Neoadjuvant toripalimab combined with inetetamab, pertuzumab, and nab-paclitaxel in HER2-positive breast cancer (TORCH): A phase II trial.

Abstract

e12658 Background: Incorporating immunotherapy into neoadjuvant therapy for HER2-positive breast cancer (BC) is an area of active investigation. Inetetamab is an engineered anti-HER2 antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC). This phase II study evaluated the PD-1 inhibitor toripalimab combined with inetetamab, pertuzumab, and nab-paclitaxel in early or locally advanced HER2-positive BC. Methods: This single-center, single-arm study used a Simon's two-stage minimax design. Eligible patients received 6 cycles of neoadjuvant therapy: toripalimab 240 mg; inetetamab (8 mg/kg load, then 6 mg/kg); pertuzumab (840 mg load, then 420 mg); and nab-paclitaxel 125 mg/m² (days 1 and 8) — all Q3W, followed by surgery. The primary endpoint was total pathological complete response (tpCR; ypT0/is ypN0). With a historical tpCR rate of 45.5% and an expected rate of 65% (α = 0.05, β = 0.2), the design required 18 evaluable patients in stage I. If > 8 achieved tpCR, the study would proceed to stage II (total N = 42). The study was registered in the Chinese Clinical Trial Registry (No. ChiCTR2500109920). Results: As of January 2026, 18 patients were evaluable at the stage I analysis, with a median follow-up duration of 5.9 months (95% confidence interval [CI]: 4.7-7.2). The objective response rate was 94.4% (17/18). Among 15 patients who underwent surgery, the tpCR rate was 66.7% (10/15) and breast pCR rate was 73.3% (11/15). No event-free survival (EFS) events or deaths were observed. Grade 3/4 treatment-related adverse events occurred in 6 patients (33.3%): neutropenia (n = 4), leukopenia (n = 3), elevated aspartate aminotransferase and (or) alanine aminotransferase (AST/ALT) (n = 3), and diarrhea (n = 1). Toripalimab was discontinued/postponed in 4 patients (22.2%) due to elevated AST/ALT (n = 3) or rash (n = 1). Conclusions: The combination of toripalimab, dual anti-HER2 blockade (inetetamab/pertuzumab), and nab-paclitaxel showed promising efficacy and manageable toxicity in the neoadjuvant setting for HER2-positive BC. These findings support further evaluation in randomized trials. Clinical trial information: No. ChiCTR2500109920.