Research in Context

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TiNivo-2: first phase 3 data on PD-1 rechallenge in advanced renal cell carcinoma.

Investigators reported no efficacy for PD-1 rechallenge with tivozanib plus nivolumab after progression on previous ICI combination therapy, while the authors noted clinical activity for full-dose tivozanib monotherapy in this setting.

  • Toni K Choueiri, MD; Laurence Albiges, MD; Philippe Barthélémy, MD; Roberto Iacovelli, MD; Sheik Emambux, MD; Javier Molina-Cerrillo, MD; et al.

  • September 13, 2024

  • The Lancet
  • The Lancet, Volume 404, Issue 10460, Pages 1309–1320
  • 10.1016/S0140-6736(24)01758-6

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Evidence before this study

Immune checkpoint inhibitors (ICIs) are a growing class of therapies that have become standard-of-care, first-line treatments for many cancers. However, questions remain regarding the optimal treatment after progression. One potential strategy is rechallenge with ICIs after progression, but the overall benefit of this strategy is unclear. A search of PubMed and major oncology congresses was conducted to identify articles regarding rechallenge with PD-(L1) inhibitors after previous PD-(L)1 inhibitor therapy in renal cell carcinoma. English language original research articles and meeting abstracts published between May 1, 2014, and May 1, 2024, using the terms “renal cell carcinoma”, “programmed death-1”, “programmed death-ligand 1”, “rechallenge”, and “second line” were included. To the best of our knowledge, CONTACT-03 was the only phase 3 study investigating ICI rechallenge in renal cell carcinoma. However, CONTACT-03 assessed rechallenge with a PD-L1 inhibitor and included only patients with an ICI as their immediate previous therapy. Additionally, the vascular endothelial growth factor receptor inhibitor tivozanib has previously shown efficacy following two or more previous systemic therapies, including a predefined subgroup with previous ICI exposure in renal cell carcinoma; however, the efficacy and safety outcomes of tivozanib following ICI combinations (the current standard-of-care for frontline treatment) as monotherapy or in combination with an ICI have not been evaluated in a phase 3 clinical study.

Added value of this study

The TiNivo-2 results are the first phase 3 data evaluating PD-1 rechallenge, showing no efficacy in this setting. Tivozanib with or without nivolumab was well tolerated and consistent with the established safety profiles of these agents. In the context of what is known from the TIVO-3 and TiNivo studies, these results showed the clinical activity of tivozanib monotherapy at 1·34 mg once a day as a second-line therapy option in patients following progression on previous ICI combination therapy.

Implications of all the available evidence

These data further support that ICI rechallenge should be discouraged in patients with advanced renal cell carcinoma. Furthermore, these data suggest that tivozanib monotherapy has efficacy in the post-ICI setting and highlight the importance of full dosing to achieve maximal efficacy.

Source: The Lancet

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