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Altered metabolism is a hallmark of cancer. In addition to glucose, glutamine is an important nutrient for cellular growth and proliferation. Non-invasive imaging via positron emission tomography (PET) may help facilitate precision treatment of cancer through patient selection and monitoring of treatment response. L-[5-11C]-glutamine (11C-glutamine) is a PET tracer designed to study glutamine uptake and metabolism. The aim of this first-in-human study was to evaluate the radiologic safety and biodistribution of 11C-glutamine for oncologic PET imaging. Methods: Nine patients with confirmed metastatic colorectal cancer underwent PET/computed tomography (CT) imaging. Patients received 337.97 ± 44.08 MBq of 11C-glutamine. Dynamic PET acquisitions centered over the abdomen or thorax were initiated simultaneously with intravenous tracer administration. Following the dynamic acquisition, a whole-body PET/CT was acquired. Volume-of-interest analyses were carried out to obtain estimates of organ-based absorbed doses of radiation. Results:11C-glutamine was well-tolerated in all patients with no observed safety concerns. Organs with the highest radiation exposure included the bladder, pancreas, and liver. The estimated effective dose was 4.46E-03 ± 7.67E-04 mSv/MBq. Accumulation of 11C-glutamine was elevated and visualized in lung, brain, bone, and liver metastases, suggesting utility for cancer imaging. Conclusion: PET using 11C-glutamine appears safe for human use and allows non-invasive visualization of metastatic colon cancer lesions in multiple organs. Further studies are needed to elucidate its potential for other cancers and for monitoring response to treatment.

PURPOSE Nivolumab received US Food and Drug Administration approval as a single agent or in combination with ipilimumab in patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) that progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan based on CheckMate 142. Presented are results of nivolumab plus low-dose ipilimumab in the first-line therapy cohort from the phase II CheckMate 142 study. PATIENTS AND METHODS Patients with no prior treatment in the metastatic setting for MSI-H/dMMR CRC were treated with nivolumab every 2 weeks plus low-dose ipilimumab every 6 weeks until disease progression. The primary end point was objective response rate (investigator assessment; RECIST v1.1). RESULTS Median age of treated patients was 66 years (N = 45). Median follow-up was 29.0 months. Objective response rate and disease control rate were 69% (95% CI, 53 to 82) and 84% (95% CI, 70.5 to 93.5), respectively, with 13% complete response rate. Median duration of response was not reached; 74% of responders had ongoing responses at data cutoff. Median progression-free survival and median overall survival were not reached with minimum follow-up of 24.2 months (24-month rates, 74% and 79%, respectively). Clinical benefit was observed regardless of baseline demographic and tumor characteristics, including BRAF or KRAS mutation status. In a post hoc analysis, of 14 patients who discontinued treatment and did not receive subsequent therapy, 10 remained progression-free. Patient-reported outcomes were stable over the treatment period. Grade 3-4 treatment-related adverse events occurred in 22% of patients; 13% discontinued because of any-grade treatment-related adverse events. CONCLUSION Nivolumab plus low-dose ipilimumab demonstrated robust and durable clinical benefit and was well tolerated as a first-line treatment for MSI-H/dMMR mCRC. Based on these promising data, randomized studies are warranted.

Introduction Immune-related adverse event (IRAE) onset may represent a clinical biomarker for anti-programmed cell death protein 1 (PD-1) antibody response based on emerging evidence from patients with various advanced malignancies. This phenomenon has not been previously reported in a multidisease cohort of patients with gastrointestinal (GI) cancer with Food and Drug Administration (FDA)-approved indications to receive immune checkpoint inhibitor therapy. Materials and Methods The study was a multicenter retrospective cohort analysis of 76 patients with GI cancer who had received anti-PD-1 antibodies for FDA-approved indications. The primary and secondary outcomes of the study were progression-free survival (PFS) and overall survival (OS) in patients based upon IRAE presence, respectively. PFS and OS were estimated by the Kaplan-Meier method; a Cox proportional-hazards model adjusted for IRAE onset, patient age, and enrolling institution was used to analyze outcomes. Results Median PFS and OS were prolonged in patients who experienced IRAEs compared with those who did not experience them (PFS: not reached [NR] vs. 3.9 months [hazard ratio (HR) 0.13, 95% confidence interval (CI) 0.05–0.3, p < .001]; OS: NR vs. 7.4 months [HR 0.11, 95% CI 0.03–0.36, p < .001]). Among patients who experienced IRAEs, there were no significant differences in PFS and OS by either initial IRAE severity, management, or time to onset. Conclusion Patients with gastrointestinal cancer who experienced IRAEs while on anti-PD-1 antibodies demonstrated significant improvements in PFS and OS compared with their counterparts who did not develop IRAEs. Although these findings add to results from studies in other tumor types, larger prospective studies are needed prior to clinical adoption of IRAE onset as a biomarker for immune checkpoint inhibitor response. Implications for Practice Predictive clinical biomarkers for immune checkpoint inhibitor response have been understudied in the field of immuno-oncology. Immune-related adverse event onset appears to be one such biomarker. Across tumor types, immune-related adverse event onset has been associated with response to anti-programmed cell death protein 1 (PD-1) antibodies. The results of this study demonstrate this for the first time in patients with gastrointestinal cancer receiving anti-PD-1 antibodies. Before immune-related adverse event onset can be adopted clinically as a predictive biomarker for immune checkpoint inhibitor response, however, larger prospective studies are needed to better understand the nuances between immune-related adverse event characteristics (severity, site, management, timing of onset) and immune checkpoint inhibitor effectiveness.

