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7055 Background: CMML is a heterogenous disease exhibiting features innate to MPN and MDS. Increasing evidence supports a close interplay between systemic inflammation and risk of myeloid malignancies, notably for those with history of infection or autoimmune disease. CMML has been associated with inflammation and end-organ damage related to CKD and CVD. Analysis of gene signatures from CMML-derived monocytes has shown them to be highly proinflammatory. High ferritin may serve as a practical biomarker of disease activity to help identify pts at higher risk of poor outcomes. Methods: Retrospective data was collected from a database of CMML pts treated at Moffitt Cancer Center. Pts were stratified in 2 cohorts based on ferritin levels ( < 1000 or ≥1000 ng/mL). Hyperferritinemia was defined as ferritin > 1000 as seen at diagnosis or during follow-up. Kaplan–Meier was used to estimate OS. Cox regression was used for multivariate analysis. Results: Between August 1995 and October 2020 729 pts with CMML were identified. Median age at diagnosis was 71 (17-95). Out of 571 pts with available ferritin levels 29% (n = 168) developed hyperferritinemia vs 71% (n = 403) who did not. mOS was 32.4 mos (95%CI 30-35 mos). Pts with higher ferritin tended to present with CMML-2 (p = 0.001) and harbor a proliferative phenotype (p = 0.01). They presented with higher marrow cellularity (mean 83%, p = 0.08), PLT (mean 177k, p = 0.038), and lower Hb (mean 9.5, p < 0.05). There was no association with % circulating IMC, monocytes, WBC or ANC at baseline. Hyperferritinemia was associated with more profound fibrosis (p = 0.007), cytopenias (p < 0.05), % peripheral blasts (p < 0.05), RBC and PLT transfusion dependence (p < 0.05). Pts with hyperferritinemia had higher risk disease per IPSS-R, CPSS and all CMML models (p < 0.05); and had higher rates of AML transformation (p < 0.05). Pts were also more likely to require treatment earlier (within 3 yrs of diagnosis) (p < 0.05). ASXL1 (p = 0.002), EZH2 (p = 0.003), and SETBP1 (p = 0.019) mutations were more common among pts with hyperferritinemia. Conversely, TET2 (p = 0.001), CBL (p = 0.028) and SRSF2 (p = 0.003) mutations were less common. mOS for pts with hyperferritinemia was 23.9 mos (95%CI 19.9-27.9 mos), much lower than for those with ferritin < 1000 (mOS 40.5 mos, 95%CI 35.4-45.5 mos) (p < 0.05). In multivariate analysis, hyperferritinemia was a significant independent covariate for OS after adjusting for CPSS, transfusion dependence and disease phenotype (dysplastic vs proliferative) (HR = 0.69; 95%CI 0.53-0.89; p = 0.005). Conclusions: Almost 1/3 of pts with CMML will develop hyperferritinemia. This is associated with more aggressive disease and higher rates of AML transformation leading to dismal outcomes. ASXL1, EZH2, and SETBP1 MTs confer a higher risk of hyperferritinemia. Our findings indicate that hyperferritinemia is an independent prognostic biomarker that may serve as a surrogate representative of disease biology and comorbidities in CMML.

e21072 Background: Current guidelines for prevention and monitoring cardiac dysfunction in patients with cancer state there is insufficient evidence to support surveillance strategies for TKIs alone. Furthermore, risk stratification for baseline and frequency of monitoring remains unclear for various products. This study evaluates the current practice for screening and monitoring for cardiotoxicity in patients treated for NSCLC with TKIs and the adherence rate to the standards of care. Methods: A single-center retrospective chart review of 113 patients with metastatic NSCLC who received TKIs at a large academic-community cancer center was performed. The current practice for screening and monitoring for cardiotoxicity and the adherence rate to the suggested standards recommended by the prescribing information of each drug were analyzed. Total incidence of cardiotoxicity was also evaluated. Descriptive statistics were calculated for all demographic variables and clinical outcome endpoints. Incidence of cardiotoxic adverse events were reported as percentages. Results: A total of 113 metastatic NSCLC patients were identified with the majority of patients taking osimertinib (67.3%), alectinib (8.0%), or dabrafenib/trametinib (7.1%) at baseline. Total adherence rate for screening and monitoring for cardiotoxicity as recommended by the prescribing information for all agents was 54%. Cardiotoxicity occurred in 46 (40.7%) patients, presenting most frequently as hypertension and bradycardia. Cohort cardiotoxicity events are summarized in the table below. Decreased left ventricular ejection fraction (LVEF) ≥ 10% or to < 50% occurred in 6/76 (7.9%) patients on osimertinib; however, only 12 (15.8%) patients were able to be assessed due to lack of baseline data. Osimertinib was held and/or discontinued in 3 (3.9%) patients and 1 (1.3%) death resulted due to cardiomyopathy. QTc interval prolongation occurred in 2 (33.3%) patients on afatinib, 1 (20%) patient on crizotinib, and 1 (1.3%) patient on osimertinib. Three (3.9%) patients on osimertinib were diagnosed with atrial fibrillation. Conclusions: The results reported in this study show higher rates of decreased LVEF and similar rates of QTc prolongation with osimertinib compared to prior studies. The increased rate of hypertension observed may be associated with the high rate of uncontrolled blood pressure at baseline. Low adherence rates to the recommendations provided by prescribing information may contribute to increased risk of cardiac dysfunction.[Table: see text]

