Multicenter phase I dose escalation and expansion study of pyrotinib in combination with camrelizumab and chemotherapy as first-line treatment for HER2-positive advanced gastric and gastroesophageal junction adenocarcinoma.

Background: Pembrolizumab plus trastuzumab and chemotherapy showed remarkable efficacy as first-line therapy for advanced HER2-positive gastric cancer. Pyrotinib is an irreversible pan-HER inhibitor. This single-arm, open-label phase 1 dose-escalation (1a) and expansion (1b) study investigated camrelizumab, an anti-PD-1 antibody, plus pyrotinib and chemotherapy as first-line treatment for advanced HER2-positive gastric and gastroesophageal junction (G/GEJ) adenocarcinoma. Methods: Between June 2020 and June 2022, 41 patients with previously untreated HER2-positive locally advanced unresectable or metastatic G/GEJ adenocarcinoma were enrolled. In phase 1a, patients underwent a 3 + 3 escalating dose design, receiving oral pyrotinib (240 mg, 320 mg, or 400 mg daily), intravenous camrelizumab (200 mg), and CapeOX (oxaliplatin 130 mg/m Findings: Among 41 patients, 10 were in phase 1a (3 at 240 mg, 3 at 400 mg, and 4 at 320 mg due to one patient withdrawing consent), and 31 were in phase 1b. In phase 1a, the MTD of pyrotinib was 320 mg daily due to dose-limiting toxicities (diarrhea [n = 3] and vomiting [n = 1]) observed at 400 mg. Based on all available data, the RP2D of pyrotinib was set at 320 mg. Among 41 patients, 20 patients (48.8%) developed grade ≥3 treatment-emergent adverse events (TEAEs), and four patients (9.8%) had any grade serious adverse events. No deaths occurred due to TEAEs. Among 27 patients who received the RP2D of pyrotinib and had a post-baseline tumor assessment, two patients (7.4%) achieved a confirmed complete response, and 19 patients (70.4%) achieved a confirmed partial response, resulting in a confirmed ORR of 77.8% (95% CI: 57.7-91.4). Interpretation: Pyrotinib plus camrelizumab and chemotherapy showed promising efficacy in the first-line treatment of advanced HER2-positive G/GEJ cancer. The safety profile was consistent with known toxicities of the agents, and no new or unexpected safety signals were identified. Funding: This study was funded by the Beijing Xisike Clinical Oncology Research Foundation (Y-HR2019-0377).