A Phase I Dose-Escalation and Dose-Expansion Study of FCN-437c, a Novel CDK4/6 Inhibitor, in Patients with Advanced Solid Tumors

SIMPLE SUMMARY: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have provided clinical benefits for a subset of patients with advanced breast cancer; however, treatment resistance generally emerges over time in patients with breast cancer, and the efficacy of existing CDK4/6 inhibitors in patients with other cancers is modest. The aim of this study was to explore the safety and preliminary antitumor efficacy of a novel, orally available CDK4/6 inhibitor, FCN-437c, in patients with advanced solid tumors. The results demonstrated promising signs of durable tumor response and disease control in this patient population. The safety profile was consistent with that of approved CDK4/6 inhibitors, with no concerning signals in terms of pulmonary, cardiac, or thrombotic risk. The efficacy and safety of FCN-437c merit further study, and this novel agent holds promise as a new alternative treatment for patients with few options. ABSTRACT: A phase I study evaluated the safety, tolerability, and maximum-tolerated dose (MTD)/recommended phase II dose (RP2D) of FCN-437c, a novel, orally available cyclin-dependent kinase inhibitor (CDK4/6i), in participants with advanced/metastatic solid tumors (aSTs). FCN-437c was escalated from 50 mg (once daily [QD] on days 1–21 of 28-day cycles) to the MTD/RP2D. In the dose-expansion phase, patients with CDK4/6i-treated breast cancer, or KRAS-mutant (KRAS(mut)) non-small-cell lung cancer (NSCLC) received the MTD. Twenty-two patients were enrolled. The most common tumors in the dose-escalation phase (n = 15) were breast, colorectal, and lung (each n = 4 [27.3%]). The dose-expansion phase included five (71.4%) patients with breast cancer and two (28.6%) with KRAS(mut) NSCLC. Twenty (90.9%) participants experienced FCN-437c–related adverse events. Dose-limiting toxicities occurred in two (33.3%) participants (200-mg dose, dose-escalation phase): grade 3 neutropenia and grade 4 neutrophil count decreased. Due to toxicities reported at 150 mg QD, the MTD was de-escalated to 100 mg QD. One (4.5%) participant (KRAS(mut) NSCLC, 100-mg dose) achieved a partial response lasting 724+ days, and five (22.7%) had stable disease lasting 56+ days. In conclusion, FCN-437c was well tolerated with encouraging signs of antitumor activity and disease control. Further exploration of FCN-437c in aSTs is warranted.