86O - Serial monitoring of circulating tumor DNA (ctDNA) as a tumor-agnostic biomarker to inform clinical outcomes of patients receiving experimental cancer medicine

Background

Targeted sequencing of ctDNA is a promising biomarker to inform the prognosis of patients (pts) with advanced cancer and guide experimental therapeutics in the heterogenous setting of phase I trials. Serial monitoring provides an early indication of response to experimental therapeutics.

Methods

We performed targeted next-generation sequencing of 122 serial ctDNA samples from 34 pts with advanced cancer who received experimental medicines within a phase I unit. Paired germline sequencing was performed to identify somatic-only genomic alterations (GAs). The mean variant allele fraction (mVAF) was defined as the mean sum of variants in a given sample. Early molecular reduction (EMR) was defined as a reduction in the mVAF by >50% from baseline within 1.5 months. A corresponding radiologic scan was available at each sample collection timepoint for response evaluation as per RECIST 1.1.

Results

A median of 3 (range 2-9) ctDNA samples per pt were collected as part of the TARGET profiling study. Pts were enrolled in 19 therapeutic trials spanning a broad range of mechanisms of action. ctDNA sampling guided trial matching in 14/34 (41%) pts with actionable GAs. The baseline mVAF was associated with worse progression-free survival (PFS) (HR: 1.06, 95%CI:1.01-1.12, p=0.014) and improved the performance of a predictive model of progression based on age, sex, cancer type, sites of disease, and prior lines of treatment (C-statistic improved from 0.57 to 0.65). The delta mVAF was significantly increasing in time points with radiological progression and decreasing in those with response (2.40 vs. -0.30, p= 0.015). Pts who had EMR on experimental therapies were associated with improved PFS (HR: 0.26, 95%CI: 0.10-1.00, p=0.05). In the subgroup of pts who had a ctDNA sample collected within 120 days prior to progression, the mVAF was stable or increased in 16/20 (80%) pts, with a mean lead time of 53 days preceding radiological progression.

Conclusions

Baseline ctDNA levels measured by mVAF provide valuable insights into the risk of disease progression with changes in ctDNA levels providing early indication of response or resistance to experimental therapies, indicating potential value in phase I setting.

Clinical trial identification

CPMS ID 39172.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

This research was co-funded by The Christie Charitable Fund, by Cancer Research UK (CRUK) via core-funding to the CRUK Manchester Institute (grant no. A27412, R.M.), the CRUK Manchester Centre (grant no. A25254, R.M.), the CRUK Manchester Experimental Cancer Medicines Centre (grant no. A25146, R.M.) and the NIHR Manchester Biomedical Research Centre (C.D. and M.K.). This research was supported by the NIHR Manchester Clinical Research Facility, the Manchester Academic Health Science Centre, the AstraZeneca iDECIDE Programme (grant no. 119106, C.D.) awarded to Manchester Cancer Research Centre, PCRF 2012 Project Grant (C.D.), CRUK Precision Panc grant (no. C480/A25235, C.D.), the EU IMI consortium CANCER-ID (grant no. 115749-Cancer-ID, C.D.) and Roche Products, Ltd. through the provision of the Foundation Medicine tumor profiling service.

Disclosure

A. Ortega Franco: Financial Interests, Personal, Invited Speaker, clinical case presentation: MSD. N. Cook: Financial Interests, Institutional, Advisory Board: Roche; Financial Interests, Institutional, Invited Speaker: Taiho, Roche, AstraZeneca, RedX, Orion, Avacta, Bayer, Eisai, UCB, Starpharma, Boehringer Ingelheim, Stemline; Non-Financial Interests, Personal, Advisory Role: Roche. D.M. Graham: Financial Interests, Personal, Advisory Board, Consulting role on advisory board: Clinigen; Financial Interests, Institutional, Invited Speaker, Institutional funding from study: MSD, Codiak Biosciences, Starpharma, Faron Pharmaceuticals, Synthon, Janssen, Incyte; Financial Interests, Institutional, Other, Sub-I: Institutional funding from study Research Funding: AstraZeneca; Financial Interests, Institutional, Other, Sub-I: Institutional funding from study: Roche, BerGenBio, GSK, Bayer, Bicycle pharmaceuticals, Carrick, Taiho pharmaceuticals, CytomX Therapeutics, RedX Pharma PLC, Eisai Inc, Octimet, Orion Pharma, Kinex pharmaceuticals, Boehringer Ingelheim, BMS, Turning Point Therapeutics, Immutep, Agalimmune, Kymab, Blueprint, Astellas, Cellcentric, UCB Biopharma USL, Eli Lily, Seagen, Repare therapeutics, Timepoint Therapeutics, Astex, Stemline, Crescendo Biologics Ltd., ADC Therapeutics, Genentech, Avacta Life Sciences Ltd., Nurix Therapeutics Inc; Financial Interests, Institutional, Other, Sub-I: Institutional finding from study: Chugai Pharmaceuticals; Non-Financial Interests, Institutional, Training, Training and support of research inclusivity seminar: Gilead. L. Carter: Financial Interests, Personal, Other, Consultancy: Bicycle Therapeutics, Boehringer Ingelheim, Athenex; Financial Interests, Personal, Full or part-time Employment, Medical Advisor: Cancer research UK Centre for Drug Development; Financial Interests, Institutional, Invited Speaker: Boehringer Ingelheim, Bicycle Therapeutics, Cellcentric, Eli Lily, Athenex, Lupin Limited, Repare Therapeutics, Cytomx therapeutics, EMD Serono/Merck KGaA, Sierra Oncology; Financial Interests, Institutional, Invited Speaker, Funding for delivering commercial trial activity: Genmab. C. Dive: Financial Interests, Institutional, Other, Research funding to centre: AstraZeneca, Amgen, Carrick Therapeutics, Merck AG, Bayer, Boehringer Ingelheim, BMS, Novartis, Celgene, Epigene Therapeutics Inc., Menarini; Financial Interests, Personal, Advisory Board: Merck, AstraZeneca, GRAIL, Boehringer Ingelheim, IFOM. M.G. Krebs: Financial Interests, Personal, Advisory Board: Bayer, Roche, Janssen, Guardant Health; Financial Interests, Personal, Invited Speaker: Roche, Janssen; Financial Interests, Institutional, Expert Testimony: AstraZeneca; Financial Interests, Institutional, Advisory Board: Seattle Genetics; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Blueprint, Astex, Bayer, BerGenBio, Carrick, Immutep, Janssen, Novartis, Nurix, Nuvalent, Pyramid Biosciences, Roche, Seattle Genetics, Turning Point Therapeutics; Financial Interests, Institutional, Research Grant: Roche, Novartis; Other, Personal, Other, Travel expenses for congress: Immutep, Janssen; Other, Personal, Other, Travel expenses: Roche. All other authors have declared no conflicts of interest.