A new phase 3 clinical trial has found that adding an immune checkpoint inhibitor to a targeted therapy does not improve outcomes for patients with advanced renal cell carcinoma who have previously received immunotherapy. The study, published on September 13, 2024 in The Lancet, assessed the efficacy and safety of combining tivozanib, a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor, with nivolumab, a PD-1 immune checkpoint inhibitor, compared to tivozanib alone in patients whose disease had progressed after prior immunotherapy.
The TiNivo-2 trial was a randomized, open-label, phase 3 study conducted at 190 sites across 16 countries in Australia, Europe, North America, and South America. It was funded by Aveo Pharmaceuticals, the developer of tivozanib. The study aimed to determine if rechallenge with immunotherapy in combination with a VEGFR inhibitor could improve clinical outcomes in the post-immunotherapy setting for advanced renal cell carcinoma.
A total of 343 patients were enrolled in the trial between November 2021 and June 2023. Eligible patients had advanced renal cell carcinoma with a clear cell component and disease progression during or after receiving one or two previous lines of therapy, one of which included an immune checkpoint inhibitor. Patients were required to have measurable disease, an ECOG performance status of 0 or 1, and adequate organ function. Key exclusion criteria included receipt of more than two prior lines of therapy, active autoimmune disease, and uncontrolled hypertension.
Participants were randomized 1:1 to receive either tivozanib 0.89 mg orally once daily for 21 days followed by a 7-day rest period plus nivolumab 480 mg intravenously every 4 weeks (n=171), or tivozanib monotherapy at the standard dose of 1.34 mg using the same schedule (n=172). Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival as assessed by blinded independent radiological review.
Baseline characteristics were well-balanced between the two groups. The median age was 63-64 years, about 75% of patients were male, and the majority had intermediate-risk disease by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. Approximately 63% of patients had undergone prior nephrectomy. About two-thirds of patients had received only one prior line of therapy, while one-third had received two prior lines. Notably, 71% of patients in each arm had received an immune checkpoint inhibitor as their most recent therapy before entering the study.
After a median follow-up of 12 months, the study failed to meet its primary endpoint. Median progression-free survival was 5.7 months in the combination arm versus 7.4 months with tivozanib monotherapy (hazard ratio 1.10, 95% CI 0.84-1.43, p=0.49). Overall response rates were similar between groups at 19-20%. Subgroup analyses did not identify any populations that derived benefit from the addition of nivolumab.
Interestingly, in patients who had received an immune checkpoint inhibitor as their most recent prior therapy, median progression-free survival was longer in both arms compared to the overall population - 7.4 months with the combination and 9.2 months with tivozanib alone. This suggests tivozanib monotherapy may be particularly effective immediately following progression on immunotherapy. In contrast, for patients whose most recent therapy was not an immune checkpoint inhibitor, median progression-free survival was only 3.7 months in both arms.
The safety profile was generally consistent with the known toxicities of the individual agents. Grade 3 or higher adverse events occurred in 61% of patients receiving the combination and 60% of those on tivozanib monotherapy. The most common high-grade adverse event was hypertension, affecting 22% in both arms. Serious adverse events were reported in 32% of combination patients and 37% of monotherapy patients. Treatment-related deaths occurred in less than 1% of patients in each arm.
Quality of life assessments using the FKSI-DRS questionnaire showed no differences between arms, with both groups demonstrating a trend toward slight improvement in disease-related symptoms over time.
The authors concluded that these results, along with the negative findings from the recent CONTACT-03 trial, indicate that rechallenge with immune checkpoint inhibition should be discouraged in patients with advanced renal cell carcinoma who have progressed on prior immunotherapy. The study also demonstrated the clinical activity of tivozanib monotherapy in the post-immunotherapy setting, particularly when used immediately following progression on an immune checkpoint inhibitor.
Several limitations of the study should be noted. The open-label design introduces the potential for bias in subjective endpoints. The reduced dose of tivozanib used in the combination arm to mitigate potential toxicity concerns may have impacted efficacy. Additionally, the study lacked data on sarcomatoid tumors, which are known to have higher PD-L1 expression and may respond differently to immunotherapy rechallenge.
The TiNivo-2 results have important clinical implications for the treatment of advanced renal cell carcinoma. They provide further evidence against the strategy of rechallenging with immune checkpoint inhibition after progression on prior immunotherapy, regardless of whether there has been an intervening period of non-immunotherapy treatment. This applies to both anti-PD-1 and anti-PD-L1 agents, as demonstrated by the concordance between TiNivo-2 and CONTACT-03.
For patients progressing after first-line immunotherapy-based treatment, the findings support the use of VEGFR tyrosine kinase inhibitor monotherapy. Tivozanib showed particular promise in this setting, with a median progression-free survival of 9.2 months when used immediately following an immune checkpoint inhibitor. This compares favorably to historical data with other VEGFR inhibitors in the post-immunotherapy setting.
The results also highlight the importance of optimal dosing of targeted therapies. The full approved dose of tivozanib (1.34 mg) used in the monotherapy arm appeared more effective than the reduced dose (0.89 mg) used in the combination, even with the addition of nivolumab. This underscores the need to use the highest tolerable dose of VEGFR inhibitors to maximize efficacy.
An ongoing question in the field is whether any subgroups of patients may benefit from immunotherapy rechallenge. While TiNivo-2 did not identify such populations, future research incorporating biomarkers or focusing on specific histologies like sarcomatoid renal cell carcinoma may help refine patient selection. Additionally, strategies to overcome immune resistance mechanisms and potentially resensitize tumors to checkpoint inhibition remain an active area of investigation.
In conclusion, the TiNivo-2 trial provides important guidance for the management of advanced renal cell carcinoma in the evolving treatment landscape dominated by first-line immunotherapy combinations. It reinforces the role of VEGFR tyrosine kinase inhibitor monotherapy as the standard approach after progression on immunotherapy and discourages routine rechallenge with immune checkpoint inhibitors. As the field continues to advance, optimizing treatment sequencing and identifying novel approaches to overcome resistance will be key priorities to improve outcomes for patients with this challenging disease.
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 [published correction appears in Lancet. 2024 Oct 26;404(10463):1644. doi: 10.1016/S0140-6736(24)02186-X]. Lancet. 2024;404(10460):1309-1320. doi:10.1016/S0140-6736(24)01758-6
