Dada, Hiba I.

Clinical trials reporting the robust antitumor activity of immune checkpoint inhibitors (ICIs) in microsatellite instability-high (MSI-H) solid tumors have used tissue-based testing to determine the MSI-H status. This study assessed if MSI-H detected by a plasma-based circulating tumor DNA liquid biopsy test predicts robust response to ICI in patients with pancreatic ductal adenocarcinoma (PDAC). Retrospective analysis of patients with PDAC and MSI-H identified on Guardant360 from October 2018 to April 2021 was performed; clinical outcomes were submitted by treating providers. From 52 patients with PDAC +MSI-H, outcomes were available for 10 (19%) with a median age of 68 years (range: 56–82 years); the majority were male (80%) and had metastatic disease (80%). Nine of 10 patients were treated with ICI. Eight out of nine patients received single-agent pembrolizumab (8/9), while one received ipilimumab plus nivolumab. The overall response rate by Response Evaluation Criteria in Solid Tumors was 77% (7/9). The median progression-free survival and overall survival were not reached in this cohort. The median duration of treatment with ICI was 8 months (range: 1–24), and six out of seven responders continued to show response at the time of data cut-off after a median follow-up of 21 months (range: 11–33). Tissue-based MSI results were concordant with plasma-based G360 results in five of six patients (83%) who had tissue-based test results available, with G360 identifying one more patient with MSI-H than tissue testing. These results suggest that detecting MSI-H by a well-validated liquid biopsy test could predict a robust response to ICI in patients with PDAC. The use of liquid biopsy may expand the identification of PDAC patients with MSI-H tumors and enable treatment with ICI resulting in improved outcomes.

9108 Background: Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related death in the U.S. The median age at diagnosis is 70 years, and NSCLC is uncommon among younger individuals ( < 50 years).Overall, outcomes in NSCLC have improved significantly with targeted therapy. A prior study demonstrated patients < 50 are more likely to have targetable alterations including EGFR, ALK, ERBB2, and ROS1. Another study reported an increased prevalence of EGFR mutations in females and KRAS mutations in males with NSCLC. The comprehensive genomic landscape of NSCLC patients in different age groups and genders remains largely unknown. In our study, we aim to investigate the genomic alterations in patients with advanced NSCLC according to age and sex. Efforts that are focused on identifying targetable alterations in NSCLC will likely help personalize treatment and improve outcomes. Methods: We performed a retrospective review of de-identified data from the Guardant Health database from March 2018 through October 2020. We reviewed 34,237 profiles from patients with NSCLC who underwent molecular profiling using the plasma-based circulating-tumor DNA (ctDNA) Next-Generation Sequencing (NGS) assay Guardant360. Single nucleotide variants (SNV), fusions, indels and copy number variations (CNV) of up to 83 genes were analyzed. We assessed for genomic differences among patients with advanced NSCLC by both sex and age (≥70 and < 70). We conducted two-tailed tests of equality of proportions comparing males to females and ≥70 to < 70. Results: Of the 34,237 profiles reviewed, somatic alterations were seen in 81.7% (n = 27,972) of the patients. The median age was 70 (range 16-102) and 55% were female. Our study demonstrated that the most common genomic alterations in both age groups and genders were TP53, EGFR, KRAS, ATM, and MET. Patients ≥70 were more likely to have ATM (21% versus 14%, p < 0.0001) and MET (12% versus 10 %, p < 0.0001) mutations than those < 70. Patients < 70 were more likely to have EGFR (30% versus 27%, p < 0.0001), STK11 (14% versus 11%, p = 0.0056), and KRAS (26% versus 24%, p < 0.0001) alterations. EGFR was seen more frequently in females (33% versus 26%, p < 0.0001). ATM (11% versus 6%, p < 0.0001) and MET (8% versus 5%, p = 0.0050) were seen more frequently in males. Conclusions: Significant differences in the distribution of targetable genomic alterations were identified among different age groups and genders in patients with advanced NSCLC. These findings highlight the importance of taking personalized approaches to diagnostic testing and treatment of advanced NSCLC.

