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Clinical Trial
. 2023 Jul 3;6(7):e2325332.
doi: 10.1001/jamanetworkopen.2023.25332.

Association of Circulating Tumor DNA Testing Before Tissue Diagnosis With Time to Treatment Among Patients With Suspected Advanced Lung Cancer: The ACCELERATE Nonrandomized Clinical Trial

Miguel García-Pardo  1   2   3 , Kasia Czarnecka-Kujawa  4 , Jennifer H Law  1 , Alexandra M Salvarrey  1   4 , Roxanne Fernandes  1 , Zhen J Fan  1 , Thomas K Waddell  4 , Kazuhiro Yasufuku  4 , Geoffrey Liu  1 , Laura L Donahoe  4 , Andrew Pierre  4 , Lisa W Le  5 , Tharsiga Gunasegaran  1 , Noor Ghumman  1 , Frances A Shepherd  1 , Penelope A Bradbury  1 , Adrian G Sacher  1 , Sabine Schmid  1   6 , Lucy Corke  1 , Jamie Feng  1 , Tracy Stockley  7 , Prodipto Pal  7 , Patrik Rogalla  8 , Christodoulos Pipinikas  9 , Karen Howarth  9 , Bana Ambasager  9 , Laura Mezquita  2   10 , Ming S Tsao  7 , Natasha B Leighl  1
Affiliations
Clinical Trial

Association of Circulating Tumor DNA Testing Before Tissue Diagnosis With Time to Treatment Among Patients With Suspected Advanced Lung Cancer: The ACCELERATE Nonrandomized Clinical Trial

Miguel García-Pardo et al. JAMA Netw Open. .

Erratum in

  • Error in Byline.
    [No authors listed] [No authors listed] JAMA Netw Open. 2025 Feb 3;8(2):e251147. doi: 10.1001/jamanetworkopen.2025.1147. JAMA Netw Open. 2025. PMID: 39951275 Free PMC article. No abstract available.

Abstract

Importance: Liquid biopsy has emerged as a complement to tumor tissue profiling for advanced non-small cell lung cancer (NSCLC). The optimal way to integrate liquid biopsy into the diagnostic algorithm for patients with newly diagnosed advanced NSCLC remains unclear.

Objective: To evaluate the use of circulating tumor DNA (ctDNA) genotyping before tissue diagnosis among patients with suspected advanced NSCLC and its association with time to treatment.

Design, setting, and participants: This single-group nonrandomized clinical trial was conducted among 150 patients at the Princess Margaret Cancer Centre-University Health Network (Toronto, Ontario, Canada) between July 1, 2021, and November 30, 2022. Patients referred for investigation and diagnosis of lung cancer were eligible if they had radiologic evidence of advanced lung cancer prior to a tissue diagnosis.

Interventions: Patients underwent plasma ctDNA testing with a next-generation sequencing (NGS) assay before lung cancer diagnosis. Diagnostic biopsy and tissue NGS were performed per standard of care.

Main outcome and measures: The primary end point was time from referral to treatment initiation among patients with advanced nonsquamous NSCLC using ctDNA testing before diagnosis (ACCELERATE [Accelerating Lung Cancer Diagnosis Through Liquid Biopsy] cohort). This cohort was compared with a reference cohort using standard tissue genotyping after tissue diagnosis.

Results: Of the 150 patients (median age at diagnosis, 68 years [range, 33-91 years]; 80 men [53%]) enrolled, 90 (60%) had advanced nonsquamous NSCLC. The median time to treatment was 39 days (IQR, 27-52 days) for the ACCELERATE cohort vs 62 days (IQR, 44-82 days) for the reference cohort (P < .001). Among the ACCELERATE cohort, the median turnaround time from sample collection to genotyping results was 7 days (IQR, 6-9 days) for plasma and 23 days (IQR, 18-28 days) for tissue NGS (P < .001). Of the 90 patients with advanced nonsquamous NSCLC, 21 (23%) started targeted therapy before tissue NGS results were available, and 11 (12%) had actionable alterations identified only through plasma testing.

