Abstract
227 Background: EGFR and HER2 are over-expressed in gastric cancer, and activation of EGFR signaling in HER2-overexpressing gastric cancer can confer resistance to HER2-directed treatment like trastuzumab. Varlitinib (also known as ASLAN001) is a small-molecule, adenosine triphosphate competitive inhibitor of the tyrosine kinases - EGFR, HER2, and HER4. We present phase 1b results of the phase1b/2 study to evaluate the safety and efficacy of varlitinib in combination with weekly paclitaxel in EGFR/HER2 co-expressing AGC patients as a second-line treatment. (KCT0003583). Methods: An open-label phase Ib trial was conducted using a 3+3 design. AGC patients who had failed first-line fluoropyrimidine-containing chemotherapy, with evidence of both EGFR and HER2 overexpression by IHC (≥1+), were enrolled. The primary objective was to assess the dose limiting toxicity (DLT) and recommended phase 2 dose (RP2D) of varlitinib [Dose 1: 300 mg BID, Dose -1: 300mg intermittent dose] and weekly paclitaxel (80 mg/m2 D1,8,15) every 4 weeks along with evaluation of anti-tumor activity. Results: From July 2019 to May 2020, 9 patients were enrolled at Dose 1 level of varlitinib 300mg bid and 6 patients were evaluable for safety per protocol. Two patients did not finish DLT period: one patient withdrew after 1 week and one patient received palliative surgery for panperitonitis caused by gastric cancer metastasis. One patient had major violation in IP administration as the patient took varlitinib intermittently. Among the 6 evaluable patients, there was 1 DLT of G4 AST/ALT elevation and G3 hyperbilirubinemia, which resolved after 3 weeks. The most common treatment related adverse events (TRAEs) were neutropenia (n=5), all of which were grade ≥ 3, but no lasting more than 7 days. Grade 2 TRAEs included rash (n=2), mucositis (n=2) and peripheral sensory neuropathy (n=2). After a median follow-up of 3.0 (range, 1.9~ 6.2) months, the best responses were stable disease in 4 patients. Currently, 4 patients are ongoing. Conclusions: The combination of varlitinib 300mg bid and weekly paclitaxel 80mg showed manageable safety profiles and determined as RP2D. Currently, multi-site phase 2 part is now underway. Clinical trial information: KCT0003583.
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