Safety and efficacy of CS2009, a first-in-class PD-1/VEGF/CTLA-4 trispecific antibody, in patients with advanced non-small cell lung cancer: Results from a phase 1/2 study.

Abstract

8558 Background: CS2009 is a novel PD-1/VEGF/CTLA-4 trispecific antibody. An ongoing phase 1/2 study is evaluating its safety, tolerability, PK, PD, and anti-tumor activity as a single agent and in combination with systemic treatment in patients (pts) with advanced solid tumors. This study comprises a phase 1 dose escalation and phase 2 dose expansion. Here, we report the initial efficacy and safety data from advanced non-small cell lung cancer (NSCLC) pts treated in first-line and later-line settings. Methods: The study enrolled both treatment-naïve (1L) and heavily pre-treated later-line (≥2L) NSCLC pts. The ≥2L group included previously treated pts without known actionable oncogenic alterations (AGA) who had progressed on at least one prior line containing an anti-PD-1/L1 antibody and platinum-based chemotherapy; these pts received CS2009 at 10, 20, 30, or 45 mg/kg, i.v., Q3W, until disease progression or intolerance. The 1L cohort enrolled treatment-naïve pts with PD-L1 TPS ≥1% NSCLC without known AGA; these pts were randomized 1:1 to receive CS2009 at 20 or 30 mg/kg, i.v., Q3W, until disease progression or intolerance. Safety was assessed in all treated pts. Efficacy was assessed in pts who had at least one post-baseline tumor assessment per RECIST v1.1. Results: As of Jan. 4, 2026, 40 pts with ≥2L NSCLC were treated with CS2009 across four dose levels (10 mg/kg, n=3; 20 mg/kg, n=12; 30 mg/kg, n=20; 45 mg/kg, n=5). Median age was 67 (range 37-78) years; 72.5% were Asian, 27.5% were White; 77.5% were male; 77.5% had ECOG PS 1 at baseline. Among 30 efficacy-evaluable pts, ORR was 20.0% (6 PRs); in 16 pts treated at 30 mg/kg, ORR was 25.0% (4 PRs). Any-grade and grade ≥3 treatment-related adverse events (TRAEs) occurred in 27 (67.5%) and 8 (20.0%) pts, respectively. The most common TRAEs were proteinuria (12.5%), hypertension (12.5%), bilirubin conjugated increased (10.0%), and fatigue (10.0%), which were mostly grade 1 or 2, except for grade ≥3 hypertension in two pts. No treatment-related deaths were reported. TRAEs led to discontinuation in 3 (7.5%) pts. More mature ≥2L efficacy data with additional evaluable pts will be presented at the conference. As of Jan. 4, 2026, 19 pts with 1L NSCLC (PD-L1 TPS ≥1%) were randomized to receive CS2009 at 20 mg/kg (n=10) or 30 mg/kg (n=9). Median age was 69 (range 52-82) years; 84.2% were male; 89.5% had ECOG PS 1 at baseline. Preliminary encouraging efficacy and favorable safety signals were observed. Updated efficacy and safety data in approximately 50 1L pts will be disclosed at the conference. Conclusions: CS2009, as a first-in-class trispecific antibody targeting PD-1, VEGF, and CTLA-4, demonstrated a favorable safety profile and clinically meaningful anti-tumor activity in advanced NSCLC pts without known AGA. These findings warrant further investigation of CS2009 in this population. Clinical trial information: NCT06741644 .