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Herein, we report on a patient with known Lynch Syndrome and periampullary adenocarcinoma that exhibited a pathological complete response to neoadjuvant nivolumab plus ipilimumab. Two MSH2 mutations, high microsatellite instability (MSI-high), high tumor mutational burden (TMB) and elevated PD-L1 expression were identified by next-generation sequencing (NGS) and immunohistochemistry (IHC). Following FOLFIRINOX (Fluorouracil/Leucovorin/Irinotecan/Oxaliplatin) administration and disease progression, nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) were administered every 3 weeks for 4 total cycles. The patient responded well with minimal adverse effects and significant improvement in epigastric pain, appetite and body weight. She then underwent resection consisting of pancreaticoduodenectomy, which demonstrated pathological complete response. Complete genomic profiling of periampullary carcinomas is crucial for optimal treatment selection as true ampullary masses and pancreatic ductal adenocarcinoma (PDAC) have different genetic profiles. This case provides an example of a patient who may have further benefited from first-line nivolumab plus ipilimumab to avoid the reduced efficacy and significant side effects associated with chemotherapy. KEY POINTS: A patient with known Lynch Syndrome and ampullary adenocarcinoma harboring two MSH2 mutations, high microsatellite instability (MSI-high), high tumor mutational burden (TMB) and elevated PD-L1 expression achieved pathological complete response with neoadjuvant nivolumab plus ipilimumab The combination of nivolumab plus ipilimumab may be a better first-line option for patients with ampullary adenocarcinomas harboring deficient mismatch repair (dMMR), MSI-high and high TMB Complete genomic profiling of periampullary adenocarcinomas is crucial for optimal treatment selection as true ampullary masses and pancreatic ductal adenocarcinoma (PDAC) have different genetic profiles The presence of either MSI-high or high TMB could be an appropriate predictive biomarker for response to nivolumab plus ipilimumab in the context of Lynch Syndrome IMPLICATIONS FOR PRACTICE: This case provides an example of a patient with MSI-high and dMMR ampullary adenocarcinoma who may have benefited from first-line checkpoint inhibitor therapy, specifically with nivolumab plus ipilimumab. Comprehensive genomic profiling is beneficial in periampullary adenocarcinomas as it can identify tumors with specific genetic characteristics, like MSI-high, dMMR or high TMB that respond well to immune checkpoint inhibitors. When these characteristics are present and the goal of treatment is to facilitate downstage and prolong progression free survival, nivolumab plus ipilimumab should be considered, but trials in periampullary adenocarcinomas are required to confirm usage.

Purpose Short-course radiation therapy (SCRT) and nonoperative management are emerging paradigms for rectal cancer treatment. This clinical trial is the first to evaluate SCRT followed by chemotherapy as a nonoperative treatment modality. Methods Patients with nonmetastatic rectal adenocarcinoma were treated on the single-arm, Nonoperative Radiation Management of Adenocarcinoma of the Lower Rectum study of SCRT followed by chemotherapy. Patients received 25 Gy in 5 fractions to the pelvis followed by FOLFOX ×8 or CAPOX ×5 cycles. Patients with clinical complete response (cCR) underwent nonoperative surveillance. The primary end point was cCR at 1 year. Secondary end points included safety profile and anorectal function. Results From June 2016 to March 2019, 19 patients were treated (21% stage I, 32% stage II, and 47% stage III disease). At a median follow-up of 27.7 months for living patients, the 1-year cCR rate was 68%. Eighteen of 19 patients are alive without evidence of disease. Patients with cCR versus without had improved 2-year disease-free survival (93% vs 67%; P = .006), distant metastasis-free survival (100% vs 67%; P = .03), and overall survival (100% vs 67%; P = .03). Involved versus uninvolved circumferential resection margin on magnetic resonance imaging was associated with less initial cCR (40% vs 93%; P = .04). Anorectal function by Functional Assessment of Cancer Therapy-Colorectal cancer score at 1 year was not different than baseline. There were no severe late effects. Conclusions Treatment with SCRT and chemotherapy resulted in high cCR rate, intact anorectal function, and no severe late effects. NCT02641691.

Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy with dire prognosis due to aggressive biology, lack of effective tools for diagnosis at an early stage, and limited treatment options. Detection of PDAC using conventional radiographic imaging is limited by the dense, hypovascular stromal component and relatively scarce neoplastic cells within the tumor microenvironment (TME). The CC motif chemokine 2 (CCL2) and its cognate receptor CCR2 (CCL2/CCR2) axis are critical in fostering and maintaining this kind of TME by recruiting immunosuppressive myeloid cells such as the tumor-associated macrophages, thereby presenting an opportunity to exploit this axis for both diagnostic and therapeutic purposes. We engineered CCR2-targeting ultrasmall copper nanoparticles (Cu@CuOx) as nanovehicles not only for targeted positron emission tomography imaging by intrinsic radiolabeling with 64Cu but also for loading and delivery of the chemotherapy drug gemcitabine to PDAC. This 64Cu-radiolabeled nanovehicle allowed sensitive and accurate detection of PDAC malignancy in autochthonous genetically engineered mouse models. The ultrasmall Cu@CuOx showed efficient renal clearance, favorable pharmacokinetics, and minimal in vivo toxicity. Systemic administration of gemcitabine-loaded Cu@CuOx effectively suppressed the progression of PDAC tumors in a syngeneic xenograft mouse model and prolonged survival. These CCR2-targeted ultrasmall nanoparticles offer a promising image-guided therapeutic agent and show great potential for translation.

TPS3172 Background: Ulixertinib (BVD-523) is a small molecule inhibitor of extracellular signal-regulated kinases 1/2 (ERK1/2) in development as a novel anti-cancer drug. Early clinical data demonstrated anti-tumor activity, especially for patients with tumors harboring atypical BRAF or MEK1/2 alterations (Sullivan et al., Cancer Discov. 2018;8(2):184-195). Atypical BRAF (non-V600) alterations can be categorized according to characteristics of molecular signaling (Class II or III), are seen in approximately 3% of all human cancers, and there are currently no approved therapies for this indication. Similar to atypical BRAF alterations, the incidence of MEK1/2 alterations are rare in human tumors (< 1 %). Preclinical data have demonstrated activity of ulixertinib in MEK mutant models. Ulixertinib has FDA fast-track designation for patients with solid tumors, other than CRC, with specific BRAF mutations (G469A, L485W, or L597Q). Designed with intent to register, the BVD-523-ABC clinical trial will continue evaluation of ulixertinib in patients with tumors harboring any atypical BRAF or MEK1/2 alteration (NCT04488003). Methods: This multi-center, phase II study, will be conducted in two parts and assess the clinical benefit, safety, pharmacokinetics, and pharmacodynamics of ulixertinib in patients with advanced malignancies. Ulixertinib will be administered at the RP2D of 600 mg BID for 28-day treatment cycles. Eligible patients will have locally advanced or metastatic cancer which progressed following standard systemic therapies, or for which the patient is not a candidate or refused systemic therapy. Planned correlative analyses include reverse phase protein array and transcriptomics of tumor tissue. Part A is open-label and tumor agnostic, except for group 4 and 6 (CRC patients only). Patients will enroll into one of six groups based on BRAF (groups 1-4) or MEK1/2 (groups 5-6) tumor alteration (38 patients per group). Overall response rate (ORR) is the primary endpoint for Part A, with secondary endpoints including duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Part B is tumor histology specific. Patients will be randomized to receive either ulixertinib or physician's choice of treatment in a 2:1 ratio. Up to three specified tumor histologies will be defined, guided by available Part A data (n = 80-100 per histology). The primary endpoint of Part B is PFS, and secondary endpoints include OS, ORR, and DOR. This study has enrolled 43 patients of the planned 228 in Part A at the time of abstract submission. Clinical trial information: NCT04488003.

TPS4168 Background: Activated NFκB has been linked to aggressive phenotype, poor survival outcomes and resistance to chemotherapy in multiple gastrointestinal cancers including gastroesophageal cancer (GEC). Preclinical studies established that: 1) Genotoxic stress incurred by chemotherapy induces TLR9, which signals through IRAK4 to drive pro-survival NFκB signaling; 2) The survival mechanism through IRAK4 is independent of cancer types and mutational profiles based on colorectal and pancreatic cancer models; and 3) IRAK4 inhibition reduces tumor desmoplasia and revitalizes intratumoral T cells, setting the stage for successful combination with immune checkpoint inhibitors in a highly aggressive autochthonous pancreatic cancer mouse model. These data combined provide a strong rationale to add CA-4948 to systemic therapy for multiple advanced gastrointestinal malignancies, where resistance to chemotherapy is inevitable and benefit of PD-1 inhibitors is limited to small population. CA-4948 is a novel, first-in-class reversible inhibitor of IRAK4. In a phase I trial, patients with relapsed/refractory hematologic malignancies tolerated CA-4948 monotherapy well with mild fatigue, neutropenia, and nausea as most common adverse events. Recommended phase 2 dose (RP2D) was determined as 300 mg orally twice daily. CA-4948 has not been tested in combination with cytotoxic chemotherapy or immune checkpoint inhibitors for solid tumors in clinic. We hypothesize that inhibition of IRAK4 with CA-4948 will potentiate the effect of immune checkpoint inhibitor while deepening the efficacy of cytotoxic chemotherapy in GEC. Methods: This is a phase I trial of CA-4948 in combination with FOLFOX/PD-1 inhibitor with or without trastuzumab for unresectable GEC. During Dose Escalation, we will investigate CA-4948 in combination with FOLFOX/nivolumab by BOIN algorithm evaluating 4 different dose levels. Starting dose of CA-4948 for Part A will be 200 mg twice daily. Once RP2D is determined, the study will proceed to Dose Expansion, including Cohorts A and B. Cohort A will enroll up to 12 patients with HER2 negative disease at the RP2D of CA-4948 determined at the Dose Escalation phase. Cohort B will investigate CA-4948 in combination with FOLFOX/pembrolizumab and trastuzumab. The initial 6 patients in Cohort B will be considered safety lead-in to confirm the safety and tolerability at the RP2D, followed by additional patients, up to 12 patients treated at the RP2D. The primary objective is to determine the safety and RP2D of CA-4948 in combination with FOLFOX/PD-1 inhibitor with or without trastuzumab. Secondary objectives are to determine the preliminary efficacy of the combination. Correlative studies to evaluate pharmacodynamic effects and to identify biomarkers associated with disease response are planned. Clinical trial information: NCT05187182.

