Savolitinib Combo Extends PFS in Frontline EGFR-Mutated NSCLC and MET Overexpression

Adding savolitinib (Orpathys) to osimertinib (Tagrisso) significantly improved progression-free survival (PFS) vs osimertinib alone in patients with treatment-naive, EGFR-mutated advanced non–small cell lung cancer (NSCLC) with MET overexpression, according to findings from the phase 3 SANOVO trial (NCT05009836) presented at the 2026 ESMO Congress.¹

In patients with MET immunohistochemistry (IHC) 3+ disease, the median investigator-assessed PFS was 24.8 months (95% CI, 19.4-27.6) with savolitinib plus osimertinib (n = 98) vs 11.1 months (95% CI, 8.3-16.6) with placebo plus osimertinib (n = 98; HR, 0.45; 95% CI, 0.31-0.66; P < .0001). In the intention-to-treat (ITT) population, the median PFS was 24.9 months (95% CI, 22.0-27.6) with the combination (n = 162) vs 13.8 months (95% CI, 10.9-16.6) with osimertinib alone (n = 164; HR, 0.56; 95% CI, 0.43-0.74; P < .0001). The median follow-up was 30.4 months in the MET IHC 3+ population and 38.6 months in the ITT population.

In the ITT population, the median overall survival (OS) was 44.5 months (95% CI, 41.3-not estimable) with the combination vs 34.9 months (95% CI, 26.3-41.1) with osimertinib alone (HR, 0.48; 95% CI, 0.33-0.68), at a median follow-up of 38.7 months and 40.5% OS maturity. The 3-year OS rates were 67.4% and 47.4%, respectively.

Presenting author Yi-Long Wu, MD, of the Guangdong Lung Cancer Institute at Guangdong Provincial People’s Hospital in Guangzhou, China, concluded that “Osimertinib plus savolitinib provides an effective, oral, biomarker-directed treatment approach and establishes a new first-line treatment option for patients with EGFR-mutated and MET-overexpressed advanced NSCLC.”

What did the phase 3 SANOVO trial examine?

Co-occurring MET overexpression is linked with inferior outcomes with first-line EGFR-directed therapy, and MET alterations are an established resistance mechanism, Wu noted in the presentation. As such, it was hypothesized that frontline dual blockade of these pathways could boost efficacy in this population.

The randomized, double-blind, multicenter, phase 3, SANOVO trial enrolled patients at 74 centers in China. Eligible patients had untreated unresectable or metastatic NSCLC with an EGFR exon 19 deletion or L858R mutation; centrally confirmed MET overexpression, defined as IHC 3+ (at least 90% of tumor cells with strong staining) or IHC 2+ (H-score of at least 220 and fewer than 90% of tumor cells with strong staining); and an ECOG performance status of 0 or 1.

Patients were randomly assigned 1:1 to savolitinib at 300 mg or 200 mg twice daily, based on body weight, or placebo, each with osimertinib at 80 mg once daily. Randomization was stratified by EGFR mutation type (exon 19 deletion vs L858R), MET IHC status (IHC 3+ vs IHV 2+), and brain metastases (yes vs no), and crossover was not permitted.

The primary end point was investigator-assessed PFS, tested hierarchically in the MET IHC 3+ population and then in the ITT population. Secondary end points included PFS by independent review committee (IRC), objective response rate (ORR), duration of response (DOR), and disease control rate (DCR), OS, and safety.

Of 1896 patients screened, 326 were randomly assigned. In the ITT population, 60.5% and 59.8% of patients in the respective arms had MET IHC 3+ disease, and 38.9% and 40.2% had brain metastases.

Topline results from SANOVO were announced in August 2026.² Separately, the combination improved PFS and OS vs platinum/pemetrexed chemotherapy in patients with MET-driven disease after progression on osimertinib in the phase 3 SAFFRON trial, also presented at the meeting.³

What secondary efficacy outcomes did savolitinib plus osimertinib produce in SANOVO?