Older patients make up the majority of patients with pancreatic cancer, with a median age of 71 years at diagnosis. However, older patients are underrepresented in clinical trials in pancreatic cancer. This study investigates trends in age distribution of patients enrolled in clinical trials for advanced pancreatic cancer over time, and examines outcomes and toxicity in older patient subgroups from two studies conducted by Eastern Cooperative Oncology Group and American College of Radiology Imaging Network (ECOG-ACRIN) in this disease.16,042 patients from 38 phase III clinical trials for locally advanced or metastatic pancreatic adenocarcinoma published between 1997 and 2016 were identified and included in this analysis. Outcomes and toxicity by age were examined in two of the trials, ECOG-ACRIN trials E2297 and E6201, which included a total of 1146 patients.The median age across the trials was 62.7 years; median ages for individual trials ranged from 57 years to 66 years. Weighted linear regression showed no significant change in median age over time. Combined analysis of the two ECOG-ACRIN trials demonstrated higher rates of fatigue, thrombocytopenia, and infection in those ≥75 years compared with those75 years, but despite this showed no difference in overall survival (OS) or progression-free survival (PFS) (OS: 5.7 vs. 5.6 months and PFS: 2.8 vs 3.5 months).Enrollment of older adults in phase III pancreatic cancer clinical trials has not increased over time, despite increasing number of older patients seen in clinic. Increased efforts are needed to enhance enrollment of older patients in clinical trials, and to promote trials specifically for older patients, in order to improve the evidence base for treating this patient population.

SummaryVantictumab is a fully human monoclonal antibody that inhibits Wnt pathway signaling through binding FZD1, 2, 5, 7, and 8 receptors. This phase Ib study evaluated vantictumab in combination with nab-paclitaxel and gemcitabine in patients with untreated metastatic pancreatic adenocarcinoma. Patients received vantictumab at escalating doses in combination with standard dosing of nab-paclitaxel and gemcitabine according to a 3 + 3 design. A total of 31 patients were treated in 5 dosing cohorts. Fragility fractures attributed to vantictumab occurred in 2 patients in Cohort 2 (7 mg/kg every 2 weeks), and this maximum administered dose (MAD) on study was considered unsafe. The dosing schedule was revised to every 4 weeks for Cohorts 3 through 5, with additional bone safety parameters added. Sequential dosing of vantictumab followed by nab-paclitaxel and gemcitabine was also explored. No fragility fractures attributed to vantictumab occurred in these cohorts; pathologic fracture not attributed to vantictumab was documented in 2 patients. The study was ultimately terminated due to concerns around bone-related safety, and thus the maximum tolerated dose (MTD) of the combination was not determined. The MAD of vantictumab according to the revised dosing schedule was 5 mg/kg (n = 16).

Pancreatic cancer is the fourth leading cause of cancer-related death among men and women in the United States. A major challenge in treatment remains patients’ advanced disease at diagnosis. The NCCN Guidelines for Pancreatic Adenocarcinoma provides recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pancreatic cancer. Although survival rates remain relatively unchanged, newer modalities of treatment, including targeted therapies, provide hope for improving patient outcomes. Sections of the manuscript have been updated to be concordant with the most recent update to the guidelines. This manuscript focuses on the available systemic therapy approaches, specifically the treatment options for locally advanced and metastatic disease.

We developed a clinical score (CS) at Vanderbilt Ingram Cancer Center (VICC) that we hoped would predict outcomes for patients with progressive well-differentiated neuroendocrine tumors (NETs) receiving therapy with Lutetium-177 (177Lu)-DOTATATE. Patients under consideration for 177Lu-DOTATATE between March 1, 2016 and March 17, 2020 at VICC were assigned a CS prospectively. The CS included 5 categories: available treatments for tumor type outside of 177Lu-DOTATATE, prior systemic treatments, patient symptoms, tumor burden in critical organs and presence of peritoneal carcinomatosis. The primary outcome of the analysis was progression-free survival (PFS). To evaluate the effect of the CS on PFS, a multivariable Cox regression analysis was performed adjusting for tumor grade, primary tumor location, and the interaction between 177Lu-DOTATATE doses received (zero, 1–2, 3–4) and CS. A total of 91 patients and 31 patients received 3–4 doses and zero doses of 177Lu-DOTATATE, respectively. On multivariable analysis, in patients treated with 3–4 doses of 177Lu-DOTATATE, for each 1-point increase in CS, the estimated hazard ratio (HR) for PFS was 2.0 (95% CI 1.61–2.48). On multivariable analysis, in patients who received zero doses of 177Lu-DOTATATE, for each 1-point increase in CS, the estimated HR for PFS was 1.22 (95% CI 0.91–1.65). Among patients treated with 3–4 doses of 177Lu-DOTATATE, those with lower CS experienced improved PFS with the treatment compared to patients with higher CS. This PFS difference, based upon CS, was not observed in patients who did not receive 177Lu-DOTATATE, suggesting the predictive utility of the score.