e21149 Background: P21-activated kinase 4 (PAK4) is a crucial effector of the Rho GTPases. It acts as a regulatory switch that controls a wide range of cellular functions and plays a pivotal role in cancer progression and metastasis. Very little is known about the expression and prognostic value of PAK4 in NSCLC. Methods: 17,689 NSCLC tumor samples were analyzed using next-generation sequencing (NextSeq, 592 Genes, or WES NovaSeq), immunohistochemistry (IHC), and whole transcriptome sequencing (NovaSeq) (Caris Life Sciences, Phoenix, AZ). PD-L1 expression was analyzed by IHC (Dako 22c3; PD-L1 positive: TPS >1%). TMB was measured by counting all somatic mutations found per tumor (TMB-high: >10 mutations/MB). Tumors with PAK4-high (H) and PAK4-low (L) expression were classified as those in top quartile and bottom 3 quartiles, respectively. Immune cell infiltrates were calculated by Quantiseq. Significance was determined using chi-square and Wilcoxon rank sum test and adjusted for multiple comparisons (q-value < 0.05). Survival was extracted from insurance claims data and calculated from the time of tissue collection to the last contact using Kaplan-Meier estimates. Results: There was no difference in median age, gender, smoking status, and histologic distribution between PAK-H and PAK-L tumors. Compared to PAK4-L, the PAK4-H was associated with higher frequency of co-mutations in TP53 (76.3% vs 63.9%, p < 0.0001) and RB1 (13.6% vs 8.1%, p < 0.0001). PAK4-H tumors were associated with greater genomic loss of heterozygosity (24.1% vs 16.4%, p < 0.0001), and expression of immune checkpoint genes ( LAG3, PDCD1, PDCD1LG2, CD274, IDO1, CTLA4, CD80, HAVCR2; p < 0.05). KRAS (including KRAS G12C) , BRAF, STK11, and EGFR mutations, and ALK and ROS1 fusions were less frequent in PAK4-H tumors (p < 0.001). A greater proportion of PAK4-H tumors were TMB-H (40.3% vs 33.3%, p < 0.0001) and PD-L1 negative (48.2% vs 40.8%, p < 0.001). PAK4-H tumors had lower infiltration of B cells, M1/M2 macrophages, CD8+ T-cells, and Tregs (p < 0.001). Overall survival (OS) was inferior among patients with PAK4-H tumors (median, 14.9 vs 21.5 months, HR = 1.28, 95% CI, 1.21-1.36, p < 0.001), which was driven by adenocarcinoma histology. Survival with immunotherapy was also inferior in patients with PAK4-H adenocarcinoma (median, 23.6 vs 30.3 months, HR = 1.23, 95% CI, 1.02-1.48, p = 0.03), but not squamous cell carcinoma. A similar trend in survival was noted in patients who received EGFR- and ALK inhibitors. Conclusions: PAK4-H expression in NSCLC is associated with a higher frequency of alterations predisposing to genomic instability, differentially modulated immune phenotype, and a lower frequency of actionable genomic alterations. Patients with PAK4-H adenocarcinoma have inferior OS, and survival with immunotherapy and targeted therapy. PAK4-H expression defines a subgroup of patients with un unmet need for novel treatment strategies.

e24063 Background: Coronavirus 19 (COVID-19) is a severe global pandemic and a public health challenge. Patients with COVID-19 and cancer are at an increased risk of poor clinical outcomes. Data is lacking in evaluating outcomes in patients with different cancers, races and ages; particularly in Florida with high proportion of elderly and the largest racial/ethnic disparities. We evaluated the in-hospital mortality of COVID-19 positive cancer patients. Methods: We used retrospective data of COVID-19 patients hospitalized at the Memorial Healthcare System between March 1, 2020 and January 18, 2021. Over 4,870 patients with COVID-19 were evaluated, of which 265 (5.4%) had cancer. The primary endpoint was in-hospital mortality in patients with cancer and COVID-19. Mortality was analyzed in COVID-19 patients with/without a cancer history. We used descriptive statistics to synthesize outcomes and characteristics from the study population. Univariate and multivariate logistic analysis were performed to define baseline clinical characteristics potentially associated with mortality in cancer patients with COVID-19. Results: 4,870 patients with COVID-19 were evaluated and 265 had malignancy. The study included all different races including Non-Hispanic Whites (NHW) 816 (16.8%), Hispanics 2,271 (46.6%), African-Americans (AA) 1,534 (31.5%) and other minorities 248 (5.1%). Of cancer patients, 24.1% NHW, 43% Hispanic, 28.7% AA and 4.2% other minorities. Amongst races, NHW with cancer accounted for the highest number of COVID-related deaths representing 37.5%, while Hispanics and AA accounted for 18.4% and 19.7% respectfully. Amid cancer subtypes, 24.6% of hematological cancers resulted in mortality and 23.5% of solid cancers resulted in mortality, but no statistical significance was seen. Additionally, after adjusting for age, gender, and race, cancer was linked to an increased in-hospital mortality. Lastly, older age (> 65), elevated creatinine levels (Cr) and elevated C-reactive protein (CRP) were associated with increased risk of death. Conclusions: Patients with COVID-19 and cancer had worse outcomes. Cancer subtypes included hematological and solid cancers, with similar in-hospital mortalities. Although NHW were the smallest group, they had the highest rate of in-hospital deaths amongst cancer patients with COVID-19, in comparison to Hispanics, the largest group in the study, had the least amount of in-hospital deaths. Additionally, factors such as advanced age, elevated Cr and CRP were associated with increased risk of COVID-related deaths. The findings indicate the need for close surveillance and monitoring of these patients as they are more likely to have complications such as mortality from COVID-19.

