Abstract 1384P
Background
Dickkopf-1 (DKK1) modulates Wnt signaling and contributes to an immune suppressive tumor microenvironment. DKN-01 (D), a neutralizing DKK1 antibody, in combination with an anti-PD1 antibody, has demonstrated safety and clinical activity in advanced previously treated DKK1-high GEA. We report response and survival outcomes in GEA patients (pts) treated with D + tislelizumab (T) + capecitabine/oxaliplatin (CAPOX) as a first line therapy.
Methods
We enrolled advanced GEA pts in a phase IIa study of D + T + CAPOX (NCT04363801). Tumoral DKK1 mRNA expression was assessed by a chromogenic in situ hybridization RNAscope assay and assigned an H-score (0-300). Objective response rate (ORR) [primary efficacy objective], duration of response (DoR), disease control rate (DCR), and progression free survival (PFS) were evaluated in a modified intent to treat (mITT) population (completed ≥ 1 cycle) as well as compared between DKK1 high (H-score ≥35) and low groups.
Results
Twenty-five GEA pts were enrolled. Median age was 61 (22, 80); 19 males, 6 females. 17 pts (68%) had gastroesophageal junction (GEJ) adenocarcinoma; 8 pts (32%) had gastric cancer (GC). 18 GEA pts had RNAscope DKK1 expression available; 9 pts DKK1-high [5 GEJ, 4 GC) and 9 pts DKK1-low [7 GEJ, 2 GC]. Mean duration of treatment 3 mos, longest duration to date on study 7 mos, 19 pts remain on therapy. Most common D + T + CAPOX regimen related TEAEs were G1/2: anemia, thrombocytopenia, fatigue, diarrhea, nausea each in 3 pts. No related G3/4 toxicities; overall four G5 events; 1 related event pulmonary embolism. mITT analysis included 22 pts. Preliminary ORR in response evaluable (RE) mITT was 68% (13 PR, 6 SD, 1 NE, 2 pending first scan) and DCR 100%. In RE DKK1 high pts (n=7) there was an ORR of 100% (6 PR, 1 NE) compared with DKK1 low pts (n=9) ORR of 56% (5 PR, 4 SD). Median DoR and PFS were not reached.
Conclusions
D + T + CAPOX was well tolerated and has encouraging early activity as first line treatment for advanced GEA (unselected for PD-L1), with a preliminary ORR of 68% and DCR of 100%. Higher ORR in biomarker RE population: DKK1 high compared with DKK1 low (ORR 100% vs 56%). Updated ORR, DoR, PFS and PD-L1 expression will be reported.
Clinical trial identification
NCT04363801.
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Leap Therapeutics, Inc.
Disclosure
S.J. Klempner: Financial Interests, Personal, Advisory Board, Stomach Cancer Advisory Board: Astellas; Financial Interests, Personal, Advisory Board, Stomach Cancer Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board, Stomach Cancer Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Stomach Cancer Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board, Stomach Cancer Advisory Board: Merck; Financial Interests, Personal, Advisory Board, One Time Advisory Board: Natera; Financial Interests, Personal, Advisory Board, Stomach Cancer Advisory Board: Pieris; Financial Interests, Personal, Stocks/Shares, Stock Ownership: Turning Point Therapeutics; Financial Interests, Personal and Institutional, Other, Local PI: Astellas; Non-Financial Interests, Institutional, Principal Investigator, Coordinating PI: Leap Therapeutics; Non-Financial Interests, Institutional, Other, Local PI: Macrogenics; Non-Financial Interests, Personal, Advisory Role, Medical Scientific Advisory Board Member: Debbies Dream Foundation; Non-Financial Interests, Personal, Advisory Role, Member of Scientific Advisory Board: Hope for Stomach Cancer; Non-Financial Interests, Personal, Other, Member of Gastric and Esophageal NCCN guideline committees: NCCN. C. Sirard: Financial Interests, Personal, Full or part-time Employment: Leap Therapeutics, Inc. J. Chao: Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: Astellas; Financial Interests, Personal, Other, consulting: AstraZeneca; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Other, consulting: Lilly; Financial Interests, Personal, Advisory Board: Macrogenics; Financial Interests, Personal, Invited Speaker: Merck; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Other, consulting: Ono Pharmaceuticals; Financial Interests, Personal, Other, consulting: Roche; Financial Interests, Personal, Advisory Board: Turning Point Therapeutics; Financial Interests, Institutional, Funding, Financial interest: Brooklyn Immunotherapeutics; Financial Interests, Institutional, Other, Financial interest: Merck. V. Chiu: Financial Interests, Institutional, Other, Local PI: Seattle Genetics/Astellas; Financial Interests, Institutional, Other, Local PI: Arcus Biosciences; Financial Interests, Institutional, Other, Local PI: Leap Therapeutics; Financial Interests, Institutional, Other, Local PI: Intra-IMMUSG Pte Ltd; Financial Interests, Institutional, Other, Local PI: Alkermes; Financial Interests, Institutional, Other, Local PI: Incyte. D. Mahalingam: Financial Interests, Personal, Speaker’s Bureau: Amgen; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Speaker’s Bureau: Eisai; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Speaker’s Bureau: Exelixis; Financial Interests, Personal, Advisory Board: Exelixis; Financial Interests, Personal, Speaker’s Bureau: BMS; Financial