Savolitinib combined with Durvalumab in EGFR wild-type advanced NSCLC patients with MET alterations (SOUND): A multicenter, open-label, Phase II trial

Background: Dysregulation of MET gene could serve as oncogenic driver in NSCLC. The efficacy of MET inhibitor monotherapy was limited in EGFR wild-type NSCLC patients(pts) with MET alterations. Pre-clinical study demonstrated that MET inhibitor combined with immunotherapy may synergistically enhance anti-tumor activity. SOUND study aims to explore the efficacy and safety of savolitinib plus durvalumab in EGFR wild-type advanced NSCLC pts with MET alterations. Methods: Pts who did not receive immunotherapy previously were enrolled into MET Ex14m cohort (Cohort 1) or MET Overexpression/AMP cohort (Cohort 2) according to MET alteration status determined by NGS, FISH or immunohistochemistry and received savolitinib (600mg [body weight≥50kg] / 400mg [body weight < 50kg], once daily) in combination with durvalumab (1,500 mg once every four weeks). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), 12-month overall survival (OS) rate, and safety. Here, we report the interim analysis results. Results: At data cutoff (January 17, 2025), forty-seven pts were enrolled and received at least one dose of study treatment, with 24 in Cohort 1(C1) and 23 in Cohort 2(C2), respectively. For C1, 83.3% pts had adenocarcinoma, 16.7% had brain metastases, 37.5% had PD-L1 ≥ 50% and 87.5% were treated in first line. For C2, 56.5% had adenocarcinoma, 34.8% had brain metastases, 56.5% had PD-L1 ≥ 50% and 87.0% were treated in first line. Median follow-up was 15.4 months(m) in C1 and 13.2 m in C2. The median PFS was not reached (maturity of 33.3%) in C1 and 5.5 m (95% CI, 3.2-9.2, maturity of 78.3%) months in C2. The confirmed ORR per investigator in C1 and C2 were 45.8% (95% CI, 25.6-67.2%) and 52.2% (95% CI, 30.6-73.2%), respectively. 12-month OS rate for C1 and C2 were 82.0% and 60.1%, respectively. Any grade treatment-related adverse events (TRAEs) were observed in 44 (93.6%) pts. The most common TRAEs were peripheral oedema (38.3%), anemia (38.3%), hypoalbuminemia (34%), aspartate aminotransferase increased (34%) and alanine aminotransferase (ALT) increased (31.9%). Grade 3 and above TRAEs were reported in 14 (58.3%) pts in C1 and 12 (52.2%) pts in C2. The most common grade 3 and above TRAE were hepatic function abnormal (14.9%), drug-induced liver injury (12.8%) and ALT (10.6%) increased. Conclusions: Savolitinib plus durvalumab showed promising clinical anti-tumor activity in pts with advanced EGFR wild-type NSCLC with MET alterations, especially in pts with MET ex14m. Close and frequent(i.e. weekly) monitoring of liver function should be conducted in pts receiving this combination. Prospective studies with larger sample sizes are needed to further evaluate the efficacy and safety of this combination in EGFR wild-type NSCLC pts with MET alterations. Clinical trial information: NCT05374603