TiNivo-2 results are the first phase III study data evaluating PD1 rechallenge, showing no efficacy in patients with advanced renal cell cancer (RCC). Tivozanib with or without nivolumab was well tolerated and consistent with the established safety profiles of these agents. The results show 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 immune checkpoint inhibition (ICI) combination therapy.
The study data suggest that tivozanib monotherapy has efficacy in the post-ICI setting and highlight the importance of full dosing to achieve maximal efficacy. The findings are reported at ESMO Congress 2024 along with a simultaneous by Prof. Toni K Choueiri of the Dana-Farber Cancer Institute, Harvard Medical School in Boston, MA, US and colleagues on 13 September 2024 in The Lancet.
Introduction of ICI combinations as first-line regimens has created uncertainty in treatment sequencing for patients whose disease has progressed after treatment with ICIs, raising questions about whether rechallenge can improve clinical outcomes either immediately following treatment or after a treatment interruption, using ICIs in the same class of PD1 or PD-L1 inhibitors, or even using the same drug in later lines of treatment.
Evidence exists that vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) have value after the first-line ICI does not work. TIVO-3 phase III study compared tivozanib to sorafenib in patients with relapsed or refractory advanced RCC after two or three previous systemic therapies, including a VEGFR TKI. It was the first phase III study to prospectively define a study population with previous ICI treatments (26% of patients) and showed an improvement in progression-free survival (PFS) with tivozanib compared with sorafenib with a median PFS of 7.3 months versus 5.1 months (hazard ratio [HR] 0.55; p = 0.028) in the subgroup that received previous ICI treatment.
The combination of tivozanib and nivolumab was first evaluated in the single-group phase Ib/II TiNivo study in metastatic RCC; previously treated patients with metastatic RCC received tivozanib at dose of 1.5 mg once a day in combination with nivolumab 240 mg every 2 weeks. With a median follow-up of 19 months, the combination showed an overall response rate (ORR) of 62%; the median PFS was not reached. Hypertension was increased with the combination compared with tivozanib monotherapy.
The only randomised, phase III evidence of ICI rechallenge in metastatic RCC is from the CONTACT-03 study, which revealed largely negative results. CONTACT-03 compared atezolizumab, a PD-L1 inhibitor, and cabozantinib, a multitargeting VEGFR TKI, to cabozantinib monotherapy in patients with advanced RCC in the second- or third-line setting whose immediate previous line of therapy was an ICI. The combination of atezolizumab and cabozantinib did not yield any clinical benefit and led to increased toxicity.
The negative outcome of CONTACT-03 left several questions unanswered, such as potential differences between anti-PD1 and anti-PD-L1 in the rechallenge setting, whether outcomes of ICI rechallenge would be affected if a non-ICI were used before subsequent ICI treatment, and whether VEGFR TKI dosing and TKI selectivity would affect tolerability or efficacy of combination therapy.
To further explore retreatment with ICI, TiNivo-2 team conducted a study aimed at comparing tivozanib with or without nivolumab in patients with metastatic RCC who have progressed following one or two lines of therapy in the post-ICI setting. TiNivo-2 is a multicentre, randomised, open-label, phase III study performed at 190 sites across 16 countries, in Australia, Europe, North America, and South America.
Patients with advanced RCC and progression during or after one to two previous lines of therapy (including one ICI) were randomised 1:1 to tivozanib (0.89 mg per day, orally) plus nivolumab (480 mg every 4 weeks, intravenously) or tivozanib (1.34 mg per day, orally). Randomisation was stratified by immediate previous therapy (ICI or non-ICI) and International Metastatic Renal Cell Carcinoma Database Consortium risk category.
The primary endpoint was PFS, defined as the time from randomisation to first documentation of objective progressive disease according to RECIST v1.1 or death from any cause, whichever came first, by independent radiology review. Efficacy was evaluated in the intention-to-treat population, and safety was assessed in patients who received one or more doses of the study drug. This study is active and not recruiting.
From 4 November 2021 to 16 June 2023, a total of 343 patients were randomly assigned, of whom 171 to tivozanib–nivolumab and 172 to tivozanib monotherapy. Median follow-up was 12.0 months. Median PFS was 5.7 months (95% confidence interval [CI] 4.0–7.4) with tivozanib–nivolumab and 7.4 months (95% CI 5.6–9.2) with tivozanib monotherapy (HR 1.10, 95% CI 0.84–1.43; p = 0.49).
Among 244 patients with an ICI as their immediate previous therapy, median PFS was 7.4 months (95% CI 5.6–9.6) with tivozanib–nivolumab and 9.2 months (95% CI 7.4–10.0) with tivozanib monotherapy. With non-ICIs as the most recent therapy, lower median PFS was observed, with no difference between groups, 3.7 months (95% CI 2.7–5.4) with tivozanib–nivolumab and 3.7 months [95% CI 1.9–7.2) with tivozanib monotherapy.
Serious adverse events occurred in 54 of 168 patients (32%) receiving tivozanib–nivolumab and 64 of 171 patients (37%) receiving tivozanib monotherapy. One (< 1%) treatment-related death occurred in tivozanib group.
The authors emphasised that the results with tivozanib monotherapy in second-line treatment following progression on ICI relative to the lower dose used in the combination group underscored the importance of using the appropriate and optimal dose of VEGFR TKI in maintaining efficacy along with a tolerable safety profile.
In an accompanied comment, Drs. Zachary A Yochum and David A Braun of the Yale Cancer Center, Yale School of Medicine in New Haven, CT, US wrote that while the TiNivo-2 study argues against the routine use of anti-PD1 plus TKI after progression on previous ICIs, individual patient circumstances should be considered. The TiNivo-2 study represents the first phase III study to both use anti-PD1 as the backbone of ICI rechallenge, and to include a substantial population who had delayed rechallenge of anti-PD1 with 29% of patients with the most recent line of therapy being non-ICI treatment. TiNivo-2 provides further evidence for the clinical activity of tivozanib in the ICI refractory setting.
The study was funded by Aveo Pharmaceuticals.
References
- 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. The Lancet; Published online 13 September 2024: DOI: https://doi.org/10.1016/S0140-6736(24)01758-6
- Yochum ZA, Braun DA. Rechallenging with anti-PD-1 therapy in advanced renal cell carcinoma. The Lancet; Published online 13 September 2024. DOI: https://doi.org/10.1016/S0140-6736(24)01866-X
- LBA73 – Choueiri TK, Motzer RJ, Beckermann K, et al. Tivozanib–Nivolumab vs Tivozanib Monotherapy in Patients with Renal Cell Carcinoma (RCC) Following 1 or 2 Prior Therapies including an Immune Checkpoint Inhibitor (ICI) – Results of the Phase III TiNivo-2 Study. Annals of Oncology 2024:35(Suppl 2):S1261-S1262.