Varlitinib (VAR, ASLAN001) is a potent pan-HER oral tyrosine kinase inhibitor, with efficacy in EGFR mutant and HER2 over-expressing tumours. We evaluated the safety, tolerability and maximum tolerated dose (MTD) of VAR with CAPOX (COX) and mFolfox6 (FOL), in pts with advanced solid tumours.
Eligible pts had advanced solid tumours, ECOG performance status (PS) 0-1 and adequate organ function. Colorectal cancer (CRC) with RAS/RAF mutations were excluded. COX (Capecitabine 850mg/m2 BID D1-D14 with oxaliplatin (OX) 130mg/m2 IV D1, Q21 days) or mFolfox6 (5-FU 400mg/m2 IV bolus D1 and 2400mg/m2 over 46 hrs with OX 85mg/m2 IV D1, Leucovorin 400mg/m2 IV D1, Q14 days) was given with VAR 200-400mg BID. Maximum 6 cycles COX or 9 cycles FOL, followed by VAR alone. Dose-limiting toxicity (DLT) period was 2 cycles.
30 pts were enrolled, 9 COX and 21 FOL arm. 15 (52%) CRC (all prior OX), 6 (21%) cholangiocarcinoma (CC), 3 (10%) gallbladder cancer and 6 (20%) others. Sex M/F 13/17, median age (range), PS, lines of prior chemo was 62yrs (36-71), 1(0-1) and 3.5(0-7) respectively. 28 pts were evaluable for MTD. MTD of VAR was 300mg/BID when given with FOL or COX.Table: 430P
|Dose||Pt enrolled/ evaluable||DLT|
|COX + VAR 400mg/BID||3/2||G3 Fatigue x2|
|COX + VAR 300mg/BID||6/6||G3 Fatigue|
|FOL + VAR 400mg/BID||4/4||G4 Transaminitis, G3 Raised Bilirubin|
|FOL + VAR 300mg/BID||11/9||G4 Encephalopathy, G3 Rash|
|FOL + VAR 200mg/BID||6/6||G3 Encephalopathy|
Grade 3/4 AEs (occurring ≥ 5%): neutropenia 5 (17%), fatigue 3(10%), transaminitis 2(7%), diarrhoea 2(7%), febrile neutropenia 2(7%), transient metabolic encephalopathy 2(7%). Of 28 pts evaluable for response, 3 (11%) had PR and 16 (57%) SD. Disease control rate (PR+SD) for ≥ 12wks was 13 (46%). 5 (18%) had long PFS (223-645 days), comprising a gallbladder and CRC (both HER2-overexpressing, prior platinum), CC, bladder and CRC (prior OX and cetuximab). PK analysis did not show VAR accumulation. Plasma cell free DNA and HER pathway inhibition results will be presented later.
MTD for VAR with COX and FOL was 300mg/BID. Durable efficacy was seen in biliary cancers and CRC. ASLAN pharmaceuticals and the Singapore National Medical Research Council supported this study.
Clinical trial identification
Legal entity responsible for the study
National Cancer Centre, Singapore.
M. Ng: Member: Aslan Pharmaceuticals advisory board; Speaker and research funding: Industry associated funding. All other authors have declared no conflicts of interest.