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Stereotactic body radiation therapy (SBRT) for patients with borderline resectable and locally advanced pancreatic adenocarcinoma (BRPC/LAPC) remains controversial. Herein, we report on surgical, pathologic, and survival outcomes in BRPC/LAPC patients treated at a high-volume institution with induction chemotherapy (CTX) followed by 5-fraction SBRT.BRPC/LAPC patients treated between 2016 and 2019 were retrospectively reviewed. Surgical and pathological outcomes were descriptively characterized. Overall survival (OS) and progression-free survival (PFS) were analyzed using Cox proportional hazard regression. Locoregional failure and distant failure were analyzed with Fine-Gray competing risk model.Of 155 patients, 91 (59%) had LAPC and 64 (41%) had BRPC. Almost all were treated with induction multi-agent CTX with either FOLFIRINOX (75%) or gemcitabine and nab-paclitaxel (24%) for a median duration of 4.0 months (1-18 months). All received SBRT to a median dose of 33 Gy. Among 64 BRPC patients, 50 (78%) underwent resection, of whom 48 (96%) achieved margin-negative (R0) resection. Among 91 LAPC patients, 57 (63%) underwent resection, of whom 50 (88%) achieved R0 resection. Despite the high R0 rate, 33% of patients experienced locoregional failure, which was a component of 44% of all failures. After SBRT, median OS and PFS were 18.7 and 7.7 months, respectively. After SBRT, 1- and 2-year OS probabilities were 70% and 45%, whereas, from diagnosis, they were 93% and 51%.Although a high proportion of BRPC/LAPC patients treated with induction multi-agent CTX followed by SBRT successfully achieved R0 resection, locoregional failure remained common, highlighting the need to continue to optimize radiation delivery in this context.

Gene variants that encode pancreatic enzymes with impaired secretion can induce pancreatic acinar endoplasmic reticulum (ER) stress, cellular injury and pancreatitis. The role of such variants in pancreatic cancer risk has received little attention. We compared the prevalence of ER stress-inducing variants in CPA1 and CPB1 in patients with pancreatic ductal adenocarcinoma (PDAC cases), enrolled in the National Familial Pancreas Tumor Registry, to their prevalence in non-cancer controls in the Genome Aggregation Database (gnomAD). Variants of unknown significance were expressed and variants with reduced secretion assessed for ER stress induction. In vitro assessments were compared with software predictions of variant function. Protein variant software was used to assess variants found in only one gnomAD control ("n-of-one" variants). A meta-analysis of prior PDAC case/control studies was also performed. Of the 1385 patients with PDAC, 0.65% were found to harbor an ER stress-inducing variant in CPA1 or CPB1, compared to 0.17% of the 64,026 controls (Odds Ratio (OR): 3.80 [1.92-7.51] P=0.0001). ER stress-inducing variants in the CPA1 gene were identified in 4 of 1385 PDAC cases versus 77 of 64,026 gnomAD controls (OR: 2.4 [0.88-6.58], p=0.087), and variants in CPB1 were detected in 5 of 1385 cases versus 33 of 64,026 controls (OR: 7.02 [2.74-18.01], p=0.0001). Meta-analysis demonstrated strong associations for pancreatic cancer and ER-stress inducing variants for both CPA1 (OR: 3.65 [1.58, 8.39], p

Background Pancreatic cancer is a lethal disease with a poor 5-year survival rate. Pathogenic germline variants in the coding regions of ATM, BRCA1, and BRCA2 are found in up to 4.8% of pancreatic cancer patients. Germline promoter methylation and gene silencing arising from a germline variant or through other mechanisms have been described as a cause of tumor suppressor gene inactivation. Methods We measured the level of promoter methylation of the ATM, BRCA1, and BRCA2 genes in peripheral blood lymphocytes from 655 patients with pancreatic cancer using real-time PCR. Results No evidence of germline promoter methylation of any of these genes was found. Promoter methylation levels were minimal with no patient having promoter methylation greater than 3.4%, 3.3%, and 7.6% for ATM, BRCA1 and BRCA2, respectively, well below levels found in patients who have inherited promoter methylation (∼50%). Conclusions We found no evidence of germline promoter methylation for the pancreatic susceptibility genes ATM, BRCA1 and BRCA2 in patients with pancreatic cancer. This study reveals that constitutive germline methylation of promoter CpG islands is rare in pancreatic cancer.

PURPOSE Genetic alterations in many components of the homologous recombination, DNA damage response, and repair (HR-DDR) pathway are involved in the hereditary cancer syndromes, including familial pancreatic cancer. HR-DDR genes beyond BRCA1, BRCA2, ATM, and PALB2 may also mutate and confer the HR-DDR deficiency in pancreatic ductal adenocarcinoma (PDAC). METHODS We conducted a study to examine the genetic alterations using a companion diagnostic 15-gene HR-DDR panel in PDACs. HR-DDR gene mutations were identified and characterized by whole-exome sequencing and whole-genome sequencing. Different HR-DDR gene mutations are associated with variable homologous recombination deficiency (HRD) scores. RESULTS Eight of 50 PDACs with at least one HR-DDR gene mutation were identified. One tumor with BRCA2 mutations is associated with a high HRD score. However, another tumor with a CHEK2 mutation is associated with a zero HRD score. Notably, four of eight PDACs in this study harbor a RAD51B gene mutation. All four RAD51B gene mutations were germline mutations. However, currently, RAD51B is not the gene panel for germline tests. CONCLUSION The finding in this study thus supports including RAD51B in the germline test of HR-DDR pathway genes.

Purpose: Immunotherapy is currently ineffective for nearly all pancreatic ductal adenocarcinomas (PDAC), largely due to its tumor microenvironment (TME) that lacks antigen-experienced T effector cells (Teff). Vaccine-based immunotherapies are known to activate antigen-specific Teffs in the peripheral blood. To evaluate the effect of vaccine therapy on the PDAC TME, we designed a neoadjuvant and adjuvant clinical trial of an irradiated, GM-CSF-secreting, allogeneic PDAC vaccine (GVAX). Patients and Methods: Eighty-seven eligible patients with resectable PDAC were randomly assigned (1:1:1) to receive GVAX alone or in combination with two forms of low-dose cyclophosphamide. Resected tumors following neoadjuvant immunotherapy were assessed for the formation of tertiary lymphoid aggregates (TLA) in response to treatment. The clinical endpoints are disease-free survival (DFS) and overall survival (OS). Results: The neoadjuvant treatment with GVAX either alone or with two forms of low-dose cyclophosphamide is safe and feasible without adversely increasing the surgical complication rate. Patients in Arm A who received neoadjuvant and adjuvant GVAX alone had a trend toward longer median OS (35.0 months) than that (24.8 months) in the historical controls who received adjuvant GVAX alone. However, Arm C, who received low-dose oral cyclophosphamide in addition to GVAX, had a significantly shorter DFS than Arm A. When comparing patients with OS > 24 months to those with OS < 15 months, longer OS was found to be associated with higher density of intratumoral TLA. Conclusions: It is safe and feasible to use a neoadjuvant immunotherapy approach for PDACs to evaluate early biologic responses. In-depth analysis of TLAs is warranted in future neoadjuvant immunotherapy clinical trials.

Background: Novel strategies are needed to decrease the high recurrence rates of pancreatic ductal adenocarcinoma (PDAC) after curative-intent surgery. Mutant KRAS (mKRAS) is an oncogenic driver found in approximately 90% of PDAC that has emerged as a target for neoantigen-specific vaccination. Methods: This is a single-arm, open-label, first-in-human phase I study of a pooled synthetic long peptide (SLP) vaccine targeting six mKRAS subtypes (G12D, G12R, G12V, G12A, G12C, G13D) combined with ipilimumab/nivolumab (ipi/nivo) in patients with resected PDAC (NCT04117087). Key inclusion criteria: presence of a vaccine-targeted KRAS mutation, disease-free status after completing adjuvant chemotherapy within 6 months of enrollment. Priming phase: mKRAS vaccine given on days 1, 8, 15, and 22 along with ipi 1 mg/kg every 6 weeks for 2 doses and nivo 3 mg/kg every 3 weeks for 4 doses. Boost phase: mKRAS vaccine given on weeks 13, 21, 29, 37, and 45 along with nivo 480 mg every 4 weeks for 10 doses. Co-primary endpoints: safety, mKRAS-specific T cell response. Secondary endpoints: disease-free survival (DFS), overall survival (OS). Results: At the time of data cutoff (December 1, 2022), 11 patients were treated with a median follow-up time of 10.7 months. 8/11 patients achieved a mKRAS-specific T cell response, defined as >5-fold change in IFN-gamma-producing mKRAS-specific T cells within 17 weeks post-vaccination, as assessed by serial ELISpot. The median fold change in IFN-gamma-producing mKRAS-specific T cells within 17 weeks post-vaccination was 10.2 (range: 1.5-686.3). The majority of all adverse events were grade 1 (79.5%) or grade 2 (15.2%) in severity per NCI CTCAE v5.0. Four grade 3 immune-related adverse events (pneumonitis, adrenal insufficiency, arthralgias, myalgias) and discontinuation of checkpoint blockade occurred in 2/11 patients. The median DFS for the entire cohort was 6.4 months and not reached for OS. Patients who mounted a mKRAS-specific T cell response demonstrated a significant improvement in median DFS compared to immune non-responders (not reached vs 2.8 months, p = 0.045). Conclusions: The combination of a pooled SLP mKRAS vaccine and dual checkpoint blockade is tolerable and immunogenic in patients with resected PDAC. Induction of an mKRAS-specific T cell response is associated with improved DFS in this cohort. Ongoing correlative studies will apply multi-omic approaches to identify novel biomarkers of immune response and resistance. Citation Format: Saurav D. Haldar, Amanda Huff, Thatcher R. Heumann, Maureen Berg, Anna Ferguson, Su Jin Lim, Hao Wang, Amy M. Thomas, Julie M. Nauroth, Marina Baretti, Katherine M. Bever, Mark Yarchoan, Daniel A. Laheru, Elizabeth M. Jaffee, Nilofer S. Azad, Neeha Zaidi. Safety and immunogenicity of a first-in-human mutant KRAS long peptide vaccine combined with ipilimumab/nivolumab in resected pancreatic cancer: Preliminary analysis from a phase I study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT036.

719 Background: Outcomes in BR and LA PDAC remain historically poor, in part due to low rates of R0 resection. A prior phase II study demonstrated that losartan (L) as a TGF-beta inhibitor combined with FOLFIRINOX (FFX) and radiation in LA PDAC led to a 61% R0 resection rate. Additionally, prior phase II studies suggest potential synergy with SBRT and nivolumab (N) in PDAC. We conducted a multi-center, randomized phase II trial to evaluate the effect of L and L+N in combination with TNT using FFX and SBRT. Methods: Patients with BR or LA PDAC by NCCN criteria, pathologically confirmed, ACE/ARB naïve, were randomized to TNT with FFX and SBRT (Arm 1), TNT + L (Arm 2), and TNT+L+N (Arm 3), stratified by BR/LA. Patients already on an ACE or ARB were enrolled on an exploratory arm of TNT+N (Arm 4) and will be reported separately. TNT consisted of FFX x 8 followed by SBRT (6.6 Gy x 5). L was given at 50 mg qd throughout TNT and for 6 mo after surgery. N was given at 240 mg flat dosing q2 wks concurrent with SBRT and for 12 doses postoperatively. All patients were recommended for surgical exploration after TNT. The study was designed to compare the R0 resection rate on each of Arms 2 and 3 independently versus Arm 1 at a one-sided 0.10 level. Secondary endpoints were PFS, OS, and pCR rates and analyzed using two-sided tests with Arm 1 as the control arm. Intent-to-treat analysis was based on eligible patients who started therapy on protocol. Results: Patients with BR or LA PDAC by NCCN criteria, pathologically confirmed, ACE/ARB naïve, were randomized to TNT with FFX and SBRT (Arm 1), TNT + L (Arm 2), and TNT+L+N (Arm 3), stratified by BR/LA. Patients already on an ACE or ARB were enrolled on an exploratory arm of TNT+N (Arm 4) and will be reported separately. TNT consisted of FFX x 8 followed by SBRT (6.6 Gy x 5). L was given at 50 mg qd throughout TNT and for 6 mo after surgery. N was given at 240 mg flat dosing q2 wks concurrent with SBRT and for 12 doses postoperatively. All patients were recommended for surgical exploration after TNT. The study was designed to compare the R0 resection rate on each of Arms 2 and 3 independently versus Arm 1 at a one-sided 0.10 level. Secondary endpoints were PFS, OS, and pCR rates and analyzed using two-sided tests with Arm 1 as the control arm. Intent-to-treat analysis was based on eligible patients who started therapy on protocol. Conclusions: We did not observe effects of L and L+N on the R0 resection rate, PFS, OS, and pCR rate when added to TNT with FFX and SBRT for BR or LA PDAC. The lack of differences may reflect heterogeneity in surgical opinion as the decision for proceeding to surgery following TNT tends to be highly variable in a population with historically low resection rates. Clinical trial information: NCT03563248 .

