AstraZeneca–Daiichi Sankyo’s Enhertu Wins DESTINY-Lung04; HUTCHMED’s Tagrisso–Orpathys Pair Wins SAFFRON in MET-Selected EGFR NSCLC

AstraZeneca and Daiichi Sankyo reported that Enhertu (trastuzumab deruxtecan) met its primary endpoint in the DESTINY-Lung04 study, showing a clear and meaningful extension of progression-free survival versus current first-line therapy in patients with HER2-mutant advanced non-squamous non-small cell lung cancer.

In parallel, HUTCHMED announced that the SAFFRON trial met both its progression-free and overall survival endpoints for Tagrisso (osimertinib) plus Orpathys (savolitinib) in EGFR-mutated NSCLC with high MET levels after progression on Tagrisso.

DESTINY-Lung04: Enhertu as first-line therapy in HER2-mutant NSCLC

The DESTINY-Lung04 Phase III trial compared Enhertu at 5.4 mg/kg against the global standard first-line regimen of platinum plus pemetrexed chemotherapy combined with pembrolizumab in adults with unresectable, locally advanced or metastatic HER2-mutant non-squamous NSCLC carrying exon 19 or 20 mutations. Patients were randomized equally, with stratification by smoking history and by presence or history of brain metastases. The primary endpoint was progression-free survival assessed by blinded independent central review, while secondary endpoints included overall survival, investigator-assessed progression-free survival, overall response rate, duration of response, pharmacokinetics and safety.

Topline findings showed a statistically significant and clinically meaningful improvement in progression-free survival for Enhertu over the chemo-immunotherapy backbone used as standard care. The trial will continue as planned to mature overall survival and other secondary readouts. Full datasets are expected to be presented at an upcoming medical congress and submitted to regulators worldwide.

Contextually, HER2 mutations occur in roughly 2 to 4 percent of NSCLC cases, and many patients still progress on first-line chemo-immunotherapy, highlighting the need for more effective options. Enhertu is already approved in previously treated metastatic HER2-mutant NSCLC and in HER2-positive solid tumours with limited options, and this new first-line evidence could broaden its role if regulators endorse the data.

SAFFRON: Tagrisso plus Orpathys in MET-driven resistance after Tagrisso

The SAFFRON Phase III study evaluated adding Orpathys 300 mg twice daily to Tagrisso 80 mg once daily versus doublet platinum chemotherapy in 338 patients with EGFR-mutated, locally advanced or metastatic NSCLC showing high MET overexpression or amplification after prior Tagrisso-based therapy. The trial was randomized, open-label and conducted across 230 centres in 29 countries spanning North America, Europe, South America and Asia. The primary endpoint was progression-free survival, with key secondary endpoints including overall survival and objective response rate.

High-level results demonstrated statistically significant and clinically meaningful improvements in both progression-free survival and overall survival for the Tagrisso plus Orpathys combination compared with chemotherapy in this MET-driven, Tagrisso-resistant population. Patients were prospectively selected using high MET thresholds previously identified in the SAVANNAH Phase II program, with MET status determined by immunohistochemistry and fluorescence in situ hybridisation assays.

MET pathway activation is a well-recognized resistance mechanism to third-generation EGFR inhibitors, occurring in about one in three cases and often linked to poorer outcomes, which makes these results clinically important. Orpathys is a selective oral MET tyrosine kinase inhibitor already approved in China for MET exon 14 skipping NSCLC and for certain MET-amplified gastric cancers, and the Tagrisso plus Orpathys regimen has approvals in China and a temporary authorization in Switzerland for EGFR-mutated NSCLC with MET amplification after EGFR-TKI progression. Tagrisso itself is a third-generation EGFR inhibitor approved in more than 120 countries across multiple lines and stages of EGFR-mutated NSCLC, including monotherapy and chemotherapy combinations.

What these results mean for practice and pipeline?

Both studies address high-need niches in targeted therapy for advanced NSCLC. DESTINY-Lung04 positions Enhertu as a potential new first-line standard for the small but distinct HER2-mutant subgroup, while SAFFRON provides a targeted strategy for EGFR-mutated disease that has evolved MET-driven resistance to Tagrisso