58 Background: In the phase 2 CheckMate 142 trial, NIVO + low-dose IPI had robust, durable clinical benefit and was well tolerated as 1L therapy for MSI-H/dMMR mCRC (median follow-up, 29.0 months [range, 24.2–33.7]) (Lenz et al. J Clin Oncol 2020;38:Abstract 4040; NCT02060188). Objective response rate (ORR) per investigator (INV) was achieved in 69% of pts (95% CI, 53–82); progressive disease rate was 13%. Median progression-free survival (PFS) and overall survival (OS) were not reached. Median duration of treatment was 19.1 months (95% CI, 11.1–29.0). Grade 3–4 treatment-related adverse events (TRAEs) occurred in 22% of pts. We present the post hoc subgroup analyses of efficacy and safety outcomes in pts from the same follow-up based on demographics and baseline disease characteristics. Methods: Pts with MSI-H/dMMR mCRC and no prior treatment for metastatic disease received NIVO 3 mg/kg Q2W + low-dose IPI 1 mg/kg Q6W until disease progression or discontinuation. ORR (primary endpoint, RECIST v1.1) and PFS were assessed per INV. Post hoc subgroup analyses of efficacy (by ECOG performance status [PS], stage at initial diagnosis, primary tumor location, and BRAF/KRAS mutation status) and safety (by age and ECOG PS) are presented. Results: Among 45 treated pts, efficacy (Table) and safety were generally consistent across evaluated subgroups. ORR was similar in pt subgroups by BRAF/ KRAS mutation status, stage at initial diagnosis, primary tumor location, and ECOG PS (Table). Median PFS and OS were not reached (NR) in evaluated subgroups after a minimum follow-up of 24.2 months (Table). Incidence of grade 3–4 TRAEs for subgroups by age and ECOG PS were consistent with the overall population. Conclusions: NIVO + low-dose IPI demonstrated robust, durable clinical benefit; was well tolerated with 2-year follow-up; and was consistent in evaluated subgroups in 1L MSI-H/dMMR mCRC. Clinical trial information: NCT02060188. [Table: see text]

Metastatic (and locally advanced) pancreatic adenocarcinoma (mPDA) represents a major challenge for the oncology community given the rising mortality burden from the disease and the preponderance of patients diagnosed with unresectable disease. Although systemic therapies have become more potent with the development of fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine plus nab-paclitaxel as first-line treatments, the median overall survival for patients treated with either of these regimens remains just above 1 year. A significant need exists to build upon the effectiveness of first-line regimens, incorporate tolerable maintenance treatments, and add effective later-line options for patients with this disease. We believe every newly diagnosed mPDA patient should undergo next-generation sequencing (NGS) testing, preferably from tumor tissue, to assess for the presence of DNA damage repair (DDR) defects, microsatellite instability, and other possible actionable molecular alterations (such as neurotrophic tropomysin receptor kinase (NTRK) fusions, anaplastic lymphoma kinase (ALK) rearrangements, or human epidermal growth factor receptor 2 (HER2) amplification). Existing clinical data suggests that patients, whose tumors harbor DDR defects, benefit from treatment with platinum-based chemotherapy and poly (ADP-ribose) polymerase (PARP) inhibitors. Preclinically, inhibitors of other critical players in DDR such as ataxia-telangiectasia and Rad3 related (ATR), ataxia-telangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK), and WEE1 have demonstrated promising anti-tumor activity in PDA cell lines and xenografts. How to move forward the preclinical promise of these newer DDR-targeting therapies into rational clinical trial combinations and sequence PARP inhibitors in relation to platinum chemotherapy remain areas of tremendous clinical research interest. We believe clinical trials should be considered early for mPDA patients, in all treatment lines, so that novel therapies may be added to the treatment armamentarium for patients with this disease. Beyond NGS testing from tumor tissue, we believe it is important to consider germline genetic testing for all patients diagnosed with PDA given recent data suggesting a much stronger hereditary component of the disease than previously understood, and the potential screening implications for family members.

Objectives Heat shock protein 90 regulates multiple signaling proteins involved in key pathways of pancreatic cancer pathogenesis. Ganetespib binds to heat shock protein 90 and interferes with its binding to client proteins thus leading to inactivation and degradation of the signaling proteins that promote cancer progression. This phase II study was designed to evaluate the efficacy of ganetespib in patients with refractory metastatic pancreatic cancer (rMPC). Methods Patients with rMPC received 175 mg/m ganetespib intravenously once weekly for 3 weeks in 4-week cycles. Primary endpoint was disease control rate at 8 weeks, with a goal of 70%. Secondary endpoints were progression-free survival, overall survival, and safety. Simon's 2-stage design was used to assess futility and efficacy. Ganetespib was considered inactive if ≤8 patients among the first 15 treated had disease control after 8 weeks of treatment. Results Fourteen patients were treated on study. Grade 3 treatment-related toxicities were diarrhea, abdominal pain, fatigue, nausea, vomiting, and hyponatremia. Disease control rate at 8 weeks was 28.6%, and median progression-free survival and overall survival were 1.58 months and 4.57 months, respectively. Early stopping rules for lack of clinical efficacy led to study closure. Conclusions Single-agent ganetespib was tolerable with only modest disease control in rMPC. This disease is resistant to chemotherapy, and given the emerging data in lung and rectal cancers, as well as in pancreatic cancer cell lines, suggesting improved activity of ganetespib in combination with cytotoxic agents, studies combining this agent with chemotherapy in rMPC are more likely to yield success.

