ICI combination rechallenge does not improve outcomes in advanced renal cell carcinoma

The addition of nivolumab (Opdivo) to low-dose (0.89 mg) tivozanib (Fotivda) did not improve clinical outcomes compared with standard-dose tivozanib (1.34 mg) monotherapy in patients with advanced metastatic renal cell carcinoma (RCC) whose tumors progressed following prior treatment with an immune checkpoint inhibitor (ICI), thus failing to meet the primary end point of the phase 3 TiNivo-2 trial (NCT04987203).

Toni K. Choueiri, MD

The data were presented at the 2024 European Society for Medical Oncology Annual Congress in Barcelona, Spain and concurrently published in The Lancet.^1,2

“I believe this trial confirms and expands key conclusions from the CONTACT-03 study, [which] is the second phase 3 trial in RCC and solid tumors that suggests that ICI rechallenge should be generally discouraged regardless of treatment sequence,” said Toni K. Choueiri, MD, who presented results on behalf of the TiNivo-2 investigators. “We believe that the reduced dose of tivozanib in the combination arm may have impacted the efficacy, and that reflects in the lower median PFS, at least by the numbers. We saw a meaningful efficacy in the second-line tivozanib monotherapy—9.2 months PFS—and these results support tivozanib at 1.34 mg as a second-line therapy option in patients following progression after previous ICI therapy.”

Choueiri noted during the presentation that the reduced dose of tivozanib in the combination arm was agreed upon in consultation with regulatory authorities due to the potential risk of grade 3/4 hypertension.

Overall, data from the trial showed a median progression-free survival (PFS) of 5.7 months (95% CI, 4.0-7.4) in the tivozanib plus nivolumab arm vs 7.4 months (95% CI, 5.6-9.2) in tivozanib monotherapy arm (HR, 1.10; 95% CI, 0.84-1.43; P = .49). The number of PFS events was 118 (69%) in the combination arm compared with 112 (65%) in the control arm.

Further, PFS was not improved with the addition of nivolumab based on the line of therapy received. In patients for whom this was their second-line therapy, the median PFS was 7.3 months (95% CI, 5.4-9.3) in the combination arm vs 9.2 months (95% CI, 7.4-10.0) in the control arm (HR, 1.15; 95% CI, 0.82-1.62; P = .4283). In patients for whom this was their third-line therapy, the median PFS was 4.8 months (95% CI, 3.2-7.5) with nivolumab plus tivozanib compared with 5.5 months (95% CI, 2.9-7.4) with tivozanib alone (HR, 0.97; 0.65-1.45; P = 8866).

There was no benefit to the addition of nivolumab across all subgroups assessed in the trial.

At the time of data report, the overall survival (OS) analysis was not yet mature, with 32% of events having occurred. However, based on these results, the median OS was 17.7 months (95% CI, 15.1-NR) in the combination arm vs 22.1 months (95% CI, 15.2-NR) in the monotherapy arm (HR, 1.00; 95% CI, 0.68-1.46; P = .9868). At the time of report, there were 53 (31%) OS events in the tivozanib plus nivolumab arm vs 57 (33%) in the tivozanib monotherapy arm.

The best overall response rate (ORR) was 19.3% (95% CI, 13.7-26.0) in the combination arm and 19.8% (95% CI, 14.1-26.5) in the monotherapy arm. The median duration of response (DOR) was 15.77 months (95% CI, 5.65-NR) in the combination arm and 9.66 months (95% CI, 3.71-NR) in the monotherapy arm.

Regarding safety, treatment-emergent adverse events (TEAEs) were experienced by 163 (97%) of patients in the tivozanib plus nivolumab arm and 167 (98%) of patients in the tivozanib monotherapy arm. Grade 3 or higher AEs occurred in 102 (61%) and 103 (60%) of patients in the treatment and control arms, respectively. There were 7 (4%) deaths due to an AE in the combination arm and 5 (3%) deaths due to an AE in the monotherapy arm.

The median duration of treatment was 6.3 months (range, 0.0-20.7) in the tivozanib plus nivolumab cohort and 7.4 months (range, 0.1-17.9) in the tivozanib monotherapy cohort.

In total, the phase 3 TiNivo-2 trial enrolled 343 adult patients with advanced RCC who had received 1 or 2 prior lines of therapy, one of which was an ICI. Patients were enrolled across clinical trial sites in North America, Latin America, and Europe.

To be eligible for enrollment, patients needed to have histologically or cytologically confirmed RCC with a clear cell component, prior progression on or following 6 weeks or longer of treatment with an ICI, at least 6 months from immediate prior line of therapy to randomization, measurable disease per RECISTv1.1, and an ECOG performance score of 0 or 1. Additionally, patients needed to have recovered from adverse events of prior therapies to grade 1 or lower or to baseline.³

For the trial, patients were randomly assigned 1:1 to receive either 0.89 mg tivozanib once daily plus 480 mg intravenous nivolumab every 4 weeks (n = 171) or to 1.34 mg tivozanib monotherapy once daily (n = 172). The median follow-up was 11.8 months in the tivozanib plus nivolumab arm and 12.5 months in the tivozanib monotherapy arm. The primary end point was PFS. Secondary end points included OS, ORR, DOR, and safety/tolerability.

Overall, Choueiri concluded in his presentation, “TiNivo-2 is a negative study, but I strongly believe it's important. It is practice changing, and it should make us think twice now.”

Reference

1. Choueiri T. 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. Presented at: 2024 European Society for Medical Oncology Annual Congress. September 13-17, 2024. Barcelona, Spain. LBA73

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. The Lancet. Published online and accessed September 13, 2024. doi:10.1016/S0140-6736(24)01758-6

3. Study to compare tivozanib in combination with nivolumab to tivozanib monotherapy in subjects with renal cell carcinoma. ClinicalTrial.gov. Last updated April 30, 2024. Accessed September 13, 2024. https://clinicaltrials.gov/study/NCT04987203