First-in-class PD-1/IL-2 bispecific antibody IBI363 in patients (Pts) with advanced immunotherapy-treated non-small cell lung cancer (NSCLC).

8509 Background: IBI363 is a first-in-class PD-1/IL-2 α-bias bispecific antibody fusion protein to block PD-1 checkpoint and rejuvenate exhausted tumor-specific T cells by cis-activating α-bias IL-2. It has potential to address the unmet clinical need of patients (pts) with immunotherapy-resistant and cold tumors. Here, we report safety and efficacy results from a phase I, multicenter, first-in-human study (NCT05460767) of IBI363 in pts with advanced NSCLC. Methods: Eligible pts with advanced NSCLC who failed or were intolerant of standard therapy were enrolled and received IBI363 intravenously at dose levels of 2/10/300/600 ug/kg every week (QW), 0.3/0.6/1 mg/kg every two weeks (Q2W) or 1.5/2/3/4 mg/kg every three weeks (Q3W). Endpoints included safety, objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and progression-free survival (PFS) by investigator per RECIST v1.1. Results: As of December 6, 2024, 136 NSCLC pts were enrolled (median age: 61 years; prior treatment lines ≥2: 72%). Most patients were treated with IBI363 at 0.6/1 mg/kg Q2W (n=56), 1.5 mg/kg Q3W (n=11) or 3 mg/kg Q3W (n=57). Treatment-emergent adverse events (TEAEs) occurred in 135/136 pts (≥G3: 42.6%). TEAEs led to treatment discontinuation in 9 (6.6%) pts and TEAEs led to death in 4 (2.9%) pts with only 1 (0.7%) event considered treatment-related (unexplained death). Most common TEAEs were arthralgia (51.5%; 3.7% ≥G3), anemia (43.4%; 3.7% ≥G3), and rash (38.2%; 4.4% ≥G3). In pts with squamous cell carcinoma who had at least 1 post-baseline tumor assessment, 30 (including 1 pt who had not received PD-(L)1 before enrolled) and 27 pts had been treated with IBI363 3 mg/kg and 1/1.5 mg/kg, respectively; more encouraging efficacy signals were observed in the 3 mg/kg group: ORR 43.3% vs 25.9%, confirmed ORR 36.7% vs 25.9%, DCR 90.0% vs 66.7%, median PFS 7.3 (95% CI: 6.0-11.7) vs 5.5 (95% CI: 1.5-8.3) months, with a median follow up time of 7.3 vs 11.1 months. In the PD-(L)1 treated adenocarcinoma pts with no actionable genomic alterations who had at least 1 post-baseline tumor assessment, 25 and 30 pts had been treated with IBI363 3 mg/kg and 0.6/1/1.5 mg/kg, respectively, similarly, 3 mg/kg group showed higher ORR (28.0% vs 16.7%), confirmed ORR (24.0% vs 13.3%), DCR (76.0% vs 63.3%) and median PFS (4.2 95% CI: 3.0-not estimable vs 2.8 95% CI: 1.4-5.1 months, with a median follow up of 5.9 vs 16.5 months). A higher ORR of 29% versus 4% and a longer PFS of 5.3 months compared to 2.7 months were observed in smokers (N=31, 56.4%). Notably, in patients at all dose levels with a tumor cell proportion score (TPS) under 1%, the ORR was 45.5% for squamous cell carcinoma (N=22) and 29.4% for adenocarcinoma (N=17). Conclusions: IBI363 was well tolerated with encouraging and durable efficacy observed in pts with advanced NSCLC who progressed to PD-(L)1, especially in the squamous subtype. Clinical trial information: NCT05460767 .