SAFFRON Data Reveal New Global SOC in EGFR+ NSCLC With MET Overexpression and/or Amplification After Osimertinib

Osimertinib (Tagrisso) plus savolitinib (Orpathys) improved progression-free survival (PFS) and overall survival (OS) vs platinum/pemetrexed chemotherapy in patients with EGFR-mutated advanced non–small cell lung cancer (NSCLC) with MET overexpression and/or amplification whose disease progressed on osimertinib, according to primary results from the phase 3 SAFFRON trial (NCT05261399) presented at the 2026 ESMO Congress.¹

At a data cutoff date of July 6, 2026, the median PFS by blinded independent central review (BICR) in the full analysis set was 7.6 months (95% CI, 5.6-9.7) with osimertinib plus savolitinib (n = 171) vs 5.4 months (95% CI, 4.2-5.8) with platinum/pemetrexed (n = 167); this translated to a 45% reduction in the risk of disease progression or death (HR, 0.55; 95% CI, 0.42-0.72; P < .001). The 12-month PFS rates were 36% vs 10%, respectively. Moreover, the median OS was 17.8 months (95% CI, 15.6-23.7) vs 12.9 months (95% CI, 10.6-16.8), which translated to a 32% reduction in the risk of death (HR, 0.68; 95% CI, 0.50-0.91; P = .010); the 12-month OS rates in the respective arms were 70% vs 53%. OS maturity was 53% at the time of analysis.

PFS by BICR in the MET-overexpressed analysis set was 8.5 months (95% CI, 5.7-11.1) with the combination (n = 124) vs 5.6 months (95% CI, 4.4-6.7) with chemotherapy (n = 118; HR, 0.51; 95% CI, 0.37-0.71; P < .001). In the MET-amplified analysis set, which was not formally tested, the median PFS in the combination (n = 129) and chemotherapy (n =116) arms was 7.6 months (95% CI, 5.6-9.7; n = 129) and 4.2 months (95% CI, 3.1-5.5), respectively (HR, 0.48; 95% CI, 0.35-0.66).

"Osimertinib plus savolitinib [establishes] a new global standard of care for patients with EGFR-mutant advanced non–small cell lung cancer with MET overexpression and/or amplification after progression on osimertinib," said presenting author Shun Lu, MD, PhD, of the Department of Medical Oncology at Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, in China as part of a presentation delivered at the second Presidential Symposium.

How was the phase 3 SAFFRON trial of osimertinib plus savolitinib in EGFR-mutated NSCLC designed?

The global SAFFRON trial randomly assigned 338 patients from 25 countries 1:1 to osimertinib at 80 mg once daily plus savolitinib at 300 mg twice daily, or pemetrexed at 500 mg/m² plus carboplatin at area under the curve 5 or cisplatin at 75 mg/m² every 3 weeks for 4 cycles followed by pemetrexed maintenance at 500 mg/m². Treatment beyond progression was permitted at investigator discretion.

Eligible patients had locally advanced or metastatic EGFR-mutated NSCLC that progressed on first- or second-line osimertinib as their most recent therapy, and an ECOG performance status of 0 or 1; they were at least 18 years of age (at least 19 years of age in the Republic of Korea). MET overexpression, defined as immunohistochemistry (IHC) 3+ staining in at least 90% of tumor cells, and/or MET amplification, defined as fluorescence in situ hybridization (FISH) showing at least 10 gene copies, had to be centrally confirmed on a postprogression tissue biopsy, using cutoffs identified in the phase 2 SAVANNAH trial (NCT03778229).

The primary end point was PFS by BICR per RECIST v1.1 in the full analysis set. Secondary or exploratory end points included investigator-assessed PFS, OS, objective response rate (ORR), duration of response (DOR), disease control rate (DCR), PFS in the MET-overexpressed or -amplified analysis set, and safety.

Baseline characteristics were balanced; the median age was 64 years (range, 34-86) in both arms. Most patients in the osimertinib/savolitinib and chemotherapy arms were female (64%; 65%), Asian (63%; 66%), had an ECOG performance status of 1 (65%; 71%), had metastatic disease (95%; 95%), and were never smokers (68%; 68%). About one-third (31%) of patients in each arm had brain metastases at baseline.

Did osimertinib plus savolitinib improve additional outcomes in SAFFRON?