Recent research on genomic profiling of pancreatic ductal adenocarcinoma (PDAC) has identified many potentially actionable alterations. However, the feasibility of using genomic profiling to guide routine clinical decision making for PDAC patients remains unclear. We retrospectively reviewed PDAC patients between October 2013 and December 2017, who underwent treatment at the Johns Hopkins Hospital and had clinical tumor next-generation sequencing (NGS) through commercial resources. Ninety-two patients with 93 tumors tested were included. Forty-eight (52%) patients had potentially curative surgeries. The median time from the tissue available to the NGS testing ordered was 229 days (interquartile range 62–415). A total of three (3%) patients had matched targeted therapies based on genomic profiling results. Genomic profiling guided personalized treatment for PDAC patients is feasible, but the percentage of patients who receive targeted therapy is low. The main challenges are ordering NGS testing early in the clinical course of the disease and the limited evidence of using a targeted approach in these patients. A real-time department level genomic testing ordering system in combination with an evidence-based flagging system for potentially actionable alterations could help address these shortcomings.

Objective: Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy, due in large part to its resistance to conventional therapies, including radiotherapy (RT). Despite RT exerting a modest antitumor response, it has also been shown to promote an immunosuppressive tumor microenvironment. Previous studies demonstrated that focal adhesion kinase inhibitors (FAKi) in clinical development inhibit the infiltration of suppressive myeloid cells and T regulatory (T regs) cells, and subsequently enhance effector T cell infiltration. FAK inhibitors in clinical development have not been investigated in combination with RT in preclinical murine models or clinical studies. Thus, we investigated the impact of FAK inhibition on RT, its potential as an RT sensitizer and immunomodulator in a murine model of PDAC. Methods: We used a syngeneic orthotopic murine model to study the effect of FAKi on hypofractionated RT. Results: In this study we showed that IN10018, a small molecular FAKi, enhanced antitumor response to RT. Antitumor activity of the combination of FAKi and RT is T cell dependent. FAKi in combination with RT enhanced CD8+ T cell infiltration significantly in comparison to the radiation or FAKi treatment alone (P < 0.05). FAKi in combination with radiation inhibited the infiltration of granulocytes but enhanced the infiltration of macrophages and T regs in comparison with the radiation or FAKi treatment alone (P < 0.01). Conclusions: These results support the clinical development of FAKi as a radiosensitizer for PDAC and combining FAKi with RT to prime the tumor microenvironment of PDAC for immunotherapy.

Purpose: This phase II study tested granulocyte-macrophage colony-stimulating factor (GM-CSF)-allogeneic pancreatic tumor cells (GVAX) and ipilimumab in metastatic pancreatic ductal adenocarcinoma (PDA) in the maintenance setting. Patients and Methods: Patients with PDA who were treated with front-line chemotherapy consisting of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) in the metastatic setting and had ongoing response or stable disease after 8–12 doses were eligible. Patients were randomized 1:1 to treatment with GVAX and ipilimumab given every 3 weeks for four doses then every 8 weeks (Arm A) or to FOLFIRINOX continuation (Arm B). The primary objective was to compare overall survival (OS) between the two arms. Results: Eighty-two patients were included in the final analysis (Arm A: 40; Arm B: 42). The study was stopped for futility after interim analysis. Median OS was 9.38 months [95% confidence interval (CI), 5.0–12.2] for Arm A and 14.7 months (95% CI, 11.6–20.0) for Arm B (HR, 1.75; P = 0.019). Using immune-related response criteria, two partial responses (5.7%) were observed in Arm A and four (13.8%) in Arm B. GVAX + ipilimumab promoted T-cell differentiation into effector memory phenotypes both in the periphery and in the tumor microenvironment and increased M1 macrophages in the tumor. Conclusions: GVAX and ipilimumab maintenance therapy did not improve OS over continuation of chemotherapy and resulted in a numerically inferior survival in metastatic PDA. However, clinical responses and biological effects on immune cells were observed. Further study of novel combinations in the maintenance treatment of metastatic PDA is feasible.

Purpose: Two studies in previously treated metastatic pancreatic cancer have been completed combining GVAX pancreas vaccine (GM-CSF–secreting allogeneic pancreatic tumor cells) with cyclophosphamide (Cy) and CRS-207 (live, attenuated Listeria monocytogenes–expressing mesothelin). In the current study, we compared Cy/GVAX followed by CRS-207 with (Arm A) or without nivolumab (Arm B). Patients and Methods: Patients with pancreatic adenocarcinoma who received one prior therapy for metastatic disease and RECIST measurable disease were randomized 1:1 to receive treatment on Arm A or Arm B. The primary objective was to compare overall survival (OS) between the arms. Additional objectives included assessment of progression-free survival, safety, tumor responses, CA19-9 responses, and immunologic correlates. Results: Ninety-three patients were treated (Arm A, 51; Arm B, 42). The median OS in Arms A and B were 5.9 [95% confidence interval (CI), 4.7–8.6] and 6.1 (95% CI, 3.5–7.0) months, respectively, with an HR of 0.86 (95% CI, 0.55–1.34). Objective responses were seen in 3 patients using immune-related response criteria (4%, 2/51, Arm A; 2%, 1/42, Arm B). The grade ≥3 related adverse event rate, whereas higher in Arm A (35.3% vs. 11.9%) was manageable. Changes in the microenvironment, including increase in CD8+ T cells and a decrease in CD68+ myeloid cells, were observed in long-term survivors in Arm A only. Conclusions: Although the study did not meet its primary endpoint of improvement in OS of Arm A over Arm B, the OS was comparable with standard therapy. Objective responses and immunologic changes in the tumor microenvironment were evident.

Background The Hedgehog (Hh) signalling pathway is overexpressed in pancreatic ductal adenocarcinoma (PDA). Preclinical studies have shown that Hh inhibitors reduce pancreatic cancer stem cells (pCSC), stroma and Hh signalling. Methods Patients with previously untreated metastatic PDA were treated with gemcitabine and nab-paclitaxel. Vismodegib was added starting on the second cycle. The primary endpoint was progression-free survival (PFS) as compared with historical controls. Tumour biopsies to assess pCSC, stroma and Hh signalling were obtained before treatment and after cycle 1 (gemcitabine and nab-paclitaxel) or after cycle 2 (gemcitabine and nab-paclitaxel plus vismodegib). Results Seventy-one patients were enrolled. Median PFS and overall survival (OS) were 5.42 months (95% confidence interval [CI]: 4.37–6.97) and 9.79 months (95% CI: 7.85–10.97), respectively. Of the 67 patients evaluable for response, 27 (40%) had a response: 26 (38.8%) partial responses and 1 complete response. In the tumour samples, there were no significant changes in ALDH + pCSC following treatment. Conclusions Adding vismodegib to chemotherapy did not improve efficacy as compared with historical rates observed with chemotherapy alone in patients with newly diagnosed metastatic pancreatic cancer. This study does not support the further evaluation of Hh inhibitors in this patient population. Trial registration ClinicalTrials.gov Identifier: NCT01088815.

Immune-checkpoint therapy has failed to demonstrate meaningful clinical benefit in unselected cases of pancreatic adenocarcinoma (PDAC), but a subset of PDACs are known to upregulate pathways involved in acquired immune suppression. Further delineation of immunologic subtypes of PDAC is necessary to improve clinical trial designs and identify patients who might benefit from immune-checkpoint therapy. We used clinical survival and RNA expression data from The Cancer Genome Atlas (TCGA) to investigate the relationship between immune-modulating pathways and immune subset markers and their impact on survival in PDAC patients. Of the adaptive immune-resistance pathways, expression of PD-L1 and IDO1 was individually associated with poor survival. Although CD8 expression alone was not correlated with survival, the combination of PD-L1− and high CD8 expression identified a subtype with favorable survival. We further extended these observations using an independent PDAC cohort from our institution via IHC, again observing that the PD-L1−/CD8high subtype was associated with positive prognosis. Although PDAC is regarded as a poorly immunogenic cancer type, these findings infer that T-cell infiltration in the absence of adaptive immune-resistance pathways is a feature of long-term survival in PDAC and imply the importance of developing future immunotherapeutic strategies based on data-supported biomarkers to refine patient selection.

Summary Single-cell technologies are emerging as powerful tools for cancer research. These technologies characterize the molecular state of each cell within a tumor, enabling new exploration of tumor heterogeneity, microenvironment cell-type composition, and cell state transitions that affect therapeutic response, particularly in the context of immunotherapy. Analyzing clinical samples has great promise for precision medicine but is technically challenging. Successfully identifying predictors of response requires well-coordinated, multi-disciplinary teams to ensure adequate sample processing for high-quality data generation and computational analysis for data interpretation. Here, we review current approaches to sample processing and computational analysis regarding their application to translational cancer immunotherapy research.

558 Background: Utilizing a vaccine that induces and activates host effector T cells and co-administering it with immune modulating agents that enhance anti-tumor T cell activity is a potential strategy for overcoming pancreatic adenocarcinoma’s (PDA) resistance to immunotherapy. Our prior clinical trial demonstrated a GM-CSF-secreting, allogeneic tumor cell vaccine (GVAX) increases infiltrating CD8+ T cells in PDA. Follow up preclinical work demonstrated therapeutic synergy between GVAX and PD-1inhibition (PD1) with efficacy further enhanced by CD137 agonism (CD137). Methods: This was a 3-arm trial of neoadjuvant & adjuvant GVAX-based therapy in resectable (r) PDA patients (pts). Adults with clinically resectable, untreated PDA were enrolled in 1 of 3 study treatments: Arm A (GVAX alone), Arm B (GVAX + PD1 [Nivolumab]), or arm C (GVAX + PD1 + CD137 [Urelumab]). Treatment was given as follows: Day 1 - Cyclophosphamide 200mg/m2 IV (All Arms), Nivolumab 480mg IV (Arms B, C), Urelumab 8mg IV (Arm C); Day 2 – GVAX ID (All Arms). Pts were treated at 3 timepoints: 1) once 2 weeks prior to surgery; 2) once post-surgical recovery prior to standard of care adjuvant chemotherapy (SOC); 3) every month (up to 4 mo) following completion of SOC (if disease-free). SOC regimes included (m)FOLFIRINOX, Gem +/- Cap/NAB-Paclitaxel. The study was powered for a primary biologic endpoint: treatment-related change in intratumoral CD8+CD137+ T cells. Clinical endpoints included disease-free survival (DFS: time from surgery to recurrence), overall survival (OS: time from surgery to death), and safety. Results: 38 pts (N = 15 [Arm A], N = 13 [Arm B], N = 10 [Arm C]) were eligible for efficacy analysis (had R0/R1 resection) and 45 pts (N = 17 [A], N = 17 [B], N = 11 [C]) were eligible for safety analysis (had ≥1 dose of study treatment). Demographics, surgical pathology features, and SOC durations were similar in all Arms. At median follow up of 23 mo [A], 26 mo [B], and 22 mo [C], median DFS (95% CI) was 14.82 mo (6.0, NA), 16.23 mo (7.49, NA) and not reached (16.33, NA) for Arms A, B, C, respectively. There was no DFS benefit to adding PD1 compared to GVAX alone (HR 0.98 [95% CI 0.42, 2.27], p = 0.96). Combination CD137 + PD1 + GVAX was associated with marginally significant improved DFS compared to GVAX alone (HR 0.38 [95%CI 0.12, 1.19], p = 0.097) and GVAX + PD1 (HR 0.38 [95%CI 0.12, 1.21], p = 0.103). Median OS (95% CI) was 25.0 mo (18.8, NA), 26.4 mo (20.3, NA), and not yet reached for Arms A, B, C, respectively. There were no serious adverse events. In Arm C, 1 pt had grade 3 rash that delayed treatment and there was 1 instance of grade 2 AST/ALT elevation. The biologic endpoint will be reported at the meeting. Conclusions: Despite a small sample size, combining GVAX with dual immune-targeting of PD-1 blockade and CD137 agonism was safe and may enhance DFS in rPDA pts treated in the perioperative and post-adjuvant settings. Clinical trial information: NCT02451982.

