Osimertinib plus savolitinib in osimertinib-resistant non-small-cell lung cancer with low level gene copy number MET: A multi-center, open-label, and phase 2 study.

Abstract

e20079 Background: MET-based resistance following osimertinib treatment for epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC) is common, but less than 25% patients with MET amplification positive (gene copy number (GCN) > 5 or MET/CEP7 > 2) which can be treated by osimertinb plus savolitinib. It’s critical important to elicit an effective method for patients with low level copy number gain of MET gene after osimertinib progression. Methods: This is a multi-center, single-arm, open-label study involving patients following disease progression on osimertinib and chemo-immunotherapy. Enrolled patients were all EGFR-mutated advanced NSCLC progressed on osimertinib and chemo-immunotherapy, with MET GCN less than 5 and MET/CEP7 less than 2 tested by FISH; all were treated by savolitinib 600 mg (Body weight ≥ 60 Kg) or 400 mg (Body Weight <60 Kg) plus osimertinib 80 mg oral daily. The Primary endpoint was response rate (ORR), and the second endpoints were progression-free survival (PFS), safety and overall survival (OS). Results: Between December 1, 2023 and December 20, 2025, 57 patients of EGFR-mutated advanced NSCLC progressed on osimertinib and chemo-immunotherapy were screened; of them, 42 (73.7%) patients had MET GCN <5 and MET/CEP7 < 2 and enrolled the study. Of the 42 patients, 12 are male and 30 are female; the median MET GCN was 3.69, and the median MET/CEP7 was 1.17. The ORR was 78.6% （33/42）, the median PFS was 5.67 months (95%CI: 3.643-7.697), and the OS was not reached. 71.4% (30/42) patients with MET 5>GCN ≥ 3, they had a higher ORR than patients with MEG GCN less than 3, that was 90.0% and 50.0%, respectively. The mPFS was 7.1 months for patients with MET 5>GCN ≥ 3, and was 3.9 months for patients with MET GCN less than 3. The main adverse events were grade II-III edema of lower extremities, it occurred 45.2% (19/42), and it could be attenuated by savolitinib dose reduction. No patient discontinued osimertinib plus savolitinib treatment induced by AE. Conclusions: Osimertinib plus savolitinib had promising results in patients of non-small cell lung cancer with low MET GCN after osimertinib resistance. The MET GCN threshold for MET TKI treatment of osimertinib resistant NSCLC should be set to 3 to benefit most osimertinib resistant patients; and it needs to be validated in the large cohort study. Clinical trial information: NCT07322783 . Clinicopathological features and patient characteristics. Factors No. of patients (n=42) (%) Gender Male 12(28.6) Female 30 (71.4) Median Age (year) 59 MET GCN (median) 3.69 <3 12 (28.6) ≥3 30 (71.4) MET/CEP7 (median) 1.17 ORRmPFS (months) 33 (78.6)5.67 ECOG PS 0 6 (14.3) 12 19 (45.2) 17 (40.5) EGFR Mutations 19 del 26 (61.9) L858R 16 (38.1) Metastatic Patterns Lymph node 13 (31.0) Lung 33 (78.6) Brain 5 (11.9) Others 29 (69.0)