Pembrolizumab Combined with Disitamab Vedotin in Human Epidermal Growth Factor Receptor 2-Positive Metastatic Colorectal Cancer

Abstract Background Late-line treatment options for microsatellite stable (MSS)/proficient mismatch repair (pMMR) metastatic colorectal cancer (mCRC) are limited. PD-1 blockade alone has minimal clinical benefit in this population. Human epidermal growth factor receptor 2 (HER2)-targeted therapies represent an emerging strategy for HER2-expressing mCRC. This study evaluated the efficacy and safety of pembrolizumab combined with disitamab vedotin (DV), an anti-HER2 antibody-drug conjugate (ADC), in pretreated patients with HER2-positive mCRC. Methods This multicenter, single-arm, phase II study enrolled patients with MSS/pMMR, HER2-positive mCRC who received 2 prior lines of systemic therapy. Patients received pembrolizumab 400 mg every 6 weeks plus DV 2.5 mg/kg every 2 weeks until disease progression, unacceptable toxicity, or death. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Results Between December 2022 and May 2024, 15 patients (median age 59.0 years; 60.0% male) were enrolled. Fourteen patients (93.3%) had HER2 IHC 3+ expressions, and two had received prior anti-HER2 therapy. Two patients achieved partial response, (ORR=13.3%; 95% CI, 1.7%-40.5%). With median follow-up of 26.7 months, median PFS was 2.9 months (95% CI, 2.3 to not reached). Median OS was not reached (95% CI, 16.7 to NR). The 6-month OS rate of 92.9% (95% CI: 6.9%-80.3%) and the 1-year OS rate was 71.4% (95% CI: 51.3%-99.5%). The most common treatment-related adverse events (TRAEs) included nausea, anorexia, alanine aminotransferase elevation, aspartate aminotransferase elevation, and alopecia. Grade 3-4 TRAEs occurred in two patients (14.3%), both neutropenia. Conclusions Pembrolizumab plus disitamab vedotin showed limited antitumor activity in pretreated HER2-positive mCRC. ClinicalTrials.gov Identifier NCT05333809