534 Background: Incorporating PROs into CTs is critical for patients with pancreatic cancer, as these individuals often experience a high symptom burden and prioritize maximizing quality of life (QOL). Methods: We reviewed protocols of completed U.S. CTs listed on ClinicalTrials.gov that investigated curative/palliative interventions in pancreatic cancer from 1995-2020. We assessed up to August 2021 if CT publications reported PRO results through linked publications and an independent search through PubMed/MEDLINE. We extracted CT details (funding, eligibility, etc), and if PROs (outcome directly reported by patients) were listed as an endpoint (primary/secondary/exploratory). We classified interventions as cancer-directed (e.g. chemotherapy), supportive care (e.g. neurolysis), or other (e.g. curcumin). Results: We reviewed 619 protocols and included 379 in the analysis. Most CTs investigated cancer-directed interventions (317, 83.6%). Only 43 (11.4%) included PROs as endpoints (Table). In these, most of the PROs assessed QOL (34, 79.1%) and pain (15, 34.9%). For the 33/43 (76.7%) protocols that listed a specific PRO instrument, EORTC-QLQ C30 (11/33, 33.3%) was the most common. Only 6 (18.2%) protocols included pancreatic cancer-specific PROs, such as QLQ-PAN26. Supportive care CTs were more likely to assess PROs than cancer-directed CTs (odds ratio, OR= 62.6, 95% CI 16.7-234.3, p

PURPOSE The aim of this work was to provide an update to the ASCO guideline on metastatic pancreatic cancer pertaining to recommendations for therapy options after first-line treatment. METHODS ASCO convened an Expert Panel and conducted a systematic review to update guideline recommendations for second-line therapy for metastatic pancreatic cancer. RESULTS One randomized controlled trial of olaparib versus placebo, one report on phase I and II studies of larotrectinib, and one report on phase I and II studies of entrectinib met the inclusion criteria and inform the guideline update. RECOMMENDATIONS New or updated recommendations for germline and somatic testing for microsatellite instability high/mismatch repair deficiency, BRCA mutations, and TRK alterations are provided for all treatment-eligible patients to select patients for recommended therapies, including pembrolizumab, olaparib, larotrectinib, or entrectinib, or potential clinical trials. The Expert Panel continues to endorse the remaining recommendations for second-line chemotherapy, as well as other recommendations related to treatment, follow-up, and palliative care from the 2018 version of this guideline. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

Purpose:Tumor mutational burden (TMB) has emerged as a potential predictive biomarker for clinical response to ICI therapy, but whether TMB also predicts toxicity remains unknown. We investigated the relationship between TMB, objective response rate (ORR), overall survival (OS), and toxicity for ICI therapy across multiple cancer types.Experimental Design:We searched MEDLINE, PubMed, and ASCO/ESMO/AACR meetings for clinical trials of anti-PD(L)1, CTLA-4, or combination in 29 cancer types. We assessed ICI administered, responses (complete or partial response), median OS, OS HR, and grade 3/4 toxicity. We conducted a systematic review, meta-analysis and meta-regression using tumor level TMB data from Foundation Medicine.Results:One hundred seventeen clinical trials, which included 12,450 patients treated with ICI therapy were analyzed. Meta-regression analysis revealed that TMB was significantly associated with ORR for anti-PD(L)1, anti–CTLA-4, and combination (P < 0.0001 for all), but not associated with toxicity in all treatment groups. OS data were unavailable for most studies included in our meta-analysis, and the relationship between TMB and OS in this subset was not significant (P = 0.26). In high TMB tumor types (≥10 mut/megabase) the improvement of ORR and increase in grade 3/4 toxicity with combination ICI therapy as compared with PD(L)1 monotherapy were 21.13% and 25.41%, respectively, as compared with 3.73% and 18.78% in low TMB tumor types (Conclusions:There is a positive association between TMB and clinical response with anti-PD(L)1, anti–CTLA-4, and combination ICIs, but no association between TMB and toxicity. These results imply a favorable risk/benefit ratio for ICIs in tumors with a higher TMB.

Purpose In 2016, ASCO published a guideline to assist in clinical decision making in metastatic pancreatic cancer for initial assessment after diagnosis, first- and second-line treatment options, palliative and supportive care, and follow-up. The purpose of this update is to incorporate new evidence related to second-line therapy for patients who have experienced disease progression or intolerable toxicity during first-line therapy. Methods ASCO convened an Expert Panel to conduct a systematic review of the literature on second-line therapy published between June 2015 and January 2018. Recommendations on other topics covered in the 2016 Metastatic Pancreatic Cancer Guideline were endorsed by the Expert Panel. Results Two new studies were found that met the inclusion criteria. Recommendations For second-line therapy, gemcitabine plus nanoparticle albumin-bound paclitaxel should be offered to patients with first-line treatment with FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin), an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 1, and a favorable comorbidity profile; fluorouracil plus nanoliposomal irinotecan can be offered to patients with first-line treatment with gemcitabine plus NAB-paclitaxel, an ECOG PS of 0 to 1, and a favorable comorbidity profile; fluorouracil plus irinotecan or fluorouracil plus oxaliplatin may be offered when there is a lack of availability of fluorouracil plus nanoliposomal irinotecan; gemcitabine or fluorouracil should be offered to patients with either an ECOG PS of 2 or a comorbidity profile that precludes other regimens. Testing select patients for mismatch repair deficiency or microsatellite instability is recommended, and pembrolizumab is recommended for patients with mismatch repair deficiency or high microsatellite instability tumors. Endorsed recommendations from the 2016 version of this guideline for computed tomography, baseline performance status and comorbidity profile, defining goals of care, first-line therapy, and palliative care are also contained within the full guideline text. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

Deploying CD40 activation to stimulate T cell responses upstream of immune checkpoint molecules is a novel clinical opportunity for cancer immunotherapy. Despite numerous active clinical trials with agonistic CD40 monoclonal antibodies (mAb), biological treatment effects especially treatment-related modulation of the tumor microenvironment (TME), remain poorly understood. Here, we performed a neoadjuvant clinical trial of agonistic CD40 mAb (selicrelumab) administered intravenously with or without chemotherapy (gemcitabine and nab-paclitaxel) to 16 resectable patients with pancreatic ductal adenocarcinoma (PDAC) prior to surgery followed by adjuvant chemotherapy and CD40 mAb. The toxicity profile was acceptable, including only grade 1 or 2 cytokine release syndrome and expected toxicities from chemotherapy. Disease-free survival was 13.8 months (95% CI 2.9 - 24.8 months) and median overall survival was 23.4 months (95% CI 18.0 - 28.8), with 8 patients alive at a median of 20.0 months after surgery (follow-up range 12.2 to 34.8 months). Neoadjuvant selicrelumab induced major pharmacodynamic differences in the TME, as revealed by a multiplex imaging platform auditing the immune ecosystem, compared to resection specimens from PDAC patient previously untreated or given neoadjuvant chemotherapy/chemoradiotherapy only. For tumors resected after selicrelumab, 82% (9/11) were T-cell enriched, compared to 37% (38/104) (p=0.004) of untreated tumors and 23% (93/13) of chemotherapy/chemoradiation-treated tumors (p=0.012). Moreover, for selicrelumab tumors, tumor-associated fibrosis was less, “M2” macrophages were fewer, dendritic cells were more mature, and T cells were activated and proliferative, compared to the non-selicrelumab groups. In the periphery, CD8+ and CD4+ T cells were more activated and proliferative, and serum inflammatory cytokines CXCL10 and CCL22 increased after treatment. This study provides proof-of-concept in patients that agonistic CD40 mAb alters the TME, enhances T-cell infiltration, and modulates systemic inflammatory responses. These findings inform design of next-generation CD40 clinical trials. Citation Format: Katelyn T. Byrne, Courtney B. Betts, Rosemarie Mick, Shamilene Sivagnanam, David L. Bajor, Daniel A. Laheru, E. Gabriela Chiorean, Mark H. O'Hara, Shannon M. Liudahl, Craig Newcomb, Cécile Alanio, Ana P. Ferreira, Byung S. Park, Takuya Ohtani, Austin P. Huffman, Sara A. Väyrynen, Andressa Dias Costa, Judith C. Kaiser, Andreanne M. Lacroix, Colleen Redlinger, Martin Stern, Jonathan A. Nowak, E. John Wherry, Martin A. Cheever, Brian M. Wolpin, Emma E. Furth, Elizabeth M. Jaffee, Lisa M. Coussens, Robert H. Vonderheide. T cell inflammation in the tumor microenvironment after agonist CD40 antibody: Clinical and translational results of a neoadjuvant clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT005.

4134 Background: Management of locally advanced pancreas cancer (LAPC) standardly involves chemotherapy with consolidative radiation and surgery in selected pts. Checkpoint inhibitors have shown limited benefit alone in pancreas cancer but may be primed by radiation and GM-CSF secreting allogeneic pancreatic cancer vaccine (GVAX). We present data from a phase 2 study for LAPC pts who have not developed metastases after standard of care chemotherapy treated with combination cyclophosphamide (CY), GVAX, pembrolizumab (pembro), and stereotactic body radiation therapy (SBRT). Methods: This is a single-arm, single institution, open-label study for pts with LAPC at diagnosis (as per NCCN guidelines, arterial involvement > 180°, or unreconstructible SMV/PV) who remained without metastatic disease after 4-8 28-day cycles FOLFIRINOX or gemcitabine/abraxane based therapy. Pts received CY (200mg/m2 IV) and pembro (200mg IV) on day 1, followed by GVAX (6 intradermal inj) on day 2 q3 wk x 2 cycles, with cycle 2 initiating concurrently with 5 days SBRT. Pts were restaged 4-6 weeks after SBRT, and if non-metastatic, pts underwent surgical resection, irreversible electroporation (IRE), or biopsy (if not undergoing surgical resection). Pts received two cycles of chemotherapy, and if metastasis free, received q3 wk CY/pembro/GVAX x 6 cycles with restaging scans q3 mos. In 5/2017, the protocol was addended to include an extended phase with q3 wk pembro x 9 cycles and q6 mo CY/GVAX x 4. Primary endpoint was distant metastasis free survival (DMFS) defined as C1D1 to distant metastases or death. Results: From Jul 2016-Jan 2021, 58 pts with LAPC were enrolled at the Johns Hopkins Hospital, 54 completed 2 cycles CY/pembro/GVAX and SBRT and were evaluable for response (2 dropouts due to thrombocytopenia, 2 due to irAE (DKA and hepatitis)), median followup was 15.8 mos. Demographics: median age 66 (range 42-84), 53% male, 84% White, 12% African American. At first restaging (N = 54), 8 (15%) had metastatic disease, 9 (17%) were unresectable, 37 (69%) were eligible for surgical resection. 35 pts proceeded to the OR (1 died of cholangitis prior to surgery and 1 declined surgery), 24 had tumors resected (44% of evaluable pts, 10 (42%) had grade 1 (marked) pathologic response), 1 IRE, 2 were unresectable, 8 were metastatic. Common related AEs were vaccine site reactions; grade 3 irAE included 1 case each of dermatitis, colitis, DKA, nephritis, and pneumonitis. DMFS was 9.7 mos [95% CI 6.3-19.3 mos]. Conclusions: We present data from a ph II study of 54 pts w LAPC treated w CY/GVAX/pembro and SBRT. Primary endpoint of DMFS > 13.6 mos not reached, however 44% of pts underwent surgical resection of whom 42% had grade 1 path response rate. Additional correlative studies are underway. Clinical trial information: NCT02648282.