9113 Background: EGFR mutations are present in more than 10% of patients (pts) with NSCLC in the US. While EGFR with tyrosine kinase inhibitors (TKIs) are effective, acquired resistance is expected. Known mechanisms include acquired EGFR mutations (e.g. 718V, c797x, 724s, 721s or T790M); copy number amplifications in MET, ERBB2, and PIK3CA; gene fusion events; and histological transformation. We herein present the prevalence of resistance mutations in the largest reported cohort of EGFR mutant NSCLC. Methods: Non-small cell lung cancer (NSCLC) tumor samples were submitted to Caris Life Sciences (Phoenix, AZ) for NextGen Sequencing (NextSeq, 592 Genes) and whole exome sequencing (NovaSeq, WES). PD-L1 expression was tested by IHC using 22c3 (Dako) and TPS scores were reported (cutoff >1). TMB was measured by totaling somatic mutations (TMB-high cut-off > 10 mutations per MB), genomic loss of heterozygosity (gLOH) was determined by WES. Patient treatment information was obtained from insurance claims data. Results: A total of 27,848 NSCLC tumors were evaluated and 3,223 (12%) had a EGFR sensitizing mutations. We found 60 tumors with common missense resistance mutations: 790 (n = 30, 0.9%), 797 (n = 38, 1.2 %), 718 (n = 11, 0.3%), 724 (n = 7, 0.2%) and 721 (n = 4, 0.1). Table 1 describes the frequencies, PD-L1 expression and the most common co-mutations. TMB-H (> = 10) was found in 12.5% of the tumors and dMMR/MSI-H in 1.8%. The most prevalent co-alterations were TP53 54%), gLOH (28%), CTNNB1 (19%), NFKB1A (13%), APC (10%), PIK3CA (11%), SMAD4 (9%) and other 15 co-mutations in less than 7% were seen. In the 30 T790M mutants, in addition to TP53 mutations, other prevalent co-mutations were PIK3CA (14%) and CTNNB1 (17%). In 797-mutant tumors, in addition to T790M, the most prevalent co-mutations were TP53 (53%), CTNNB1 (22%), APC (16%) and PIK3CA (11%). L718 mutations co-occurred with either L858R (8/11), exon 19 (3/11) or T790M mutations (3/11). G724 mutations were found in 7 patients (0.02%) and G721 mutations in 4 patients (0.01%). Conclusions: Acquired resistance in EGFR mutant NSCLC is very heterogeneous and their frequency is still low most likely due to lack of enough sequencing of EGFR resistant tumors. While T790M and C797S mutations are well described, this report also notes a significant number of L718V mutations, primarily in osimertinib-treated pts with an original L858R. These data support the NGS evaluation of patients with resistant EGFR mutant lung cancers. [Table: see text]

TPS8601 Background: Taletrectinib (AB-106/DS-6051b) is a next-generation, brain-penetrant, ROS1/ NTRK tyrosine kinase inhibitor (TKI) and has shown clinically meaningful effect and safety profile in ROS1+ Non-Small Cell Lung Cancer (NSCLC) patients in phase 1 studies (Fujiwara et al, Oncotarget 2018; 9(34): 23729-23737; Ou et al, JTO Clin Res Rep. 2020 Oct 21;2(1):100108). Taletrectinib has also demonstrated activity against ROS1 G2032R resistance mutation and CNS metastases in the ongoing phase 2 TRUST study (NCT04395677) in China. Also, taletrectinib has shown preliminary efficacy against NTRK positive solid tumors in an ongoing phase 2 study (NCT04617054). Methods: TRUST-II study (NCT04919811) is a phase 2, global, multicenter, open-label, single-arm multi-cohort study evaluating the efficacy and safety of taletrectinib for ROS1 fusion-positive advanced metastatic NSCLC and other solid tumors. Taletrectinib will be given at 600 mg once daily in 21-day cycle. The patients with ROS1 fusions detected by local tests are eligible to enroll with retrospective confirmation by a central laboratory. The study consists of four cohorts: cohort 1: systemic chemotherapy naïve or ≤ one prior line and ROS1 TKI naïve NSCLC (N = 53); cohort 2: previously treated with one ROS1 TKI (crizotinib or entrectinib) and with progression who are either chemotherapy naïve or ≤ one line of platinum and/or pemetrexed based therapy for NSCLC (N = 46); cohort 3: ≤ 2 prior ROS1 TKIs and with progression who are either chemotherapy naïve or ≤ 2 lines of platinum and/or pemetrexed based therapy for NSCLC (N = 10); and cohort 4: systemic chemotherapy naïve or ≤ 2 prior lines of chemotherapy, but ROS1-TKI naïve ROS1 positive solid tumor other than NSCLC (N = 10). The primary endpoint is objective response rate (ORR) (RECIST v1.1) by independent review committee (IRC) assessment for cohorts 1 and 2. Key secondary endpoints include IRC-assessed duration of response, IRC-assessed intra-cranial ORR, progression free survival (PFS), overall survival (OS), and safety. This study is currently recruiting in Japan, Republic of Korea, and USA. Additional accrual is planned in Canada, China, and European Union. Clinical trial information: NCT04919811.

