Phase 1 study of SHR-1826, a c-MET–directed antibody-drug-conjugate (ADC), in advanced solid tumors.

106 Background: MET alterations are key drivers of diverse oncogenic processes, including tumor invasion, growth, and metastasis, and are associated with poor prognosis. SHR-1826 is a novel ADC of a humanized c-MET-directed IgG2 monoclonal antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. We conducted a multi-center, first-in-human, phase 1 trial of SHR-1826 in advanced solid tumors, and here report preliminary results from the dose-escalation and expansion portions. Methods: Patients (pts) with advanced solid tumors harboring MET alterations (overexpression, amplification, or activating mutation) who had failed standard therapy or no available standard therapy, were enrolled. The study consisted of dose-escalation (i3+3 design), dose-expansion and efficacy-expansion phases, during which pts received SHR-1826 at 2.2–6.0 mg/kg, Q3W, iv. Primary objectives were to assess safety and tolerability. Results: As of Dec.5, 2024, 116 pts were enrolled and treated (NSCLC/CRC/GC/PC, n=72/32/10/2; median age, 59.2 yrs; ECOG PS 1, 87.9%; ≥3 lines of prior therapy, 44.0%; median c-MET H-score, 163 [range 9-300]). During dose-escalation, 1 DLT was observed at 6.0 mg/kg (grade 3 febrile neutropenia). Grade ≥3 TRAEs were reported in 56 (48.3%) pts, with the most common being decreased neutrophil count (32.8%), decreased white blood cell count (22.4%), anaemia (13.8%), and decreased platelet count (11.2%). Interstitial lung disease occurred in 3 (2.6%; grade 1-2, n=2; grade 3, n=1) pts. 2 (1.7%) pts discontinued treatment due to TRAE. There were no treatment-related deaths. Among 58 evaluable pts with NSCLC, ORR was 39.7% (95% CI 27.0–53.4) and DCR was 94.8% (95% CI 85.6–98.9; Table 1); response was observed across a range of c-MET expression levels, and in both EGFR -mutated and wild-type tumors. Median duration of response was not reached, with 21 of 23 responses ongoing. In all 72 NSCLC pts, median progression-free survival was 6.8 mo (95% CI 4.5–7.2). Conclusions: SHR-1826 demonstrated a manageable safety profile in pts with heavily pretreated advanced solid tumors. Promising anti-cancer activity was observed in MET-altered NSCLC, warranting further investigation in this population. Clinical trial information: NCT06094556 . Efficacy in pts with NSCLC. 2.2 mg/kg (n=2) 4 mg/kg (n=24) 5 mg/kg (n=31) 6 mg/kg (n=1) All patients (n=58) Best overall response, n (%) Complete response 0 0 0 0 0 Partial response * 0 9 (37.5) 13 (41.9) 1 (100.0) 23 (39.7) Stable disease 2 (100.0) 14 (60.9) 16 (51.6) 0 32 (55.2) Progressive disease 0 0 2 (6.5) 0 2 (3.4) Not evaluable 0 1 (4.2) 0 0 1 (1.7) ORR * , % (95% CI) 0.0 (0.0–84.2) 37.5 (18.8–59.4) 41.9 (24.5–60.9) 100.0 (2.5–100.0) 39.7 (27.0–53.4) DCR, % (95% CI) 100.0 (15.8–100.0) 95.8 (78.9–99.9) 93.5 (78.6–99.2) 100.0 (2.5–100.0) 94.8 (85.6–98.9) Data are shown for pts with ≥1 post-baseline assessment. * Including 6 unconfirmed responses across groups.