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4124 Background: Despite the frequent use of capecitabine and temozolomide (CAPTEM) to treat metastatic, well-differentiated pancreatic neuroendocrine tumors (PNETs), no reliable genomic predictors of response currently exist. PNETs commonly harbor mutations in MEN1, ATRX, DAXX, and the PI3K/AKT/mTOR pathway. We sought to determine whether the mutational status of these genes correlates with response to CAPTEM. Methods: A retrospective cohort of PNET cases seen at Cedars-Sinai Medical Center or from Perthera’s Real-World Evidence Database included 23 patients who were treated with CAPTEM in 1st or 2nd line and had targeted next-generation sequencing (NGS) of their tumors available. Genomic alterations were correlated with progression-free survival (PFS) using multivariate Cox regression analysis. Results: We analyzed 23 PNET patients, 4 (17.4%) of whom had documented functional tumors. We identified MEN1 mutations as positively associated with CAPTEM response, but this effect was less pronounced for the subset with co-occurring DAXX mutations, which are commonly found alongside MEN1 alterations. With and without accounting for line of therapy, we found that PFS on CAPTEM was significantly longer in MEN1-mutated, DAXX-wildtype tumors compared to other mutation profiles ( P < 0.01, see Table). ATRX (67%) and PTEN (33%) alterations were also enriched in the MEN1-mutated/ DAXX-wildtype subset; however, other PI3K/AKT/mTOR alterations were common across all MEN1-mutated cases. Conclusions: We describe a novel genomic signature ( MEN1 mut/ DAXX wt) that correlates with PNET response to CAPTEM therapy and is exploratory in nature. Prospective validation of these associations is warranted while taking into account other therapies, histopathologic factors, and other genomic correlates. [Table: see text]

e16746 Background: Ataxia telangiectasia mutated (ATM) protein is a DNA damage repair enzyme and regulates normal cell-cycle mechanisms. Germline ATM mutations are associated with increased risk for developing pancreatic cancer (PC), occurring in approximately 2% of PC patients (pts). The role of germline ATM mutations in PC is not well defined. The objective of this study was to compare survival outcomes in patients with germline ATM mutations compared to somatic ATM mutations in PC. Methods: Tumor genomic profiling was completed in 144 PC patients at a single institution in the US, where pts were included in the analysis if they had either germline ATM mutations or somatic ATM mutations. Clinical outcomes were compared between pts with germline ATM mutations and pts with somatic ATM mutations only. Adjusted Cox regression models were fit to evaluate the impact of ATM mutation on overall survival (OS), calculated from treatment (tx) initiation to death, and progression free survival (PFS) calculated from tx initiation to first progression. Results: From 144 PC pts evaluated, 7 pts (4.9%) had germline ATM mutations, all of whom presented with metastatic disease, and 14 pts (9.7%) with somatic ATM mutations only, of whom 10 presented with metastatic disease and 4 who initially presented with locally advanced PC. The majority of pts (15/21), including all 7 pts with germline ATM mutations and 8 with somatic ATM mutations, were treated with first line gemcitabine and abraxane. Median OS was not reached in patients with germline mutations, and 11 months for patients with somatic mutations. Pts with germline ATM mutations had significantly higher OS (HR: 0.12, 95% CI 0.03-0.62, p = 0.01) and PFS (HR:0.26, 95%CI 0.07-0.91, p = 0.04) compared to patients with somatic ATM mutations only after adjusting for age, sex, and first-line tx. Conclusions: Pts with germline ATM mutations may experience greater survival benefit from tx compared to those with only somatic ATM mutations. Further research into the underlying mechanism is warranted.

