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641 Background: Tumors of neuroendocrine origin are a rare, heterogenous group of neoplasms. Neuroendocrine neoplasms (NENs) are categorized by site of origin, differentiation status, and by grade (Ki-67 expression and/or mitotic rate), with prognostic variability accordingly. These tumors frequently metastasize to bone, with reported incidence between 6-12% by older SSTR imaging. Our study evaluates patients with well-differentiated tumors of neuroendocrine origin to determine the incidence of osseous metastases when evaluated with higher-sensitivity Ga68 DOTATATE PET scans. The study characterizes the clinical features. Methods: This study was performed at a single, 3-site, US tertiary-care institution. IRB approval was obtained. An automated data extraction tool was used to mine the electronic medical record by searching all positron emission tomography (PET) studies for keywords. Identified scans had to include a combination of the following keywords: “Dotatate” AND “met*” or “lesion” AND “bone” or “osse*” or “skel*”. The individual medical records from the generated report were reviewed to include only patients with 1) well-differentiated NETs of GI and pancreatic origin, lung carcinoid, paraganglioma/pheochromocytoma, or other/unknown primary site, and 2) patients with confirmed osseous metastatic disease. Patient data was entered into a database and evaluated in aggregate. Results: 1,948 PET scans of 1,473 patients were extracted from the EMR, from which 424 patients were identified for inclusion; scans were performed between 5/2018 and 5/2021. Calculated incidence of bone metastasis by Ga68 DOTATATE PET was 28.8%. Median age of included population was 61 years (range 14-92), 49.5% being male. Site of origin was 47.2% bowel NET, 18.9% pancreatic NET, 10.8% lung carcinoid, 10.6% paraganglioma/pheochromocytoma, 2.1% other site, and 10.4% unknown primary. Majority of patients were asymptomatic (64.0%), had sclerotic appearance (76.7%), Krenning 4 (71.4%), and >3 sites (68.3%) of osseous disease. 94.6% of the population had disease of the axial skeleton; 65.6% appendicular. Only 57 patients (13.4%) with osseous disease suffered a fracture, despite metastases at high-risk sites. Fracture occurred at disproportionately low rates in NETs originating in bowel (22.8% of fractures), with proportionately higher rates among pancreatic NETS and paragangliomas/pheochromocytomas (31.6% and 22.8%, respectively). Fractures occurred at proportionately higher rates in higher-grade disease compared to low-grade. Conclusions: Osseous metastatic disease in well-differentiated NENs is evident at much higher rates when imaging with Ga68 DOTATATE PET compared with previously reported data. Nevertheless, fracture occurred at a low rate, suggesting that these patients are at a relatively low risk for skeletal-related events.

688 Background: Guidelines recommend patients with pancreatic ductal adenocarcinoma (PDAC) undergo genetic testing for germline pathogenic variants (PV). The aim of this study was to evaluate compliance with recently updated guidelines (May 2019) and assess subsequent uptake and outcomes of genetic testing in PDAC patients. In addition, social and clinical factors associated with genetic testing were assessed. Methods: A retrospective chart review of patients diagnosed with PDAC between May 2018 and August 2020 was performed. Discussion and subsequent uptake of genetic testing was reviewed and compared between a 12-month period before (pre-guideline) and a 12-month period after (post-guideline) guidelines were updated, accounting for a three-month transition period. Univariate and multivariate logistic regression analysis was used to assess factors predictive of undergoing genetic testing. Results: In total, 534 patients with PDAC were identified; 321 (60.1%) in the pre-guideline period and 213 (39.9%) in the post-guideline period. The mean age at diagnosis was 68 years and 47% were female. Genetic testing was discussed in 34% (109/321) of pre-guideline and in 39% (84/213) of post-guideline patients ( P = .23). Of those, 82% (89/109) of patients in pre-guideline and 75% (63/84) in post-guideline groups underwent subsequent genetic testing ( P = .71). In 26 (17.1%) of 152 tested patients, a PV was identified, of which 17 (11.2%; 17/152) had a PDAC-associated PV. Age, cancer stage at diagnosis, length of survival, and having a first-degree relative with pancreatic cancer were significant predictors of genetic testing on multivariate analysis. Conclusions: Adherence to recently updated guidelines is poor and germline genetic testing in PDAC patients remains insufficient. Efforts to increase awareness of benefits of testing, which include personalized therapies for patients and cascade testing in family members for subsequent enrollment in pancreatic cancer surveillance programs, could improve future uptake.[Table: see text]

199 Background: The progression of neoplasia in colorectal cancer (CRC) has been well characterized, with the evolution typically involving mutations in APC, KRAS, and p53, among others. POLE/POLD1 genes encode for proteins essential in enzymatic DNA polymerase function, yet POLE/POLD1 mutations in tumors are poorly characterized. Pathogenic mutations in POLE/POLD1 lead to decreased fidelity of DNA replication, resulting in a high tumor mutational burden (TMB-H) independent of deficient mismatch repair (dMMR) and high microsatellite instability (MSI-H). Studies have shown associations between this hypermutated phenotype and susceptibility to immune checkpoint inhibition, which may be attributable to neoantigen creation. As such, these tumors are a clinically relevant phenotype requiring further investigation. Here, we characterized POLE/POLD1 alterations in a large, real-world cohort of patients with CRC. Methods: We retrospectively analyzed de-identified records of 9,136 primary CRC patients profiled with the Tempus xT assay. The assay includes DNA-seq of 595-648 genes at 500x to evaluate single-nucleotide variants, insertions/deletions, and copy number changes. Immunological markers analyzed included tumor mutational burden (TMB), MSI, and dMMR. MSI-H was determined by the assay through assessment of 239 loci. dMMR was determined by immunohistochemistry. Results: A total of 217 patient tumors harbored somatic POLE/POLD1 mutations (n = 203 POLE, n = 13 POLD1, and n = 1 POLE and POLD1; none germline), with no differences noted in baseline demographics including gender and age. Among the POLE/POLD1-mutant cohort, POLE copy number losses accounted for most mutations (n = 127, 59%), with short variants and copy number amplifications accounting for 35% (n = 76). The remainder of tumors exhibited POLD1 copy number changes (n = 14), including one with both POLE and POLD1 copy number loss. POLE/POLD1-mutated tumors presented with a lower frequency of MSI-H compared to wild-type (1.8% vs 6.1%, P= 0.018). Conversely, there was a higher frequency of TMB-high cases ( > 10 mut/Mb) for POLE/POLD1-mutated compared to wild-type tumors (22% vs 9.9%, P< 0.001). Differences between POLE/POLD1-mutated and wild-type tumors were also observed among many co-mutated genes, including APC (80% vs 65%, P< 0.001), ALK (31% vs 11%, P< 0.001), ATM (12% vs 3.6%, P< 0.001), BRCA2 (12% vs. 3.2%), and RET (24% vs 8.9%, P< 0.001). Conclusions: Patients with POLE/POLD1 mutations exhibited significant differences across immunological markers and molecular co-alterations. POLE/POLD1 mutations in CRC have been previously described to present with a hypermutated phenotype; however, 78% of tumors exhibited low TMB despite POLE/POLD1 mutations. Thus, these results have identified POLE/POLD1-mutated tumors as a unique genomic subpopulation, and further studies are needed to better characterize POLE/POLD1 mutations in CRC.

3601 Background: Two cfDNA assays are FDA-approved for use in advanced cancer pts across solid tumors. While several NCCN guidelines recommend cfDNA as a valid and useful method for molecular testing, the utility varies by cancer type. Despite the growing number of molecular alterations pertinent to first-line treatment in mCRC, current guidelines offer little guidance on the use of cfDNA in mCRC. Here we assess the ability of cfDNA to detect guideline-relevant actionable biomarkers informative for first-line therapy selection and beyond in patients with mCRC. Methods: We queried consecutive samples from advanced cancer pts with a diagnosis of CRC who underwent testing via a commercially available cfDNA assay (Guardant360) from September 2018 to January 2022. Validation and content of this assay has been previously described. To enrich for less heavily treated pts, we limited analysis to those whose first cfDNA test was done during the study period and only included the pt’s first test. The maximum variant allele fraction (maxVAF) for each test was used as a proxy for tumor shed and was compared between cancers with a Mann-Whitney test. The frequency of suspected germline alterations was assessed only in pts who received testing via a panel version with expanded mismatch repair (MMR) gene coverage. Tissue frequencies for select biomarkers were obtained from the MSK-IMPACT Clinical Sequencing Cohort in cBioPortal. Results: In total, 14,345 pts with mCRC received their first cfDNA test during the study period, with 92% of pts (13,190) having >1 cfDNA alteration detected. Median age was 62 and 44% of pts were female. The frequencies of key biomarkers are listed in Table 1. The median maxVAF was 5.6%, compared to 2.5% and 1.8% for pts with advanced gastric and NSCLC, respectively (p = < 0.0001 for both). The average turnaround time (TAT) for tests was 7 calendar days. Conclusions: cfDNA results from pts with mCRC demonstrated detection of biomarkers essential to first-line treatment decisions at a frequency comparable to what has been reported via tissue genotyping. mCRC pts had significantly higher tumor shed compared to other cancer types with guidelines that recommend cfDNA as an option for molecular testing, suggesting a potential gap in coverage. Tissue availability in mCRC does not guarantee comprehensive testing is completed quickly (compared to the 7-day TAT seen for cfDNA here), making it an attractive alternative strategy for first-line therapy selection in mCRC. [Table: see text]

