Clinical Summary: 

• Design/Population: The phase 3 SAFFRON trial evaluated osimertinib plus savolitinib versus platinum-pemetrexed chemotherapy in patients with EGFR-mutated, MET-overexpressed and/or MET-amplified advanced non-small cell lung cancer (NSCLC) following first- or second-line osimertinib.
• Key Outcomes: Osimertinib plus savolitinib significantly improved progression-free survival (PFS) and overall survival (OS) compared with platinum-pemetrexed chemotherapy, reducing the risk of disease progression or death by 45% and the risk of death by 32%. The PFS benefit was consistent across MET-overexpressed and MET-amplified subgroups.
• Clinical Relevance: These findings support dual EGFR/MET inhibition as a potential treatment strategy for patients with EGFR-mutated, MET-altered advanced NSCLC following osimertinib progression, providing an oral targeted alternative to platinum-based chemotherapy.

Results from the phase 3 SAFFRON trial demonstrated that osimertinib plus savolitinib significantly improved survival compared with platinum-pemetrexed chemotherapy in patients with EGFR-mutated, MET-overexpressed and/or MET-amplified advanced non-small cell lung cancer (NSCLC) following osimertinib treatment, supporting dual EGFR/MET inhibition as a potential new treatment standard.

These findings were presented by Shun Lu, MD, PhD, Shanghai Chest Hospital, Shanghai, China, during a Presidential Symposium at the European Society for Medical Oncology (ESMO) Congress.

In this trial, researchers enrolled 338 patients with advanced NSCLC harboring EGFR exon 19 deletions, L858R mutations, and/or T790M mutations, along with MET overexpression and/or amplification. MET overexpression was defined as IHC 3+ staining in at least 90% of tumor cells, and MET amplification as at least 10 MET gene copies.

Patients were randomized 1:1 to receive either 80 mg of osimertinib once daily plus 300 mg of savolitinib twice daily (n = 171) or platinum-pemetrexed chemotherapy (n = 167). Patients in the chemotherapy arm received pemetrexed plus carboplatin or cisplatin every 3 weeks for 4 cycles, followed by maintenance pemetrexed every 3 weeks. Treatment continued until disease progression according to RECIST version 1.1 or treatment discontinuation. 

The primary end point was progression-free survival (PFS), assessed via blinded independent central review. Key secondary and exploratory end points included overall survival (OS), investigator-assessed PFS, and safety.

At analysis, median PFS by blinded independent central review was 7.6 months in the osimertinib plus savolitinib arm and 5.4 months in the platinum-pemetrexed chemotherapy arm, reducing the risk of disease progression or death by 45% (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.42 to 0.72; P < .001). The PFS benefit was consistent among patients with MET overexpression and those with MET amplification. 

Investigator-assessed PFS was 7.4 months and 4.2 months, respectively. Median OS was 17.8 months in the osimertinib plus savolitinib arm and 12.9 months in the platinum-pemetrexed chemotherapy arm, reducing the risk of death by 32% (HR, 0.68; 95% CI, 0.50 to 0.91; P = .010).

Responses were also more durable with the combination. Median duration of response was 9.7 months in the osimertinib plus savolitinib arm and 5.7 months in the chemotherapy arm. 

These findings demonstrate that targeting EGFR and MET simultaneously can improve disease control and survival in patients with MET-altered advanced NSCLC following osimertinib treatment.

Any-grade treatment-emergent adverse events occurred in 99% of patients receiving osimertinib plus savolitinib compared with 97% of patients receiving platinum-pemetrexed chemotherapy. Grade ≥3 treatment-emergent adverse events occurred in 64% and 63% of patients, respectively.

Serious treatment-emergent adverse events were reported in 41% of patients receiving osimertinib plus savolitinib compared with 28% receiving chemotherapy. Treatment-emergent adverse events led to treatment discontinuation in 14% and 8% of patients, respectively.

Treatment-related adverse events occurred in 93% of patients receiving osimertinib plus savolitinib and 92% receiving chemotherapy. Grade ≥3 treatment-related adverse events occurred in 40% and 52% of patients, respectively.

Although serious adverse events and treatment discontinuations were more frequent with osimertinib plus savolitinib, the incidence of grade ≥3 treatment-related adverse events was lower than with platinum-pemetrexed chemotherapy.

As Dr Lu concluded, “these data support simertinib plus savolitinib as an effective, oral, targeted treatment for these patients and establish a new global standard of care.” 

Source: 

Lu S, et al. Osimertinib (osi) + savolitinib (savo) vs platinum–pemetrexed (plat–pem) in EGFRm MET-overexpressed (OE) and/or -amplified (AMP) advanced NSCLC post-osi: SAFFRON phase (Ph) 3 primary results. Presented at ESMO Congress. October 23-27, 2026; Madrid, Spain. LBA6.