e16564 Background: In rGC ( > cT2), we investigated the impact of various neoadjuvant and/or adjuvant treatment modalities on pathologic complete response (pCR), surgical margins, and overall survival (OS). Methods: The National Cancer Database (NCDB) was interrogated to identify rGC patients (pts) between 2004-2015. Gastric adenocarcinoma cases that were cT2-T4b, any N, M0 and underwent definitive surgery were included. We analyzed the association of 9 treatment groups: neoadjuvant chemoradiation only (nCRT), neoadjuvant chemo only (nCT), adjuvant chemo only (aCT), adjuvant chemoradiation only (aCRT), neoadjuvant chemo and adjuvant radiation (nCTaRT), received any chemo at all (any CT), received any chemoradiation at all (any CRT), received any radiation at all (any RT), and no perioperative therapy (NT) across 3 endpoints: pCR, margin status, and OS using logistic regression and Cox proportional hazards models with adjustment for baseline characteristics. Results: From 183,204 GC cases screened, a total 3061 pts were available with a median follow-up of 41.6 mos and median OS of 29.0 mos. On multivariable analyses, nCRT was associated with the greatest odds of having a pCR (odds ratio or OR 59.6, 95% confidence interval (CI) 10.6-334.1, p < 0.001) with NT as the reference. Having received any RT (OR 0.42, 0.10-1.86), nCRT (OR 0.68, 0.33-1.37), or nCT (OR 0.83, 0.60-1.15) was associated with the lowest odds for having positive surgical margins although none reached p < 0.05. For OS, having received any CT (hazard ratio or HR 0.41, 0.35-0.48) was associated with the lowest risk of death followed by nCRT (HR 0.48, 0.35-0.66), aCT (HR 0.52, 0.43-0.62), aCRT (HR 0.55, 0.48-0.63), any CRT (HR 0.61, 0.41-0.91), nCT (HR 0.62, 0.54-0.71), and nCTaRT (HR 0.67, 0.52-0.87, all p < 0.05). Median OS was greatest in pts treated with any CT (53.9 mos) followed by nCRT (39.1 mos) and aCT (36.1 mos) with 2-year OS rates being 65.6% (95% CI 61.3-69.5%), 63.6% (52.3-73.0%), and 59.7% (54.2-64.7%), respectively. Conclusions: Although nCRT had a high pCR rate, receipt of any CT (neoadjuvant and/or adjuvant) afforded the greatest OS in this modality-by-modality comparison in a large cohort of rGC pts.

4641 Background: Approximately 90% of PDAC tumors are driven by activating KRAS mutations. The biological and clinical impact of common KRAS variants (e.g. G12D, G12V, G12R) and less common variants (e.g. G12C, Q61H, Q61R) remains largely unknown despite the emergence of variant-specific treatment strategies. Methods: We retrospectively analyzed real-world outcomes from 1475 PDAC pts who underwent molecular profiling via the Know Your Tumor program. Overall survival (OS) and progression-free survival (PFS) were analyzed by choice of 1st line standard therapies. Outcomes in pts with specific KRAS mutations were compared against the KRAS G12D cohort using Cox regression. Based on our prior data, tumor profiles with actionable molecular findings (DDR mutations or other drivers) were evaluated separately. Results: The prognostic/predictive value of specific KRAS variants revealed differences in real-world outcomes (Table). OS was greater in pts with KRAS G12V and G12R variants, as was PFS on 5FU-Based Therapy (e.g. FOLFIRINOX) but not for Gemcitabine/nab-Paclitaxel. Opposing trends were noted for KRAS Q61. Pts with KRAS wild type tumors as well as both actionable subgroups also had an improved OS. Conclusions: In this large national dataset, we demonstrate that KRAS mutation status and specific variants appear to be prognostic as well as predictive in pancreatic cancer. [Table: see text]

