Abstract 26P
Background
The PEGASUS trial (NCT04259944) demonstrated that circulating tumor DNA (ctDNA, LB) and ctDNA dynamics can detect postsurgical minimal residual disease (MRD) and may be a surrogate of tumor response to adjuvant therapy (ACT) aimed at guiding post-surgical treatment of stages II-T4/III colon cancer (CC) patients. No data are available on the potential of patient-derived models [xenografts (PDXs) and organoids (PDOs)] to predict ctDNA dynamics after ACT in LB-positive patients.
Methods
PEGASUS is piggybacked to the AlfaOmega Master Observational Trial (NCT04120935) for PDO/PDX derivation. We used Guardant REVEALTM assay (v L1.2) to detect ctDNA at 3-4 weeks post-surgery (LB1), after ACT with CAPOX [capecitabine, oxaliplatin (OXA)] (LB2) and post-molecular metastatic treatment with FOLFIRI [5-fluorouracil (5FU), irinotecan (IRI)] or capecitabine (LB3). In PEGASUS, 35 patients were LB1-positive and received CAPOX and 24 of them received FOLFIRI (LB2-positive). We generated avatars in 8/35 (23%) LB1-positive patients (5 PDXs, 3 PDOs, 1 matched). Avatars were treated with 5FU, OXA and SN38 (PDOs) or IRI (PDXs) to prove whether ex vivo/in vivo treatments could recapitulate the MRD dynamics based on ctDNA evaluation. Response was measured as viability rate over fold control (PDOs) or tumor volume changes compared to baseline (pretreatment) measurements (PDXs).
Results
Response in avatars recapitulated ‘MRD response’ (i.e. the undetectable/detectable ctDNA after treatment) of matched patients in 87% of cases [95% CL = 0.47-0.99, 7/8 cases). Concordance to either OXA or IRI was respectively 100% and 75% of responding and resistant matched patients/avatars (N 4 each) and occurred also in the only case with both avatars.
Conclusions
Objective changes in avatar tumor growth were mostly consistent with the monitored ctDNA dynamics in matched patients. Avatars models appear to be a faithful proxy of the ‘MRD response’ to LB-guided adjuvant treatment in CC patients and can be confidently used to unveil mechanistic and functional insights into OXA/IRI resistance mechanisms.
Clinical trial identification
NCT04259944; EudraCT 2019-002074-32.
Legal entity responsible for the study
IFOM ETS - The AIRC Institute of Molecular Oncology, Milan, Italy.
Funding
AIRC under 5 per Mille 2018-ID. 21091 programme - P.I.Bardelli Alberto (AB), G.L. Silvia Marsoni (SM), G.L. Salvatore Siena (SS).
Disclosure
G. Mauri: Financial Interests, Personal, Other, Honoraria: COR2ED. J. Vidal Barrull: Financial Interests, Personal, Invited Speaker: Merck Serono, Amgen, Pierre Fabre, Novartis; Financial Interests, Personal, Advisory Board: Merck Serono, Amgen, BMS. A. Sartore Bianchi: Financial Interests, Personal, Advisory Board: Amgen, Bayer, Pierre Fabre, Servier, Takeda. M. Mandalà: Financial Interests, Personal, Research Grant: Novartis; Financial Interests, Personal, Advisory Board: MSD, BMS, Novartis, Pierre Fabre, Sanofi, Sun Pharma. S. Ghezzi: Financial Interests, Personal, Other, Engagement with AstraZeneca in regards GI Study Coordinator Panel: AstraZeneca. S. Lonardi: Financial Interests, Institutional, Funding, Research funding: Amgen, Merck Serono, Bayer, Roche, Eli Lilly, AstraZeneca, Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker, Honoraria: Roche, Eli Lilly, Bristol Myers Squibb, Servier, Merck Serono, Pierre Fabre, GSK, Amgen; Financial Interests, Personal, Advisory Board: Amgen, Astellas, Bayer, Merck Serono, Eli Lilly, AstraZeneca, Incyte, Daiichi Sankyo, Bristol Myers Squibb, Servier, Merck Sharp & Dohme, GSK, Takeda. A. Bardelli: Financial Interests, Personal, Research Grant: Neophore, AstraZeneca, Boehringer Ingelheim; Financial Interests, Personal, Other, Honoraria, Consultant fees: Guardant Health, Inivata; Financial Interests, Personal, Stocks/Shares, Stock shareholder: Neophore, Kither Biotech; Financial Interests, Personal, Advisory Board: Inivata, Neophore, Roche/Genentech. S. Siena: Financial Interests, Personal, Advisory Board: Agenus, AstraZeneca, Bayer, Bristol Myers Squibb, CheckmAb, Daiichi Sankyo, Guardant Health, Merck, Novartis, Roche-Genentech, Seagen, GSK, MSD, Pierre Fabre, T-One Therapeutics. L. Trusolino: Financial Interests, Personal, Research Grant: Menarini, Merck KGaA, Merus, Pfizer, Servier, Symphogen. All other authors have declared no conflicts of interest.