Ongoing Trials Aim to Build on Systemic Therapy Combinations in Advanced RCC

Wenxin (Vincent) Xu, MD, a physician at the Dana-Farber Cancer Institute, and an assistant professor of medicine at Harvard Medical School, both in Boston, Massachusetts, shared recent updates in the treatment of renal cell carcinoma (RCC), including sharing insights into ongoing research and trials within the space, in an interview with OncLive® at the 17th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies, an event hosted by Physician’s Education Resource (PER®), in New York, New York.

He provided an overview of what oncologists and treating physicians should know about dose adjustments and holds with checkpoint inhibitors in the treatment of RCC; and discussed the importance of continuing to investigate combination treatments for patients, including those in the non–clear cell RCC population. In a previous article, Xu provided further insights into the need for established biomarkers to drive treatment decisions in advanced RCC.

OncLive: For community oncologists, what should be known regarding dose adjustments or pauses with checkpoint inhibitors in the treatment of RCC?

Xu: For immune checkpoint inhibitors, such as the PD-1 inhibitors nivolumab [Opdivo] or pembrolizumab [Keytruda], or CTLA-4 inhibitors like ipilimumab [Yervoy], there are no dose reductions. Patients get treated, and if they have toxicity, we have to hold the dose, treat their toxicity with steroids or immunosuppressants, and—depending on the grade of toxicity—decide whether we want to rechallenge. Holding treatment is very common, and many patients who [need to have treatment held], especially for low-grade toxicities, can eventually restart treatment.

One important recently published trial was the phase 2 PRISM trial [ISRCTN95351638], which randomly assigned patients [with treatment-naive advanced RCC] to 2 different ipilimumab/nivolumab dosing regimens. Either all the ipilimumab [was given] up-front with nivolumab, or nivolumab [was given] with intermittent ipilimumab. In that small, randomized trial, intermittent dosing of ipilimumab did not seem to compromise efficacy, but it significantly decreased toxicity. What we learned from that trial is that it's okay to hold immunotherapy for toxicity or even for preference, because exposing [a patient to a] CTLA-4 [inhibitor] later still has benefit.

Is there any ongoing or planned research in RCC you would like to highlight?

There are a few ongoing trials that are going to be very exciting to see what the data show. For example, there is an ongoing large triplet therapy study [the phase 3 MK-6482-012 trial (NCT04736706)], which is investigating the addition of a third medication to the lenvatinib [Lenvima]/pembrolizumab backbone. Lenvatinib [plus] pembrolizumab is already very active, as we saw in the [phase 3] CLEAR trial [NCT02811861], and adding a CTLA-4 [inhibitor such as] quavonlimab [MK-1308] or belzutifan [Welireg] to this backbone may improve outcomes further, which would be a great result for patients.

Other interesting trials include the ongoing [phase 3] PDIGREE trial [NCT03793166], [which is] looking at the early addition of cabozantinib [Cabometyx] to patients who have stable disease, or at least non–progressive disease and a non–complete response on first-line ipilimumab/nivolumab. We have smaller trials looking at completely new treatment strategies for kidney cancer, including cell therapies and CAR T-cell therapies. [In 2023], we saw that several of the CAR T-cell therapy phase 1 trials did report patients having clinical responses.

Regarding non–clear cell RCC, what updates have been seen in this space?

In non–clear cell RCC, although we've learned a lot, this still remains an area where we lag behind compared with clear cell RCC. We've had several phase 2 trials showing that lenvatinib plus pembrolizumab and cabozantinib plus nivolumab are active in several non–clear cell histologies.

More and more, we hope to get more targeted medications in non–clear cell [RCC] that are biologically rational based on the underlying patient biology. It's hard because these are rare histologies, [and] they require scientists who can tell us what new compounds are [most likely to be active], instead of just blindly extrapolating from clear cell RCC. However, many people are working on this, and there's more to come.

What is important for patients with RCC to take away from this conversation?

It's important to listen to the patient community, [which], especially in kidney cancer, is highly active and has given us lots of useful feedback to help drive the clinical knowledge forward. What we see now is that overall survival for metastatic clear cell kidney cancer is approaching 5 years and even longer; [therefore] people are living longer, but also living longer with toxicity.

We need to listen to patients to hear about what's important to them, which in many cases, is cure. However, it’s also longevity with quality of life and treatment-free survival, and [patient] voices are going to be increasingly important as they live longer.