Circulating Tumor DNA Monitoring on Chemo-immunotherapy for Risk Stratification in Advanced Non–Small Cell Lung Cancer

Abstract

Purpose: Chemoimmunotherapy (chemoIO) is a prevalent first-line treatment for advanced driver-negative non–small cell lung cancer (NSCLC), with maintenance therapy given after induction. However, there is significant clinical variability in the duration, dosing, and timing of maintenance therapy after induction chemoIO. We used circulating tumor DNA (ctDNA) monitoring to inform outcomes in patients with advanced NSCLC receiving chemoIO. Experimental Design: This retrospective study included 221 patients from a phase III trial of atezolizumab+carboplatin+nab-paclitaxel versus carboplatin+nab-paclitaxel in squamous NSCLC (IMpower131). ctDNA monitoring used the FoundationOne Tracker involving comprehensive genomic profiling of pretreatment tumor tissue, variant selection using an algorithm to exclude nontumor variants, and multiplex PCR of up to 16 variants to detect and quantify ctDNA. Results: ctDNA was detected (ctDNA+) in 96% of pretreatment samples (median, 93 mean tumor molecules/mL), and similar ctDNA dynamics were noted across treatment arms during chemoIO. ctDNA decrease from baseline to C4D1 was associated with improved outcomes across multiple cutoffs for patients treated with chemoIO. When including patients with missing plasma or ctDNA- at baseline, patients with ctDNA- at C4D1 (clearance), had more favorable progression-free survival (median 8.8 vs. 3.5 months; HR, 0.32;0.20–0.52) and OS (median not reached vs. 8.9 months; HR, 0.22; 0.12–0.39) from C4D1 than ctDNA+ patients. Conclusions: ctDNA monitoring during induction chemoIO can inform treatment outcomes in patients with advanced NSCLC. Importantly, monitoring remains feasible and informative for patients missing baseline ctDNA. ctDNA testing during induction chemoIO identifies patients at higher risk for disease progression and may inform patient selection for novel personalized maintenance or second-line treatment strategies.

Analytical validation of a novel comprehensive genomic profiling informed circulating tumor DNA monitoring assay for solid tumors

“…By designing the sensitivity study samples with 2 monitorable alterations, we sought to estimate lowest possible sensitivity of the assay and show it to be >97.3% in low ctDNA samples (5–10 MTM/mL). Sensitivity and precision of the assay will be less reliable at lower levels of ctDNA, however recent data suggests the assay is capable of detecting ctDNA down to the 0.4 MTM/mL level in metastatic colorectal cancer [ 2 ], and the performance of assay is sufficient to identify response to immunotherapy in patients with metastatic cancer [ 13 , 35 ] To address the possible limitation of evaluable patients, we show that 90.0% of patients with tissue CGP would have ≥2 monitorable alterations ( Fig 2B ). This was consistent among many of the most prevalent tumor types in our database, including NSCLC, CRC, and breast cancer.…”

Early Changes in Tumor-Naive Cell-Free Methylomes and Fragmentomes Predict Outcomes in Pembrolizumab-Treated Solid Tumors

“…However, another study in non–small cell lung cancer has suggested that the optimal time point to detect ctDNA decrease may be later (i.e., cycle 4 in patients treated with a combination of immunotherapy and chemotherapy; ref. 29 ). The lack of a standardized on-treatment analysis time point is a challenge in the implementation of ctDNA in clinical practice.…”

ctDNA for the Evaluation and Management of EGFR-Mutant Non-Small Cell Lung Cancer

“…Apart from its established role in comprehensive genomic profiling for advanced NSCLC, ctDNA enables the identification of resistance mechanisms at the time of disease progression [ 44 ]. It can also serve as a supplementary disease monitoring strategy by helping with risk stratification during treatment [ 45 , 46 ].…”