A multicenter, randomized, controlled, open-label, phase II trial of autologous tumor-infiltrating lymphocytes (GC101 TIL) in patients with advanced melanoma.

LBA9509 Background: Tumor-infiltrating lymphocyte (TIL) therapy is effective in advanced melanoma but hampered by toxicity from high-dose IL-2 and lymphodepletion (cyclophosphamide/fludarabine). We explored a modified TIL therapy (GC101) featuring an IL-2-free protocol and a low-intensity preconditioning regimen. This phase II study evaluates the modified GC101 TIL therapy in anti-PD-1-resistant melanoma. Methods: MIZAR-003 (NCT06703398) is a multicenter, phase II, randomized, open-label trial across 25 sites in China enrolling advanced melanoma patients resistant to PD-1 antibodies. Key eligibility: ECOG 0–1, adequate organ function. Exclusion: uveal melanoma, prior cellular therapy within 6 months. A total of 98 patients will be randomized 1:1 to Arm A (GC101 TIL) or Arm B (investigator-choice chemotherapy). GC101 therapy consists of tumor resection, low-intensity preconditioning (cyclophosphamide 20 mg/kg/d, pre-infusion d -5 to- 3; hydroxychloroquine 600 mg, pre-infusion d -5), followed by infusion of IL-2-free TIL and sintilimab (100 mg at infusion, then 100 mg Q6W × 4). Patients in Arm B with IRC-confirmed disease progression may cross over to receive GC101 TIL. The primary endpoint is IRC-assessed PFS per RECIST v1.1. Secondary endpoints include IRC-assessed ORR, CR rate, DOR, and OS; investigator-assessed ORR, PFS, CR rate, DOR, and PFS2; and safety. Results: In this exploratory interim analysis (70% of expected events), 84 patients were randomized (Arm A: 44; Arm B: 40) between 02/2025 and 01/2026, with a median follow-up of 5.2M (range 1.1-12.0). Baseline characteristics were balanced. As assessed by IRC, Arm A significantly improved mPFS (4.1M 95% CI 2.8–5.6 vs 1.6M 95% CI 1.3-4.0; HR 0.53 95% CI 0.30-0.94, p=0.0310), ORR (45.2% vs 5.4%; p=0.0018), and DCR (80.6% vs 43.2%; p=0.0017). OS data are immature. In mucosal melanoma (n=6 per arm), mPFS was not reached vs 1.3M, with DCR of 100.0% vs 33.3%. Grade ≥3 treatment-related AEs (TRAEs) occurred in 36.8% (Arm A) vs 27.5% (Arm B); treatment-related SAEs in 13.2% vs 7.5%. No new safety signals were observed, and no TRAEs led to treatment discontinuation or death. Conclusions: GC101 TIL significantly improved PFS and ORR versus investigator-choice chemotherapy in anti-PD-1-resistant melanoma, with manageable safety, supporting its potential as a new later-line therapy. Clinical trial information: NCT06703398 .