McWilliams, Robert R.

4130 Background: KRAS is mutationally activated in over 90% of pancreatic ductal adenocarcinoma (PDAC). Compared to pts with KRAS mutation, KRAS wild-type (wt) PDAC seem to have better response to therapy and may harbor potentially actionable molecular alterations. Here, we analyze the molecular profile and clinical outcome of a cohort of pts with KRAS wt PDAC. Methods: A retrospective review was conducted on pts with PDAC who underwent CLIA-certified Next Generation Sequencing (NGS) testing at Mayo Clinic between December 1, 2018 and December 1, 2021. Pts with KRAS wt PDAC with available reports were included. Their genomic drivers, RNA expression, demographics, disease characteristics, therapies offered, and clinical outcome data were collected. The study was approved by the institutional IRB. Results: Of the 241 eligible pts, 8% (19) has KRAS wt PDAC. Among those, 2 pts had no mutation identified by the gene/molecular panel used. Of the 17 pts (89%) with identified alterations, mutations found in ³ 2 pts were TP53 (53%), CDKN2A (16%) and CDKN2B/ERBB2/PTEN/MSH3/RNF43/FBXW7/KMT2D/GNAS (11% each). Chromosomal rearrangements were identified in 5 (26%): CADPS2-BRAF, GP2-ERBB2, PTPRK-RSPO3, EML4-NTRK3 and TFG-MET. RNA expression results were available in 12 pts: common overexpression were ERBB2 (27%) and MET/NRAS/MYC/CCDN1/CCNE1/AR (18% each); and the under-expression MGMT (18%). Among the 13 pts with available MSI status via NGS, 2 (11%) were MSI-high (both had high TMB [28.4 and 23.7 m/MB]) while all others were TMB < 10 m/MB. The median age at diagnosis was 61 years (68% males). 8/19 (42%) were Stage IV at diagnosis with 15/19 (79%) pts ultimately diagnosed with metastatic disease. Among metastatic pts, median lines of treatment received was 2.5 (range:0-4). 4 pts received FOLFIRINOX (FFX), 2 gemcitabine/ nab-paclitaxel (GP) and tumor response were comparable to previously reported results. 1 received 1st-line pembrolizumab and remained on therapy at the time of analysis. The median length of follow up from diagnosis was 29 months. A patient with TFG-MET re-arrangement previously progressed on FFX and GP was treated using a MET inhibitor, and achieved significant CA19-9 drop and pancreas tumor shrinkage at 1st restaging, with ongoing response. Conclusions: The molecular profile of KRAS wt PDAC is highly heterogeneous and difficult to generalize. Novel approaches (e.g., basket trials) are needed to develop therapy for this rare PDAC subgroup.

Abstract Purpose: This phase Ib/2 trial investigated pembrolizumab-containing trimodality therapy in patients with gastroesophageal junction (GEJ) adenocarcinoma. Patients and Methods: Patients with GEJ adenocarcinoma (cT1–3NanyM0) received neoadjuvant pembrolizumab-containing chemoradiation (CROSS regimen) followed by surgical resection and adjuvant pembrolizumab. The primary endpoints were tolerability in the first 16 patients and pathologic complete response [pCR (ypT0N0)]. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). An independent propensity-score-matched cohort (treated with CROSS without immunotherapy) was used for comparison. Exploratory analyses included immune biomarkers in the tumor microenvironment (TME) and plasma. Results: We enrolled 31 eligible patients, of whom 29 received all expected doses of neoadjuvant pembrolizumab and 28 underwent R0 resection. Safety endpoints were met. The primary efficacy endpoint was not met [7/31 (22.6%) achieved pCR]. Patients with high [i.e., combined positive score (CPS) ≥ 10] baseline expression of programmed death (PD)-L1 in the TME had a significantly higher pCR rate than those with low expression [50.0% (4/8) vs. 13.6% (3/22); P = 0.046]. Patients with high PD-L1 expression also experienced longer PFS and OS than propensity-score-matched patients. Among trial patients with PD-L1 CPS &lt; 10, unprespecified analysis explored whether extracellular vesicles (EV) could identify further responders: an elevated plasma level of PD-L1–expressing EVs was significantly associated with higher pCR. Conclusions: Adding pembrolizumab to trimodality therapy showed acceptable tolerability but did not meet the pre-specified pCR endpoint. Exploratory analyses suggested that high PD-L1 expression in the TME and/or on EVs may identify patients most likely to achieve tumor response.

