Sitravatinib may boost nivolumab efficacy in advanced clear-cell RCC
medwireNews: Adding sitravatinib to nivolumab results in a higher response rate and longer disease control in patients with advanced clear-cell renal cell carcinoma (RCC) than has historically been achieved with nivolumab monotherapy, with no unacceptable toxicity, research shows.
The findings, presented at the 2020 Genitourinary Cancers Symposium in San Francisco, California, USA, were based on a phase 1/2 study among 40 patients who had progressed on up to two prior VEGF-targeted therapies.
Presenting author Pavlos Msaouel, from The University of Texas MD Anderson Cancer Center in Houston, USA, explained that the patients received the oral receptor tyrosine kinase inhibitor sitravatinib as monotherapy during the first 14-day cycle, to allow the drug, which targets TAM family, Split family and c-MET receptors, to reach a steady state.
For the next five cycles they received sitravatinib in combination with standard-dose nivolumab. In the absence of disease progression or unacceptable toxicity, cycles were extended to 28 days and continued until disease progression or toxicity.
The dosing for sitravatinib was calculated using a Bayesian EffTox design that takes both safety and efficacy into account. Three patients were initially treated at a dose of 80 mg/day, the dose of the next three patients was then adjusted according to the EffTox algorithm to 60 mg/day or 120 mg/day, with the process repeated for each set of three patients.
The maximum dose given was 150 mg/day, but the majority received 120 mg/day. No patients were given the 60 mg/day dose.
Msaouel reported that, among the 38 patients evaluable for efficacy, 39% had an objective response and 92% had clinical benefit, defined as a complete or partial response or stable disease. After a median 17.7 months of follow-up, median progression-free survival (PFS) was 10.3 months and median overall survival was not reached, with 79% of patients still alive at the time of analysis.
By comparison, Msaouel said that the objective response rate (ORR) with nivolumab in the CheckMate 025 study, which had similar inclusion criteria, was 25% and the median PFS was 4.6 months, while the ORR and PFS with cabozantinib in the METEOR trial were 17–21% and 7.4 months, respectively.
The most common treatment-related adverse events (AEs) of any grade were diarrhea, fatigue, and elevated alanine aminotransferase and lipase levels. There was one nivolumab-related grade 5 AE (myasthenia gravis), and eight grade 4 AEs including asymptomatic increases in lipase (n=3) and amylase (n=2), and acute kidney injury, sepsis, and hypertension in one patient each.
One in 10 patients discontinued treatment due to AEs, and just over half (52.5%) required a sitravatinib dose reduction from the initial dose chosen by EffTox.
All three patients who received sitravatinib 150 mg/day experienced dose-limiting toxicity. The recommended phase 2 sitravatinib dose was therefore set at 120 mg/day. This dose is now being explored in combination with nivolumab in multiple tumor types, Msaouel remarked.
He concluded: “[I]n this single arm phase 1/2 study of sitravatinib in combination with nivolumab using similar enrollment criteria as CheckMate 025, we observed higher objective response rate and longer PFS than historically reported with single-agent nivolumab or single-agent cabozantinib.”
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