4146 Background: Targeting focal adhesion kinase (FAK) renders checkpoint immunotherapy effective in pancreatic ductal adenocarcinoma (PDAC) mouse models. Defactinib is a highly potent oral FAK inhibitor shown to have a tolerable safety profile. We evaluated the safety and recommended phase 2 dose (RP2D) of defactinib in combination with pembrolizumab and gemcitabine for PDAC patients. Methods: We conducted a multicenter, open-label, phase I study with dose escalation and expansion phases. In 3x3 dose escalation, patients with refractory solid tumors were treated at five escalating dose levels of defactinib and gemcitabine to identify a RP2D. In expansion phase, patients with metastatic PDAC who progressed on frontline treatment (refractory cohort) or had treatment response or stable disease (SD) on standard gemcitabine/nab-paclitaxel (maintenance cohort) were treated at RP2D. Pre- and post-treatment tumor biopsies were performed to evaluate changes in tumor immunity. Results: The triple drug combination was well-tolerated with no dose-limiting toxicities. Among 17 treated patients with refractory PDAC, the disease control rate (DCR) was 58.8% with one partial response (PR) and nine SDs and the median progression-free survival (PFS) and overall survival (OS) were 4.2 months and 9.1 months, respectively. Among the evaluable patients in the maintenance cohort, DCR was 63.6% with one PR and six SD. Three patients with SD came off study due to treatment- or disease-related complications. The median PFS and OS were 5.0 months and 8.3 months, respectively. Conclusions: The combination of defactinib, pembrolizumab, and gemcitabine was well-tolerated, had promising preliminary efficacy, and showed increased infiltrative T lymphocytes in post-treatment tumor biopsies. Incorporation of a more potent chemotherapy backbone should be considered to achieve better clinical response in future trial design. Clinical trial information: NCT02546531.

Simple Summary Chronic inflammation is a major mechanism that underlies the aggressive nature and treatment resistance of pancreatic cancer. In many ways, the molecular mechanisms that drive chronic inflammation in pancreatic cancer are very similar to our body’s normal innate immune response to injury or invading microorganisms. Therefore, during cancer development, pancreatic cancer cells hijack the innate immune pathway to foster a chronically inflamed tumor environment that helps shield them from immune attack and therapeutics. While blocking the innate immune pathway is theoretically reasonable, untoward side effects must also be addressed. In this review, we comprehensively summarize the literature that describe the role of innate immune signaling in pancreatic cancer, emphasizing the specific role of this pathway in different cell types. We review the interaction of the innate immune pathway and cancer-driving signaling in pancreatic cancer and provide an updated overview of novel therapeutic opportunities against this mechanism. Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with no effective treatment option. A predominant hallmark of PDAC is the intense fibro-inflammatory stroma which not only physically collapses vasculature but also functionally suppresses anti-tumor immunity. Constitutive and induced activation of the NF-κB transcription factors is a major mechanism that drives inflammation in PDAC. While targeting this pathway is widely supported as a promising therapeutic strategy, clinical success is elusive due to a lack of safe and effective anti-NF-κB pathway therapeutics. Furthermore, the cell type-specific contribution of this pathway, specifically in neoplastic cells, stromal fibroblasts, and immune cells, has not been critically appraised. In this article, we highlighted seminal and recent literature on molecular mechanisms that drive NF-κB activity in each of these major cell types in PDAC, focusing specifically on the innate immune Toll-like/IL-1 receptor pathway. We reviewed recent evidence on the signaling interplay between the NF-κB and oncogenic KRAS signaling pathways in PDAC cells and their collective contribution to cancer inflammation. Lastly, we reviewed clinical trials on agents that target the NF-κB pathway and novel therapeutic strategies that have been proposed in preclinical studies.

Novel effective treatment is direly needed for patients with pancreatic ductal adenocarcinoma (PDAC). Therapeutics that target the driver mutations, especially the KRAS oncoprotein and its effector cascades, have been ineffective. It is increasing clear that the extensive fibro-inflammatory stroma (or desmoplasia) of PDAC plays an active role in the progression and therapeutic resistance of PDAC. The desmoplastic stroma is composed of dense extracellular matrix (ECM) deposited mainly by the cancer-associated-fibroblasts (CAFs) and infiltrated with various types of immune cells. The dense ECM functions as a physical barrier that limits tumor vasculatures and distribution of therapeutics to PDAC cells. In addition, mounting evidence have demonstrated that both CAFs and ECM promote PDAC cells aggressiveness through multiple mechanisms, particularly engagement of the epithelial-mesenchymal transition (EMT) program. Acquisition of a mesenchymal-like phenotype renders PDAC cells more invasive and resistant to therapy-induced apoptosis. Here, we critically review seminal and recent articles on the signaling mechanisms by which each stromal element promotes EMT in PDAC. We discussed the experimental models that are currently employed and best suited to study EMT in PDAC, which are instrumental in increasing the chance of successful clinical translation.

IMPORTANCE: Standard first-line regimens for patients with metastatic gastroesophageal adenocarcinomas have an approximate 40% objective response rate (ORR). The combination of leucovorin, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) has been efficacious as first-line therapy for other gastrointestinal cancers, such as pancreatic and colon cancers. OBJECTIVE: To evaluate the clinical activity and safety of FOLFIRINOX as first-line treatment for patients with advanced gastroesophageal adenocarcinoma. DESIGN, SETTING, AND PARTICIPANTS: This is an open-label, single-arm phase 2 study of first-line FOLFIRINOX in patients with advanced gastroesophageal adenocarcinoma. Estimated sample size included 41 patients with ERBB2-negative disease with 90% power to detect an ORR of 60% or greater with α of .10. No enrollment goal was planned for ERBB2-positive patients, but they were allowed to receive trastuzumab in combination with FOLFIRINOX. INTERVENTIONS: Starting doses were fluorouracil, 400 mg/m(2) bolus, followed by 2400 mg/m(2) over 46 hours; leucovorin, 400 mg/m(2); irinotecan, 180 mg/m(2); and oxaliplatin, 85 mg/m(2). Trastuzumab was administered as a 6 mg/kg loading dose, followed by 4 mg/kg every 14 days in patients with ERBB2-positive disease. MAIN OUTCOMES AND MEASURES: The primary end point was ORR by the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included safety profile, progression-free survival (PFS), overall survival (OS), and duration of response. RESULTS: From November 2013 to May 2018, 67 patients were enrolled (median [range] age, 59.0 [34-78] years; including 56 [84%] men), and 26 of 67 (39%) had ERBB2-positive disease. Median follow-up was 17.4 months. The ORR was 61%(95% CI, 44.5%-75.8%) (25 of 41) in the ERBB2-negative group and 85% (95% CI, 65.1%-95.6%) (22 of 26) in the ERBB2-positive group, including 1 patient with complete response. For ERBB2-negative patients, median PFS was 8.4 months and median OS was 15.5 months; for ERBB2-positive patients, median PFS was 13.8 months and median OS was 19.6 months. Fifty-six patients (84%) had dose modifications or treatment delays. The most common toxic effects were neutropenia (91%, n = 61), diarrhea (63%, n = 42), peripheral sensory neuropathy (61%, n = 41), and nausea (48%, n = 32), with no unexpected toxic effects. CONCLUSIONS AND RELEVANCE: The FOLFIRINOX regimen with or without trastuzumab was associated with improved ORR and PFS in patients with advanced gastroesophageal adenocarcinoma in the first-line setting. This regimen may be a reasonable therapeutic option for patients with preserved performance status. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01928290