Pancreatic adenocarcinoma remains a major therapeutic challenge, as the poor (

Objectives The programmed death 1 (PD-1) pathway is upregulated in the immune microenvironment of many cancers. In this study, we examined the PD-1 pathway and the immune microenvironment of small intestinal adenocarcinomas by immunohistochemistry. Methods From our department pathology archives we identified 42 small intestinal adenocarcinomas from between 2000 and 2015, with blocks available for IHC studies. Tumors were immunohistochemically stained for CD3, CD4, CD8, CD20, PD-1, and programmed death ligand 1 (PD-L1) expression. Results PD-1 was expressed by intratumoral and peritumoral lymphocytes in 35 of 42 (83%) cases. PD-L1 expression on tumor cells and immune cells was observed in seven of 42 (17%), and 18 of 42 (43%) cases, respectively. PD-L1 was mainly expressed by histiocytes capping cancerous glands/nests at the invasive front or by most tumor cells in medullary carcinomas. All the PD-L1+ tumors also expressed PD-1. The tumors expressing PD-L1 contained more CD3+, CD4+, and CD8+ T cells, but showed a lower CD4+/CD8+ ratio than those without expression of PD-L1. Conclusions PD-1 and PD-L1 are highly expressed by most small intestinal adenocarcinomas. Blockage of the PD-1 pathway should be evaluated in the treatment of small intestinal adenocarcinomas.

Lessons Learned This trial evaluating a novel plant extract, PBI-05204, did not meet its primary endpoint of overall survival but did show signals of efficacy in heavily pretreated mPDA. PBI-05204 was generally well tolerated, with the most common side effects related to treatment being vomiting (23.7%), nausea (18.4%), decreased appetite (18.4%), and diarrhea (15.8%). Additional trials are needed to explore the role of PBI-05204 in cancer treatment. Background Survival for metastatic pancreatic ductal adenocarcinoma (mPDA) is dismal, and novel agents are needed. PBI-05204 is a modified supercritical carbon dioxide extract of Nerium oleander leaves. Oleandrin, the extract's major cytotoxic component, is a cardiac glycoside that has demonstrated antitumor activity in various tumor cell lines with a mechanism involving inhibition of Akt phosphorylation and through downregulation of mTOR. Methods A phase II, single-arm, open-label study to determine the efficacy of PBI-05204 in patients with refractory mPDA therapy was conducted. The primary endpoint was overall survival (OS), with the hypothesis that 50% of patients would be alive at 4.5 months. Secondary objectives included safety, progression-free survival (PFS), and overall response rate. Patients received oral PBI-05204 daily until progressive disease (PD), unacceptable toxicity, or patient withdrawal. Radiographic response was assessed every two cycles. Results Forty-two patients were enrolled, and 38 were analyzed. Ten patients were alive at 4.5 months (26.3%) with a median PFS of 56 days. One objective response (2.6%) was observed for 162 days. Grade ≥ 3 treatment-emergent adverse events occurred in 63.2% of patients with the most common being fatigue, vomiting, nausea, decreased appetite, and diarrhea. Conclusion PBI-05204 did not meet its primary endpoint for OS in this study. Recent preclinical data indicate a role for PBI-05204 against glioblastoma multiforme when combined with chemotherapy and radiotherapy. A randomized phase II trial is currently being designed.

11 Background: In the phase 2 CheckMate 142 trial, nivolumab plus low-dose ipilimumab provided robust and durable clinical benefit and was well tolerated as first-line therapy for microsatellite instability-high/DNA mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) (Lenz et al. Ann Oncol 2018;29:LBA18). Longer follow-up data will be presented. Methods: Patients with MSI-H/dMMR mCRC and no prior treatment for metastatic disease received nivolumab 3 mg/kg every 2 weeks plus low-dose ipilimumab 1 mg/kg every 6 weeks until disease progression or discontinuation. The primary endpoint was investigator-assessed objective response rate (ORR). Results: For all 45 patients (median follow-up was 13.8 months), ORR was 60% (95% CI 44.3–74.3). Responses were consistent with the overall population across subgroups including age, Eastern Cooperative Oncology Group (ECOG) performance status, prior adjuvant/neoadjuvant therapy, and mutation status (Table). Seven patients (16%) had grade 3–4 treatment-related adverse events; 3 (7%) had any grade treatment-related adverse events leading to discontinuation. Updated response, survival, and safety data after a longer follow-up (median 19.9 months) will be presented. Conclusions: Nivolumab plus low-dose ipilimumab demonstrated robust and durable clinical benefit and was well tolerated. Evaluated subgroups had responses consistent with the overall population. Nivolumab plus low-dose ipilimumab may represent a new first-line treatment option for patients with MSI-H/dMMR mCRC. Clinical trial information: NCT02060188. [Table: see text]

