LBA9 - Clinical insights from ultra-sensitive tumour-informed ctDNA tracking across the TRACERx cohort

Background

Clinical adoption of sensitive and specific circulating tumor DNA (ctDNA) detection assays has the potential to revolutionize patient care. The limited sensitivity of current assays restricts the pre-operative and post-operative prognostic value of ctDNA. Here, we analyse post-operative ctDNA from a completed cohort of patients with non-small cell lung cancer (NSCLC) from the TRACERx study.

Methods

Plasma was collected prior to surgical resection, during adjuvant chemotherapy, follow-up, relapse, and in late-stage disease. ctDNA was profiled using NeXT PersonalTM, an ultrasensitive tumour-informed assay that tracks up to 1,800 tumour-specific variants to attain 1-3 parts per million (PPM) sensitivity.

Results

3005 plasma samples from 432 patients in the TRACERx cohort were analysed. The sensitivity of ‘landmark’ ctDNA detection (10-120 days following surgical resection) for clinical relapse was 61%. 94% of non-relapsing patients were landmark negative. The median follow-up for non-relapsing patients was 1826 days. Low-level ctDNA detections below 80 PPM (the 95% limit of detection of a previously published approach in TRACERx) were observed in 42% of the landmark positive patients, and significantly correlated with intermediate survival relative to landmark negative and higher landmark ctDNA burden (<80PPM vs. negative: adjusted HR for OS: 3.7, DFS: 3.6; <80PPM vs. >=80PPM: OS: 0.3, DFS: 0.3, all p<0.001). ctDNA clearance during adjuvant chemotherapy was associated with good clinical outcome, whilst ctDNA positivity in longitudinal plasma was predictive of poor outcome (adjusted HR for OS 18.8, 95%CI 9.6 to 36.7, p<0.001).

Conclusions

We explored ultra-sensitive ctDNA detection in the largest cohort of relapsing NSCLC patients published to date, including its use for patient stratification and early detection of disease relapse. We observed that landmark positivity and ctDNA clearance were prognostic of patient outcome, including below 80 PPM. These results have implications for the advancement of personalised treatment strategies for NSCLC patients.

Clinical trial identification

NCT01888601.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

CRUK, Personalis Inc.

Disclosure

C. Abbott: Financial Interests, Personal, Full or part-time Employment: Personalis, Inc; Financial Interests, Personal, Stocks/Shares: Personalis, Inc.. S. Boyle: Financial Interests, Personal, Full or part-time Employment: Personalis, Inc.; Financial Interests, Personal, Stocks/Shares: Personalis, Inc.. B. Li: Financial Interests, Personal, Full or part-time Employment: Personalis; Financial Interests, Personal, Stocks/Shares: Personalis. M. Al Bakir: Financial Interests, Personal, Speaker, Consultant, Advisor: Achilles Therapeutics. M. Jamal-Hanjani: Financial Interests, Personal, Invited Speaker, Invited speaker honorarium: Oslo Cancer Cluster, Astex Pharmaceutical; Financial Interests, Personal, Invited Speaker, Speaker honorarium: Pfizer, Bristol Myers Squibb; Financial Interests, Personal, Advisory Board, Cancer cachexia research advisory board: Pfizer; Non-Financial Interests, Advisory Role, Scientific Advisory Board and Steering Committee member: Achilles Therapeutics; Other, I am named as co-inventor on patent PCT/US2017/028013 relating to methods for lung cancer detection: Patent. N. McGranahan: Financial Interests, Institutional, Stocks/Shares: Achilles Therapeutics. R. Chen: Financial Interests, Full or part-time Employment: Personalis Inc.; Financial Interests, Stocks/Shares: Personalis Inc.. C. Swanton: Financial Interests, Personal, Invited Speaker, Activity took place in 2016: Pfizer, Celgene; Financial Interests, Personal, Invited Speaker, October 26th 2020: Novartis; Financial Interests, Personal, Invited Speaker: Roche/Ventana, BMS, AstraZeneca, MSD, Illumina, GSK; Financial Interests, Personal, Advisory Board, AdBoard - November 12th, 2020: Amgen; Financial Interests, Personal, Advisory Board, Current - since 2018: Genentech; Financial Interests, Personal, Advisory Board: Sarah Canon Research Institute; Financial Interests, Personal, Advisory Board, Joined October 2020. Also have stock options: Bicycle Therapeutics; Financial Interests, Personal, Other, Consultancy: Medicxi; Financial Interests, Personal, Advisory Board, Member of the Science Advisory Board. Also had stock options until June 2021: GRAIL; Financial Interests, Personal, Other, Consultancy agreement: Roche Innovation Centre Shanghai; Financial Interests, Personal, Advisory Board, 29 November - 1 December 2022: Novartis; Financial Interests, Personal, Invited Speaker, Oncology Collective - 2nd Nov - 4 Nov 2022 - Atlanta, USA: Roche; Financial Interests, Personal, Advisory Board, ctDNA advisory Board - 24th March 2023: AstraZeneca; Financial Interests, Personal, Invited Speaker, Pfizer Oncology 'Leading the revolution for the future: Pfizer; Financial Interests, Personal, Advisory Board, Scientific Advisory Board and Stock options from September 2023: Relay Therapeutics; Financial Interests, Personal, Advisory Board, Member of the Scientific Advisory Board: SAGA Diagnostics; Financial Interests, Personal, Full or part-time Employment, Chief Clinician since October 2017: Cancer Research UK; Financial Interests, Personal, Ownership Interest, Co-Founder of Achilles Therapeutics. Also, have stock options in this company: Achilles Therapeutics; Financial Interests, Personal, Stocks/Shares, Stocks owned until June 2021: GRAIL, Apogen Biotechnologies; Financial Interests, Personal, Stocks/Shares: Epic Biosciences, Bicycle Therapeutics; Financial Interests, Personal, Stocks/Shares, Stock options: Relay Therapeutics; Financial Interests, Institutional, Research Grant, Funded RUBICON grant - October 2018 - April 2021: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant, Collaboration in minimal residual disease sequencing technologies: Archer Dx Inc; Financial Interests, Institutional, Research Grant: Pfizer, Boehringer Ingelheim; Financial Interests, Institutional, Trial Chair, Chief Investigator for the MeRmaiD 1and 2 clinical trials and chair of the steering committee: AstraZeneca; Financial Interests, Institutional, Research Grant, Research grant from Oct 2019 - July 2023 - Genetics of CIN and SCNAs for Targeted Discovery (SCEPTRE): Ono Pharmaceutical; Financial Interests, Institutional, Research Grant, Research Grants from 2015: Roche; Financial Interests, Personal, Other, Co-chief investigator: NHS-Galleri Clinical Trial; Financial Interests, Institutional, Research Grant, from October 2022: Personalis; Non-Financial Interests, Principal Investigator, Chief Investigator for MeRmaiD 1and 2 clinical trials: AstraZeneca; Non-Financial Interests, Member of Board of Directors, From 2019-2022: AACR; Non-Financial Interests, Other, Board of Directors: AACR; Non-Financial Interests, Advisory Role, EACR Advisory Council member: EACR. All other authors have declared no conflicts of interest.