4634 Background: Interleukin-1-alpha (IL-1α) promotes tumor inflammation by shaping the tumor microenvironment, including tumor infiltrating myeloid cell recruitment, angiogenesis, and skewing and suppression of anti-tumor immunity. IL-1a inhibition in cancer subjects increased lean body mass and decreased fatigue, pain, and appetite loss. We report results of a single site phase 1 trial for an IL-1α antagonist (bermekimab) in combination with nanoliposomal irinotecan (Nal-Iri) and 5-fluorouracil (5FU)/folinic acid (FA) in patients with advanced pancreatic adenocarcinoma and cachexia who have failed gemcitabine-based chemotherapy. Methods: A Bayesian adaptive design based on escalation with overdose control was used. Data are presented as frequency (percentage, %) for categorical variables and mean (± standard deviation) for continuous variables. Lean body mass (LBM) and fat mass were assessed at cycle 1 and 3, and T-test was used to assess changes. Results: Of 21 pts enrolled, 18 were evaluable. Median age was 68. Bermekimab in combination with nanoliposomal irinotecan (70 mg/m2) and 5-fluorouracil (2400mg/m2) was well tolerated at the highest dose level (12mg/kg). 10 pts experienced grade 3/4 toxicities including sepsis, anemia, hypokalemia, neutropenia, or leukopenia. There were no instances of grade 3/4 diarrhea. Ten pts (56%) had weight stability ( < 0.1 kg/BMI). Efficacy results include PR (n = 4, 22%), SD (n = 13, 72%), and PD (n = 1, 6%). PFS 7.7 m (95% CI: 4.34-12.73) and OS 10.5 m (95% CI: 5.79-17.70) were reported. LBM and fat mass change was -1.6 kg (± 2.0; p-value = 0.003) and -1.4 kg (± 1.7; p-value = 0.004). CRP was 20.4 (± 35.6) at cycle 1 and decreased significantly (p-value = 0.005). Serum VEGF decreased from C1 to C3 (p-value = 0.007). QLQ-PAN26 domains improved, particularly hepatic function (p = 0.04). FAACT scores improved for functional well-being (p = 0.02). Average daily step counts increased by 589 steps/day (p = 0.29) and resting heart rate decreased by 2.5 beats per minute (p = 0.005), as assessed by actigraphy. Conclusions: Bermekimab, nano-liposomal irinotecan and 5-fluorouracil in refractory pancreatic cancer patients with cachexia was well-tolerated with promising efficacy and improvements in patient performance. Clinical trial information: NCT03207724 .

Background: Patients with pancreatic cancer often develop progressive weight loss and sarcopenia, described as cancer cachexia syndrome. Despite evidence showing that pancreatic cancer cachexia is associated with a poor prognosis, reduced tolerance to therapy, and diminished quality of life, no predictive biomarkers have been identified to date. Certain mutant KRAS isoforms are associated with significant alterations to tumor metabolism and have been correlated with changes in weight and survival. However, the clinical implications resulting from specific KRAS mutations in pancreatic cancer have yet to be fully explored. Methods: A retrospective analysis was performed to compare weight changes and survival in 150 pancreatic cancer patients with various KRAS alterations identified by next-generation sequencing (Foundation Medicine, Inc., Cambridge, MA). Survival data and weights documented between 6 months prior to diagnosis and the date of death or the last follow-up visit were abstracted from the medical record and evaluated using statistical analyses, including functional principal component analysis for sparse functional data, Ward cluster, logistic regression, analysis of variance, and Cox regression. Using derivative principal component scores, we separated patients into two groups demonstrating either constant or decreasing weight over time. Results: 77% of evaluated patients had a KRAS mutation, and 21% had KRAS wild-type. Of patients with mutant KRAS, 84% had an alteration at G12, 10% at Q61, and 3% at G13. While there was no significant difference in weight changes between KRAS wild-type patients and patients with a Q61 mutation, patients with non-Q61 mutations were 2.5 times more likely (p = 0.05) than wild-type patients to demonstrate weight loss over time. Furthermore, KRAS mutants had worse survival when compared to KRAS wild-type patients. Irrespective of mutational status, patients whose weight did not decrease were 69% less likely to die (p = 0.039). Conclusion: We demonstrated that mutant KRAS isoforms G12 and G13 mutations correlate with weight loss, whereas Q61 KRAS mutations and wild-type KRAS do not. Furthermore, weight loss in all patients increased their risk of death. These findings suggest that KRAS subtypes may have unique genotype-to-phenotype features, particularly with weight loss that could warrant tailored therapeutic strategies in at-risk subgroups. Future studies of larger scope, and ideally prospective in nature, are warranted in patients stratified by KRAS isoform. Citation Format: Haesoo Kim, Camille Ng, Marcio A. Diniz, Michel H. Montoril, Michelle Guan, Victor Brodsky, Eric Vail, Richard Tuli, Edik Blais, Sungjin Kim, Emanuel Petricoin III, Jun Gong, Veronica R. Placencio-Hickok, Andrew E. Hendifar. Association of mutant KRAS isoforms with weight loss in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C27.