Purpose: The RAS/RAF/MEK/ERK signaling pathway is critical to the development of colorectal cancers, and KRAS, NRAS, and BRAF mutations foster resistance to radiation. We performed a phase I trial to determine the safety of trametinib, a potent MEK1/2 inhibitor, with 5-fluorouracil (5-FU) chemoradiation therapy (CRT) in patients with locally advanced rectal cancer (LARC). Patients and Methods: Patients with stage II/III rectal cancer were enrolled on a phase I study with 3+3 study design, with an expansion cohort of 9 patients at the MTD. Following a 5-day trametinib lead-in, with pre- and posttreatment tumor biopsies, patients received trametinib and CRT, surgery, and adjuvant chemotherapy. Trametinib was given orally daily at 3 dose levels: 0.5 mg, 1 mg, and 2 mg. CRT consisted of infusional 5-FU 225 mg/m2/day and radiation dose of 28 daily fractions of 1.8 Gy (total 50.4 Gy). The primary endpoint was to identify the MTD and recommended phase II dose. IHC staining for phosphorylated ERK (pERK) and genomic profiling was performed on the tumor samples. Results: Patients were enrolled to all dose levels, and 18 patients were evaluable for toxicities and responses. Treatment was well tolerated, and there was one dose-limiting toxicity of diarrhea, which was attributed to CRT rather than trametinib. At the 2 mg dose level, 25% had pathologic complete response. IHC staining confirmed dose-dependent decrease in pERK with increasing trametinib doses. Conclusions: The combination of trametinib with 5-FU CRT is safe and well tolerated, and may warrant additional study in a phase II trial, perhaps in a RAS/RAF-mutant selected population.

Purpose: This two-part phase Ib trial determined the maximum tolerated dose (MTD) of the combination of trifluridine/tipiracil (FTD/TPI) and irinotecan in patients with advanced gastrointestinal tumors, and evaluated the safety, pharmacokinetics, and antitumor activity of the FTD/TPI, irinotecan, and bevacizumab triplet combination in previously treated metastatic colorectal cancer (mCRC). Patients and Methods: Dose escalation (3+3 design) in advanced gastrointestinal tumors was followed by expansion in mCRC. During dose escalation, patients received FTD/TPI (20–35 mg/m2 twice daily; days 1–5 of a 14-day cycle) and irinotecan (120–180 mg/m2; day 1). During expansion, the MTD of FTD/TPI and irinotecan plus bevacizumab (5 mg/kg; day 1) was administered. Results: Fifty patients (26 across six dose-escalation cohorts and 24 in the expansion phase) were enrolled. Two dose-limiting toxicities (fatigue and neutropenia) were observed in the dose-escalation phase, and MTD was defined as FTD/TPI 25 mg/m2 twice daily plus irinotecan 180 mg/m2. In the expansion phase, 83% (20/24) experienced any-cause grade ≥3 adverse events (AEs) with the triplet combination, most frequently neutropenia (42%), leukopenia (25%), and diarrhea (12%). AEs of any-cause led to dosing interruptions, modifications, and discontinuations in 29%, 17%, and 4% of patients, respectively. No treatment-related deaths occurred. Three patients (12%) experienced partial responses and 16 (67%) patients had stable disease lasting >4 months. The median progression-free survival was 7.9 months (95% confidence interval, 5.1–13.4 months). Conclusions: Tolerability and activity observed in this phase I trial support further investigation of the FTD/TPI–irinotecan–bevacizumab combination in previously treated mCRC.

3521 Background: In the phase 2 CheckMate 142 trial, NIVO + low-dose IPI provided robust and durable clinical benefit and was well tolerated as 1L therapy for MSI-H/dMMR mCRC (Lenz et al. Ann Oncol 2018;29:LBA18). Longer follow-up data will be presented. Methods: Patients with MSI-H/dMMR mCRC and no prior treatment for metastatic disease received NIVO 3 mg/kg every 2 weeks + low-dose IPI 1 mg/kg every 6 weeks until disease progression or discontinuation. The primary endpoint was investigator-assessed objective response rate (ORR). Results: For all 45 patients (median follow-up was 13.8 months), ORR was 60% (95% CI 44.3–74.3). Responses were consistent with the overall population across subgroups including age, Eastern Cooperative Oncology Group (ECOG) performance status, prior adjuvant/neoadjuvant therapy, and mutation status (Table). Seven patients (16%) had grade 3–4 treatment-related adverse events (TRAEs); 3 (7%) had any grade TRAEs leading to discontinuation. Updated response, survival, and safety data after a longer follow-up (median 19.9 months) will be presented. Conclusions: NIVO + low-dose IPI demonstrated robust and durable clinical benefit and was well tolerated. Evaluated subgroups had responses consistent with the overall population. NIVO + low-dose IPI may represent a new 1L treatment option for patients with MSI-H/dMMR mCRC. Clinical trial information: NCT02060188. [Table: see text]

