Hartgers, Mindy L.

727 Background: PARP inhibition (PARPi) is a standard maintenance therapy for patients (pts) with germline BRCA1/2 mutations in pancreatic cancer. Combination of PARPi therapy and immunotherapy has potential to increase efficacy and may offer benefit beyond germline BRCA1/2 . Methods: We performed a multisite single-arm phase 2 study using the highly potent PARPi niraparib with anti-PD1 drug dostarlimab in pts with germline or somatic HRD mutations in BRCA1/2, PALB2, RAD51C/D, or BARD1 . Pts were required to have metastasis, progressed on ≥1 regimen, and prior platinum-exposure unless refused/intolerant. Pts were treated with niraparib 200 mg orally once daily continuously. Dostarlimab 500 mg was administered IV every 3 weeks for 4 cycles, then 1000 mg IV every 6 weeks. The primary endpoint was disease control rate (DCR) at 12 weeks (DCR12) using iRECIST criteria. At least 8 pts with DCR12 in the first 19 eligible pts (41%) would be considered promising for further trials. Results: 22 pts were enrolled from Dec 2020 to Oct 2023. Two pts withdrew prior to receiving therapy, and 2 were later found to be ineligible, leaving 18 eligible pts for final analyses. Median age was 63.0 yrs, 39% male, 94% non-Hispanic white, 1 black (6%). 17 pts were platinum exposed, 7 were platinum-refractory, and 5 had previously progressed on PARPi maintenance. Mutation distribution was: BRCA2 13/18 (72%), BRCA1 4/18 (22%), BARD1 2/18 (11%). One pt had both BRCA1 (somatic) and BRCA2 (germline) mutations. Germline mutations were identified in 14/18 (78%). DCR12 was achieved in 5/18 (27.8%), so the primary endpoint (>41%) was not met. Pts received a median 2 cycles (range 1-8) of niraparib + dostarlimab. No clinical factors were significantly associated with improved DCR12 (all p > 0.05) in subgroup analyses, but we did observe the following statistically nonsignificant associations. Pts who were platinum-refractory had a lower DCR12 compared to those not (14.3% vs. 36.4%). Counterintuitively, PARPi exposed/refractory pts had a higher DCR12 than non-exposed/non-refractory (50 vs 17% exposed/nonexposed and 40% vs 23% refractory/nonrefractory). Pts with germline mutations had a higher DCR12 compared to those without (38.5% vs. 0%). Non- BRCA2 mutations had a higher DCR12 than those with BRCA2 mutations (50% vs.17%), with highest DCR12 rates among BRCA1 patients (67%). Tolerability was in line with similar combinations, with 60% non-hematologic Gr3 or higher, including fatigue (15%), AST increase (10%), nausea/vomiting (10%), sepsis (10%). Two grade 5 events were not attributed to treatment. Conclusions: PARPi plus anti-PD1 checkpoint inhibition was not sufficiently active as later line therapy in metastatic pancreatic cancer for the majority of patients with HRD mutations. Additional molecular analyses to elucidate predictive markers of sensitivity/resistance are ongoing. Clinical trial information: NCT04493060 .

Abstract Background We sought to determine the safety and efficacy of trifluridine/tipiracil in combination with irinotecan in a phase II trial setting for refractory, advanced unresectable biliary tract carcinoma (BTC). Methods A total of 28 patients (27 were evaluable) with advanced BTCs who progressed on at least one prior systemic therapy were enrolled and were treated with trifluridine/tipiracil 25 mg/m2 (days 1-5 of 14-day cycle) and irinotecan 180 mg/m2 (day 1 of the 14-day cycle). The primary endpoint for the study was 16-week progression-free survival (PFS16) rate. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety were pre-specified secondary endpoints. Results Of 27 patients, PFS16 rate was 37% (10/27; 95% CI: 19%-58%), thereby meeting the criteria for success for the primary endpoint. The median PFS and OS of the entire cohort were 3.9 months (95% CI: 2.5-7.4) and 9.1 months (95% CI: 8.0-14.3), respectively. In the patients evaluable for tumor response (n = 20), the ORR and DCR were 10% and 50%, respectively. Twenty patients (74.1%) had at least one grade 3 or worse adverse event (AE), and 4 patients (14.8%) had grade 4 AEs. A total of 37% (n = 10/27) and 51.9% (n = 14/27) experienced dose reductions in trifluridine/tipiracil and irinotecan, respectively. Delay in therapy was noted in 56% of the patients while 1 patient discontinued the therapy, primarily due to hematologic AEs. Conclusion The combination of trifluridine/tipiracil plus irinotecan is a potential treatment option for patients with advanced, refractory BTCs with good functional status and no targetable mutations. A larger randomized trial is needed to confirm these results. (ClinicalTrials.gov Identifier: NCT04072445)

