Meeting
2021 ASCO Annual Meeting
Predictive value of germline ATM mutations in the CCTG PA.7 trial: Gemcitabine (GEM) and nab-paclitaxel (Nab-P) versus GEM, nab-P, durvalumab (D) and tremelimumab (T) as first-line therapy in metastatic pancreatic ductal adenocarcinoma (mPDAC).
Authors
Daniel John Renouf
BC Cancer Agency, Vancouver, BC, Canada
Daniel John Renouf , Jonathan M. Loree , Jennifer J. Knox , Petr Kavan , Derek J. Jonker , Stephen Welch , Felix Couture , Frederic Lemay , Mustapha Tehfe , Mohammed Harb , Nathalie Aucoin , Yoo-Joung Ko , Patricia A. Tang , James T. Topham , Shidong Jia , Pan Du , David F. Schaeffer , Sharlene Gill , Dongsheng Tu , Christopher J. O'Callaghan
Organizations
BC Cancer Agency, Vancouver, BC, Canada, BC Cancer, Vancouver, BC, Canada, Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada, McGill University, Montréal, QC, Canada, Ottawa Hospital Research Institute, Ottawa, ON, Canada, London Regional Cancer Program, London, ON, Canada, Centre Hospitalier Universitaire de Québec, Quebec City, QC, Canada, Centre Hospitalier Universitaire de Sherbrooke (CHUS), Sherbrooke, QC, Canada, Centre Hospitalier de l'Université de Montréal (CHUM), Montréal, QC, Canada, Moncton Hospital, Moncton, NB, Canada, Hôpital Cité de la Santé de Laval, Laval, QC, Canada, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada, Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada, Genome Sciences Center, Vancouver, BC, Canada, Predicine, Inc., Hayward, CA, Predicine, Inc, Hayward, CA, Department of Pathology & Laboratory Medicine Vancouver General Hospital, Vancouver, BC, Canada, Queen's University, Canadian Cancer Trials Group, Kingston, ON, Canada
Research Funding
Other
Canadian Cancer Trials Group (CCTG), Pharmaceutical/Biotech Company
Background: PA.7 evaluated whether combining PD-L1 and CTLA-4 inhibition with GEM and Nab-P increases efficacy. A previous analysis of the PA.7 data demonstrated high plasma based TMB (≥9 mut/Mb) was associated with improved OS in the Gem, Nab-P, D+T arm. DNA repair pathway aberrations beyond mismatch repair have been associated with potential immune sensitivity. We assessed the predictive value of germline ATM mutations in the PA.7 trial. Methods: This randomized phase II study (ClinicalTrials.gov NCT02879318) assessed the efficacy and safety of GEM, Nab-P, D, and T (arm A) vs. GEM and Nab-P (arm B) in patients (pts) with mPDAC (n = 180). The primary endpoint was overall survival (OS). Pre-treatment plasma was sequenced with the Predicine ATLAS next generation assay (600 gene, 2.4 Mb panel). 2-sided alpha set at 0.1. Results: 180 pts were randomized (119 to arm A and 61 to arm B) There was no significant difference in OS (9.8 months in arm A vs. 8.8 months in arm B, p-value 0.72) or PFS (5.5 months and 5.4 months respectively, HR 0.98, p-value 0.91). Plasma analysis was performed on 174/180 pts with available samples. 16/174 (9.2%) pts had germline ATM mutations, 12 in arm A and 4 in arm B. GEM, Nab-P, D+T was associated with improved OS in patients with ATM mutations (HR 0.10, 90% CI 0.03-0.37; median OS 13.9 months vs. 4.9 months) while no activity was seen in pts with ATM Wild Type (HR 0.99, 90% CI 0.73-1.33; median OS 9.79 months vs. 10.2 months); interaction p = 0.014. Germline ATM mutation status was independent of plasma TMB levels (Wilcoxon p = 0.76). Conclusions: Germline ATM mutation appeared predictive of benefit from the addition of dual immune checkpoint inhibitors (D and T) to Gem and Nab-P, with a significant interaction p-value. In addition to previous data from this trial regarding the predictive value of high plasma TMB (≥9 mut/Mb), this data further supports that there may be independent subgroups of PDAC, beyond MSI-H, that may benefit from immunotherapy, and trials evaluating immunotherapy in subgroups of PDAC with these profiles are warranted. Clinical trial information: NCT02879318
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Abstract Details
Session Type
Poster Session
Session Title
Gastrointestinal Cancer—Gastroesophageal, Pancreatic, and Hepatobiliary
Track
Gastrointestinal Cancer—Gastroesophageal, Pancreatic, and Hepatobiliary
Sub Track
Pancreatic Cancer
Clinical Trial Registration Number
NCT02879318
Citation
J Clin Oncol 39, 2021 (suppl 15; abstr 4135)
DOI
10.1200/JCO.2021.39.15_suppl.4135
Abstract #
4135
Poster Bd #
Online Only
Abstract Disclosures
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