284 Background: Ramucirumab, a humanized monoclonal antibody targeting VEGFR2, is used for treatment of metastatic gastroesophageal adenocarcinoma after disease progression on first-line chemotherapy. Superior survival outcome is expected when combined with paclitaxel. However, many patients suffer from chemotherapy-induced peripheral neuropathy after oxaliplatin-containing first-line treatment and are unable to tolerate paclitaxel. Irinotecan has shown survival benefit as a single agent or in combination with other agents for treating gastroesophageal cancer, but has not been evaluated with ramucirumab. We hypothesized that the combination regimen of irinotecan and ramucirumab administered as second-line treatment for advanced gastroesophageal adenocarcinoma will be better tolerated than ramucirumab and paclitaxel with similar clinical efficacy. Methods: The primary objective of this multi-institutional, single-arm phase 2 clinical trial is to determine the progression-free survival (PFS) after disease progression on up to one line of cytotoxic chemotherapy. Secondary objectives include objective response rate, overall survival, time to progression, and clinical benefit; and to evaluate toxicity and tolerability. Patient-derived xenograft and organoid models generated in a subgroup of patients. Investigation of blood-based angiome profiling and cell-free DNA are planned. Patients received 8 mg/kg ramucirumab with 180 mg/m2 irinotecan IV every 14 days. A sample of 40 achieves 85.7% power at a one-sided significance level of 5% to detect a median PFS of 4 months compared to historic control of 2.5 months assuming the accrual time of 12 months and additional follow-up of 12 months and using a one-sample log rank test. NCT03141034. Results: Forty patients were enrolled from four institutions from December 2017 through May 2021. All patients received platinum-based chemotherapy prior to enrollment, 8 patients had HER2 positive disease, and 6 patients had received an immune checkpoint inhibitor. As of September 2021, median follow up time was 7.7 months. Median PFS was 4.6 months (95% CI 2.7 – 5.4). Of 31 patients evaluable for response, 9 patients (29%) had objective responses (1 complete response, 8 partial responses) and 5 patients (16%) had stable disease greater than 6 months. Diarrhea, nausea, vomiting, and neutropenia were common adverse events; no G3/4 neuropathy was reported. Patient-derived organoid and xenograft models were generated from 9 patient samples, treated in vitro to correlate with each patient’s disease response. Conclusions: Ramucirumab and irinotecan appears to be effective and well-tolerated in patients with previously treated gastroesophageal adenocarcinoma. This regimen is now part of standard guidelines and could be a preferred option for patients after disease progression on first-line chemotherapy. Clinical trial information: NCT03141034.

566 Background: 5-FU-based chemotherapy is the standard of care for patients with advanced pancreatic cancer progressed on gemcitabine-based therapy. Based on the NAPOLI-1 study, liposomal irinotecan and 5-FU/LV is currently an FDA-approved regimen in this setting with median progression free survival (mPFS) 3.1 months, median overall survival (mOS) 6.1 months and ORR 16%. In pancreatic cancer mouse models, vitamin D was shown to remodel the desmoplastic stroma and when combined with chemotherapy significantly improved animal survival. Methods: We conducted a pilot study in patients with advanced pancreatic cancer progressed on gemcitabine-based therapy treated with 5FU (2,400mg/m2)/LV (400mg/m2)/liposomal irinotecan (70mg/m2) with paricalcitol in two dose level cohorts: paricalcitol 75mcg IV on day 1 weekly (N = 10, dose level 1) or 7mcg/kg IV on day 1 weekly (N = 10, dose level 2). The primary endpoint was the occurrence of grade 3 and 4 toxicities. Dose-limiting toxicities (DLT) were assessed during cycle 1. Secondary endpoints include objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: Between 8/29/2019 to 5/6/2021, a total of 20 patients were enrolled in the study. No DLTs or grade 4 adverse events were observed in either paricalcitol cohort. The most common toxicities were gastrointestinal (nausea, diarrhea), fatigue and anemia and were similar in both cohorts. Only one grade 3 adverse event was possibly due to paricalcitol (spinal fracture). 2/10 patients experienced an objective response, one of which was confirmed. Median follow up was 6.1 months. At the time of analysis, one patient remains on liposomal irinotecan and 5-FU/LV and mPFS of all patients is 3.57 months and mOS is 6.15 months. The mPFS is 3.55 months for dose level 1 and 5.34 months for dose level 2 (p = 0.3). The mOS is 6.15 months for dose level 1 and 6.66 months for dose level 2 (p = 0.4). Conclusions: Administration of paricalcitol in combination with liposomal irinotecan and 5-FU/LV is well tolerated in patients with advanced pancreatic cancer, however does not appear to improve response rate or survival outcomes. Correlative analyses are ongoing. Clinical trial information: NCT03883919.

Effective treatment for pancreatic ductal adenocarcinoma (PDAC) is an urgent, unmet medical need. Targeting KRAS, the oncogene that is present in >95% of PDAC, is a heavily pursued strategy, but remains unsuccessful in the clinic. Therefore, targeting key effector cascades of KRAS oncoprotein, particularly the mitogenic RAF–MEK–ERK pathway, represents the next best strategy. However, RAF or MEK inhibitors have failed to show clinical efficacy in PDAC. Several studies have shown that cancer cells treated with RAF or MEK inhibitors adopt multiple mechanisms to reactivate ERK signaling. Therefore, development of ERK-specific inhibitors carries the promise to effectively abrogate this pathway. Ulixertinib (or BVD-523) is a first-in-class ERK-specific inhibitor that has demonstrated promising antitumor activity in a phase I clinical trial for advanced solid tumors with NRAS and BRAF mutations, providing a strong rationale to test this inhibitor in PDAC. In this study, we show that ulixertinib effectively inhibits in vitro growth of multiple PDAC lines and potentiates the cytotoxic effect of gemcitabine. Moreover, we found that PDAC cells treated with ulixertinib upregulates the parallel PI3K–AKT pathway through activating the HER/ErbB family proteins. Concurrent inhibition of PI3K or HER proteins synergizes with ulixertinib in suppressing PDAC cell growth in vitro and in vivo. Overall, our study provides the preclinical rationale for testing combinations of ulixertinib with chemotherapy or PI3K and HER inhibitors in PDAC patients. Mol Cancer Ther; 17(10); 2144–55. ©2018 AACR.

Targeting the desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) holds promise to augment the effect of chemotherapy, but success in the clinic has thus far been limited. Preclinical mouse models suggest that near-depletion of cancer-associated fibroblasts (CAF) carries a risk of accelerating PDAC progression, underscoring the need to concurrently target key signaling mechanisms that drive the malignant attributes of both CAF and PDAC cells. We previously reported that inhibition of IL1 receptor–associated kinase 4 (IRAK4) suppresses NFκB activity and promotes response to chemotherapy in PDAC cells. In this study, we report that CAF in PDAC tumors robustly express activated IRAK4 and NFκB. IRAK4 expression in CAF promoted NFκB activity, drove tumor fibrosis, and supported PDAC cell proliferation, survival, and chemoresistance. Cytokine array analysis of CAF and microarray analysis of PDAC cells identified IL1β as a key cytokine that activated IRAK4 in CAF. Targeting IRAK4 or IL1β rendered PDAC tumors less fibrotic and more sensitive to gemcitabine. In clinical specimens of human PDAC, high stromal IL1β expression associated strongly with poor overall survival. Together, our studies establish a tumor–stroma IL1β-IRAK4 feedforward signal that can be therapeutically disrupted to increase chemotherapeutic efficacy in PDAC. Significance: Targeting the IL1β-IRAK4 signaling pathway potentiates the effect of chemotherapy in pancreatic cancer. Cancer Res; 78(7); 1700–12. ©2018 AACR.

Simple Summary Oncogenic KRAS signaling drives several effector cascades that contribute not only to the malignant behavior of pancreatic cancer cells but also formation of the fibro-inflammatory microenvironment. The non-neoplastic cells in the tumor microenvironment interact with tumor cells, creating a complex onco-inflammatory signaling network that enhances the resilience of cancer cells and potentially explaining why targeting KRAS effectors is clinically ineffective. We provide a focused review of this onco-inflammatory network and discuss novel therapeutic opportunities that can be developed. Abstract Pancreatic ductal adenocarcinoma (PDAC) remains highly refractory to treatment. While the KRAS oncogene is present in almost all PDAC cases and accounts for many of the malignant feats of PDAC, targeting KRAS or its canonical, direct effector cascades remains unsuccessful in patients. The recalcitrant nature of PDAC is also heavily influenced by its highly fibro-inflammatory tumor microenvironment (TME), which comprises an acellular extracellular matrix and various types of non-neoplastic cells including fibroblasts, immune cells, and adipocytes, underscoring the critical need to delineate the bidirectional signaling interplay between PDAC cells and the TME in order to develop novel therapeutic strategies. The impact of tumor-cell KRAS signaling on various cell types in the TME has been well covered by several reviews. In this article, we critically reviewed evidence, including work from our group, on how the feedback inflammatory signals from the TME impact and synergize with oncogenic KRAS signaling in PDAC cells, ultimately augmenting their malignant behavior. We discussed past and ongoing clinical trials that target key inflammatory pathways in PDAC and highlight lessons to be learned from outcomes. Lastly, we provided our perspective on the future of developing therapeutic strategies for PDAC through understanding the breadth and complexity of KRAS and the inflammatory signaling network.

There are few effective therapies for unresectable or metastatic hepatocellular carcinoma. Recent data have demonstrated efficacy of immune checkpoint blockade in this difficult to treat disease; however, clinical experience is limited. We report a case of hepatocellular carcinoma displaying pseudoprogression followed by a late response with novel magnetic resonance imaging features following treatment with the anti-programmed cell death protein 1 agent pembrolizumab. (Hepatology Communications 2018;2:148-151).

Gastrointestinal (GI) cancers such as gastric, esophageal, pancreas, hepatobiliary, colorectal and anal cancers are a major cause of cancer related mortality worldwide. Traditional treatment options such as chemotherapy, surgery, radiation therapy, monoclonal antibodies and anti-angiogenic agents have been the backbone of treatment of GI cancers in various stages. Current cancer research is moving forward to incorporate immunotherapies in the treatment of GI cancers either as single agent or in combination with current available treatment modalities. This review summarizes the existing and ongoing immunotherapies in the treatment of GI cancers.