The confirmed ORR by BICR was 51% with osimertinib plus savolitinib vs 27% with platinum/pemetrexed (odds ratio [OR], 2.90; 95% CI, 1.85-4.61). Additionally, the median DOR was 9.7 months (95% CI, 7.6-12.5) vs 5.7 months (95% CI, 4.4-8.1). The DCR was 85% vs 65% in the respective arms (OR, 3.18; 95% CI, 1.88-5.50). Moreover, the median best percentage change in target lesion size was –44% vs –25%.

Subgroup analyses revealed that PFS benefit was consistent across prespecified subgroups, including patients with baseline brain metastases (HR, 0.50; 95% CI, 0.31-0.82; combination, n = 53; chemotherapy, n = 51) and those with both FISH-defined amplification and IHC-defined overexpression (HR, 0.39; 95% CI, 0.26-0.59; combination, n = 83; chemotherapy, n = 68). At the time of data cutoff, 26% of treated patients in the combination arm remained on any study treatment vs 2% in the chemotherapy arm.

What was the safety profile of osimertinib plus savolitinib in SAFFRON?

In the safety analysis set (combination, n = 170; chemotherapy, n = 145), the median duration of exposure was 8.5 months (range, 0.7-37.9) vs 3.5 months (range, 0-20.3). Treatment-emergent adverse effects (TEAEs) occurred in 99% of those who were given osimertinib/savolitinib vs 97% of those who received chemotherapy; these effects were grade 3 or higher in 64% vs 63% of patients, respectively. Moreover, serious TEAEs occurred in 41% vs 28% of patients. TEAEs were fatal in 12 patients (7%) in the combination arm and no TEAES were fatal in the chemotherapy arm; 9 of these 12 patients had documented disease progression before death or progression cited as a cause of death. TEAEs led to discontinuation of any treatment in 14% vs 8% of patients, respectively.

Treatment-related adverse effects (TRAEs) were reported in 93% of patients in the osimertinib/savolitinib arm vs 92% of those in the chemotherapy arm; they were grade 3 or higher for 40% vs 52% of patients. One fatal TRAE, pneumonitis, occurred in the combination arm.

The most common TEAEs experienced by at least 15% of patients who received the combination were peripheral edema (all grade, 49%; grade 3 or higher, 8%), anemia (26%; 5%), diarrhea (26%; 1%), and nausea (25%; 4%), vs anemia (54%; 18%) and nausea (37%; 1%) with chemotherapy.

What is the regulatory status of osimertinib plus savolitinib in MET-driven, EGFR-mutated NSCLC?

In August 2026, topline results showed that SAFFRON met its primary end point of PFS and its key secondary end point of OS.² A new drug application seeking approval of savolitinib plus osimertinib for patients with locally advanced or metastatic NSCLC with MET overexpression or amplification whose disease progressed on or after EGFR-targeted therapy was submitted to the FDA in September 2026.³

In China, the combination is approved for patients with EGFR-mutated, MET-amplified nonsquamous NSCLC after progression on an EGFR tyrosine kinase inhibitor, based on the phase 3 SACHI trial (NCT05015608).

According to Lu, the SAFFRON primary results were published simultaneously in the New England Journal of Medicine.¹

Disclosures: Lu reported serving in consulting or advisory roles for AstraZeneca, Pfizer, and Takeda; and receiving research support from AstraZeneca.

References

1. Lu S, Girard N, Okuma Y, et al. Osimertinib plus savolitinib versus platinum-pemetrexed in patients with EGFRm advanced NSCLC with MET overexpression and/or amplification after progression on osimertinib: SAFFRON phase III primary results. Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA6.
2. Osimertinib plus savolitinib improves PFS and OS in pretreated, MET+, EGFR+ NSCLC. OncLive. Published August 17, 2026. Accessed October 25, 2026. https://www.onclive.com/view/osimertinib-plus-savolitinib-improves-pfs-and-os-in-pretreated-met-egfr-nsclc
3. Savolitinib plus osimertinib NDA submitted to FDA for MET-Driven, EGFR-mutated NSCLC after EGFR TKI. OncLive. Published September 29, 2026. Accessed October 25, 2026. https://www.onclive.com/view/savolitinib-plus-osimertinib-nda-submitted-to-fda-for-met-driven-egfr-mutated-nsclc