TPS4179 Background: Poorly differentiated, extrapulmonary small cell NEC are rare cancers with median overall survival (OS) < 1 year. Treatment is extrapolated from small cell lung cancer (SCLC) with use of P (cisplatin or carboplatin) + E. More effective treatment regimens and predictive biomarkers are needed to improve outcomes. In SCLC, induction therapy with combination of P/E + PD-L1 checkpoint inhibitor atezolizumab and maintenance atezolizumab improved OS (12.3 months vs 10.3 months; HR 0.70, 95% CI 0.54 – 0.91, P = 0.007) vs P/E alone (Horn L, et al. N Engl J Med 2018). No study to date has compared PD-1/PD-L1 inhibition during induction only vs during induction and maintenance therapy. In SCLC, distinct molecular subtypes can be identified by the presence of specific transcription factors (e.g., ASCL1, NEUROD1, POU2F3) or an Inflamed gene signature (SCLC-I), with SCLC-I pts more likely to benefit clinically from the addition of immunotherapy (Gay CM, et al. Cancer Cell 2021). In this study we plan to test the benefit of adding atezolizumab to induction P/E plus maintenance vs P/E alone, as well as the role of adding maintenance atezolizumab vs observation after induction chemo-immunotherapy. We also plan to correlate tumor- and blood-based subtype biomarkers with response to therapy. Methods: Eligible pts ≥18 years old have evaluable, histologically confirmed extrapulmonary small cell NEC, Zubrod PS ≤2, and are allowed to have up to 1 cycle of P/E prior to enrollment. P (cisplatin 75 mg/m2 or carboplatin AUC 5, iv) on day 1, E 100 mg/m2 iv on days 1-3, and atezolizumab 1200 mg iv on day 1 of q21 day cycles. Treatment consists of an induction phase x 4 cycles, and if no disease progression, a maintenance/observation phase given until disease progression for up to 1 year. Pts are randomized to 1 of 3 arms: A) Induction P/E + atezolizumab → maintenance atezolizumab B) Induction P/E + atezolizumab → observation C) Induction P/E → observation. The primary endpoint is to compare the OS (from randomization) between arms in a fixed sequence: A vs C → B vs C → A vs B. Secondary endpoints include comparing OS (from start of maintenance/observation), progression free survival, response rate, duration of response, and safety/tolerability across arms. Tumor and blood samples will be banked for future biomarker analyses, including immunohistochemistry of transcription factors on tissue and whole exome sequencing on tumor and circulating tumor DNA. With 189 pts, the study is powered to detect an improvement in 12-months OS from 35% to 57.5% (HR 0.53). Both phase 2 and phase 3 portions include interim analyses. Accrual will not pause for phase 2 analysis, expected early 2024. This study was activated December, 2021 and is open to accrual across the NCI National Clinical Trials Network (NCTN). Clinical trial information: NCT05058651.

e16123 Background: Hepatocellular carcinoma (HCC) is an aggressive malignancy for which liver transplantation can be curative. Unfortunately, ̃8-20% of HCC patients will go on to relapse post-transplantation. Personalized and tumor-informed circulating tumor DNA (ctDNA) testing (Signatera, bespoke mPCR NGS assay) has been validated to accurately predict relapse across solid tumors, ahead of radiological imaging. Here, we demonstrate the feasibility of ctDNA testing for monitoring relapse in HCC patients who underwent liver transplantation with curative intent. Methods: A total of 10 HCC patients, stage I-IV, who underwent curative liver transplantation with longitudinal ctDNA monitoring were included in the analysis. Alpha-fetoprotein (AFP) levels and images were measured during surveillance in a subset of patients. Results: In this cohort of 10 patients, 2 (20%) tested ctDNA positive during surveillance, both of whom relapsed. Of these, one tested ctDNA positive two months prior to imaging. Of the 8 patients who did not test ctDNA positive during surveillance, all remained disease-free by imaging. Two patients had elevated AFP, neither of whom relapsed. Of the 2 patients who relapsed, AFP levels were available for one patient and fell within the normal range. Conclusions: Our study illustrated the feasibility of performing longitudinal ctDNA assessment in patients with HCC (post-transplantation) during surveillance. ctDNA status but not AFP was associated with recurrence and was able to inform disease status ahead of imaging. To facilitate clinical decision-making, specifically with adjuvant therapy and immunosuppression management, additional studies with larger patient cohorts will be needed to validate the clinical utility of ctDNA testing in HCC.

3590 Background: Co-occurring alterations (COAs) in the HER2 and MAPK pathway are rare in mCRC. RAS, HER2 and BRAF alterations have been associated with resistance to EGFR inhibitor therapy (EGFR-mab). Typical co-occurring mutually exclusive gene mutations such as in KRAS and BRAF have been reported. This study aims to evaluate the prevalence of co-occurring alterations in the MAPK pathway or across MAPK/ HER2 and correlate to outcomes in patients with mCRC treated with EGFR-mab. Methods: This is a retrospective study of patients with mCRC within the Mayo Clinic database who have available blood-based NGS Guardant 360 data (September 2017-November 2021) and contained co-alterations in the MAPK pathway or across MAPK/ HER2. MSI-high cases were excluded. Typical-RAS was defined as alterations in codons 12, 13, 59, 61, 117, and 146 of KRAS, HRAS, and NRAS. Atypical-RAS alterations were considered mutations at other codons of these genes. Patient characteristics, specific mutations, and outcome data were assessed. Results: 692 patients (pts) with mCRC were identified and 66 (9.5%) of those had COAs detected. 59/66 pts had clinical data available. Median age was 52 years, 55.9% were male, and 61.0% had left-sided tumors. The frequency of detected alterations was: BRAF-V600E (7.3%), BRAF-non-V600E (7%), BRAF-amplification (3.04%), RAS-typical (39.5%), RAS-atypical (2.1%), HER2 amp (0.5%), HER2-mutation (1.2%) and PIK3CA (13%). COAs are described in the table. Twenty-three pts received EGFR-mab; COAs developed in 19 of them after progression on EGFR-mab. Four pts received EGFR-mab with documented COAs at baseline with none of them responding to treatment. Conclusions: COAs in MAPK and MAPK/ HER2 pathway are not uncommon in pts with mCRC emphasizing on the importance and feasibility of blood based NGS vs. selected gene testing. In pts with prior EGFR-mab treatment, COAs were detected after progression on treatment in the majority of pts, suggesting a mechanism of secondary treatment resistance. Further data including prospective validation is warranted. [Table: see text]

2583 Background: MT-5111 is a 55kD engineered toxin body (ETB) targeting HER2 in solid tumors that binds to an epitope distinct from trastuzumab and pertuzumab, offering potential combination strategies with other HER2-targeting agents. MT-5111 may demonstrate efficacy in patients (pts) resistant to other HER2-targeting agents, as its mechanism of action induces direct cell kill via enzymatic and permanent ribosome destruction. Methods: This is a phase 1 study in adults with advanced HER2+ solid tumors. The dose-escalation portion (Part A) enrolls pts into sequential dose cohorts, followed by Part B expansion cohorts for HER2+ breast cancer (BC), gastroesophageal adenocarcinoma (GEA), and any other HER2+ cancer (CA). MT-5111 is dosed weekly IV over 30 min in each 21-day treatment (tx) cycle until disease progression, unacceptable toxicity, death or withdrawn consent. Results: As of Jan 2022, 27 pts had enrolled in Part A cohorts (0.5 to 10 µg/kg/dose) with completed DLT assessments: 9 (33%) pts were male and 18 (67%) female, median age 67 and a median of 4 prior systemic and 2 prior HER2-targeting tx. Common tissue types were BC (9/30%), biliary CA (6/22%), GEA (4/15%). The following safety data reflect 33 treated pts to date including ongoing 13 µg/kg/dose Part A and 10 µg/kg/dose BC expansion cohorts. No Grade (G) 4/5 tx-emergent adverse events (AEs) or DLTs occurred. Tx-related AEs occurred in 17 (52%) pts, most commonly G1/2 fatigue (8/24%). 3 pts had G1 troponin elevations without clinical signs or symptoms of cardiac distress: 1 at 6.75 µg/kg/dose, 2 at 10 µg/kg/dose. 2 pts (3 and 4.5 µg/kg/dose) had reversible G2 and G1, respectively, infusion-related reactions (IRR)s. A comparison of cytokines from baseline to on-treatment timepoints reveals no evidence of significant changes, even in pts with IRR. Best response per RECIST thus far was stable disease (SD) in 7 pts or non-CR/non-PD in 2 pts: 1 pt had SD for 12 weeks (wks) (4.5 μg/kg, pancreatic CA); 1 pt (1 μg/kg/dose, BC) had non-CR/non-PD for 30 wks; 1 pt (10 μg/kg/dose, GEA) has ongoing SD for 18 wks. AUClast data match PK simulations in non-human primate studies. Cmax at 10 µg/kg/dose is ≥5 times the IC50 values of high HER2 expressing gastric CA and BC cell lines while approaching the IC50 of a moderately HER2 expressing liver CA cell line. Conclusions: MT-5111 is well tolerated to-date with no clinically significant immuno/cardiotoxicity. Dose escalation is ongoing at a dose of 13µg/kg, expected to be required for efficacious exposure. Clinical trial information: NCT04029922.

4145 Background: Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer death. Outcomes remain poor, due to irresectability at diagnosis for many and sub-optimal responses to systemic therapy. Cytotoxic chemotherapy remains the standard of care. High microsatellite instability (MSI-H) predicts response to immune checkpoint inhibition (ICI) in many cancers. Detecting high MSI is rare in PDAC (incidence 5 mos. 4 patients did not receive ICI; all patients died, with a median survival of 7.5 mos. Conclusions: MSI-H PDAC represents a rare but important subtype of PDAC with unique clinical behavior. Given its rarity, large-scale analyses and trials are unlikely to be performed, making case series such as ours crucial. In our cohort, we observe impressive, durable responses to ICI, along with very poor responses to cytotoxic chemotherapy. Our data argues for consideration of ICI in any patient presenting with MSI-H PDAC, including in the first-line and neoadjuvant settings.

