Investigational Treatments for Refractory RCC Expand Beyond Immunotherapy

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Brian I. Rini, MD, discusses standard and investigational treatment options for patients with RCC who are refractory to immunotherapy; the potential role of biomarkers in future targeted treatments; and the need for novel mechanisms such as HIF inhibition to meet the needs of patients who don’t respond to immunotherapy or VEGF TKIs.

Brian I. Rini, MD

Brian I. Rini, MD

Hypoxia-inducible factor (HIF) and AXL inhibition may work synergistically with checkpoint inhibitors to benefit patients with refractory renal cell carcinoma (RCC), according to Brian I. Rini, MD. Research is investigating novel treatment mechanisms in this population beyond those that patients have already progressed on, such as PD-1 inhibitors like pembrolizumab (Keytruda) or VEGF TKIs like sorafenib (Nexavar).

“The next wave of advances in kidney cancer is more likely to be in the refractory setting than in the front line,” said Rini.

In an interview with OncLive®, Rini discussed standard and investigational treatment options for patients with RCC who are refractory to immunotherapy; the potential role of biomarkers in future targeted treatments; and the need for novel mechanisms such as HIF inhibition to meet the needs of patients who don’t respond to immunotherapy or VEGF TKIs.

The phase 3 TIVO-3 trial (NCT02627963) established tivozanib (Fotivda) as a later-line standard of care (SOC), as patients with advanced RCC who received the agent had a median progression-free survival (PFS) of 5.6 months vs 3.9 months with sorafenib.1 Rini explained how this trial supported the use of TKIs in refractory RCC and explained remaining needs in this population. He elaborated on novel agents under evaluation in this setting, such as the phase 3 MK-6482-005 trial (NCT04195750), which is investigating the efficacy of belzutifan (Welireg) vs everolimus (Afinitor) in patients with advanced RCC who have progressed on prior VEGF-targeted therapies and PD-1 or PD-L1 inhibitors.2

Rini is a professor of medicine in the Division of Hematology Oncology at Vanderbilt University Medical Center in Nashville, Tennessee.

OncLive®: What does treatment sequencing currently look like in RCC, and what unmet needs remain regarding effective later-line therapies?

Rini: Most patients will receive an immune-based doublet as frontline therapy for kidney cancer. Multiple trials show a survival advantage [with this approach]. Barring contraindications, [most] frontline kidney cancers will be treated with an immune therapy, which means that when we’re talking about refractory kidney cancer, we’re talking about immune-refractory kidney cancer.

Right now, the unexciting SOC [in the refractory setting] is single-agent VEGF TKIs. Several studies, which weren’t done in the TKI-refractory setting but were done in the general refractory setting, showed activity with various TKIs. One [may not be] meaningfully better than the other. Practitioners pick mostly based on [factors such as] familiarity and adverse effect [AE] profile. All practitioners have their favorites.

The TIVO-3 study investigated tivozanib vs sorafenib in the third- and fourth-line settings. About a quarter of those patients were immune refractory. This is 1 of the biggest datasets [in this setting], although it [comes from] a subset of immune-refractory patients. This trial showed advantages with tivozanib that led to its FDA approval.

[There are some] emerging data in a more modern population, but still with a single-agent TKI. The biggest question the field has right now is whether a patient can benefit from immune therapy after having progressed on prior immune therapy.

Single-arm data with the combination of lenvatinib [Lenvima] and pembrolizumab show activity, but they’re single-arm data. We don’t know whether that [activity is] just from the lenvatinib or whether pembrolizumab is contributing to that doublet. Two randomized trials, 1 that has completed accrual and 1 that is ongoing, will hopefully address this question.

The [phase 3] CONTACT-03 trial [NCT04338269] is investigating cabozantinib [Cabometyx] plus atezolizumab [Tecentriq] vs cabozantinib in immunotherapy-refractory patients. It completed accrual and we may see PFS and overall survival data in the next year. The ongoing trial is investigating tivozanib plus nivolumab [Opdivo] vs tivozanib in a similar immunotherapy-refractory setting. Both trials included patients who progressed on adjuvant pembrolizumab, which is an emerging immunotherapy-refractory population.

