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Allelic fractions for all variants detected in tDNA and ctDNA* in patients for whom both plasma and tissue samples were obtained (n=50)

Summary of driver and resistance mutations in EGFR and ALK detected in ctDNA, tDNA, and both ctDNA and tDNA

Tissue next-generation sequencing gene coverage. A: Illumina TruSeq panel (47 genes), and B: Penn Precision Panel (20 genes)

Analysis of discordant EGFR driver and resistance mutations detected in tDNA or ctDNA

All mutations detected in patient ctDNA (n=102)

Circulating tumor DNA next-generation sequencing gene coverage

Total amount of cfDNA extracted from each patient sample

Purpose: The expanding number of targeted therapeutics for non–small cell lung cancer (NSCLC) necessitates real-time tumor genotyping, yet tissue biopsies are difficult to perform serially and often yield inadequate DNA for next-generation sequencing (NGS). We evaluated the feasibility of using cell-free circulating tumor DNA (ctDNA) NGS as a complement or alternative to tissue NGS.Experimental Design: A total of 112 plasma samples obtained from a consecutive study of 102 prospectively enrolled patients with advanced NSCLC were subjected to ultra-deep sequencing of up to 70 genes and matched with tissue samples, when possible.Results: We detected 275 alterations in 45 genes, and at least one alteration in the ctDNA for 86 of 102 patients (84%), with EGFR variants being most common. ctDNA NGS detected 50 driver and 12 resistance mutations, and mutations in 22 additional genes for which experimental therapies, including clinical trials, are available. Although ctDNA NGS was completed for 102 consecutive patients, tissue sequencing was only successful for 50 patients (49%). Actionable EGFR mutations were detected in 24 tissue and 19 ctDNA samples, yielding concordance of 79%, with a shorter time interval between tissue and blood collection associated with increased concordance (P = 0.038). ctDNA sequencing identified eight patients harboring a resistance mutation who developed progressive disease while on targeted therapy, and for whom tissue sequencing was not possible.Conclusions: Therapeutically targetable driver and resistance mutations can be detected by ctDNA NGS, even when tissue is unavailable, thus allowing more accurate diagnosis, improved patient management, and serial sampling to monitor disease progression and clonal evolution. Clin Cancer Res; 22(23); 5772–82. ©2016 AACR.

362 Background: Despite current guidelines, less than 50% of patients with metastatic (m) non-squamous (NSq) NSCLC undergo comprehensive molecular genotyping. At our institution, based on improved comprehensiveness of genotyping with use of concurrent tissue (T) and plasma (P) next generation sequencing (NGS), we designed an electronic medical record (EMR)-based “nudge intervention” to auto-generate an order for P NGS at the time of initial consultation, while T NGS was carried out reflexively based on institutional pathways. Methods: A prospective study was conducted at the Abramson Cancer Center and 2 community sites within the University of Pennsylvania Health System after IRB approval. A provider team-focused EMR-based “nudge intervention” was designed to order P NGS at the time of new patient consultation. Eligible patients for the nudge were identified using an EMR based checklist, that included 3 criteria i. newly diagnosed, ii. treatment naïve, iii. mNSq NSCLC. Results from the intervention period (4/2021-12/2021) were compared to baseline data from similar patients treated at our institution between 01/2019 and 03/2021. Categories of NCCN guideline recommended molecular genotyping were defined as: i) comprehensive: EGFR, ALK, BRAF, ROS1, MET, RET, NTRK testing, and ii) incomplete or no testing performed. The proportion of patients with comprehensive molecular genotyping prior to 1st-line therapy were compared in the pre- and post-intervention groups using the chi-square test. Results: 526 patients with mNSq NSCLC were included in this analysis: 381 in the pre-intervention cohort, 145 in the post-intervention cohort. After implementation of the EMR-based nudge, a higher proportion of patients underwent concurrent T+P testing resulting in improved comprehensive molecular genotyping. In addition, a greater proportion of patients had comprehensive genotyping available prior to 1st-line therapy in the post-intervention vs pre-intervention cohort (Table). Conclusions: Across 3 practice sites, a provider team-focused EMR-based nudge intervention was associated with a significantly higher proportion of patients with mNSq NSCLC undergoing comprehensive molecular genotyping, both overall and prior to 1st-line therapy. These findings demonstrate that behavioral, EMR-based nudges can promote guideline concordant diagnostic testing at both community and academic sites and should be studied further as a tool to improve rates of molecular testing in NSCLC.[Table: see text]

