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Dr. Zhang on second-line treatment and beyond in refractory metastatic renal cell carcinoma


“One of the key challenges in the refractory renal cell population is identifying mechanisms of resistance to immune checkpoint inhibitors, and really delving in and figuring out how to target those mechanisms of resistance,” says Zhang.

In this video, Tian Zhang, MD, associate professor of Medicine at UT Southwestern Medical Center, provides highlights from the presentation she gave as part of the Renal Cell Cancer track at the 2023 Genitourinary Cancers Symposium titled, “Systemic Treatment for Recurrent Metastatic Disease, Beyond Second Line.


My assigned topic for the education session at ASCO GU was on refractory treatments for second line and beyond for metastatic renal cell carcinoma. And so, in clear cell renal cell carcinoma, we have multiple monotherapies approved with axitinib (Inlyta), tivozanib (Fotivda), and everolimus (Afinitor), as well as a combination of lenvatinib (Lenvima) with everolimus, and the immunotherapy checkpoint inhibitor nivolumab (Opdivo) and cabozantinib (Cabometyx).

And so these treatments have made a difference in the refractory setting, and we've been using them in sequence for patients with refractory disease. Now, what we wanted to highlight during the course of the discussion was that there were also 4 trials. We know combination immunotherapies are very effective in the frontline setting. So how do we sequence after those? And also, can we use ipilimumab (Yervoy), which is one of our immunotherapies, in the refractory setting?

So along those lines, there were 4 trials that were done in the post-immunotherapy setting, testing the addition of ipilimumab to nivolumab. And unfortunately, none of those trials really showed good complete responses. Although there were a fraction of patients in each trial that had objective responses with partial responses. So I think as a totality, the data shows that we shouldn't be using ipilimumab if people have already had nivolumab. And if we're going to use ipilimumab, we should use that in the frontline setting.

Now, we know also that VEGF and immunotherapy combinations have really made a splash, several of which have gained approvals in the first-line setting. And so are those effective in the refractory setting? So of those, lenvatinib and pembrolizumab (Keytruda) had a cohort of over 100 patients, it was about 104 patients, who had prior checkpoint inhibitors. And in those patient populations, the vast majority had stable disease or better. And a good number of those patients achieved objective responses with partial responders. And so we can say that from that data, led by my good friend Dr. Joe Lee and his colleagues at Memorial Sloan Kettering Cancer Center, that we have effective strategies in the post–checkpoint inhibitor phase, with lenvatinib/pembrolizumab being one of them.

Now, there's also 2 other combinations that have been tested. One is cabozantinib with atezolizumab (Tecentriq) and the other one tivozanib with nivolumab. Both of those showed good response rates in the early phase trials and we're awaiting the phase 3 trials. CONTACT-03 is testing cabozantinib with atezolizumab and it’s about to read out, hopefully, and tivozanib with nivolumab is in an ongoing trial. So those trials are all very exciting.

And then I think one of the key challenges in the refractory renal cell population is identifying mechanisms of resistance to immune checkpoint inhibitors, and really delving in and figuring out how to target those mechanisms of resistance. So I do think there's a charge across the community now to think about other strategies in the refractory patient population. I did highlight 2 of these trials that have been done in the early phase setting with 2 different treatments for enhancing immunotherapy responses. One a bispecific antibody of sorts combining CTLA-4 and PD-1 blockade and trying to give a continuous dose not only for 4 cycles, but across the treatment. That one showed good responses when presented at ASCO last year. And then the second trial that we highlighted was on CD70-directed CAR T cells that was presented at SITC last year. So as we understand mechanisms of immunotherapy resistance further, we will be able to more rationally design better therapeutics in the metastatic refractory setting.

The transcript has been edited for clarity.

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