Biliary tract cancers (BTC) is a group of malignancies that arise from the epithelial cells of the biliary tree. These cancers are typically classified by anatomic site of origin: intrahepatic cholangiocarcinoma (IHCC) and extrahepatic cholangiocarcinoma (EHCC), and gallbladder cancer (GBC). To date, complete surgical resection remains the mainstay of treatment especially for earlier stage disease. Unfortunately, most patients present with advanced or metastatic disease, when systemic chemotherapy is the only treatment option. Due to the paucity of effective treatments, BTCs have a dismal prognosis. There is a tremendous need to better understand the disease biology, discover new therapies, and improve clinical outcomes for this challenging disease. Next-generation sequencing has produced a more accurate and detailed picture of the molecular signatures in BTCs. The three BTC histologic subtypes are, in fact, quite molecularly distinct. IHCC commonly contain FGFR2 fusions and IDH 1 and 2 mutations, whereas EHCC and GBC tend to carry mutations in EGFR, HER2, and MAPK pathway. In light of this emerging knowledge, clinical trials have become more biomarker-driven, which allows capturing of subsets of patients that are most likely to respond to certain therapies. Many new and promising targeted therapeutics are currently in the pipeline. Here we review the genetic landscape of BTCs while focusing on new molecular targets and targeted therapeutics currently being investigated in biomarker-driven clinical trials.

Purpose: Aberrant activation of the NF-κB transcription factors underlies the aggressive behavior and poor outcome of pancreatic ductal adenocarcinoma (PDAC). However, clinically effective and safe NF-κB inhibitors are not yet available. Because NF-κB transcription factors can be activated by the interleukin-1 receptor-associated kinases (IRAKs) downstream of the Toll-like receptors (TLRs), but has not been explored in PDAC, we sought to investigate the role of IRAKs in the pathobiology of PDAC. Experimental Design: We examined the phosphorylation status of IRAK4 (p-IRAK4), the master regulator of TLR signaling, in PDAC cell lines, in surgical samples and commercial tissue microarray. We then performed functional studies using small-molecule IRAK1/4 inhibitor, RNA-interference, and CRISPR/Cas9n techniques to delineate the role of IRAK4 in NF-κB activity, chemoresistance, cytokine production, and growth of PDAC cells in vitro and in vivo. Results: p-IRAK4 staining was detectable in the majority of PDAC lines and about 60% of human PDAC samples. The presence of p-IRAK4 strongly correlated with phospho-NF-κB/p65 staining in PDAC samples and is predictive of postoperative relapse and poor overall survival. Inhibition of IRAK4 potently reduced NF-κB activity, anchorage-independent growth, chemoresistance, and secretion of proinflammatory cytokines from PDAC cells. Both pharmacologic suppression and genetic ablation of IRAK4 greatly abolished PDAC growth in mice and augmented the therapeutic effect of gemcitabine by promoting apoptosis, reducing tumor cell proliferation and tumor fibrosis. Conclusions: Our data established IRAK4 as a novel therapeutic target for PDAC treatment. Development of potent IRAK4 inhibitors is needed for clinical testing. Clin Cancer Res; 23(7); 1748–59. ©2016 AACR.

// Kian-Huat Lim 1 , Emma Langley 5 , Feng Gao 4 , Jingqin Luo 4 , Lin Li 1 , Gary Meyer 5 , Phillip Kim 5 , Sharat Singh 5 , Vladamir M. Kushnir 2 , Dayna S. Early 2 , Daniel K. Mullady 2 , Steven A. Edmundowicz 6 , Sachin Wani 6 , Faris M. Murad 7 , Dengfeng Cao 3 , Riad R. Azar 2 and Andrea Wang-Gillam 1 1 Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA 2 Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA 3 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA 4 Department of Surgery, Division of Public Health Sciences, Washington University School of Medicine, St. Louis, MO, USA 5 Prometheus Laboratories Inc., San Diego, CA, USA 6 Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA 7 NorthShore University HealthSystem, Evanston, IL, USA Correspondence to: Andrea Wang-Gillam, email: // Keywords : pancreatic cancer, proteomics, fine-needle aspiration, signaling events, prognosis Received : January 28, 2017 Accepted : February 16, 2017 Published : February 23, 2017 Abstract To date, targeted therapy for pancreatic ductal adenocarcinoma (PDAC) remains largely unsuccessful in the clinic. Current genomics-based technologies are unable to reflect the quantitative, dynamic signaling changes in the tumor, and require larger tumor samples that are difficult to obtain in PDAC patients. Therefore, a highly sensitive functional tool that can reliably and comprehensively inform intra-tumoral signaling events is direly needed to guide treatment decision. We tested the utility of a highly sensitive proteomics-based functional diagnostic platform, Collaborative Enzyme Enhanced Reactive-immunoassay (CEER TM ), on fine-needle aspiration (FNA) samples obtained from 102 patients with radiographically-evident pancreatic tumors. Two FNA passes were collected from each patient, hybridized to customized chips coated with an array of capture antibodies, and detected using two enzyme-conjugated antibodies which emit quantifiable signals. We demonstrate that this technique is highly sensitive in detecting total and phosphorylated forms of multiple signaling molecules in FNA specimens, with reasonable correlation of marker intensities between two different FNA passes. Notably, signals of several markers were significantly higher in PDAC compared to non-cancerous samples. In PDAC samples, we found high total c-Met signal to be associated with poor survival, and confirmed this finding using an independent PDAC tissue microarray.

Aberrant activation of the NF-κB transcription factors underlies chemoresistance in various cancer types, including colorectal cancer (CRC). Targeting the activating mechanisms, particularly with inhibitors to the upstream IκB kinase (IKK) complex, is a promising strategy to augment the effect of chemotherapy. However, clinical success has been limited, largely because of low specificity and toxicities of tested compounds. In solid cancers, the IKKs are driven predominantly by the Toll-like receptor (TLR)/IL-1 receptor family members, which signal through the IL-1 receptor–associated kinases (IRAKs), with isoform 4 (IRAK4) being the most critical. The pathogenic role and therapeutic value of IRAK4 in CRC have not been investigated. We found that IRAK4 inhibition significantly abrogates colitis-induced neoplasm in APC(Min/+) mice, and bone marrow transplant experiments showed an essential role of IRAK4 in immune cells during neoplastic progression. Chemotherapy significantly enhances IRAK4 and NF-κB activity in CRC cells through upregulating TLR9 expression, which can in turn be suppressed by IRAK4 and IKK inhibitors, suggesting a feed-forward pathway that protects CRC cells from chemotherapy. Lastly, increased tumor phospho-IRAK4 staining or IRAK4 mRNA expression is associated with significantly worse survival in CRC patients. Our results support targeting IRAK4 to improve the effects of chemotherapy and outcomes in CRC.

Folate receptor α (FRα) is a well-studied tumor biomarker highly expressed in many epithelial tumors such as breast, ovarian, and lung cancers. Mirvetuximab soravtansine (IMGN853) is the antibody-drug conjugate of FRα-binding humanized monoclonal antibody M9346A and cytotoxic maytansinoid drug DM4. IMGN853 is currently being evaluated in multiple clinical trials, in which the immunohistochemical evaluation of an archival tumor or biopsy specimen is used for patient screening. However, limited tissue collection may lead to inaccurate diagnosis due to tumor heterogeneity. Herein, we developed a zirconium-89 (

ObjectiveWe investigated how pancreatic cancer developed resistance to focal adhesion kinase (FAK) inhibition over time.DesignPancreatic ductal adenocarcinoma (PDAC) tumours from KPC mice (p48-CRE; LSL-KRasG12D/wt; p53flox/wt) treated with FAK inhibitor were analysed for the activation of a compensatory survival pathway in resistant tumours. We identified pathways involved in the regulation of signal transducer and activator of transcription 3 (STAT3) signalling on FAK inhibition by gene set enrichment analysis and verified these outcomes by RNA interference studies. We also tested combinatorial approaches targeting FAK and STAT3 in syngeneic transplantable mouse models of PDAC and KPC mice.ResultsIn KPC mice, the expression levels of phosphorylated STAT3 (pSTAT3) were increased in PDAC cells as they progressed on FAK inhibitor therapy. This progression corresponded to decreased collagen density, lowered numbers of SMA+ fibroblasts and downregulation of the transforming growth factor beta (TGF-β)/SMAD signalling pathway in FAK inhibitor-treated PDAC tumours. Furthermore, TGF-β production by fibroblasts in vitro drives repression of STAT3 signalling and enhanced responsiveness to FAK inhibitor therapy. Knockdown of SMAD3 in pancreatic cancer cells abolished the inhibitory effects of TGF-β on pSTAT3. We further found that tumour-intrinsic STAT3 regulates the durability of the antiproliferative activity of FAK inhibitor, and combinatorial targeting of FAK and Janus kinase/STAT3 act synergistically to suppress pancreatic cancer progression in mouse models.ConclusionStromal depletion by FAK inhibitor therapy leads to eventual treatment resistance through the activation of STAT3 signalling. These data suggest that, similar to tumour-targeted therapies, resistance mechanisms to therapies targeting stromal desmoplasia may be critical to treatment durability.

