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PURPOSEIt has recently been described that alternative oncogenic drivers may be found in KRAS wild-type ( KRASWT) pancreatic cancers. This study aimed to determine the incidence of targetable gene fusions present in KRASWTpancreatic adenocarcinoma and response to targeted therapy.METHODSOne hundred consecutive patients with pancreatic adenocarcinoma who underwent targeted next-generation sequencing using DNA sequencing with RNA sequencing (n = 47) or without RNA sequencing (n = 53) at a single institution were included in the study. The frequency and landscape of targetable fusions in KRASWTpancreatic adenocarcinoma was characterized and compared with the frequency of fusions in KRAS-mutated ( KRASMUT) pancreatic adenocarcinoma. Results were validated in two independent cohorts using data from AACR GENIE (n = 1,252) and TCGA (n = 150). The clinical history of fusion-positive patients who received targeted treatment is described.RESULTSPancreatic cancers from 13 of 100 patients (13%) were found to be KRASWT. Targetable fusions were identified in 4/13 (31%) KRASWTtumors compared with 0/87 (0%) KRASMUTpancreatic adenocarcinomas ( P = .0002). One patient with a novel MET fusion had a complete response to targeted therapy with crizotinib that is ongoing at 12+ months of treatment. In the validation cohorts, gene fusions were identified in 18/97 (19%) and 2/10 (20%) KRASWTtumors reported in the AACR GENIE and TCGA cohorts, respectively.CONCLUSIONOncogene fusions are present in KRASWTpancreatic adenocarcinomas at an increased frequency when compared with KRASMUTpancreatic adenocarcinomas. As these fusions may be susceptible to targeted therapy, molecular analyses for the detection of fusions in KRASWTpancreatic adenocarcinomas may warrant increased consideration.

302 Background: The RAINBOW trial established the standard of care for treatment of metastatic GEAs with ramucirumab and paclitaxel after failure of fluoropyrimidine and platinum-based chemotherapy. While the combination achieved an objective response rate (ORR) of 28%, the incidence of any grade neuropathy was 46%. Therefore, there is an unmet need for novel treatment combinations that minimize the long-term toxicity of neuropathy. In a recently published Asian study, the combination of RAM+TAS-102 showed good disease control and acceptable toxicity profile. Methods: This was a single arm, single institution phase II trial using the combination of TAS-102 plus RAM in refractory GEAs. Patients (pts) received RAM 8mg/kg intravenously on day 1 and 15, and TAS-102 35mg/m2 orally twice daily on days 1-5 and days 8-12 every 28-day cycle. The primary endpoint was 6-months overall survival (OS) rate and secondary endpoints were progression free survival (PFS), ORR and safety profile. The trial was registered at www.clinicaltrials.gov (NCT03686488). Results: At data cut-off of August 15, 2021, 23 pts were enrolled. Baseline demographics are as follows: median age of 62 years (range: 23-74), median lines of prior therapy of 1 (1: 14 pts vs ≥2: 9 pts) and location of primary tumor (GEJ:19 vs GC: 4). 6-month OS rate was 56.2%. Median OS was 6.2 month (95% CI: 5.4-7.0) and median PFS was 4.9 months with median observation of 2.3 months. Of 17 evaluable pts defined as more than one baseline imaging, 1 (6%) had partial response (PR) and 15 (88%) had stable disease (RECIST v1.1). Eleven pts came off the study due to progression of disease, 8 for toxicities and 4 for consent withdrawal. Most common treatment-emergent adverse events (TEAEs) were diarrhea (39%), fatigue (39%) and hypertension (39%). Total 11 pts (48%) experienced grade 3 and 4 TEAEs, and most common Gr3 and 4 TEAEs were neutropenia (17%) and anemia (13%). Conclusions: The combination of RAM and TAS-102 showed very similar disease control rate as the study in Asia. The combination has now shown modest activity in advanced GEAs and should be investigated further now in the context of patients receiving immunotherapy-based treatment as first-line treatment. A randomized phase II study is currently enrolling patients with ramucirumab and TAS-102 or paclitaxel. Clinical trial information: NCT03686488.