AbstractImmune checkpoint inhibitors (ICIs), as a novel class of anticancer therapy, can be more efficacious and less toxic than chemotherapy, but their clinical success is confined to certain tumor types. Elucidating their targets, mechanisms and scope of action, and potential synergism with chemotherapy and/or targeted therapies are critical to widen their clinical indications. Treatment response to an ICI targeting programmed death‐1 (anti‐PD‐1) is sought to be understood here by conducting a preplanned correlative analysis of a phase II clinical trial in patients with small bowel adenocarcinoma (SBA). The cytolytic capacity of circulating immune cells in cancer patients using a novel ex vivo cytotoxicity assay is evaluated, and the utility of circulating biomarkers is investigated to predict and monitor the treatment effect of anti‐PD‐1. Baseline expression of Bim and NKG7 and upregulation of CX3CR1 in circulating T cells are associated with the clinical benefit of anti‐PD‐1 in patients with SBA. Overall, these findings suggest that the frequency and cytolytic capacity of circulating, effector immune cells may differentiate clinical response to ICIs, providing a strong rationale to support immune monitoring using patient peripheral blood.

563 Background: RUB is an oral PARP1,2,3 inhibitor that demonstrated efficacy in patients (pts) with ovarian and prostate cancers harboring deleterious BRCA mutations. RUB exerts synergistic anti-tumor effect with IRI preclinically though the combination has overlapping toxicities. We previously published on the population PK of nal-IRI (Adiwijaya, Ma et al, Clin Pharm Ther 2017). We conducted a phase I study to evaluate a novel sequential dosing of RUB with nal-IRI/5FU in mGI cancer pts. Methods: Eligible pts had incurable mGI cancer previously received > 1 line of therapy (rx), ECOG PS 0-1, had RECIST measurable disease, adequate organ reserves and not received IRI for metastatic disease. Previous PARPi rx was excluded. The endpoints included dose limiting toxicity (DLT), maximum tolerated dose (MTD) and toxicity profile. The dose escalation utilized the 3+3 design. RUB was given oral bid on Day 4 to 13 and 18 to 27 with nal-IRI i.v. and 5FU i.v. 2400 mg/m2 over 46 hr on Day 1 and 15, every 28 day. Planned dose levels were RUB 400 mg/nal-IRI 50 mg/m2 (DL1), 400 mg/70 mg/m2 (DL2) and 600 mg/70 mg/m2 (DL3). Adverse events (AEs) were scored per CTCAE v4.03. Molecular profile was evaluated by CLIA-certified NGS testing. Results: Eighteen pts including 11 colorectal (CRC), 6 PANC, 1 gastroesophageal (GE) were enrolled and 12 were evaluable for DLTs. DL2 was not tolerable (DLT: G3 diarrhea, nausea and vomiting) and DL2A was added (RUB 600 mg/nal-IRI 50 mg/m2). DL2A enrolled 6 pts with no DLT and was determined as the MTD. Of DLT-evaluable pts, G3 and worse treatment-related AEs from all cycles were diarrhea (33%), fatigue (25%), leukopenia (25%), neutropenia (25%), anemia (8%) and nausea (8%). Four of 12 response evaluable pts had partial response: 2 CRC (1 had ATM mut), 1 PANC ( ATM mut), 1 GE ( BRCA2 mut) whilst 3 responders previously had platinum (PLA). Five pts had stable disease beyond 16 weeks (range 18.9 to 100.7 weeks), and all had prior PLA. Conclusions: The study successfully determined the MTD of RUB in combination with nal-IRI and 5FU. Encouraging efficacy was observed in PLA-treated mGI cancers including responses in those harboring ATM and BRCA alterations. The study is proceeding to evaluate the efficacy of the combination in metastatic pancreas cancer pts with and without BRCA1/2 or PALB2 alterations. Clinical trial information: NCT03337087.

Abstract Performing genetic epidemiology studies in underrepresented populations is challenging, but is extremely important in order to understand how cancer impacts differing populations, This can then allow more tailored and nuanced management of persons at risk. Our group at Mayo Clinic encountered some interesting preliminary findings regarding CDKN2A, but given small numbers of subjects in our registry, we needed to partner with other collaborators to have enough statistical power to make sense of the findings and generate a publishable result. This talk will focus on the means of doing this, the importance of team-based science across centers, and future opportunities. Background: Pathogenic germline mutations in the CDKN2A tumor suppressor gene are rare and associated with highly penetrant familial melanoma and pancreatic cancer in non-Hispanic whites. WeTo date, the prevalence and impact of CDKN2A rare coding variants (RCV) in racial minority groups remain poorly characterized. We examined the role of CDKN2A RCVs on the risk of pancreatic cancer among minority subjects. Methods: We performed a case-control study of germline mutations in CDKN2A among patients with incident pancreatic cancer and controls, focused on underrepresented minority populations. We sequenced CDKN2A in 220 African American pancreatic cancer cases, 900 noncancer African American controls, and 183 Nigerian controls. RCV frequencies were determined for each group and compared with that of 1,537 Non-Hispanic White patients with pancreatic cancer. Odds ratios (OR) and 95% confidence intervals (CI) were calculated for both a case–case comparison of RCV frequencies in African Americans versus Non-Hispanic Whites, and case–control comparison between AA cases versus noncancer AA controls plus Nigerian controls. Smaller sets of Hispanic and Native American cases and controls also were sequenced. Race/ethnicity categorization was from self-report. Results: One novel missense RCV and one novel frameshift RCV were found among AA patients: 400G&gt;A and 258_278del. RCV carrier status was associated with increased risk of pancreatic cancer among AA cases (11/220; OR, 3.3; 95% CI, 1.5–7.1; P ¼ 0.004) compared with African American and Nigerian controls (17/1,083). Further, African American cases had higher frequency of RCVs: 5.0% (OR, 13.4;95%CI, 4.9–36.7; P &lt; 0.001) compared with Non-Hispanic White cases (0.4%). Conclusions: CDKN2A RCVs are more common in African Americans than in Non-Hispanic White patients with pancreatic cancer and associated with moderately increased pancreatic cancer risk among African Americans. Citation Format: Robert McWilliams. CDKN2A germline rare coding variants and risk of pancreatic cancer in minority populations [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr IA-40.