e20508 Background: Lung cancer is the leading cause of cancer deaths for Hispanics (HIS). Similarly, non-Hispanic blacks (NHB) are often disproportionately represented among cancer deaths compared to other racial/ethnic groups with lung cancer being the second most common cancer in black men and women, as well as the leading cause of cancer death. Despite these statistics, HIS and NHB remain underrepresented in non-small cell lung cancer (NSCLC) research. The aim of this study was to determine if there was a difference in outcomes between HIS, NHB and NH Whites (NHW) who had NSCLC and were treated with surgery, immunotherapy or chemotherapy. Methods: We studied 645,221 observations from the 2004-2018 National Cancer Database (NCDB), categorized as HIS, NHB or NHW, who received surgery, immunotherapy or chemotherapy for NSCLC. Categorical variables were analyzed using Pearson’s chi-square test or Fisher’s exact test. Continuous variables were analyzed using ANOVA. Survival outcomes were assessed using a Cox regression model and Kaplan-Meier curves with log-rank tests. Results: Regardless of treatment types, HIS had the highest median overall survival (OS) compared to other groups (NHW: 14.7 months; NHB: 15.0 months; HIS: 16.4 months) (P < 0.001). Regardless of the type of systematic therapy received (immunotherapy or chemotherapy), HIS had the highest median OS (P < 0.001) with HIS in the immunotherapy cohort having the highest survival advantage of all other race/ethnicity and chemotherapy groups. Multivariate Cox regression model further support the survival advantage of HIS compared to NHW (HR = 0.86; P = 0.009). OS was also assessed between patients who received surgery and/or chemotherapy. Patients who received a combination of surgery and chemotherapy had the highest OS compared to patients who underwent surgery only or received chemotherapy only. Among the cohort who received both, HIS had the highest median OS (NHW: 55.2 months; NHB: 55.5 months; HIS: 61.5 months). The surgery only cohort had the next highest median OS of all treatment groups; however, the HIS ethnicity group was non-estimable due to the small sample size. Of all three treatment groups, the chemotherapy only cohort had the lowest median OS while HIS had the highest median OS (NHW: 11.8 months; NHB: 12.9 months; H: 13.5 months) (P < 0.001). Conclusions: Results of our study suggest immunotherapy may offer an increased survival advantage for HIS and NHB compared to chemotherapy. For patients receiving chemotherapy, a combination of surgery and chemotherapy may offer a greater survival advantage for NSCLC patients. Hispanic ethnicity was associated with better survival regardless of the type of treatment received.

e18548 Background: There are biological differences in the clinical outcomes of Black or Hispanic cancer patients compared with non-Hispanic Whites (NHWs); however minorities have disadvantages in social determinants of health (SDOH) that influence cancer outcomes too. The World Health Organization defines SODH as the conditions in which people are born, grow, live, work, age, and maintains that they are largely responsible for health inequities . Most the oncology professionals do not consider that this issue is necessarily part of their scope of practice and they rely on social workers and others to address these issues, and they are not aware that SDOH can impact clinical outcomes of cancer patients. Methods: Memorial Cancer Institute (MCI) part of the Memorial Healthcare System (MHS) is the 3rd largest Public Health Care System in the country. We found important disparities in immunotherapy outcomes in our MCI minority lung cancer patients ( Raez LE. Research Trends. 2021 Feb (20) 63–74 and Dickson F. JTO Vol. 16 (10) S904–5), some of these are related to SDOH. In order to increase awareness of SDOH and identify the impact of SDOH on cancer outcomes, our MHS value-based care team has been working to incorporate SDOH screening and follow-up as an important part of treatment plan development since 2018. At that time, MHS implemented an SDOH dashboard in our EPIC EMR to show the SDOH areas of risk. In 2021, MHS built a best practice alert in Epic to notify health care providers about SDOH issues that might impact treatment outcomes. Results: MHS has implemented a SDOH dashboard in the EPIC EMR that is accessible and easily noticed by the providers and updated constantly by our social workers and other health professionals screening for SDOH. Providers do not need to do extra work other than to be aware that the best cancer treatment that they are recommending for a patient might not have the desired outcome if some of these 13 SDOH are not considered during the planning phase of treatment. The SDOH dashboard uses color coding to indicate if any SDOH is at risk (red) or not at risk or low risk (green) allowing the provider to easily focus in on areas of concern when SDOH is reviewed. Conclusions: Using an easy to access and easy to read SDOH dashboard in the EMR allows oncology providers to address SDOH in the development of oncology treatment plans which we believe will lead to improved health care outcomes.[Table: see text]

e21043 Background: Differences in tumor gene expression profile (GEP) may contribute to disparities in lung cancer incidence and survival between racial and ethnic groups. For patients with stage IV NSCLC, tumor biomarker analysis is important for identification of potentially effective targeted therapies. However, despite advancements in biomarker testing and targeted therapy, minority patient enrollment in clinical trials remains low and it has been shown that minority patients are less likely to undergo next-generation sequencing (NGS) compared to Non-Hispanic Whites (NHW). As such, frequencies of tumor biomarkers in minority populations in the United States are not well-defined. This study aimed to determine the extent of tumor GEP diversity in minority patients vs NHW. Methods: This retrospective study included 196 adult patients with stage IV NSCLC that had a baseline NGS of tumor tissue or blood (liquid biopsy) performed between July 1, 2015 and June 30, 2021. Minority populations included Hispanic, African American, and Asian patients. Data collected utilizing the electronic medical record included patient demographics, detection of tumor biomarkers and treatment initiated. Descriptive statistics were calculated for all demographic and clinical variables. Comparisons of actionable epidermal growth factor receptor (EGFR) mutation frequency between NHW and minority patients were done using Chi-squared and Fisher’s exact tests. Results: Of the 196 patients evaluated, baseline characteristics included 46% male, 67% former smokers, 54% NHW, 31% Hispanic, 9% African American, 5% Asian, and 1% other. The median age at diagnosis was 66 ± 12 years. Actionable mutations (EGFR, KRAS, BRAF, ROS-1, ALK, MET, NTRK 1-3) were found in 50% of patients (see Table). The frequency of actionable EGFR mutations was higher in minority patients overall compared to NHW (39.3% vs 21.5%; p < 0.01). The frequency of actionable EGFR mutations was similar between NHW and Hispanic patients (21.5% vs 27.9%; p = 0.35), however differences were observed comparing NHW to African American (21.5% vs 50%; p = 0.02) and Asian (21.5% vs 90%; p < 0.01) patients, respectively. Conclusions: Among patients with stage IV NSCLC, the GEP of minority patients varied from that of NHW. Asian patients had the highest frequency of EGFR mutations, followed by African American and Hispanic patients, respectively. Larger studies are needed to validate these findings.[Table: see text]