363 Background: Despite the benefit of PRRT for patients with WD NETs, questions remain regarding sequencing and optimal patient selection for the treatment. We developed a CS at Vanderbilt Ingram Cancer Center (VICC) that we hoped would predict outcomes for patients with WD NETs receiving PRRT. Methods: Patients with progressive WD NETs (N = 146) under consideration for PRRT with Lu 177-dotatate between 3/1/2016-3/17/2020 at VICC (N = 122) and Rush Medical Center (RMC) (N = 24) were scored. The CS included 5 categories: available non-PRRT treatments for tumor type, prior systemic treatments, patient symptoms, tumor burden in critical organs and peritoneal carcinomatosis presence. All categories were scored from 0-2 except the peritoneal carcinomatosis category which was scored from 0-1; scoring criteria were determined by the VICC NET tumor board. All patients at VICC were prospectively scored, while patients from RMC were scored retrospectively with the investigator blinded to patient outcomes. The primary outcome, progression-free survival (PFS) was estimated by the Kaplan‐Meier method; a Cox proportional‐hazards model adjusting primary tumor site, tumor grade and number of PRRT doses administered (none, 1-2 doses or 3-4 doses) was used to analyze effect of CS. Results: Median patient age was 62.7 while median CS was 5 (range 1-8); the most common primary tumor sites were small intestinal (N = 81) and pancreatic (N = 37). A total of 101 patients and 31 patients received 3-4 doses and no doses of PRRT, respectively. On multivariable analysis, in patients treated with 3-4 doses of PRRT, for each 2-point increase in CS, the estimated hazard ratio (HR) for PFS was 3.26 (95% confidence interval (CI) 2.05-5.19). On multivariable analysis, in patients who received no doses of PRRT, for each 2-point increase in CS, the estimated HR for PFS was 1.37 (95% CI .78-2.41). Conclusions: Among patients treated with 3-4 doses PRRT, those with lower CS had better PFS with the treatment compared to patients with higher CS. This PFS difference, based upon CS, was not observed in patients who did not receive PRRT, suggesting the predictive utility of the CS for patients with WD NETs receiving PRRT with Lu 177-dotatate. Though the CS needs to be validated, it is the first of its kind reported.

Background: Gln metabolism plays a critical role in cancer. In CRC, the epidermal growth factor receptor (EGFR) and Gln cooperate to provide signal transduction and fuel for mitogen activated protein kinase-dependent cell growth. Our preclinical data illustrate that Gln abrogates EGFR inhibition and blockade of Gln metabolism restores EGFR sensitivity, forming the basis of a phase I/II clinical trial exploring dual EGFR and Gln metabolism in mCRC (NCT03263429). As a biomarker correlate, we are performing dual tracer PET imaging of Gln flux (11C-Gln) and Gln to glutamate conversion (18F-FSPG). We hypothesize that tumors dependent on Gln will exhibit high 11C-Gln uptake at baseline, while inhibition of Gln metabolism will reduce 18F-FSPG uptake. Notably, this is the first-in-human study with 11C-Gln. Methods: Adult patients (pts) with previously treated anti-EGFR, RAS WT, mCRC are enrolling and receive panitumumab (6 mg/kg Day 1 and 15) and CB-839 (800 mg twice daily) in 28-day treatment cycles. 11C-Gln and 18F-FSPG scans are performed at baseline and Cycle 1 Day 28. Lesion to blood pool ratio (LBR) is calculated for each target lesion and compared with change in tumor size as measured by RECIST 1.1 after 2 cycles of therapy. Results: The study is ongoing. To date, we have collected pre- and post-therapy PET data on 4 pts; individual lesion data for 2 pts are presented in the table. A mixed response with 11C-Gln uptake was observed for Pt #1, which could reflect different underlying lesion pathology; varying degree of lesion size change was also observed in this patient. The greatest decrease in 18F-FSPG uptake corresponded to the lesion with the smallest growth. For Pt #2, 11C-Gln uptake at baseline was highest in the lesion with the largest decrease in tumor size at Day 56; 18F-FSPG uptake was greatly reduced in all lesions, which corresponded to decreases in tumor size. Best overall response was progressive disease and partial response for Pt #1 and #2, respectively. Gln PET as a function of lesion response11C-Gln18F-FSPG% Change in lesion size at Day 56Baseline LBRDay 28 LBR% ChangeBaseline LBRDay 28 LBR% ChangePatient#1L lung nodule+44%2.171.93-11.1%2.001.06-47.0%Posterior hepatic lobe+6%5.404.27-20.9%6.422.84-55.8%Segment IVA liver+107%5.114.88-4.5%5.583.90-30.1%Adrenal mass+152%3.504.4727.7%2.862.84-0.7%Patient#2R infrahilar pulmonary metastasis-15%2.471.74-29.6%3.131.72-45.0%L pulmonary metastasis-15%0.750.784.0%0.960.82-14.6%Hepatic Metastasis #1-100%8.976.81-24.1%7.003.50-50.0% Conclusions: Quantitative biomarkers that predict response early in the course of therapy are a means to achieve the promise of precision medicine. Our preliminary clinical imaging data suggest that the employed investigational PET molecular imaging tracers have potential for prioritizing patients for combined EGFR/Gln targeted therapy and to predict response early in the treatment course. Additional PET data for all pts and summary statistics will be presented. Citation Format: Jennifer Gray Whisenant, Gary Smith, Allison Cohen, Kristen K. Ciombor, Dana Cardin, Cathy Eng, Laura Goff, Satya Das, Tiffany Hickman, Anna Fisher, Adria Payne, Robert Coffey, G. Dan Ayers, Jordan D. Berlin, H. Charles Manning. Molecular imaging of glutamine (Gln) metabolism in RAS wildtype (WT) metastatic colorectal cancer (mCRC) [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 4260.

