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TiNivo-2 (final analysis) — Tivozanib (Fotivda) ± nivolumab (Opdivo), metastatic renal cell carcinoma, second-line after immune checkpoint inhibitor

Session: Genitourinary Cancer — Kidney and Bladder, 2026 ASCO Annual Meeting · Presenter: Robert J. Motzer, MD (Memorial Sloan Kettering Cancer Center, New York) · Embargo: ASCO 2026 (May 29 – Jun 2, 2026)

At a glance

  • Sponsor: AVEO Oncology (an LG Chem company); nivolumab supplied by Bristol Myers Squibb
  • PI / presenter: Robert J. Motzer, MD (Memorial Sloan Kettering Cancer Center)
  • NCT ID: NCT04987203
  • Phase: 3
  • Design: Randomized, controlled, multicenter, open-label; 1:1 to tivozanib 0.89 mg/day PO (21 days on/7 off) + nivolumab 480 mg IV q4w vs tivozanib monotherapy 1.34 mg/day PO (21 days on/7 off)
  • N: 343 randomized (combination n=171; monotherapy n=172)
  • Primary endpoint(s): Progression-free survival (PFS) by blinded independent central review
  • Comparator: Tivozanib monotherapy (standard 1.34 mg dose)
  • Indication: Advanced/metastatic renal cell carcinoma after progression on 1–2 prior lines including an immune checkpoint inhibitor (ICI)
  • Line: Second/third-line (post-ICI)

Headline result

The final long-term analysis confirmed the negative primary readout: adding nivolumab to low-dose tivozanib did not improve outcomes versus standard-dose tivozanib monotherapy. In the ITT population, median PFS was 5.7 months with tivozanib + nivolumab vs 7.4 months with tivozanib monotherapy (HR 1.10, P=0.49), median OS was 17.7 vs 22.1 months, and ORR was 19.3% vs 19.8%. With extended follow-up approaching 28 months, standard-dose tivozanib monotherapy showed durable activity — median PFS of 7.43 months in the ITT population and 9.23 months in second-line patients, with median OS exceeding 22 months across analyzed populations. The long-term safety profile was consistent with prior reports, with no new safety signals and numerically fewer treatment-emergent adverse events in the combination arm (driven by the lower tivozanib dose). Investigators concluded the data support standard-dose tivozanib monotherapy as an effective option in the second- and third-line post-ICI setting and underscore the limited benefit of ICI retreatment via this combination.

Mechanism / class

Tivozanib is a potent, selective oral VEGFR-1/2/3 tyrosine kinase inhibitor (VEGFR-TKI), FDA-approved (FOTIVDA) for relapsed/refractory advanced RCC after ≥2 prior systemic therapies on the strength of TIVO-3. Nivolumab is an anti–PD-1 immune checkpoint inhibitor. TiNivo-2 tested whether re-introducing PD-1 blockade alongside a VEGFR-TKI improves outcomes in patients who progressed after a prior ICI — a strategy this trial did not validate.

Discussant takeaway

The result reinforces that ICI retreatment/continuation after prior checkpoint-inhibitor exposure has not shown benefit in randomized RCC trials (echoing CONTACT-03 and the broader signal against "re-challenge" PD-1/PD-L1 in this setting). A confound is the deliberately reduced tivozanib dose (0.89 mg) in the combination arm versus the full 1.34 mg control dose, which limits clean attribution but does not rescue the combination.

Practice-changing?

No for the combination — tivozanib + nivolumab is not adopted in the post-ICI setting given the negative primary endpoint and numerically inferior PFS/OS. Indirectly supportive for standard-dose tivozanib monotherapy, whose durable PFS/OS in the control arm reinforces its role as a viable VEGFR-TKI option for second- and third-line post-ICI mRCC.

Sources

  • ASCO Meeting Library (UroToday ASCO 2026 conference coverage): https://www.urotoday.com/conference-highlights/asco-2026/asco-2026-kidney-cancer/169488-asco-2026-final-analysis-of-the-tinivo-2-phase-3-trial-long-term-outcome-of-tivozanib-in-patients-with-mrcc.html
  • GU Oncology Now: https://www.guoncologynow.com/post/tinivo-2-tivozanib-nivolumab-combination-fails-to-improve-pfs-in-advanced-rcc-compared-to-tivozanib-monotherapy
  • Targeted Oncology: https://www.targetedonc.com/view/tinivo-2-study-of-nivolumab-and-tivozanib-fails-to-meet-primary-end-point-in-rcc
  • OncLive: https://www.onclive.com/view/tinivo-2-data-underscore-challenges-with-ici-retreatment-in-advanced-rcc
  • Primary publication (Lancet 2024; Choueiri/Motzer et al.): https://pubmed.ncbi.nlm.nih.gov/39284329/
  • ClinicalTrials.gov: https://clinicaltrials.gov/study/NCT04987203