Pyrotinib combined with CDK4/6 inhibitor in HER2-positive metastatic gastric cancer: A promising strategy from AVATAR mouse to patients

Abstract

Background: Pyrotinib was well tolerated but its efficacy was unsatisfactory in patients with HER2-positive gastric cancer (GC) (NCT02378389). This study was to optimize the efficacy of pyrotinib.

Methods: Human GC cell lines and AVATAR mice were used to explore the refractory mechanisms of pyrotinib. A pyrotinib-combined strategy was proposed, which was validated in preclinical AVATAR mouse and in clinical patients enrolled in a phase I clinical trial (NCT03480256).

Results: Dysregulation of CCND1-CDK4/6-Rb axis might be the key to pyrotinib refractory. The strategy of pyrotinib combined with a CDK4/6 inhibitor SHR6390 was proposed and validated in preclinical AVATAR mouse, which was successfully verified in clinical patients. For five patients treated with pyrotinib plus SHR6390 who had available response evaluation, the best response was partial response in three patients, stable disease in one patient, and progressive disease in one patient. The progression-free survival times were 120, 200, 532, 109, and 57 days, respectively.

Conclusions: This translational study suggests that pyrotinib combined with SHR6390 may serve as a promising strategy for patients with HER2-positive GC.

Trial registration: The ClinicalTrials.gov identifiers are NCT02378389 (https://clinicaltrials.gov/ct2/show/study/NCT02378389, registered in 11 February 2015) and NCT03480256 (https://clinicaltrials.gov/ct2/show/study/NCT03480256, registered in 8 March 2018).

Keywords: CDK inhibitor; pyrotinib; refractory mechanisms.