SAFFRON Dual Survival Win Validated by SACHI but Narrow MET Label Looms

SAFFRON Trial Shows Tagrisso Plus Orpathys Improves Survival in MET-Driven NSCLC

Positive results from the SAFFRON Phase III trial demonstrated that Tagrisso (osimertinib) plus Orpathys (savolitinib) significantly improved both progression-free survival (PFS) and overall survival (OS) compared to doublet platinum-based chemotherapy. The trial involved patients with EGFR-mutated non-small cell lung cancer (NSCLC) whose tumors had high levels of MET overexpression or amplification and had progressed on prior Tagrisso treatment. The combination reduced the risk of disease progression or death by 45% (PFS HR 0.55) and the risk of death by 32% (OS HR 0.68), extending median OS by nearly five months. These findings establish SAFFRON as the first global Phase III trial to show such a benefit in this setting, reinforcing Tagrisso as a backbone therapy. A New Drug Application (NDA) for the combination has been submitted to the US FDA.

• The SAFFRON trial showed Tagrisso plus Orpathys reduced the risk of disease progression or death by 45% (HR 0.55; 95% CI 0.42-0.72; p<0.001) compared to chemotherapy. Median PFS was 7.6 months for the combination versus 5.4 months for the comparator arm. This PFS benefit was consistent across all prespecified subgroups, including those with MET-overexpression or MET-amplification, with 36% of patients progression-free at one year compared to 10% on chemotherapy.
• For the key secondary endpoint of overall survival, Tagrisso plus Orpathys reduced the risk of death by 32% (OS HR 0.68; 95% CI 0.50-0.91; p=0.010) versus chemotherapy. The combination extended median OS by 4.9 months (17.8 months vs. 12.9 months), with an estimated 70% of patients alive at one year compared to 53% in the comparator arm. This establishes a new clinical benchmark for patients with MET-driven resistance after osimertinib.
• The safety profile of Tagrisso plus Orpathys was manageable and consistent with the known profiles of each medicine, with no new safety concerns. Grade 3 or higher treatment-emergent adverse events were similar between arms (64% vs 63%). Based on these results, a New Drug Application (NDA) for Tagrisso plus Orpathys has been submitted to the US FDA for this patient population, building on its existing approval in China for a similar indication.
• The combination of Tagrisso and Orpathys offers a precision inhibition strategy that directly addresses MET-driven resistance, a frequent driver of disease progression in EGFRm NSCLC after EGFR-TKI therapy. This all-oral, biomarker-directed treatment option has the potential to become a new global standard of care, reinforcing the critical need for MET testing to guide patient management and improve outcomes.

Addressing the Challenge of MET-Driven Resistance in EGFRm NSCLC

Treatment of EGFR-mutated non-small cell lung cancer with coexisting MET amplification or overexpression is constrained by biological heterogeneity and imperfect diagnostic stratification. Acquired resistance to osimertinib is multifaceted, with MET amplification conferring resistance via bypass activation of both ERK and AKT signaling cascades and concurrent resistance mechanisms detected in 24.4% of patients.

• Heterogeneous and co-occurring resistance biology: In EGFR T790M-positive lung adenocarcinoma after osimertinib, predominant pathways included C797S mutations in EGFR (23.3%), amplification of MET (15.1%), amplification of HER2 (8.1%), mutations in PIK3CA (7.0%), transformation to small cell lung cancer (9.3%), and epithelial-mesenchymal transition (12.8%), with concurrent presence of multiple resistance mechanisms in 24.4% of patients. Diverse on-target resistance including MET D1246H and EGFR C797S or T790M was detected after MET inhibitor plus EGFR inhibitor combination, and MET amplification was detected in 15% of cases upon systemic disease progression.