Preclinical studies have shown synergy between everolimus, an mTOR inhibitor, radiation, and platinum agents. We conducted a phase IB trial to determine the recommended phase II dose of everolimus with carboplatin and radiation.Patients with stage II/III esophageal cancer were enrolled. Following 2 cycles of Capecitabine/Oxaliplatin (XELOX), patients with no disease progression, received 50.4 Gy in 28 fractions and concurrent weekly carboplatin (area under the curve=2), with escalating doses of everolimus. A standard 3+3 dose escalation design was used.Nineteen patients were enrolled. Two patients were screen failures and 4 were removed due to poor tolerance to XELOX (n=2) or disease progression (n=2). All treated patients had adenocarcinoma. Median age was 58 (44 to 71 y) and 85% were male patients. One patient at dose level 1 was replaced due to ongoing anxiety. One of 6 patients had a dose-limiting toxicity of bowel ischemia that was fatal. At dose level 2, two of 6 patients had a dose-limiting toxicity (fever with neutropenia and nausea). The recommended phase II dose of everolimus was 2.5 mg QOD. Grade ≥3 toxicities included lymphopenia (11%), nausea (10%), low white blood cell (8.0%) vomiting (5.5%), decreased neutrophils (4.0%). All patients achieved an R0 resection with a pathologic response rate of 40% and a pathologic complete response (ypCR) rate of 23%. The 2-year progression-free survival and overall survival were 50% and 49.6%, respectively.The recommended phase II dose of everolimus with concurrent weekly carboplatin and radiation is 2.5 mg QOD.

4040 Background: In the phase 2 CheckMate 142 trial, NIVO + low-dose IPI had robust, durable clinical benefit and was well tolerated as 1L therapy for MSI-H/dMMR mCRC (median follow-up 13.8 months [mo; range, 9–19]; Lenz et al. Ann Oncol 2018;29:LBA18). Longer follow-up is presented here. Methods: Patients (pts) with MSI-H/dMMR mCRC and no prior treatment for metastatic disease received NIVO 3 mg/kg Q2W + low-dose IPI 1 mg/kg Q6W until disease progression or discontinuation. The primary endpoint was investigator-assessed (INV) objective response rate (ORR) per RECIST v1.1. Results: In 45 pts with median follow-up of 29.0 mo, ORR (95% CI) increased to 69% (53–82) (Table) from 60% (44.3–74.3); complete response (CR) rate increased to 13% from 7%. The concordance rate of INV and blinded independent central review was 89%. Median duration of response (DOR) was not reached (Table). Median progression-free survival (PFS) and overall survival (OS) were not reached, and 24-mo rates were 74% and 79%, respectively (Table). Nineteen pts discontinued study treatment without subsequent therapy. An analysis of tumor response post discontinuation will be presented. Ten (22%) pts had grade 3–4 treatment-related adverse events (TRAEs); 3 (7%) had grade 3–4 TRAEs leading to discontinuation. Conclusions: NIVO + low-dose IPI continued to show robust, durable clinical benefit with a deepening of response, and was well tolerated with no new safety signals identified with longer follow-up. NIVO + low-dose IPI may represent a new 1L therapy option for pts with MSI-H/dMMR mCRC. Clinical trial information: NTC02060188 . [Table: see text]

Managing patients with metastatic pancreatic adenocarcinoma (mPDA) is a challenging proposition for any treating oncologist. Although the potency of first-line therapies has improved with the approvals of FOLFIRINOX and gemcitabine plus nab-paclitaxel, many patients are unable to derive significant benefit from later lines of therapy upon progression. Enrollment on clinical trials remains among the best options for patients with mPDA in all lines of therapy. At our institution, we routinely check for microsatellite instability (MSI-H) and perform next-generation sequencing (NGS) at the time of diagnosis in all good performance status mPDA patients. Although MSI-H status is only found in 1% of patients with mPDA, given pembrolizumab’s tissue-agnostic approval for MSI-H tumors in later-line settings, it is a viable option when deciding on subsequent lines of therapy. Any use of immune therapy in mPDA is investigational outside the MSI-H setting. NGS can identify BRCA or other DNA damage response (DDR) defects in patients which can predict sensitivity to platinum-based therapies and influence choice of both initial and later lines of therapy. It can also identify rare actionable genomic alterations such as HER2 (2%) and TRK fusions (0.1%) and offer patients the option of enrollment on clinical trials with agents targeting these or other identified alterations. We believe enrolling mPDA patients on clinical trials with immune-modulating agents is critical to determine if there are other patient subsets, outside of the MSI-H setting, who would benefit from these approaches. Immunotherapy’s general tolerability and potential to generate durable responses make it particularly appealing for mPDA patients. Although single-modality immunotherapy such as checkpoint inhibitors or vaccines have not demonstrated efficacy in this disease, combinatorial strategies targeting unique aspects of PDA including the tumor micro-environment and desmoplastic stroma have shown preclinical or early-phase success. Validating these treatments with later-phase prospective studies is essential to making immunotherapy a routine component of the treatment armamentarium for mPDA patients.

Ductal adenocarcinoma and its variants account for most pancreatic malignancies. High-quality multiphase imaging can help to preoperatively distinguish between patients eligible for resection with curative intent and those with unresectable disease. Systemic therapy is used in the neoadjuvant or adjuvant pancreatic cancer setting, as well as in the management of locally advanced unresectable and metastatic disease. Clinical trials are critical for making progress in treatment of pancreatic cancer. The NCCN Guidelines for Pancreatic Adenocarcinoma focus on diagnosis and treatment with systemic therapy, radiation therapy, and surgical resection.

