Kimbrough, ErinMarie O.

Genomic mutations impact non-small cell lung cancer (NSCLC) biology. The influence of sex and age on the distribution of these alterations is unclear. We analyzed circulating-tumor DNA from individuals with advanced NSCLC from March 2018 to October 2020. EGFR, KRAS, ALK, ROS1, BRAF, NTRK, ERBB2, RET, MET, PIK3CA, STK11, and TP53 alterations were assessed. We evaluated the differences by sex and age (<70 and ≥70) using Fisher’s exact test. Of the 34,277 samples, 30,790 (89.83%) had a detectable mutation and 19,923 (58.12%) had an alteration of interest. The median age of the ctDNA positive population was 69 (18–102), 16,756 (54.42%) were female, and 28,835 (93.65%) had adenocarcinoma. Females had more alterations in all the assessed EGFR mutations, KRAS G12C, and ERBB2 ex20 ins. Males had higher numbers of MET amp and alterations in STK11 and TP53. Patients <70 years were more likely to have alterations in EGFR exon 19 del/exon 20 ins/T790M, KRAS G12C/D, ALK, ROS1, BRAF V600E, ERBB2 Ex20ins, MET amp, STK11, and TP53. Individuals ≥70 years were more likely to have alterations in EGFR L861Q, MET exon 14 skipping, and PIK3CA. We provided evidence of sex- and age-associated differences in the distribution of genomic alterations in individuals with advanced NSCLC.

e20540 Background: Mesothelioma is an aggressive malignancy with few approved treatment options. Rare malignancies are often seen in higher volume at academic centers which are considered equipped with better expertise. Outcomes of mesothelioma in the novel therapeutic era and impact of initial treatment at academic versus community centers have not been reported. Methods: Mesothelioma cases from 2004-2019 were collected from The National Cancer Database (NCDB). Epidemiologic factors including sex, age, income, education, insurance status and location were assessed as well as overall survival across academic and community centers. Overall survival (OS) was plotted by type of treatment facility, accounting for several factors available in NCDB. Results: A total of 30136 mesothelioma patients were included in the analysis. 13482 (44.7%) were treated in academic centers and 16654 (55.3%) were treated in community practice locations. A higher proportion of patients with comorbidity scores of 2 or higher were seen in the community setting as compared to the academic setting (12.2% vs 7.6%). The distribution of diagnostic stages was similar between academic and community settings (14.1% vs 14.5% Stage I; 28.5% vs 30.7% Stage IV). A higher number of patients received surgery (39.6% vs 21.3%), chemotherapy (59% vs 45.3%), and immunotherapy (5.2% vs 3.5%) when presenting to academic rather than community settings, respectively (p value < 0.001). OS for all patients was 1.093 years (range: 0-16.47 years) for those treated in an academic center and 0.66 years (95% CI: 0-16.690; p < 0.001) for those treated in the community. Conclusions: Data from NCDB database shows that treatment of mesothelioma at academic centers was associated with improved overall survival when compared to receiving treatment in the community despite seeing similar proportions of early and late-stage disease at presentation. Patients were more likely to receive treatment of any kind if presenting to academic centers.

The development of targeted therapies over the past two decades has led to a dramatic change in the management of EGFR-mutant non-small cell lung cancer (NSCLC). While there are currently five approved EGFR tyrosine kinase inhibitors (TKIs) for treating EGFR-mutant NSCLC in the first-line setting, therapy selection after progression on EGFR TKIs remains complex. Multiple groups are investigating novel therapies and drug combinations to determine the optimal therapy and treatment sequence for these patients. In this review, we summarize the landmark trials and history of the approval of EGFR TKIs, their efficacy and tolerability, and the role of these therapies in patients with central nervous system metastasis. We also briefly discuss the mechanisms of resistance to EGFR TKIs, ongoing attempts to overcome resistance and improve outcomes, and finalize by offering treatment sequencing recommendations.

e21016 Background: BRAF mutations are grouped (class I, II or III) according to kinase activity, dependence on RAS, and dimerization. BRAF class I mutations are targeted with BRAF/MEK inhibitors. The management of class II/III mutations has not been fully elucidated. We aimed to further characterize BRAF-mutant NSCLC. Methods: Moffitt patients with BRAF-mutant NSCLC were identified through retrospective review of a clinical molecular database and electronic health record from 1/1/2012 - 03/31/2020. Demographics, PD-L1 expression, responses to chemotherapy/immunotherapy, and overall survival were collected. The correlation between BRAF mutation classes and these variables was determined using a pairwise comparison of p-values and corrected for testing using the Benjamini-Hochberg method. For survival analysis, we used the Kaplan-Meier method with log-rank test. Results: 153 patients were included. Table summarizes the demographic data. 14 evaluable patients with class I mutations received anti-BRAF therapy. The DCR was 79% (11/14) and 83% when PD-L1 ≥1% (5/6). 36 response-evaluable patients received immunotherapy. The DCR was 79% (11/14) for patients with class I, 69% (9/13) for class II, and 78% (7/9) for class III mutations (p=0.89). The DCR was 73% in those with PD-L1 ≥1% (22/30) and 44% in those with PD-L1 <1% (7/16; p= 0.02). 43 response-evaluable patients received chemotherapy. The DCR was 86% (18/21) for patients with class I, 69% (9/13) for class II, and 78% (7/9) for class III mutations (p=0.49). The mOS was 26.2 months for all patients. The mOS was 31.2 months for class I, 15.6 months for class II, 28.8 months for class III, 34.8 months for AMP, and 24 months for VUS (p=0.6). Conclusions: To our knowledge, this is the largest retrospective study of patients with BRAF-mutant NSCLC. BRAFmutations were more common in patients with adenocarcinoma and those with a smoking history. PD-L1 levels ≥1% were seen more frequently in all BRAF-mutant patients. Class I mutations were significantly more common than other mutations and responded well to BRAF-targeted therapy, particularly when PD-L1 ≥1%. All BRAF-mutant classes responded similarly to immunotherapy and better responses were seen among those with PD-L1 ≥1%. Responses to chemotherapy were similar across all classes. Improved OS in class I-mutant disease was seen. These findings were not statistically significant. Additional research is needed to better characterize these patients to individualize management and improve outcomes.[Table: see text]

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.