BACKGROUND: The standard of care for unresectable intrahepatic cholangiocarcinoma (ICC) is palliative systemic chemotherapy with cisplatin and gemcitabine. The use of hepatic arterial infusion (HAI) floxuridine (FUDR) with systemic chemotherapy may improve outcomes. We conducted a phase 1 study of HAI FUDR with systemic gemcitabine and oxaliplatin. METHODS: We enrolled patients in three cohorts: FUDR 0.16 mg/kg/day ×14 days (Cohort 1), FUDR 0.12 mg/kg/day ×14 days with gemcitabine 1,000 mg/m(2) on days 1, 8, 15 (Cohort 2), and FUDR 0.10 mg/kg/day ×14 days with gemcitabine 800 mg/m(2) days 1, 15 and oxaliplatin 85 mg/m(2) days 1, 15 (Cohort 3). The primary endpoint was the recommended phase 2 dose (RP2D). Dose limiting toxicities (DLTs) were assessed during cycle 1. Secondary objectives were response rate and survival. RESULTS: We enrolled 24 patients, 6 male, age range 42–81 years (median 64). No DLTs were observed in Cohort 1. In Cohort 2, the addition of gemcitabine 1,000 mg/m(2) days 1, 8, 15 resulted in grade 3 LFT elevation in 2 patients; for subsequent patients, the gemcitabine dose was reduced to 800 mg/m(2). No DLT were observed in Cohort 3. Most patients experienced stable disease (SD) or partial response (PR). Conversion to resectable disease occurred in all cohorts. CONCLUSIONS: Administration of FUDR via HAI pump in combination with systemic gemcitabine and oxaliplatin is well-tolerated in patients with unresectable cholangiocarcinoma. Preliminary analysis suggests a high rate of response and disease control, with some patients proceeding to resection. Based on Cohort 3, the RP2D is FUDR 0.10 mg/kg/day ×14 days, with gemcitabine 800 mg/m(2) days 1, 15 and oxaliplatin 85 mg/m(2) days 1, 15 for future studies. Future studies of this promising regimen will utilize this dosing schedule.

TPS449 Background: NRG1 (Neuregulin-1) gene fusions are rare oncogenic drivers found in 0.2% of solid tumors, including lung, pancreatic, gallbladder, breast, ovarian, colorectal, neuroendocrine, and sarcomas. NRG1 is the predominant ligand of HER3 and to a lesser extent HER4. NRG1 fusion proteins retaining an active EGF-like domain drive tumorigenesis and proliferation through aberrant HER3 activation. Importantly, NRG1 fusions are often mutually exclusive with other known driver alterations. NRG1 fusions have been correlated with worse overall and disease-free survival and poor response to treatment with standard therapies including chemotherapy, PD-(L)1 checkpoint inhibitors and combinations of these agents. Inhibition of HER3 and its dimerization partners represents a rational and novel therapeutic approach for tumors harboring an NRG1 fusion supported by case studies of clinical responses to anti-HER3 antibodies or pan-ERBB (tyrosine kinase inhibitors) TKIs like afatinib. Seribantumab is a fully human IgG2 mAb against HER3 uniquely able to inhibit NRG1-dependent activation of HER3, HER3-HER2 dimerization, and downstream signaling through the PI3K/AKT and MAPK pathways. The clinical safety profile of seribantumab has been well characterized through prior monotherapy and combination studies in over 800 patients. Methods: CRESTONE is an open label, multicenter phase 2 basket trial of seribantumab in adult patients with NRG1 fusion-positive locally advanced or metastatic solid tumors who have progressed on or are nonresponsive to available therapies. The trial will enroll at least 75 previously treated patients across three cohorts. Cohort 1 (N=55) will include patients who have not received prior treatment with any ERBB targeted therapy. Cohort 2 (up to N=10) will include patients who have progressed after prior treatment which includes ERBB targeted therapy. Cohort 3 (up to N=10) will include patients harboring NRG1 fusions without an EGF-like binding domain. NRG1 fusion status for enrollment will be determined through a local CLIA or similarly accredited molecular assay. NRG1 fusion status for patients in Cohort 1 will be centrally confirmed using an RNA-based NGS assay. This study will evaluate a novel dosing regimen of weekly induction, biweekly consolidation, and Q3W maintenance designed to rapidly achieve steady state levels, optimize exposure, and deliver maximal NRG1 inhibition. The primary endpoint is ORR per RECIST v1.1 by independent radiologic review. Secondary endpoints include duration of response (DoR), safety, PFS, OS, and overall clinical benefit rate. An interim analysis is planned following enrollment of 20 patients in Cohort 1. CRESTONE is open and accruing patients in the United States. Clinical trial information: NCT04383210.

437 Background: SM-88 (racemetyrosine, Tyme Inc) is a dysfunctional tyrosine derivative used with MPS (methoxsalen 10mg, phenytoin 50mg and sirolimus 0.5mg). SM-88 was well tolerated with improvement in survival among select heavily pretreated PDAC patients who achieved stable disease (HR 0.08, p = 0.02) (Noel et al. Annal Oncol 2019). Circulating tumor cells (CTCs) were prognostic in identifying a PDAC subgroup that may be more likely to benefit from SM-88. Preliminary radiomic analysis of the largest metastases at baseline correlated with baseline CTCs (Ocean et al, Annal Oncol 2019). Here we describe the subsequent randomized portion of the trial in third-line patients only, of SM-88 vs physician/patient choice chemotherapy, to evaluate the potential role of SM-88 in metastatic PDAC through analysis of CTCs and passively acquired biometrics data from a wearable device. Methods:Prospective open-label RCT (Tyme 88 Panc Part 2, NCT03512756) after 2 prior lines for metastatic PDAC. A cell adhesion matrix (CAM) was used to enrich solitary CTCs and cells in clusters floating in the medium after 24 hour culture. Isolated CTCs were collected each cycle on day 1, isolated, and enumerated by flow cytometry using the epithelial cell surface marker Epi+ and cellular uptake of green fluorescent labeled CAM (GCAM+). Results:As of Sept 15, 67 subjects were consented. Randomized and evaluable subjects (n=38) included: mean age 65y (45-86); BMI 24.6 (18.8-38.7); female 39.5%; White 76.3%. Of treated subjects 65.8% (25/38) had 166 AEs, with 25.7% (26/101) being at least possibly SM-88-related, with 1 Grade 3. Four CTC subpopulations defined by GCAM, Epi+ and cluster status, were enumerated and correlated to each other (r=0.03-0.71). At least one CTC subpopulation was detected at baseline (mean 33.8 cells/2mL) in all subjects (n=27). The longest metastatic lesion diameter at baseline correlated with baseline CTCs (r=0.55 for Epi+ cluster; r=0.52 for GCAM+ cluster). CTCs were successfully separated and enumerated at each cycle for correlation with survival, response and other parameters. The median baseline daily step count during the first two weeks on treatment was 3993.8 (IQR: 2745.6 - 5078) for those alive vs. 689.3 (IQR: 630.0-2083.6) among deaths in evaluable subjects (p = NS). Passively acquired mean heart rate during week 3 on trial was 89.3 (SD 10.5) among those who died vs. 78.0 (SD 9.2) among those living; medians are 87.0 for deaths vs. 79.2 for alive (p= NS). Conclusions: In a preliminary exploratory analysis, passively acquired biometrics from a wearable device can be collected for correlation with other clinical outcomes. CTC collection and enumeration is also feasible for correlation with traditional trial outcomes. Given that the longest lesion diameter is correlated with CTCs at baseline, additional radiologic feature analysis (eg radiomics) may be important predictor of CTCs. SM-88 was well tolerated with no treatment-related Grade 4 or 5 events. Clinical trial information: NCT03512756.

Summary Background In pancreatic ductal adenocarcinoma, the CCL2–CCR2 chemokine axis is used to recruit tumour-associated macrophages for construction of an immunosuppressive tumour microenvironment. This pathway has prognostic implications in pancreatic cancer, and blockade of CCR2 restores anti-tumour immunity in preclinical models. We aimed to establish the safety, tolerability, and recommended phase 2 oral dose of the CCR2 inhibitor PF-04136309 in combination with FOLFIRINOX chemotherapy (oxaliplatin and irinotecan plus leucovorin and fluorouracil). Methods We did this open-label, dose-finding, non-randomised, phase 1b study at one centre in the USA. We enrolled treatment-naive patients aged 18 years or older with borderline resectable or locally advanced biopsy-proven pancreatic ductal adenocarcinoma, an Eastern Cooperative Oncology Group performance status of 1 or less, measurable disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1, and normal end-organ function. Patients were allocated to receive either FOLFIRINOX alone (oxaliplatin 85 mg/m 2 , irinotecan 180 mg/m 2 , leucovorin 400 mg/m 2 , and bolus fluorouracil 400 mg/m 2 , followed by 2400 mg/m 2 46-h continuous infusion), administered every 2 weeks for a total of six treatment cycles, or in combination with oral PF-04136309, administered at a starting dose of 500 mg twice daily in a standard 3 + 3 dose de-escalation design. Both FOLFIRINOX and PF-04136309 were simultaneously initiated with a total treatment duration of 12 weeks. The primary endpoints were the safety, tolerability, and recommended phase 2 dose of PF-04136309 plus FOLFIRINOX, with an expansion phase planned at the recommended dose. We analysed the primary outcome by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01413022. Results Between April 19, 2012, and Nov 12, 2014, we treated 47 patients with FOLFIRINOX alone (n=8) or with FOLFIRINOX plus PF-04136309 (n=39). One patient had a dose-limiting toxic effect in the dose de-escalation group receiving FOLFIRINOX plus PF-04136309 at 500 mg twice daily (n=6); this dose was established as the recommended phase 2 dose. We pooled patients in the expansion-phase group (n=33) with those in the dose de-escalation group that received PF-04136309 at the recommended phase 2 dose for assessment of treatment-related toxicity. Six (75%) of the eight patients receiving FOLFIRINOX alone were assessed for treatment toxicity, after exclusion of two (25%) patients due to insurance coverage issues. The median duration of follow-up for treatment toxicity was 72·0 days (IQR 49·5–89·0) in the FOLFIRINOX alone group and 77·0 days (70·0–90·5) in the FOLFIRINOX plus PF-04136309 group. No treatment-related deaths occurred. Two (5%) patients in the FOLFIRINOX plus PF-04136309 group stopped treatment earlier than planned due to treatment-related toxic effects. Grade 3 or higher adverse events reported in at least 10% of the patients receiving PF-04136309 included neutropenia (n=27), febrile neutropenia (n=7), lymphopenia (n=4), diarrhoea (n=6), and hypokalaemia (n=7). Grade 3 or higher adverse events reported in at least 10% of patients receiving FOLFIRINOX alone were neutropenia (n=6), febrile neutropenia (n=1), anaemia (n=2), lymphopenia (n=1), diarrhoea (n=2), hypoalbuminaemia (n=1), and hypokalaemia (n=3). Therapy was terminated because of treatment-related toxicity in one (17%) of the six patients receiving FOLFIRINOX alone. 16 (49%) of 33 patients receiving FOLFIRINOX plus PF-04136309 who had undergone repeat imaging achieved an objective tumour response, with local tumour control achieved in 32 (97%) patients. In the FOLFIRINOX alone group, none of the five patients with repeat imaging achieved an objective response, although four (80%) of those patients achieved stable disease. Interpretation CCR2-targeted therapy with PF-04136309 in combination with FOLFIRINOX is safe and tolerable. Funding Washington University–Pfizer Biomedical Collaborative.