3040 Background: Pembrolizumab was recently FDA approved across solid tumors for TMB scores ≥ 10mut/Mb as assessed by next-generation sequencing (NGS) of tissue (tTMB). A prior study of advanced cancer patients treated with immunotherapy found that higher somatic TMB, as defined by the 80th percentile in each histology, was associated with better overall survival. Previously, bTMB assessed by ctDNA from patients with newly diagnosed advanced NSCLC at a score of 16 mut/MB correlated with a tTMB score of 10 mut/MB. TMB levels vary by cancer type, line of treatment, and therapy received; the distribution of bTMB scores across solid tumor types has not been well characterized. Here we report the distribution of bTMB scores in patients with advanced malignancies. Methods: We queried 5,610 samples from patients with different cancer types undergoing clinical cell-free DNA testing (Guardant360; Redwood City, CA) and assessed bTMB scores from October 2020 - January 2021. bTMB score was derived via a previously described computational algorithm examining the total number of synonymous and non-synonymous SNVs and indels across a 1.0MB genomic footprint. We assessed the success rate of bTMB evaluation, overlap with microsatellite instability (MSI) status, and defined the distribution of bTMB levels across indications in this dataset. Results: bTMB score was successfully assessed in 4,275/5,610 (76.3%) samples (Table). The majority of samples (58%) were tested at disease progression as compared to initial diagnosis (42%). The median turnaround time from sample receipt to clinical reporting was 11 days and decreased to 9 days over the course of the study. For the majority of cancer types the 80th percentile TMB was ≥ 16 mut/MB tissue equivalency. Conclusions: Our analysis demonstrates the feasibility of measuring bTMB using a commercially available liquid biopsy assay. bTMB scores trended higher than tTMB previously reported in these cancer types, reflecting the ability of ctDNA to better capture tumor heterogeneity. cfDNA may allow for exploration of bTMB evolution throughout treatment. TMB should be interpreted in the context of disease, treatment, and method; these data establish a pan-cancer benchmark for bTMB which will serve as a resource for further studies.[Table: see text]

Abstract Purpose Recent advances in molecular diagnostic technologies allow for the evaluation of solid tumor malignancies through noninvasive blood sampling, including circulating tumor DNA profiling (ctDNA). Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, often because of late presentation of disease. Diagnosis is often made using endoscopic ultrasound or endoscopic retrograde cholangiopancreatography, which often does not yield enough tissue for next-generation sequencing. With this study, we sought to characterize the ctDNA genomic alteration landscape in patients with advanced PDAC with a focus on actionable findings. Materials and Methods From December 2014 through October 2019, 357 samples collected from 282 patients with PDAC at Mayo Clinic underwent ctDNA testing using a clinically available assay. The majority of samples were tested using the 73-gene panel which includes somatic genomic targets, including complete or critical exon coverage in 30 and 40 genes, respectively, and in some, amplifications, fusions, and indels. Clinical data and outcome variables were available for 165 patients; with 104 patients at initial presentation. Results All patients included in this study had locally advanced or metastatic PDAC. Samples having at least one alteration, when variants of unknown significance (VUS) were excluded, numbered 266 (75%). After excluding VUS, therapeutically relevant alterations were observed in 170 (48%) of the total 357 cohort, including KRAS (G12C), EGFR, ATM, MYC, BRCA, PIK3CA, and BRAF mutations. KRAS, SMAD, CCND2, or TP53 alterations were seen in higher frequency in patients with advanced disease. Conclusion Our study is the largest cohort to date that demonstrates the feasibility of ctDNA testing in PDAC. We provide a benchmark landscape upon which the field can continue to grow. Future applications may include use of ctDNA to guide treatment and serial monitoring of ctDNA during disease course to identify novel therapeutic targets for improved prognosis. Implications for Practice Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis often due to late presentation of disease. Biopsy tissue sampling is invasive and samples are often inadequate, requiring repeated invasive procedures and delays in treatment. Noninvasive methods to identify PDAC early in its course may improve prognosis in PDAC. Using ctDNA, targetable genes can be identified and used for treatment.