9022 Background: Current guidelines recommend comprehensive molecular genotyping for newly diagnosed patients (pts) with metastatic non-squamous (non-Sq) NSCLC. We have previously demonstrated that concurrent plasma (P) and tissue (T) based next-generation sequencing (NGS) improves detection of clinically actionable mutations in pts with advanced NSCLC. We analyzed the impact of concurrent T+P NGS on comprehensiveness of molecular genotyping and on overall survival (OS). Methods: A retrospective cohort study of pts with newly diagnosed stage IV non-Sq NSCLC who received therapy at our institution between 01/2019 and 12/2020 was performed. Categories of NCCN guideline testing were defined, i) comprehensive: EGFR, ALK, BRAF, ROS1, MET, RET, and NTRK testing, ii) incomplete: 2-6 genes tested, and iii) no testing performed. The proportion of pts with comprehensive molecular testing performed, prior to 1st-line therapy and by detection modality (T NGS vs. T+P NGS), were compared using Fisher’s exact test. Median OS was estimated using Kaplan-Meier methodology from diagnosis to death or censored at most recent follow-up. Results: 335 patients were included in this analysis, 98.5% (330/335) underwent molecular testing: either comprehensive: n = 291 (86.9%), incomplete testing: n = 39 (11.6%); or no testing n = 5 (1.5%). Testing with T NGS was completed in 32.7% (108/330); 67.2% (222/330) underwent concurrent T+P NGS. These groups were well balanced for baseline characteristics, with the exception of a higher number of never smokers in T+P vs. T NGS (30.2% vs. 14.8%, p < 0.0001). Proportion of pts with comprehensive molecular testing was higher among pts with T+P NGS: 99.5% (221/222) vs. T NGS: 64.8% (70/108), p < 0.0001. All pts with T+P NGS testing had results available prior to 1st line therapy; 100% (204/204) compared to 60.7% (51/84) for T NGS, p < 0.0001. With median follow up of 20.5 months (mos, range 0.3 - 33.1), median OS was 18.6 mos. Median OS for pts tested with T+P NGS vs T alone was numerically longer at 23.2 vs. 14.1 mos, but not statistically significant (p = 0.078). However, regardless of testing modality, patients with comprehensive molecular genotyping had superior OS compared to those with incomplete or no testing (22.1 mos vs. 11.6 mos, p = 0.017). The institution of oral targeted therapy had no bearing on this difference in OS (test for interaction, p = 0.6509). Conclusions: Performance of concurrent T+P NGS testing was associated with a higher likelihood of comprehensive molecular genotyping, as well as improved availability of results, including prior to first line therapy. Patients with comprehensive genotyping have improved OS compared to patients with incomplete or no testing. These results support implementation of a concurrent T+P NGS approach upon initial diagnosis of metastatic non-Sq NSCLC.

8523 Background: The PACIFIC trial demonstrated a 10% improvement in 5-year survival with the addition of consolidation durvalumab versus placebo after chemoradiation (CRT) in good performance status patients (pts) with stage III non-small cell lung cancer (NSCLC). However, not all patients who complete CRT go on to receive consolidation durvalumab. We sought to describe real-world use of consolidation durvalumab or other immune checkpoint inhibitors (ICI) in this setting within a single academic health system. Methods: We retrospectively identified pts with unresectable stage III NSCLC treated with definitive CRT between October 2017 and October 2020 within the University of Pennsylvania Health System, including two urban hospitals and two satellite centers. Pts either received consolidation ICI (ICI group) or did not (no ICI group). Baseline characteristics of the groups were compared with the Chi-squared, Fisher exact, or Wilcoxon rank-sum test as appropriate. Overall survival (OS), measured from the last day of CRT, was compared using the Kaplan-Meier method and log-rank test. Results: Of the 148 consecutively treated pts who completed CRT, 108 (73%) received consolidation ICI; 40 (27%) did not. Within the ICI group, 42% completed 1 year (yr) of treatment. Within the no ICI group, reasons for non-receipt included disease progression (n = 14, 35%), CRT toxicity (n = 7, 18%), comorbidity or decline unrelated to CRT (n = 7, 18%), provider choice (n = 6, 15%) due to EGFR mutation (n = 5) or atypical histology (n = 1), pt refusal (n = 3, 8%), and death without progression (n = 3, 8%). The ICI group had better performance status (ECOG 0/1/2, 46%/49%/5% ICI vs 25%/48%/28% no ICI, p < 0.001) lower Charlson Comorbidity Index (median, 5 [IQR 4-6] ICI vs 6 [IQR 5-8] no ICI, p = 0.02), and lower rates of active autoimmune disease or immunosuppression (5% ICI vs 15% no ICI, p = 0.03). There were no differences between groups in age (median, 68 yrs [IQR 63-73] ICI vs 71 yrs [IQR 65-73] no ICI, p = 0.25), sex (female, 60% ICI vs 50% no ICI, p = 0.27), race (Black, 19% ICI vs 20% no ICI, p = 0.82), stage (IIIA/B/C, 42%/48%/11% ICI vs 40%/50%/10% no ICI, p = 0.96), and PD-L1 expression ( < 1%/1-50%/ > 50%/unknown, 36%/25%/29%/10% ICI vs 40%/25%/28%/8% no ICI, p = 0.97). 1- and 2-yr OS were 83% and 61% in the ICI group versus 52% and 34% in the no ICI group, respectively (p < 0.001). Within the no ICI group, OS was worse among those with versus those without disease progression (PD) post-CRT (1-yr OS 24% vs 74%, p = 0.03). Conclusions: In this retrospective study within a large academic health system, we found that over one-quarter of pts who completed chemoradiation for stage III NSCLC did not receive consolidation ICI, most commonly due to disease progression, CRT toxicity, or comorbidity. Survival amongst these pts is particularly poor, especially for those who experience PD shortly after CRT.