Background: NRG1 (Neuregulin-1) gene fusions are rare oncogenic drivers found in 0.2% of solid tumors, including lung, pancreatic, gallbladder, breast, ovarian, colorectal, neuroendocrine, and sarcomas. NRG1 is the predominant ligand of HER3 and to a lesser extent HER4. NRG1 fusion proteins retaining an active EGF-like domain drive tumorigenesis and proliferation through aberrant HER3 activation. Importantly, NRG1 fusions are often mutually exclusive with other known driver alterations. NRG1 fusions have been correlated with worse overall and disease-free survival and poor response to treatment with standard therapies including chemotherapy, PD-(L)1 checkpoint inhibitors and combinations of these agents. Inhibition of HER3 and its dimerization partners represents a rational and novel therapeutic approach for tumors harboring an NRG1 fusion supported by case studies of clinical responses to anti-HER3 antibodies or pan-ERBB (tyrosine kinase inhibitors) TKIs like afatinib. Seribantumab is a fully human IgG2 mAb against HER3 uniquely able to inhibit NRG1-dependent activation of HER3, HER3-HER2 dimerization, and downstream signaling through the PI3K/AKT and MAPK pathways. The clinical safety profile of seribantumab has been well characterized through prior monotherapy and combination studies in over 800 patients. Methods: CRESTONE is an open label, multicenter Phase 2 basket trial of seribantumab in adult patients with NRG1 fusion-positive locally advanced or metastatic solid tumors who have progressed on or are nonresponsive to available therapies. The trial will enroll at least 75 previously treated patients across three cohorts. Cohort 1 (N=55) will include patients who have not received prior treatment with any ERBB targeted therapy. Cohort 2 (up to N=10) will include patients who have progressed after prior treatment which includes ERBB targeted therapy. Cohort 3 (up to N=10) will include patients harboring NRG1 fusions without an EGF-like binding domain. NRG1 fusion status for enrollment will be determined through a local CLIA or similarly accredited molecular assay. NRG1 fusion status for patients in Cohort 1 will be centrally confirmed using an RNA-based NGS assay. This study will evaluate a novel dosing regimen of weekly induction, biweekly consolidation, and Q3W maintenance designed to rapidly achieve steady state levels, optimize exposure, and deliver maximal NRG1 inhibition. The primary endpoint is ORR per RECIST v1.1 by independent radiologic review. Secondary endpoints include duration of response (DoR), safety, PFS, OS, and overall clinical benefit rate. An interim analysis is planned following enrollment of 20 patients in Cohort 1. CRESTONE is open and accruing patients in the United States. Clinical trial information: NCT04383210. Citation Format: Johanna C. Bendell, Kian-Huat Lim, Mark E. Burkard, Jessica J. Lin, Young Kwang Chae, Mark A. Socinski, Gazala Khan, Karen L. Reckamp, Shawn Leland, Douglas Plessinger, Lori Kunkel, Efrat Dotan, Gregory Otterson, Sai-Hong Ignatius Ou, Tejas Patil, John V. Heymach, Edward S. Kim. CRESTONE – Clinical study of response to seribantumab in tumors with neuregulin-1 (NRG1) Fusions – A phase 2 study of the anti-HER3 mAb for advanced or metastatic solid tumors (NCT04383210) [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 PO-003.

Effective immunotherapy in pancreatic ductal adenocarcinoma (PDAC) is impeded by multiple barriers in the tumor microenvironment. These include the dense extracellular matrix (ECM), excessive inhibitory myeloid cells, cytokines and chemokines, which collectively incapacitate anti-tumour T cells. Constitutive activation the NF-kB pathway is a mechanism that drives intrinsic survival of PDAC cells and stromal fibrosis, but its impact on anti-tumour immunity has not been investigated. Using The Cancer Genome Atlas database, we found that expression of RELA, a canonical NF-kB factor, in PDAC samples is associated with activated stroma and lower cytotoxic T cell signatures. In a PDAC tissue microarray, the staining intensity of activated IRAK4, the innate immune kinase that drives NF-kB signaling, negatively correlates with T cell abundance. Based on these findings, we investigated the immunological impact role of IRAK4 in PDAC. Transcriptomic analysis showed that ablation of IRAK4 in PDAC cells downregulates NF-kB and inflammatory signatures, and markedly decreases transcription of hyaluronan synthase 2 (HAS2). Accordingly, pharmacologic inhibition of IRAK4 significantly decreased intratumoral hyaluronan, as well as collagen, in autochthonous PDAC mice and potentiated standard chemotherapy. Furthermore, IRAK4 inhibition also significantly reduced production of several suppressive chemokines and checkpoint ligands PD-L1 and Nectin2, leading to revitalization of infiltrative CD4+ and CD8+ T cells. These effects were partly mediated through reduction of intratumoural hyaluronan, which we recapitulated with HAS inhibitor, 4-MU. Accordingly, combined IRAK4 inhibitors with immune checkpoint blockade (ICB) especially anti-CTLA4, were highly efficacious in abrogating tumour growth in autochthonous PDAC mice and doubling their survival. In summary, we showed that targeting the NF-kB pathway through IRAK4 renders ICB effective via multiple mechanisms and should be tested in clinical trials for PDAC patients. Citation Format: Daoxiang Zhang, Vikas Somani, Paarth B. Dodhiawala, Patrick M. Grierson, Lin Li, Kuljeet Seehra, Xiuting Liu, Brett L. Knolhoff, Marianna B. Ruzinova, David G. DeNardo, Kian-Huat Lim. Targeting NF-kB pathway through IRAK4 renders immune checkpoint blockade effective in pancreatic cancer [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 PO-017.

Background: Epacadostat is an orally active, potent and selective inhibitor of indoleamine 2, 3-dioxygenase 1 (IDO1). IDO1 inhibition enhances cytotoxic T cell activation by dendritic cells, and significantly decreases regulatory T cell proliferation. We developed preclinical data supporting combination of epacadostat with radiation therapy in rectal cancer. In rectal cancer samples obtained from patients who received hypofractionated radiation, IDO1 was overexpressed in tumor tissue as compensatory response after radiation in both microsatellite stable and unstable cell lines. IDO1 inhibition with epacadostat selectively reduced survival of cancer cells and enhanced radiosensitivity without impacting normal epithelial cells. Epacadostat in addition to radiation showed both increased tumor cytotoxicity and enhanced immune activation in tumor microenvironment in a syngeneic mouse model of colorectal cancer. Literature also supports the choice of high dose, hypofractionated radiation to induce a more favorable anti-tumor immune response. Therefore, we hypothesized that IDO1 expression is a mechanism of radioresistance in rectal cancer and IDO1 inhibition is a safe and well-tolerated combination therapy to enhance tumor radiosensitivity. Methods: Patients with locally advanced rectal cancer who are candidates for neoadjuvant therapy using short-course radiation and chemotherapy are included in this study. Primary objective of the study is to determine the recommended phase II dose (RP2D) of epacadostat for combination with short course radiation and chemotherapy in preoperative treatment of locally advanced rectal cancer. This study includes dose-escalation part of patients receiving epacadostat with radiation and chemotherapy (n=6-18) followed by dose-expansion (n=up to 27 including those treated at RP2D during escalation). Two dose levels of epacadostat (300mg and 600mg orally twice daily) will be explored. Epacadostat will be combined with short-course radiation (5Gy x 5 fractions) followed by 6 cycles of CAPOX chemotherapy, until the day of surgery for a total of approximately 24 weeks of therapy. Research biopsies of tumor and adjacent non-tumor tissue along with blood sample collection will be performed before and after the radiation, and at the time of surgery. Tryptophan pathway metabolites, immune checkpoint biomarkers, markers of cell death, proliferation and potentially prognostic molecular biomarkers will be measured in tumor tissues before and after radiation therapy. In addition, patient-derived organoid and xenograft models from rectal biopsy samples will be used to determine the success rate of organoid generation, to evaluate treatment response and to characterize molecular changes to identify potential predictors of response and mechanisms of resistance. Enrollment began in November 2019. NCT03516708 Citation Format: Haeseong Park, Ebunoluwa Otegbeye, Hyun Kim, Matthew Mutch, Katrina Pedersen, Manik Amin, Benjamin Tan, Nikolaos Trikalinos, Kian-Huat Lim, Olivia Aranha, Rama Suresh, Shahed Badiyan, Matthew Silviera, Lauren Henke, Paul Wise, Steven Hunt, Jonathan Mitchem, Esther Lu, Andrea Wang-Gillam, Matthew Ciorba. Phase I study of epacadostat added to preoperative chemoradiation in patients with locally advanced rectal cancer [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 CT234.

Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival of 9% and effective treatment options remain elusive. Oncogenic mutations of KRAS occur in >95% of PDACs and are well-established as the bona fide driver event. However, inhibition of KRAS oncoprotein or its downstream signaling cascades remains unsuccessful in PDAC patients. Furthermore, parallel survival pathways including constitutive activation of the NF-κB pathway poses an additional therapeutic barrier. Previous work from our lab showed that Interleukin-1 Receptor associated kinase 4 (IRAK4) is a major driver of NF-kB cascade in PDAC. Here, through an unbiased reverse phase protein array screen and RNA sequencing, we discovered IRAK4 controls MAPK activity downstream of KRAS. Ablation of IRAK4 completely abolishes RAS-induced transformation in human and murine cell lines. Mechanistically, we implicate a KRAS-driven IL-1β signaling loop that activates IRAK4 and uncover MAP3K8 (or TPL2/COT) as the kinase through which IRAK4 activates MEK and ERK. Suppression of TPL2 abrogates KRAS-driven MEK-ERK activity and transformed growth of PDAC cell lines. In addition, TPL2 inhibition suppresses p105/p50 NF-kB activation, a valuable phenomenon that distinguishes TPL2 inhibition from MEK inhibition. We find TPL2 inhibition synergizes with chemotherapy to suppress growth of PDAC cell lines in vitro and patient-derived xenograft tumor model in vivo. Analyses of PDAC tissue microarray showed TPL2 expression to be marginally associated with poor prognosis. Additionally, we are the first to characterize gain-of-function point mutations in TPL2 which hyperactivate MAPK and NF-kB, in part by preventing TPL2 protein degradation. Together, our study broadens the understanding of the oncogenic RAS signaling network and reveals IRAK4 and TPL2 as novel practical therapeutic targets in RAS-driven cancers. Citation Format: Paarth B. Dodhiawala, Namrata Khurana, Daoxiang Zhang, Yi Cheng, Lin Li, Kuljeet Seehra, Hongmei Jiang, Patrick M. Grierson, Andrea Wang-Gillam, Marianna B. Ruzinova, Kian-Huat Lim. Essential role of IRAK4/TPL2 signaling axis in MAPK activation by oncogenic RAS and genotoxic stress [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 3039.

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.

Background: Focal adhesion kinase (FAK) is consistently hyperactivated in multiple tumor types including PDAC. Our preclinical work showed that FAK and PD-1 inhibitors elicit significant tumor regression, and that combining FAK and PD-1 inhibitors with gemcitabine achieves a maximal response. This suggests the need for a cytotoxic agent to bolster antigen presentation. Defactinib is an orally available, well-tolerated, potent FAK inhibitor. Methods: This study included a dose escalation phase (all solid tumors) and dose expansion phase (metastatic PDAC). A 3+3 design with five dose levels was used in the dose escalation phase. For the expansion phase, 10 PDAC patients with stable disease on front-line gemcitabine/nab-paclitaxel were enrolled in the Maintenance cohort (A), while 10 patients who progressed on at least one line of therapy were enrolled in the Refractory cohort (B). Pre and on-treatment biopsied were collected from all PDAC patients. The primary endpoint was to determine the recommended phase 2 dose (RP2D). Secondary endpoints included safety, toxicity, objective response rate, progression-free survival (PFS) and overall survival (OS). The exploratory endpoints included developing a molecular and immune profile for treatment response. Results: In dose escalation, the common low grade (G1/2) treatment-emergent adverse events included fatigue, anorexia, nausea and vomiting. No DLTs were seen. The RP2D was defactinib 400mg twice daily, gemcitabine 1000 mg/m2 days 1, 8 and pembrolizumab 200mg day 1 of a 21-day cycle. Safety and toxicity results in the escalation cohort were reported at the 2018 ASCO Annual Meeting. Among 8 evaluable PDAC patients enrolled on the dose escalation phase, we observed 1 (13%) partial response (PR), 3 (38%) stable disease (SD), 4 (50%) progressive disease (PD). In the Maintenance cohort, 1 (10%) PR, 6 (60%) SD, and 3 (30%) PD were observed. Two patients in the Maintenance cohort remain on study, and the median time on treatment was 4.6 months. In the Refractory cohort, 5 (50%) had SD, 4 (40%) PD, 1 not evaluable; median PFS was 2.9 months and median OS was 7.6 months. Interestingly, two confirmed PR patients both have MSS disease. Paired biopsies in PDAC patients show increased proliferating CD8+ T cells, while Tregs, macrophages, and stromal density decrease with treatment. Conclusions: The combination regimen was well tolerated. Encouraging efficacy signals were observed in both Maintenance and Refractory cohorts. Updated outcomes and correlative analyses are forthcoming. Citation Format: Andrea Wang-Gillam, Robert McWilliams, A. Craig Lockhart, Benjamin R Tan, Rama Suresh, Kian-Huat Lim, Katrina S. Pedersen, Nikolaos Trikalinos, Olivia Aranha, Haeseong Park, Lee Ratner, Nicholas Boice, David G. Denardo. Phase I study of defactinib combined with pembrolizumab and gemcitabine in patients with advanced cancer: Experiences of pancreatic ductal adenocarcinoma (PDAC) patients [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 CT118.

4532 Background: Standard first-line regimens for patients with metastatic gastroesophageal adenocarcinomas have moderate clinical benefit with objective response rates (ORR) of approximately 40-50%. FOLFIRINOX has been shown to be an effective and well-tolerated first line therapy in other GI cancers. In this open-label, single-arm phase II study of patients with advanced gastroesophageal adenocarcinomas, we sought to evaluate the safety and clinical activity of FOLFIRINOX. Methods: The primary endpoint was ORR, and secondary endpoints included safety profile, progression free survival (PFS), overall survival (OS), time to progression (TTP), clinical benefit rate (CBR), and duration of response. Estimated sample size included 41 patients with HER2 negative disease with 90% power to detect an ORR≥60% with alpha of 0.10. No enrollment goal was planned for HER2 positive patients, but they were allowed participation to receive study treatment in combination with trastuzumab. Treatment consisted of 400mg/m2 5-FU bolus, 400 mg/m2 leucovorin, 2400 mg/m2 5-FU infusion over 46 hours, 180 mg/m2 irinotecan, and 85 mg/m2 oxaliplatin. Trastuzumab was administered intravenously as a 6 mg/kg loading dose then given 4 mg/kg every 14 days for HER2 positive patients. This trial is registered with ClinicalTrials.gov, NCT01928290. Results: From November 2013 to May 2019, 67 patients were enrolled, of which 26 (39%) had HER2 positive disease. Median follow-up was 16.1 months. ORR was 61% (25/41) for HER2 negative and 85% (22/26) for HER2 positive groups. Overall, one patient (2%) had a complete response, 36 patients (69%) had partial responses, and 13 patients (19%) had stable disease for >6 months; therefore, CBR was 96%. Median PFS was 11.9 months, median OS was 17.4 months. 41 patients (83.7%) had dose modification or treatment delay with the most common toxicities being neutropenia, diarrhea, peripheral sensory neuropathy, and nausea with no unexpected toxicities. Conclusions: FOLFIRINOX is a highly effective three-drug regimen for first-line treatment of advanced gastroesophageal cancer with expected, tolerable toxicities. Clinical trial information: NCT01928290 .

Importance Unresectable intrahepatic cholangiocarcinoma (IHC) carries a poor prognosis, with a median overall survival (OS) of 11 months. Hepatic arterial infusion (HAI) of high-dose chemotherapy may have potential benefit in these patients. Objective To evaluate clinical outcomes when HAI chemotherapy is combined with systemic chemotherapy in patients with unresectable IHC. Design, Setting, and Participants A single-institution, phase 2 clinical trial including 38 patients was conducted with HAI floxuridine plus systemic gemcitabine and oxaliplatin in patients with unresectable IHC at Memorial Sloan Kettering Cancer Center between May 20, 2013, and June 27, 2019. A confirmatory phase 1/2 study using the same therapy was conducted during the same time period at Washington University in St Louis. Patients with histologically confirmed, unresectable IHC were eligible. Resectable metastatic disease to regional lymph nodes and prior systemic therapy were permitted. Patients with distant metastatic disease were excluded. Interventions Hepatic arterial infusion of floxuridine and systemic administration of gemcitabine and oxaliplatin. Main Outcomes and Measures The primary outcome was progression-free survival (PFS) of 80% at 6 months. Results For the phase 2 clinical trial at Memorial Sloan Kettering Cancer Center, 42 patients with unresectable IHC were included and, of these, 38 patients were treated (13 [34%] men; median [range] age at diagnosis, 64 [39-81] years). The median follow-up was 30.5 months. Twenty-two patients (58%) achieved a partial radiographic response, and 32 patients (84%) achieved disease control at 6 months. Four patients had sufficient response to undergo resection, and 1 patient had a complete pathologic response. The median PFS was 11.8 months (1-sided 90% CI, 11.1) with a 6-month PFS rate of 84.1% (90% CI, 74.8%-infinity), thereby meeting the primary end point (6-month PFS rate, 80%). The median OS was 25.0 months (95% CI, 20.6-not reached), and the 1-year OS rate was 89.5% (95% CI, 80.2%-99.8%). Patients with resectable regional lymph nodes (18 [47%]) showed no difference in OS compared with patients with node-negative disease (24-month OS: lymph node negative: 60%; 95% CI, 40%-91% vs lymph node positive: 50%; 95% CI, 30%-83%;P = .66). Four patients (11%) had grade 4 toxic effects requiring removal from the study (1 portal hypertension, 2 gastroduodenal artery aneurysms, 1 infection in the pump pocket). Subgroup analysis showed significant improvement in survival in patients withIDH1/2mutated tumors (2-year OS, 90%; 95% CI, 73%-99%) vs wild-type (2-year OS, 33%; 95% CI, 18%-63%) (P = .01). In the Washington University in St Louis confirmatory cohort, 9 patients (90%) achieved disease control at 6 months; the most common grade 3 toxic effect was elevated results of liver function tests, and median PFS was 12.8 months (1-sided 90% CI, 6.4). Conclusions and Relevance Hepatic arterial infusion plus systemic chemotherapy appears to be highly active and tolerable in patients with unresectable IHC; further evaluation is warranted.

