Navigating Refractory RCC: Insights from the TiNivo-2 Trial

Targeted Oncology: Which options are approved for patients with immuno-oncology (IO)–refractory clear cell renal cell carcinoma (RCC)?

Kathryn E. Beckermann, MD, PhD: A couple of years ago, the NCCN guidelines changed the way that they put forth the options in the refractory setting.¹ For any patient who's progressed on frontline treatment, the way it changed was that we recognized that IO therapy in the frontline setting was becoming the standard of care. The goal is that the guidelines would be able to help put forth what we would recommend in that IO-refractory setting. Where it says preferred regimen there, is none, because we don't have any current studies that have looked specifically sequencing of therapies. In the other recommended regimens...there is [axitinib (Inlyta)], tyrosine kinase inhibitor [TKI] combination therapy of lenvatinib [Lenvima] and everolimus, a new mechanism of action with belzutifan [Welireg], and then the most recently approved TKI, which is tivozanib [Fotivda].

What are the difference among the TKIs available in metastatic, refractory RCC?

The first generation highlights sunitinib [Sutent]. In the second generation, cabozantinib [Cabometyx] has broader targeting properties, hitting things like MET, [among others]. Lenvatinib, in addition to VEGF, targets FGFR. With the third generation, you're getting more selective TKIs that were developed to have favorable pharmacokinetic properties, being VEGF specific; those TKIs are axitinib and then the most recently approved tivozanib.

Can you discuss some newer data for combinations with these third-generation TKIs?

We've recently reported at the European Society for Medical Oncology Congress 2024 the phase 3 TiNivo-2 study [NCT04987203].² This study looked at a combination of tivozanib with nivolumab [Opdivo] PD-1 inhibitor vs tivozanib monotherapy. This trial allowed patients who'd had prior intervening TKI, so that was unique and different. Then the other big thing to highlight was the actual treatment. In discussions with the FDA, the company was advised for concerns of increased hypertension to consider a decreased TKI dosage in the combination arm. So tivozanib...in the combination arm was not at full dose; it was at 0.89 mg. The monotherapy was given at full dose, which was 1.34 mg daily. The primary end point was progression-free survival [PFS].

The patient characteristics for patients who went on TiNivo-2 showed the majority of patients had had only 1 prior line of therapy, and the majority of the patients who went on this trial did have the immune checkpoint inhibitor [ICI] as the most recent therapy. But still, about 30% of patients did have an intervening TKI. For those patients who went on the trial, one-third of the patient population probably IO/IO in that frontline setting. Then the remaining patients had received either sequential or IO/TKI in the frontline setting. The patient characteristics were well balanced between the combination and the tivozanib monotherapy arm.

In the frontline, a third of patients had received no prior TKI, and they received PD-1 and CTLA-4 with ipilimumab [Yervoy]/nivolumab. The next largest group of patients received pembrolizumab [Keytruda]/axitinib. In those patients who went on this trial as a third line, the majority had received cabozantinib in the second-line setting. There were 59% of patients who had received nivolumab as their prior ICI.

What was the efficacy seen on the TiNivo-2 trial in this RCC population?

If you look at the data for a long time like we have, we can recognize some small differences [in PFS]. Tivozanib monotherapy being a full dose of 1.34 mg compared with the reduced dose of the TKI in the combination arm, the median PFS hazard ratio was 1.1 [95% CI, 0.84-1.43; P = .49], so there was no benefit to continuing nivolumab in combination with tivozanib in the study.

When we look against all the subgroups, we didn't see a specific subgroup who would have benefited, for example, TKI being the most recent or not being the most recent [line of therapy], or number of prior therapies.

What we did see were some trends. For patients who received ICI as the most recent prior therapy, most of those patients given PD-1 and CTLA-4, and then getting tivozanib as their first TKI essentially for their disease, tended to do better in the full dose tivozanib monotherapy arm, having a median PFS of 9.2 months. But then with patients who are multiple refractory, who are getting tivozanib or combination in the third-line setting, the PFS was approximately 3.7 months in either arm.

The objective response rate for both arms were pretty similar at 19% in either arm and the median duration of response was 15.8 months in the combination arm and not reached in the higher-dose tivozanib monotherapy arm.

Relevant Disclosures

Beckermann previously reported a consultant/advisor/speaker position for Aravive, Arcus, Alpine Bioscience, Aveo, Bristol Myers Squibb, Eisai, Exelixis, Merck, Nimbus, and Xencor.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 3.2025. Accessed February 5, 2025. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf}

_{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}