TPS780 Background: Pancreatic adenocarcinoma is an aggressive malignancy with a limited number of therapeutic options. One subset of patients (up to 15%) carries germline and/or somatic mutations in homologous recombination repair genes, most notably BRCA1, BRCA2 and PALB2 amongst others, that confer sensitivity to PARP inhibition. Combinations of PARP inhibitors with anti-PD1 immunotherapy have shown activity in breast and ovarian cancer and have not yet been thoroughly studied in pancreatic cancer. Methods: We designed a single-arm phase 2 investigator-initiated study utilizing the combination of niraparib, a highly selective PARP inhibitor and a dostarlimab, an anti PD1 antibody, in the subset of pancreatic cancer patients with germline or somatic mutations in BRCA1/2, PALB2, BARD1, RAD51C, or RAD51D. Additional inclusion criteria include metastatic pancreatic adenocarcinoma, receipt of a platinum agent in 1st or 2nd line unless contraindicated, and at least 1 but not more than 2 prior lines of systemic therapy not including maintenance. Prior PARP inhibition is allowed, but not immediately prior to enrollment. Exclusion criteria include active unstable autoimmune disease or prior malignancy requiring active treatment within 2 years. Patients are treated with niraparib 200 mg orally once daily on days 1 through 21 of a 21 day cycle. Dostarlimab is administered IV 500 mg every 3 weeks for the 1st 4 cycles and then 1000 mg IV every 6 weeks subsequently. The primary endpoint of the study is the disease control rate at 12 weeks using standard iRECIST criteria. Twenty patients will be enrolled to ensure 19 evaluable. The design has 80% power to detected improvement in disease control rate from 25-50% with significance level of 0.10. Descriptive factors include gene mutated for inclusion, germline/somatic, and platinum refractoriness. Given the size of the study along with genetic heterogeneity there will be no interim analysis. Patients are being enrolled at 3 Mayo clinic sites in Rochester Minnesota, Phoenix Arizona, Jacksonville Florida. To date, 13 patients have been enrolled across all 3 sites. Full accrual is anticipated by early 2023. Correlative studies include genomic characterization of baseline tumors, assessment of immune infiltration of tumor microenvironment, tumor collection for organoid/xenograft, and serial circulating cell-free DNA and immune biomarkers. Trial Identifiers: NCT04493060, Mayo: MC1841. Supported by Glaxo Smith Kline. Clinical trial information: NCT04493060 .

751 Background: Pancreatic adenosquamous carcinomas (PASC) are rare malignancies, with limited evidence regarding best treatment options. The Mayo Clinic Pancreatic Cancer SPORE Registry was utilized to compare/contrast outcomes for pancreatic cancers with a squamous component to pancreatic ductal adenocarcinoma (PDAC). Methods: Patients were identified from the SPORE Registry (2000-2019), were reviewed and confirmed by expert pathologists. Demographic and clinical information was ascertained from medical records and risk factor questionnaires. A case control study of patients with PASC vs PDAC was constructed. PASC patients were also followed for outcome and treatment records were extracted. Results: Of 2,584 total patients with pancreatic cancers, 45 cases of PASC and 2,438 with PDAC were identified. There were no differences in age (median 69 vs 67 years, p=0.42), sex (male 64.4vs 56.6%, p= 0.29), BMI (27.41 vs 27.78 kg/m2, P=0.50), or ever-smoking (61.0 vs 55.3%, P=0.47), with a borderline association with reported diabetes (17.8 vs 29.9%, p =0.08). Compared to PDAC, PASCs were more likely to involve the body/tail (48.9 vs 33.2%, p= 0.02) and had poorer overall survival, adjusted for age, gender, and stage (median 7.1 m vs 12.8m, HR 1.89, p=0.0004). Of 9 PASC pts treated with neoadjuvant intent, 4 were surgically resected, median survival was 7 months. Eleven pts underwent upfront surgery, with variable adjuvant treatments. Median OS post- surgery was 18m (range 7-51). Of 14 patients presenting with metastatic disease, median survival was 4.5 m (range 1-22). With regard to systemic chemotherapy, for neoadjuvant or metastatic disease median duration of treatment was 3 months (range 0.5-7m) for Gemcitabine + nab-paclitaxel (N=9) and also 3 months (range 2-6m) for FOLFIRINOX (N-13). Conclusions: The diagnosis of PASC carries an even poorer outcome than pancreatic adenocarcinoma. Tumors are more likely to arise in the distal pancreas, and patients may be less likely to report associated diabetes. Limited antitumor activity was noted with multi-agent chemotherapeutic regimens. Prospective trials will be needed to clarify choice of regimen in the future.

