Abstract 1253P
Background
Immune checkpoint inhibitor (ICI) monotherapy has limited efficacy in patients (pts) with mismatch repair proficient (MMRp) oesophagogastric adenocarcinoma (OGA). Dickkopf-1 (DKK1) modulates Wnt/β-Catenin signaling and promotes a T-cell excluded or ‘immune desert’ tumour microenvironment (TME). DKN-01, a DKK1 neutralising antibody, can favourably reprogram the TME by reducing levels of myeloid-derived suppressor cells (MDSCs) and increasing entry of effector T-cells and may improve responses when added to ICI monotherapy.
Methods
This phase IIa study (3+3 design) evaluated the safety and efficacy of DKN-01 (300mg/600mg) and atezolizumab (840mg) given intravenously q2W in pts with pre-treated, anti PD1/PDL1 naïve, MMRp advanced OGA. The primary endpoint was to establish the safety, tolerability, and recommended phase II dose (RP2D) for the efficacy phase. Safety, efficacy, and translational analyses (including intratumoural DKK1/PD-L1, peripheral MDSC and NK cell populations, TCR diversity analysis, tumour genomics and stool microbiome) are ongoing.
Results
Eleven pts were treated on study (5 pts at DKN-01 300mg, 6 at 600mg). Eight pts completed the DLT period (3 at 300mg, 5 at 600mg) and were therefore evaluated for the safety endpoint. No dose limiting toxicities were observed. Of the 11 treated pts, 10 (90.9%) experienced at least one treatment-related AE (TRAE). The most common TRAEs (experienced by ≥ 2 pts) were fatigue (36%), anaemia (18%), hypothyroidism (18%), diarrhoea (18%) and pain (18%). One pt experienced G3 urticaria and 1 experienced an SAE of G2 pneumonitis, both were treatment related. Of the 8 pts evaluated for the safety endpoint, 1 pt (12.5%) had PR and 4 pts (50%) had SD as their best response. No clear trend between peripheral MDSC levels at baseline and during treatment have yet been observed. Additional biomarker work is ongoing.
Conclusions
DKN-01 plus atezolizumab has a manageable safety profile with no new safety signals in pts with advanced OGA. DKN-01 600mg plus atezolizumab 840mg q2W was the RP2D taken through to the ongoing expansion phase to confirm efficacy.
Clinical trial identification
NCT04166721.
Editorial acknowledgement
Legal entity responsible for the study
The Royal Marsden Hospital.
Funding
WAKING was collaboratively supported by the imCORE network on behalf of F. Hoffmann-La Roche.
Disclosure
E. Smyth: Financial Interests, Personal, Invited Speaker: Amgen, Bristol-Myers Squibb, Imedex, Merck, Novartis, Prova Education, Servier, TouchIME; Financial Interests, Personal, Other, TSC: Amgen; Financial Interests, Personal, Advisory Board: Astellas, AstraZeneca, Bristol-Myers Squibb, My Personal Therapeutics, Novartis, Roche, Servier, Zymeworks; Financial Interests, Personal, Other, IDMC: Beigene, Zymeworks; Financial Interests, Personal, Expert Testimony: Bristol-Myers Squibb; Financial Interests, Personal, Other, IDMC chair: Everest Clinical Research; Financial Interests, Personal, Officer: EORTC GI Clinical Trials Group; Financial Interests, Institutional, Invited Speaker: Daiichi Sankyo, Roche, AstraZeneca, Merus, Basilea, MSD; Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb. S. Rao: Financial Interests, Personal, Advisory Board: Hoopika, Bayer; Financial Interests, Personal, Expert Testimony: Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Merck Serono; Non-Financial Interests, Principal Investigator, Chief investigator phase II and III trials: Incyte. I. Chau: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Eli-Lilly, MSD, Roche, Merck-Serono, AstraZeneca, OncXerna, Pierre Fabre, Boehinger Ingelheim, Astella, Incyte, GSK, Sotio, Daiichi-Sankyo, Eisai; Financial Interests, Personal, Other, DMC chairman: Five Prime Therapeutics; Financial Interests, Personal, Invited Speaker: Eisai, Eli-Lilly, Servier; Financial Interests, Institutional, Invited Speaker: Cilag-Janssen, Eli-Lilly. N. Starling: Financial Interests, Personal, Advisory Board: GSK, Novartis, MSD Oncology, Servier, AstraZeneca, Pfizer; Financial Interests, Personal, Invited Speaker: Clinical Options, Eli Lilly, Pierre Fabre, Amgen, Merck Serono; Financial Interests, Institutional, Research Grant, Sept 2017 (24m) Paid to institution research: Merck; Financial Interests, Institutional, Research Grant, Nov 2017 (48m) -Paid to institution research fund: AstraZeneca; Financial Interests, Institutional, Research Grant, Jan 2018 - Paid to institution research fund: Pfizer; Financial Interests, Institutional, Research Grant, July 2018 (36m) Paid to institution research fund: BMS. D. Cunningham: Financial Interests, Institutional, Research Grant: MedImmune/AZ, Clovis, Eli Lilly, 4SC, Bayer, Celgene, Leap, Roche; Non-Financial Interests, Advisory Role: OVIBIO. All other authors have declared no conflicts of interest.