512 Background: The role of immune checkpoint inhibitors (ICIs) in the treatment of extrapulmonary neuroendocrine carcinoma (EP-NEC) has yet to be established. While objective responses have been observed, it is still unknown which patients are likely to derive benefit. We investigated the genomic profiles of patients who did and did not benefit from ICIs. Methods: Previously we reported the objective responses to ICI in a retrospective series of patients with EP-NEC. RECIST 1.1 criteria were used to categorize patients as achieving disease control (DC = CR, PR, or SD) vs progressive disease (PD). The EMR was reviewed to identify patients who had genomic panels performed, and results were extracted for analysis. Results: Of 31 patients eligible for RECIST assessment, 19 had genomic panels available (9 with DC: 4 SD, 5 PR vs 10 with PD). Of those with NEC histology specified, 9 were small cell, 1 combined large and small cell, 3 were large cell. All tumors were microsatellite-stable. All but one (with TMB = 25) of 16 tumors with TMB status available were < 10 m/MB. Of those with disease control, 67% had both TP53 and RB1 alterations, compared with only 10% in those with progressive disease; this was statistically significant ( p = 0.0198, Fisher exact). Of 7 tumors with TP53 + RB1 alterations, 4 were specified as small cell carcinoma. Half of those with PD showed alterations in β-catenin pathway genes CTNNB1 or APC, compared to only one of the DC group, but this did not reach significance ( p = 0.1409, Fisher exact). In an analysis of all Mayo patients (not just those treated with ICI) with NGS data available (Tempus and FoundationOne), concurrent TP53 + RB1 alteration was significantly more common in SCLC than in EP-NEC (Table). Conclusions: In this small series of patients with EP-NEC treated with ICIs, the SCLC-like genomic signature of concurrent TP53 + RB1 alterations was significantly more common in those with disease control than in those with progressive disease. An analysis of all patients with NGS data (not just on ICI) showed that the dual alteration was more common in SCLC, and SCLC also had more TMB-high tumors. This may explain why ICIs are more effective in SCLC than in EP-NEC. Further study is warranted to determine whether TP53 + RB1 mutations predict response to ICI in NEC.[Table: see text]

100 Background: CRC is a common cancer world-wide, accounting for ̃10% of cancer cases and mortality. Treatment options are limited, and survival is poor for pts with advanced disease, particularly those with mKRAS. After failure of 1L treatment for mCRC, regardless of KRAS mutation status, the ORR for FOLFIRI-bev is 5-13%, with PFS 4-6 mos, and OS 10-12 mos. Onvansertib is a highly selective, ATP-competitive, orally bioavailable PLK1 inhibitor that is synergistic with irinotecan and with 5FU in xenograft models of mKRAS CRC. We present preliminary safety, efficacy, and biomarker data from an ongoing Ph1b/2 trial of onvansertib + FOLFIRI-bev in pts with mKRAS mCRC progressing after 1L treatment with fluoropyrimidine + oxaliplatin, +/- bev. Methods: Pts with mCRC with a KRAS mutation detected by a CLIA-certified lab were eligible. In the Ph1b portion of the study, onvansertib was given on a 3+3 dose escalation at 12, 15 or 18 mg/m2 on days 1-5 and 15-19 of each 28-day cycle in combination with FOLFIRI-bev. The MTD was 15 mg/m2 and was chosen as the RP2D. The primary endpoint for the Ph2 was ORR, and radiographic response was assessed every 8 wks per RECIST v1.1. Safety was evaluated continuously, and AEs were recorded using CTCAE v5.0. Baseline and post-treatment blood samples were collected for biomarker analyses, including mutant allele frequency (MAF) of the pt’s known KRAS mutation. Results: As of 16Sep2021, a total of 50 pts had been treated: 18 on the Ph1b and 32 on the Ph2, including 35 pts at the RP2D, and median follow up was 4.7 mos (range 0.4-18). Of the 50 pts, 26 remain on treatment, as do 24 of 35 RP2D pts. The combination was well-tolerated: fatigue, neutropenia, and nausea were the most common treatment-emergent adverse events (TEAE) and were generally low-grade. Neutropenia was managed by removing the 5FU bolus from subsequent cycles of FOLFIRI and adding growth factor. Of the 50 pts, 44 were evaluable for efficacy, including 31 of 35 RP2D pts. ORR was 36% for the total group (1CR and 15 PR in 44 pts) and 35% for the RP2D group (1 CR and 10 PR in 31 pts). First responses were seen between 2 and 6 months after the start of therapy. Responses were observed across different KRAS variants. Pts achieving a CR or PR showed the greatest decreases in plasma MAF after the first cycle of therapy. Of the 50 pts, 24 pts have discontinued for the following reasons: progressive disease (13), toxicity (4), patient decision (4), proceeding to potentially curative surgery or other localized therapy (3). Conclusions: The combination of onvansertib with FOLFIRI-bev was well tolerated: observed TEAEs have been generally low-grade and manageable. The combination has demonstrated a promising ORR in 2L treatment of mCRC pts harboring various KRAS mutations, and efficacy was correlated with early changes in plasma mKRAS. Updated safety, efficacy, and biomarker analyses will be presented. Clinical trial information: NCT03829410.

607 Background: Immunotherapy (IO) is known to have robust anti-tumor activity in patients with MSI-H solid tumors. However, clinical trials investigating IO activity have used tissue-based testing to determine MSI-H status. Pancreatic tumor biopsy often does not provide sufficient tumor tissue for MSI testing. We investigated if the MSI-H status detected by plasma-based circulating tumor DNA (ctDNA) testing predicts robust response to IO in patients with PC. Methods: Genomic results from a well-validated plasma-based ctDNA assay (Guardant360[G360]) performed as part of routine clinical care between October 1, 2018 and September 7, 2021 in patients with PC were queried to identify patients with MSI-H tumors. Patient characteristics, tumor characteristics, treatment details, and outcomes were reported by ordering clinicians where available. The data cut-off date was September 1, 2021. Results: A total of 52 patients with PC who had MSI-H tumors on G360 were identified. Clinical outcomes data were available for 10/52 (19%) patients who were included for analysis. This patient cohort had a median age of 68 years (range: 56-82); 80% were male and 80% of patients had metastatic disease. 9/10 patients received IO: 3 in the first-line, 3 in the second-line, 3 in the third-line setting; most received pembrolizumab (8/9) while 1 received ipilimumab plus nivolumab. The median duration of IO was 8 months (range: 1-24). The overall response rate was 77% (7/9) and 6 of the 7 responders continue to show response at the time of data cut-off after a median follow-up of 21 months (range:11-33). The median progression-free survival and overall survival were not reached in the IO-treated cohort. Tissue-based MSI testing results were concordant with plasma-based G360 results in 5 of 6 patients (83%) who had tissue-based test results available. The patient with the discordant result was MSI-H by G360 but had intact mismatch repair protein expression by immunohistochemistry. This patient received neoadjuvant IO followed by surgery and the resected specimen confirmed pathological complete response. Conclusions: The detection of MSI-H status by plasma-based ctDNA testing is highly concordant to tissue-based testing and predicts robust and durable response to IO in patients with PC. The use of a well-validated plasma-based ctDNA analysis may expand the identification of MSI-H tumors in patients with PC and enable treatment with IO resulting in improved outcomes.

56 Background: Identification of MSI-H is clinically meaningful in patients with aGI given the associated approval of multiple immune checkpoint inhibitors. MSI-H has long been assessed via tissue analysis; and insights from plasma-based approaches are limited to small validation studies. We sought to assess prevalence of initial and acquired MSI-H status across aGI and report real-world outcomes of colorectal (CRC) patients who received ICI after MSI-H identification by a commercially available liquid biopsy (LBx) assay. Methods: Genomic results from a well-validated LBx assay (Guardant360) completed as part of usual clinical care between 10/1/2018-9/7/2021 in patients with aGI were queried to assess MSI-H prevalence and identify cases of potential acquired MSI-H. Real-world evidence (RWE) was sourced from the GuardantINFORM database comprised of aggregated payer claims and de-identified records from 11/1/2018-3/31/2021. Patients with plasma-identified MSI-H who started new therapy < 60 days after assay report date were sorted into treatment groups: chemotherapy +/- biologic therapy (“chemo”) or immunotherapy via pembrolizumab or nivolumab (“ICI”). Real-world time to discontinuation (rwTTD) and real-world time to next treatment (rwTTNT) were assessed as proxies for progression free survival. Log-rank tests were used to assess differences in rwTTD, rwTTNT and overall survival. Results: Prevalence of MSI-H was ̃2% across aGI (Table). Five cases were observed to have potential acquired MSI not attributable to tumor shed identified on serial LBx tests. Of 222 MSI-H CRC patients eligible for RWE analysis, 89(40%) started new therapy within 60 days of results: 42(48%) received ICI, 39(44%) received chemo, 8(9%) received other/mixed regimens. Patients who received ICI had significantly longer rwTTD and rwTTNT compared to patients who received chemo [median months to discontinuation = 7.5 (95% CI 3.4-12.3) vs. 2 (95% 1.4-3.3) p

