Serial Monitoring of Circulating Tumor DNA by Next-Generation Gene Sequencing as a Biomarker of Response and Survival in Patients With Advanced NSCLC Receiving Pembrolizumab-Based Therapy

Abstract

PURPOSE Although the majority of patients with metastatic non–small-cell lung cancer (mNSCLC) lacking a detectable targetable mutation will receive pembrolizumab-based therapy in the frontline setting, predicting which patients will experience a durable clinical benefit (DCB) remains challenging. MATERIALS AND METHODS Patients with mNSCLC receiving pembrolizumab monotherapy or in combination with chemotherapy underwent a 74-gene next-generation sequencing panel on blood samples obtained at baseline and at 9 weeks. The change in circulating tumor DNA levels on-therapy (molecular response) was quantified using a ratio calculation with response defined by a > 50% decrease in mean variant allele fraction. Patient response was assessed using RECIST 1.1; DCB was defined as complete or partial response or stable disease that lasted > 6 months. Progression-free survival and overall survival were recorded. RESULTS Among 67 patients, 51 (76.1%) had > 1 variant detected at a variant allele fraction > 0.3% and thus were eligible for calculation of molecular response from paired baseline and 9-week samples. Molecular response values were significantly lower in patients with an objective radiologic response (log mean 1.25% v 27.7%, P < .001). Patients achieving a DCB had significantly lower molecular response values compared to patients with no durable benefit (log mean 3.5% v 49.4%, P < .001). Molecular responders had significantly longer progression-free survival (hazard ratio, 0.25; 95% CI, 0.13 to 0.50) and overall survival (hazard ratio, 0.27; 95% CI, 0.12 to 0.64) compared with molecular nonresponders. CONCLUSION Molecular response assessment using circulating tumor DNA may serve as a noninvasive, on-therapy predictor of response to pembrolizumab-based therapy in addition to standard of care imaging in mNSCLC. This strategy requires validation in independent prospective studies.

Circulating tumor DNA predicts neoadjuvant immunotherapy efficacy and recurrence-free survival in surgical non-small cell lung cancer patients

“…To evaluate the effects of ctDNA change on predicting pathological response, relative delta mean variant allele fraction (R∆mean VAF) was calculated to depict dynamic changes of ctDNA upon NAT among pathological responders (MPR) and non-responders (non-MPR). Relative delta mean VAF = (mean VAF on treatment − mean VAF at baseline)/mean VAF at baseline (29,30). A receiver operator characteristic (ROC) curve was generated to analyze the sensitivity and specificity of R∆mean VAF predicting pathological response.…”

Prognostic Impact of Circulating Methylated Homeobox A9 DNA in Patients Undergoing Treatment for Recurrent Ovarian Cancer

“…One of the major issues of incorporating ctDNA in the monitoring of treatment efficacy is that despite the evidence of clinical validity, there is no evidence of clinical utility [ 34 ]. Moreover, there is currently no consensus on how to evaluate and report ctDNA during treatment, and several different definitions have been reported, e.g., ‘relative change from baseline’, ‘x-fold reduction/increase’ and statistical calculations, with comparisons and validation of the definitions still lacking [ 21 , 37 , 38 , 39 ].…”

Plasma Genotyping at the Time of Diagnostic Tissue Biopsy Decreases Time-to-Treatment in Patients With Advanced NSCLC—Results From a Prospective Pilot Study

“…Blood was collected before the time of diagnostic biopsy and sequenced using the Guardant360 74-gene next-generation sequencing (NGS) assay. 7 Biopsy specimens with nonsquamous NSCLC were reflexed for sequencing using a 152-gene NGS panel on the basis of institutional standard of care (SOC). The primary end point was time-to-treatment, defined as the time from diagnostic tissue biopsy to selection of a first-line systemic therapy.…”