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The addition of nivolumab (Opdivo) to tivozanib (Fotivda) compared with tivozanib alone failed to improve outcomes as second- or third-line treatment for patients with renal cell carcinoma (RCC) who progressed after immune checkpoint inhibitor (ICI) therapy, according to results from the phase III TiNivo-2 trial.

At a median follow-up of 12 months, median progression-free survival (PFS) was 5.7 months with tivozanib -- a vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR TKI) -- plus the PD-1 inhibitor nivolumab, compared with 7.4 months with tivozanib monotherapy (HR 1.10, 95% CI 0.84-1.43, P=0.49), reported Toni Choueiri, MD, of the Dana-Farber Cancer Institute in Boston, at the European Society for Medical Oncology annual congress.

Furthermore, adding nivolumab to tivozanib failed to improve PFS no matter whether patients received a checkpoint inhibitor as the most recent prior therapy or earlier.

"I believe this trial confirms and expands the key conclusions from the CONTACT-03 study ... that suggest that ICI rechallenge should generally be discouraged regardless of treatment sequence," Choueiri said. "TiNivo-2 is a negative study, but I strongly believe it is important, it is practice-changing, and it should make us think twice."

Results from the study were published simultaneously in .

In patients who received ICI as part of their most recent therapy (mostly second-line), median PFS was 7.4 months with tivozanib plus nivolumab versus 9.2 months with tivozanib monotherapy (HR 1.10, 95% 0.80-1.52, P=0.56), while for those patients who received non-ICIs as the most recent therapy median PFS was 3.7 months in each group (HR 0.95, 95% CI 0.61-1.50, P=0.85).

That median PFS of 9.2 months demonstrated in the tivozanib monotherapy arm was "meaningful," Choueiri said. "These results support tivozanib monotherapy at 1.34 mg as a second-line therapy option following progression after previous ICI therapy."

As for the lower PFS of 3.7 months demonstrated in patients who received non-ICIs as the most recent prior therapy, Choueiri said this "debunks" the notion outcomes could be improved by providing patients with a "break" by treating them with a TKI before an ICI rechallenge.

As for secondary outcomes, Choueiri reported overall survival was immature at data cutoff, response rates were similar between the two groups, and no subgroups benefitted with the addition of nivolumab to tivozanib.

Regarding safety, serious treatment-related adverse events occurred in 8% of patients in the combination arm, and 9% in the tivozanib monotherapy arm. There were more treatment-emergent adverse events (TEAEs) leading to discontinuation and dose interruption in the monotherapy arm, as well as more TEAEs leading to dose reductions of tivozanib in the monotherapy arm.

Did Dose Impact Efficacy?

Choueiri said a reduced dose of tivozanib (0.89 mg) in combination with nivolumab was in agreement with regulatory authorities and was due to the potential of a high risk of grade 3/4 hypertension seen with this combination. However, he also noted the reduced dose of tivozanib in the combination arm "may have impacted efficacy as reflected by the numerically lower median PFS."

However, invited discussant Manuela Schmidinger, MD, of the Medical University of Vienna, said it is unlikely that hypertension would be more an issue with tivozanib combined with nivolumab, that it is usually well managed, and is "a key adverse event linked to efficacy and appropriate drug exposure."

"I don't understand the choice of dose," she said. "The [maximum tolerated dose] of tivozanib in all combination trials was defined as 1.5 mg once daily, even in trials combining tivozanib with chemotherapy."

"Can we conclude that [tivozanib-nivolumab] failed to improve outcomes versus tivozanib alone after prior immunotherapy?" she asked. "Or was it rather that the addition of nivolumab was unable to overcome the disadvantage of an underdosed tivozanib regimen?"

The dose of tivozanib in this trial "hindered the ability to answer the scientific question," she suggested. "You don't win the race with the brakes on."

In a accompanying the study in The Lancet, Zachary Yochum, MD, PhD, and David Braun, MD, PhD, both of the Yale School of Medicine in New Haven, Connecticut, also noted that the dose of tivozanib in the combination was lower than when used as a single agent, but added that while a higher dose of tivozanib "would have undoubtedly increased adverse events, it is unclear whether this would also have improved response rates or altered the primary endpoint."

They agreed that TiNivo-2 is practice-changing "as it provides clear evidence that rechallenging with anti-PD-1 therapy, specifically the combination of anti-PD-1 therapy plus VEGFR TKIs, should not be used as routine practice in the ICI refractory setting in renal cell carcinoma."

However, results from the study shouldn't be overinterpreted, they said, and individual patient circumstances should also be considered. "[A]ddressing the challenge of how to provide long-term, durable responses in patients with renal cell carcinoma after progression on ICI therapy remains an open and urgent clinical and scientific question."

The study was a multicenter, randomized phase III trial at 190 sites across 16 countries in Australia, Europe, North America, and South America. It included 343 patients with advanced RCC who had progressed during or after one or two previous lines of therapy, including one ICI.

Patients were randomized 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).

The median age of patients was 63-64 years, 76% of patients were male, 47% had an ECOG performance status of 0, and 67% had a previous nephrectomy.

Before entering the study 63% of patients had received one line of therapy, and the remaining 37% had received two lines. Overall, 14% of patients had adjuvant therapy. The most recent therapy was an ICI in 71% of patients and non-ICI agents in 29%.