Interim Survival Analysis of Sitravatinib Allows for SAPPHIRE Study Continuation in NSCLC

The combination of sitravatinib (MGCD516) and nivolumab (Opdivo) for patients with non-squamous non–small cell lung cancer (NSCLC) who were resistant to chemotherapy and immune checkpoint inhibitor therapy showed promising results in an interim analysis of overall survival (OS), according to a press release from Mirati Therapeutics.¹ 

The clinical-stage biotechnology company announced that based off the interim analysis, the randomized phase 3 SAPPHIRE study (NCT03906071) will continue to its final analysis, which is expected to be reached halfway through 2023. However, they have yet to announce a readout of the OS data.

"We remain committed to developing our portfolio of oncology candidates and advancing our lung cancer strategy to positively impact the lives of patients with cancer. We look forward to providing an update based on the full analysis of the SAPPHIRE study in mid-2023," said Charles Baum, MD, PhD, president, founder and head of research and development at Mirati Therapeutics, Inc, in the press release.

The global, randomized, open-label phase 3 study is comparing the tyrosine kinase inhibitor plus nivolumab against docetaxel.² A total of 532 patients will be enrolled in the trial and randomized 1:1 to either 120 mg of oral sitravatinib given once daily in continuous 28-day cycles combined with 240 mg of nivolumab given intravenously (IV) every 2 weeks or 480 mg every 4 weeks compared with docetaxel 75 mg/m2 given IV every 3 weeks.

The primary end point is OS at a median of 36 months. Secondary outcomes include the frequency of adverse events in patients during the 36-month time frame, the objective response rate, and progression-free survival during the follow up period.

For patients to be included in the study they must have 1, but no more than 2, prior treatment regimens in the advanced setting and be set to receive docetaxel as a second- or third-line therapy. Patients excluded from the trial had uncontrolled brain metastases, tested positive for EGFR, ROS1, ALK mutations, or ALK fusions in their tumors, and/or had an unacceptable toxicity with their prior checkpoint inhibition therapy.

The investigational agent sitravatinib inhibits receptor tyrosine kinases that include the TAM family of receptors, TYRO3, Axl, and Mer, as well as split family receptors like VEGFR2, KIT, and RET mutations. Due to the drug’s inhibition of TAM and receptor tyrosine kinases, researchers believe it can overcome resistances that develop to other checkpoint inhibition therapy. This is due to the targeted reversal of an immunosuppressive tumor microenvironment, which enhances antigen-specific T-cell response in patients and then expands dendritic cell-dependent in an antigen presentation.

In combination with nivolumab, the human IgG monoclonal antibody binds the PD-1 receptor in the patient and blocks the interaction of the PD-L1 and PD-L2 ligands that creates and anti-tumor response. By combining this with sitravatinib, inhibition of receptor tyrosine kinases could enhance an anti-tumor response that nivolumab creates and overcome resistance to therapy.

At this time, the researchers are estimating a completed study date of July 2023 now that they have reached their estimated primary completion date.

References

1. Mirati Therapeutics announces update for the phase 3 SAPPHIRE study. News Release. December 2, 2022. Accessed December 6, 2022. https://bit.ly/3h2fSUn

2. Phase 3 study of sitravatinib plus nivolumab vs docetaxel in patients with advanced non-squamous non-small cell lung cancer (SAPPHIRE). ClinicalTrials.gov. Updated May 6, 2022. Accessed December 6, 2022. https://bit.ly/3VA98fb