Recently, the researchers have obviously sought for the introduction of immunotherapy alone or in combination and after the failure of a first-line immunotherapy.

Novel treatment approaches are needed to overcome innate and acquired mechanisms of resistance to current anticancer therapies in cancer cells and the tumor immune microenvironment. The TAM (TYRO3, AXL and MERTK) family receptor tyrosine kinases (RTKs) are potential therapeutic targets in a wide range of cancers.

In cancer cells, TAM RTKs activate signaling pathways that promote cell survival, metastasis and resistance to a variety of chemotherapeutic agents and targeted therapies. TAM RTKs also function in innate immune cells, contributing to various mechanisms that suppress antitumor immunity and promote resistance to immune checkpoint inhibitors(1).

In the SAPPHIRE study, sitravatinib is an oral spectrum-selective tyrosine kinase inhibitor that targets the TAM (TYRO3/AXL/MERTK) and splits (VEGFR2/KIT) the family receptor tyrosine kinases, as well as MET. The 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 proinflammatory M1 phenotype. The 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 with non-small cell lung cancer (NSCLC).

Unfortunately, in the SAPPHIRE study, sitravatinib plus nivolumab did not improve the survival in NSCLC after immunotherapy and chemotherapy.

The SAPPHIRE trial failed to meet its primary endpoint compared with chemotherapy.

According to the results from the phase III SAPPHIRE trial presented at the ESMO Congress 2023 (Madrid, 20-24 October), there was no difference in the overall survival (OS) of patients who received sitravatinib with nivolumab compared with docetaxel as second- or third-line treatment for advanced non-squamous non-small cell lung cancer following progression or after immune checkpoint inhibition and chemotherapy (LBA63). In the 577 patients, the median OS was 12.2 months with sitravatinib plus nivolumab versus 10.6 months with docetaxel (hazard ratio [HR] 0.86; 95% confidence interval [CI]; 0.70-1.05; p=0.144). In addition, no significant differences between sitravatinib plus nivolumab and docetaxel were seen in median progression-free survival (4.4 months versus 5.4 months, respectively; HR 1.08; 95% CI; 0.89-1.32; p=0.452) or objective response rate (16% versus 17%, respectively; p=0.597). The clinical benefit rate was 76% in the sitravatinib plus nivolumab arm, which was significantly higher than in the docetaxel arm (65%; p=0.004)(2).

The conclusion is that we have to wait the new study: the phase III SAFFRON-301 trial, that will be completed in 2024. This study evaluates sitravatinib in combination with the PD-1 inhibitor tislelizumab in patients with locally advanced/metastatic NSCLC who experienced disease progression after ICI and chemotherapy. This rechallenge of immunotherapy remains a therapeutic challenge(3).


Conflict of interest: none declared.

Financial support: none declared.

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