Abstract Background: ABO blood group is associated with pancreatic cancer risk. Whether ABO blood group alone or when combined with inherited mutation status of index pancreatic cancer cases (probands) can enhance pancreatic cancer risk estimation in first-degree relatives (FDR) is unclear. We examined FDRs' risk for pancreatic cancer based on probands' ABO blood group and probands' cancer susceptibility gene mutation status. Methods: Data on 23,739 FDRs, identified through 3,268 pancreatic cancer probands, were analyzed. Probands' ABO blood groups were determined serologically or genetically, and 20 cancer susceptibility genes were used to classify probands as “mutation-positive” or “mutation-negative.” SIRs and 95% confidence intervals (CI) were calculated, comparing observed pancreatic cancer cases in the FDRs with the number expected in SEER-21 (reference population). Results: Overall, FDRs had 2-fold risk of pancreatic cancer (SIR = 2.00; 95% CI = 1.79–2.22). Pancreatic cancer risk was higher in FDRs of mutation-positive (SIR = 3.80; 95% CI = 2.81–5.02) than mutation-negative (SIR = 1.79; 95% CI = 1.57–2.04) probands (P &lt; 0.001). The magnitude of risk did not differ by ABO blood group alone (SIRblood-group-O = 1.57; 95% CI = 1.20–2.03, SIRnon-O = 1.83; 95% CI = 1.53–2.17; P = 0.33). Among FDRs of probands with non-O blood group, pancreatic cancer risk was higher in FDRs of mutation-positive (SIR = 3.98; 95% CI = 2.62–5.80) than mutation-negative (SIR = 1.66; 95% CI = 1.35–2.03) probands (P &lt; 0.001), but risk magnitudes were statistically similar when probands had blood group O (SIRmutation-positive = 2.65; 95% CI = 1.09–5.47, SIRmutation-negative = 1.48; 95% CI = 1.06–5.47; P = 0.16). Conclusions: There is a range of pancreatic cancer risk to FDRs according to probands' germline mutation status and ABO blood group, ranging from 1.48 for FDRs of probands with blood group O and mutation-negative to 3.98 for FDRs of probands with non-O blood group and mutation-positive. Impact: Combined ABO blood group and germline mutation status of probands can inform pancreatic cancer risk estimation in FDRs.

Objectives This study sought to better characterize patient characteristics, treatment options, and outcomes for osteoclast-like giant cell carcinoma of the pancreas, a rare subtype of pancreatic adenocarcinoma. Methods This is a retrospective study of all patients with osteoclast-like giant cell carcinoma of pancreatic origin treated at Mayo Clinic from 2000 to present. Baseline patient characteristics, treatment modalities utilized, and outcomes were compiled. Overall survival (OS) and progression-free survival were assessed using Kaplan-Meier analysis with a significance level of P ≤ 0.05. Results Fifteen patients met criteria for inclusion. Four patients had distant metastases at diagnosis, the remaining 11 with locoregional disease. Median OS for the entire cohort was 11 months. Metastatic disease was associated with significantly shorter OS (3.5 vs 14.1 months; P = 0.005). Three patients had no evidence of disease at time of analysis; all 3 were treated with complete resection followed by adjuvant chemotherapy. Conclusions Osteoclast-like giant cell carcinoma of the pancreas is an aggressive malignancy with poor prognosis. For patients with locoregional disease, surgical resection followed by adjuvant chemoradiation may play a role in extended disease-free survival. Metastatic disease presents a challenging entity to treat with little data to support any effective chemotherapy regimens.

