4MO - Role of ctDNA tumor fraction to select immunotherapy based regimens in advanced non-small cell lung cancer

Background

The emergence of immune checkpoint blockers (ICBs) transformed treatment for advanced non-small cell lung cancer (aNSCLC), but determining when to combine them with chemotherapy remains challenging. Biomarkers like PD-L1 expression and Tumor Mutation Burden guide treatment decisions, but are imperfect, and direct comparison data between ICB monotherapy and chemo-immunotherapy are lacking. Imaging-based tumor burden and liquid biopsy (LBx), particularly circulating tumor DNA (ctDNA) levels, offer promise in this regard.

Methods

The role of LBx and PET imaging was studied in patients treated at Gustave Roussy. Patients treated with ICB-based regimen for aNSCLC were enrolled and LBx date, molecular profile, and clinico-pathological data were collected. Calculation of ctDNA Tumor Fraction (TF) was performed through hybrid capture-based next-generation sequencing (NGS) of plasma ctDNA. Outcomes were assessed in the de-identified Flatiron Health-FMI clinico-genomic database (FH-FMI CGDB, 280 US cancer clinics).

Results

Liquid biopsies from 217 patients were first analyzed alongside PET scans. The median time between biopsies and PET scans was 15 days. A correlation was found between ctDNA tumor fraction (TF) and metabolic tumor volume (MTV). TP53 and RB1 mutations were associated with increased TF after adjusting for MTV. In FH-FMI CGDB, TF from 820 patients proved to be a prognostic biomarker for NSCLC patients receiving immunotherapy, with high TF associated with poorer outcomes. Combination therapy showed improved outcomes in patients with TF higher than 5% (HR 0.55; 95% CI 0.37 – 0.79; p 0.001 for OS and HR 0.44; 95% CI 0.29 – 0.65; p 0.0003 for PFS) but not in those with lower TF.

Conclusions

The study explores ctDNA TF as a surrogate for tumor burden and a prognostic biomarker of aNSCLC. Significant correlation between ctDNA and tumor burden was found though molecular characteristics may also play a role. In patients with High TF, chemotherapy in combination with ICBs is superior to single agent ICB. In contrast, single agent ICBs were not inferior to the combination in patients with low TF. TF can be used as a selection tool for patients eligible for ICB alone or in combination with chemotherapy.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

D. Planchard: Financial Interests, Personal, Advisory Board: AstraZeneca, BMS, Merck, Novartis, Pfizer, Roche, Samsung, Celgene, AbbVie, Daiichi Sankyo, Janssen, Seagen, Gilead, Pierre Fabre; Financial Interests, Personal, Invited Speaker: AstraZeneca, Novartis, Pfizer, priME Oncology, Peer CME, Samsung, AbbVie, Janssen, Gilead, Seagen; Non-Financial Interests, Personal, Principal Investigator, Institutional financial interests: AstraZeneca, BMS, Merck, Novartis, Pfizer, Roche, Daiichi Sankyo, Sanofi-Aventis, Pierre Fabre, AbbVie, Sanofi, Janssen. F. Barlesi: Financial Interests, Institutional, Advisory Board: AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, Mirati, MSD, Pierre Fabre, Pfizer, Sanofi Aventis, Seattle Genetics, Takeda, AbbVie, ACEA, Amgen, Eisai, Ignyta; Non-Financial Interests, Personal, Principal Investigator: AstraZeneca, BMS, Merck, Pierre Fabre, F. Hoffmann-La Roche Ltd., Innate Pharma, Mirati. A. Italiano: Financial Interests, Personal and Institutional, Advisory Board: Roche, Domain Therapeutics, AstraZeneca, BMS, MSD. L. Pasquina, R. Madison: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine. B. Besse: Financial Interests, Institutional, Advisory Board: Amgen, AstraZeneca, BeiGene, Blueprint Medicine, Cergentis, Chugai pharmaceutical, Daiichi Sankyo, F. Hoffmann-La Roche, Inivata, Pfizer, PharmaMar, Sanofi Aventis, Springer Healthcare Ltd, 4D Pharma, AbbVie, Da Voltera, Eli Lilly, Ellipse Pharma Ltd, F-Star, GSK, Janssen, Onxeo, Ose Immunotherapeutics, Socar Research, Taiho Oncology, Turning Point Therapeutics; Financial Interests, Institutional, Invited Speaker: Genzyme Corporation, Hedera Dx, Medscape, MSD; Financial Interests, Institutional, Local PI: AbbVie, Amgen, Blueprint Medicines, Daiichi Sankyo, Pfizer, Roche-Genentech, Turning Point Therapeutics, Nuvalent, Enliven, Prelude Therapeutics; Financial Interests, Institutional, Coordinating PI: AstraZeneca, OSE immunotherapeutics, Sanofi, Taiho; Financial Interests, Institutional, Steering Committee Member: BeiGene, GSK, Janssen, Takeda, Genmab; Financial Interests, Institutional, Funding: Cristal Therapeutics. All other authors have declared no conflicts of interest.