Early detection of disease progression in NSCLC patients undergoing immunotherapy through ctDNA analysis

BackgroundDespite the improvement in survival achieved with immunotherapy (IO)-based treatments for advanced non-small cell lung cancer (NSCLC), some patients experience rapid disease progression. Here, we sought to evaluate the clinical utility of ctDNA fluctuations after the first cycle to predict survival outcomes.MethodsA total of 64 plasma samples were analyzed. Paired basal (PT) and post cycle 1 (PC1) liquid biopsies were collected from 32 stage IV NSCLC patients treated with first-line IO or chemo-IO. Cell-free DNA was isolated using QIAamp Circulating Nucleic Acid Kit and analyzed by next-generation sequencing using the Oncomine Pan-Cancer Cell-Free Assay on an Ion S5 sequencer. Variant files were obtained with the Ion Reporter analysis platform and variant filtering was performed using an in-house bioinformatic pipeline. Tumor response was evaluated with PET-CT and CT according to the RECIST v. 1.1 criteria. Statistical analysis was conducted using R software.ResultsctDNA levels, calculated as the sum of the mutant allele frequency (MAF) of all detected variants (SumMAF), were compared in the PT and PC1 samples, identifying 14 patients (43.75%) with increased ctDNA (non-responders, NR), and 18 being responders (R) with equal or decreased ctDNA. Significant differences in progression-free survival (PFS) and overall survival (OS) were observed between the two groups with a median PFS and OS of 4.44 and 6.33 months, respectively, in NR patients and not reached in R patients (PFS, HR:4.1; 95% CI 1.40-12.0; OS, HR:3.9; 95% CI 1.30-12.0). Specifically, 78.57% of NR patients experienced disease progression in less than 6 months compared to 27.78% of R patients. Other parameters to quantify ctDNA such as mean MAF, median MAF, maximum MAF or number of variants (NV) validated these results. Furthermore, all patients with an increase in both sumMAF and NV experienced disease progression.ConclusionsThe integration of baseline and early on-treatment ctDNA analysis enables the identification of patients that do not benefit from IO-based treatments as early as three weeks after the initiation of the therapy, anticipating disease progression and being useful to tailor patient management.Legal entity responsible for the studyFundación Para La Investigación Biomédica Del Hospital Universitario Puerta De Hierro Majadahonda.FundingThis study was funded by the Ministry of Science and Innovation (grant no.RTC2019-007359-1). Additionally, Lucia Robado de Lope is supported by a Juan de la Cierva fellowship (grant no. JDC2022-049091-I).DisclosureV. Calvo de Juan: Financial Interests, Speaker, Consultant, Advisor: Roche, MSD, BMS, AstraZeneca, Takeda, Amgen, Janssen, Pfizer; Financial Interests, Advisory Board: Sanofi, GSK. A. Collazo Lorduy: Financial Interests, Speaker, Consultant, Advisor: AstraZeneca, Janssen. B. Massuti Sureda: Financial Interests, Speaker, Consultant, Advisor: Roche, BMS, Boehringer Ingelheim, Takeda. P. Diz Tain: Financial Interests, Speaker, Consultant, Advisor: BMS, AstraZeneca, Roche, MSD, Takeda, Pfizer, Amgen; Financial Interests, Advisory Board: Boehringer Ingelheim. M.A. Sala Gonzalez: Financial Interests, Speaker, Consultant, Advisor: Takeda, Roche. A. Lopez Martin: Financial Interests, Speaker, Consultant, Advisor: GSK, BMS, AstraZeneca. J. Rogado: Financial Interests, Speaker, Consultant, Advisor: Roche, AstraZeneca, MSD, Merck, Ferrer, Persan Farma, Fresenius Kabi, Sanofi. A. Sanchez Hernandez: Financial Interests, Speaker, Consultant, Advisor: Roche, MSD, AstraZeneca, Janssen. J.L. Gonzalez-Larriba: Financial Interests, Speaker, Consultant, Advisor: MSD, Janssen, BMS, Boehringer Ingelheim, Amgen, AstraZeneca, Roche, Pfizer, Novartis, Astella. A.M. Martinez De Castro: Financial Interests, Speaker, Consultant, Advisor: BMS, MSD, Pfizer. A. Romero: Financial Interests, Speaker, Consultant, Advisor: Takeda, Illumina, Health in Code, Thermo Fisher. M. Provencio Pulla: Financial Interests, Speaker, Consultant, Advisor: BMS, AstraZeneca, MSD, Roche, Takeda. All other authors have declared no conflicts of interest.