The use of neoadjuvant chemotherapy or radiation for borderline resectable pancreatic adenocarcinoma (BL‐PDAC) is increasing. However, the impact of neoadjuvant chemotherapy and radiation therapy on the outcome of BL‐PDAC remains to be elucidated. We performed a retrospective analysis of 93 consecutive patients who were diagnosed with BL‐PDAC and primarily followed at Johns Hopkins Hospital between February 2007 and December 2012. Among 93 patients, 62% received upfront neoadjuvant chemotherapy followed by chemoradiation, whereas 20% received neoadjuvant chemoradiation alone and 15% neoadjuvant chemotherapy alone. Resectability following all neoadjuvant therapy was 44%. Patients who underwent resection with a curative intent had a median overall survival (mOS) of 25.8 months, whereas those who did not undergo surgery had a mOS of 11.9 months. However, resectability and overall survival were not significantly different between the three types of neoadjuvant therapy. Nevertheless, 22% (95% CI, 0.13–0.36) of the 58 patients who received upfront chemotherapy followed by chemoradiation remained alive for a minimum of 48 months compared to none of the 19 patients who received upfront chemoradiation. Among patients who underwent curative surgical resection, 32% (95% CI, 0.19–0.55) of those who received upfront chemotherapy remained disease free at least 48 months following surgical resection, whereas none of the eight patients who received upfront chemoradiation remained disease free beyond 24 months following surgical resection. Neoadjuvant therapy with upfront chemotherapy may result in long‐term survival in a subpopulation of patients with BL‐PDAC.

Background: Pancreatic cancer has become the third leading cause of cancer death with minimal improvements in outcome for over 40 years. Recent trials of therapies that target-defective DNA maintenance using poly (ADP-ribose) polymerase (PARP) inhibitors are showing promising results, yet invariably patients recur and succumb to disease. Mechanisms of resistance to platinum-based and PARP inhibitor therapy in other cancer types include secondary mutations, which restore the integrity of DNA repair through an increasing number of different mechanisms. Methods: Here we present a case of a 63-year-old female patient with a germ line pathogenic BRCA2 mutation (6714 deletion) who developed pancreatic cancer and had an exceptional response to platinum and PARP inhibitor therapy. Through next-generation sequencing and clinical follow-up, we correlated tumour response and resistance to the BRCA2 mutational status in the tumour. Results: Initially, the patient had an exceptional response to platinum and PARP inhibitor therapy, most likely due to the BRCA2 mutation. However, the primary lesion recurred while on PARP inhibitor therapy and contained a secondary mutation in BRCA2, which mostly likely restored BRCA2 function in PARP inhibitor-resistant tumour cells. Conclusions: To our knowledge, this is the first report of a BRCA2 reversion mutation that conferred resistance to PARP inhibitor-based therapy in a pancreatic ductal adenocarcinoma patient. Future studies are needed to understand this important mechanism of resistance and how it may impact the choice of therapy for patients with pancreatic cancer.

Background Mismatch repair proficient (MMRp) colorectal cancer (CRC) has been refractory to single‐agent programmed cell death protein 1 (PD1) inhibitor therapy. Colon GVAX is an allogeneic, whole‐cell, granulocyte‐macrophage colony‐stimulating factor ‐secreting cellular immunotherapy that induces T‐cell immunity against tumor‐associated antigens and has previously been studied in combination with low‐dose cyclophosphamide (Cy) to inhibit regulatory T cells. Methods We conducted a single‐arm study of GVAX/Cy in combination with the PD1 inhibitor pembrolizumab in patients with advanced MMRp CRC. Patients received pembrolizumab plus Cy on day 1, GVAX on day 2, of a 21‐day cycle. The primary endpoint was the objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary objectives included safety, overall survival, progression‐free survival, changes in carcinoembryonic antigen (CEA) levels, and immune‐related correlates. Results Seventeen patients were enrolled. There were no objective responses, and the disease control rate was 18% by RECIST 1.1. The median progression‐free survival was 82 days (95% confidence interval [CI], 48‐97 days) and the median overall survival was 213 days (95% CI 179‐441 days). Biochemical responses (≥30% decline in CEA) were observed in 7/17 (41%) of patients. Grade ≥ 3 treatment‐related adverse events were observed in two patients (hemolytic anemia and corneal transplant rejection). Paired pre‐ and on‐treatment biopsy specimens showed increases in programmed death‐ligand 1 expression and tumor necrosis in a subset of patients. Conclusions GVAX/Cy plus pembrolizumab failed to meet its primary objective in MMRp CRC. Biochemical responses were observed in a subset of patients and have not previously been observed with pembrolizumab monotherapy in MMRp CRC, indicating that GVAX may modulate the antitumor immune response., Mismatch repair proficient colorectal cancer has been refractory to single‐agent programmed cell death protein 1 inhibitor therapy. Colon GVAX is an allogeneic, whole‐cell, granulocyte‐macrophage colony‐stimulating factor‐secreting cellular immunotherapy that induces T‐cell immunity against tumor‐associated antigens and has previously been studied in combination with low‐dose cyclophosphamide (Cy) to inhibit regulatory T cells. In this single‐arm study, we find that GVAX/Cy plus pembrolizumab results in biochemical responses but not radiographic responses.

Importance Autophagy is a mechanism of treatment resistance to chemotherapy that has a role in the maintenance of pancreatic cancer. Hydroxychloroquine sulfate (HCQ) is an inhibitor of autophagy that inhibits the fusion of the autophagosome to the lysosome. Objective To determine whether HCQ improves overall survival at 1 year in combination with gemcitabine hydrochloride and nab-paclitaxel (GA) among patients with metastatic pancreatic cancer. Design, Setting, and Participants Open-label, phase 2 randomized clinical trial conducted between March 18, 2013, and November 16, 2017, at the University of Pennsylvania, HonorHealth, and The Johns Hopkins University among 112 patients with previously untreated metastatic or advanced pancreatic ductal adenocarcinoma, Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate marrow and organ function. All efficacy analyses were performed for the intention-to-treat population. Interventions Patients were randomized in a 1:1 ratio to receive GA with or without HCQ. All patients received standard doses of GA, and those randomized to receive HCQ were treated continuously with 600 mg orally twice daily. Main Outcome and Measure Overall survival at 1 year. Results A total of 112 patients (45 women and 67 men; median age, 65 years; range, 43-86 years) were enrolled; 55 were randomized to receive GA plus HCQ, and 57 to receive GA. Overall survival at 12 months was 41% (95% CI, 27%-53%) in the HCQ group and 49% (95% CI, 35%-61%) in the non-HCQ group. Median progression-free survival was 5.7 months (95% CI, 4.0-9.3 months) in the HCQ group and 6.4 months (95% CI, 4.5-7.6 months) in the non-HCQ group. Median overall survival was 11.1 months (95% CI, 9.0-14.2 months) in the HCQ group and 12.1 months (95% CI, 9.3-15.5 months) in the non-HCQ group. Overall response rate was 38.2% (n = 21) in the HCQ group and 21.1% (n = 12) in the non-HCQ group (P = .047). Treatment-related grade 3 or 4 adverse events that differed between the HCQ and non-HCQ groups were neutropenia (23 of 54 [42.6%] vs 12 of 53 [22.6%]), anemia (2 of 54 [3.7%] vs 9 of 53 [17.0%]), fatigue (4 of 54 [7.4%] vs 0), nausea (5 of 54 [9.3%] vs 0), peripheral neuropathy (7 of 54 [13.0%] vs 3 of 53 [5.7%]), visual changes (3 of 54 [5.6%] vs 0), and neuropsychiatric symptoms (3 of 54 [5.6%] vs 0). Conclusions and Relevance The addition of HCQ to block autophagy did not improve the primary end point of overall survival at 12 months. These data do not support the routine use of GA plus HCQ for metastatic pancreatic cancer in the absence of a biomarker. However, improvement seen in the overall response rate with HCQ may indicate a role for HCQ in the locally advanced setting, where tumor response may permit resection. Trial Registration ClinicalTrials.gov identifier:NCT01506973

421 Background: PDAC has a propensity for early systemic dissemination and most pts with primary tumors radiographically confined to the pancreas harbor micro-metastases. cfDNA based CGP offers a non-invasive mechanism to identify actionable genomic targets in PDAC and account for serial clonal evolution in response to therapeutic selection pressure. We interrogated the Foundation Medicine database to characterize cfDNA based CGP in pts with PDAC. Methods: We performed a retrospective analysis of pts with PDAC who underwent cfDNA based CGP between May 2016 and February 2020. cfDNA based CGP was done utilizing either the FoundationOne Liquid (F1-Liquid) or the Foundation-ACT (F-ACT) testing platform. Samples were interrogated for exonic and select intronic regions of cancer-related genes for both F1-Liquid (Exons: 70 genes; Select Introns: 7 genes) and F-ACT (Exons: 59 genes; Select Introns: 6 genes). Variant zygosity and somatic/germline status (SGZ) for short variant mutations was computationally predicted without matched normal tissue using an investigational method. A Gaussian Mixture Model (GMM) was used to identify latent molecular classes in samples harboring somatic, pathogenic variants (n=613); the Bayesian Information Criteria (BIC) was used for model selection. Results: We identified 1,009 pts with cfDNA based CGP - median age was 65, 55% were male, and median cfDNA concentration was 24 ng/µL. cfDNA yield had an influence on the detection of somatic alterations (p