In the MET IHC 3+ population, the median IRC-assessed PFS was 22.2 months (95% CI, 19.4-not estimable) with the combination vs 13.7 months (95% CI, 8.3-19.4) with osimertinib alone (HR, 0.48; 95% CI, 0.32-0.72). In the ITT population, the respective medians were 27.9 months (95% CI, 22.1-35.8) and 16.4 months (95% CI, 9.7-16.6; HR, 0.53; 95% CI, 0.39-0.71).

In the ITT population, the investigator-assessed ORR was 80.9% (95% CI, 74.0%-86.6%) with the combination vs 67.7% (95% CI, 59.9%-74.8%) with osimertinib alone, and the DCR was 97.5% (95% CI, 93.8%-99.3%) vs 88.4% (95% CI, 82.5%-92.9%). The median DOR was 23.5 months (95% CI, 20.1-26.4) vs 15.2 months (95% CI, 12.4-18.0).

In subgroup analyses of the ITT population, the PFS HR by investigator assessment was 0.42 (95% CI, 0.28-0.64) in patients with brain metastases. The PFS HRs were 0.52 (95% CI, 0.36-0.73) in patients with MET IHC 3+ disease and 0.85 (95% CI, 0.57-1.27) in those with IHC 2+ disease; the corresponding OS HRs were 0.40 (95% CI, 0.24-0.66) and 0.64 (95% CI, 0.38-1.06).

Subsequent anticancer therapy was received by 46.9% of patients in the combination arm and 59.1% of patients in the control arm. Subsequent treatments included chemotherapy (26.5%; 35.4%), EGFR TKI (24.1%; 30.5%), immunotherapy (13.6%; 21.3%), antiangiogenic therapy (12.3%; 28.7%), antibody-drug conjugate and antibody (7.4%; 10.4%), other targeted therapy (1.2%; 1.8%), MET TKI (1.2%; 4.3%), and other systemic therapy 4.9%; 5.5%).

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

The median treatment exposure was 22.1 months (range, 0.4-44.2) with the combination and 12.9 months (range, 0.4-45.5) with osimertinib alone. Treatment-emergent adverse effects (TEAEs) occurred in all patients in the doublet arm (n = 162) vs 99.4% of those in the monotherapy arm (n = 164); they were grade 3 or higher in 77.2% vs 38.4% of patients, respectively. Serious TEAEs occurred in 54.9% vs 28.7% of patients in the respective arms. TEAEs led to dose modification in 73.5% vs 34.8% of patients and to discontinuation in 14.8% vs 4.3% of patients. TEAEs leading to death, excluding disease progression, occurred in 4.3% vs 4.8% of patients.

The most common TEAEs of any grade experienced by at least 2% of patients who received the combination vs osimertinib alone included peripheral edema (65% vs 7%), hypoalbuminemia (63% vs 22%), decreased platelet count (51% vs 32%), anemia (49% vs 40%), and increased blood creatinine (47% vs 23%). The investigators reported no new safety concerns.

Disclosures: Wu reported receiving honoraria from AstraZeneca, Lilly, Roche, Pfizer, Boehringer Ingelheim, MSD Oncology, Bristol Myers Squibb, and Hengrui; serving in a consulting or advisory role for AstraZeneca, Roche, and Boehringer Ingelheim; and receiving research funding from Boehringer Ingelheim, Roche, Pfizer, and Bristol Myers Squibb.

References

1. Wu YL, Zhou Q, Sun L, et al. Savolitinib or placebo combined with osimertinib in treatment-naive advanced NSCLC with EGFR mutation and MET overexpression: results from the phase 3 SANOVO study. Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA69.
2. Savolitinib plus osimertinib improves first-line PFS in MET-overexpressing EGFR-mutated NSCLC. OncLive. Published August 31, 2026. Accessed October 26, 2026. https://www.onclive.com/view/savolitinib-plus-osimertinib-improves-first-line-pfs-in-met-overexpressing-egfr-mutated-nsclc
3. SAFFRON data reveal new global SOC in EGFR+ NSCLC with MET overexpression and/or amplification after osimertinib. OncLive. Published October 25, 2026. Accessed October 26, 2026. https://www.onclive.com/view/saffron-data-reveal-new-global-soc-in-egfr-nsclc-with-met-overexpression-and-or-amplification-after-osimertinib