SHR-1701 combined with fuzuloparib and chemotherapy as first-line therapy for advanced lung squamous cell carcinoma: Efficacy and safety results from a phase II study.

Abstract

8569 Background: Although immune checkpoint inhibitors are established in the treatment of advanced lung squamous cell carcinoma (LUSC), many patients derive limited or no durable benefit, underscoring the need for novel therapeutic strategies. However, poly (ADP-ribose) polymerase inhibitors (PARPi) can upregulate PD-L1 expression and promote immune-mediated response, which may increase the efficacy of anti-PD-(L)1 based therapy. Additionally, blocking TGF-b signaling has the potential to facilitate the recovery from chemo-induced myelosuppression. This phase II study evaluates the efficacy and safety for first-line approach combining SHR-1701, a bifunctional anti–PD-L1/TGF-β trap, with the PARP inhibitor fuzuloparib, combined with standard chemotherapy, which may potentiate anti-tumor immunity. To our knowledge, this is the first clinical investigation of this multi-pathway targeting strategy in advanced LUSC. Methods: Treatment-naïve patients with advanced LUSC received induction therapy with SHR-1701 (30 mg/kg IV q3w) plus platinum-based chemotherapy (investigator’s choice) for 4 cycles. Patients with disease control proceeded to maintenance therapy with SHR-1701 (same dose) plus oral fuzuloparib (100 mg twice daily) until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) by Blinded Independent Review Committee (BIRC) per RECIST v1.1. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Results: Between February 2023 and June 2025, 71 treatment-naïve advanced LUSC patients were enrolled (median age 65 years; 96% male). As of data cutoff (December 1, 2025; median follow-up 17.4 months), 57 patients (80.3%) had started maintenance therapy (median 12 cycles). Disease progression or death had occurred in 27 of 71 patients (38.0%) by the cutoff date. Median PFS was 11.0 months (95% CI, 8.1 to not estimable). Among 69 response-evaluable patients, best overall response included 1 complete response (1.4%), 56 partial responses (81.2%, including 46 confirmed), and 11 stable disease (15.9%), yielding an unconfirmed ORR of 82.6% (57/69), a confirmed ORR of 68.1% (47/69), and a DCR of 98.6% (68/69). OS data were immature; the 12-month OS rate was 83.0% (95% CI 71.1–90.2). Treatment-related adverse events occurred in 94.4% (67/71) of patients, most commonly anemia (42.3%), increased blood creatinine (19.7%), and proteinuria (18.3%). No new safety signals were observed. Conclusions: SHR-1701 plus fuzuloparib and chemotherapy as first-line therapy demonstrated promising anti-tumor activity and a manageable safety profile in patients with advanced LUSC. Clinical trial information: NCT04937972 .