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the US. Despite multiple large-scale genetic sequencing studies, identification of predictors of patient survival remains challenging. We performed a comprehensive assessment and integrative analysis of large-scale gene expression datasets, across multiple platforms, to enable discovery of a prognostic gene signature for patient survival in pancreatic cancer. PDAC RNA-Sequencing data from The Cancer Genome Atlas was stratified into Survival+ (>2-year survival) and Survival–(

SummaryRecurrent mutations in the spliceosome are observed in several human cancers, but their functional and therapeutic significance remains elusive. SF3B1, the most frequently mutated component of the spliceosome in cancer, is involved in the recognition of the branch point sequence (BPS) during selection of the 3′ splice site (ss) in RNA splicing. Here, we report that common and tumor-specific splicing aberrations are induced by SF3B1 mutations and establish aberrant 3′ ss selection as the most frequent splicing defect. Strikingly, mutant SF3B1 utilizes a BPS that differs from that used by wild-type SF3B1 and requires the canonical 3′ ss to enable aberrant splicing during the second step. Approximately 50% of the aberrantly spliced mRNAs are subjected to nonsense-mediated decay resulting in downregulation of gene and protein expression. These findings ascribe functional significance to the consequences of SF3B1 mutations in cancer.

The historical approach of diagnosing cancer types based entirely on anatomic origin and histologic features, and the "one-size-fit-all" therapeutic approach, are inadequate in modern cancer treatment. From decades of research we now know that cancer is a highly heterogeneous disease driven by complex genetic or epigenetic alterations. The advent of various high throughput molecular tools has now enabled us to view and sub-classify each cancer type based on their distinct molecular features, in addition to histologic classification, with the promise of individualized treatment strategies tailored towards each specific subtype to improve patient outcomes. In this review, we have made an effort to systematically review the most up-to-date, leading literature in molecular analysis and/or subtyping of major gastrointestinal cancers. These include esophageal squamous cell carcinoma (ESCC), gastric cancer (GC) adenocarcinoma, pancreatic ductal adenocarcinoma (PDAC), hepatocellular carcinoma (HCC), gallbladder cancer (GBC), and colorectal cancer (CRC). For each cancer type we summarized the global mutational landscape, subgroup classification based on genomics, epigenetics, gene expression and/or proteomic analysis, and their salient clinicopathological features. We have highlighted the actionable mutations or mutational pathways that could help guide targeted therapies in the future.

Cell-of-origin determination has emerged as an important prognostic factor for patients initially diagnosed with diffuse large B cell lymphoma (DLBCL). Specifically, the nongerminal center B cell–like (non-GCB) subtype, composed predominantly of the activated B cell–like (ABC) molecular subtype, has been shown to portend poor prognosis because of its more aggressive nature and resistance to standard cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone (CHOP)-like chemotherapy compared with the GCB subtype. The recurrent MyD88 L265P mutation, present in 29% of ABC DLBCL, was reported as an independent poor prognostic factor for patients with newly diagnosed DLBCL. For patients whose disease relapses or is refractory to first-line chemotherapy, high-dose chemotherapy with autologous stem cell transplantation (ASCT) is frequently offered as salvage therapy. However, the impact of MyD88 mutation status on post-ASCT outcome has not been reported. Here, we retrospectively analyzed, with up to 20 years of follow-up, 165 patients who underwent ASCT for relapsed/refractory DLBCL at our institution. We found that MyD88 mutation status did not correlate with overall survival (OS), post-ASCT OS, or progression-free survival (PFS). Patients with non-GCB subtype had significantly worse OS from initial diagnosis and after ASCT. Notably, high International Prognostic Index score was predictive of poor pre- and post-transplant PFS and post-transplant OS.

TPS4150 Background: Ramucirumab is used for treatment of metastatic gastroesophageal adenocarcinoma after disease progression on first-line chemotherapy. Superior survival outcome is expected when combined with paclitaxel. However, many patients suffer from neuropathy after oxaliplatin-containing first-line chemotherapy and are unable to tolerate paclitaxel. Irinotecan has shown survival benefit as a single agent or in combination with other agents, but has not been used in combination with ramucirumab for treatment with gastroesophageal cancer. We hypothesize that this combination regimen of irinotecan plus ramucirumab administered as second-line treatment will be well-tolerated with improved outcomes similar to paclitaxel plus ramucirumab in patients with advanced gastroesophageal cancer. Circulating levels of angiogenic factors are correlatives of particular interest in this study. Methods: This is a multi-institutional, single-arm phase II clinical trial of ramucirumab and irinotecan. Primary objective of the study is to determine the progression-free survival in patients treated with this combination after disease progression on first-line chemotherapy. Secondary objectives are to determine other indices of efficacy including overall survival, time to progression, objective response rate, and clinical benefit rate; and to evaluate toxicity and tolerability. Patients with confirmed diagnosis of gastroesophageal adenocarcinoma with measurable disease are included. Patients are required of have disease progression during or within 4 months of first line chemotherapy. Key exclusion criteria include squamous histology; prior irinotecan or ramucirumab use; active brain metastases; or other contraindications to ramucirumab including recent history of gastrointestinal bleeding or perforation, thromboembolic event, and uncontrolled hypertension. Patients receive ramucirumab 8mg/kg with irinotecan 180mg/m2 IV every 14 days. We plan to enroll 40 patients which will provide 85% power at a 0.05 significance level to detect a median progression free survival time of 4 months compared to historic control of 2.5 months. 25% of patient accrual is complete as of February 2019. Clinical trial information: NCT03141034.

65 Background: Trastuzumab (T) + chemo is standard first-line therapy (tx) for HER2+ gastroesophageal adenocarcinoma (GEA) pts, though progression ensues in 6-8 months. The approved second-line tx is ramucirumab +/- paclitaxel (R+PAC). Pts with GC are less responsive to R+PAC than gastroesophageal junction (GEJ) pts, in particular HER2+ GC, and no anti-HER2 agents are approved in post-T setting. We report results of combination M+P in HER2+ GC pts and describe a biological rationale for this population. M is an anti-HER2 mAb Fc optimized for enhanced binding to activating FcgRIIIa (CD16A) and decreased binding to inhibitory FcgRIIb (CD32B). M demonstrated an enhanced Fc-dependent MoA, including enhanced ADCC. Methods: HER2+, PD-L1-unselected, second-line GEA pts post T progression received M (15 mg/kg) + P (200 mg) Q3wk. Safety, objective response rate (ORR), median overall & progression-free survival (mOS, mPFS), disease control rate (DCR), circulating tumor DNA, & tumor PD-L1 expression were assessed. Results: To date, 66 GEA pts were dosed; 35 (53%) GC and 31 (47%) GEJ. Overall, 12/66 (18.2%) had tx-related adverse events ≥ grade 3; 5 had drug-related SAEs: dehydration, diabetic ketoacidosis, hypotension and pneumonitis, each a single event, and 2 events of autoimmune hepatitis. Eligibility was based on archival HER2 expression; an exploratory endpoint measured retention of HER2 expression post-T by ERBB2 ctDNA. HER2 expression was lost in 23/56 (41.1%) of pts tested post T. HER2 retention was higher in pts with GC versus GEJ (65.8% vs. 44.8%) and in GEA pts with IHC 3+ vs 2+ archival tumors (61.7% vs 47.4%, respectively). Furthermore, GC had higher PD-L1 expression than GEJ, 53.3 vs. 33.3%, respectively. This coincided with more responses in IHC3+ GC pts, ORR 12/29 (41.4%; 95% CI 23.5-61.1), DCR 21/29 (72.4%; 95% CI 52.8-87.3), mPFS 5.5 months (95% CI 2.3-7.6), mOS not reached, with lower bound of 9.1 months for 95% CI. Enrollment of an additional 25 pts enriched for IHC3+ GC is ongoing. Conclusions: Results suggest that M+P, a chemo-free regimen, demonstrates acceptable tolerability and has encouraging preliminary activity in second-line HER2+ GEA, specifically in GC pts who retain ERBB2 amp prior to second-line tx. Clinical trial information: NCT02689284.