients who are still able to get [another] TKI. My goal for many patients is to be able to sequence these treatments so that they have the best number of chances of getting a great response.

How do you approach treatment decisions for patients with refractory RCC?

We don't have large, randomized trials comparing lenvatinib and everolimus with modern TKIs such as tivozanib or cabozantinib. We [should] to look into the trials that we do have, and, for example, [where] toxicities are different. Lenvatinib and everolimus may lead to more hyperglycemia, peripheral edema, or oral mucositis.

Patients who have those toxicities or have poorly controlled diabetes may not tolerate that kind of treatment. On the other hand, medications like cabozantinib and tivozanib have their own toxicities, and these can be individualized to the patient.

Sometimes, what distinguishes lenvatinib and everolimus is the addition of an mTOR inhibitor. We know that single-agent mTOR inhibitors are not that active in refractory RCC despite being approved. For many patients, that is the only chance they have of getting exposure to mTOR inhibition.

Reference

FDA approves belzutifan for advanced renal cell carcinoma. FDA. December 14, 2023. Accessed December 14, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-advanced-renal-cell-carcinoma