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Sitravatinib plus nivolumab safe, active in advanced urothelial carcinoma
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NATIONAL HARBOR, Md. — The combination of sitravatinib and nivolumab induced encouraging clinical activity among patients with advanced urothelial carcinoma who experienced progression after immune checkpoint inhibitor therapy, according to results of a phase 2 study presented at Society for Immunotherapy of Cancer Annual Meeting.
Adverse events associated with the regimen appeared manageable.
Sitravatinib (Mirati Therapeutics), an investigational oral tyrosine kinase inhibitor, potently inhibits the TAM family of receptor tyrosine kinases (Tyro3, Axl and MerTK), which are known to modulate the immune microenvironment, according to Pavlos Msaouel, MD, PhD, assistant professor in the department of genitourinary medical oncology at The University of Texas MD Anderson Cancer Center and a HemOnc Today Next Gen Innovator.
Sitravatinib also inhibits vascular endothelial growth factor receptor 2 and c-Met, which play a role in antitumor immunity, he told HemOnc Today.
“This led us to explore whether the inhibition of these pathways by sitravatinib can induce, enhance or restore responses to immune checkpoint inhibition [ICI] in patients with locally advanced or metastatic urothelial carcinoma who had previously progressed on immunotherapy,” Msaouel said. “We used nivolumab [Opdivo, Bristol-Myers Squibb] as our ICI backbone and tested whether its combination with sitravatinib would produce objective responses in immunotherapy-resistant urothelial carcinoma.”
Msaouel and colleagues presented results from cohort 1 of the study, which included 33 patients (median age, 68 years; range, 47-83; 70% men) with locally advanced (9%) or metastatic (91%) urothelial carcinoma who previously received platinum-based chemotherapy and progressed on a checkpoint inhibitor. Patients received a median two (range, 1-4) previous lines of therapy in the metastatic or advanced setting.
“In platinum-experienced patients with locally advanced or metastatic urothelial carcinoma who have previously progressed on anti-PD-1/PD-L1 therapy, rechallenge with anti-PD-1, such as with single-agent nivolumab, will generally produce objective responses in less than 10% of patients,” Msaouel said. “Responses to chemotherapy are also generally poor in this setting.”
Patients in cohort 1 received 120 mg oral sitravatinib once daily, plus 240 mg IV nivolumab once every 2 weeks or 480 mg once every 4 weeks in continuous 28-day cycles. Investigators assessed tumors every 8 weeks.
Clinical activity as assessed by objective response rate per RECIST version 1.1 criteria served as the primary objective. Secondary objectives included safety, tolerability, duration of response, clinical benefit rate, PFS, OS and pharmacokinetics of sitravatinib.
Among 22 patients evaluable for response, 21 (95%) demonstrated complete response, partial response or stable disease. Six patients had confirmed complete (n = 1) or partial (n = 5) responses, for an ORR of 27%.
Nineteen patients (86%) had either a complete response, partial response or stable disease lasting longer than 12 weeks, and eight (36%) patients had tumor regression of more than 30%.
The most frequent treatment-related adverse events experienced by at least 20% of patients included fatigue (58%), diarrhea (48%), decreased appetite (33%), dysphonia (33%), nausea (33%) and increased alanine aminotransferase (21%).
Grade 3 treatment-related adverse events that occurred in more than one study patient included fatigue (12%), hypertension (12%), diarrhea (9%) and increased lipase (9%).
There were no reported grade 4 or grade 5 treatment-related adverse events.
“The combination of sitravatinib with anti-PD-1 therapy has a reasonable toxicity profile and shows promising clinical activity, including tumor regression and prolonged duration of treatment, in patients with locally advanced or metastatic urothelial carcinoma who have progressed following prior anti-PD-1/PD-L1 therapy,” Msaouel said.
He added that preliminary clinical activity is being evaluated in other patient cohorts, including platinum-ineligible patients and those who have progressed on previous immunotherapy combinations.
“Our study provides an encouraging early signal for clinical activity with acceptable toxicity, but this will need to be validated in larger patient numbers and pass regulatory muster before the combination of sitravatinib with immunotherapy can be incorporated in daily clinical practice,” Msaouel said. – by Drew Amorosi
Reference:
Msaouel P, et al. Abstract O23. Presented at: Society for Immunotherapy of Cancer Annual Meeting; Nov. 7-10, 2019; National Harbor, Md.
Disclosures: Mirati Therapeutics Inc. sponsored the study. Msaouel reports advisory board roles with and honoraria from Bristol-Myers Squibb and Mirati Therapeutics; nonbranded educational programs with Exelixis and Pfizer; and clinical trials with grant support from Bristol-Myers Squibb, Mirati Therapeutics and Takeda Pharmaceutical Co. Please see the abstract for all other authors’ relevant financial disclosures.