Reviewing Second-Line RCC Therapy After Immune Checkpoint Inhibition

Benjamin Garmezy, MD

Assistant Director of Genitourinary Research

Sarah Cannon Research Institute

Tennessee Oncology

Nashville, TN

Targeted Oncology: Can you discuss the trials for second-line therapies used in renal cell carcinoma (RCC)?

Benjamin Garmezy, MD: There are 3 different trials [with second-line data post immune checkpoint inhibition (ICI)]: cabozantinib [Cabometyx] and atezolizumab [Tecentriq] vs cabozantinib in the CONTACT-03 study [NCT04338269],¹ tivozanib [Fotivda] plus nivolumab [Opdivo] vs tivozanib in the TiNivo-2 study [NCT04987203],² which I was heavily involved with, so I'm a little conflicted there; and then belzutifan [Welireg] vs everolimus in the LITESPARK-005 study [NCT04195750].³ All these studies are in very important trials.

CONTACT-03 and TiNivo-2 showed the continuation of ICI.^1,2 Is it helpful or not? And the answer is no, not really. These were both negative studies, but they also can provide information on how we can treat patients in clinic. So if a patient has progression on an immunotherapy/tyrosine kinase inhibitor or ipilimumab [Yervoy]/nivolumab, it should be an exception to a rule that you continue immunotherapy. Otherwise, those patients should be going on lenvatinib [Lenvima]/everolimus or some kind of monotherapy without immunotherapy, or some situations ipilimumab/nivolumab may be reasonable, if you think they could use more ICI and have more time to reach a response.

What were the relevant data in these trials for the RCC space?

These show us how these drugs behave in large, randomized phase 3 studies. Let's look at the cabozantinib arm, the control arm, in CONTACT-03. Overall response rate was about 41%, so it's a bit higher, but the median progression-free survival [PFS] was 10.8 months.¹ That is consistent with other cabozantinib studies, showing that this drug is acting exactly as we'd expect. There were 87% [of patients] with dose reductions or interruptions, and 62% grade 3 or 4 toxicity. This is all what we expect with cabozantinib.

In CONTACT-03, they had progression with ICI as the immediate prior line of therapy. TiNivo-2 allowed it to be the immediate prior line of therapy, or you could have a gap.² So you [could have received] ipilimumab/nivolumab, cabozantinib, and then went on the study, for example. There [could be] a gap between the ICI. That's the nuance. Overall, the median PFS was 7.4 months for tivozanib, but if they had ICI as the immediate prior treatment, which is more like the CONTACT-03 population, the PFS was 9.2 months; it looked more similar to the cabozantinib data, basically off by a month. There was also a very similar toxicity, with 60% grade 3 or greater [adverse events], but dose reduction [rates] were dramatically [lower]—22% reductions and interruptions, which is telling you something about how those patients may be tolerating that therapy. We don't want to read too much into these cross-trial comparisons, but also, it's not helpful to say, “Don't do cross-trial comparisons,” because in clinic you have to make a decision for a patient. So the differences in response rates are something to look at, and that does seem to be a little different. PFS is more similar than different. Toxicity seems to be different as well.

Belzutifan in LITESPARK-005...[did better than everolimus with a] response rate of 23%.³ That is not super high, but median PFS was the lowest at 5.6 months, [comparatively with the other 2 trials]. Overall survival was 21.4 months. We don't have those data yet for the other 2 studies. The toxicity is pretty similar at 63%. Most of the patients in the belzutifan vs everolimus trial...were mostly [on their third] line of therapy, so they weren't similar. Only 12% were [receiving] it as a second line. TiNivo-2 had some third-line patients as well; 65% were in the second line, and then 35% would have been in the third line, so it was a mix.

_References:

_{1. Pal SK, Albiges L, Tomczak P, et al. Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. Lancet. 2023;402(10397):185-195. doi:10.1016/S0140-6736(23)00922-4}

_{2. Choueiri TK, Albiges L, Barthélémy P, et al. Tivozanib plus nivolumab versus tivozanib monotherapy in patients with renal cell carcinoma following an immune checkpoint inhibitor: results of the phase 3 TiNivo-2 Study. Lancet. 2024;404(10460):1309-1320. doi:10.1016/S0140-6736(24)01758-6}

_{3. Choueiri TK, Powles T, Peltola K, et al. Belzutifan versus everolimus for advanced renal-cell carcinoma. N Engl J Med. 2024;391(8):710-721. doi:10.1056/NEJMoa2313906}