Interests, Personal, Advisory Board: BMS. H. Uronis: Financial Interests, Institutional, Other, Local PI: Merck; Financial Interests, Institutional, Other, Local PI: Macrogenics; Financial Interests, Institutional, Other, Local PI: BMS; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Institutional, Other, Local PI: Leap Therapeutics; Financial Interests, Personal, Other, Consultant- DSMB: AstraZeneca; Financial Interests, Institutional, Other, Local PI: Genetech. M. Kagey: Financial Interests, Personal, Full or part-time Employment: Leap Therapeutics, Inc. J. Baum: Financial Interests, Personal, Full or part-time Employment: Leap Therapeutics, Inc. F. Dayyani: Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: Deciphera; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Invited Speaker: Exelixis; Financial Interests, Personal, Advisory Board: Exelixis; Financial Interests, Personal, Advisory Board: FMI; Financial Interests, Personal, Invited Speaker: Ipsen; Financial Interests, Personal, Advisory Board: QED; Financial Interests, Personal, Invited Speaker: Signatera; Financial Interests, Personal, Advisory Board: Signatera; Financial Interests, Personal, Invited Speaker: Sirtex; Non-Financial Interests, Institutional, Other, Local PI: AstraZeneca; Non-Financial Interests, Institutional, Other, Local PI: Bayer; Non-Financial Interests, Institutional, Other, Local PI: BMS; Non-Financial Interests, Institutional, Other, Coordinating PI: Exelixis; Non-Financial Interests, Institutional, Other, Local PI: Ipsen; Non-Financial Interests, Institutional, Other, Local PI: Merck; Non-Financial Interests, Institutional, Other, Local PI: Roche; Non-Financial Interests, Institutional, Other, Coordinating PI: Signatera; Non-Financial Interests, Institutional, Other, Coordiating PI: Taiho; Non-Financial Interests, Institutional, Other, Local PI: Tishula. J. Song: Financial Interests, Personal, Full or part-time Employment: BeiGene, Ltd. J. Wang: Financial Interests, Personal, Full or part-time Employment: BeiGene, Ltd. S. Iqbal: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Speaker series to faculty on esophageal cancer: BeiGene; Financial Interests, Personal, Advisory Board: Eisai. A.J. Scott: Financial Interests, Personal, Invited Speaker: ACCC; Financial Interests, Personal, Advisory Board: Exelixis; Financial Interests, Personal, Advisory Board: QED; Financial Interests, Personal, Stocks/Shares: Johnson and Johnson; Financial Interests, Personal, Other, Local PI: Eli Lilly; Financial Interests, Personal, Other, Local PI: Incyte; Financial Interests, Personal, Other, Local PI: Leap Therapeutics; Financial Interests, Personal, Other, Local PI: Macrogenics; Financial Interests, Personal and Institutional, Other, Local PI: Merck; Financial Interests, Personal, Other, Local PI: Seagen. Z. Wainberg: Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Daiichi; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Ipsen; Financial Interests, Personal, Advisory Board: Five Prime; Financial Interests, Personal, Advisory Board: Gilead; Financial Interests, Personal, Advisory Board: Arcus; Financial Interests, Personal, Advisory Board: Astellas; Financial Interests, Personal, Advisory Board: Molecular Templates; Financial Interests, Personal, Advisory Board: Array; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Daiichi; Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Ipsen; Financial Interests, Institutional, Research Grant: Five Prime; Financial Interests, Institutional, Research Grant: Gilead; Financial Interests, Institutional, Research Grant: Arcus; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Research Grant: Molecular Therapeutics; Financial Interests, Institutional, Research Grant: Roche/Genentech; Financial Interests, Institutional, Research Grant: Array/Pfizer. J.A. Ajani: Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Astellas; Financial Interests, Personal, Advisory Role: Taiho; Financial Interests, Personal, Advisory Role: More Health; Financial Interests, Personal, Advisory Role: Zymeworks; Financial Interests, Personal, Advisory Role: BeiGene; Financial Interests, Personal, Advisory Role: Dava; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Acrotech; Financial Interests, Personal, Advisory Role: Daiichi; Financial Interests, Personal, Advisory Role: Vaccinogen; Financial Interests, Personal, Advisory Role: Innocent; Financial Interests, Personal, Advisory Role: Merck Serrono; Financial Interests, Personal, Advisory Role: Oncotherics; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: OncLive; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: Turning Point; Financial Interests, Personal, Advisory Role: GRAIL; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Research Grant: Taiho; Financial Interests, Institutional, Research Grant: Delta Fly; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Prolinix; Financial Interests, Institutional, Research Grant: Zymeworks; Financial Interests, Institutional, Research Grant: Daiichi; Financial Interests, Institutional, Research Grant: Leap; Financial Interests, Institutional, Research Grant: Gilead. All other authors have declared no conflicts of interest.