Targeting MET After Lung Cancer Drug Resistance: Phase 3 Trial of Two Oral Targeted Therapies Extends Both Progression-Free and Overall Survival

Osimertinib has transformed the treatment landscape for EGFR-mutated lung cancer, but once tumors activate MET signaling as a bypass pathway, the original targeted therapy often gradually loses effectiveness. HUTCHMED and AstraZeneca announced that the global Phase 3 SAFFRON trial met its primary and key secondary endpoints: savolitinib plus osimertinib significantly improved both progression-free survival and overall survival compared with platinum-doublet chemotherapy.

The clinical significance of this result is that the treatment strategy is no longer limited to discontinuing the original targeted therapy and switching entirely to chemotherapy. Instead, it identifies the tumor’s newly developed escape pathway and uses a MET inhibitor to block the resistance mechanism while retaining osimertinib’s suppression of EGFR. Both drugs are oral formulations and may reduce the burden of infusion therapy; however, an “all-oral” regimen does not mean fewer side effects, and a complete safety analysis is still needed.

SAFFRON is a randomized, open-label, global Phase 3 study that enrolled patients with locally advanced or metastatic non-small cell lung cancer whose disease progressed after first- or second-line osimertinib, whose tumors harbored EGFR mutations, and who had MET overexpression or gene amplification. The trial compared savolitinib plus osimertinib with a platinum agent plus pemetrexed. According to the trial registration data, the experimental group received savolitinib 300 mg twice daily and osimertinib 80 mg once daily.

Materials previously filed by the company with the U.S. Securities and Exchange Commission showed that 338 patients underwent randomization at more than 230 trial sites across 29 countries. The primary endpoint was progression-free survival assessed according to RECIST 1.1 by blinded independent central review; overall survival, tumor response, duration of response, and safety were listed as other key endpoints. AstraZeneca’s trial record currently lists 345 participants, a slight difference from the previously disclosed randomized population that may reflect a registry update or differing statistical definitions.

MET amplification or protein overexpression is one of the common resistance mechanisms after osimertinib treatment, but different specimen types, testing methods, and positivity thresholds may identify patient populations that do not completely overlap. If this combination enters clinical practice, MET testing standards, the availability of tumor tissue, and how liquid biopsy and tissue testing are used together will directly affect the number of eligible patients and treatment outcomes.

Only topline results have been announced so far. The median survival times, hazard ratios, confidence intervals, serious adverse events, and treatment discontinuation rates for the two groups have not yet been disclosed, and it is not possible to determine whether the benefit consistently extends across different MET testing subgroups. The two companies plan to submit applications to regulators worldwide. Before the complete data are presented at a medical conference or published through peer review, the trial has established a clear basis for registration, but there is not yet enough information to assess the magnitude of benefit, the toxicity trade-off, or its actual place in the treatment sequence.