Osimertinib/Savolitinib Shows Meaningful Responses in EGFR+ NSCLC

"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," according to trial investigator Myung-Ju Ahn, MD, PhD.

Combining osimertinib (Tagrisso) with savolitinib (Orpathys) demonstrated a clinically meaningful, enduring objective response rate (ORR) among patients with non–small cell lung cancer (NSCLC) harboring EGFR mutations and high METoverexpression and/or amplification following prior disease progression on osimertinib monotherapy, according to a press release on findings from the phase 2 SAVANNAH trial (NCT03778229).¹

Investigators intend to present these data at a future medical meeting and share their findings with regulatory health authorities across the world. Of note, fast track designation was given in 2023 to this combination for the aforementioned patient population.²

“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,” lead trial investigator Myung-Ju Ahn, MD, PhD, a professor of Hemato-Oncology at the Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea, said in the press release.¹ “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.”

Developers designed savolitinib as an orally available, highly selective MET tyrosine kinase inhibitor. The agent may prevent the MET receptor tyrosine kinase pathway from atypically activating due to mutations, gene amplification, or protein overexpression. According to the press release, savolitinib previously received approval in China as a treatment option for those with NSCLC harboring MET exon 14 skipping alterations who have disease progression on prior systemic therapy or are ineligible to receive chemotherapy.

Investigators previously presented initial findings from the SAVANNAH trial at the IASLC 2022 World Conference on Lung Cancer (WCLC).³

Across the overall population (n = 193), the ORR was 32% (95% CI, 26%-39%), and the median duration of response (DOR) was 8.3 months (95% CI, 6.9-9.7). Additionally, osimertinib/savolitinib produced a median progression-free survival (PFS) of 5.3 months (95% CI, 4.2-5.8) and a disease control rate (DCR) of 61% (95% CI, 53%-68%).

Among those with high levels of MET expression, the ORR was 49% (95% CI, 39%-59%) for all patients in this subgroup (n = 108) and 52% (95% CI, 41%-63%) among those without prior chemotherapy (n = 87). In each respective group, the median DOR was 9.3 months (95% CI, 7.6-10.6) and 9.6 months (95% CI, 7.6-14.9), the median PFS was 7.1 months (95% CI, 5.3-8.0) and 7.2 months (95% CI, 4.7-9.2), and the DCR was 74% (95% CI, 65%-82%) and 75% (95% CI, 64%-83%).

At the time of this analysis, the safety profile of osimertinib plus savolitinib was comparable with prior reports of each agent; investigators reported no new safety signals. Grade 3 or higher adverse effects (AEs) occurred in 45% of patients and included pulmonary embolism, dyspnea, neutrophil count decreases, and pneumonia.

Investigators of the ongoing, randomized SAVANNAH trial are evaluating treatment with osimertinib/savolitinib among patients with locally advanced or metastatic EGFR-mutated NSCLC harboring MET overexpression and/or amplification following disease progression on osimertinib. As part of the original single-arm design, patients received savolitinib at 300 mg or 600 once daily or 300 mg twice daily plus oral osimertinib at 80 mg once daily. Investigators added a registrational component to the trial in 2022, with patients being randomly assigned to receive savolitinib at 300 mg twice daily plus osimertinib at 80 mg once daily or matched placebo.

The trial’s primary end point is ORR. Secondary end points include PFS and DOR.

“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 and Development at AstraZeneca, one of the developers of savolitinib, stated in the press release.¹ “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.”

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 Limited. October 16, 2024. Accessed October 16, 2024. https://tinyurl.com/yz8427c5
2. HUTCHMED reports 2023 full year results and provides business updates. News release. HUTCHMED. February 28, 2024. Accessed October 16, 2024. https://tinyurl.com/2yf743eb
3. 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://tinyurl.com/44mxcpz2