SAFFRON trial

Background

Phase 3, international, open-label, randomized (1:1) trial. N=338 (screened 1746) with EGFR-mutated locally advanced/metastatic NSCLC progressing on osimertinib, with MET overexpression (IHC 3+ in ≥90% of cells), MET amplification (FISH ≥10 copies), or both. Savolitinib is a selective oral MET-TKI.

Results

Interventions and follow up: Arm A: osimertinib 80 mg daily + savolitinib 300 mg BID (n=171)
Arm B: IV platinum-pemetrexed (n=167)
Primary endpoint: PFS by BICR
Key secondary: OS, safety
mFollow up: NR (not in abstract)
Results: PFS: HR 0.55 (95% CI 0.42–0.72), P<.001; 12-mo PFS 36% vs 10%
OS (final analysis): HR 0.68 (95% CI 0.50–0.91), P=.01; 12-mo OS 70% vs 53%

Adverse events

Grade ≥3 (any): 64% vs 63%
Most frequent (osimertinib-savolitinib): peripheral edema 49%, anemia 26%, diarrhea 26%

Conclusions

Osimertinib-savolitinib significantly improved PFS and OS over platinum-pemetrexed in EGFR-mutated NSCLC with MET overexpression and/or amplification after osimertinib progression. It is the first randomized phase 3 evidence supporting a MET-directed combination in this setting.

Key Limitations

Open-label design; PFS by BICR mitigates but does not remove bias. Comparator was platinum-pemetrexed without post-osimertinib chemo-immunotherapy or amivantamab-based options. Selection by high MET thresholds (IHC 3+ ≥90% or FISH ≥10 copies) limits applicability to broader MET-positive populations. Subsequent-therapy crossover and CNS data NR from abstract.

Clinical Context

Addresses the large unmet need after first-line osimertinib, where platinum-pemetrexed has been the standard. Regulatory status and guideline positioning not confirmed here; check current FDA/EMA and NCCN/ESMO updates.

References