e16266 Background: Pancreatic cancer is one of the deadliest malignancies, with a 5 year OS of around 3%. Up to 3% of unselected patients (pts) with (PDAC) have the BRCA 1/2 mutation, while up to 15% possess HRD (ARID1A, ATM, BAP1, BARD1, BRIP1, CHEK1/2, FANCA, PALB2, RAD50, RAD51). PARP inhibitors, like olaparib, demonstrate clinical benefit in metastatic PDAC with BRCA mutations (mBRCA) and may have a role in those with HRD. The objective of this study is to determine the role of PARP inhibition in PDAC with HRD. Methods: This was a retrospective chart review of metastatic PDAC pts with germline (g) or somatic (s) mBRCA or HRD who received olaparib. An analysis of PFS and OS was performed for PDAC pts with mBRCA vs. HRD. Results: Forty-six pts with metastatic pancreatic cancer were identified to have mBRCA (n = 13) or HRD (n = 23) and received olaparib in our database. Median age was 73 years for mBRCA and 66 years for HRD. Five pts received olaparib as maintenance therapy after disease control with platinum: 2 mBRCA and 3 HRD pts. Six pts with mBRCA and 7 pts with HRD were platinum naïve prior to olaparib. Zero pts with mBRCA and 3 pts with HRD received olaparib after disease progression on platinum. The median (med)PFS for mBRCA vs. HRD was 6.1 months vs. 2.8 months (HR 0.5, 95% CI: 0.2-1.1, p = 0.07). The medOS for mBRCA vs. HRD was 7.7 vs. 5.3 months (HR 0.7, 95% CI: 0.2-1.9, p = 0.4). Of those with mBRCA who received olaparib, prior cisplatin exposure (n = 8) vs. cisplatin naïve (n = 5) led to medPFS of 6.1 vs. 7.8 months (HR 1.8, 95% CI 0.5-6.7, p = 0.3) and medOS of 6.8 months vs. 9.5 months (HR 1.5, 95% 0.3-6.4, p = 0.6). Six pts with HRD including gCHEK2 c.407T > C, gCHEK2 c.1461+1 G > A, gPALB2 gain (exon 11), sFANCI p.N1252S, sATM p.V2716A, sARID1A Q944fs*14 were noted to have disease control of at least 3 months on olaparib. Only one of these pts received olaparib as maintenance therapy after platinum. The medPFS was 6.1 months and medOS was not reached. One pt with HRD (sFANCI N1252S) had progressive disease on platinum prior to olaparib, but had stable disease > 5 months with olaparib. Conclusions: Our study suggests olaparib may have anticancer activity in PDAC with certain HRD. In addition, olaparib may have a role outside maintenance therapy in PDAC with mBRCA. Prospective studies are needed to confirm these findings.

415 Background: Immune checkpoint inhibitors (ICI) have been approved in solid tumors with dMMR. However, only limited data are available for PDAC with dMMR given the rarity of dMMR in PDAC. We evaluated efficacy of ICIs in PDAC with dMMR. Methods: Retrospective clinical and pathologic data were collected for patients (pts) with pancreatic adenocarcinoma from May 2017 to June 2020 at Moffitt cancer center. Results: We identified 10 pts with dMMR PDAC. The median age was 64.5 years (range: 42-86) and 4 pts were male. 4 pts had resectable disease, 3 had locally advanced and 3 had metastatic disease at initial diagnosis. MSH6 deficiency (def) was found in 2 cases, PMS2 def in 2, MLH/PMS2 def in 5, and MSH2/MSH6 in 1. 7 pts were treated with ICIs. 3 pts had locally advanced and 4 had metastatic disease when they started ICIs. 5 received Pembrolizumab (pem), 1 received ipilimumab/ nivolumab (ipi/nivo), and 1 received pem then ipi/nivo after progressive disease (PD) on pem. The median number of prior lines of chemotherapy was 1 (range 0-2). 6 pts were evaluable, and 1 had rapid disease progression after 1 dose of pem. Among 6 evaluable pts, 3 had an objective response (1: complete response and 2: partial response), and 2 had stable disease (SD). Median progression-free survival was 8.2 mo, and median overall survival was not reached with median follow-up (FU) of 6.8 mo. The median duration of response was not reached with a median FU of 22.6 mo. The pt with CR remained disease-free for up to 22 months. The pt whose treatment was switched to ipi/nivo after PD on pem achieved SD > 4mo on ipi/nivo. While on immunotherapy, one patient with ipi/nivo developed immunotherapy associated rash requiring systemic steroids, and another on pem developed hypothyroidism requiring levothyroxine. Conclusions: This series suggest ICIs can provide durable clinical efficacy in pts with dMMR PDAC.

222 Background: Secretory tumor markers traditionally measured in patients with NET, such as chromogranin A, are lacking in sensitivity and specificity, and consequently are of limited clinical utility. The NETest, a novel blood multigene RNA transcript assay, has been found to be highly sensitive and specific. We sought to validate the sensitivity of the NETest in a population consisting of metastatic well-differentiated NETs, and evaluate the specificity of the test in a mixed population of metastatic non-NET GI malignancies and healthy individuals. Methods: 100 individuals consented to be tested, comprising of 49 patients with metastatic well-differentiated NETs of gastroenteropancreatic and lung origin, 25 patients with other gastrointestinal cancers, and 26 healthy individuals. Samples were sent in a blinded fashion to a central laboratory (Wren Laboratories). A NETest value of 0-13% was considered within normal range. Results: Using the ULN of 13%, the sensitivity of the NETest was 98% (CI 89%-100%) with 48 true positive results and one false negative. The overall specificity (in a mixed population of healthy individuals and non-NET cancer patients) was 63% (CI 49%-75%), with 32 true negative and 19 false positive results. Among the 26 healthy individuals the specificity was 81% (CI 62%-92%); among patients with other GI cancers, specificity was 44% (CI 27%-63%). Using an alternate and updated normal range of 0-20%, sensitivity was unchanged (98%), but specificity improved to 100% among healthy patients, and 64% among patients with other cancers. Conclusions: The sensitivity of the NETest is exceptionally high in a population of metastatic well-differentiated NETs. Specificity within a healthy population of patients is exceptionally high when using a normal range of 0-20%, and moderately high when using a normal range of 0-13%. Specificity is lower when evaluating patients with other GI malignancies. Clinical trial information: NCT02948946.