Efficient use of nivolumab in non-small-cell lung cancer (NSCLC) has been limited by the lack of a definitive predictive biomarker. In patients with metastatic melanoma treated with ipilimumab, a pretreatment neutrophil-to-lymphocyte ratio (NLR)5 has been associated with improved survival. This retrospective cohort study aimed to determine whether the pretreatment NLR was associated with outcomes in NSCLC patients treated with nivolumab.We reviewed the medical records of all patients with previously treated advanced NSCLC who received nivolumab between March 2015 and March 2016 outside of a clinical trial at the University of Pennsylvania. Patients were dichotomized according to pretreatment NLR5 vs. ≥5. Multivariable logistic regression and Cox proportional hazards models were used to assess the impact of pretreatment NLR on overall survival (OS), progression-free survival (PFS), and overall response rate (ORR).175 patients were treated. Median age was 68 (range, 33-88); 54% were female. Twenty-five percent of patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥2; 46% had received ≥2 prior systemic therapies. In multivariate analyses, pretreatment neutrophil-to-lymphocyte ratio (NLR) ≥5 was independently associated with inferior OS (median 5.5 vs. 8.4 months; HR 2.07, 95% CI 1.3-3.3; p=0.002) and inferior PFS (median 1.9 vs. 2.8 months; HR 1.43, 95% CI 1.02-2.0; p=0.04).In a cohort of patients with NSCLC treated with nivolumab in routine practice, pretreatment NLR≥5 was associated with inferior outcomes. It is unclear whether this marker is predictive or prognostic. Prospective studies are warranted to determine the utility of NLR in the context of other biomarkers of programmed death-1 (PD-1) therapy.

Purpose: The expanding number of targeted therapeutics for non–small cell lung cancer (NSCLC) necessitates real-time tumor genotyping, yet tissue biopsies are difficult to perform serially and often yield inadequate DNA for next-generation sequencing (NGS). We evaluated the feasibility of using cell-free circulating tumor DNA (ctDNA) NGS as a complement or alternative to tissue NGS. Experimental Design: A total of 112 plasma samples obtained from a consecutive study of 102 prospectively enrolled patients with advanced NSCLC were subjected to ultra-deep sequencing of up to 70 genes and matched with tissue samples, when possible. Results: We detected 275 alterations in 45 genes, and at least one alteration in the ctDNA for 86 of 102 patients (84%), with EGFR variants being most common. ctDNA NGS detected 50 driver and 12 resistance mutations, and mutations in 22 additional genes for which experimental therapies, including clinical trials, are available. Although ctDNA NGS was completed for 102 consecutive patients, tissue sequencing was only successful for 50 patients (49%). Actionable EGFR mutations were detected in 24 tissue and 19 ctDNA samples, yielding concordance of 79%, with a shorter time interval between tissue and blood collection associated with increased concordance (P = 0.038). ctDNA sequencing identified eight patients harboring a resistance mutation who developed progressive disease while on targeted therapy, and for whom tissue sequencing was not possible. Conclusions: Therapeutically targetable driver and resistance mutations can be detected by ctDNA NGS, even when tissue is unavailable, thus allowing more accurate diagnosis, improved patient management, and serial sampling to monitor disease progression and clonal evolution. Clin Cancer Res; 22(23); 5772–82. ©2016 AACR.

Introduction Nivolumab is a programmed death 1 (PD-1) immune-checkpoint inhibitor antibody currently approved for second-line therapy of metastatic non-small-cell lung cancer (NSCLC). PD-1 inhibitors including nivolumab are associated with a unique spectrum of immune-related adverse events (irAEs), though hematologic irAEs are rare and have not been previously reported in patients with NSCLC. Presentation of case Here we report a patient who experienced an exacerbation of underlying immune thrombocytopenia (ITP) while receiving nivolumab for NSCLC. The patient's ITP was successfully managed with romiplostim during nivolumab therapy, allowing for 7 months of clinical benefit and a partial tumor response. Discussion Using this case as an example, we provide a brief review of irAEs associated with PD-1 blockade, with particular attention to hematologic events. We also describe our approach to the use of nivolumab in this patient with underlying autoimmune disease. Conclusion Patients with NSCLC and underlying autoimmune disease may experience a flare of the autoimmune condition while receiving immune checkpoint inhibition. As illustrated by this case of ITP exacerbated by nivolumab, careful management of the autoimmune disease may allow for the safe administration of PD-1 directed agents in these patients.