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8540 Background: The standard of care for patients with inoperable early stage or locally advanced NSCLC is definitive stereotactic body radiotherapy (SBRT) or conventional radiation therapy (RT) with systemic therapy. Circulating tumor DNA (ctDNA) testing can be used for the assessment of MRD and predict risk of recurrence. Few studies have prospectively evaluated MRD detection and ctDNA dynamics specifically among patients with early or locally advanced NSCLC receiving definitive RT. Methods: In a prospective clinical cohort of patients with stage I-III NSCLC (n = 17), serial plasma samples (n = 70) were collected before and after SBRT as well as before, during, and after conventional RT with or without concurrent systemic therapy and adjuvant durvalumab. Patients were followed-up for a median of 29 months (range: 4 to 54 months) with the last serial plasma collected at a median of 5 months from completion of RT (range: 1 – 26 months). A personalized, tumor-informed multiplex PCR assay (Signatera™ bespoke mPCR NGS assay) was used for the detection and quantification of ctDNA and tracked 16 tumor variants among 16 patients and 15 tumor variants in one patient. This study evaluated the prognostic value of ctDNA, correlating MRD status with clinical outcomes, in addition to ctDNA clearance kinetics during RT. Results: Among 17 patients with early-stage and locally advanced NSCLC, baseline ctDNA was detected in 82% of patients (14/17). Clinical progression was confirmed radiographically for 53% (9/17). All events of clinical progression were detectable by ctDNA (sensitivity 100%, 0.63 – 1.0), with a median lead-time of 5.5 months for MRD detection compared to radiographic disease progression. Durable ctDNA clearance was observed in 29% (5/17) of patients, all of whom then remained recurrence-free until the end of follow-up (median 12 months; specificity 100%, 95% CI 0.6 – 1.0). Transient ctDNA clearance was observed in 3 patients, and recurrent ctDNA was detected before or at the time of disease progression in all 3. ctDNA status after treatment at a single time point and longitudinally were highly predictive of disease recurrence (p < 0.0001). Conclusions: ctDNA detection is feasible for patients with stage I-III NSCLC undergoing definitive chemoradiation. and can serve as a powerful predictive biomarker for disease recurrence. High baseline detection rate is essential for feasibility of a ctDNA-based MRD assay. Residual detectable ctDNA represents a powerful predictive tool to identify patients who might benefit from intensification of adjuvant therapy following definitive RT.

9009 Background: The effectiveness of circulating tumor DNA (ctDNA) at matching patients to life prolonging therapy has been studied mostly in small cohorts with limited follow up. The prognostic value of ctDNA alterations, particularly those absent on tissue, is also unclear. To address these questions, we studied survival outcomes in a prospective cohort of patients (N = 1002) with non-small cell lung cancer (NSCLC). Methods: Adults with metastatic or recurrent NSCLC were eligible if they had no known driver mutation or a known driver with progression following targeted therapy. Patients were enrolled at Memorial Sloan Kettering Cancer Center (New York, NY) starting October 21, 2016; analysis here is from a snapshot November 1, 2020. All patients had ctDNA sequenced via the Resolution ctDx Lung platform. To reduce inclusion of incidental germline mutations, we excluded non-functionally significant mutations with an allele frequency 35-65% that were present in gnomAD. Patients could also receive, at their provider’s discretion, tissue sequencing with MSK-IMPACT, which filters germline and clonal hematopoietic (CH) mutations with matched white blood cell sequencing. We performed survival analyses using Cox proportional hazards models from time of diagnosis of advanced disease to death, left truncating at time of study entry. Results: Of 1002 patients, 348 (35%) were treated with targeted therapy; in 181 of these (52%) the targetable alteration was detected in ctDNA. Patients treated with targeted therapy had prolonged survival whether matched by tissue-based methods (HR 0.39, 95%CI 0.30-0.51) or ctDNA (HR 0.47, 95%CI 0.37-0.61). These benefits persisted across multiple subgroups. ctDNA alterations themselves were associated with worse survival (HR 2.2, 95%CI 1.8-2.8), in a manner that scaled with allele fraction and burden. Of 401 patients with time-matched tissue sampling, 62 (15%) had ctDNA alterations that were absent on IMPACT (“unique” ctDNA alterations). Three such patients had unique ctDNA EGFR T790M mutations leading to changes in therapy. However, unique ctDNA alterations were generally associated with worse survival than no ctDNA alterations (HR 2.5, 95%CI 1.7-3.7) and even tissue-matched ctDNA alterations (HR 1.7, 95%CI 1.1-2.4). Of 98 unique ctDNA mutations, 48 (49%) were detectable in tissue at subthreshold levels, 12 (12%) were filtered by IMPACT as CH or germline, and 38 mutations (39%) were absent even at subthreshold levels. ctDNA alteration burden correlated with radiographic disease extent. In multivariate models with radiographic disease extent and other clinical variables, ctDNA alterations were the strongest independent predictor of worse survival. Conclusions: Our results show that ctDNA may match patients to life-prolonging targeted therapy and have prognostic importance. ctDNA may provide data about a patient’s cancer missed by spatially restricted tissue sequencing. Clinical trial information: NCT01775072.

