Phase III trial of sitravatinib plus nivolumab vs. docetaxel for treatment of NSCLC after platinum-based chemotherapy and immunotherapy (SAPPHIRE).

Abstract

TPS9635 Background: Sitravatinib is an oral spectrum-selective tyrosine kinase inhibitor that targets the TAM (TYRO3/AXL/MERTK) and split (VEGFR2/KIT) family receptor tyrosine kinases (RTKs), as well as MET. Inhibition of TAM RTKs may promote the depletion of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) and repolarize tumor associated macrophages towards the pro-inflammatory M1 phenotype. Inhibition of the split RTKs may reduce immunosuppressive regulatory T cells in addition to MDSCs within the TME. Given these pleiotropic immune-stimulating effects, sitravatinib may reverse resistance to checkpoint inhibitor therapy (CIT) and augment the antitumor immune response of nivolumab in patients (pts) with non-small cell lung cancer (NSCLC). An ongoing Phase 2 study (MRTX-500) demonstrates clinical activity of this combination in pts with metastatic non-squamous NSCLC after progression on or after CIT. Methods: Global, randomized, open-label, Phase 3 study of sitravatinib in combination with nivolumab vs docetaxel in pts with advanced non-squamous NSCLC who have progressed on or after CIT. Pts must have also received platinum-based chemotherapy either in combination with CIT or prior to CIT. Pts are randomized (1:1) to receive oral sitravatinib 120 mg once daily in continuous 28-day cycles combined with nivolumab IV 240 mg every 2 weeks or 480 mg every 4 weeks vs treatment with docetaxel 75 mg/m2 IV every 3 weeks. Patients are stratified based on number of prior treatment regimens in the advanced setting, ECOG performance status, and presence of brain metastases. Key eligibility criteria include duration of treatment of CIT of at least 4 months, discontinuation of prior treatment with CIT < 90 days prior to the date of randomization, and absence of symptomatic or uncontrolled brain metastases. The primary endpoint is overall survival (OS). Key secondary endpoints include safety and tolerability, ORR, PFS, PROs, and PK. OS will be analyzed using Kaplan-Meier methods and the stratified log-rank test to estimate and compare the median OS between the two treatment arms with 95% CI. An IDMC will review safety at regular intervals and efficacy at a planned interim analysis based on OS. Enrollment is ongoing. Clinical trial information: NCT03906071 .

Managing Resistance to Immune Checkpoint Inhibitors in Lung Cancer: Treatment and Novel Strategies

“…98 On the basis of these results, the LEAP program is ongoing, testing lenvatinib plus pembrolizumab combinations in phase III trials in both the first-line and further-line setting. 99 In addition, sitravatinib plus nivolumab combination is under evaluation in a phase III trial in ICI-resistant patients, 100 after a phase II trial showing high tumor regression rate (. 80%) and prolonged treatment duration, despite 17% of treatment discontinuation because of adverse events.…”

“…98 On the basis of these results, the LEAP program is ongoing, testing lenvatinib plus pembrolizumab combinations in phase III trials in both the first-line and further-line setting. 99 In addition, sitravatinib plus nivolumab combination is under evaluation in a phase III trial in ICI-resistant patients, 100 after a phase II trial showing high tumor regression rate (> 80%) and prolonged treatment duration, despite 17% of treatment discontinuation because of adverse events. 101 Similarly, the combination of pembrolizumab with the anti–vascular endothelial growth factor receptor-2 ramucirumab was well-tolerated and active in patients with NSCLC in a phase I trial 102,103 ; this combination is currently tested within the Lung-MAP master protocol.…”

Harnessing epithelial-mesenchymal plasticity to boost cancer immunotherapy

“…GT90001 is an anti-activin receptor-like kinase-1 (ALK-1) antibody [ 280 ]. Sitravatinib and lenvatinib target intracellular signaling kinases [ 281 , 282 ], and are combined with anti-PD-1/PD-L1 or anti-CTLA-4 treatment in different cancer types. These combination trials are remarkable advances, although most of the trials are still ongoing.…”

Addressing CPI resistance in NSCLC: targeting TAM receptors to modulate the tumor microenvironment and future prospects

“…96 Based on these results, the phase 3 SAPPHIRE trial was initiated to compare the combination of sitravatinib and nivolumab versus docetaxel alone in patients with advanced nonsquamous NSCLC who had progressed during or after platinum-based chemotherapy in combination with CPI treatment (NCT03906071); this trial is Open access currently ongoing. 97 Sitravatinib is also being investigated in a phase 3 trial in combination with another CPI, anti-PD-1 therapy tislelizumab, vs docetaxel alone in patients with advanced/metastatic NSCLC who have disease progression following platinum-based chemotherapy with CPI treatment (NCT04921358); this trial is currently recruiting.…”