Pyrotinib alone or in combination with docetaxel in refractory HER2-positive gastric cancer: A dose-escalation phase I study

Abstract

Aim: Pyrotinib (an irreversible pan-ErbB small-molecular tyrosine kinase inhibitor) was approved in human epidermal growth factor receptor 2 (HER2)-positive breast cancer and showed great antitumor activity in preclinical studies of gastric cancer (GC). This study was first designed to prospectively assess pyrotinib in pretreated HER2-positive GC.

Methods: This multicenter, phase I study followed a standard "3 + 3" design and included two parts. In the pyrotinib part, pyrotinib was administered orally, once per day at dose levels of 240, 320, 400, and 480 mg. In the pyrotinib plus docetaxel part, patients received pyrotinib (qd, d1-21, q3W) combined with docetaxel (60 mg/m² , d1, q3W) at dose levels of 240, 320, and 400 mg. Primary endpoints were to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of pyrotinib as monotherapy or coadministered with docetaxel.

Results: A total of 25 patients were enrolled and received pyrotinib (n = 15) or pyrotinib plus docetaxel (n = 10). One DLT was observed in pyrotinib monotherapy part (Grade 3 uncontrolled diarrhea after supportive care) and pyrotinib plus docetaxel part (Grade 4 neutropenia and leukopenia). In the pyrotinib monotherapy part, MTD was not reached. Diarrhea, anemia, neutropenia, and leukopenia were the most common treatment-related adverse events (TRAEs). The RP2D for pyrotinib monotherapy was recommended as 400 mg. After combining with docetaxel, the risk of leukopenia and neutropenia was increased. Grade ≥3 TRAEs were reported for four patients in the monotherapy part and for eight patients in the combination part. Mean t_1/2 was approximately 20 h. Pyrotinib exposure was dose-dependent with a nonlinear relationship versus dose. There were five patients who had confirmed partial response (monotherapy: one each at 240, 400, and 480 mg dose cohort; combination therapy: two at 240 mg dose cohort), resulting in an objective response rate of 21% and 20%, respectively.

Conclusions: Pyrotinib alone and combined with docetaxel showed acceptable toxicities in patients with pretreated HER2-positive GC.

Trial registration: This study was registered with ClinicalTrials.gov, NCT02378389.

Keywords: HER2; docetaxel; gastric cancer; phase I study; pyrotinib.

FIGURE 1

Study design.

FIGURE 2

Mean plasma concentration of pyrotinib following (A) single and (B) multiple doses in the monotherapy part (PK population).

FIGURE 3

Waterfall plot of best objective response of all enrolled patients. Maximum reduction in target lesions from baseline for patients in the 240–480 mg dose cohorts in (A) the monotherapy part and (B) the combination therapy part. The best response for target lesions per patient was determined on the basis of RECIST 1.1 criteria. Dashed lines at −30 and 20 indicate RECIST 1.1 criteria for partial response and progressive disease, respectively. ^aOne patient had a 52.6% reduction in target lesion size after two cycles of treatment, but had progressive disease with partial bowel obstruction after four cycles of treatment. So, the confirmed overall response was therefore classified as stable disease.