Assessment of efficacy of LBL-024, a novel and uniquely designed bispecific antibody against PD-L1 and 4-1BB, combined with etoposide/platinum-based chemotherapy in treatment-naive advanced extrapulmonary neuroendocrine carcinoma (EP-NEC): A multicenter phase Ib/II trial.

Abstract

2500 Background: The prognosis for patients with EP-NEC is very poor. A recognized 1L treatment for advanced disease is etoposide/platinum-based chemotherapy with no standard 2L/3L treatment. LBL-024 blocks the immunosuppressive pathway of tumor cells by targeting PD-L1 and effectively co-stimulates T cells by targeting 4-1BB, to improve the anti-tumor immune response. Here we report the safety and efficacy of LBL-024 combined with etoposide and cisplatin or carboplatin (EP/EC) as first line treatment in patients with advanced NEC. (NCT06157827). Methods: This is a phase Ib dose escalation and phase II dose optimization/expansion clinical trial. Phase Ⅰb enrolled previously untreated advanced EP-NEC and SCLC patients, phase Ⅱ enrolled previously untreated advanced EP-NEC patients. Three dose levels of LBL-024 (6, 10 and 15 mg/kg, i.v. Q3W) plus EP/EC in phase Ib were evaluated, 2 dose levels (6 and 15 mg/kg, i.v. Q3W) of LBL-024 plus EP/EC were evaluated in a randomized dose optimization. The primary endpoints were tolerability, safety, efficacy (RECIST 1.1) and RP2D, the secondary endpoints were PK, PD and ADA. Results: As of December 26, 2024, a total of 53 patients were enrolled, with 13 patients in Phase Ib and 40 patients in dose optimization stage of Phase II. Phase Ib included 2 patients with SCLC, 1 with MiNEN, and 10 with EP-NEC. All 40 patients in Phase II were EP-NEC. During the Dose escalation stage, no DLTs were observed. During the Dose optimization stage, 15 mg/kg of LBL-024 was selected as RP2D based on PK/PD, efficacy, safety and ER analysis. Out of 49 patients, the ORR across all dose levels is 77.6% and the DCR is 93.9% among which 9 patients were unconfirmed. The ORR in 21 EP-NEC patients at RP2D dose is 81.0% and DCR is 95.2% among which 3 patients were unconfirmed. Additionally, 2 patients with SCLC achieved 100% ORR. LBL-024 TRAEs of all-grade occurred in 53 patients (100%), with grade ≥3 TRAEs in 17/53 patients (32.1%). Conclusions: LBL-024 combined with chemotherapy was well-tolerated. The extremely improved response observed in EP-NECs is significantly higher than the historic reports (about 30%~55%). Data including ER analysis of this ongoing study will be updated by a follow-up submission to ASCO. Clinical trial information: NCT06157827 . Clinical benefits of first line treatment in evaluable patients bin phase Ib/II. Phase Ib(Dose escalation) Phase II(Dose optimization) 15 mg/kg(N=21)EP-NECs Total(N=49) 6 mg/kg(N=3) 10 mg/kg(N=4) 15 mg/kg(N=6*) 6 mg/kg(N=18) 15 mg/kg(N=18) ORR,N (%) 2 (66.7%) 3 (75.0%) 4 (66.7%) 14 (77.8%) 15 (83.3%) 17 (81.0%) 38 (77.6%) DCR,N (%) 3 (100.0%) 4 (100.0%) 4 (66.7%) 17 (94.4%) 18 (100.0%) 20 (95.2%) 46 (93.9%) *2 patients with SCLC, 1 with MiNEN and 3 with EP-NEC.