Duma, Narjust

93 Background: Tumor mutational load (TML) has been proposed as a biomarker of responsiveness to novel immune checkpoint inhibitors (ICIs) due its association with increased neoantigen formation and tumor immunogenicity. Gastrointestinal cancers (GICs) are generally insensitive to ICIs; therefore the aim of this study was to evaluate the TML, clinically relevant genomic alterations (CRGAs), and PDL-1 status of GIC patients (pts). Methods: We analyzed samples of pts with GICs using a multiplatform profiling tool (Caris Life Sciences, Phoenix, AZ). TML and CRGAs were calculated based on next generation sequencing and mutational load was stratified as high (≥17 mut/Mb), intermediate (8-16 mut/Mb), and low (≤ 7 mut/Mb). PD-L1 status was determined by IHC. Descriptive statistics and simple linear regression were used for analysis. Results: A total of 85 pts with GICs were analyzed. The median pt age was 65. 53% were males and 47% were females. Tumors were colorectal 51%, pancreatic 13%, esophageal 13%, gastric 9%, hepatobiliary 11%, anal canal 4%, and small intestine 1%. 80 cases (94%) had an adequate sample for profiling and TML was available in 59 cases (74%). Cases were 5% TML-high, 56% TML-intermediate, and 39% TML-low. The median TML was 9 mut/Mb and median CRGAs was 3. The most commonly detected CRGAs were TP53 (56%), APC (44%), KRAS (40%), ATM (18%) and PTEN (6%). A positive but very weak correlation was found between TML and number of CRGAs (R2 = 0.3). PD-L1 status was available in 74 cases (93%) with 86% being PD-L1 negative and 14% PD-L1 positive. PD-L1 expression was most commonly seen in esophageal (50%) and anal canal (30%) cancers. Among 57 tumors tested for both biomarkers, no correlation was found between a high TML and PD-L1 expression. Conclusions: TML varies among GICs, and higher TML scores were not associated with PD-L1 expression, but there was a weak correlation between TML and the number of CRGAs. Further analysis by stratification of GIC type and prognostic analysis to assess the correlation between TMB and response to ICIs is warranted.

186 Background: The optimal sequence strategy of BRAF/MEK inhibitors, anti-PD- 1/PDL-1 and anti-CTLA-4 in metastatic BRAF-mutated melanoma patients (pts) is unknown and no treatment guidelines exist. Therefore, we report a single-institution experience of different treatment approaches using targeted therapy (TT) and immunotherapy and its impact on outcomes. Methods: BRAF-mutated metastatic melanoma pts treated with TT and immunotherapy from 2012 to2017 were analyzed. Six groups were identified based on treatment strategy. All time-to-event analyses were calculated using the Kaplan-Meier method and Wilcoxon test. Results: Forty-four pts were identified. The median age at diagnosis was 49 years (range 21-73), 54% pts were females and 43% developed brain metastases during disease course. The most common approach strategy was immunotherapy followed by TT, the median duration of treatment was 11 and 19 weeks, respectively. Time-to-next therapy (TTNT) following 1st line treatment was similar in pts treated with TT (median 23 weeks [95% CI: 15-31]) or immunotherapy (median 26 weeks [95% CI: 10-33], p = 0.94). A trend towards better overall survival (OS) was seen in pts who received immunotherapy followed by TT (p = 0.09); patients who received salvage chemotherapy (carboplatin/paclitaxel) had significantly longer OS (median 7 years [95% CI: 3.2-7.08]) ( p = 0.03). Conclusions: No differences in TTNT were seen with immunotherapy, TT or combined (triple therapy) when used as 1st or 2nd line. The significant longer OS benefit with 1st line immunotherapy was only seen in patients who received chemotherapy later in their treatment course. [Table: see text]