706 Background: In recent years, there has been a shift towards neo-adjuvant treatment (NAT) of non-metastatic pancreas cancer in the hopes of improving negative margin rate, lymph node negativity, recurrence and survival. Even patients deemed resectable based on NCCN criteria are receiving NAT but data for these patients remains limited. This current study evaluated the outcomes of patients diagnosed with resectable pancreatic adenocarcinoma. Methods: Patients were retrospectively identified through the Mayo Clinic, Rochester SPORE pancreatic cancer registry as well as search of the electronic medical record via Advanced Cohort Explorer from May 2011 to 2016. Baseline demographics, tumor characteristics, treatments rendered, and outcomes were collected. Variables were analyzed for association with recurrence from time of surgery and survival from time of diagnosis using Kaplan-Meier curves and Cox proportional hazards regression. Results: A total of 520 patients with resectable pancreatic adenocarcinoma were identified. 72 patients received upfront chemotherapy with 44 (61.1%) proceeding to surgical resection. 62 patients received upfront chemotherapy followed by radiation with 33 (53.2%) proceeding to surgical resection. 12 patients received upfront radiation alone with 7 (58.3%) proceeding to surgical resection. 374 patients did not receive any NAT with 293 (78.3%) proceeding to surgical resection. In total, 377 (72.5%) went to resection. Median time to recurrence from surgery was 27.7 months vs. 21.7 months for NAT and upfront resection, respectively (HR 0.87, 95% CI 0.60-1.72, p = 0.48). Median overall survival from diagnosis for those receiving NAT was 40.6 months vs. 24.7 months for those receiving upfront resection (HR 0.62, 95% CI 0.41-0.92, p = 0.02). Conclusions: This study shows an approximate 16 month improvement in overall survival of patients receiving upfront NAT for resectable pancreatic adenocarcinoma. This might be due to a better selection of patients. It also highlights that not all patients with resectable cancer undergo resection. Further studies are warranted to identify why resectable patients are not proceeding to resection and which specific NAT approaches benefit patients the most.

AbstractTrial InformationClick here to access other published clinical trials.Lessons LearnedTrifluridine/tipiracil (FTD/TPI) shows promising antitumor activity in heavily pretreated patients with advanced biliary tract carcinoma, including patients with 5-fluorouracil refractory tumors. FTD/TPI has an acceptable safety profile and should be studied further in patients with advanced biliary tract carcinoma after progression on standard first-line therapy.BackgroundPatients with advanced biliary tract carcinoma (BTC) refractory to first-line therapy lack an established second-line option. Trifluridine/tipiracil (FTD/TPI) has activity in both fluoropyrimidine-sensitive and -resistant tumors, which led us to conduct a single arm phase II trial to evaluate the safety and efficacy of FTD/TPI for patients previously treated for advanced BTC.MethodsPatients with advanced BTC previously treated with at least one line of chemotherapy were enrolled and treated with FTD/TPI until disease progression or unacceptable toxicity. The primary endpoint target was to have at least 6 patients who were progression free and alive at 16 weeks among 25 evaluable patients. Secondary endpoints included overall survival (OS), overall response rate (ORR), progression-free survival (PFS), and toxicity.ResultsOf 27 evaluable patients, 59.3% received at least three prior lines of therapy, and 81.5% had previous exposure to fluoropyrimidine. Eight (32%, 95% confidence interval [CI], 14.9%–53.5%) patients were progression free at 16 weeks in the primary analysis population (n = 25), which met the predefined efficacy criteria. Median PFS and OS were 3.8 (95% CI, 2–5.8 months) and 6.1 (95% CI, 4.4–11.4 months) months, respectively. No objective responses were seen. There were no unexpected safety signals noted.ConclusionFTD/TPI demonstrated promising antitumor activity, with acceptable toxicity, in heavily pretreated patients with advanced BTC.

452 Background: Surgical resection is the only curative treatment for patients with gallbladder cancer, despite surgical advances many patients ultimately develop recurrent disease. Management of resected gallbladder cancer mostly relies on single-arm trials and retrospective observations. The purpose of our study is to assess the role of adjuvant therapy in stage I-III gallbladder cancer patients who have undergone surgical resection. Methods: Clinical data were collected on 251 patients who underwent surgical resection for stage I-III gallbladder cancer and presented to Mayo clinic from January 2000-December 2015. Patients were then classified into adjuvant treatment group and surveillance only group. Overall survival and recurrence were compared between the two groups. Results: 78 (31.1%) patients received adjuvant therapy while 173 patients were observed only. Patients who received adjuvant tended to be younger (63.0[SD 11] vs 66.2 [SD 13.1]), have higher stage, and underwent extended surgery. Most patients received chemoradiotherapy (55) with 5-Fluorouracil (67.3%) and capecitabine (25.5%) as radiosensitizing agents. 21 patients received additional adjuvant chemotherapy. 27% of patients received chemotherapy as the sole adjuvant treatment. The most common chemo regimens included gemcitabine (52.3%) and gemcitabine plus cisplatin combination (23.8%). On multivariate analysis patients > 65 years(HR 1.53 [1.07-2.19], p = 0.02), males (HR 1.7 [1.2-2.4], p = 0.003), positive margins (2.77 [1.69-4.38], p < 0.01), and stage III (HR 1.91 [1.35-2.70], p < 0.01) had worse overall survival. Patients who underwent extended radical resection (HR 0.73 [0.51-1.05], p = 0.09) had better overall survival. Adjuvant therapy had no statistical significant effect on overall survival (HR 1.10 [0.75-1.59], p = 0.63 or disease free survival (HR 1.05 [0.69-1.59], p = 0.81) on overall population. However, in stage IIIB, patients receiving adjuvant therapy had better overall survival (HR 0.51 [0.25-1.01], p = 0.05) and disease free survival (HR 0.45 [0.19-1.09], p = 0.06). Conclusions: In our study, adjuvant treatment, especially chemoradiation therapy, was only beneficial in patients with stage IIIb gallbladder cancer patients.