• Imperfect patient stratification and detection limitations: MET inhibitors have shown activity in NSCLC patients with MET amplification and exon 14 skipping, but patient stratification is imperfect and response rates have varied widely. Conventional methods such as FISH are limited by tissue availability, and ctDNA-based liquid biopsy shows limited sensitivity for amplification detection. The sensitivity, specificity and agreement of detecting MET amplification by NGS in tissue were 39.5% (17/43), 98.6% (72/73) and 76.7% (89/116), respectively, 66.7% (16/24), 98.6% (72/73) and 90.7% (88/97) for focal MET amplification in tissue and 29.2% (7/24), 94.5% (69/73), 78.4% (76/97) for focal amplification in plasma. FISH failed to identify three patients (30%) with very-high MET RNA expression, among which one received MET tyrosine kinase inhibitor treatment deriving clinical benefit, and the utility of MET overexpression as a biomarker remains unclear due to discrepancies in its occurrence and non-standardized cut-off thresholds.

• Concurrent genomic alterations reduce MET inhibitor benefit: Concurrent mutations may deteriorate the PFS of MET TKIs in NSCLC patients with MET amplification or METex14 skipping mutations. TP53, the most common concurrent mutation, was associated with worse survival outcomes as compared to the wild type, and the MET amplification cohort with a concurrent PIK3CA mutation exhibited primary resistance to MET TKIs and showed disease progression (80%).

• Toxicity-driven discontinuation limits combination durability: A combination of MET inhibitor and EGFR inhibitor showed overall response rate of 74.4% and median progression-free survival (PFS) of 5.3 months [95% confidence interval (CI): 3.3-7.3], but 23 patients (52.3%) required either or both treatment discontinuation due to adverse effects, with pneumonitis as the main cause (69.2%). Patients who stopped MET inhibitor within 63 days of initiation showed poorer PFS compared to those who discontinued after (HR, 2.78; 95% CI: 1.00-7.75; P=0.050), and in a case of osimertinib combined with crizotinib with dramatic tumor shrinkage, the progression-free survival (PFS) was only two months.

SAFFRON Phase III: Landmark PFS and OS Benefits

Key trials in EGFR-mutated NSCLC with MET overexpression or amplification focus on dual EGFR and MET inhibition after progression on osimertinib. Both evaluate combination regimens with osimertinib 80 mg once daily plus a MET-directed agent, with response-based primary endpoints and survival and safety secondary endpoints.

Osimertinib + Savolitinib: A New Standard for Post-Tagrisso?

Combination treatment with MET inhibitor plus EGFR inhibitor has shown promising antitumor activity in advanced EGFR-mutant and MET-amplified non-small cell lung cancer after progression with EGFR inhibitor. In a retrospective analysis of 44 patients, the overall response rate was 74.4% and median progression-free survival (PFS) was 5.3 months [95% confidence interval (CI): 3.3-7.3]. Twenty-three patients (52.3%) required either or both treatment discontinuation due to adverse effects, with pneumonitis as the main cause of discontinuation (69.2%). There was no significant difference in the PFS of patients with or without MET inhibitor discontinuation [hazard ratio (HR), 0.93; 95% CI: 0.49-1.78; P=0.83], but median clearance time of MET amplification in plasma circulating tumor DNA was measured as 63 days and patients who stopped MET inhibitor within 63 days of initiation showed poorer PFS compared to those who discontinued after (HR, 2.78; 95% CI: 1.00-7.75; P=0.050). Diverse resistance mechanisms including on-target mutations in MET (D1246H) and EGFR (C797S or T790M) were detected in 14 patients, with one MET D1246H-mutant case and one EGFR C797S-mutant case responding to sitravatinib and amivantamab, respectively.