341 Background: Brain metastases from esophageal cancer are extremely rare with an estimated incidence of 1.7% but limited survival. Some reports highlight the rich microvascular density of such tumors and their distinctive degree of HER2, HIF1-a and EGFR expression, further emphasizing the potential role of angiogenesis in their neurotropic behavior. With this in mind, we aimed to illustrate the transcriptomic landscape of brain metastases from esophageal cancers and better understand the disease biology. Methods: Following IRB approval, we collected retrospective data on patients with a diagnosis of esophageal cancer with histology-proven brain metastases treated at our institution between 2008 and 2020. We identified 10 adequate, paired samples with available tissue for RNA extraction. Expression data was generated using NanoString TS 360 panels to characterize gene signatures of interest and analyzed using GSEA_4.1.0. Results: All 10 patients were Caucasian, 90% were male. Median age was 63 years. All had adenocarcinoma with G2-G3 histology. Median follow-up was 39.4 mos (95%CI, 27.4 to 51.4). At data cutoff, 6 patients had died. Median OS was 24.6 mos. Median time from curative surgery to CNS recurrence was 8.3 mos. Ninety percent of patients developed brain metastases within 24 mos of surgery. Median time from brain metastases to death was 4.7 mos. Almost a third of patients had HER2 positive disease. 48 gene signatures were analyzed; 5 being significantly enriched between metastatic and primary site accounting for cell cycle, DNA damage repair, MYC, mTOR signaling and immortality and stemness. Out of a pool of 760, significant overlap was seen between 12 genes across the 5 signatures of interest: POLE, LIG1, FEN1 (involved in DNA repair and replication); AURKA and PLK1 (cell proliferation and triggers for G2/M transition), BUB1 (establishment of the mitotic spindle checkpoint and chromosome congression), MCM2 and MCM4 (initiation of genome replication); BRIP1 and RAD51 (critical in homologous recombinational repair); CCNE1 (cell cycle G1/S transition) and WRAP53 (dual role as p53 regulator and protein involved in telomere elongation and DNA repair). ERBB2 was similarly enriched in primary and metastatic sites. Conclusions: These preliminary data demonstrate that the genomic basis of brain metastases in esophageal cancer goes beyond EGFR/ERBB2 signaling. A complex genomic interaction is present in brain metastases as compared to primary site that offers these cells the advantage for neurotropism. To our knowledge this is the first study attempting to illustrate genomic differences between primary and matched brain metastasis sites in esophageal cancer.

e20533 Background: Nuclear protein transport is essential in guiding the organized traffic of important proteins and RNAs between the nucleus and cytoplasm of the cell. Export of proteins from the nucleus is exclusively regulated by Exportin 1(XPO1). In cancer, XPO1 is universally hyperactive and can promote the export of important tumor suppressors to the cytoplasm, leading to their functional inactivation. XPO1 is aberrantly over expressed in NSCLC and this over expression has been linked to poor overall survival. The underlying mechanisms of XPO1 over expression are not known. Currently there are no studies evaluating the impact of XPO1 mutations on NSCLC incidence and therapy resistance. Additionally, there are no studies that examined the XPO1 related pathways in NSCLC harboring co-alterations with other driver mutations such as EGFR or ALK. Methods: Tumor samples were analyzed using next-generation sequencing (NextSeq, 592 Genes), IHC, and whole transcriptome sequencing (WTS ,NovaSeq) (Caris Life Sciences, Phoenix, AZ). PD-L1 expression was tested by IHC using 22c3 (Dako) and TPS scores were reported (cutoff > 1%). TMB was measured by totaling somatic mutations (TMB-high cut-off ³ 10 mutations per Megabase). Gene fusions were detected by RNA sequencing using either the Archer FusionPlex panel or WTS. Survival was extracted from insurance claims data and calculated from time of tissue collection to last contact using Kaplan-Meier estimate. Statistical significance was determined using chi-square and Wilcoxon rank sum test and adjusted for multiple comparisons. Results: Among 18,218 NSCLC tumors sequenced, 26 harbored XPO1 mutations. XPO1 mutant tumors were more likely to be TMB High(79% vs. 52%, p = 0.007) and less likely to have high PDL1(32% vs. 68%, p = 0.03). KRAS mutations were seen in 19%(n = 5), EGFR mutation were rare (n = 2), and no targetable fusions were seen. Among the 17,449 NSCLC tumors with clinical data, there were 24 XPO1 mutant tumors with no histology imbalance observed in mutant vs. wild-type(WT). Comparison of survival in the NSCLC group between XPO1 mutant and WT showed a negative association with a hazard ratio(HR) of 1.932 (95% CI: 1.144- 3.264 p = 0.012). Comparing the survival within the subgroup with confirmed adenocarcinoma histology (9973 XPO1 WT and 14 XPO1 mutant) showed a similar negative correlation in survival with a HR of 2.156 (95% CI: 1.027- 4.525 P = 0.037). Conclusions: Presence of XPO1 pathogenic mutations was associated with a poor survival in both the entire NSCLC cohort and the adenocarcinoma subgroup. Further studies of this negative association at the molecular level along with effect of other co-existing mutations can result in development of novel treatment strategies.