3529 Background: Circulating cell-free DNA (cfDNA) next-generation sequencing (NGS) is a promising strategy for non-invasive molecular profiling of cancers. MSK-ACCESS (Analysis of Circulating cfDNA to Evaluate Somatic Status) is a hybridization-capture targeted NGS assay that detects somatic variants in select exons of 129 genes with matched white blood cell sequencing. We present the initial clinical experience with MSK-ACCESS among patients with advanced non-small cell lung cancer (NSCLC). Methods: Patients with stage IV NSCLC underwent prospective MSK-ACCESS testing at initial diagnosis or progression of disease on targeted therapy between June 2019 and January 2020. A subset of patients had matched tissue-based NGS testing with the MSK-IMPACT 468 gene assay. We assessed oncogenic driver detection, turnaround time, plasma-tissue concordance, and matching to therapy. National Comprehensive-Cancer Network designated driver alterations were included in evaluation of tissue-plasma concordance (EGFR, ALK, KRAS, MET, RET, BRAF, HER2, ROS1, NTRK). Turnaround time was compared by a two-sided Wilcoxon signed-rank test. Results: A total of 201 patients with NSCLC had MSK-ACCESS testing at initial diagnosis (n = 79) or following progression of disease (n = 122). The median turn-around-time from plasma collection to MSK-ACCESS report was 16 days (range: 9 – 36 days) compared to 19 days from lab receipt of tissue to report (range: 12 – 57) for MSK-IMPACT (p < 0.001). Among patients with a driver detected on MSK-ACCESS, 100% (92/92) had an identical driver detected on MSK-IMPACT. Among patients with a driver detected on MSK-IMPACT, 75% (92/123) had an identical driver detected on MSK-ACCESS. This rate was similar among patients who were treatment-naive (74%; 64/86) and had disease progression (76%, 28/37) at the time of MSK-ACCESS. MSK-ACCESS identified driver alterations that directly guided first-line targeted therapy (n = 18) with response in all patients with available radiographic follow-up (n = 10), including a patient without confirmatory tissue testing. MSK-ACCESS identified resistance alterations among patients with disease progression including EGFR T790M, EGFR C797S, ROS1 G2032R, as well as a BRAF fusion. Conclusions: MSK-ACCESS successfully identified driver alterations with high concordance to tissue-based testing, directly guided patients to therapy with clinical responses, and detected known and novel resistance mechanisms. This assay warrants further clinical development to guide and facilitate precision oncology.

9067 Background: Small cell lung cancer (SCLC) is an aggressive disease, characterized by inevitable chemotherapy resistance and rapid progression. We hypothesized that circulating tumor DNA (ctDNA) analysis can rapidly identify sensitivity to platinum-based therapy. Methods: Patients with SCLC at Memorial Sloan Kettering Cancer Center underwent serial plasma collections, including prior to the start of treatment and prior to Cycle 2 Day 1 of therapy (C2D1). Tumor mutations were identified from pre-treatment biopsies by MSK-IMPACT and/or pre-treatment plasma by CAncer Personalized Profiling by deep Sequencing (CAPP-Seq). Median variant allele fraction (VAF) of all mutations was monitored on subsequent blood draws using CAPP-Seq. Progression free survival (PFS) was measured from the time of first pre-treatment blood draw. Results: Plasma was collected from 19 patients treated with carboplatin and etoposide, including three who received concurrent atezolizumab. Seven were female, and mean age was 64.5 years. ctDNA was detected in 17 patients (89%), including in the two patients in our series with limited stage disease. The most common mutations were in TP53 and RB1 in 14 and 6 patients, respectively. Fourteen patients had available plasma at C2D1. At baseline prior to treatment, median VAF did not differ significantly between radiologic responders and non-responders (9.4% versus 30.3%, p = 0.35). After one cycle of chemotherapy, the VAF percent decrease was significantly more in responders versus non-responders (-96.9% versus -10.3%, p < 0.001). Median VAF was therefore significantly lower by C2D1 in patients who responded compared to non-responders (0.51% versus 27.2%, p = 0.02). Those who ultimately responded to therapy all had a > 2 fold decrease in VAF by C2D1. With a median follow-up of 180 days, PFS was significantly longer in patients with > 2 fold decrease in VAF by C2D1 (6.4 versus 1.9 months, log rank p < 0.001). Conclusions: A 2-fold decrease in plasma VAF by C2D1 predicted platinum-sensitivity in SCLC and was associated with longer PFS. ctDNA may permit early assessment of benefit and expedite alternative treatment options for those without significant decrease in median VAF after one cycle of therapy.