223P - Tumor whole genome sequencing-based ultrasensitive ctDNA analysis as an early biomarker for clinical outcome in immune checkpoint inhibitor (ICI) phase I clinical trials (Ph1) and a tool for beyond progressive disease by iRECIST

Background

Reliable biomarkers are needed to identify which patients might benefit from ICI. Additionally, improved tools are required to manage ICI-related pseudoprogression and prevent some patients from being kept on ICI without further benefit while others are taken off treatment prematurely despite the potential for ongoing longer benefit.

Methods

We here present data on an ultrasensitive circulating tumor DNA (ctDNA) assay on >1,000 plasma samples of a cohort of >200 patients with refractory metastatic tumors from 18 different cancer types, each receiving 1-3 ICI in Ph1. Thus far, cfDNA from 135 patients has been processed using the NeXT Personal assay, a liquid biopsy platform that employs whole-genome sequencing of tumor and normal tissue to create customized, patient-specific panels, each containing up to 1,800 somatic variants.

Results

NeXT Personal assay detected positive levels of ctDNA in 99% of plasma baseline samples. Lower ctDNA values at baseline were correlated with increased duration of PFS (log-rank p=0.017, HR=0.57, 95% CI 0.36-0.91) and extended OS (log-rank p=0.002, HR=0.46, 95% CI 0.28-0.75). Early reduction in ctDNA level from baseline to treatment cycle 3 was associated with significant increases in PFS (log-rank p=0.001, HR=0.36, 95% CI 0.19-0.67) and OS (log-rank p=0.015, HR=0.44, 95% CI 0.22-0.87), representing a >3-fold increase in both median PFS and OS. ctDNA clearance resulted in significant improvement in both PFS and OS (PFS: log-rank p=0.002, HR=0.24, 95% CI 0.09-0.62; OS: log-rank p=0.01, HR=0.29, 95% CI 0.1-0.8). Changes in ctDNA levels at timepoints immediately preceding and coinciding with immune-related unconfirmed progressive disease (iuPD) correlated with either subsequent confirmed progressive disease or extended therapeutic benefit in most of these cases (12/14,86%).

Conclusions

Early ctDNA dynamics determined by ultra-sensitive assay are predictive of long-term ICI response in the advanced, pan-cancer setting. ctDNA analyses emerges as a potential clinically useful tool for dealing with the ICI-related pseudoprogression phenomena.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Personalis.

Disclosure

R.D.A. Toledo: Financial Interests, Institutional, Research Grant, Research Funding: Novartis, AstraZeneca, BeiGene Pharmaceuticals. O. Mirallas: Financial Interests, Personal, Invited Speaker: Rovi; Financial Interests, Institutional, Writing Engagement: Roche, Merck; Other, Travel Expenses: Kyowa kirin, Almirall; Other, Travel Expenses and Conference Fee: Sanofi; Other, Travel expenses: Recordati. M. Vieito: Financial Interests, Personal, Invited Speaker: Novocure; Financial Interests, Personal, Other, Steering committee member: BMS; Non-Financial Interests, Principal Investigator: Roche, BMS, Taiho, Hutchinson Pharma, Novartis, Mundipharma, Enterome, Debiopharm. I. Braña: Financial Interests, Personal, Advisory Board: Achilles Therapeutics, Bristol Myers Squibb, Cancer Expert Now, eTheRNA Immunotherapies, Merck Serono, Merck Sharp & Dohme (MSD), Rakuten Pharma, Boehringer Ingelheim, PCI Biotech, Guidepoint; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Merck Serono, Merck Sharp & Dohme (MSD), Roche; Financial Interests, Institutional, Local PI: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, GSK, Gliknik, Incyte, ISA pharmaceuticals, Janssen Oncology, Kura, Merck Serono, Debiopharm, Merck Sharp & Dohme (MSD), Nanobiotix, Novartis, Northern Biologics, Regeneron, Pfizer, Seattle Genetics, Shattuck Labs, VCN Biosciences, Roche, Immutep, MacroGenics, Sanofi, PharmaMar, Odonate Therapeutics, Bicycle Therapeutics, Dragonfly therapeutics, Gilead; Non-Financial Interests, Principal Investigator, Basket of baskets: Cancer Core Europe; Non-Financial Interests, Member, Head and Neck Group: EORTC; Non-Financial Interests, Member: SEOM, ASCO. M.J. Lostes Bardaji: Non-Financial Interests, Advisory Board: SEOM, ESMO. K.C. Keough: Financial Interests, Institutional, Full or part-time Employment: Personalis; Financial Interests, Institutional, Stocks/Shares: Personalis. F. Navarro: Financial Interests, Institutional, Full or part-time Employment: Personalis, Inc; Financial Interests, Institutional, Stocks/Shares: Personalis, Inc. P.G. Nuciforo: Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: MSD Oncology, Bayer; Financial Interests, Personal, Other, Consultant: Targos Molecular Pathology GmbH. C. Abbott: Financial Interests, Personal, Full or part-time Employment: Personalis, Inc; Financial Interests, Personal, Stocks/Shares: Personalis, Inc.. J.L. Pugh: Financial Interests, Institutional, Full or part-time Employment: Personalis, Inc; Financial Interests, Institutional, Stocks/Shares: Personalis, Inc. R. Chen: Financial Interests, Institutional, Officer, Chief Medical Officer and EVP of R&D at Personalis: Personalis; Financial Interests, Institutional, Stocks/Shares: Personalis. S. Boyle: Financial Interests, Personal, Full or part-time Employment: Personalis, Inc.; Financial Interests, Personal, Stocks/Shares: Personalis, Inc.. E. Garralda: Financial Interests, Personal, Invited Speaker: MSD, Roche, Thermo Fisher, Novartis, SeaGen; Financial Interests, Personal, Advisory Board: Roche, Ellipses Pharma, Boehringer Ingelheim, Janssen Global Services, Seattle Genetics, Thermo Fisher, MabDiscovery, Anaveon, Hengrui, F-Star Therapeutics, Sanofi, Incyte, Medscape; Financial Interests, Personal, Full or part-time Employment: NEXT Oncology; Financial Interests, Personal, Stocks/Shares: 1TRIALSP; Financial Interests, Institutional, Funding: Novartis, Roche, Thermo Fisher, AstraZeneca, Taiho; Financial Interests, Institutional, Research Grant: BeiGene, Janssen. All other authors have declared no conflicts of interest.