Phase 3 SAPPHIRE Trial of Sitravatinib Misses Primary End Point in NSCLC

The primary end point of overall survival was not met in the phase 3 SAPPHIRE study of sitravatinib plus nivolumab in patients with advanced non-squamous non–small cell lung cancer.

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Image Credit: © appledesign []

The phase 3 SAPPHIRE trial (NCT00231270) of sitravatinib (MGCD516) in combination with nivolumab (Opdivo) vs docetaxel did not meet its primary end point of overall survival (OS) at the final analysis in patients with second- or third-line advanced non-squamous non–small cell lung cancer (NSCLC) who progressed on prior therapy with chemotherapy and immune checkpoint inhibitor therapy.1

Principal investigators on the trial can decide to continue therapy for patients who are experiencing clinical benefit and would like to remain on treatment. Full data from the trial will be disclosed at a future date.

"Mirati extends gratitude to the patients who participated in this clinical trial, their loved ones, and the trial investigators, without whom important work like this would not have been possible," said Alan Sandler, MD, chief medical officer. "As we move forward, we are optimistic about our ability to positively impact the lives of patients living with cancer through the advancement of our broad and differentiated pipeline of targeted oncology programs."

Sitravatinib is an investigational spectrum-selective kinase inhibitor that potently inhibits receptor tyrosine kinases (RTKs), including the TAM family of receptors like TYRO3, Axl, Mer, as well as split family receptors such as VEGFR2, KIT, and RET.

Investigators believe the agent can overcome resistances that develop to other checkpoint inhibition therapy based on the drug’s inhibition of TAM and RTKs and due to the targeted reversal of an immunosuppressive tumor microenvironment. This enhances antigen-specific T-cell response in patients and then expands dendritic cell-dependent in an antigen presentation.

In the randomized, phase 3 SAPPHIRE study, sitravatinib was evaluated in combination with nivolumab, an anti-PD-1 checkpoint inhibitor for the treatment of patients with non-squamous NSCLC with disease progression on or after platinum-based chemotherapy. The study sought to compare the efficacy of the investigational agent combined with nivolumab vs docetaxel in this patient population.2

The study enrolled patients aged 18 years and older with a diagnosis of non-squamous NSCLC who had received at least 1 but not more than 2 prior treatment regimens in the advanced setting and previous treatment with a PD-1/PD-L1 checkpoint inhibitor therapy and platinum-based chemotherapy in combination or in sequence. Additionally, the patient’s most recent treatment regimen must have included a checkpoint inhibitor therapy with radiographic disease progression on or after treatment, and the patient must be a candidate to receive docetaxel as second- or third-line therapy to be eligible for enrollment.

Patients included in the experimental arm were given nivolumab via intravenous (IV) infusion over 30 minutes at 240 mg every 2 weeks or at 480 mg every 4 weeks in addition to sitravatinib administered orally, once daily. In the comparator arm, docetaxel was given to patients via IV infusion at 75 mg/m2 over 1 hour every 3 weeks.

The primary end point assessed in the trial was OS and secondary end points consisted of adverse events, objective response rate, and progression-free survival.

  1. Mirati Therapeutics provides an update on the phase 3 SAPPHIRE study evaluating sitravatinib in combination with OPDIVO. News release. Mirati Therapeutics, Inc. May 24, 2023. Accessed May 25, 2023.
  2. Phase 3 study of sitravatinib plus nivolumab vs docetaxel in patients with advanced non-squamous non-small cell lung cancer (SAPPHIRE). Updated May 6, 2022. Accessed May 25, 2023.
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