Osimertinib Plus Savolitinib Generates Durable Responses in EGFR-Mutant, MET-Amplified NSCLC

Myung-Ju Ahn, MD, PhD

Treatment with osimertinib (Tagrisso) in combination with savolitinib (Orpathys) generated a high, durable overall response rate (ORR) in patients with EGFR-mutant, MET-overexpressed and/or -amplified non–small cell lung cancer (NSCLC) who experienced disease progression on osimertinib, according to updated data from the phase 2 SAVANNAH trial (NCT03778229).¹

In an announcement from HUTCHMED, the company noted that the combination’s safety profile in SAVANNAH was consistent with the known profiles of both the combination and each individual agent. No new safety signals were reported.

HUTCHMED said detailed results will be presented at an upcoming medical meeting and submitted to global regulatory bodies for review.

“Osimertinib can provide patients with EGFR-mutated lung cancer unprecedented survival and has transformed the treatment landscape, but patients can develop resistance due to genes like MET—a common resistance biomarker,” Myung-Ju Ahn, MD, PhD, principal investigator of the SAVANNAH trial, stated in a news release. “These results show that adding savolitinib, a selective MET inhibitor, while continuing osimertinib treatment, helped to deliver a meaningful response among patients whose disease progressed, providing a potential new treatment option following standard-of-care osimertinib.” Ahn also serves as a professor of hemato-oncology at the Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine in Seoul, South Korea.

Notably, the FDA granted fast track designation to osimertinib plus savolitinib for this indication in 2023.

“These positive SAVANNAH results show the benefit of a targeted treatment approach in [patients with] EGFR-mutated lung cancer who experience MET-driven resistance,” Susan Galbraith, executive vice president of Oncology Research & Development at AstraZeneca, added in the news release. “The improved response rates from [savolitinib] added to [osimertinib], which is the backbone EGFR-mutated lung cancer therapy, reinforce the importance of identifying MET aberration and validate our combination strategy to address resistance while allowing continued [osimertinib] treatment.”

Overview of SAVANNAH

The ongoing global, randomized trial is evaluating the efficacy of adding savolitinib to osimertinib in patients with EGFR-mutant, locally advanced or metastatic NSCLC with MET overexpression and/or amplification, defined as immunohistochemistry 90+ and/or fluorescent in situ hybridization 10+, who experienced disease progression after first- or second-line treatment with osimertinib.

In accordance with the original single-arm trial design, patients received 80 mg of oral osimertinib per day alongside savolitinib at either a once-daily 300 or 600 mg-dose or a twice-daily 300-mg dose. Notably, a registrational component was added to the trial in 2022 comparing the 300 mg of savolitinib twice daily plus osimertinib vs savolitinib plus placebo.

The study’s primary end point is ORR. Key secondary end points consist of progression-free survival and duration of response.

Over 360 patients have been enrolled onto the trial across more than 80 centers globally, including locations in North America, Europe, South America, and Asia.

Prior Data and Ongoing Investigations With Osimertinib Plus Savolitinib

Initial results from the SAVANNAH trial were shared in August 2022 and showed an ORR of 49% (95% CI, 39%-59%) with osimertinib plus savolitinib in patients with high levels of MET overexpression/amplification (n = 108). At the data cutoff of August 27, 2021, patients with high levels of MET expression who had not been previously exposed to chemotherapy (n = 87) demonstrated the highest ORR at 52% (95% CI, 41%-63%). The ORR was 9% (95% CI, 4%-18%) for patients who did not express high levels of MET overexpression and/or amplification (n = 77).²

Regarding safety, 45% of patients experienced grade 3 or higher adverse effects (Aes), and treatment discontinuation due to AEs occurred in 13% of patients. The most frequently reported AEs comprised pulmonary embolism, dyspnea, decreased neutrophil counts, and pneumonia.

“Previous results from the SAVANNAH trial provided a novel biomarker approach for identifying patients with MET overexpression and/or amplification who are most likely to benefit from a MET-directed therapy, an existing unmet need,” Weiguo Su, chief executive officer and chief scientific officer, of HUTCHMED, stated in the news release.¹ “These new, positive results affirm our selective, patient-centric approach, which could allow us to deliver the first biomarker-driven targeted therapy combination option in this setting.”

The efficacy and safety of osimertinib plus savolitinib will be compared with platinum-based chemotherapy in the global, randomized, phase 3 SAFFRON trial (NCT05261399). The study will include patients with EGFR-mutant, locally advanced or metastatic NSCLC with MET overexpression and/or amplification and prior progression on osimertinib. Notably, the high MET cutoff identified in SAVANNAH will be utilized to select patients for enrollment.

References

1. HUTCHMED announces that Tagrisso plus Orpathys demonstrated high, clinically meaningful response rate in lung cancer patients with high levels of MET overexpression and/or amplification in SAVANNAH phase II trial.News release. HUTCHMED. October 16, 2024. Accessed October 16, 2024. https://www.hutch-med.com/tagrisso-orpathys-savannah-phase-ii-trial/
2. Tagrisso plus savolitinib demonstrated 49% objective response rate in lung cancer patients with high levels of MET overexpression and/or amplification in SAVANNAH phase II trial. News Release. AstraZeneca. August 8, 2022. Accessed October 16, 2024. https://www.astrazeneca.com/media-centre/press-releases/2022/tagrisso-plus-savolitinib-demonstrated-49-objective-response-rate-in-lung-cancer-patients-in-savannah-phase-ii-trial.html#