422 Background: Early systemic dissemination is a salient feature of PDAC and the ability to reliably detect as well as monitor cfDNA based alterations may have predictive and/or prognostic value. However, a clear correlation between the clonality of the primary tumor and micro-metastatic disease has not been established in PDAC. We examined the correlation between T-CGP and cfDNA based CGP in pts with PDAC. Methods: We performed a retrospective analysis of PDAC pts who had both T-CGP (October 2010 – March 2020) and cfDNA based CGP (May 2016 – March 2020), with an average of 645 days between tests (Range: 21 – 2101 days) For T-CGP, exonic regions and select intronic regions of cancer related genes were sequenced to a high uniform depth (>500X median coverage) using FoundationOne Heme (Exons: 315 genes; Select Introns: 28 genes) and FoundationOne CDx (Exons: 310 genes; Select Introns: 34 genes). cfDNA based CGP, was performed using either FoundationOne Liquid (Exons: 70 genes; Select Introns: 7 genes) or Foundation-ACT (Exons: 59 genes; Select Introns: 6 genes) platform. Results: Eighty-one pts were identified with both T-CGP and cfDNA based CGP - median age was 61 years, 59.3% (48/81) were male and 66.2% (49/74) had reported metastatic disease. The median tumor DNA content available for T-CGP analysis was 112.3 ng. The median cfDNA concentration was 1.7 ng/µL, and the number of reported ct-DNA based somatic alterations correlated significantly with the concentration of ct-DNA (Spearman’s R = 0.19, p < 10-8). 75/81 (92.6%) and 41/81 (50.6%) of pts had at least one pathogenic somatic alteration detected by T-CGP and cfDNA based CGP, respectively. KRAS, TP53 and CDKN2A were the most frequently altered genes in both T-CGP and cfDNA based CGP (Table1). Homologous Recombination DNA Damage Repair (HR-DDR) gene alterations [ BRCA2, ATM, and CHEK2 alterations] were detected in 7.4% (6/81) of T-CGP and 7.4% (6/81) cfDNA based CGP, respectively. Two BRAF fusions were detected from samples tested with T-CGP, however these were not detected with the cfDNA assay. Conversely, an ALK-EML4 fusion was detected using both platforms. Conclusions: The concordance between T-CGP and cfDNA based CGP in HR-DDR gene alterations may be indicative of the germline status of some of these alterations; nevertheless, it suggests the predictive utility of cfDNA based CGP in PDAC. The differential prevalence of other gene alterations between the two modalities is likely reflective of the cfDNA yield available for CGP and to a lesser extent, clonal evolution. cfDNA based CGP holds promise as a complimentary predictive tool to T-CGP. [Table: see text]

444 Background: The benefit of stereotactic body radiation therapy (SBRT) in the neoadjuvant setting for patients with localized pancreatic adenocarcinoma (PDAC) remains an area of active investigation. Herein, we report on surgical, pathologic, and survival outcomes in a modern cohort of borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC) patients (pts) who were treated at a high-volume institution with upfront chemotherapy (CTX) followed by SBRT. Methods: A prospectively collected institutional IRB-approved database was reviewed to identify PDAC pts diagnosed between 2015-2018. All pts were seen in our multidisciplinary clinic and treated with multiagent induction CTX followed by 5-fraction SBRT. In general, it was our institutional preference that ECOG 0-1 pts were recommended modified FOLFIRINOX (mFFX), whereas others were recommended gemcitabine/abraxane. Pathological outcomes by stage were characterized. Kaplan-Meier analysis was used to generate survival curves, and factors prognostic for survival were identified. Results: Our cohort consisted of 156 pts, including 92 LAPC pts (59%) and 63 BRPC pts (41%). Median follow-up from diagnosis was 21.0 months (range 4-49 mos). Of the entire cohort, 117 (75%) received mFFX and 37 (24%) received gemcitabine/abraxane. Median duration of upfront CTX before SBRT was 4.0 months, with 126 pts (80.8%) receiving greater than 4 months. After SBRT, 130 pts (84%) were surgically explored with 106 pts (68%) successfully resected. Of 106 pts who were resected, 97 pts (92%) achieved negative margins, 63 pts (59%) were node-negative, and eight pts (8%) achieved a pathological complete response (pCR). Among 63 BRPC pts, 49 pts (78%) underwent resection, of whom 47 pts (96%) achieved margin negative resection. Among 92 LAPC pts, 57 pts (62%) underwent resection, of whom 50 pts (88%) achieved margin negative resection. For the entire cohort, median overall survival (mOS) from diagnosis was 25.4 mos (95% CI: 22.2 to NR) and 17.6 mos from SBRT (95% CI: 16.1 to NR). ECOG 0-1, initial biopsy grade (well-to-moderately differentiated), duration of neaodjuvant CTX (≥ 4 mos), surgical resection, and receipt of adjuvant CTX were all associated with improved survival from diagnosis (all p < 0.05), but stage (BR vs. LAPC) was not ( p = 0.43). Conclusions: In a modern cohort of patients receiving mFFX (75%) followed by SBRT, a high proportion of pts were successfully resected with favorable pathologic outcomes. Interestingly, OS was not significantly different for BRPC vs LAPC. Factors that proved to be important with respect to OS included duration of neoaduvant CTX, performance status, initial biopsy grade, and receipt of adjuvant CTX, After maximal multiagent CTX, factors other than stage should be considered in determining which pts will benefit from SBRT and/or subsequent surgery.

440 Background: We previously reported a multi-center study in which gemcitabine and stereotactic body radiation therapy (SBRT) were shown to be safe with outcomes comparable to chemoradiation in locally advanced pancreatic cancer (LAPC). This prospective clinical trial was developed to evaluate the efficacy of adding SBRT to multi-agent chemotherapy in LAPC. Herein, we report on the long-term survival outcomes. Methods: From 2012 to 2015, 48 patients (pts) were prospectively enrolled after multidisciplinary evaluation at a single high-volume pancreatic center. Pts received multi-agent chemotherapy (CTX) with modified mFOLFIRINOX (mFFX) or gemcitabine/abraxane followed by 5 fractions of SBRT (median 33 Gy; range, 25-33 Gy). At the time of fiducial placement, biopsies were obtained and DNA extracted for targeted sequencing using MSK-IMPACT. Kaplan-Meier curves were generated to compare survival outcomes by sub-group. Multivariate analysis (MVA) was performed to identify factors prognostic for survival. Results: 44 pts (91.7%) had LAPC disease and 4 (8.3%) had locally recurrent disease. The median follow-up interval was 21.5 months (mo) from diagnosis. CTX consisted of mFFX in 25 pts (52.1%) with 24 pts (50.0%) receiving therapy for a duration ≥4 mo. Of 44 pts with LAPC, 15 (34.1%) were surgically explored, and 11 (73.3%) achieved a margin-negative resection. From diagnosis and after completion of SBRT, respectively, the median overall survival (OS) was 21.6 (95% CI 16-29.7 mo) and 14.6 mo (95% CI: 11.6-23.0 mo); median progression free survival (PFS) was 13.2 (95% CI 11.9-18.1mo) and 6.4 mo (95% CI: 5-12.7 mo); median local PFS (LPFS) was 23.9 (95% CI 18.9-56.9 mo) and 15.8 mo (95% CI: 12.9-27.6 mo); and median distant metastasis free survival (DMFS) was 18.4 (95% CI 12.6-29.3 mo) and 8.5 mo (95% CI: 6.3-17.2 mo). Resected pts experienced better DMFS at 1-year (78% vs. 34%, p= 0.004) with an improved trend for 1-year OS (73% vs. 52%, p= 0.331). If CTX duration was ≥4 mo, 1-year OS (75% vs. 42%, p= 0.018), PFS (50% vs. 21%, p= 0.022), and DMFS (72% vs. 29%, p= 0.031) were significantly improved. In 44 LAPC pts, MVA confirmed ≥4 mo duration of CTX was associated with OS, PFS, and DMFS. Surgical resection was associated with improved DMFS, and CA19-9 level prior to SBRT was associated with PFS and LPFS. The most common mutations detected from biopsy specimens were KRAS (64.3%) , TP53 (50%), and SMAD4 (16.7%). Conclusions: In a prospective trial of pts with LAPC receiving multiagent CTX and SBRT, clinical outcomes were improved with longer durations of CT ( > 4 mo). A high proportion of LAPC pts underwent margin negative resection with favorable outcomes. Future studies should focus on which pts are most likely to benefit from SBRT and surgery following multiagent CTX. In pts who cannot undergo resection, escalated doses of SBRT may be indicated. Clinical trial information: NCT01781728.

335 Background: Only 10-15% of newly diagnosed HCC patients are candidates for a potentially curative resection, and most patients who receive resection eventually recur. Historical systemic therapies including sorafenib, as well as locoregional therapies, have not demonstrated benefit in the perioperative setting. Novel combinations of targeted therapies and immunotherapies demonstrate higher response rates than sorafenib in HCC. Here, we report the feasibility and efficacy of neoadjuvant combination therapy with cabozantinib plus nivolumab, followed by surgical resection, in patients with borderline resectable or locally advanced HCC. Methods: We conducted an open-label, single-arm, phase I study in patients with HCC with borderline resectable or locally advanced HCC (including multinodular disease, portal vein involvement, or other high-risk features). Patients received 8 weeks of therapy with cabozantinib 40 mg oral daily plus nivolumab 240 mg IV every two weeks, followed by restaging and possible surgical resection. The primary endpoint was feasibility, defined by the percentage of patients experiencing a treatment-related adverse event that precluded continuing on to surgery within 60 days of the planned date for surgical evaluation. Results: We enrolled 15 patients of whom 14 patients completed neoadjuvant therapy and underwent surgical evaluation. Adverse events were consistent with prior experience with these agents, and the trial met its primary endpoint, with no patients experiencing a treatment-related adverse event that precluded timely surgical assessment. Of patients completing neoadjuvant therapy, 1 patient declined surgery, 1 tumor could not be resected, and 12 patients underwent successful R0 surgical resection. 5/12 (41.7%) resected patients had a major or complete pathologic response. At a median follow up of one year, 4/5 pathologic responders are without recurrence. We performed an in-depth profiling of the surgical resection biospecimens and identified an enrichment of IFNγ+ effector memory CD4+ and granzyme B+ effector CD8+ T cells as well as tertiary lymphoid aggregates in the pathologic responders. We further analyzed the spatial relationships of cell types in responders and non-responders, which identified distinct spatial arrangement of B cells in responders, and proximity of arginase-1 expressing myeloid cells to T cells in nonresponders. Conclusions: This study is, to our knowledge, the first use of a targeted therapy in combination with an immune checkpoint inhibitor in the neoadjuvant setting in HCC, and the first use of modern systemic therapies to expand surgical resection criteria. Neoadjuvant cabozantinib and nivolumab is feasible, and may result in pathologic responses and long-term disease-free survival in a group of patients who may be outside traditional resection criteria. Clinical trial information: NCT03299946.

443 Background: Patients (pts) withborderline resectable pancreatic cancer (BRPC) or locally advanced pancreatic cancer (LAPC) are at high risk of margin positive resection with upfront surgery. Pre-operative stereotactic body radiation therapy (SBRT) may help sterilize vascular margins, but its additive benefit beyond multi-agent chemotherapy (CTX) is unclear. We report on long-term outcomes from a high-volume institution of BRPC/LAPC pts who were reviewed by a multidisciplinary team and explored after either multi-agent CTX alone or multi-agent CTX followed by SBRT. Methods: Consecutive BRPC/LAPC pts diagnosed 2011-2016 who underwent resection following CTX alone or CTX followed by 5-fraction SBRT (CTX-SBRT) were retrospectively reviewed. Baseline demographic, clinical, and treatment factors were compared between cohorts, and survival analysis was conducted to compare pathologic and survival outcomes. Results: Of 199 pts, 77 received CTX alone and 122 received CTX-SBRT. There was no significant difference between cohorts in age, gender, performance status, tumor location, CA19-9 at diagnosis, or post-CTX CA19-9 values (all p > 0.05). The CTX-SBRT cohort had a higher proportion of pts with LAPC as compared to the CTX cohort (53% vs 22%, p< 0.001). Modified FOLFIRINOX (mFFX) was administered to 55% of pts, while 70% of pts received either mFFX or gemcitabine/abraxane, with no difference between cohorts. Duration of CTX was longer in the CTX-SBRT cohort as compared to the CTX cohort (median 4.6 vs. 2.9 mos, p= 0.03), but adjuvant CTX was not given as often in the CTX-SBRT arm (60.4% vs. 86.4%, p= < 0.001). Notably, 30% of the CTX cohort also received adjuvant chemoradiation. Pathologic response was significantly improved in the CTX-SBRT cohort vs the CTX cohort, specifically negative margins (92% vs 70%, p< 0.001), node negative (59% vs. 42%, p< 0.001), and pathologic complete response (7% vs. 0%, p= 0.02). On multivariable analysis, after controlling for prognostic factors, CTX-SBRT remained significantly associated with margin negative resection ( p< 0.001). Despite having more advanced stage and less adjuvant therapy administration in the CTX-SBRT cohort, there was no significant difference in overall survival after surgery (median OS: 24.6 vs. 22.2 mo, p= 0.79), local progression free survival (14.0 vs. 13.6 mo, p= 0.33), or distant metastasis free survival (16.4 vs. 11.8 mo, p= 0.33). Conclusions: Despite more advanced disease at presentation, BRPC/LAPC pts treated with CTX-SBRT were more likely to undergo margin negative resection and experienced similar survival outcomes, as compared to CTX alone. More data are needed to refine which patients benefit from neoadjuvant SBRT and how RT administration can be optimized to impact survival outcomes.

