A phase 1 study of dalpiciclib, a cyclin-dependent kinase 4/6 inhibitor in Chinese patients with advanced breast cancer

Abstract

Background Dalpiciclib (SHR6390) is a novel inhibitor of cyclin-dependent kinase 4/6 which demonstrated promising anti-tumor potency in preclinical models. This first-in-human study was conducted to evaluate the tolerability, pharmacokinetics, safety, and preliminary antitumor activity of dalpiciclib in patients with advanced breast cancer (ABC). Methods In this open-label, phase 1 study, Chinese patients who had failed standard therapy were enrolled to receive oral dalpiciclib in 3 + 3 dose-escalation pattern at doses of 25–175 mg. Eligible patients were given a single-dose of dalpiciclib in week 1, followed by once daily continuous doses for 3 weeks, and 1 week off in 28-day cycles. Based on the tolerability, pharmacokinetics, and activity data revealed from the dose-escalation phase, three dose cohorts were selected to expand to 8–10 patients. The primary endpoints were maximum tolerated dose (MTD) and pharmacokinetics. Results Between Apr 15, 2016 and Dec 21, 2018, 40 patients were enrolled; all were diagnosed of hormone receptor-positive and HER2-negative ABC. Dalpiciclib 100 mg, 125 mg, and 150 mg cohorts were expanded to 10 patients. No dose-limiting toxicity was observed and the MTD was not reached. Adverse events (AEs) of grade 3 or 4 were observed in 22 (55.0%) of 40 patients, being neutropenia (52.5%), leukopenia (35.0%), thrombocytopenia (5.0%), and hypertension (2.5%). No serious AEs were reported. At the doses of 50–175 mg, steady state areas under the concentration-time curve and peak concentration increased almost proportionally with dose. The disease control rate (DCR) was 62.5% (25/40, 95% CI: 45.8–77.3). Two patients (5%; 125 mg and 150 mg cohorts) achieved partial response, with responses lasting 169 and 356+ days, respectively. Among the three expansion cohorts, the 150 mg cohort had the numerically highest DCR of 80.0% (95% CI: 44.4–97.5) and longest median progression-free survival of 8.4 months (95% CI: 2.1–not reached). Conclusions Dalpiciclib showed acceptable safety profile and dose-dependent plasma exposure in Chinese patients with ABC. The recommended phase 2 dose was 150 mg. Preliminary evidence of clinical activity was observed, which warrants further validation. Trial registration ClinicalTrials.gov identifier: NCT02684266. Registered Feb 17, 2016.

Dalpiciclib Combined With Pyrotinib and Letrozole in Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer (LORDSHIPS): A Phase Ib Study

“…This approach showed promising anticancer activities and tolerable toxicities. The TRAEs of the combination of pyrotinib, dalpiciclib, and letrozole observed in this study were as expected for each drug toxicity profile, with mild or moderate neutropenia (100%), leukopenia (100%), anemia (100%), oral mucositis (93.3%) and diarrhea (86.7%) as the most common TRAEs (17,19,23). Similar to dalpiciclib combined with fulvestrant in DAWNA-1 study, the incidence of hematological toxicities with dalpiciclib, pyrotinib plus letrozole was high, whereas grade≥3 neutropenia and leukopenia were reported less frequently (grade ≥3 neutropenia: 84.2% vs 46.7%; grade ≥ 3 leukopenia: 62.1% vs 33.3%) (24).…”

“…Dalpiciclib (SHR6390) is an oral, novel, efficient, and highly selective small-molecule CDK4/6 inhibitor ( 17 ). Phase III trial (DAWNA-1) has demonstrated improved PFS with dalpiciclib plus fulvestrant versus placebo plus fulvestrant (15.7 vs 7.2 months; hazard ratio, 0.42; p<0.0001] in pretreated HR-positive, HER2-negative advanced breast cancer ( 18 ) Pyrotinib, an irreversible pan-HER receptor tyrosine kinase inhibitor (TKI) targeting epidermal growth factor receptor/HER1, HER2, and HER4 ( 19 ), is approved for the treatment of HER2-positive metastatic breast cancer in China.…”

Role of CDK4/6 inhibitors in patients with hormone receptor (HR)-positive, human epidermal receptor-2 negative (HER-2) metastatic breast cancer study protocol for a systematic review, network meta-analysis and cost-effectiveness analysis

“… 58 A novel, highly selective, small molecule CDK4/6 inhibitor dalpiciclib is currently under active investigation. 59 The results from the phase III DAWNA-1 trial showed that dalpiciclib plus fulvestrant improved PFS compared with fulvestrant alone in patients with HR positive, HER2-negative metastatic endocrine - resistant breast cancer. However, the most common grade 3–4 adverse events in the dalpiciclib plus fulvestrant group were haematologic toxicities, 60 which was consistent with palbociclib and ribociclib but different from abemaciclib.…”

Precision Medicine Highlights Dysregulation of the CDK4/6 Cell Cycle Regulatory Pathway in Pediatric, Adolescents and Young Adult Sarcomas

“…To date, there are no clinical trials to investigate the efficacy and safety of trilaciclib in pediatric and AYA sarcomas. In addition to four U.S. FDA-approved CDK4/6 inhibitors, a novel CDK4/6 inhibitor, dalpiciclib (SHR6390), is approved by China’s National Medical Products Administration (NMPA) for the treatment of HR+ and HER2- recurrent or metastatic breast cancer with endocrine agents [ 125 , 126 ]. Dalpiciclib has a similar potency against CDK4 and CDK6 [ 126 ].…”