28P Dose determination and pharmacokinetics (PK) of pralsetinib: Results from the phase I ARROW study
The phase 1/2 ARROW (NCT03037385) study supported approval of pralsetinib, a highly potent oral selective RET inhibitor, for RET-altered non-small cell lung cancer (NSCLC) in the US, EU, and other countries, and thyroid cancer (TC) in the US. Here we report data from the phase 1 dose-escalation part of ARROW. In phase 1, pralsetinib once daily (QD; 30–600 mg) or twice daily (BID; 200/100 mg or 100/100 mg) was assessed in advanced solid tumors (RET-altered for doses >120 mg per day). Key endpoints were maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety (all primary); PK and overall response rate (ORR) (both secondary). At data cut-off (November 18, 2019), 60 of 62 patients enrolled in phase 1 were included in the dose-determining population (QD, n=51; BID, n=9); 2 who received <75% of study drug with no dose-limiting toxicities (DLTs) were excluded. Median age was 56.5 years (range 19‒85), 58% were male, and 61% had Eastern Cooperative Oncology Group Performance Status 1. Median time to maximum plasma concentration of pralsetinib was 2–3 hours at 30–600 mg QD. Mean plasma elimination half-life was 11–23 hours at 200–400 mg QD; steady state was reached with <3-fold accumulation, consistent with half-life and dosing frequency. Exposure at 400 mg QD sustained coverage above predicted 90% inhibitory concentration for RET in tumor and brain. ORR was 42% (95% confidence interval 15‒72) in 12 patients treated at 400 mg QD (RET-fusion positive NSCLC [n=3], differentiated TC [n=2], and medullary TC [n=6 RET-mutant, n=1 unknown mutation status]). DLTs occurred in 11 patients, including 2/4 at 600 mg QD (hypertension, hyponatremia), 2/12 at 400 mg QD (hypertension, myositis), 2/11 at 300 mg QD (hypertension, tumor lysis syndrome [TLS]), 2/4 at 200/100 mg BID (both hypertension), and 2/5 at 100/100 mg BID (hypertension, TLS). Based on safety and exposure, 400 mg QD was chosen as MTD and RP2D. Six patients discontinued due to treatment-related adverse events. Pralsetinib 400 mg QD was well tolerated, showed promising antitumor activity, and was chosen as the RP2D for the registrational phase 2 part of ARROW.