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

Sheng Li; Jun Bao; Xiaoyou Li; Quanliang Yang; Junying Xu; Surong Chen; Ge Feng; Chao Gao; Lin Feng; Bin Lu; Min Miao; Xinchu Ni; Guofang Wang; Lei Yang; Liangjun Zhu

doi:10.1016/j.eclinm.2023.102314

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

EClinicalMedicine. 2023 Nov 20:66:102314. doi: 10.1016/j.eclinm.2023.102314. eCollection 2023 Dec.

Authors

Sheng Li¹, Jun Bao¹, Xiaoyou Li¹, Quanliang Yang², Junying Xu³, Surong Chen⁴, Ge Feng⁵, Chao Gao⁶, Lin Feng⁷, Bin Lu⁸, Min Miao⁹, Xinchu Ni¹⁰, Guofang Wang¹¹, Lei Yang¹², Liangjun Zhu¹

Affiliations

¹ Department of Medical Oncology, Jiangsu Cancer Hospital, Nanjing, China.
² Department of Medical Oncology, Changzhou Tumor Hospital, Changzhou, China.
³ Department of Medical Oncology, Wuxi People's Hospital, Wuxi, China.
⁴ Department of Medical Oncology, Yancheng No. 1 People's Hospital, Yancheng, China.
⁵ Department of Medical Oncology, Nanjing Jiangbei People's Hospital, Nanjing, China.
⁶ Department of Medical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
⁷ Department of Medical Oncology, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou, China.
⁸ Department of Medical Oncology, People's Hospital of Yangzhong City, Yangzhong, China.
⁹ Department of Medical Oncology, Yangzhou Jiangdu People's Hospital, Yangzhou, China.
¹⁰ Department of Radiation Therapy, The Affiliated Changzhou No 2 People's Hospital of Nanjing Medical University, Nanjing, China.
¹¹ Department of Oncology, Danyang Hospital of Traditional Chinese Medicine, Danyang, China.
¹² Department of Oncology, Nantong Tumor Hospital, Nantong, China.

Abstract

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/m² on day 1 and capecitabine 1000 mg/m² twice daily for two weeks) every 3 weeks until progression, intolerable toxicity or consent withdrawal. The recommended phase 2 dose (RP2D) of pyrotinib was determined and used in the phase 1b. The primary endpoints were the safety, maximum tolerated dose (MTD), RP2D, and confirmed objective response rate (ORR). This trial was registered with chictr.org, number ChiCTR2000029717.

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).

Keywords: Advanced gastric adenocarcinoma; First-line therapy; Phase 1 study; Pyrotinib in combination with camrelizumab and chemotherapy.