Background: Metastatic pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis with a 5-year survival rate of 10%. For patients with metastatic PDA who respond to but cannot tolerate multi-agent chemotherapy, such as FOLFIRINOX, beyond 4-6 months, the optimal approach is unknown. Few studies have evaluated immunotherapy in the maintenance setting for PDA. Previously, a phase 2 trial in advanced PDA showed the promise of a GM-CSF-secreting allogeneic pancreatic tumor cell-based vaccine (GVAX) with CTLA-4 inhibitor, ipilimumab (IPI) [1]. Here we describe the first clinical testing of GVAX + IPI in the maintenance setting for patients with metastatic PDA who had ongoing response or stable disease after front-line FOLFIRINOX and evaluation of immune cell changes within the peripheral blood and tumor. Methods: From 40 vaccinated patients, we obtained paired peripheral blood lymphocytes (PBLs) from 20 patients and metastatic PDA biopsies from 6 of these 20 patients at baseline and week 7 (after at least two doses of GVAX + IPI). Samples were stratified into “stable” or “progressive” cohorts based on disease status on first restaging scan. To profile peripheral immune responses to treatment, we performed mass cytometry (CyTOF) analysis using a T cell-focused panel on PBLs. To profile intratumoral immune responses, biopsies containing >30% tumor cellularity were chosen for 10-plex multiplex immunohistochemistry with T cell and myeloid cell-focused panels allowing us to examine changes in immune cell subsets after GVAX + IPI. Results. GVAX + IPI led to noticeable changes in PBLs including increases in T helper and cytotoxic effector memory cells and decrease in naïve cytotoxic T cells, regardless of disease status. Among co-inhibitory markers assayed on PBLs, GVAX + IPI upregulated TIM3 and PD-1 in most helper and cytotoxic T cells, while CTLA-4 was largely maintained. Interrogation of the metastatic tumor microenvironment at baseline and on-treatment revealed significant increases in CD8+ T cells and pro-inflammatory M1 macrophages and decrease in pro-tumor M2 macrophages. Based on the CD8+ T cell functional status, there were increases in late effector (EOMES-PD-1+) and memory (EOMES-PD-1-) CD8+ T cells in the metastatic tumor after immunotherapy. Conclusions: In summary, we have proposed a mechanism for our immunotherapy in the maintenance setting. GVAX may be inducing systemic and intratumoral activation of naïve T cells to antigen-specific T cells and promoting a decrease in immunosuppressive cells in the metastatic PDA microenvironment. Meanwhile, IPI may be blocking CTLA-4, which improves priming of T cells, but also may be leading to upregulation of regulatory markers TIM3 and PD-1 on T cell subsets as a compensatory mechanism. This trial highlights the challenge to inducing effective anti-tumor immune responses in metastatic PDA with inducible counterregulatory mechanisms. These compensatory increases could provide targets for the next generation of studies. 1Le DT, et al. J Immunother. 2013 Citation Format: Annie A. Wu, Katherine M. Bever, Won Jin Ho, Elana J. Fertig, Nan Niu, Lei Zheng, Rose M. Parkinson, Jennifer N. Durham, Beth Onners, Anna K. Ferguson, Cara Wilt, Andrew H. Ko, Andrea Wang-Gillam, Daniel A. Laheru, Robert A. Anders, Elizabeth D. Thompson, Elizabeth A. Sugar, Elizabeth M. Jaffee, Dung T. Le. Systemic and intratumoral immune profiling in metastatic pancreatic cancer patients who received front-line FOLFIRINOX and were treated with combination immunotherapy with CTLA-4 blockade in the maintenance setting [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PR-004.

Contrary to patients with a cationic trypsinogen gene (PRSS1) mutations, Serine protease inhibitor Kazal-type 1 (SPINK1) heterozygote gene mutation carriers have a very low penetrance for acute, acute recurrent and/or chronic pancreatitis. Despite this, heterozygote SPINK 1 gene mutation patients have a similar age of onset of pancreatitis as PRSS 1 gene mutation patients. While the substantially elevated risk of pancreatic cancer in patients with PRSS1 gene mutations with chronic pancreatitis has been well established, little is known about the risk of pancreatic cancer in SPINK 1 gene mutation carriers with pancreatitis. We describe a case of malignant pancreatic cancer diagnosed in a young patient with chronic pancreatitis who is a SPINK 1 heterozygote gene mutation carrier. The risk of pancreatic cancer in gene mutation patients with chronic pancreatitis, in addition to screening options and management options for these patients is discussed.

Purpose To provide evidence-based recommendations to oncologists and others for the treatment of patients with metastatic pancreatic cancer. Methods American Society of Clinical Oncology convened an Expert Panel of medical oncology, radiation oncology, surgical oncology, gastroenterology, palliative care, and advocacy experts to conduct a systematic review of the literature from April 2004 to June 2015. Outcomes were overall survival, disease-free survival, progression-free survival, and adverse events. Results Twenty-four randomized controlled trials met the systematic review criteria. Recommendations A multiphase computed tomography scan of the chest, abdomen, and pelvis should be performed. Baseline performance status and comorbidity profile should be evaluated. Goals of care, patient preferences, treatment response, psychological status, support systems, and symptom burden should guide decisions for treatments. A palliative care referral should occur at first visit. FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin; favorable comorbidity profile) or gemcitabine plus nanoparticle albumin-bound (NAB) -paclitaxel (adequate comorbidity profile) should be offered to patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 0 to 1 based on patient preference and support system available. Gemcitabine alone is recommended for patients with ECOG PS 2 or with a comorbidity profile that precludes other regimens; the addition of capecitabine or erlotinib may be offered. Patients with an ECOG PS ≥ 3 and poorly controlled comorbid conditions should be offered cancer-directed therapy only on a case-by-case basis; supportive care should be emphasized. For second-line therapy, gemcitabine plus NAB-paclitaxel should be offered to patients with first-line treatment with FOLFIRINOX, an ECOG PS 0 to 1, and a favorable comorbidity profile; fluorouracil plus oxaliplatin, irinotecan, or nanoliposomal irinotecan should be offered to patients with first-line treatment with gemcitabine plus NAB-paclitaxel, ECOG PS 0 to 1, and favorable comorbidity profile, and gemcitabine or fluorouracil should be offered to patients with either an ECOG PS 2 or a comorbidity profile that precludes other regimens. Additional information is available at www.asco.org/guidelines/MetPC and www.asco.org/guidelineswiki .

Radiation-induced lymphopenia (RIL) is associated with inferior survival in patients with glioblastoma, lung cancer, and pancreatic cancer. We asked whether stereotactic body radiation therapy (SBRT) decreases severity of RIL compared to conventional chemoradiation therapy (CRT) in locally advanced pancreatic cancer (LAPC).Serial total lymphocyte counts (TLCs) from patients enrolled in a prospective trial of SBRT for LAPC were compared to TLCs from an existing database of LAPC patients undergoing definitive CRT. SBRT patients received 33 Gy (6.6 Gy × 5 fractions). CRT patients received a median dose of 50.4 Gy (1.8 Gy × 28 fractions) with concurrent 5-fluorouracil (77%) or gemcitabine (23%) therapy. Univariate and multivariate analyses (MVA) were used to identify associations between clinical factors and post-treatment TLC and between TLC and survival.Thirty-two patients received SBRT and 101 received CRT. Median planning target volume (PTV) was smaller in SBRT (88.7 cm(3)) than in CRT (344.6 cm(3); P.001); median tumor diameter was larger for SBRT (4.6 cm) than for CRT (3.6 cm; P=.01). SBRT and CRT groups had similar median baseline TLCs. One month after starting radiation, 71.7% of CRT patients had severe lymphopenia (ie, TLC500 cells/mm(3) vs 13.8% of SBRT patients; P.001). At 2 months, 46.0% of CRT patients remained severely lymphopenic compared with 13.6% of SBRT patients (P=.007). MVA demonstrated that treatment technique and baseline TLCs were significantly associated with post-treatment TLC at 1 but not 2 months after treatment. Higher post-treatment TLC was associated with improved survival regardless of treatment technique (hazard ratio [HR] for death: 2.059; 95% confidence interval: 1.310-3.237; P=.002).SBRT is associated with significantly less severe RIL than CRT at 1 month in LAPC, suggesting that radiation technique affects RIL and supporting previous modeling studies. Given the association of severe RIL with survival in LAPC, further study of the effect of radiation technique on immune status is warranted.

Objectives At diagnosis, 30% of patients with pancreatic cancer are unresectable stage 3 locally advanced. The standard treatment for locally advanced pancreatic cancer (LAPC) is not defined. The current study was conducted to assess the roles of chemotherapy and chemoradiation for LAPC treatment. Materials and methods Between June 2006 and March 2011, 100 patients with LAPC were treated at the Johns Hopkins Hospital. Retrospective analysis was performed to compare cumulative incidence of progression (CIP) and overall survival (OS) among different subgroups. Results For the 100 patients, the median OS was 15.8 months and the median CIP was 8.4 months. The combination of chemotherapy and chemoradiation before disease progression was significantly associated with improved CIP (P=0.001) and improved OS when compared with chemoradiation alone (median OS: 16.4 vs. 11.1 mo, P=0.03). Among patients receiving combination treatment, patients who received chemotherapy first followed by chemoradiation had a trend toward lower CIP (P=0.09) and improved OS (median OS: 18.1 vs. 11.0 mo, P=0.09). Patients who received >2 cycles of chemotherapy before chemoradiation had a significantly decreased CIP (P=0.008) and a trend toward better OS (median OS: 19.4 vs. 15.7 mo, P=0.10). On multivariate analysis, receiving >2 cycles of chemotherapy before chemoradiation was associated with improved CIP. Conclusions Although combination chemotherapy and chemoradiation is favored in the treatment of LAPC, longer induction chemotherapy may play a more important role in sensitization of tumors to subsequent chemoradiation. Our results support treating patients with induction chemotherapy for at least 3 cycles followed by consolidative chemoradiation. These results merit further validation by a prospective study.