Those 2 trials [will be] important [for determining] whether patients having 2 chances at immune therapy means they have 2 chances at a cure. When I change from an immune-based regimen to a non–immune based regimen, I’m no longer thinking I can cure the patient. I’m just trying to control the disease. It is a different mindset in terms of [factors like] approach and tolerance of AEs. Hopefully in the next 12 to 18 months, we’ll have 2 large trials that address that important question.

[Regarding novel therapies], belzutifan, a HIF inhibitor, is now approved in von Hippel-Lindau syndrome. Several trials are ongoing, most notably in the refractory setting, [such as 1 investigating belzutifan] monotherapy vs everolimus with registrational intent, as well as doublets and triplets [with belzutifan]. [Belzutifan is] an active drug, and it’s actively being developed in kidney cancer.

Other mechanisms include other checkpoint inhibitors. We’ve worked with an AXL inhibitor, batiraxcept [AVB-S6-500]. Other drugs are directed at metabolism. Many mechanisms are being investigated in the refractory setting. HIF inhibition with belzutifan is the most developed, but several others are in that promising phase 1/2 category.

How might novel combinations influence the refractory RCC treatment landscape in the future?

They’re not affecting it yet because they’re still in early-phase studies. Some will pan out and some won’t. However, [regarding unmet needs and drug development] in kidney cancer, we have many immune agents and VEGF inhibitors, but we need other mechanisms. HIF inhibition is related to VEGF inhibition, but is distinct. We need novel mechanisms, because there’s probably a whole biologic subset of patients who aren’t immune responsive and aren’t VEGF responsive. They’re left out, and they have other mechanisms driving their tumors. We need to discover what those mechanisms are and target them. It’s good to see other mechanisms being developed.

What unmet needs exist regarding effective biomarker-based treatments in RCC?

Biomarkers are a big topic. The short summary is that we have no clinically useful biomarkers in kidney cancer. PD-1 and PD-L1 expression didn’t turn out to be useful. They probably enrich for response to immune therapy, specifically the ipilimumab [Ipilimumab]/nivolumab doublet, but clinically, we’re not using PD-L1 to select patients because patients with PD-1–negative disease still benefit.

Sarcomatoid histology is a good biomarker for response to ipilimumab/nivolumab. I use that, and clinically, it’s 1 of our best biomarkers. However, we have yet to develop true biomarkers that are selecting for 1 therapy or against another therapy in kidney cancer, although massive efforts are ongoing. We’re doing a better job of investigating that than we have in the past.

In the frontline [phase 2] OPTIC RCC study [NCT05361720], we’re taking newly diagnosed patients, biopsying metastatic tissue, running RNA sequencing on that tissue, and determining their cluster, a biologic assignment that came out of an analysis of the phase 3 IMmotion151 study [NCT02420821]. Those clusters are either more angiogenic or more immune inflammatory. We’re taking the angiogenic cluster patients, about 30% or 40% of patients, and treating them with cabozantinib/nivolumab, a standard frontline regimen that has a VEGF inhibitor. The immune [inflammatory cluster] patients, around 20% or 25% of patients, are getting ipilimumab/nivolumab.

The hypothesis is that we can improve response rates compared with historical controls by enriching for the right biology and matching that biology to treatment. That trial is up and running. We’ve screened many patients and are accruing. This is an example of where we need to go. Although that biomarker is probably not perfect, we’ll refine it. We’re at least trying to treat patients based on their biology and not clinical factors, doctor bias, or other methods we tend to use right now.

What is your main message for colleagues regarding the future of refractory RCC treatment?

Much attention has been paid in the frontline setting over the past 5 years with large trials that have redefined the SOC. However, now, much of the attention is moving toward that refractory space, which has been a bit neglected. Large phase 3 trials [are ongoing] with novel mechanisms like HIF inhibition. Hopefully, in the next 12 to 18 months, this refractory landscape will be redefined.


  1. Rini BI, Pal SK, Escudier BJ, et al. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol. 2020;21(1):95-104. doi:10.1016/S1470-2045(19)30735-1
  2. A study of belzutifan (MK-6482) versus everolimus in participants with advanced renal cell carcinoma (MK-6482-005). Updated August 1, 2022. Accessed February 14, 2023.

Editor’s Note: This interview was conducted prior to the 2023 Genitourinary Cancers Symposium.

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