e20531 Background: The PACIFIC trial demonstrated that durvalumab improved 3-year overall survival in unresectable Stage III non-small-cell lung cancer (NSCLC) following chemoradiotherapy (CRT). However, there is no consensus on the preferred therapy after patients progress on durvalumab. This study aimed to determine the real-world outcomes of patients treated with durvalumab and subsequent therapies after disease progression. Methods: Forty-five NSCLC patients previously treated in a large multi-site community cancer center with concurrent CRT followed by durvalumab were evaluated for progression-free survival (PFS). Subsequent lines of therapy for patients who progressed on durvalumab were also evaluated. Treatment characteristics of the patients were also reviewed. PFS was reported using the Kaplan-Meier method using a p-value of < 0.05 for statistical significance. Results: Baseline characteristics of patients included a median age of 65 years (46-90), 99% with ECOG 0 or 1, and 89% with PDL-1>50%. The median duration between the end of CRT and initiation of durvalumab was 1.3 months and the median treatment duration was 8.1 months the A total of 13 patients (29%) progressed on durvalumab; the 12-month PFS was 65.9% (49-79.7) and the 18-month PFS was 59.1% (36.7-76.1). The median PFS observed was 38.4 months (Table 1). The subsequent lines of therapy for the 14 patients that progressed were as follows: 8(62%). immunotherapy/chemotherapy combination, 2(15%) chemotherapy only, 2(15%) targeted therapy, and 1(8%) radiation therapy. Conclusions: Evaluation of consolidation durvalumab in patients with locally advanced NSCLC finds PFS in clinical practice to be consistent with trial data. Subsequent lines of therapy were consistent with guideline recommendations for newly diagnosed stage IV NSCLC. Longer follow-up will be needed to determine the PFS associated with the different subsequent therapies and how immunotherapy failure could potentially affect outcomes of subsequent chemo/immunotherapy combinations.[Table: see text]

e17562 Background: Leiomyosarcomas (LMS) are one of the most frequently occurring subtypes of soft tissue sarcomas and are associated with poor prognosis and high risk of recurrence even in the early stages of the disease. Primary management involves surgical excision followed by chemotherapy for all stages. We sought to determine the prognostic factors on associated with leiomyosarcoma survival. Methods: The National Cancer Database from 2004-2016 was utilized to obtain demographics, tumor characteristics and treatment factors of LMS. LMS was divided into three groups for analysis- women with uterine LMS, women with ex-uterine LMS and men with LMS. Univariate and backward stepwise multivariate logistic regression models were used to determine prognostic factors associated with long-term survival in each group. Kaplan-Meier method with log rank test was used to compare overall survival (OS) rates among the three groups. Results: A total of 23194 patients were identified. Only 18.7% of men with LMS utilized chemotherapy as compared to 47.4% women with uterine and 25.0% with ex-uterine LMS. Both men and women had comparable palliative care use- 3.9% in women with uterine LMS, 3.5% in women with ex-uterine LMS and 3.0% in men with LMS. There were statistically significant differences (P=0.000) between overall survival among the three groups. Median OS was highest among men with LMS (72m) followed by women with ex-uterine LMS (57.2m) and women with uterine LMS (36.7 m). On multivariate analysis, in women with uterine LMS, increasing age (OR =0.95, P=0.018), presence of lymphovascular invasion (OR=0.25, P=0.000) were associated with decrease in the likelihood of survival. In women with ex-uterine LMS, increasing age (OR=0.97, P=0.000), increasing stage (I-IV) (OR=0.56, P=0.000), presence of tumor (OR=0.39, P=0.001), those with residual tumor and surgical margins (OR=0.87, P=0.009), and patients who received systemic therapy and surgery (OR= 0.85, P=.0016) had a reduced likelihood of survival. In men with LMS, factors such as increasing age (OR=0.96, P=0.000), increasing number of regional lymph nodes (OR=0.91, P=0.027), having had a surgical diagnostic or staging procedure (OR= 0.69, P=0.004), increasing stage (OR = 0.64, P=0.005), and residual tumor or margins (OR=-0.76, P=0.013) were associated with reduced likelihood of survival. Results also suggest that increasing year of diagnosis was associated with an increased likelihood of survival (OR=1.51; P=0.000). Conclusions: Women were found to comprise almost two third of the patient population with LMS. Men were found to have longer survival than women with LMS, despite low utilization of chemotherapy. It may be due to poor prognosis of LMS in the female reproductive organs while LMS in the extremities has better prognosis. Future prospective trials should stratify based on sex and in women location.

9087 Background: Recent data suggest inferior responses to immune checkpoint inhibitors (ICIs) in STK11-mt NSCLC. TP53 is a critical tumor suppressor gene regulating DNA repair by arresting cells in the G1 phase in response to critical double strand breaks. We hypothesized that accumulated DNA damage from mutations in the TP53 gene might increase immunogenicity and potentially enhance benefit of ICIs in STK11-mt NSCLC. Methods: A total of 16,896 NSCLC tumors submitted to Caris Life Sciences (Phoenix, AZ) for targeted NGS (DNA-Seq, 592 genes) were analyzed. A subset (N = 5034 tumors) had gene expression profiling (RNA-Seq, whole transcriptome). PD-L1 (TPS) was tested with 22c3 antibody (Dako). Exome-level neoantigen load for STK11-mt NSCLC was obtained from published TCGA Pan-immune analysis (Thorsson et al. 2018). Non-parametric tests were used for comparing differences in tumor mutational burden (TMB) and neoantigen load. Transcriptomic analysis included differential gene expression and hierarchical clustering. Tumor immune cell content was obtained from transcriptome using Microenvironment Cell Population-counter (MCP). Publicly available data from the POPLAR/OAK trials of atezolizumab in advanced NSCLC were used to model PFS and OS for STK11-mt with TP53-mt (n = 14) and without TP53-mt (n = 20). Results: Of 16,896 NSCLC samples, 12.6% had an STK11-mt with the proportions of TMB-high (≥10 Mut/Mb), PD-L1 ≥ 50% and MSI-high being 55.9%, 11.8%, and 0.72%, respectively. STK11-mt vs. STK11-wt NSCLC did not differ in median TMB (Caris:10 vs. 10 Mut/Mb; p > 0.1) or neoantigen load (TCGA: 154.5 vs. 165; p > 0.1). Median TMB (13 vs. 9 Mut/Mb; p < 0.001) and neoantigen load (263 vs. 134; p < 0.001) were higher in STK11-mt/ TP53-mt vs. STK11-mt/ TP53-wt. MCP analysis showed higher CD8, NK-cell and lower myeloid dendritic cell infiltration in STK11-mt/ TP53-mt vs. STK11-mt/ TP53-wt (p < 0.01). Expression of MYC and HIF-α were increased in the STK11-mt/ TP53-mt vs. STK11-mt/ TP53-wt (p < 0.01) along with higher expression (p < 0.01) of genes associated with both glycolysis ( HK2, LDHA, ALDOA) and glutamine metabolism ( GOT2, PPAT2). Hierarchical clustering of STK11-mt adenocarcinomas (n = 463) for STING pathway genes (CCL5, CXCL10, cGAS) identified a STING-high and a STING low cluster. The STING high cluster was significantly enriched in TP53-mt (48 vs. 32%; p < 0.01).In the OAK/POPLAR cohort, median OS (HR is 1.14, 95% CI 0.53 - 2.48); p > 0.1) and PFS (HR 1.88, 95% CI 0.89-3.97, p = 0.098) were not statistically different between STK11-mt/ TP53-mt vs. STK-mt/ TP53-wt. However, the 15-months PFS was 21% in the STK11-mt/ TP53-mt vs 0% in the STK11-mt/ TP53-wt. Conclusions: STK11-mt NSCLC with TP53-mt are associated with an immunologically active TME with metabolic reprogramming. These intrinsic properties could be exploited to improve outcomes to ICIs in combination with metabolically directed agents.