297 Background: MT-5111 is a 55 kD engineered toxin body (ETB) targeting HER2 in solid tumors that binds to an epitope distinct from trastuzumab and pertuzumab, offering potential combination strategies with other HER2-targeting agents. MT-5111 may demonstrate efficacy in patients (pts) resistant to other HER2-targeting agents, as its mechanism of action induces direct cell kill via enzymatic and permanent ribosome destruction and does not rely on inhibition of kinase signaling or cytoskeletal or DNA damage. Methods: This is a phase 1 study in adult pts with advanced HER2+ solid tumors. The dose-escalation portion (modified 3+3 design) enrolls pts into sequential cohorts followed by expansion cohorts for HER2+ breast cancer (BC), gastric or gastroesophageal junction adenocarcinoma (GEA), and other HER2+ tumors. MT-5111 is dosed weekly IV over 30 min in each 21-day treatment (tx) cycle until disease progression, unacceptable toxicity, death, or withdrawn consent. Results: As of Sep 2021 (contains preliminary data), 24 pts (mean age 64 yrs) were treated, 13 (54%) of whom had gastrointestinal (GI) tumors (6 biliary, 3 GEA, 2 pancreatic, 2 colo/rectal) (Table). Pts with GI tumors had a median of 3 prior systemic tx and 1 prior HER2-targeting tx. No Grade (G) 4/5 tx-emergent adverse events (AEs) occurred. Tx-related AEs occurred in 13 (54%) pts, most commonly fatigue (n=7, 29%). One pt with biliary cancer and concurrent lymphangitic carcinomatosis and H. influenzae infection (4.5 µg/kg) had a possibly related G3 serious AE (SAE) of dyspnea, which resolved 9 days later. Another related SAE occurred in a pt with GEA (6.75 µg/kg) who had a G1 transient troponin increase that resolved during hospitalization, with no clinical symptoms or ECG/ECHO changes; the pt withdrew from study before further dosing. All other related AEs were ≤G2. No other clinically significant changes in cardiac biomarkers (troponin, ECG, LVEF) or cases of capillary leak syndrome occurred. Two pts (3 and 4.5 µg/kg) had reversible G2 infusion-related reactions. Best response to date has been stable disease. AUClast data matched PK simulations based on non-human primate studies. Cmax data at 10 µg/kg indicate that current in-pt exposure was between IC50 values of high and medium HER2-expressing cell lines (approx 10-89 ng/mL). Thus, at least 10 µg/kg may be required to achieve effective exposure. No dose-limiting toxicities have been observed. The 10 µg/kg cohort is now accruing. Following this cohort, an expansion cohort for pts with BC will open. Conclusions: MT-5111 was well tolerated with no clinically significant immuno/cardiotoxicity. Dose escalation is ongoing and is nearing levels expected to be required for efficacious exposure. Clinical trial information: NCT04029922. [Table: see text]

4130 Background: Circulating cell-free tumor DNA (ctDNA) genomic profiling is an emerging tool for pancreatic cancer. The impact of detected genomic alterations in tumor response to systemic treatments and outcomes is under investigation. Methods: Patients with advanced pancreatic cancer and ctDNA collected at time of initial diagnosis were retrospectively evaluated. Results of ctDNA analysis were correlated with patients’ demographics, systemic treatment response, progression-free survival (PFS) and overall survival (OS). Results: A total of 104 patients were included in the analysis. The mean age was 70.5 years (SD: 8.3), 50% were male, 37% with locally advanced disease and 63% with metastatic disease. Somatic alterations were detected in 84.6 % of the patients, no genetic alterations were detected in 15.4%, and were associated more with locally advanced pancreatic cancer as opposed to metastatic, p = 0.025. 60.6 % of the cohort had ≥ 2 genomic alterations detected. 28% were treated with FOLFIRINOX and 63% with gemcitabine plus nab-paclitaxel as first-line systemic treatment. Patients with any detectable genomic alterations when compared to patients with no detectable variant had worse median PFS (6.2 versus 15.3 months, p = 0.005) and patients with ≥ 2 detectable genomic alterations had worse median PFS (5.6 versus 11.0 months, p < 0.001) and worse median OS (11.5 versus 24.2 months, p = 0.001). KRAS was detected in 62.5% of the patients and was associated with PD to systemic treatments (80.4% vs 19.6%, p = 0.006), worse median PFS (5.8 versus 13.0 months, p < 0.001) and worse median OS (11.5 versus 26.3 months, p = 0.002). TP53 was detected in 60% of patients and was associated with worse median PFS (5.9 versus 10.9 months, p = 0.02) and worse median OS (13.5 versus 24.2 months, p = 0.001). CCND2 was detected in 14% of the patients and was associated with worse median PFS (3.6 versus 8.2 months, p = 0.004). Conclusions: Our study showed that initial detection of ctDNA may identify different genomic alterations that help predict disease outcomes, confirmation of these findings in larger studies are warranted.

TPS3161 Background: The p53 pathway has been implicated in antitumor immunity, including antigen presentation and T-cell proliferation. Loss of p53 function can increase resistance to immunotherapy across many tumor types. Eprenetapopt (eprenet) is a small molecule that stabilizes the folded structure of p53, resulting in activation of mutant p53 and stabilization of wild-type (WT) p53. It also targets the cellular redox homeostasis, resulting in induction of apoptosis in tumor cells. In vivo, mice carrying supernumerary copies of the TP53 gene harbor a pro-inflammatory tumor microenvironment, an effect recapitulated in TP53 normal-copy mice treated with eprenetapopt. Combining eprenetapopt and anti-PD1 or anti-CTLA4 therapy resulted in enhanced tumor growth inhibition and improved survival in TP53 WT mice inoculated with B16 melanoma and MC38 colon adenocarcinoma cells . Based on these results, we hypothesized that eprenet-induced p53 stabilization may augment response to immunotherapy. To test this hypothesis, we are conducting a phase 1b/2 study of eprenet in combination with pembrolizumab (eprenet+pembro) in pts with solid tumors. Methods: The primary objectives are to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) and to assess the safety and tolerability of eprenet+pembro in pts with advanced solid tumors. The secondary objectives are to estimate the anti-tumor activity and to describe the pharmacokinetics of the combination. Exploratory objectives include assessing predictive and pharmacodynamic markers of response. The study includes a safety lead-in with a 3+3 dose de-escalation design for pts with advanced solid tumors with known tumor TP53 mutation status ( TP53 WT is acceptable) (max 18 pts), followed by expansion cohorts in pts with NSCLC, gastric/GEJ and urothelial cancer (max 100 pts). In expansion, pts with urothelial and gastric cancers must be naïve to anti-PD-1/ L1 therapy. Eprenet is given IV once daily on Days 1–4 while pembro is administered on Day 3 of each 21-day cycle. The RP2D of eprenet+pembro is considered the dose at which ≤ 1 of 6 pts in a cohort has a dose-limiting toxicity (DLT). Primary endpoints are occurrence of DLTs, adverse events (AEs) and serious AEs with eprenet+pembro. Key secondary endpoints are best objective response, progression free survival and overall survival. Exploratory endpoints include gene mutations by next generation sequencing (including TP53), mRNA expression, multiplex immunohistochemistry and transcriptomics, multiplex flow cytometry on peripheral blood mononuclear cells and cytokines in serum. Continuous monitoring of toxicity will be conducted. The trial opened in May 2020 and is actively enrolling patients. Clinical trial information: NCT04383938.

3523 Background: Small bowel adenocarcinoma (SBA) is a rare malignancy, with lower incidence, later stage at diagnosis, and worse overall survival compared to other intestinal cancers, such as colorectal cancer (CRC). Since the majority of small bowel tumors are not accessible to endoscopic biopsy, comprehensive genomic profiling using circulating tumor DNA (ctDNA) may enable non-invasive detection of targetable genomic alterations (GA) in SBA patients. In this study, we characterize the ctDNA GA landscape in SBA. Methods: Analysis of 299 ctDNA samples prospectively collected from 265 SBA patients between 2017 to 2020 was performed using a 73 gene next generation sequencing panel (Guardant360). A subset of patients underwent longitudinal analysis of changes in GA associated with systemic therapy. Results: Of the 265 patients, 160 (60.3%) were male; the median age was 66 (range: 21-93 years). The most common GA identified in SBA patients included TP53 [58%], KRAS [44%], and APC [40%]. MSI was detected in 3.4% of SBA patients. When stratified by primary tumor location, APC, KRAS, TP53, PIK3CA, and ARID1A were the most common GA identified in both duodenal and jejunal adenocarcinomas. ERBB2, BRCA2 and CDK6 alterations were enriched in duodenal adenocarcinoma, while NOTCH and BRAF alterations were enriched in jejunal adenocarcinoma. The most common currently-targetable GA identified were ATM [18%], PIK3CA [17%], EGFR [15%], CDK4/6 [11%], BRAF [10%], and ERBB2 [10%]. Unique differences in GA between SBA and CRC were identified: i) the majority of ERBB2 alterations are mutations (89%) in the extracellular domain and kinase domain, not amplifications (11%); ii) the majority of BRAF alterations are non V600E mutations (69%) and amplifications (28%); iii) there is a significantly lower rate of APC mutations (40%). Alterations in DNA damage response pathway proteins, including ATM and BRCA 1/2, were identified in 30% of SBA patients. ATM alterations were more common in patients ³65 years old. The most common mutations predicted to be related to clonal hematopoiesis of indeterminate potential were TP53, KRAS and GNAS. Longitudinal ctDNA analysis in 4 SBA patients revealed loss of mutations associated with therapeutic response (TP53 R342*, MAPK3 R189Q) and acquired mutations associated with therapeutic resistance (NF1 R1968*, MET S170N, RAF1 L613V). Conclusions: This study represents the first large-scale blood-based ctDNA genomic profiling of SBA. SBA represents a unique molecular entity with differences in frequency and types of GA compared to CRC. Variations in GA were noted based on anatomic origin within the small intestine. Longitudinal ctDNA monitoring revealed novel GA associated with therapeutic resistance. Identification of multiple targetable GA may facilitate clinical decision making and improve patient outcomes in SBA, especially when a tissue biopsy is not feasible or sufficient for comprehensive genomic profiling.

