Phase I / II study of ASP8273 in patients with non-small-cell lung cancer (NSCLC) harboring EGFR activating mutations

Abstract

Background: ASP8273 is a small molecule, irreversible tyrosine kinase inhibitor (TKI) that inhibits the kinase activity of both EGFR activating mutations and T790M resistance mutation, with higher potency than wild type EGFR. Methods: NSCLC patients previously treated with at least one EGFR-TKI were enrolled into the phase 1 part of this open-label Phase I/II study in Japan. ASP8273 was administered orally once daily (QD) and all patients were assessed for AEs, PK and preliminary anti-tumor activity. Dose-escalation and MTD estimation were conducted based on Bayesian-CRM. Since establishing the recommended phase 2 dose (RP2D), NSCLC patients with T790M have been enrolled into the phase 2 part of the study in Japan, Korea and Taiwan. Results: As of 14 Nov. 2014, 45 Japanese patients were enrolled into the phase 1 part across 7 dose levels (25 - 600 mg). Patient characteristics; median age 65, female 73%, ECOG PS1 62%, received immediate prior EGFR-TKI therapy 51%, T790M mutation - positive 49%, - negative 13% and - unknown 38%. Grade 3 AEs were observed at dose of ≥ 200 mg and AEs determined as DLTs were reported at doses of 400 and 600 mg. DLTs were diarrhea (3), colitis (2), nausea (2), biliary tract infection (1), and hyponatremia (1). Most common AEs (≥ 30%) were diarrhea (56%), nausea (31%), vomiting (31%) and thrombocytopenia (31%). AEs such as rash (9%), QTc prolongation (7%), ILD-like events (2%) and hyperglycemia (0%) were also observed. MTD was determined to be 400 mg based on these safety findings. Steady state plasma concentrations of ASP8273 appeared to be achieved by day 8 after QD dosing. Median AUC and Cmax of ASP8273 were increased with dose proportionality, respectively. 50% (18/36) of all evaluable patients and 80% (12/15) patients with T790M have achieved partial responses (PRs) by RECIST1.1 (includes confirmed and unconfirmed PRs). Based on these findings, RP2D has been identified as 300 mg QD. Preliminary phase 2 data will be incorporated into the presentation. Conclusions: ASP8273 was well tolerated at doses of ≤ 400mg and has shown dose dependent PK profile and preliminary anti-tumor activity in NSCLC patients with acquired resistance to previous EGFR-TKIs. Further investigation of clinical activity of ASP8273 at the RP2D in NSCLC patients with T790M is being explored in the phase 2 part.