Fig 1: VAR free Cmax in combination with COX or FOL; ● COX + VAR, ● FOL + VAR

C1D1 C1D15 /C2D1

200mg 200mg300mg 300mg400mg 400mg

0 20 40 60 80 100

BTCBTCCLRNPCBTCCLRBRSCLRBTCBTCBTCCLRCLRESOCLRCLRCLR

PANCCLRCLRCLRCLRCLRBTCCUPCLRCLRBLABTCBTC

Weeks

Time on study (weeks)

24

3+3 dose escalation except FOL + VAR 300mg/BID with 3+3+3. Dose-limiting toxicity (DLT) period was 2 cycles of VAR + chemo. Data cut-off was 12 April 18.

Phase I study safety and tolerability of Varlitinib (VAR) in combination with Oxaliplatin and Capecitabine (COX) or Oxaliplatin and 5-FU (FOL) in advanced solid tumours

Amanda Seet1, Su Pin Choo1, David WM Tai1, Justina YC Lam1, Wan Tian Teng2, Grace SH Ang2, Cindy Lim2, Tony KH Lim3, Iain BH Tan1, Matthew CH Ng1

1Division of Medical Oncology, 2Clinical Trial and Epidemiology, National Cancer Centre Singapore; 3Department of Pathology, Singapore General Hospital

Varlitinib (VAR, ASLAN001) is a reversible, pan-HER oral tyrosine kinase inhibitor, with efficacy in EGFR mutant and HER2over-expressing tumours. VAR is more potent than lapatinib and neratinib.

• To evaluate the safety, efficacy and tolerability of VAR in combination with COX and FOL, in pts with advanced solidtumours.

• Determine the maximum tolerated dose (MTD) of VAR with CAPOX or FOL.

Patient Characteristics (n=30) No. (%)

Median Age (range) 62 (36-71)

Male 13(43)Female 17 (57)

Median ECOG (range) 1 (0-1)Tumour Type

Colorectal 15 (52)Biliary tract cancers (BTC) 9 (31)Bladder 1 (3)Breast 1 (3)Oesophageal 1 (3)Nasopharyngeal 1 (3)Pancreas 1 (3)Unknown Primary 1 (3)

Lines of prior chemotherapyMedian (range) 3 (0-7)

Study armCOX 9 (30)FOL 21 (70)

Introduction

Objectives

Methods

Key Inclusion Criteria• Advanced solid tumours• Treatment refractory or suitable for COX or FOL chemo. • ECOG Performance Status 0-1• Adequate organ function• Total bilirubin ≤ ULN.• Aspartate aminotransferase and alanine

aminotransferase ≤ 2.5 x ULN Key Exclusion Criteria• RAS or RAF mutant colorectal cancer

Drug administrationCOX: Capecitabine 850mg/m2 BID D1-D14 with oxaliplatin 130mg/m2

IV D1, Q21 days)

FOL: 5-FU 400mg/m2 IV bolus D1 and 2400mg/m2 over 46 hrs with oxaliplatin 85mg/m2 IV D1, Leucovorin 400mg/m2 IV D1, Q14 days.

VAR: 200-400mg/BID continuous.Ø VAR + chemo up to 18 weeks followed by VAR alone.

Table 1: Baseline Patient Demographics

Table 2: Dose limiting toxicities and MTD[*Transient and reversible metabolic encephalopathy]** G3 rash in patient who had immunotherapy prior to trial.

Results

Dose Pt enrolled/evaluable DLTs MTD

COX + VAR 400mg/BID 3/2 G3 Fatigue (2 pts)

COX + VAR 300mg/BID 6/6 G3 Fatigue YES

FOL + VAR 400mg/BID 4/4

G4 Transaminitis, G3 Raised Bilirubin

FOL + VAR 300mg/BID 11/10

G4 Encephalopathy*, G3 Rash** YES

FOL + VAR 200mg/BID 6/6 G3 Encephalopathy*

• Overall response rate in evaluable patients was 11% (3/28). Disease control rate(PR+SD) for ≥ 12wks was 13/28 (46%). 7 (25%) pts had PFS ≥ 24 weeks, comprising 3BTC, 2 CRC (HER2 IHC 3+; FISH+; no prior anti-EGFR rx and HER2 IHC 2+; FISH-,prior cetuximab respectively), 1 mucinous bladder and 1 carcinoma of unknown primary(see Fig. 3). All 7 cases had prior platinum exposure.