4079 Background: Cell-free circulating tumor DNA (ctDNA) holds significant promise and is being used for clinical decision making in multiple tumors. This study aimed to evaluate the prognostic value of pre-treatment ctDNA in metastatic biliary tract cancers (BTC) treated with platinum based first-line chemotherapy treatment. Methods: We performed a retrospective analysis of 67 patients who underwent ctDNA testing before platinum-based chemotherapy for first-line treatment for metastatic BTC. For analysis we considered the detected gene with highest variant allele frequency (VAF). Results of ctDNA analysis were correlated with patients’ demographics, progression-free survival (PFS) and overall survival (OS). Results: The median age of patients was 67 y/o (27-90). 54 (80.6%) of 67 patients evaluated had intrahepatic cholangiocarcinoma; seven had extrahepatic cholangiocarcinoma and six gallbladder cancer. 46 (68.6%) of the patients were treated with cisplatin plus gemcitabine, 14 (21%) patients received gemcitabine and other platinum (carboplatin or oxaliplatin) combinations while 7 (10.4%) patients were treated on a clinical trial with gemcitabine and cisplatin plus additional targeted agents (CX4945 or PEGPH20). TP53, KRAS, APC, FGFR2 and IDH1 were the genes with highest frequency as dominant clone. The median dominant clone allele frequency (DCAF) was 3% (0-97%). DCAF >3% was associated with statistically significant worse PFS (median PFS: 4.05 vs. 7.70 months, p=0.046) and OS (median OS: 10.8 vs. 18.8 months, p=0.056). Each 1% increase in DCAF is associated with a hazard ratio of 26.21 in OS when adjusting for subtypes, age, treatment type, and CA19-9 [Table]. Conclusions: Patients with metastatic BTC with DCAF > 3% at diagnosis have worse PFS and OS compared to patients with low ctDNA when treated with upfront platinum-based chemotherapy.[Table: see text]

TPS258 Background: Engineered toxin bodies (ETBs) are comprised of a proprietarily engineered form of Shiga-like Toxin A subunit genetically fused to antibody-like binding domains. ETBs work through novel mechanisms of action & are capable of forcing internalization, self-routing through intracellular compartments to the cytosol & inducing potent cell-kill via the enzymatic & permanent inactivation of ribosomes. MT-5111 is a de-immunized ETB targeting HER2+ solid tumors. Its novel mechanism of action, via enzymatic ribosome inactivation, may not be subject to resistance mechanisms that exist for tyrosine kinase inhibitors, antibody-drug conjugates, or antibody modalities. MT-5111 binds an epitope on HER2, distinct from trastuzumab or pertuzumab, that may provide for combination potential with other HER2-targeting agents. MT-5111 is a 55 kilodalton protein & may have improved tumor penetration capability. The objective of this trial will be to determine the safety, tolerability, & maximum tolerated dose (MTD) of MT-5111 in patients (pts) with advanced HER2+ solid tumors. Methods: This Phase 1, first-in-human, open-label, dose escalation & expansion study will evaluate MT-5111 monotherapy in pts with HER2-positive solid tumors. The primary objective is to determine the MTD; secondary objectives include pharmacokinetics, tumor response & immunogenicity. Part 1 consists of MT-5111 dose escalation (0.5, 1.0, 2.0, 3.0, 4.5, 6.75, 10µg/kg/dose) based on a modified 3+3 design (n≤42 pts); Part 2 (dose expansion) will evaluate MT-5111 at the MTD in ≤98 pts. All pts will be administered MT-5111 over 30 min via IV infusion on Days 1, 8, & 15 of each 21-day cycle until disease progression, unacceptable toxicity, death, withdrawal of consent, or another reason for withdrawal. Part 1 will include pts with any HER2+ solid cancers. Part 2 will enroll 3 expansion cohorts: HER2+ breast (BC), HER2+ gastric or gastroesophageal junction adenocarcinomas (collectively referred as gastroesophageal adenocarcinomas [GEA]) & other HER2+ solid cancers. Immunohistochemistry (IHC) status must be 2+ or 3+, regardless of in situ hybridization (ISH) results; if no IHC is available for pts with BC or GEA, ISH criteria per the American Society of Clinical Oncology College of American Pathologists guidelines will be used. In metastatic cases, HER2 positivity must be demonstrated on metastatic lesions. Pts with HER2+ BC should have had ≥2 lines of HER2-directed therapy; pts with HER2+ GEA should have received or been intolerant to trastuzumab. Pts with evaluable disease may be included in Part 1; in Part 2, all pts must have ≥1 measurable lesion per Response Evaluation Criteria in Solid Tumors v1.1. Further details can be found on clinicaltrials.gov (NCT04029922). Enrollment, which began in September 2019, is ongoing. Clinical trial information: NCT04029922.

423 Background: Advanced PDAC remains a deadly disease with a 5-year survival rate of less than 10%. cfDNA - based next generation sequencing (NGS) may identify actionable alterations in patients with PDAC. In this study, we aim to determine the feasibility of utilizing serial cfDNA NGS testing and its potential relevance in predicting therapeutics outcomes. Methods: A total of 23 PDAC patients with PDAC cfDNA isolated from plasma collected at diagnosis and upon disease progression to first line SOC therapy and were analyzed on a 73-74 gene NGS panel (Guardant Health). Changes in molecular profiles from baseline to progression were analyzed for overall survival, progression free survival (PFS), and treatment response. PFS and OS were analyzed using the Kaplan-Meier method and the log-rank test was used to compare the survival of different groups of patients. All p-values were two-sided. Analyses were performed using R (version 3.5.1, R Foundation, Vienna, Austria). Results: In this retrospective study, the 1-year probability of survival was 71% (median 473 days) and the 1-year PFS was 14% (median 212 days). TP53 and KRAS were the most frequently mutated genes identified in baseline samples, with 78% prevalence for each. Patients with clearance of TP53 17% (3/18) patients and/or KRAS 33% (6/18) patients clones after first line therapy significantly increases PFS (p=0.0056 and p=0.037, with HR of 0.087 and 0.32, respectively). However, appearance of TP53 or KRAS alterations upon progression does not significantly affect overall survival or PFS. Conclusions: The preliminary results from this study suggest that cfDNA clearance of TP53 and/or KRAS alterations may predict for improved PFS in PDAC. Confirmation of these findings in larger studies is warranted.

e21575 Background: The clinical significance of brain metastases in patients with bronchopulmonary neuroendocrine (NE) tumors is unknown; we therefore conducted a population based analysis to evaluate the implications of brain metastases in these patients. Methods: The NCDB database was queried to identify patients with stage IV bronchopulmonary NE tumors treated between the years of 2004-2012. Patients were split into two groups based on the presence of brain metastases at diagnosis and survival probabilities with multivariate models were performed. Results: A total of 7,725 patients with Stage IV bronchopulmonary NE tumors were identified. The histological subtypes studied in this cohort were NE carcinoma (65.4%), large cell NE carcinoma (30.5%), typical carcinoid (2.8%) and atypical carcinoid (1.3%) . The patients included in this study were mainly white (86.4%) men (56.8%) with a median age of 67 years who had liver (9.5%), bone (6.2%) and brain (5.9%) metastases at diagnosis. The median overall survival (OS) of the cohort was 5.59 (95% CI: 5.4-5.8) months, but when OS was stratified by histological subtype it was significantly better in patients with typical carcinoid (table). In the whole cohort, the median OS did not differ between patients with and without brain metastases (5.55 vs. 5.68; p = 0.24). However, a sensitivity analysis by histology showed that the presence of brain metastases worsen the median OS of patients with typical carcinoid only (15.1 vs 4.6, p = 0.04). An adjusted multivariate analysis restricted to patients with brain metastases showed that administration of systemic chemotherapy (HR:0.5; 95% CI:0.35-0.72, p < 0.001) and resection of distant metastases (HR:0.5; 95% CI:0.29-0.88, p = 0.017) were the two most powerful independent prognostic factors. Conclusions: The presence of brain metastases negatively impact survival of patients with typical carcinoids but not in those with the other histological subtypes included in this study. Staging MRI should be strongly considered at diagnosis in patients with bronchopulmonary NE tumors, due to the sizable proportion of these patients presenting with brain metastases and also due to its prognostic value in a subset of this population. [Table: see text]

4108 Background: Circulating tumor DNA (ctDNA) testing can be used for the assessment of molecular residual disease (MRD) in patients with early-stage or advanced colorectal cancer (CRC). Prospective evaluation of this methodology in clinical practice has been limited to-date. Methods: A personalized and tumor-informed multiplex PCR assay (Signatera 16-plex bespoke mPCR NGS assay) was used for the detection and quantification of ctDNA for MRD assessment. We analyze and present results from an ongoing early adopter program of ctDNA testing across the spectrum of CRC management. Results: Here we present a total of 250 patients with colon (n=200), rectal (n=40), and other lower gastrointestinal cancers (n =10; anal, appendiceal, small bowel). MRD positivity rates and ctDNA quantification (mean tumor molecules/mL) are shown in Table. ctDNA detection was significantly associated with stage of disease (p

e24011 Background: Advanced care planning and living wills are critical components of caring for patients at the end of their lives. Advance directives are designed to be implemented when a patient meets the legal definition of terminal and is deemed incapacitated. By reviewing the electronic health record (EHR) in patients with terminal cancer, we sought to evaluate whether advance directives were appropriately implemented. Methods: A retrospective analysis of the EHR of 500 cancer patients from 1/1/2013 to 12/31/2016 was performed. Data points were manually collected and entered in a central database, and data analysis was completed using SAS. Results: Of the 500 patients, 160 (32%) had an advance directive (AD). The most common clinical terminology used by physicians indicating a terminal diagnosis was “progressive” (36.6%) and “palliative” (31%). The most common clinical terminology indicating incapacity was “altered mental status” (25.6%), and “not oriented” (14%). 34 patients (6.8%) met all criteria of having a terminal diagnosis, a documented AD, and deemed incapacitated. Of these patients who met all of these data points, their ADs were implemented on average 1.7 days (SD: 4.4 days) after which they should have been. This resulted in a total of 58 days of additional care provided to these patients. Conclusions: End-of-life care is a challenging albeit vital part of the practice of medicine. This study provided insight on to how ADs are managed in day to day practice in a hospital. From our analysis, it is clear that physicians are able to identify when a patient is terminal; however, it is typically later than it should have been recognized (and thereby, leading to delays in the implementation of the patient’s AD). Further studies should be performed focusing on harnessing the power of the EHR and providing physicians formative and evaluative feedback of practice patterns to ensure that ADs are honored when appropriate.