Conclusions and relevance: This nonrandomized clinical trial found that the use of plasma ctDNA genotyping before tissue diagnosis among patients with suspected advanced NSCLC was associated with accelerated time to treatment compared with a reference cohort undergoing standard tissue testing.

Trial registration: ClinicalTrials.gov Identifier: NCT04863924.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Czarnecka-Kujawa reported receiving personal fees from Olympus America outside the submitted work. Ms Law reported receiving grants from the Lung Health Foundation, Princess Margaret Cancer Foundation, and MaRS Discovery District Lung Cancer Innovation Challenge during the conduct of the study. Dr Bradbury reported receiving nonfinancial support from Inivata outside the submitted work. Dr Sacher reported serving as a clinical trial principal investigator for and receiving institutional research funding from Amgen, Bristol Myers Squibb, CRISPR Therapeutics, Lilly/LOXO, GSK, Iovance, Merck, Pfizer, and Spectrum and serving as a consultant for AstraZeneca and Genentech outside the submitted work. Dr Schmid reported serving on the advisory board for AstraZeneca, Bristol Myers Squibb, MSD, Roche, and Merck; receiving grants paid to the institution from AstraZeneca, Janssen, and Bristol Myers Squibb; and receiving travel support from Takeda, MSD, and Amgen outside the submitted work. Dr Feng reported receiving personal fees from AstraZeneca outside the submitted work. Dr Stockley reported receiving personal fees from Janssen, Bayer, AstraZeneca, Merck, and Pfizer outside the submitted work. Dr Rogalla reported receiving nonfinancial support from Canon Medical Systems outside the submitted work. Dr Howarth reported being an employee of Inivata Ltd in the last 2 years during the conduct of the study and being an employee of and shareholder in SAGA Diagnostics AB outside the submitted work. Dr Mezquita reported performing lectures and educational activities for Bristol Myers Squibb, AstraZeneca, Roche, Takeda, Janssen, and MSD; serving as a consultant for Roche, Takeda, and Janssen; receiving grants from Amgen, Stilla, Inivata, and AstraZeneca; and receiving funds for travel, accommodations, and expenses from Bristol Myers Squibb, Roche, Takeda, AstraZeneca, and Janssen outside the submitted work. Dr Tsao reported receiving grants from AstraZeneca, Bayer, and Sanofi and personal fees from AstraZeneca, Bayer, Sanofi, AbbVie, Amgen, Regeneron, Daiichi Sankyo, and Nucleix outside the submitted work. Dr Leighl reported receiving grants from Inivata to University Health Network (provision of study materials) during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flow Diagram of Enrolled Patients
ctDNA indicates circulating tumor DNA; NGS, next-generation sequencing; NSCLC, non–small cell lung cancer; and SCLC, small cell lung cancer. aThree patients with insufficient tissue for diagnosis had a plasma variant detected (STK11, KRASG12V, and PTEN). bThree patients with no biopsy had a plasma variant detected (TP53, U2AF1, and ERBB2 [formerly HER2 or HER2/neu] amplification). cThree patients with stage IA NSCLC (1 benign pleural effusion, 1 benign bone lesion, and 1 benign liver cyst). dNine patients had unresectable stage III disease (6 adenocarcinoma and 3 squamous carcinoma). eNo patients with squamous carcinoma or atypical cardinoid histologic characteristics had informative plasma results. fOf 7 patients with an actionable alteration in tissue only, 6 had undetectable ctDNA. gOf 11 patients with an actionable alteration in plasma only, 6 had insufficient tissue for NGS.
Figure 2.
Figure 2.. Turnaround Times
aA total of 74 patients had enough tissue for next-generation sequencing. bA total of 72 patients started systemic therapy.
Figure 3.
Figure 3.. Plasma-First Approach Proposed Algorithm
ctDNA indicates circulating tumor DNA; NGS, next-generation sequencing; and PD-L1, programmed cell death ligand 1. aPrioritize tissue sampling (required), pathologic diagnosis, and subtyping (if possible) prior to treatment initiation based on ctDNA results. bSome may consider tissue NGS testing optional in this scenario as the frequency of actionable coalterations is uncommon in the presence of another driver alteration.
See this image and copyright information in PMC

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