In the global phase III MARIPOSA-2 trial, 657 patients with EGFR-mutated (exon 19 deletions or L858R) locally advanced or metastatic NSCLC after disease progression on osimertinib were randomized 2:2:1 to receive amivantamab-lazertinib-chemotherapy, chemotherapy, or amivantamab-chemotherapy, with dual primary endpoints of PFS of amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy. PFS was significantly longer for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy [hazard ratio (HR) for disease progression or death 0.48 and 0.44, respectively; P < 0.001 for both; median of 6.3 and 8.3 versus 4.2 months, respectively], with consistent results by investigator assessment (HR for disease progression or death 0.41 and 0.38, respectively; P < 0.001 for both; median of 8.2 and 8.3 versus 4.2 months, respectively). Objective response rate was significantly higher for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (64% and 63% versus 36%, respectively; P < 0.001 for both), and median intracranial PFS was 12.5 and 12.8 versus 8.3 months (HR for intracranial disease progression or death 0.55 and 0.58, respectively). Predominant adverse events in the amivantamab-containing regimens were hematologic, EGFR-, and MET-related toxicities, with amivantamab-chemotherapy having lower rates of hematologic adverse events than amivantamab-lazertinib-chemotherapy.

Accurate identification of MET amplification remains central to interpreting these comparisons, as MET amplification identified by fluorescence in situ hybridization (FISH) remains the optimal biomarker to identify suitable candidates for MET-tyrosine kinase inhibitor therapy. In 40 patients with advanced NSCLC treated with MET inhibitors, the concordance rate among FISH and next-generation sequencing (NGS) was 62.5% (25/40), where MET amplification by FISH was defined as a MET/CEP7 ratio of > 2.0 and/or copy number > 5 and MET amplification by NGS was defined as gene copy number ≥ 5. MET amplification identified by FISH showed the optimal predictive value, with partial response rate of 68.0% (17/25 with MET amplification) vs. 6.7% (1/15 without MET amplification) and median PFS of 5.4 months versus 1.0 months (P < 0.001), whereas amplification identified by NGS failed to distinguish significant clinical outcomes with partial response rate of 60.0% (6/10, with MET GCN ≥ 5) vs. 40.0% (12/30, with MET GCN < 5) and median PFS of 4.8 months vs. 2.2 months (P = 0.357). The partial response rate was 68.8% (11/16) and the median PFS was 4.8 months in patients with focal amplification by NGS.

SAFFRON: A New Standard for Post-Osimertinib MET-Driven NSCLC

The recent announcement of positive Phase III SAFFRON trial results for the osimertinib and savolitinib combination marks a significant milestone in the ongoing battle against EGFR-mutated non-small cell lung cancer (NSCLC). For years, osimertinib has served as the cornerstone first-line therapy, delivering substantial benefits to patients. However, the inevitable development of acquired resistance has presented a persistent challenge, with MET amplification emerging as a particularly common and aggressive bypass pathway.

The SAFFRON trial's success in demonstrating superior progression-free survival (PFS) and overall survival (OS) compared to platinum-based chemotherapy in patients with high MET overexpression or amplification post-osimertinib is a game-changer. This is the first global Phase III study to achieve such a robust outcome in this specific, high-need population, reducing the risk of disease progression or death by 45% and the risk of death by 32%. This data strongly positions the combination as a new, targeted standard of care, offering a clinically meaningful extension of nearly five months in median overall survival.

This breakthrough carries several strategic implications. It reinforces osimertinib's role as a foundational therapy, now with a clear, targeted solution for a prevalent resistance mechanism. Consequently, the importance of comprehensive molecular testing at progression, specifically for MET alterations, will be amplified, driving a shift in diagnostic practices. However, several considerations warrant attention. The precise and consistent identification of 'high levels' of MET amplification or overexpression in real-world settings will be crucial, as varying diagnostic thresholds could impact patient selection and observed efficacy. Furthermore, while addressing MET-driven resistance, the potential for the emergence of new, diverse resistance mechanisms to the combination therapy remains a long-term challenge. Finally, while generally well-tolerated, the safety profile of a dual-targeted regimen requires careful management, as combining agents can introduce unique or increased adverse events compared to monotherapy. This development underscores the continuous evolution of precision oncology, moving beyond initial targeted therapy to address complex resistance pathways with increasingly sophisticated, biomarker-guided approaches.