e19088 Background: Significant disparities in the stage at diagnosis and survival outcomes exist between various groups diagnosed with hepatocellular carcinoma (HCC) based on sex, race, insurance coverage, and marital status. Previously published data shows disparities more in patients who are African-American, Asian and low income. Little data has been published on factors that influence timeliness to treatment initiation in patients diagnosed with HCC. Methods: Retrospective analysis was performed on 96,586 patients diagnosed with HCC from 2004-2014 using data in the National Cancer Database (NCDB). Time to treatment was divided into two categories: ≤40 days (early, n = 66322) and > 40 days (late, n = 30264). We carried out univariate and multivariate analyses to compare demographic, clinical, treatment, and facility-related factors influencing the timeliness of treatment initiation in HCC. Results: Univariate analysis revealed a significant difference in time to treatment initiation based on age, race, income, insurance status, type of area, geographic region, type of facility, and cancer stage (P < 0.001). Multivariate analysis showed that household income < $30,000/year, Pacific region, urban area of residence, black race, age 70-79 years old or ≥80 years old, academic centers, stage II disease and medicaid insurance were all factors with longer time to treatment initiation. Discussion: HCC is the sixth most common cancer and the second leading cause of cancer mortality worldwide. The 5-year relative survival for localized, regional, and distant stages are 32.6%, 10.8% and 2.4% respectively. In our results we noted significant disparities in time to treatment with respect to various socioeconomic factors. These results are comparable to that reported in other cancer types. Further subgroup analysis of our data shows 2581 patients who received their first treatment after 200 days. In a similar study done in Taiwan, those treated more than 181 days and 61–180 days after diagnosis had a 1.68 and a 1.39 increased risk of death respectively, which were statistically significant. Many factors contribute to delayed treatment, some of which are difficult to circumvent, however where possible efforts should be made to overcome these. Conclusions: Various socioeconomic factors were found to affect the time to treatment initiation in HCC patients. The next step would be to strategically implement policies and practices to address these factors.

617 Background: Currently, there is no published data on the efficacy of SSAs for well-differentiated G3 NETs. Randomized trials have demonstrated a progression-free survival (PFS) benefit and limited tumor response for lower grade 1-2 NETs, but the optimal systemic therapy for metastatic/unresectable G3 NETs is unknown. We sought to evaluate the efficacy of SSAs in G3 NETs. Methods: We performed a retrospective analysis of Mayo Clinic patients treated with SSAs for metastatic/unresectable G3 NETs, querying data from 1992 - present. Inclusion criteria were: centrally reviewed pathology confirming well-differentiated morphology, G3 based on WHO classification, SSA monotherapy, and radiological data available to assess response. Patients who had prior lines of treatment were included as long they subsequently were treated with single-agent SSA. Poorly-differentiated tumors were excluded. The primary endpoint was PFS. Best overall response was determined by radiographic regression, stabilization, or progression of tumor size. Results: Ninety patient records were reviewed, with 14 meeting inclusion criteria (diagnosed 2014 – 2018). Median Ki-67 proliferative index was 25%. Two patients (14%) had a partial response to SSA therapy, five (36%) had stable disease, and seven (50%) had progressive disease. The estimated median PFS was 4.4 months (95% CI 2.9 – 24). Of the 7 patients with stable disease or partial response, the median time to progression was 8.7 months. Three patients had stable disease for greater than 9 months (24, 29 and 42 months, respectively). Overall survival was not estimable. There was no association of Ki-67 index with PFS based on a proportional hazards model. Conclusions: This is the first report on the efficacy of SSAs for G3 NETs. Although half of the patients in our series had at least stable disease, the PFS was modest at only 4.4 months. Given their favorable side-effect profile compared to cytotoxic chemotherapy, SSAs may present an attractive option to be further explored in a prospective fashion. We are presently updating this data by reassessing response using RECIST criteria.

e15066 Background: Circulating cell-free tumor-DNA (ctDNA) testing (‘liquid biopsy’) is increasingly being employed both in clinical trials as well as clinical practice. We aimed to contrast and compare the differences in the number of somatic mutations observed on ctDNA testing between mismatch repair deficient/microsatellite instability-high (dMMR/MSI-High) versus mismatch repair proficient/microsatellite stable (pMMR/MSS) colorectal cancers (CRC). Methods: We had 20 patients at Mayo Clinic Florida that were dMMR/MSI-High with testing through the commercially available platform (Guardant360) that uses a 73-gene panel. Median numbers of somatic mutations were compared between the 2 subset of CRC. Results: Patients with dMMR/MSI-High CRC had a median of 8 mutations (range: 2-15) versus a median of 4 mutations (range: 1-22) in pMMR/MSS patients, p-value of 0.001. Similarly, the mean number of somatic mutations were 7.47 (S.D. ± 4.15) versus 5.02 mutations (S.D. ± 3.83) in patients with dMMR/MSI-H and pMMR/MSS, tumors respectively. Though it is simplistic, we could still potentially identify patients who may be candidates for immunotherapy by gauging the mutational burden reported (Table). Furthermore, on serial testing, decline in mutational burden as early as few weeks into therapy was predictive of response later on imaging. Conclusions: Analysis of number of somatic mutations on ctDNA testing can be complementary to MMR/MSI-testing, especially in situations when tissue is not available or safe to obtain. This can also be of value in predicting and/or following response to immunotherapy. The utility of this may go beyond CRC in identifying patients who may benefit from immunotherapy. [Table: see text]

4110 Background: Neuroendocrine tumors (NET) comprise around 2% of all malignant tumors of the gastrointestinal system. The genomic landscape of NET has not been well studied. The aim of this study was to confirm the feasibility of next generation sequencing (NGS) using ctDNA in NET and characterize common alterations in the genomic profile. Methods: Molecular alterations in 114 plasma samples from 114 patients with NET using clinical-grade NGS of ctDNA (Guardant360Ò) across multiple institutions were evaluated. The test detects single nucleotide variants in 54-73 genes, copy number amplifications, fusions, and indels in selected genes. Results: A total of 114 NET patients were evaluated, of which 64 (56.1%) were female. Mean age was 59.7 years with a range between 23-89 years. ctDNA NGS testing was performed on 114 plasma samples; 1 patient had testing performed twice. Genomic alterations were defined in 94 (n = 94/114, 82.5%) samples with a total of 289 alterations identified after excluding variants of uncertain significance (VUSs) and synonymous mutations. Alterations were identified in at least one sample from 83 patients; TP53 associated genes were most commonly altered (n = 83/289, 28.7%), followed by KRAS (n = 22, 7.6%), PI3CA (n = 15, 5.2%), CCNE1 (n = 15, 5.2%), BRAF (n = 13, 4.5%), MYC (n = 12, 4.1%), ERBB2 (n = 11, 3.8%), APC (n = 10, 3.5%), EGFR (n = 10, 3.5%), MET (n = 10, 3.5%), PTEN (n = 9, 3.1%), RB1 (n = 9, 3.1%), CDK6 (n = 7, 2.4%), AR (n = 5, 1.7%), ARID1A (n = 5, 1.7%), FGFR1 (n = 5, 1.7%), and PDGFRA (n = 5, 1.7%). Other genomic alterations of low frequency, but clinical relevance included: CDK4 (n = 4, 1.3%), NF1 (n = 4, 1.3%), RAF1 (n = 4, 1.3%), GNAS (n = 3, 1.0%), KIT (n = 3, 1.3%), BRCA2 (n = 2, 0.7%), CCND2 (n = 2, 0.7%), CTNNB1 (n = 2, 0.7%), JAK2 (n = 2, 0.7%), NRAS (n = 2, 0.7%), SMAD4 (n = 2, 0.7%), and TERT (n = 2, 0.7%). Alterations in AKT1, ALK, ATM, BRCA1, CCND1, CDKN2A, FGFR2, MTOR, RHOA, SMO and STK11 were all reported once (n = 1, 0.3%). Conclusions: Evaluation of ctDNA is feasible among individuals with NET. Liquid biopsies are not invasive and can provide personalized options for targeted therapies in NET patients.

