LBA55 - An ultra-sensitive and specific ctDNA assay provides novel pre-operative disease stratification in early stage lung cancer

Background

Circulating tumour DNA (ctDNA) detection has significant promise to inform patient care to predict clinical risk in early-stage tumours, optimise personalised adjuvant treatment regimens, and monitor for relapse in the minimal residual disease (MRD) setting. However, clinical applications, especially in low-shedding tumours such as lung adenocarcinomas (LUADs), are constrained by the limited sensitivity of clinically validated ctDNA detection approaches.

Methods

We developed NeXT Personal, a whole genome based, tumour-informed platform for ultra-sensitive ctDNA detection, and analytically validated detection thresholds consistently within 1-3 parts per million (PPM) of ctDNA with >99.95% specificity. We analysed pre-operative plasma samples from an interim cohort of 171 patients with early stage lung cancer from the TRACERx study.

Results

ctDNA was detected pre-operatively in 81% of patients with lung adenocarcinomas (LUADs), including 52%, 88%, and 100% of those with pathological TNM (pTNM) stage I, II, and III disease, respectively; and in 100% of non-LUAD patients. Elevated pre-operative ctDNA levels correlated with poor overall survival (OS; ctDNA low HR=9.1; 95% CI:1·1-72.5; ctDNA high HR=23.6, 95% CI: 2·7-206.0) and relapse-free survival (RFS) in LUADs independent of stage (including in stage I patients). Importantly, this remained true among ctDNA-positive samples when ctDNA level was treated as a continuous variable (HR=1.5; 95% CI: 1.1-2.1), whilst elevated ctDNA levels also correlated with reduced RFS in non-LUADs (HR= 2.1, 95% CI= 1·0 to 4.4), independent of disease stage. Critically, LUAD patients with ctDNA present at below 80 PPM (the 95% limit of detection for our recently published ctDNA detection approach in TRACERx) experienced reduced OS compared to those in which ctDNA was not detected (p=0.002, HR=12.2).

Conclusions

Our ultra-sensitive approach demonstrates superior analytic performance and prognostic prediction compared to other assays previously clinically validated in non-small cell lung cancer and provides an advanced stratification tool to guide adjuvant therapy in early-stage ctDNA-positive disease at high risk of relapse.

Clinical trial identification

NCT01888601.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Personalis Inc.

Disclosure

A.M. Frankell: Financial Interests, Personal and Institutional, Other, Co-inventor on a patent application to determine methods and systems for tumour monitoring: Patent: PCT/EP2022/077987. C.W. Abbott: Financial Interests, Personal, Full or part-time Employment: Personalis, Inc.; Financial Interests, Personal, Stocks/Shares: Personalis, Inc.. S.M. Boyle: Financial Interests, Personal, Full or part-time Employment: Personalis, Inc.; Financial Interests, Personal, Stocks/Shares: Personalis, Inc.; Financial Interests, Personal, Leadership Role: Personalis, Inc.. B. Li: Financial Interests, Personal, Full or part-time Employment: Personalis, Inc.; Financial Interests, Personal, Stocks/Shares: Personalis, Inc.. R. Chen: Financial Interests, Personal, Full or part-time Employment: Personalis, Inc.; Financial Interests, Personal, Leadership Role, CMO: Personalis, Inc.; Financial Interests, Personal, Stocks/Shares: Personalis, Inc.. M. Al Bakir: Financial Interests, 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; 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. 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, 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, 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.