450 Background: The standard treatment for patients with gallbladder cancer is a combination of gemcitabine and cisplatin based on ABC-02 trial. However, there are no guidelines regarding treatment after first-line therapy. We retrospectively analyzed the efficacy and overall survival of different second-line regimens. Methods: We identified 203 patients with advanced gallbladder cancer who received palliative treatment between January 2000 and December 2015 at Mayo Clinic, Rochester. RECIST criteria was used to assess response. Results: 68 patients received second-line chemotherapy. Median age was 63 years (range: 32-86) and majority were males (60.6%). The median time from the diagnosis to the start of the second line chemotherapy was 8 (1-120) months. The most common used second-line chemotherapy were FOLFOX (14), gemcitabine alone (10), single agent fluoropyrimidine (11), gemcitabine with capecitabine (5), and capecitabine with oxaliplatin (4). There were 30 patients that received 5-fluorouracil based regimens, 20 patients received gemcitabine-based regimen, 3 patients received taxane-based regimen, and 15 patients received other types of chemotherapy. Median progression free survival and overall survival was 2.1 (1.8-2.7) and 16.7 (13.2-21.3) months respectively. There were 10 (52%), 11 (37%), 2 (67%), 5 (33%) with partial response and stable disease in 5-fluorouracil-based, gemcitabine-based, taxane-based, and others, respectively. There were no difference in PFS, with median PFS of 2.5, 2.0, 2.8 and 2.3 months, respectively (p=0.43). The overall survival were 15.7 (8.9-40.2), 15.0 (10.7-21.3), 40.3 (22.0-47.0), and 20.4 (9.2-30.7) months, respectively (p=0.83). There were 27 patients that received single agent chemotherapy and 41 patients that received combined regimen. There were 17 (42%) patients and 13 (48%) patients with partial response or stable disease in single and combined regimen. There were no differences in progression free survival and overall survival between single and multi agent chemotherapy. Conclusions: In this largest single institution study, second-line chemotherapy regimens for gallbladder cancer provided benefit in select patients and there is an urgent need to develop more active therapeutic regimens.

e15797 Background: Duodenal adenocarcinoma is a rare tumor representing approximately 0.3% of all gastrointestinal tract cancers. Prognostic factors in relation to survival outcomes for these patients are sporadically reported in the medical literature. We aimed to evaluate outcomes of patients with duodenal adenocarcinoma who underwent pancreaticojejunostomy treated at Mayo Clinic Rochester from January 1, 2006 to December 31, 2016. Methods: Clinicopathological data of 52 duodenal cancer patients were collected. JMP software was used for statistical analysis. Kaplan-Meier method and log-rank tests were used for survival analysis, and multivariate cox proportional hazards model was used to evaluate the prognostic effect of pertinent clinical variables. All tests were two sided and a P value of < 0.05 was considered significant. Results: The median age at diagnosis was 65.9 years (range 39-81). The median overall survival was 51 months (95% CI 31.3-105.4) and the median progression free survival was 30.4 months with median follow up of 73.4 months. There were 3, 9, 21, and 19 patients with stage I, II, III, and IV disease, respectively. Depth of tumor invasion (p = 0.0156) and lymph node metastasis (p = 0.0441) were associated with overall survival on multivariate analysis. Advanced clinical staging influenced overall survival in univariate analysis, but lost prognostic significance in multivariate analysis. Age, gender, surgical technique, presence of metastases, tumor size, number of lymph nodes removed, location of duodenal segment involvement, and adjuvant treatment had no significant impact on overall survival. Laparoscopic approach did not influence survival but was associated with less hospital days (p = 0.0437). Conclusions: Depth of tumor invasion and lymph node status were associated with improved overall survival in patients with duodenal adenocarcinoma. Laparoscopic procedure decreased the hospital stay without affecting outcomes.