Pyrotinib combined with SHR6390 in the treatment of refractory advanced HER2-positive gastric cancer or solid tumors: Safety and efficacy results from a phase Id trial.
Authors: Liu Dan , Gong Jifang , Xu Yingying , Yang Fen , Li Huajun , Shen Lin 
Published: January 2023

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Background: Pyrotinib (an irreversible pan-ErbB inhibitor, RP2D 400mg qd) monotherapy showed limited efficacy in patients with HER2 positive GC. In pyrotinib-resistant PDX models, pyrotinib combined with SHR6390 (a novel oral CDK4/6 inhibitor, RP2D 150mg qd) showed encouraging anti-tumor activity. A phase Id trial was conducted to evaluate the safety of pyrotinib combined with SHR6390 in refractory advanced HER2 positive gastric cancer or solid tumors (NCT03480256). Methods: This study followed a “3+3” design. Patients (Pts) received pyrotinib (qd, d1-28; q4w) combined SHR6390 (qd, d1-21; q4w) at dose of 400/100mg (cohort A), 400/125mg (cohort B), 400/150mg (cohort C), 400/175mg (cohort D) until disease progression or intolerable toxicity. The primary endpoint was safety and MTD. Results: From Aug. 2018 to Jul. 2022, 25 pts (GC, n=19; CRC, n=4; others, n=2) were enrolled with 19 pts experiencing prior anti-HER2 regimens. In cohort A (n=6), 1 patient withdrew consent. No DLT was observed. However, ≥G3 hematological toxicities were commonly reported, including neutropenia (G4, lasting< 3 days, n=2), anemia (G3, n=1) and thrombocytopenia (G3, n=1). After SMC discussion, another 3 dose levels (cohort E, 320/100mg; cohort F, 400/75mg; cohort G, 320/75mg) were designed for safety consideration. One DLT (G4 neutropenia, lasting≥3 days) was observed in cohort E (n=6). In cohort F (n=7), no DLT was observed. One patient did not finish the DLT assessment for clinical PD, and one had clinical PD after DLT assessment without radiologic confirmation. The ORR of cohort A, E, F was 60.0% (3/5), 33.3% (2/6), 40.0% (2/5). To determine RP2D, 6 pts were included in cohort B. One DLT was observed with G4 neutropenia lasting ≥3 days. One patient suffered G3 thrombocytopenia. The ORR was 33.3% (2/6). Although MTD was not reached, the remaining cohort (G, C and D) would not be continued based on the current data. In all, the most common AEs were leukopenia (100%), neutropenia (95.8%), anemia (91.7%) and thrombocytopenia (66.7%), diarrhea (79.2%) and mucositis (33.3%). The most common G3-4 AEs included leukopenia (41.7%), neutropenia (41.7%), anemia (12.5%) and diarrhea (12.5%). The overall ORR was 40.9%, with median PFS and OS of 3.88 (95%CI 3.46, 4.30) and 11.14 (95%CI 4.50, 17.78) months, respectively. Among GC patients (n=18), 16 pts finished efficacy assessment, 8 pts achieved PR (5 pts having prior anti-HER2 regimens) and 7 achieved SD, with ORR and DCR of 50.0% and 93.8%, respectively. The median PFS was 3.88 months (95%CI 3.59, 4.17) and the median OS was 12.48 months (95%CI 3.82, 21.1). Considering the safety profile and efficacy trend, the RP2D was defined as pyrotinib 400mg+SHR6390 100mg. Conclusions: Pyrotinib combined with SHR6390 showed acceptable safety profile and encouraging efficacy. Further expansion would be conducted at the dose level of cohort A. Clinical trial information: NCT03480256 .