SAFFRON Sets a New Survival Benchmark: Savolitinib Plus Osimertinib Outperforms Chemotherapy in MET-Driven, EGFR-Mutated NSCLC
Savolitinib (ORPATHYS) plus osimertinib (TAGRISSO) represents a targeted combination strategy for advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor mutations (EGFRm) that develops MET-driven resistance following osimertinib treatment. Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI), while savolitinib is an oral, selective MET TKI designed to inhibit signaling associated with MET overexpression and amplification. Combining these agents aims to suppress both the original EGFR driver and the acquired MET-mediated resistance pathway.
The global, randomized Phase III SAFFRON trial (NCT05261399) evaluated osimertinib plus savolitinib against platinum–pemetrexed chemotherapy in patients with locally advanced or metastatic EGFRm NSCLC with MET overexpression and/or amplification whose disease had progressed during osimertinib treatment. The study enrolled 338 patients randomized to the combination (n = 171) or chemotherapy (n = 167). Presented at ESMO Congress 2026 and simultaneously published in The New England Journal of Medicine, the results demonstrated statistically significant improvements in both progression-free survival (PFS) and overall survival (OS).
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Key Efficacy and Safety Highlights | |||
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Category |
Parameter |
Osimertinib + Savolitinib |
Platinum–Pemetrexed |
|
Efficacy |
Patients randomized |
171 |
167 |
|
Median PFS by BICR |
7.6 months |
5.4 months | |
|
PFS hazard ratio |
0.55 |
Comparator arm | |
|
PFS statistical significance |
p < 0.001 |
Comparator arm | |
|
PFS rate at 12 months |
36% |
10% | |
|
Median OS |
17.8 months |
12.9 months | |
|
OS hazard ratio |
0.68 |
13% | |
|
OS statistical significance |
p= 0.010 |
Comparator arm | |
|
OS rate at 12 months |
70% |
53% | |
|
Objective response rate |
51% |
27% | |
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Safety |
Median duration of response |
9.7 months |
5.7 months |
|
Grade ≥3 treatment-emergent adverse events |
64% |
63% | |
|
Grade ≥3 treatment-related adverse events |
40% |
52% | |
|
Adverse events leading to treatment discontinuation |
14% |
8% | |
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Most common adverse events with combination |
Peripheral edema (49%), anemia (26%), diarrhea (26%) |
Comparator arm | |
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BICR: Blinded Independent Central Review; PFS: Progression-Free Survival; OS: Overall Survival | |||
Conclusion-
The Phase III SAFFRON findings establish a clinically meaningful advance in the management of advanced EGFR-mutated NSCLC with MET overexpression and/or amplification following osimertinib progression. By improving both PFS and OS over platinum–pemetrexed chemotherapy, savolitinib plus osimertinib strengthens the rationale for identifying and therapeutically targeting acquired MET-driven resistance rather than relying exclusively on conventional chemotherapy. The results could support a new global treatment option in this biomarker-defined population, subject to regulatory review and local access. More broadly, SAFFRON reinforces the evolution of NSCLC care toward mechanism-based treatment sequencing, in which molecular reassessment at progression can guide therapy beyond the original oncogenic driver.