Palbociclib (P), an oral cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, has shown antitumor activity in preclinical PDAC models. In Avatar PDAC models, P+ nab-paclitaxel (A) was more effective than either agent alone and similar to P+A+gemcitabine. This study assessed safety, pharmacokinetics (PK), pharmacodynamics (PD), preliminary efficacy, and maximum tolerated dose (MTD) of P+A in pts with advanced PDAC. Pts with metastatic PDAC, Karnofsky performance status ≥70 and adequate organ function were eligible. In the dose escalation phase, P was administered orally once daily at doses ranging from 75-125 mg/d for 21 of every 28 days (3/1 schedule). A was administered intravenously at 100-125 mg on days 1, 8 and 15 every 28 days. Additional cohorts were P 75 mg (3/1 schedule or continuously) with A (100- and 125-mg dose, biweekly). The prespecified efficacy target was 12-month survival probability >65% at MTD. In total, 76 pts (median age 61 years [range 39-75], 45% female) received a median of 4 treatment cycles (range 1-21); 44 (57.9%) pts had liver disease and 61 (80.3%) had prior treatment for advanced disease. Four dose-limiting toxicities were observed: grade 3 mucositis (1), grade 4 neutropenia (2), and febrile neutropenia (1). Grade 3/4 adverse events were reported in 67 (88.2%) pts; events reported for ≥5% of pts were neutropenia (61.8%), leukopenia (26.3%), anemia (22.4%), asthenia (9.2%), lymphopenia (7.9%), and peripheral neuropathy (5.3%). PK demonstrated no significant drug-drug interactions. MTD was P 100 mg (3/1 schedule) and A 125 mg (days 1, 8 and 15 every 28 days). Objective response rate and disease control rate in the 23 pts treated at MTD were 13% and 65.2%, respectively. In these pts, median progression-free survival, median overall survival, and survival probability at 12 months were 5.3 months (95% CI: 3.5-9.7), 12.1 months (95% CI: 6.4-14.8), and 50% (95% CI: 29.9%-67.2%), respectively. Thirty of 57 analyzed pts (52.6%) had an on-treatment maximum Ca 19-9 reduction >50% from baseline. In paired skin punch biopsies (26 pts at any dose level, including 13 pts at MTD), pRb decreased during P dosing, increased above baseline during the week off P, and decreased again following P dosing, demonstrating PD modulation of Rb phosphorylation. CDKN2A, RAS, and TP53 mutations were analyzed in plasma DNA; clinical outcome of pts without alterations detected (n=58, 26, and 28, respectively) was superior to those with alterations detected (n=12, 44, and 42 pts, respectively). In conclusion, P+A was tolerated, with side effects as expected based on single agent profiles, and no significant PK interactions. MTD was P 100 mg (3/1 schedule) + A 125 mg (days 1, 8, and 15 every 28 days). PD observations were consistent with CDK4/6 inhibition. The combination regimen did not meet the prespecified efficacy threshold.Pfizer (NCT02501902) Citation Format: Manuel Hidalgo, Rocio Garcia Carbonero, Kian-Huat Lim, Wells Messersmith, Ignacio Garrido-Laguna, Erkut Borazanci, Andrew Lowy, Laura Medina Rodriguez, Daniel Laheru, Xin Huang, Meggan Tammaro, Jean-François Martini, Arthur Kudla, Kenneth Kern, Teresa Macarulla. A phase 1b study of palbociclib + nab-paclitaxel in patients (pts) with metastatic adenocarcinoma of the pancreas (PDAC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT135.

e19207 Background: Expanding systemic therapy options continue to improve outcomes for patients (pts) with pancreatic cancer (PCa) in both the unresectable and resectable disease settings. We developed an online treatment (Tx) decision support tool designed to provide community healthcare providers (HCPs) with case-specific recommendations from 5 PCa experts. Here, we report an analysis of cases entered into the tool by HCPs, comparing their planned Tx with expert recommendations and assessing the impact of those recommendations on intended HCP Tx decisions. Methods: In July 2019, 5 expert panelists provided Tx recommendations for numerous distinct PCa cases. To use the tool, HCPs entered specific pt/disease factors along with their intended Tx plan for the case, after which they received expert Tx recommendations followed by a survey asking if the recommendations had changed their planned Tx course. Results: 251 HCPs entered 347 pt cases into the tool (83% by physicians). 68% of respondents reported treating < 15 pts with PCa per yr, and 60% sought recommendations for a specific pt. Variance was observed between experts and HCPs for cases in several Tx settings (Table); eg, although FOLFIRINOX was the primary panel recommendation for many younger, healthier pts requiring neoadjuvant or adjuvant therapy or first-line Tx for unresectable disease, most HCPs did not select this therapy for these pts at baseline. Among HCPs whose planned Tx differed from the experts, 51% indicated that they would change their Tx based on panel recommendations. Conclusions: Analysis of data from an online Tx decision support tool for PCa revealed variance between expert recommendations and the intended Tx of HCPs for numerous scenarios, with education provided by the tool potentially increasing the number of clinicians who made optimal Tx decisions. A full analysis of Tx trends will be presented. [Table: see text]

TPS839 Background: Cancers deficient in DNA mismatch repair (dMMR) are highly immunogenic tumors exhibiting high rates of response to immune checkpoint inhibitors targeting the programmed cell death-1 (PD-1)/PD-1 ligand (PD-L1) interaction. These tumors are characterized by high levels of microsatellite instability (MSI-H) and an exceptionally high tumor mutation burden, thought to underlie responsiveness to immunotherapy, with higher predicted immunogenicity of mutation-associated neoantigens. However, primary and acquired resistance are observed and diversity in responses is not fully explained by variations in mutation burden. Other immune checkpoints may be acting in parallel with PD-1/PD-L1. In particular, lymphocyte activation gene 3 (LAG3) mediates exhaustion of activated T cells and may have a role in resistance to PD-(L)1 inhibitors (PD-(L)1i); therefore, we hypothesized that the addition of LAG3 inhibitor (relatlimab) to the PD-1i nivolumab may overcome resistance in these tumors. Methods: Patients with advanced dMMR/MSI-H cancer who have progressive disease (by RECIST 1.1) during or within 6 months of PD-(L)1i containing therapy, and after at least 12 weeks of therapy, and meet other eligibility will be enrolled. All patients will receive nivolumab 480mg + relatlimab 160mg every 4 weeks until intolerance or progression, or up to a maximum of 2 years. The primary endpoint is objective response rate. Key secondary endpoints include safety, progression free and overall survival, and other response endpoints as measured by RECIST 1.1 and iRECIST criteria. Exploratory objectives will include analysis of the tumor microenvironment on biopsies obtained at baseline and on-treatment, analysis of T cell populations in the tumor and in the periphery and functional characterization of mutation-associated neoantigen-specific T cells. Studies of the microbiome will be conducted on stool and oral wash samples. Enrollment of 21 patients is planned. Clinical trial information: NCT03607890.

812 Background: Hospice Length of service (LOS) is a Quality Oncology Practice Initiative (QOPI) measure, and an established metric of end-of-life (EOL) care. Short hospice LOS is associated with lower-quality EOL care, poor symptom control, and patient and caregiver dissatisfaction. Oncologist- and/ or system-specific factors may contribute to shorter hospice LOS. Methods: We conducted a retrospective chart review of patients with advanced gastrointestinal (GI) cancers referred to hospice from a comprehensive cancer center in 2018, and compared data to 2015. We analyzed LOS under hospice care, looking specifically at median LOS and percent of short enrollments (%LOS ≤ 7 days), and examined the variation between individual oncologists within the GI oncology division. The coefficient of variation (Cv) represents degree of variability between oncologists, and was calculated based on median LOS for each oncologist. Mean and SD of oncologist LOS were calculated. Cv was defined as SD/mean; Cv > 100% is typically considered a high variance distribution. Results: A total of 114 patients with advanced GI cancers were discharged to hospice in 2015, and 115 patients in 2018. The median age of patients was 66 years, 47% women, and 80% white. The number of GI oncologists were 9 in both years and median patients per oncologist were 12 in 2015, and 13 in 2018. The median hospice LOS was 16 days in 2015, which decreased to 9 days in 2018. The %LOS ≤ 7 days increased from 25% in 2015 to 47% in 2018. The Cv% was < 100% in both 2015 (63%) and 2018 (44%). Conclusions: In this retrospective study of hospice LOS among patients with advanced GI cancer at a single cancer center, median hospice LOS declined, and %LOS ≤ 7 days increased from 2015 to 2018. We did not find significant variation in hospice referral patterns between oncologists within the GI oncology division. These data point to system level factors responsible for sub-optimal hospice LOS. We will present our data at division meetings, and use mixed-methods design for investigating and eventually addressing barriers to low hospice LOS.

700 Background: Few studies have examined maintenance therapy in unselected pts with metastatic PDA (mPDA). mTOR signaling is central to several oncogenic pathways in PDA and also has a role in T cell differentiation and activation, and we hypothesized a role for mTOR inhibition (mTORi) in the maintenance setting. Methods: This was a randomized open-label study conducted at 2 sites. Eligible pts had mPDA with stable disease for ≥6 months on chemotherapy and ECOG PS 0/1. Pts were randomized 1:1 to Met 850mg BID alone (Arm A) or with Rapa 4mg daily (Arm B), stratified by prior FOLFIRINOX. Baseline and on-treatment PET scans and peripheral blood mononuclear cells were obtained for exploratory analyses. Results: 23 pts were randomized. Median age was 64 (range 34-77) and 82% had ECOG PS 1. 12 of 23 received prior FOLFIRINOX; 8 received >1 prior line of therapy. 22 subjects (11 per arm) were treated per protocol. Treatment related adverse events of Grade ≥3 were seen in 0% vs 27% of pts in Arm A vs B and were all asymptomatic hematologic or electrolyte abnormalities that were not clinically significant. Median PFS/OS were 3.5 (95% CI: 2.9-9.2)/13.2 mos (95% CI: 7.8 to not reached) respectively, with 2 yr OS rate of 37% (95% CI: 21-66%); there were no differences between treatment arms. As expected in the maximally debulked setting, no responses were observed by RECIST; however, decreases in FDG avidity and/or CA199 were observed in several long-term survivors. Better survival was associated with low baseline neutrophil to lymphocyte ratio, baseline lack of assessable disease by PET, and with expansion of dendritic cells following treatment. Compared to Met alone, Met + Rapa was associated with decreased mTOR activity on some immune cell subsets and decreased metabolic fitness, but this was not correlated with outcome. Conclusions: Met +/- rapa maintenance for mPDA was well-tolerated and several pts achieved stable disease associated with exceptionally long survival. Further prospective studies are needed to clarify the role of mTORi in the maintenance setting and to enhance pt selection for such approaches. Clinical trial information: NCT02048384.

Purpose: Limited options exist for patients with advanced pancreatic cancer progressing after 1 or more lines of therapy. A phase II study in patients with previously treated metastatic pancreatic cancer showed that combining GVAX pancreas (granulocyte-macrophage colony-stimulating factor-secreting allogeneic pancreatic tumor cells) with cyclophosphamide (Cy) and CRS-207 (live, attenuated Listeria monocytogenes expressing mesothelin) resulted in median overall survival (OS) of 6.1 months, which compares favorably with historical OS achieved with chemotherapy. In the current study, we compared Cy/GVAX + CRS-207, CRS-207 alone, and standard chemotherapy in a three-arm, randomized, controlled phase IIb trial. Patients and Methods: Patients with previously treated metastatic pancreatic adenocarcinoma were randomized 1:1:1 to receive Cy/GVAX + CRS-207 (arm A), CRS-207 (arm B), or physician's choice of single-agent chemotherapy (arm C). The primary cohort included patients who had failed ≥2 prior lines of therapy, including gemcitabine. The primary objective compared OS between arms A and C in the primary cohort. The second-line cohort included patients who had received 1 prior line of therapy. Additional objectives included OS between all treatment arms, safety, and tumor responses. Results: The study did not meet its primary efficacy endpoint. At the final study analysis, median OS [95% confidence interval (CI)] in the primary cohort (N = 213) was 3.7 (2.9–5.3), 5.4 (4.2–6.4), and 4.6 (4.2–5.7) months in arms A, B, and C, respectively, showing no significant difference between arm A and arm C [P = not significant (NS), HR = 1.17; 95% CI, 0.84–1.64]. The most frequently reported adverse events in all treatment groups were chills, pyrexia, fatigue, and nausea. No treatment-related deaths occurred. Conclusions: The combination of Cy/GVAX + CRS-207 did not improve survival over chemotherapy. (ClinicalTrials.gov ID: NCT02004262) See related commentary by Salas-Benito et al., p. 5435

Purpose:Chemotherapeutic resistance eventually develops in all patients with metastatic colorectal cancer (mCRC). Gene silencing through promoter demethylation is one potential reversible mechanism of resistance with administration of hypomethylating agents. We evaluated the safety and tolerability of guadecitabine and irinotecan in patients with mCRC previously treated with irinotecan.Patients and Methods:In this 3+3 dose-escalation study, patients with mCRC previously exposed to irinotecan received guadecitabine days 1 to 5 of a 28-day cycle and irinotecan 125 mg/m2 days 8 and 15 [dose level (DL) 1, guadecitabine 45 mg/m2; DL −1: guadecitabine 30 mg/m2; DL −1G: guadecitabine 30 mg/m2 with growth factor support (GFS); DL 1G: guadecitabine 45 mg/m2 with GFS].Results:Twenty-two patients were treated across four DLs. Dose-limiting toxicities were neutropenic fever (DL 1 and −1G), biliary drain infection (DL −1), colonic obstruction (DL −1), and severe dehydration (DL 1G). Most common toxicities were neutropenia (82% any grade, 77% Grade 3/4), neutropenic fever (23%), leukopenia (73% any grade, 50% Grade 3/4), and injection site reactions (64% total, 0% Grade 3/4). Patients received a median of 4.5 cycles of treatment; 12/17 evaluable patients had stable disease as best response, with one having initial disease progression but subsequently durable partial response. Circulating tumor DNA showed decrease in global demethylation by LINE-1 after treatment.Conclusions:We report the first study of chemo-priming with epigenetic therapy in gastrointestinal cancers. Guadecitabine 45 mg/m2 and irinotecan 125 mg/m2 with GFS was safe and tolerable in patients with mCRC, with early indication of benefit. These data have provided the basis for an ongoing phase II randomized, multicenter trial.

