85O - Low-pass whole genome sequencing (lpWGS) to quantify circulating tumor DNA (ctDNA) burden as a pharmacodynamic response biomarker in patients on early phase trials

Background

Traditionally, dose finding relies on dose-limiting toxicities and maximum tolerated dose. However, novel therapies may have a wide therapeutic index without dose-dependent toxicities. ctDNA enables early dynamic tumor assessments for potential optimal biological dosing. Quantifying ctDNA burden with lpWGS has advantages with faster turnaround, lower plasma volumes required and lower cost.

Methods

Patients (pts) on early phase trials at the National Cancer Centre Singapore had serial blood collection at pre-defined timepoints (baseline, mid-cycle 1, end cycle 1, first imaging scan). Plasma underwent lpWGS and targeted sequencing, with germline DNA from PBMC, and tissue whole exome sequencing in a subset. ctDNA burden was quantified with established (ichorCNA; DNA copy number) and novel (Fragle; cell-free DNA fragmentation patterns) bioinformatic methods. Early ctDNA kinetics (reduction as response; increase as progression) was correlated with imaging (RECIST v1.1).

Results

From 2021-23, 68 advanced cancer pts were screened. 34 pts had serial (including baseline) samples (total 102 samples, median 3, range 2-5). Pts were on targeted therapy (50%), immunotherapy (44%) or combination (6%) trials. ctDNA burden quantified by Fragle vs ichorCNA showed enhanced limit of detection, at baseline (100 vs 53%, n=34) and on-treatment (100 vs 41%, n=68). In all (100%) pts with PR, early ctDNA kinetics (via Fragle but not ichorCNA) showed ctDNA response (Table 85O) prior to imaging. Of 8 pts with SD/PD but early ctDNA response, n=4 had serial timepoints to further evaluate ctDNA kinetics. In all 4 (100%) pts, ctDNA burden subsequently increased consistent with imaging. Table: 85O

Correlation of radiologic and early ctDNA response

Conclusions

Early ctDNA kinetics may represent a pharmacodynamic biomarker for therapeutic response and biologic proof of concept, with implications for dose decision making on early phase trials.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

National Cancer Centre Singapore.

Funding

National Cancer Centre Singapore.

Disclosure

A.C. Tan: Financial Interests, Personal, Invited Speaker: Amgen, Pfizer, Bayer, AstraZeneca. T.J.Y. Tan: Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, Everest Medicines (Singapore) Pte Ltd., DKSH; Financial Interests, Personal, Invited Speaker: DKSH, AstraZeneca, Novartis, MSD; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Roche, Novartis, AstraZeneca, Daiichi Sankyo, Genentech, Sanofi; Non-Financial Interests, Personal, Member: ASCO; Other, Personal, Other, Conference sponsorship: DKSH, AstraZeneca, Novartis. P.L.S. Saw: Financial Interests, Institutional, Invited Speaker: AstraZeneca, MSD; Financial Interests, Institutional, Advisory Board: Pfizer, Bayer, AstraZeneca; Financial Interests, Institutional, Research Grant: Guardant Health, AstraZeneca; Non-Financial Interests, Personal, Principal Investigator: AstraZeneca, Novartis, BeiGene, Dracen. D.W. Lim: Financial Interests, Institutional, Invited Speaker: Boehringer Ingelheim, Novartis; Financial Interests, Institutional, Advisory Board: MSD, Roche, Beigene; Financial Interests, Institutional, Invited Speaker, Grant funding for investigator-sponsored study: Bristol Myers Squibb. M.C.H. Ng: Financial Interests, Personal, Advisory Board, Advisory board, Invited Speaker and Chairing Industry symposium,: BMS; Financial Interests, Personal, Advisory Board: AstraZeneca, Novartis; Financial Interests, Personal, Advisory Board, Advisory board, Invited speaker: MSD; Financial Interests, Personal, Invited Speaker: Taiho, DKSH; Financial Interests, Personal, Stocks/Shares: AstraZeneca, Amgen, CARsgen Therapeutics; Other, Personal, Other, Travel support: Eisai. D.S.W. Tan: Financial Interests, Personal, Advisory Board: Amgen, Novartis, Boehringer Ingelheim, C4 Therapeutics, AstraZeneca, GSK, Takeda, Eisai, Guardant, Merck, Pfizer, Roche; Financial Interests, Institutional, Research Grant: AstraZeneca, Amgen, Pfizer, ACM Biolabs; Financial Interests, Personal, Invited Speaker: Novartis. All other authors have declared no conflicts of interest.