Abstract 1213P
Background
Despite recent approval of anti-PD-1 antibodies as 1L therapy in advanced GEA, benefit is largely limited to PD-L1 combined positive scores (CPS) ≥5 patients (pts); novel therapeutic approaches are needed. DKN-01 is a targeted anti-DKK1 mAb which has demonstrated activity in GEA pts with elevated tumoral DKK1 expression, a subset of pts with more aggressive disease and shorter overall survival.
Methods
Phase IIa single arm trial investigating DKN-01 300 mg (D) + tislelizumab (TS) + CAPOX as 1L therapy in advanced HER2(-) GEA regardless of DKK1 status. Tumoral DKK1 mRNA expression was assessed by a chromogenic in situ hybridization RNAscope assay and assigned an H-score (0-300). Primary endpoint was ORR in modified intent to treat (mITT) population (>1 dose D); secondary endpoints included PFS and OS in intent to treat (ITT) population overall and by DKK1 expression: high (H-score ≥35) vs low.
Results
25 pts enrolled (01 Sept 2020 - 08 Apr 2021). Median age 61 years (22, 80); 17 pts gastroesophageal junction adenocarcinoma; 8 pts gastric cancer. 21 GEA pts had RNAscope DKK1 expression; 57% were DKK1-high. 22 of 25 pts had vCPS: 73% were vCPS <5. Median duration of treatment 11.3 mos. 7 pts on therapy and only 9 of 25 pts have died. 12 mo survival: 76%. 14 pts (56%) experienced D-TRAEs (treatment related adverse events), most (96%) were G1/2. Most common regimen TRAEs were nausea (72%), fatigue (64%), and diarrhoea (56%). 5 pts experienced ≥G3 D-TRAEs: hypophosphatemia (2), pulmonary embolism (2, one regimen related G5), neutropenia (1), diarrhoea (1). Table: 1213P
| ORR mITT*, n=22 (n,%) | Median DoR, mos (n=15)* | Median PFS, mos, ITT (n=25) | |||||
| CR | PR | SD | NE | ||||
| Overall | 15 (68) | 1 (5) | 14 (64) | 6 (27) | 1 (5) | 10.0 | 11.3 |
| DKK1 high, n=10 | 9 (90) | - | 9 (90) | - | 1 (10) | 10.6 | 11.6 |
| DKK1 low, n=9 | 5 (56) | 1 (11) | 4 (44) | 4 (44) | - | 10.6 | 12.0 |
| DKK1 unk, n=3 | 1 (33) | - | 1(33) | 2 (67) | - | 7.0 | 8.4 |
*4 responders ongoing (2 high, 2 low)
Conclusions
D/TS + CAPOX is a well-tolerated, active 1L combination, including in DKK1-high and CPS low patients, aggressive subpopulations of GEA. With only 36% of pts deceased as of the data cut, OS is not mature. Further study with DKN-01 plus standard of care therapy in IL GEA is warranted.
Clinical trial identification
NCT04363801.
Editorial acknowledgement
Legal entity responsible for the study
Leap Therapeutics, Inc.
Funding
Leap Therapeutics, Inc.
Disclosure
S.J. Klempner: Financial Interests, Personal, Advisory Board, Stomach Cancer Advisory Board: Eli Lilly, Merck, Bristol Myers Squibb, Astellas, Daiichi Sankyo, Pieris; Financial Interests, Personal, Advisory Board, One Time Advisory Board: Natera; Financial Interests, Personal, Advisory Board, Stomach cancer advisory board x 1: Mersana, Sanofi-Aventis; Financial Interests, Personal, Stocks/Shares, Stock Ownership: Turning Point Therapeutics; Financial Interests, Personal, Stocks/Shares, Early investor, company is not public: MBrace; Financial Interests, Institutional, Invited Speaker, National PI for trial: Leap Therapeutics; Financial Interests, Personal and Institutional, Invited Speaker, Local PI for trial, also served on advisory board as noted above: Astellas; Financial Interests, Institutional, Invited Speaker: Macrogenics; Financial Interests, Institutional, Invited Speaker, Trial PI: Silverback; Non-Financial Interests, Advisory Role, Medical-Scientific Advisory Board Member: Debbies Dream Foundation; Non-Financial Interests, Advisory Role, Member of Scientific Advisory Board: Hope for Stomach Cancer; Non-Financial Interests, Other, Member of Gastric and Esophageal NCCN Guideline Committees: NCCN. J. Chao: Financial Interests, Personal, Advisory Board: Merck, Amgen, Daiichi Sankyo, Macrogenics, Bristol Myers Squibb, Astellas, Turning Point Therapeutics; Financial Interests, Personal, Invited Speaker: Merck, Bristol Myers Squibb; Financial Interests, Personal, Other, Consulting: Lilly, AstraZeneca, Ono Pharmaceuticals, Roche; Financial Interests, Institutional, Funding: Merck, Brooklyn Immunotherapeutics. H. Uronis: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Other, DSMB: Astra Zeneca; Financial Interests, Institutional, Invited Speaker: Merck, Leap Therapeutics, Bristol-Myers Squibb, Merrimack Pharmaceuticals. C. Sirard: Financial Interests, Personal, Full or part-time Employment, Chief Medical Officer: Leap Therapeutics, Inc.; Financial Interests, Personal, Stocks/Shares, Full time employee/Chief Medical Officer: Leap Therapeutics, Inc.; Financial Interests, Personal, Other, Pending and issued patents with DKN-01: Leap Therapeutics, Inc.. M. Kagey: Financial Interests, Personal, Full or part-time Employment, Full time employee: Leap Therapeutics; Financial Interests, Personal, Stocks/Shares, Stock option holder: Leap Therapeutics. J. Baum: Financial Interests, Personal, Full or part-time Employment: Leap Therapeutics; Financial Interests, Personal, Stocks/Shares: Leap Therapeutics. J. Song: Financial Interests, Personal, Full or part-time Employment: BeiGene; Financial Interests, Personal, Stocks/Shares: BeiGene. J. Wang: Financial Interests, Personal, Full or part-time Employment: BeiGene; Financial Interests, Personal, Stocks/Shares: BeiGene. M.B. Sonbol: Financial Interests, Institutional, Research Grant, Research support to institution supporting ACCRU 1810 study: Taiho, Eli Lilly. Z.A. Wainberg: Financial Interests, Personal, Advisory Role: Amgen, Astra Zeneca, Daiichi, Bayer, BMS, Merck, Ipsen, Five Prime, Gilead, Arcus, Astellas, Molecular Templates, Array; Financial Interests, Institutional, Research Grant: Amgen, Astra Zeneca, Daiichi, Bayer, BMS, Merck, Ipsen, Five Prime, Gilead, Arcus, Astellas, Molecular Templates, Roche/Genentech, Array/Pfizer. J.A. Ajani: Financial Interests, Personal, Advisory Role: BMS, Merck, Taiho, AZ, Daiichi, Novartis, Amgen, Gilead, Astellas, Zymeworks, Beigene, Innovent, OncLive, Geneos, Arcus, Servier, Grail; Financial Interests, Institutional, Funding: Leap Therapeutics, BMS, Astellas, Amgen, Taiho, DeltaFly, Zymeworks, Prolinx, Gilead, Daiichi, LaNova, Macrogenics ; Non-Financial Interests, Member: ASCO; Non-Financial Interests, Other: NCCN.