Multicenter phase Ib/II study of second-line varlitinib and paclitaxel in patients with EGFR/HER2 co-expressing advanced gastric cancer (K-MASTER-13)

Abstract

Background Varlitinib is a small-molecule inhibitor of the tyrosine kinases EGFR, HER2, and HER4. We present a phase Ib/II study to evaluate the safety and efficacy of varlitinib in combination with weekly paclitaxel in EGFR/HER2 co-expressing advanced gastric cancer (AGC) patients. (KCT0003583).

Methods AGC patients who had failed 1st line fluoropyrimidine-containing chemotherapy, with evidence of both EGFR and HER2 overexpression by IHC (≥1+), were enrolled. Varlitinib [Dose 1: 300 mg BID, Dose -1: 300mg intermittent dose] and paclitaxel (80 mg/m2 D1,8,15) were investigated every 4 weeks. After determining the DLT and RP2D in phase Ib, phase II part was conducted to evaluate the anti-tumor activity with a primary endpoint of PFS.

Results In the phase Ib study, 9 subjects were enrolled at the dose 1 level of varlitinib 300mg, of which 6 patients were evaluable for safety per protocol. Among the 6 evaluable patients, there was 1 DLT of Grade 4 AST/ALT elevation. The RP2D was varlitinib 300mg once daily combined with paclitaxel (80mg/m2 on days 1, 8, and 15). The median follow-up duration of 9.3 months [95% confidence interval (CI), 6.1-12.5]. Among 27 patients treated with RP2D including 5 subjects from Phase Ib, median PFS and OS were 4.1 (95% CI, 2.4-4.9 months) and 7.9 months (95% CI, 3.3-12.5 months), respectively. Among 16 patients with measurable disease and administered with RP2D, confirmed response and disease control was observed in 5 patients (ORR=31.3%) and 14 patients (DCR=87.5%), respectively. No definite association between EGFR or HER2 high expression and the efficacy of varlitinib and paclitaxel could be determined. Most common any grade of adverse events (AEs) were neutropenia (51.8% and 22.2% of Grade 3), diarrhea (27.3%), and AST/ALT elevation (22.2% and 11.1% of Grade 3). No treatment related death or unexpected AEs resulting in treatment cessation were observed with the RP2D.

Conclusions Varlitinib combined with paclitaxel revealed manageable toxicities and antitumor activity in patients with EGFR/HER2 co-expressing AGC who progressed after first-line chemotherapy. Updated outcomes for ongoing patients and biomarker analysis will be presented.

Clinical trial identification KCT0003583