Purpose: Many cancer clinical trials lack appropriate representation of specific patient populations, limiting their generalizability. Therefore, we determined the representation of ethnic minorities and women in cancer clinical trials. Methods: Enrollment data from all therapeutic trials reported as completed in ClinicalTrials.gov from 2003 to 2016 were analyzed. We calculated enrollment fractions (EFs) for each group, defined as the number of enrollees divided by the 2013 Surveillance, Epidemiology, and End Results (SEER) database cancer prevalence. Results: Of 1,012 clinical trials, 310 (31%) reported ethnicity with a total of 55,689 enrollees. Participation varied significantly across ethnic groups. Non-Hispanic whites were more likely to be enrolled in clinical trials (EF, 1.2%) than African Americans (EF, 0.7%; P < .001) and Hispanics (EF, 0.4%; P < .001). A decrease in African American (6% v 9.2%) and Hispanic (2.6% v 3.1%) enrollment was observed when compared with historical data from 1996 to 2002. Younger patients (age younger than 65 years) were more likely to be enrolled in clinical trials than the elderly (64% v 36%; P < .001). Low recruitment of female patients was observed in clinical trials for melanoma (35%), lung cancer (39%), and pancreatic cancer (40%). Conclusion: We observed a decrease in recruitment of minorities over the past 14 years compared with historical data. African Americans, Hispanics, and women were less likely to be enrolled in cancer clinical trials. Future trials should take extra measures to recruit participants that adequately represent the US cancer population.

Background/Aims. Autonomic dysfunction (AD) after allogeneic stem cell transplant (SCT) is a rare occurrence and likely immune-mediated in etiology. There is limited literature on this topic and hence, we wish to briefly describe management of two cases at our institution and their outcomes. Methods. We retrospectively identified two patients with immune-mediated AD after SCT from our database. Immune-mediated AD was defined as AD secondary to an immune-mediated etiology without an alternative cause and responding to immunosuppression. Results. The first case is of a 32-year-old man with acute myeloid leukemia (AML) who underwent double umbilical cord allogeneic SCT. The second patient was a 51-year-old woman with secondary AML who underwent matched-related donor allogeneic SCT. Both underwent an extensive work-up for an underlying etiology prior to treatment with intravenous immunoglobulin (IVIG). Conclusions. AD after SCT is a rare yet significant clinical entity. A work-up of underlying etiology should be performed. IVIG is a treatment option for these patients.

Abstract Background: Early phase trials (EPCT) provide significant value by evaluating the possible benefits of new agents. The eligibility criteria in EPCT are usually rigorous and may exclude many patients (pts) commonly seen in clinical practice. Our objective was to identify the most common comorbidities excluded in EPCT for NSCLC. Methods: ClinicalTrials.gov was queried on August 1st of 2016. 299 interventional drug trials were extracted from 2010 to 2016. We studied the trial characteristics including: experimental therapy, location, funding and eligibility criteria. Exclusion of CNS metastasis was treated as a binary variable (strict exclusion vs. allowed). Logistic regressions were used for statistical analysis. Results: Of the 299 trials, 164 (55%) were phase II, 81 (27%) phase I and 54 (18%) phase Ib/II. 164 (55%) were conducted in the United States (US), 45 (15%) in Asia, 39 (13%) in Europe and 51 (17%) were international. 171 (57%) trials were funded by the industry, 54 (18%) by government agencies and 74 (25%) were investigator initiated. Survival was an end-point in 97 (32%) trials. 70 (23%) trials required a repeat lung biopsy. 54 (18%) trials excluded pts &gt;75 years of age. 99 (33%) trials required creatinine levels &lt;1.5 mg/dl, 132 (44%) liver enzymes &lt;2.5 and total bilirubin &lt;1.5 of the upper limit of normal. 88 (29%) trials required Hgb&gt;9 g/dl and 141 (47%) excluded pts with platelets &lt;100,000/dl. In terms of comorbidities, 84 (28%) trials excluded pts with atrial fibrillation, 94 (31%) with any anticoagulation therapy and 120 (40%) HIV positive pts. CNS involvement was a significant exclusion factor, 123 (41%) trials excluded pts with CNS metastasis. On univariate analysis, the odds of CNS metastasis exclusion were significantly higher in immunotherapy trials (OR 1.72, 95%CI 1.2-2.4, p&lt;0.01) and lower in European trials (OR 0.76, 95%CI 0.6-0.9, p&lt;0.005). In multivariate analysis, US based trials had higher odds of exclusion of CNS metastasis (OR: 3.2, 95%CI 1.4-7.5, p&lt;0.05). Conclusions: Many of the EPCTs excluded pts with advanced age, cytopenias and other common comorbidities, eliminating the possibility of many of our aging pts from participation. Regarding CNS disease, our analysis suggests the type of agent and location may influence the trial design about CNS metastasis inclusion. Investigators should review whether sufficient justification exists for every exclusion criterion before their incorporation in future trial protocols. Citation Format: Narjust Duma, Yucai Wang, Aaron Mansfield. Comorbidities limiting recruitment of non-small cell lung cancer (NSCLC) patients in early phase trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 766. doi:10.1158/1538-7445.AM2017-766

