Neoadjuvant toripalimab combined with TIP chemotherapy for locally advanced penile squamous cell carcinoma: A multicenter prospective, single-arm, phase II clinical trial.

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Background: The neoadjuvant regimen of paclitaxel, ifosfamide, and platinum (TIP) regimen is recommended for local advanced penile squamous cell carcinoma (La-PSCC) by NCCN guideline; however, its objective response rate (ORR) is only 50%, with limited long-term survival benefits. This phase II study was designed to evaluate the efficacy and safety of toripalimab (anti-PD-1 monoclonal antibody) combined with TIP chemotherapy as neoadjuvant therapy in chemotherapy-naïve patients with La-PSCC. Methods: This was a prospective, multicenter, single-arm phase II study utilizing a Simon’s two-stage design. Patients with T4 or N2-3 M0 PSCC received up to four cycles of neoadjuvant toripalimab combined with TIP chemotherapy, followed by consolidative surgery. Postoperatively, toripalimab maintenance therapy was administered every three weeks for up to 17 cycles. The primary endpoint was the ORR assessed according to RECIST v1.1. Secondary endpoints include pathological complete response (pCR), event-free survival (EFS), overall survival (OS), and the incidence of treatment-related adverse events (TRAEs). This trial is registered on ClinicalTrials.gov (Identifier: NCT06415318). Results: From May 30, 2024, to Jun 1, 2025, a total of 25 patients with La-PSCC were enrolled (median age 60 years, range 31-71). All received ≥2 cycles of toripalimab combined with TIP chemotherapy. The ORR was 84.0% (21/25), with 2 patients (8.0%) achieving CR and 19 (76.0%) achieving PR. Twenty-one patients received following consolidative surgery, with a pCR rate of 48.0% (12/25). All patients (100%) experienced TRAE of any grade; grade 3-4 TRAEs occurred in 84.0% (21/25). The most common grade 1-2 TRAEs were alopecia (100%), peripheral neuropathy (96.0%), and fatigue (84.0%). The predominant grade 3–4 TRAEs were neutropenia (72.0%, 18/25) and leukopenia (60.0%, 15/25). Hypothyroidism (grade 1–2) was the main immune-related adverse event (irAE), affecting 2/25 patients (8%). No grade 5 TRAEs or treatment-related deaths occurred. At a median follow-up of 14.8 months, the 12-month EFS and OS rates were 71.6% (95% CI: 55.8–91.9) and 87.8% (95% CI: 75.8–100), respectively. Median EFS and OS were not reached. Mature survival data are awaited with longer follow-up. Conclusions: Neoadjuvant toripalimab combined with TIP chemotherapy exhibits significant efficacy in chemotherapy-naïve patients with La-PSCC, with acceptable treatment-related toxicity. This combination holds great promise as a new standard neoadjuvant treatment for La-PSCC. Clinical trial information: NCT06415318 .