PURPOSECholangiocarcinomas (CCA) are a group of heterogeneous tumors arising from the biliary epithelia. Significant sequencing efforts have provided further insights into the molecular mechanisms of this disease including fibroblast growth factor receptor ( FGFR) alterations, which occurs in approximately 15%-20% of intrahepatic CCAs. Herein, we describe the FGFR inhibitor (FGFRi)-associated treatment toxicity and cancer-specific outcomes from a multicenter single-institution cohort.METHODSThis is a retrospective study of patients with CCA and known FGFR alterations treated with FGFRi. We describe the toxicity and efficacy in patients treated at Mayo Clinic between January 2010 and December 2020.RESULTSOur group identified 61 patients with advanced or metastatic CCA, 19 males (31%) and 42 females (69%), harboring FGFR alterations who received FGFRi. The most common grade 1 or higher adverse events for all patients included fatigue (92%), AST elevations (78%), anemia (80%), decreased platelet count (63%), and hyperphosphatemia (74%). Median progression-free survival on FGFRi was 5.8 months for all patients (95% CI, 4.9 to 9.0). Females had significantly longer progression-free survival at 6.9 months (95% CI, 5.2 to 11.8) on FGFRi compared with males at 4.9 months (95% CI, 2.8 to not estimable; P = .038).CONCLUSIONFGFRi are well tolerated with clinical efficacy. With the recent approval of FGFRi by the US Food and Drug Administration and ongoing clinical trials for new FGFRi, understanding outcomes and toxicity associated with these medications is important for precision oncology.

PURPOSE: The benefit of routine pre-emptive screening for severe acute respiratory syndrome coronavirus 2 infections in patients with cancer before cancer-directed therapies is unclear. Herein, we characterize the outcomes of a cohort of patients with cancer who were diagnosed with COVID-19 by routine screening (RS) in comparison with those diagnosed on the basis of clinical suspicion or exposure history (nonroutine screening [NRS]). METHODS: A multisite prospective observational study was conducted at three major and five satellite campuses of the Mayo Clinic Cancer Center between March 18 and July 31, 2020. The primary outcome was COVID-19–related hospital admission. Secondary outcomes included intensive care unit admissions and all-cause mortality. RESULTS: Five thousand four hundred fifty-two patients underwent RS in the outpatient setting only, and 44 (0.81%) were diagnosed with COVID-19. RS detected 19 additional patients from the scheduled inpatient admissions for surgical or interventional procedures or inpatient chemotherapy. One hundred sixty-one patients were diagnosed with COVID-19 on the basis of NRS. COVID-19–related hospitalization rate (17.5% v 26.7%; P = .14), intensive care unit admission (1.6% v 5.6%; P = .19), and mortality (4.8% v 3.7%; P = .72) were not significantly different between the RS and NRS groups. In the multivariable analysis, age ≥ 60 years (odds ratio, 4.4; P = .023) and an absolute lymphocyte count ≤ 1.4 × 109/L (odds ratio, 9.2; P = .002) were independent predictors of COVID-19–related hospital admission. CONCLUSION: The COVID-19 positivity rate was low on the basis of RS. Comparing the hospital admission and mortality outcomes with the NRS cohort, there were no significant differences. The value of routine pre-emptive screening of asymptomatic patients with cancer for COVID-19 remains low.

Background The indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that, in cancer, is exploited by tumors to evade antitumor immunity. Indoximod is a small-molecule IDO pathway inhibitor that reverses the immunosuppressive effects of low tryptophan (Trp) and high kynurenine (Kyn) that result from IDO activity. In this study, indoximod was used in combination with a checkpoint inhibitor (CPI) pembrolizumab for the treatment for advanced melanoma. Methods Patients with advanced melanoma were enrolled in a single-arm phase II clinical trial evaluating the addition of indoximod to standard of care CPI approved for melanoma. Investigators administered their choice of CPI including pembrolizumab (P), nivolumab (N), or ipilimumab (I). Indoximod was administered continuously (1200 mg orally two times per day), with concurrent CPI dosed per US Food and Drug Administration (FDA)-approved label. Results Between July 2014 and July 2017, 131 patients were enrolled. (P) was used more frequently (n=114, 87%) per investigator’s choice. The efficacy evaluable population consisted of 89 patients from the phase II cohort with non-ocular melanoma who received indoximod combined with (P). The objective response rate (ORR) for the evaluable population was 51% with confirmed complete response of 20% and disease control rate of 70%. Median progression-free survival was 12.4 months (95% CI 6.4 to 24.9). The ORR for Programmed Death-Ligand 1 (PD-L1)-positive patients was 70% compared with 46% for PD-L1-negative patients. The combination was well tolerated, and side effects were similar to what was expected from single agent (P). Conclusion In this study, the combination of indoximod and (P) was well tolerated and showed antitumor efficacy that is worth further evaluation in selected patients with advanced melanoma.