e18521 Background: About 40% of the US population are from minority groups. Minority pts are under-represented in oncology clinical trials, which limits the applicability of results to the general population and perpetuates poor relationships between healthcare systems and minority communities. This assessment investigated underlying causes of this lack of minority representation in clinical trials and proposes plans to promote diversity. Methods: To better understand the limited inclusion of under-represented pts in oncology clinical trials, 10 specialists in cancer care were selected to provide their perspectives. Specialists were chosen because of their experience enrolling minority pts in clinical trials and met virtually in Dec 2020 via Within3, a secure digital communication platform, to discuss obstacles faced in recruiting minority pts and potential strategies to address these concerns. Specificity and alignment in responses were achieved through software analytics and follow-up queries. Results: The 10 specialists identified as Asian (10%), Black (30%), White (50%), and Hispanic (10%), and began practicing medicine in the 1980s-2010s. All are involved in clinical research and treat a range of minority pts in both urban and suburban settings. Most specialists (8/10) reported treating > 20 minority pts with cancer annually. However, few specialists (2/10) reported that > 20% of their minority pts have enrolled in clinical trials. Specialists agreed that minority pts experience barriers to participation in clinical research, including lack of trust in the healthcare system, materials in their native languages, financial support, minority investigators involved in clinical trials, and accessible study sites. The specialists proposed strategies that could be implemented to increase minority enrollment. These included study sites where minority populations live and industry funded outreach and educational efforts in minority communities. If sites are more accessible, this can reduce time and financial pressures associated with study participation. The specialists recommended that studies be designed to be more supportive of minority populations, specifically regarding inclusion and exclusion criteria and reimbursement of costs. They also advised that increased diversity among clinical researchers and allied personnel may increase the ability of the clinical team to connect with pts and assist in building trust in their communities. Finally, they emphasized the importance of providing informed consent forms and study materials in pts’ native languages. Conclusions: While challenges exist to increasing diversity in oncology clinical studies, a broad consortium of clinical specialists agreed that they can be addressed by community outreach and education, making study sites more accessible, availability of study materials in pts’ native languages, and improving diversity of clinical teams.

e21044 Background: Overweight and obesity have been associated with improved overall survival (OS) and progression-free survival (PFS) in patients treated with immune checkpoint inhibitors (ICI). EPSILoN score (EPSILoN), comprised of five clinical variables (smoking, Eastern Cooperative Oncology Group performance status, liver metastases, lactate dehydrogenase (LDH), and neutrophil-lymphocyte ratio), is a known predictive marker of response to ICI. This study aims to validate body mass index (BMI) and EPSILoN as predictive markers of response in frontline treatment of advanced non-small cell lung cancer (NSCLC) with ICI with or without concomitant chemotherapy. Methods: Patients with advanced NSCLC who received frontline ICI were identified using the electronic medical record. PFS and OS were retrospectively evaluated and stratified based on baseline BMI and EPSILoN. Due to lack of routine LDH testing, a modified EPSILoN (mEPSILoN) was used. For statistical analysis, log-rank tests were used to compare PFS and OS between groups, and Kaplan-Meier survival curves were used to report PFS and OS. Results: Thirty-six normal weight (NW) and 25 overweight and obese (OWO) patients were studied. Median PFS (mPFS) for OWO vs NW patients was 8.90 months vs 5.53 months (HR 0.54; 95% CI, 0.30-0.96; p = 0.04). mPFS at 12 months was 45% for OWO patients vs 23% for NW patients. Of the patients with PD-L1 ≥ 50%, 14 patients were NW and 11 patients were OWO. Among patients with PD-L1 ≥ 50%, mPFS for OWO was not reached (NR) vs 6.73 months in NW patients (HR 0.23; 95% CI, 0.09-0.60; p = 0.003), and the percent of patients that were PF at 12 months was 71% vs 15%. Of 56 patients with a calculable mEPSILoN, 29 patients had baseline mEPSILoN 1 and 27 patients had mEPSILoN 2-3. Median OS for patients with mEPSILoN 1 vs 2-3 was NR vs 11.13 months (HR 0.32; 95% CI, 0.14-0.76; p = 0.01) and 78% vs 49% survived at 12 months. Conclusions: OWO and lower mEPSILoN were associated with longer PFS and OS, respectively, in patients with advanced NSCLC who were treated with frontline ICI with or without concomitant chemotherapy, regardless of PD-L1 expression. These findings are consistent with recent studies that have reported these parameters as predictive markers of response in patients with NSCLC. However, this is the first study to our knowledge to evaluate these markers in frontline ICI treatment with or without chemotherapy.[Table: see text]