Purpose GVAX pancreas, granulocyte-macrophage colony-stimulating factor–secreting allogeneic pancreatic tumor cells, induces T-cell immunity to cancer antigens, including mesothelin. GVAX is administered with low-dose cyclophosphamide (Cy) to inhibit regulatory T cells. CRS-207, live-attenuated Listeria monocytogenes–expressing mesothelin, induces innate and adaptive immunity. On the basis of preclinical synergy, we tested prime/boost vaccination with GVAX and CRS-207 in pancreatic adenocarcinoma. Patients and Methods Previously treated patients with metastatic pancreatic adenocarcinoma were randomly assigned at a ratio of 2:1 to two doses of Cy/GVAX followed by four doses of CRS-207 (arm A) or six doses of Cy/GVAX (arm B) every 3 weeks. Stable patients were offered additional courses. The primary end point was overall survival (OS) between arms. Secondary end points were safety and clinical response. Results A total of 90 patients were treated (arm A, n = 61; arm B, n = 29); 97% had received prior chemotherapy; 51% had received ≥ two regimens for metastatic disease. Mean number of doses (± standard deviation) administered in arms A and B were 5.5 ± 4.5 and 3.7 ± 2.2, respectively. The most frequent grade 3 to 4 related toxicities were transient fevers, lymphopenia, elevated liver enzymes, and fatigue. OS was 6.1 months in arm A versus 3.9 months in arm B (hazard ratio [HR], 0.59; P = .02). In a prespecified per-protocol analysis of patients who received at least three doses (two doses of Cy/GVAX plus one of CRS-207 or three of Cy/GVAX), OS was 9.7 versus 4.6 months (arm A v B; HR, 0.53; P = .02). Enhanced mesothelin-specific CD8 T-cell responses were associated with longer OS, regardless of treatment arm. Conclusion Heterologous prime/boost with Cy/GVAX and CRS-207 extended survival for patients with pancreatic cancer, with minimal toxicity.

Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis due to late detection and resistance to conventional therapies. Published studies show that the PDA tumor microenvironment is predominantly infiltrated with immune suppressive cells and signals that if altered, would allow effective immunotherapy. However, single-agent checkpoint inhibitors including agents that alter immune suppressive signals in other human cancers such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), and its ligand PD-L1, have failed to demonstrate objective responses when given as single agents to PDA patients. We recently reported that inhibition of the CTLA-4 pathway when given together with a T cell inducing vaccine gives objective responses in metastatic PDA patients. In this study, we evaluated blockade of the PD-1/PD-L1 pathway. We found that PD-L1 is weakly expressed at a low frequency in untreated human and murine PDAs but treatment with a granulocyte macrophage colony-stimulating factor secreting PDA vaccine (GVAX) significantly upregulates PD-L1 membranous expression after treatment of tumor-bearing mice. In addition, combination therapy with vaccine and PD-1 antibody blockade improved murine survival compared with PD-1 antibody monotherapy or GVAX therapy alone. Furthermore, PD-1 blockade increased effector CD8 T lymphocytes and tumor-specific interferon-γ production of CD8 T cells in the tumor microenvironment. Immunosuppressive pathways, including regulatory T cells and CTLA-4 expression on T cells were overcome by the addition of vaccine and low-dose cyclophosphamide to PD-1 blockade. Collectively, our study supports combining PD-1 or PD-L1 antibody therapy with a T cell inducing agent for PDA treatment.

Background This phase 2 multi-institutional study was designed to determine whether gemcitabine (GEM) with fractionated stereotactic body radiotherapy (SBRT) results in acceptable late grade 2 to 4 gastrointestinal toxicity when compared with a prior trial of GEM with single-fraction SBRT in patients with locally advanced pancreatic cancer (LAPC). Methods A total of 49 patients with LAPC received up to 3 doses of GEM (1000 mg/m2) followed by a 1-week break and SBRT (33.0 gray [Gy] in 5 fractions). After SBRT, patients continued to receive GEM until disease progression or toxicity. Toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0] and the Radiation Therapy Oncology Group radiation morbidity scoring criteria. Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and pancreatic cancer-specific QLQ-PAN26 module before SBRT and at 4 weeks and 4 months after SBRT. Results The median follow-up was 13.9 months (range, 3.9-45.2 months). The median age of the patients was 67 years and 84% had tumors of the pancreatic head. Rates of acute and late (primary endpoint) grade ≥2 gastritis, fistula, enteritis, or ulcer toxicities were 2% and 11%, respectively. QLQ-C30 global quality of life scores remained stable from baseline to after SBRT (67 at baseline, median change of 0 at both follow-ups; P>.05 for both). Patients reported a significant improvement in pancreatic pain (P = .001) 4 weeks after SBRT on the QLQ-PAN26 questionnaire. The median plasma carbohydrate antigen 19-9 (CA 19-9) level was reduced after SBRT (median time after SBRT, 4.2 weeks; 220 U/mL vs 62 U/mL [P

Purpose To explore seromarker levels for associations with outcomes in locally advanced pancreatic cancer (LAPC) patients who received chemotherapy and stereotactic body radiation therapy (SBRT). Methods and Materials Serum from LAPC patients in 2 prospective trials of hypofractionated SBRT (5-6.6 Gy × 5) was collected before SBRT. Proximity ligation assay quantified the expression levels of 36 pancreatic cancer–specific candidate seromarkers: Axl, BMP2, CA 125, CA 19-9, CEA, CXCL-1/6/9/10, EGFR, Gas6, Her2, IGF-2, IGFBP-2/3/7, IL-6/6Ra/7/8/12, mesothelin, MMP-1/2/3/7, osteopontin, PDGFRa, PDK1, PF4, RegIV, SPARC, TGF-β, VEGF-A/D, and YKL40. Seromarker values were log transformed owing to log-normal distribution of the values, and Cox regression analysis was performed to assess for any association with overall survival. The Benjamini-Hochberg method was used to control for a false discovery rate (FDR) of only 10%. Results Sixty-four patients with LAPC were included. No clinical factors (including surgical resection, receipt of pre-SBRT chemotherapy, receipt of post-SBRT chemotherapy, performance status, and age) or potential biomarkers in the panel were associated with improved survival in this cohort after application of the FDR correction. Potential prognostic factors for improved survival for future investigation included surgical resection (P=.007, adjusted P=.153) and the serum expression of IL-8 (P=.006, adjusted P=.153), CA 19-9 (P=.031, adjusted P=.377), and MMP-1 (P=.036, adjusted P=.377). Conclusions These data explore the expression of a panel of proteins in pre-SBRT serum of LAPC patients in the context of a conservative FDR correction. None of the clinical factors or expression levels of the serum proteins were found to be associated with survival; however, IL-8, CA 19-9, and MMP-1 were highlighted as possible candidates warranting inclusion in future seromarker studies in the ongoing efforts to identify tools for risk stratification and treatment allocation in LAPC.

Predicting responses to immunotherapy Colon cancers with loss-of-function mutations in the mismatch repair (MMR) pathway have favorable responses to PD-1 blockade immunotherapy. In a phase 2 clinical trial, Le et al. showed that treatment success is not just limited to colon cancer (see the Perspective by Goswami and Sharma). They found that a wide range of different cancer types with MMR deficiency also responded to PD-1 blockade. The trial included some patients with pancreatic cancer, which is one of the deadliest forms of cancer. The clinical trial is still ongoing, and around 20% of patients have so far achieved a complete response. MMR deficiency appears to be a biomarker for predicting successful treatment outcomes for several solid tumors and indicates a new therapeutic option for patients harboring MMR-deficient cancers. Science , this issue p. 409 ; see also p. 358

Immunotherapy has changed the standard of care for multiple deadly cancers, including lung, head and neck, gastric, and some colorectal cancers. However, single-agent immunotherapy has had little effect in pancreatic ductal adenocarcinoma (PDAC). Increasing evidence suggests that the PDAC microenvironment is comprised of an intricate network of signals between immune cells, PDAC cells, and stroma, resulting in an immunosuppressive environment resistant to single-agent immunotherapies. In this review, we discuss differences between immunotherapy-sensitive cancers and PDAC, the complex interactions between PDAC stroma and suppressive tumor-infiltrating cells that facilitate PDAC development and progression, the immunologic targets within these complex networks that are druggable, and data supporting combination drug approaches that modulate multiple PDAC signals, which should lead to improved clinical outcomes. Clin Cancer Res; 23(7); 1656–69. ©2017 AACR. See all articles in this CCR Focus section, “Pancreatic Cancer: Challenge and Inspiration.”

Background: We completed a phase I clinical trial to test the safety and toxicity of combined treatment with cixutumumab (anti-IGF-1R antibody) and selumetinib (MEK 1/2 inhibitor). Methods: Patients with advanced solid tumours, refractory to standard therapy received selumetinib hydrogen sulphate capsules orally twice daily, and cixutumumab intravenously on days 1 and 15 of each 28-day cycle. The study used a 3+3 design, with a dose-finding cohort followed by an expansion cohort at the maximally tolerated dose that included pharmacokinetic and pharmacodynamic correlative studies. Results: Thirty patients were enrolled, with 16 in the dose-finding cohort and 14 in the expansion cohort. Grade 3 or greater toxicities included nausea and vomiting, anaemia, CVA, hypertension, hyperglycaemia, and ophthalmic symptoms. The maximally tolerated combination dose was 50 mg twice daily of selumetinib and 12 mg kg−1 every 2 weeks of cixutumumab. Two patients achieved a partial response (one unconfirmed), including a patient with BRAF wild-type thyroid carcinoma, and a patient with squamous cell carcinoma of the tongue, and six patients achieved time to progression of >6 months, including patients with thyroid carcinoma, colorectal carcinoma, and basal cell carcinoma. Comparison of pre- and on-treatment biopsies showed significant suppression of pERK and pS6 activity with treatment. Conclusions: Our study of anti-IGF-1R antibody cixutumumab and MEK 1/2 inhibitor selumetinib showed that the combination is safe and well-tolerated at these doses, with preliminary evidence of clinical benefit and pharmacodynamic evidence of target inhibition.