A new drug application (NDA) has been submitted to the FDA seeking approval of savolitinib (Orpathys) plus osimertinib (Tagrisso) for the treatment of patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) with MET overexpression or amplification whose disease progressed on or after EGFR TKI therapy.1 AstraZeneca, which codevelops savolitinib with Hutchmed and is responsible for its commercialization, submitted the application.
The submission is supported by data from the global phase 3 SAFFRON trial (NCT05261399), in which the all-oral combination generated statistically significant and clinically meaningful improvements in progression-free survival (PFS) and overall survival (OS) vs platinum-based doublet chemotherapy in patients with EGFR-mutated NSCLC with MET overexpression or amplification whose disease progressed on osimertinib. The companies first reported the
Although third-generation EGFR TKIs have improved outcomes in EGFR-mutated NSCLC, MET overexpression or amplification is one of the most common mechanisms of resistance to these agents.1 The company estimates that approximately 34% of tumors develop high levels of MET overexpression or amplification after progression on a third-generation EGFR TKI, and MET-driven progression is associated with a poor prognosis.
Savolitinib is an oral, highly selective MET TKI that inhibits aberrant MET signaling driven by mutations such as MET exon 14 skipping, gene amplification, or protein overexpression; osimertinib is an irreversible, third-generation EGFR TKI with activity in central nervous system metastases. The combination is
SAFFRON is a randomized, open-label, multicenter, global phase 3 study that enrolled 338 patients with EGFR-mutated, locally advanced or metastatic NSCLC with MET overexpression or amplification whose disease progressed after first- or second-line osimertinib.1 The trial was conducted at 230 centers in 29 countries across North America, Europe, South America, and Asia.
Patients were randomly assigned to receive savolitinib at 300 mg twice daily plus osimertinib at 80 mg once daily or platinum-based doublet chemotherapy. Patients were prospectively selected using the high MET cutoffs identified in the phase 2 SAVANNAH trial (NCT03778229), which assessed MET status by immunohistochemistry for protein overexpression and fluorescence in situ hybridization for gene amplification. PFS served as the primary end point, and OS was the key secondary end point.
SAFFRON builds on the phase 3 SACHI trial (NCT05015608), which supported the approval of the combination in China.1,4 In SACHI, 211 patients with EGFR-mutated, MET-amplified NSCLC who experienced EGFR TKI failure were randomly assigned 1:1 at 68 hospitals in China to savolitinib plus osimertinib (n = 106) or pemetrexed plus cisplatin or carboplatin (n = 105).2
At the interim analysis published in The Lancet, investigator-assessed median PFS in the intention-to-treat population was 8.2 months (95% CI, 6.9-11.2) with the combination vs 4.5 months (95% CI, 3.0-5.4) with chemotherapy (HR, 0.34; 95% CI, 0.23-0.49; P < .0001).2 In the third-generation EGFR TKI–naive population (n = 137), median PFS was 9.8 months (95% CI, 6.9-12.5) vs 5.4 months (95% CI, 4.2-6.0), respectively (HR, 0.34; 95% CI, 0.21-0.56; P < .0001).
According to Hutchmed, the safety profile of the combination in SAFFRON was consistent with the known profiles of each agent, and no new safety concerns were identified; specific adverse effect rates from the trial have not yet been reported.1
In SACHI, grade 3 or higher treatment-emergent adverse effects occurred in 57% of patients in both the savolitinib/osimertinib arm (n = 60 of 106) and the chemotherapy arm (n = 55 of 96).2