e21103 Background: Current literature has demonstrated non-inferiority of liquid biopsies relative to tissue genotyping to identify detectable biomarkers in patients with metastatic non-small cell lung cancer (NSCLC). However, liquid biopsies have the ability to report next generation sequencing (NGS) results faster than tissue NGS. Tissue NGS has the disadvantage that depends on the amount of tumor available after the original pathology report is issued and it is not infrequent that there is an insufficient sample for NGS (QNS). Another major disadvantage is that the results of tissue NGS usually take longer than blood NGS due to the process of requesting and shipping tissue. This study aimed to illustrate that liquid biopsies can be the new standard in front line decision making for patients with stage IV NSCLC when compared with tissue NGS. Methods: This was a retrospective review of adult patients within the Memorial Cancer Institute who were diagnosed with stage IV NSCLC and received, at the same time, a tissue and liquid biopsy between July 1, 2015 and June 30, 2020. Patients were excluded if biopsies were not performed within one month apart or the treatment decision was not determined. Data collected utilizing the electronic medical record included: demographics, biopsy turnaround time, biopsy type used to make the final treatment decision, insufficient tissue samples, date of disease progression and death, and detection of genomic biomarkers. Descriptive statistics and logistic regression analysis were calculated for all demographic and clinical outcomes. Results: One hundred and thirty-one patients were evaluated. Of the evaluated patients, 53% were female, 47% were men, 74% had a smoking history and 26% never smoked. Non-Hispanic Whites were 56%, Hispanics 29%, and African Americans 8%. The average age at diagnosis was 66 ± 13 years of age. Of the 122 tumors where genomic biomarkers were detected by liquid NGS, 75% had actionable genetic aberrations (EGFR, ALK, ROS-1, NTRK 1-3, BRAFv600, RET, METexon14skipping). While only 53% had actionable genetic alterations out of 111 tumors with detectable mutations by tissue NGS. Final treatment decisions were made in 70% of the patients based on the results of the liquid NGS that generally arrived first and only 30% of the treatment decisions on the tissue NGS. The median time to start therapy was 9 days with liquid NGS vs 33.5 days with tissue NGS. More than 90% of the patients with an actionable mutation with liquid NGS were able to start therapy within 11 ± 5 days. Progression free survival was similar for patients in which the treatment decision was based on liquid NGS vs tissue NGS (p = 0.99). Conclusions: In patients with stage IV NSCLC, NGS done by liquid biopsies may be used as the standard of care to make the front line therapeutic decision in patients with NSCLC. A prospective study with a larger sample is probably needed to validate these results.

TPS9136 Background: METamp is a mechanism of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). METamp occurs in ̃30% of patients who progress on EGFR TKI therapy as measured using fluorescence in situ hybridization (FISH). There is an unmet need for targeted treatment options in these patients. Combination treatment with a MET TKI may overcome MET-related osimertinib resistance. Tepotinib is an oral, once daily (QD), highly selective, potent MET TKI. In the INSIGHT study (NCT01982955), the combination of tepotinib and the EGFR TKI gefitinib improved outcomes in patients with EGFR-mutant METamp NSCLC and EGFR TKI resistance compared to chemotherapy (INSIGHT). Median progression-free survival (PFS) was 16.6 vs 4.2 months (hazard ratio [HR] = 0.13; 90% confidence interval [CI]: 0.04, 0.43) and median overall survival (OS) was 37.3 vs 13.1 months (HR = 0.08; 90% CI: 0.01, 0.51). Methods: INSIGHT 2 is a global, open-label, Phase II trial of tepotinib + osimertinib in patients with advanced EGFR-mutant NSCLC. Following a protocol amendment in Apr 2020, the study is enrolling patients with acquired resistance to 1L osimertinib (radiological documentation of disease progression following previous objective clinical benefit) due to METamp by FISH (GCN ≥5 or MET/CEP7 ratio ≥2). Patients must be ≥18 years old, have an Eastern Cooperative Oncology Group performance status of 0/1, and normal organ function. Both tissue and liquid biopsy, obtained at the time of progression to osimertinib, will be sent for central confirmation of METamp. Liquid biopsy samples will also be used for exploratory biomarker evaluation. Enrollment is allowed based on local FISH testing while awaiting central confirmation of METamp. Patients will receive 500 mg QD (450 mg active moiety) tepotinib + 80 mg QD osimertinib until disease progression, unacceptable toxicity, or consent withdrawal. The study is anticipated to enroll 120 patients. The primary endpoint is objective response rate (ORR) by independent review (RECIST v1.1) in patients with METamp, centrally confirmed by FISH. Secondary endpoints include ORR by investigator assessment, duration of response, disease control, PFS, OS, pharmacokinetics, health-related quality of life, tolerability, and safety. An exploratory tepotinib monotherapy arm will enroll 12 patients to assess the contribution of tepotinib to the activity of the combination. At progression (determined by independent review committee), monotherapy patients can switch to combination treatment. These patients will be analyzed separately. Recruitment is ongoing, with > 300 patients prescreened. Approximately 100 sites in 17 countries in Europe, Asia, and North America are expected to participate. Approximately 15 sites will recruit patients in the US. Clinical trial information: NCT03940703.