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).

Targeting HER3 or MEK overcomes acquired Trastuzumab resistance in HER2-positive gastric cancer-derived xenograft

“…Although the antitumor activity of Trastuzumab combined with CDK4/6 inhibitor was slightly lower than other combinative strategies, this strategy also worth to be validated by clinical trials. In our recent report, we verified the strong synergistic tumor inhibition of pyrotinib (a novel small-molecule tyrosine kinase inhibitor mainly targeting HER2) combined with CDK4/6 inhibitor in HER2-positive GC patients [ 26 ]. For Trastuzumab combined with PI3K/mTOR inhibitor or c-Myc inhibitor, considering its very good efficacy, further investigations were worth to be conducted by adjusting the drug doses to achieve higher efficiency and lower toxicity.…”

HER2 Inhibition in Gastric Cancer—Novel Therapeutic Approaches for an Established Target

“…Enhanced efficacy was seen when pyrotinib was used in conjunction with docetaxel (ORR 21%). Dysregulation of the CCND1-CDK4/6-Rb axis has been shown to contribute to pyrotinib resistance, which was reversed by the administration of the CDK4/6 inhibitor SHR6390 in murine models [ 93 ]. The combination of pyrotinib and SHR6390 resulted in an ORR of 60% in a small phase I trial consisting of five gastric cancer patients who failed standard systemic therapy, demonstrating proof-of-concept of this combination clinically [ 93 ].…”

HER2-targeted advanced metastatic gastric/gastroesophageal junction adenocarcinoma: treatment landscape and future perspectives

“…A trial of pyrotinib combined with chemotherapy in patients with advanced HER2-overexpressing solid tumors included 9 patients with GC, whose outcomes were not promising (mPFS: 2.9 months, mOS: 5.9 months) and in whom diarrhea was the most common adverse event [95]. Another phase Ib trial combining pyrotinib with the CDK4/6 inhibitor SHR6390 showed a satisfactory benefit in patients with HER2-positive advanced GC who had received standard therapy, which suggests that this regimen may be a viable treatment strategy for patients with HER2-positive GC, but this requires confirmation in a larger sample [96].…”