Cross Currents: Dual EGFR/MET Inhibition in EGFR-Mutated NSCLC

"I think also data like this really reinforce the need to do MET testing, not just NGS, but IHC. We already do it for some other approved MET ADCs, but I think this is another reason to do MET testing in EGFR-mutant lung cancer."

In a 3-part joint interview recorded at the 2026 ESMO Congress, Pasi A. Jänne, MD, PhD, senior vice president for translational medicine at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, and Yi-Long Wu, MD, FACS, chief expert at Guangdong Provincial People’s Hospital and honorary director of the Guangdong Lung Cancer Institute, discussed how dual EGFR/MET inhibition with savolitinib (Orpathys) plus osimertinib (Tagrisso) may fit into the care of patients with EGFR-mutated non–small cell lung cancer (NSCLC) and MET overexpression or amplification.

The discussion is part of Cross Currents: Where East Meets West in Cancer Care, a video series produced through a collaboration between OncLive and China-based digital health platform DXY. In Cross Currents, oncologists from the United States and China compare clinical practice in their regions and discuss key data from major meetings.

At the 2026 ESMO Congress, a pair of phase 3 trials evaluated the all-oral combination at different points in the disease course. In the global SAFFRON trial (NCT05261399), savolitinib plus osimertinib improved median progression-free survival (PFS) by blinded independent central review vs platinum/pemetrexed chemotherapy in patients whose disease progressed on osimertinib (7.6 vs 5.4 months; HR, 0.55; 95% CI, 0.42-0.72; P < .001); median overall survival (OS) was 17.8 vs 12.9 months (HR, 0.68; 95% CI, 0.50-0.91; P = .010).¹

These SAFFRON findings were presented alongside the China-based SANOVO trial (NCT05009836), for which Wu was the presenting author.³ In SANOVO, adding savolitinib to first-line osimertinib improved median investigator-assessed PFS in patients with MET immunohistochemistry (IHC) 3+ disease (24.8 vs 11.1 months; HR, 0.45; 95% CI, 0.31-0.66; P < .0001) and in the intention-to-treat population (24.9 vs 13.8 months; HR, 0.56; 95% CI, 0.43-0.74; P < .0001); OS data, at 40.5% maturity, favored the combination (HR, 0.48; 95% CI, 0.33-0.68).²,⁴

Grade 3 or higher treatment-emergent adverse effects occurred in 64% vs 63% of patients in SAFFRON and in 77.2% vs 38.4% in SANOVO.

In part 1, Jänne outlined the first-line approach in the United States, where combination regimens are standard for patients who can tolerate them: osimertinib plus chemotherapy, as evaluated in the phase 3 FLAURA2 trial (NCT04035486), or amivantamab-vmjw (Rybrevant) plus lazertinib (Lazcluze), as evaluated in the phase 3 MARIPOSA trial (NCT04487080). Single-agent osimertinib remains an option for some patients, including older patients who may not tolerate chemotherapy.

Jänne noted that detectable baseline circulating tumor DNA (ctDNA) and TP53 co-mutations are poor prognostic factors that can inform decisions about intensifying treatment, and that patients and physicians at his institution often prefer osimertinib plus chemotherapy as the combination approach. Wu said that in China, roughly 30% of patients receive osimertinib plus chemotherapy, most receive osimertinib monotherapy, and fewer than 10% receive amivantamab plus lazertinib, largely because of cost. Jänne added that a predictive biomarker to guide the choice of combination is still lacking.

In part 2, the conversation turned to MET. Jänne described MET amplification as more convincing evidence of resistance than MET overexpression and identified a central challenge: definitions of MET positivity, including expression levels, copy number thresholds, and testing by next-generation sequencing (NGS) versus fluorescence in situ hybridization (FISH), vary across trials. Wu reviewed the design of SAFFRON, which enrolled patients with MET overexpression, defined as IHC 3+ in at least 90% of tumor cells, and/or MET amplification, and SANOVO, which selected first-line patients by MET overexpression on IHC alone.

Jänne said the 2 trials represent more personalized ways to either intensify first-line therapy or select treatment at resistance. In SANOVO subgroup analyses, the PFS HR was 0.52 (95% CI, 0.36-0.73) in patients with IHC 3+ disease and 0.85 (95% CI, 0.57-1.27) in those with IHC 2+ disease.

In part 3, Jänne and Wu considered how therapy will be selected across lines as options expand. Jänne noted that MET-targeted therapies require a biomarker, whereas biomarker expression has not correlated with efficacy for some antibody-drug conjugates. He identified the lack of effective immune-based approaches for EGFR-mutated disease as a key gap, pointing to T-cell engagers, cellular therapies, and vaccines as areas under investigation.

The pair also discussed next-generation EGFR tyrosine kinase inhibitors designed to overcome resistance mutations such as EGFR C797S. Jänne cautioned that C797S is a less common resistance mechanism than MET alterations, that comparing such agents with osimertinib in the first line would require a long trial, and that earlier use could shift resistance toward MET, reinforcing the need for comprehensive testing at progression.