e15698 Background: Neuroendocrine tumors (NETs) and carcinomas (NECs) are a diverse group of tumors with an equally diverse biology and clinical behavior. Data on tissue-based genomic profiling of NETs exists, however, there is limited data using circulating tumor DNA (ctDNA) technology. We sought out to characterize NETs via ctDNA to identify genomic alterations. Methods: 27 patients with metastatic NET/NEC with 32 total plasma samples were analyzed using Guardant360 ctDNA assay. Breakdown of NET/NEC by location: 14 pancreatic NET (pNET), 11 NEC, 1 small bowel NET, 1 lung NET. The ctDNA test detects single nucleotide variants in 54-73 genes, copy number amplifications, fusions, and indels in selected genes. Results: Of the 27 patients, 19 (70%) had a detectable genomic alteration. The detectable (non-synonymous) alterations are as follows: TP53 (n = 14, 70%), NF1 (n = 8, 40%), EGFR (n = 5, 25%), BRCA2 (n = 4, 20%), KRAS (n = 4, 20%), ARID1A (n = 3, 15%), CDK6 (n = 3, 15%), ALK (n = 3, 15%), MET (n = 2, 10%), PTEN (n = 2, 10%), BRAF (n = 2, 10%), MTOR (n = 2, 10%) AKT1 (n = 1), BRCA1 (n = 1), CCND2 (n = 1), CCNE1 (n = 1), CTNNB1 (n = 1), ESR1 (n = 1), FGFR2 (n = 1), HRAS (n = 1), IDH1 (n = 1), KIT (n = 1), MYC (n = 1), NOTCH1 (n = 1), NRAS (n = 1), PDGFRA (n = 1), RAF1 (n = 1), RB1 (n = 1), SMAD4 (n = 1), STK11 (n = 1), TSC1 (n = 1), ERBB2 (n = 1), PIK3CA (n = 1). Conclusions: This experience highlights the feasibility of ctDNA to help identify genomic alterations in this patient population. Further studies incorporating ctDNA testing in this patient population are warranted.

291 Background: Cholangiocarcinoma (CCA) has limited treatment options. Genomic analyses have led to development of targeted therapies now in clinical trials, and may enable discovery of new treatment options. However, biopsy often yields limited tissue, thus hampering tissue-based profiling opportunities. Comparative data regarding circulating tumor DNA (ctDNA) analysis and tissue based profiling in CCA are limited. Methods: We performed ctDNA NGS analysis along with tissue based profiling in pts with advanced CCA (January 2015- February 2018). ctDNA analysis was performed using Guardant 360 (Guardant Health, CA) which detects single nucleotide variants, amplifications, fusions, and specific insertion/deletion mutations in up to 73 different genes and the majority of tissue based profiling using Foundation One. The mutant allele fraction (MAF) for detected alterations was calculated relative to wild type in ctDNA. Therapeutic relevance was defined as alterations within OncoKB levels 1-3B and R1. The study was conducted in accordance with Mayo Clinic IRB requirements. Results: Among 124 pts and 139 total samples, ctDNA NGS revealed at least one genomic alteration (excluding variants of uncertain significance and synonymous mutations) in 89% of pts. Median number of alterations per pt was 3 [range, 1-15], with a median MAF of 0.42% (range, 0.1% - 94.2%). The total number of unique alterations was 321. The most commonly altered genes: TP53 (31%), KRAS (11%), FGFR2 (7%), APC and PIK3CA (each 5%) and ARID1A (3%). Amplifications were noted in 14 genes: BRAF, CCND1, CCND2, CCNE1, CDK4, CDK6, EGFR, ERBB2, FGFR1, FGFR2, MET, MYC, PDGFRA, and PIK3CA. Tissue-based profiling was available in 57 (46%) pts, with a median of 63 days between liquid and tissue biopsy. IDH1, FGFR2, TP53 and KRAS were most common gene mutations found in pts who had both liquid and tissue biopsy done. (Comparative results to be shown). Conclusions: ctDNA plasma profiling of pts with advanced CCA is a feasible alternative method to gather comprehensive genomic data. Further larger cohort studies comparing landscape of alterations seen on ctDNA versus tissue-based assays are needed.

289 Background: PDAC has limited treatment options. Genomic analyses have led to development of targeted therapies now in several clinical trials, and may enable the discovery of new treatment options. However, biopsy often yields limited tissue, thus hampering tissue-based profiling opportunities. Data regarding circulating tumor DNA (ctDNA) profiling in PDAC during real time clinical practice is limited. Methods: We performed ctDNA NGS analysis in pts with advanced PDAC (December 2014–August 2018). ctDNA analysis was performed using Guardant 360 (Guardant Health, CA), which detects single nucleotide variants, amplifications, fusions, and specific insertion/deletion mutations in up to 73 different genes. The mutant allele fraction (MAF) for detected alterations was calculated relative to wild type in ctDNA. Therapeutic relevance (TR) was defined as possible treatments within OncoKB levels 1-3B and R1. The study was conducted in accordance with Mayo Clinic Institutional Review Board requirements. Results: Among 171 pts and 206 total samples, ctDNA NGS revealed at least one genomic alteration in 150 pts (88%). Median number of alterations per patient was 3 [range, 1-15]. The total number of unique alterations was 450 with the most commonly altered genes being: TP53 (181 alterations, 40%), followed by KRAS (118 alterations, 26%), CDKN2A (23 alterations, 5%), SMAD4 (15 alterations, 3%), EGFR (11 alterations, 2.4%), PIK3CA (9 alterations, 2%), GNAS (8 alterations, 1.5%). Amplifications were noted in 16 genes, including BRAF, CCND2, CCNE1, CDK4, CDK6, EGFR, ERBB2, FGFR1, FGFR2, KIT, KRAS, MET, MYC, PDGFRA, PIK3CA and RAF1. Therapeutically relevant alterations were seen in 95 pts of the 150 pts (63%). Tissue based profiling (Results to be shown) was done in 56 (33%) pts of total 171 pts with a median of 130 days between ctDNA and tissue biopsy. KRAS and TP53 were the most common gene mutations found in patients with both liquid and tissue biopsy results. Conclusions: ctDNA plasma profiling of pts with advanced PDAC is a feasible alternative method to gather comprehensive genomic data.

288 Background: Obesity is a risk factor for developing cholangiocarcinoma (CCA). However, the effect of obesity on survival of CCA is unclear. The primary aim of this study was to analyze the impact of obesity upon overall survival of CCA patients. Secondary aims were to analyze impact of obesity upon other disease characteristics such as tumor site, stage, age, sex, BMI and Ca 19-9. Methods: A total of 411 unique pts diagnosed with CCA at Mayo Clinic Florida between 2000 and 2018 were retrieved from our collective SDMS database. Variables evaluated included:demographics, Body Mass Index (BMI), AJCC stage, tumor location and Ca 19-9.A total of 185 pts had all data available pertaining to these variables. We further restricted the analysis to pts with intrahepatic CCA classified BMI as per CDC criteria normal (18.5-25kg/m2), overweight (25-29.9kg/m2) and obese (≥30 kg/m2), thus leaving a total of 152 pts. Continuous and categorical variables were compared across BMI groups using Chi-squared or Fisher’s exact test. Overall survival rates after diagnosis at 1, 2 and 3 years were estimated using Kaplan-Meier method. Results: Among 152 pts included in the study, 28% were normal weight, 40% were overweight and 32% were obese. The overall survival rate at 1, 2 and 3 years for normal weight pts with all stages combined was 54.1%, 35%, and 30.7%, respectively. The overall survival rate at 1, 2 and 3 years for overweight pts with all stages combined was 59.7 %, 32.6%, and 25.4%, respectively. The overall survival rate at 1, 2 and 3 years for obese pts with all stages combined was 63.9%, 37.6%, and 26.7%, respectively(p = 0.8766). Multivariate analysis demonstrated is no significant difference in overall survival for obese pts compared to normal or overweight pts.(Table to be shown) However it showed, gender and Ca19-9 were statistically significant predictors of overall survival, with males and pts with Ca19-9≥100 doing worse (HR1.65 (CI = 1.05, 2.61, p = 0.031) and HR 2.31 (CI = 1.49, 3.59, p = < 0.01), respectively). Conclusions: BMI did not make a significant impact on the overall survival, though there may be a trend toward worse OS for ptswith higher BMI. A larger, stage focused evaluation is warranted for further exploration of this trend.

267 Background: Subcutaneous venous access devices, specifically implantable ports, are vital in the care of oncology patients. Despite routine use, complications remain prevalent. This retrospective single-institutional review was performed to identify rates of complications following port placement and target areas to improve patient outcomes. Methods: Retrospective analysis of 539 cancer patients who underwent port insertion in a one-year span at University of Florida was conducted. Data examining 18 potentially predictive factors was collected, and multivariate analysis was conducted using logistic regression and odds ratios with standard errors to determine predictive factors. Results: Of 539 patients, 100 (19%) experienced a complication, and 12 (2%) experienced 2 or more complications. An overall lower rate of complications was seen in patients on therapeutic anticoagulation (OR 0.17, p < 0.001) or on antiplatelet agents (OR 0.47, p = 0.02). No patients on therapeutic anticoagulation developed VTE (0%). Right-sided port insertion was associated with decreased rates of infection (OR 0.44, p = 0.04). Insertion as inpatient was associated with increased risk for mechanical failure (OR 4.60, p < 0.01) and catheter migration (OR 4.33, p < 0.01). Conclusions: This analysis identified multiple predictive factors that can potentially put patients at higher risk of complication following port insertion. A thorough risk assessment for VTE should be done prior to port insertion, and high-risk patients (i.e. prior VTE, Khorana score > 3) should be considered for prophylactic anticoagulation. Further analysis on optimal port insertion site (right/left) and location (inpatient/outpatient) are also targets that can potentially decrease complication rates. As ports inserted while inpatient had increased risk of both mechanical failure and catheter migration, and as ports inserted on the left side had increased risk of infectious complications, a prospective quality improvement initiative coordinated between Oncology and Interventional Radiology departments as to whether insertion of right-sided ports on an outpatient basis may improve outcomes is the next step in our investigation.

e18767Background: Central venous access devices, specifically implantable ports, play an essential role in the care of oncology patients. Despite their routine use in cancer patients complications ...

