Osimertinib, Savolitinib Improve PFS and OS in MET-Driven EGFR-Mutated NSCLC

Positive topline results from the phase 3 SAFFRON trial (NCT05261399) showed osimertinib (Tagrisso; AstraZeneca) plus savolitinib (Orpathys; AstraZeneca/HUTCHMED) produced statistically significant and clinically meaningful improvements in progression-free survival (PFS) and overall survival (OS) compared with platinum-based doublet chemotherapy in patients with MET-driven, EGFR-mutated non–small cell lung cancer (NSCLC).¹

These findings mark the first global phase 3 trial to demonstrate significant PFS and OS benefits in this setting. Patients enrolled in SAFFRON had locally advanced or metastatic EGFR-mutated NSCLC with high MET overexpression or amplification and experienced disease progression following first- or second-line osimertinib.¹

Numerical efficacy results, including hazard ratios and median PFS and OS, were not included in the August 17, 2026, topline announcement. Investigators plan to present the complete findings at an upcoming medical meeting, and the results will be shared with global regulatory authorities.¹

SAFFRON Evaluates an All-Oral, Biomarker-Directed Combination

SAFFRON was a randomized, open-label, multicenter trial that enrolled 338 patients across more than 230 centers in 29 countries. Participants were randomly assigned to receive oral savolitinib at 300 mg twice daily plus oral osimertinib at 80 mg once daily or platinum-based doublet chemotherapy.¹^,²

The chemotherapy arm consisted of pemetrexed plus either cisplatin or carboplatin administered every 3 weeks for 4 cycles, followed by pemetrexed maintenance. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, or another prespecified discontinuation criterion.²

The primary end point was PFS, with key secondary end points including OS and objective response rate. Additional assessments included duration of response, disease control rate, time to response, and safety.¹^,³

Patients were prospectively selected using the high-MET thresholds identified in the phase 2 SAVANNAH trial (NCT03778229). MET status was determined using immunohistochemistry to evaluate protein overexpression and fluorescence in situ hybridization to identify gene amplification.¹

Combination Targets a Common Mechanism of Osimertinib Resistance

Osimertinib is a third-generation, irreversible EGFR tyrosine kinase inhibitor (TKI) used across several stages of EGFR-mutated NSCLC. Although EGFR-directed therapy has substantially improved patient outcomes, acquired resistance remains a central treatment challenge.

Approximately one-third of tumors develop high levels of MET overexpression or amplification after progression on a third-generation EGFR TKI.¹ MET activation provide cancer cells with an alternative signaling pathway, allowing tumor growth to continue despite EGFR inhibition.

Savolitinib is a potent, highly selective oral MET TKI. Combining it with osimertinib is intended to suppress MET-mediated resistance while maintaining inhibition of the original EGFR-driven pathway. The approach could provide a chemotherapy-free, biomarker-directed option for patients whose tumors develop MET alterations following osimertinib.

In the preceding SAVANNAH study (NCT03778229), savolitinib plus osimertinib produced an investigator-assessed objective response rate of 56.3% among patients with high MET expression or amplification following progression on first-line osimertinib. Median duration of response was 7.1 months, and median PFS was 7.4 months. The most common adverse events included peripheral edema, nausea, and diarrhea.⁴

These findings informed the MET-selection criteria and dosing regimen used in SAFFRON.

Safety and Pharmacy Considerations

According to the data, the safety profile of osimertinib plus savolitinib in SAFFRON was consistent with the known profiles of the individual agents, with no new safety findings identified. Detailed rates of treatment-related adverse events, grade 3 or higher toxicities, dose modifications, and treatment discontinuations have not yet been reported.¹

If the combination enters wider clinical practice, oncology pharmacists may have an important role in confirming biomarker testing, assessing interacting medications, supporting adherence to the twice-daily and once-daily oral regimen, and monitoring for overlapping toxicities.

Osimertinib is associated with interstitial lung disease or pneumonitis, QT-interval prolongation, cardiomyopathy, hematologic abnormalities, diarrhea, and dermatologic toxicities. Periodic complete blood cell counts are recommended, with electrocardiogram, electrolyte, and cardiac monitoring indicated for patients with relevant risk factors.⁵ Prior savolitinib data also highlight peripheral edema, gastrointestinal effects, and laboratory abnormalities as areas requiring surveillance.⁴

The lack of complete numerical data currently limits assessment of the magnitude of benefit and the comparative safety profile. Nevertheless, the simultaneous PFS and OS findings position osimertinib plus savolitinib as a potentially important biomarker-directed strategy for patients with MET-driven resistance after osimertinib.

References

1. AstraZeneca. TAGRISSO plus savolitinib demonstrated statistically significant and clinically meaningful improvements in progression-free and overall survival in MET-driven EGFR-mutated lung cancer after progression on TAGRISSO. Published August 17, 2026. Accessed August 17, 2026. https://www.astrazeneca.com/media-centre/press-releases/2026/tagrisso-orpathys-improved-pfs-os-egfrm-lung.html

2. AstraZeneca. A study of savolitinib in combination with osimertinib versus platinum-based doublet chemotherapy in participants with EGFR-mutated, MET-overexpressed and/or amplified NSCLC. NCT05261399. Accessed August 17, 2026. https://www.astrazenecaclinicaltrials.com/study/D5087C00001/

3. HUTCHMED. HUTCHMED announces enrollment completed for SAFFRON global phase III study of ORPATHYS plus TAGRISSO. Published November 5, 2025. Accessed August 17, 2026. https://www.hutch-med.com/saffron-global-phiii-enrollment-completion/

4. de Marinis F, Kim TM, Bonanno L, et al. Savolitinib plus osimertinib in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer with MET overexpression and/or amplification following disease progression on osimertinib: primary results from the phase II SAVANNAH study. Ann Oncol. 2025;36(8):920-933. doi:10.1016/j.annonc.2025.04.003

5. US Food and Drug Administration. FDA approves osimertinib with chemotherapy for EGFR-mutated non-small cell lung cancer. Published February 20, 2024. Accessed August 17, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-chemotherapy-egfr-mutated-non-small-cell-lung-cancer