Pharmacodynamics• cfDNA: No emergent RAS/RAF/PIK3CA mutations were detected in 27 paired end of

study samples compared with baseline. Discordant RAS and RAF mutations betweentumour and cfDNA was seen in 4/27 (15%) pts. Amongst long responders (PFS ≥ 24wks), no emergent RAS/RAF/PIK3CA mutations were observed on cfDNA.

• pHER1 IHC knockdown seen in 1 CRC pt on FOL + VAR 300mg (see Fig. 4)

Adverse event (n=30) Any Grade (%) G3/4 (%)Fatigue 23 (77) 3 (10)Anorexia 18 (60) 0 (0)Diarrhoea 17 (57) 2 (7)Nausea 14 (47) 1 (3)Neuropathy 13 (43) 1 (3)Rash 10 (33) 1 (3)Vomiting 10 (33) 1 (3)Weight loss 10 (33) 0 (0)Bilirubin Rise 10 (33) 1 (3)Dyspepsia 10 (33) 1 (3)Thrombocytopenia 7 (23) 1 (3)Dysgeusia 5 (17) 0 (0)Oral Mucositis 5 (17) 0 (0)Anaemia 5 (17) 1 (3)Abdominal pain 4 (13) 0 (0)Myalgia 4 (13) 0 (0)Constipation 3 (10) 0 (0)AST elevation 3 (10) 2 (7)Encephalopathy 2 (7) 2 (7)ALT elevation 2 (7) 2 (7)Abdominal Bloating 2 (7) 0 (0)Febrile Neutropenia 2 (7) 2 (7)Paraesthesia 2 (7) 0 (0)Abdominal Colic 2 (7) 0 (0)

ConclusionsMTD was VAR 300mg BID given with FOL or COX with good tolerability and disease control ≥ 24wks seen in 7 (25%) of patients. No emergent RAS/RAF/PIK3CA mutations was detected in cfDNA. Promising activity was seen in biliary tract cancers and HER2 over-expressing colorectal cancers.

COX + VAR 400mg/BID COX + VAR 300mg/BID FOL + VAR 400mg/BIDFOL + VAR 300mg/BIDFOL + VAR 200mg/BIDOngoing study

Results

COX + VAR 400mg/BID COX + VAR 300mg/BID FOL + VAR 400mg/BIDFOL + VAR 300mg/BIDFOL + VAR 200mg/BID

Pharmacokinetics (Fig. 1)• VAR plasma levels similar with COX and FOL.• VAR plasma concentrations showed high variability with

increasing exposure with dose. There was a suggestion of VAR accumulation with repeat dosing.

CLR

CLR

BTC

CLR

ESO

CLR

CLR

CLR

BTC

BTC

NPC

BTC

CLR

CLR

BLA

CLR

CLR

Fig 4: pHER1 IHC knockdown seen baseline (a) and on treatment (b) biopsy of CRC patient on FOL + VAR 300mg

(a) (b)

• 30 pts were enrolled, 28 pts were evaluable for MTD• List of adverse events in Table 3.• MTD of VAR was 300mg BID when given with COL or FOL

Fig 3: Time on study. BTC: biliary tract, BLA: bladder, CLR: colorectal, PANC: pancreas, ESO: esophageal, BRS: breast, NPC: nasopharyngeal, CUP: Carcinoma of unknown primary

Truncating Mutation

Fig 2: Best tumour response with corresponding tumour molecular profile. NGS (tissue and cfDNA combined). NGS: Oncomine Cancer Research Panel v1, Somatic Solid Tumour Panel, Lung Colon Panel (Ion Torrent – PGM), Illumina HiSeq 4k (cfDNA)IHC: HER2 (Ventana 4B5), PTEN (Cell Signaling 138G6), CMET (Leica Novocastra 8F11). VUS not reported. See Fig.3 for glossary of abbreviated tumour types.

Amplification

Missense Mutation

No Mutation/negative

Deletion

Results not available/ Not analysed

EquivocalOverexpression

-50

0

50Best response

Max

cha

nge

in tu

mou

r si

ze c

/w b

asel

ine

(%)

#

#

# new lesion

#

FISH HER2

IHC PTEN

IHC CMET

NGS PTEN

NGS HER2

NGS MET

IHC HER2

NGS KRAS

NGS EGFR

NGS PIK3CA

This study was sponsored by National Cancer Centre Singapore and supported by the National Medical Research Council (NMRC) Singapore and ASLAN Pharmaceuticals.

Correspondence: matthew.ng.c.h@singhealth.com.sg

Table 3: Treatment related AEs in≥ 𝟓%.