803 Background: The routine use of comprehensive genomic profiling (CGP) has led to better genomic characterization, more personalized treatments and higher enrollment in clinical trials for many solid cancers. The aim of this study was to evaluate the clinical and genomic prolife of patients (pts) with gastrointestinal cancers (GIC) with the use of a CGP assay and their potential therapeutic benefit at a large comprehensive cancer center. Methods: We retrospectively analyzed 83 consecutive pts with GIC that had CGP at the JTCC between 01/2014-09/2016. Demographics, CGP results, and clinical characteristics were studied. Clinically relevant genomic alterations (CRGAs) were identified using the FoundationOne assay (Foundation Medicine, Cambridge, MA), and were defined as alterations linked to approved therapies and those under evaluation in genotype-driven clinical trials. Results: 83 pts with GIC were analyzed. 46.9% males and 53.0% females. The median age at diagnosis was 58.5 years. 73 (88%) patients were stage III/IV at diagnosis. Tumors consisted of colorectal (36%), gastric (24%), pancreatic (12%) and cholangiocarcinoma (6%). All the pts were found to have at least one genomic alteration (GA). CRGAs were identified in 63 (76%) of cases, with an average of 2 per pt. The most frequently identified GAs were TP53 43 (29.9%), APC 24 (16.7%), KRAS 31 (21.5%), ARID1A 12 (8.3%), PIK3CA 11 (7.6%), and SMAD4 11 (7.6%). Of the 63 pts with CRGAs, 23 (36%) received one of the therapies suggested by the NGS assay, and 9 (14%) were enrolled in a clinical trial. Conclusions: The use of CGP assay identified a high frequency of CRGAs in GIC pts. The assay provided information for genomic-directed therapy in 36% of the patients. The routine use of CGP in GIC may lead to pts receive more personalized treatments. The potential benefit of selected targeted therapies in individual cases suggests that larger studies of treatment guided by routine CGP in gastrointestinal malignancies are warranted.

791 Background: With the surge of drug development in the past decade, early phase clinical trials (EPCT) have gained value evaluating the potential benefits of new therapies. The inclusion/exclusion criteria in EPCT are usually rigorous and may exclude many patients (pts) commonly seen in clinical practice. Our objective was to identify the most common comorbidities excluded in EPCT for CRC. Methods: ClinicalTrials.gov was queried on December 1stof 2015. We reviewed the characteristics and eligibility criteria of 369 phase I/II interventional drug trials including: experimental arm therapy, location, and exclusion/inclusion criteria. Logistic regressions were completed and exclusion was studied as a binary variable. Results: Of the 369 trials, 68% were phase II and 32% phase I. 46% were conducted in the United States, 30% in Europe, 15% in Asia and 9% in other locations. 74 (20%) trials excluded pts > 70 years of age. 142 (39%) trials required creatinine levels < 1.5 mg/dl, liver enzymes (AST/ALT) < 2.5 and bilirubin < 1.5 of the upper limit of normal. Cytopenia was a significant exclusion factor: 147 (47%) trials required Hgb > 9 g/dl and 218 (59%) excluded pts with platelets < 100,000/dl. In terms of comorbidities, 98 (27%) trials excluded pts with heart failure (NYHA class 3/4), 74 (20%) with atrial fibrillation, 112 (31%) with any anticoagulation therapy and 155 (42%) with positive HIV. Trials located in the US were more likely to exclude pts with Hgb < 9g/dl (OR: 1.5, 95%CI: 1.1-2.3, p < 0.05), immunotherapy trials were more likely to exclude pts on any anticoagulation (OR:1.8, 95%CI: 1.2-2.8, p < 0.007) and targeted therapy trials were more likely to exclude pts with history of DVT/PE or cardiovascular diseases (OR: 3.4, 95%CI: 1.9-5.8, p < 0.0001; OR: 2.3, 95%CI: 1.3-3.8, p < 0.002, respectively). Conclusions: 20% of EPCTs on CRC excluded pts with advanced age, organ dysfunction and common comorbidities. Many of the EPCT reviewed were not inclusive of our aging oncology population who are more likely to have multiple comorbidities. Investigators should review whether sufficient justification exists for every exclusion criterion before their incorporation in future trial protocols.