3593Background: DNA mismatch repair deficient (dMMR) or microsatellite instability high (MSI-H) CRC is found in ~15% of early stage and ~5% of metastatic disease. Universal or reflex testing to ide...

318 Background: The collection and enumeration of circulating tumor cells (CTCs) are feasible in metastatic breast, prostate and colorectal cancers. CTCs have diagnostic, prognostic and treatment monitoring implications, but have been challenging to detect in pancreatic cancer (PCa). We have proven feasibility of CTCs in PCa. This study is a pilot to assess use of CTCs as a surrogate for imaging response. Methods: Blood samples (7-10mL) from newly diagnosed metastatic PCa were collected within 1 month of treatment initiation (T0) and at repeat scan after 2mo of treatment (T1). Specimens were processed within 6 hours of collection. A UF developed microfluidic device was used to capture and identify EpCam+ CTCs. Isolated cells were verified as CTCs consistent with FDA-approved definitions (cytokeratin+, DAPI+, CD45-). CTC enumeration and changes were correlated with scan RECIST results at T0 and T1. The study was approved by the UF IRB. Results: A total of 16 patients had matched pair CTCs collected and analyzed (Table 1). For the entire cohort, the median CTC count at T0 was 7/mL of blood (range 2-11.5/mL) and decreased to 4.5/mL (range 2-8.5/mL) at T1 (36% reduction). CTCs were reduced to some degree in all patients with therapy. Disease control at T1 was confirmed in 13/16 (81%) with stable disease (n=11), partial (n=1) or complete (n=1) response. Progressive disease was noted in 3 patients. CTCs were reduced by 35% in radiographic stable or responders vs 24% in those with clear progressive disease. Conclusions: This study demonstrated the feasibility of microfluidic technology to reliably and consistently identify CTCs in advanced PCa. While all patients had reduced CTCs with therapy, a trend towards higher reductions were in those with radiographic stable or improved disease. Continued assessment of CTCs in PCa for treatment monitoring are warranted and are ongoing. [Table: see text]

796 Background: In colorectal cancer (CRC), clinical guidelines and immunotherapy treatment selection requires knowledge of tumor DNA mismatch repair gene deficiencies (dMMR) or accumulation of microsatellite repeats through genomic errors (MSI-H). Tumors harboring dMMR/MSI-H are found in 15- 20% of early stage CRC while the prevalence is ~5% in metastatic disease. Reflex testing of CRC to identify these important subsets has been proposed as a system-solution to improve identification. We present a large, single-institutional database of CRC reflexively profiled for MSI/MMR status at the University of Florida (UF). Methods: Beginning in 2009, stage IV CRC underwent reflex testing for MSI/MMR status. Earlier stage CRC testing began in subsequent years. For all new CRC diagnosed at UF, concurrent testing for dMMR by IHC (MLH1, PMS2, MSH2, MSH6), MSI by PCR (Promega MSI kit) and NGS is performed with appropriate positive and negative controls. IHC protein loss is confirmed by second GI pathologist. MSI is not performed if inadequate adjacent normal tissue. We conducted a retrospective analysis of all CRC samples analyzed between 2009 and 2017. Clinical data was collected from the EMR. This study was approved by the UF IRB. Results: A total of 388 new CRC cases were reflex tested (16% Stage I, 23% Stage II, 35% Stage III, and 25% Stage IV). Median age at diagnosis was 63 yrs (range: 17-98 yrs), 51% male and 79% white. Both MMR and MSI were performed in 244 (63%) tumors with 100% concordance when concurrently tested. dMMR/MSI-H incidence (20% in overall population) decreased with stage: I/II (31%), III (18%) and IV (~9%) and was associated with BRAF V600E mut in 36/76 cases (47%). Importantly, in pts < 50 yrs, 13% of stage IV patients were dMMR/MSI-H. Conclusions: Reflex testing of MMR/MSI status in CRC is feasible with concordant results. Routine testing results in identification of dMMR/MSI-H at or higher than published rates. Notable findings include the high prevalence in those with sporadic CRC and/or younger than 50 yrs. Continued impact analysis of this approach is warranted to maximize IO therapy offering.

304 Background: Circulating tumor cells (CTCs) represent real time dissemination of solid tumors. Historically, CTC enumeration has been challenging to perform successfully in pancreatic cancer (PCa). Using a previously published microfluidic device designed to increase cell capture, we analyzed CTC characteristics in a cohort of newly diagnosed patients with metastatic PCa. Methods: After provision of informed consent, blood samples (7-10mL) were collected within 1 month of treatment initiation. Specimens were processed within 6 hours of collection. A UF developed microfluidic device was used to capture and identify EpCam+ CTCs. Isolated cells were verified as CTCs consistent with FDA-approved definitions (cytokeratin+, DAPI+, CD45-). Statistical analysis was performed using Scheffe’s method along with analysis of variance to test interactions between the clinical demographics and groups. The study was approved by the UF IRB. Results: A cohort of 27 patients had CTC determination at treatment onset with multi-agent chemotherapy for metastatic PCa. Cohort characteristics included: median age 65 (range 29-76), 63% male, 92% white, 85% with intact primary pancreatic tumor, pancreatic tumor location: head (n = 12), body (n = 5), tail (n = 6), number of sites of metastasis: 1 (n = 18), 2 (n = 7), 3 (n = 2), and median albumin 3.9 g/dl. Median CTC for the entire cohort was 7/mL of blood (range 2-12). CTCs were detected and quantified in all patients analyzed. In those with intact primary tumors, there were no significant differences in CTCs based on age (≥65), sex, albumin (≥3.5 g/dl), or number of metastatic organ sites (1, 2, or 3). However, primary tumor location in the head vs. tail was different (mean 7.7 vs. 4.3/mL; p = 0.02; CI -5.78 – [-] 0.41). Conclusions: This analysis demonstrates the feasibility of measuring CTCs in patients with metastatic PCa. CTC amount does not appear impacted by systemic tumor burden or demographic differences. However, anatomic differences in primary tumor location may be important in CTC studies. Further analysis of a larger and more diverse patient data set is planned.

504 Background: Systemic chemotherapy for pancreatic adenocarcinoma (PCa) improves survival but most targeted agents have consistently failed to demonstrate clinical benefits. Src is overexpressed in PCa and promotes an aggressive cancer phenotype. Dasatinib (D) is an oral multi-tyrosine kinase inhibitor (TKI) affecting tumor proliferation through inhibition of Src, Bcr-Abl, CKit and other pathways. Inhibition of Src is associated with biologic modifications favorably modifying the PCa phenotype and has synergy with restoring inherent chemosensitivity. Src inhibition can also increase oxaliplatin activity and modulate Tcell responses. The addition of D to the well-established backbone of FOLFOX represents a multifaceted line of scientific investigation. Methods: This single arm phase II trial is to determine activity and toxicity of FOLFOX + D in previously untreated metastatic PCa. Pts must have at least 1 RECIST measurable target lesion, ECOG PS 0-2, normal QTc and adequate organ function. Treatment is standard q14d cycles of mFOLFOX6 with continuous D (150mg PO daily). Tumor assessments occur q8w. Endpoints are PFS (primary), objective and biochemical response rates, clinical benefit rate, freedom from metastases, overall survival (OS), toxicity, and quality of life. Exploratory tissue, circulating tumor cell and serum analyses to identify predictors of response are planned, particularly in those with durable disease control or exceptional response. Sample size is based on a 50% improved median PFS from 4 (historical) to 6 months. Results: Enrollment is now closed on this prospective phase II study with 42 of 42 evaluable pts. Baseline demographics are in Table 1. Toxicity and outcomes continue to be assessed. Conclusions: Final toxicity data will be presented at the meeting for this novel combination treatment in advanced PCa. Clinical trial information: NCT01652976. [Table: see text]

TPS517 Background: Systemic chemotherapy for pancreatic adenocarcinoma improves survival and cancer related symptoms. Most targeted agents combined with gemcitabine have consistently failed to demonstrate clinical benefits. Src is overexpressed in pancreatic cancer and promotes an aggressive cancer phenotype. Dasatinib (D) is an oral multi-tyrosine kinase inhibitor (TKI) affecting tumor proliferation through inhibition of Src, Bcr-Abl, CKit and other pathways. Inhibition of Src is associated with biologic modifications favorably modifying the pancreatic cancer phenotype and has synergy with restoring inherent chemosensitivity. Src inhibition can also increase oxaliplatin activity and modulate Tcell responses. The addition of D to the well-established backbone of FOLFOX represents a multifaceted line of scientific investigation. Methods: This is a multicenter phase II trial to determine activity and toxicity of FOLFOX + D in previously untreated metastatic pancreatic adenocarcinoma. Eligible pts must have at least 1 measurable target lesion by RECIST, ECOG PS 0-2, normal QTc and adequate organ function. Pts received standard cycles of mFOLFOX6 repeated q14d with continuous D (150mg PO daily). Tumor assessments occur q8w. Endpoints included progression-free survival (primary; PFS), objective and biochemical response rates, clinical benefit rate, freedom from metastases, overall survival (OS), toxicity, and quality of life. Exploratory tissue, circulating tumor cell and serum analyses to identify predictors of response are planned, particularly in those demonstrating durable disease control or exceptional response. Sample size was based on a 50% improved median PFS from 4 (historical) to 6 months. NCT01652976. Results: Enrollment continues on this prospective phase II study with 38 of 42 evaluable patients. There are no unexpected toxicities noted thus far. Clinical trial information: NCT01652976. [Table: see text]