5034 Background: Patients with advanced penile cancer progressing on cisplatin-based chemotherapy have limited options. Anti-EGFR therapy has not demonstrated significant survival benefit, and immune checkpoint inhibitors (ICIs) remain uncommon. Preclinical evidence suggests HER-2-targeted antibody-drug conjugates (ADCs) may synergize with ICIs by redirecting immune cells to the tumor microenvironment and overcoming immunosuppression. The HER-2 ADC (Disitamab Vedotin, DV) has shown preclinical activity in HER-2-positive and cisplatin-resistant penile cancer models. This study evaluated DV plus a PD-1 inhibitor (Toripalimab, T) in the cisplatin-resistant and advanced penile cancer patients. Methods: In this single-arm prospective study, patients received DV (2.0 mg/kg every 2-3 weeks) plus T (240 mg every 3 weeks) until progression or unacceptable toxicity. Tumor assessments tested by CT/MRI were performed every 8-12 weeks for RECIST v1.1. PD-L1 by combined positive score (CPS), tumor mutational burden (TMB) and HER-2 expression were analyzed. Follow-up continued until death or December 31, 2025. Results: Eight patients (median age 52 years; range 38-66) were enrolled, all previously treated with ≥4 cycles of cisplatin chemotherapy and 3 had received ICIs as second-line therapy (1 with ICIs plus cetuximab). Baseline staging included T4 (n = 2), N3 (n = 7), and M1 (n = 5); all target lesions were > 5 cm (perineal/inguinopelvic). After ≥3 treatment cycles and first scan at 8 weeks, best responses were partial response (PR) in 3 patients (1 patient achieved at first assessment, with ongoing response at 18 months and conversion of ctDNA from positive to negative; 1 with sustained response for 17 months, accompanied by reduction in circulating tumor cells; 1 with PR followed by treatment discontinuation and survival of 4 months), stable disease (SD) in 1, and progressive disease (PD) in 4 (median overall survival 5 months). Objective response rate (ORR) was 37.5% (3/8) and disease control rate (DCR) 50% (4/8). Median PFS and mOS were 3 and 5 months, respectively (Kaplan-Meier estimate). One grade ≥3 adverse event occurred (immune-mediated colitis with hematochezia). Grade 1-2 toxicities included leukopenia (n = 2), infusion-related fever (n = 1), sinus tachycardia (n = 1), fatigue (n = 6), rash (n = 1), and peripheral neuropathy (n = 5). Notably, HER-2 expression was assessed as negative in all patients. The patient with clearance of ctDNA had high TMB but low PD-L1 expression; others evaluable tumors had PD-L1 CPS > 40 (TMB not assessed). Conclusions: The combination of DV and T shows promising antitumor activity and a manageable safety profile in cisplatin-refractory advanced penile cancer patients, independent of HER-2 or PD-L1 status. These findings support further evaluation in this patients with high unmet clinical need. Clinical trial information: ChiCTR2400086605.
Fang Yuan (Wed,) studied this question.