Envafolimab combined with lenvatinib and gemcitabine plus cisplatin in advanced biliary tract cancer as first-line treatment: A multicenter, single-arm, open-label, phase II study (ENLIGHTEN study).

4152 Background: The prognosis of advanced biliary tract cancer (BTC) remains unsatisfactory despite the use of first-line gemcitabine and cisplatin in combination with PD-1/PD-L1 inhibitors. Lenvatinib (LEN), an anti-angiogenic multi-kinase inhibitor, has recently demonstrated promising antitumor activity in various tumors. This study aimed to determine the efficacy and safety of envafolimab (PD-L1 inhibitor) and LEN in combination with gemcitabine and cisplatin as first-line treatment in advanced BTCs. Methods: This investigator-initiated, multicenter, single-arm, phase 2 trial enrolled patients with advanced BTCs from three centers. A Simon's two-stage optimal design was employed: if 4 or more patients achieved partial responses (PR) among the first 10 patients in stage 1, enrollment would expand to a total of 39 patients. The therapy would be considered promising if 15 or more patients achieved PR in total. Including a 10% dropout allowance, the total sample size was set at 43. All patients received subcutaneous envafolimab (400mg, day 1, Q3W) and LEN (8 mg, orally once daily) combined with gemcitabine (1000mg/m2, iv. drip, days 1, 8, Q3W) plus cisplatin (25mg/m2, iv. drip, days 1, 8, Q3W) up for 6-8 cycles, followed by maintenance envafolimab and LEN until disease progression (PD) or unacceptable toxicity. The primary endpoint was objective response rate (ORR) assessed per RECIST 1.1. Secondary endpoints included overall survival (OS), progression-free survival (PFS), disease control rate (DCR), and safety. Results: A total of 43 patients were enrolled in this study from October 2022 to July 2025. However, one patient withdrew consent due to personal reasons after completing one cycle of therapy and was therefore considered off-study. Forty-two patients were included in the final analysis, with a median age of 57 years (range, 29-73). The ORR and DCR were 42.9% (95% CI, 27.7%-59%) and 88.1% (95% CI, 74.4%-96%), respectively. The observed outcomes were 18 patients (42.9%) with a partial response (PR), 19 (45.2%) with stable disease (SD), and 5 (11.9%) with PD, which met the predefined threshold for a positive study endpoint. The median follow-up time, estimated by the reverse Kaplan-Meier method, was 21.5 months (range, 18.7-29.1). The median PFS was 8.8 months (95% CI, 8.0-14.1), and the median OS was 15.9 months (95% CI, 13.4-not reached). The most common grade 3/4 treatment-related adverse events (TRAEs) were platelet decreased (n = 9, 20.9%) and neutropenia (n = 7, 16.3%). No treatment-related deaths occurred. Conclusions: In summary, our study demonstrates that the quadruplet regimen of envafolimab, lenvatinib, gemcitabine, and cisplatin demonstrates promising efficacy and well-tolerated first-line therapy for advanced BTC. Clinical trial information: NCT05410197 .