AC0010 (Avitinib) is a third generation irreversible EGFR inhibitor. Overcoming T790M-induced resistance by AC0010 has been demonstrated in preclinical studies. This is a first-in-human dose escalation study of AC0010 in EGFR-TKIs resistant patients (NCT02274337).
NSCLC patients with EGFR positive mutation who developed resistance to the 1st generation EGFR TKIs were enrolled including both T790M positive and negative patients. Patients were orally administrated with AC0010 capsules in total 8 dose cohorts: 6 QD dose cohorts (50 mg QD, 100 mg QD, 200 mg QD, 350 mg QD and 550 mg QD), and 3 BID dose cohorts (175 mg BID, 250 mg BID and 300 mg BID). All patients were assessed for pharmacokinetics (PK), overall response rate (ORR), disease control rate (DCR), and adverse events (AEs). Prior to the treatment, biopsy for genotyping was required to confirm T790M status.
As of 5 May 2016, 51 patients (26/25 (49%) female, median age 55, 44/7 (86%) T790M m+) were enrolled. Maximum tolerated dose has not been reached. Most of AEs were grade 1 and transient. Common drug related AEs ≥grade 3 were rash (4%), ALT/AST elevation (4%) and Pneumonia(2%). No hyperglycemia and grade 3 QTc prolongation were observed. PK was dose proportional, median plasma half life was 7.8 (7.6-8.0) hours. BID dosing method could reduce fluctuation coefficient of plasma concentration by 0.40 fold, and improve AUC by 1.28 fold, compared to QD dosing, and no food effects were seen. Among all evaluated patients at the data cut-off, ORR was 41.7% (20/48), and DCR was 75.0% (36/48). Responses were observed at dose levels ≥200mg QD. In AC0010 dose level ≥350mg cohort, the ORR was 57.6% (19/33) and DCR was 87.9% (29/33), and BID dosing schedule had better ORR (66.7% vs 33.3%) and DCR (94.4% vs 77.8%) than QD dosing schedule. The longest duration of response was >11 months at data cut-off.
AC0010 demonstrates a safety profile and promising anticancer activity for NSCLC patients with T790M mutation who develop the resistance to 1st generation TKIs.
Clinical trial identification
NIH(clinicalTrials.gov) number: NCT02274337
Legal entity responsible for the study
ACEA Pharmaceutical Research, Hangzhou, China, and ACEA Biosciences Inc. San Diego, USA.
All authors have declared no conflicts of interest.