Pancreatic ductal adenocarcinoma is one of the deadliest solid tumor malignancies and is projected to become a leading cause of cancer-related death in coming years. Improving quality of life and survival amongst these patients will require new ideas and novel therapies in a multidisciplinary approach. This review will cover the most recent advances in the comprehensive treatment of pancreatic cancer and place them within a historical context when necessary. Treatment of all disease stages will be discussed, but the focus is on systemic therapy as novel drugs and new treatment combinations enter the clinic. This will include more aggressive chemotherapy in earlier disease stages, approved uses for immunotherapy, and targetable mutations. In addition, negative trials of importance and controversial topics will be noted.

4116 Background: Despite the therapeutic promise of ICIs for patients (pts) with some advanced malignancies, they are FDA-approved for only a few GI cancer pts. In NSCLC, melanoma and urothelial carcinoma, there is emerging data that pts who experience IRAEs while on ICIs have improved outcomes compared with pts who do not. This association in GI cancer pts has not been reported. Methods: We retrospectively analyzed outcomes for metastatic GI cancer pts receiving ICIs for FDA-approved indications (later-line MSI-H tumors, 2nd line hepatocellular carcinoma (HCC), 3rd line PD-L1+ gastric (GA)/gastroesophageal junction (GEJ) adenocarcinoma), at Vanderbilt Ingram Cancer Center, Winship Cancer Institute and Stanford Cancer Institute. Our primary aim was to compare progression-free survival (PFS) and overall survival (OS) between pts who did and did not experience IRAEs. Secondary aims were comparison of these outcomes within pts who experienced IRAEs, by initial IRAE severity (Grade (G)3/G4 vs G1/G2) (CTCAE v5.0), time-to-onset (TTO) (≤ 6 weeks (w) vs > 6 w) and management (steroids vs drug cessation vs observation). PFS and OS were determined by Kaplan-Meier (KM) analysis; KM comparisons were done by the logrank test. Results: Between 1/2015-12/2018 61 GI cancer pts with HCC (28), colorectal cancer (27) and GA/GEJ cancer (6) were treated with ICIs; median age was 63 years. The majority (59) received single-agent nivolumab or pembrolizumab while minority (2) received nivolumab and ipilimumab; median time on ICIs was 5.9 months (mos). Twenty-four pts experienced initial IRAEs (6 G3/G4, 18 G1/G2); median TTO was 3.8 mos. Pts who experienced any IRAE had improvements in PFS and OS compared to those who did not (PFS: 32.4 mos (95% confidence interval (CI), 32.4-not reached (NR)) vs 4.8 mos (95% CI, 2.9-8.7), p = 0.0001; OS: 32.4 mos (95% CI, 32.4-NR) vs 8.5 mos (95% CI, 6-NR), p = 0.0036). Among pts who experienced IRAEs, PFS and OS differences between above-specified subgroups did not meet statistical significance. Conclusions: GI cancer pts who experienced IRAEs while on ICIs had marked improvements in PFS and OS compared to those who did not, suggesting the predictive potential for IRAEs as a clinical biomarker in this population.

Background Targeting angiogenesis in advanced colorectal cancer (CRC) has been one of the many factors prolonging survival. Bevacizumab was the first agent to demonstrate this, but even after progression on bevacizumab, continued VEGF-inhibition continues to improve survival. Combining epidermal growth factor receptor monoclonal antibodies with standard frontline therapies have also improved clinical outcomes, yet the improved benefit is not observed in patients with mutant KRAS. Thus, an unmet medical need exists to develop additional therapeutic options for patients with KRAS mutant CRC. Methods Patients received the anti-angiogenic agent linifanib at the recommended phase II dose of 17.5 mg. Primary endpoint was objective response rate (ORR), with a goal of 10%. Secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Simon’s optimal two-stage design was used to assess futility. Linifanib was considered inactive if two or fewer patients among the first 30 achieved an objective response. Results Thirty patients were enrolled on study. Grade 3 treatment-related toxicities occurring in at least two patients were fatigue, hypertension, proteinuria, diarrhea, nausea, oral pain, vomiting, thrombocytopenia, and arthralgia. Although no responses were observed, 63.5% of patients achieved stable disease. The median PFS and OS were 4.7 months and 9.5 months, respectively. Stopping rules for lack of clinical efficacy led to study closure. Conclusion Despite observing zero responses, a majority of patients had stable disease and eight patients had stable disease lasting longer than 5 months. These results suggest that linifanib has some anti-tumor activity in KRAS mutant metastatic and refractory CRC.

Background and purpose This single institution phase I trial determined the maximum tolerated dose (MTD) of concurrent vorinostat and capecitabine with radiation in non-metastatic pancreatic cancer. Material and methods Twenty-one patients received escalating doses of vorinostat (100–400mg daily) during radiation. Capecitabine was given 1000mg q12 on the days of radiation. Radiation consisted of 30Gy in 10 fractions. Vorinostat dose escalation followed the standard 3+3 design. No dose escalation beyond 400mg vorinostat was planned. Diffusion-weighted (DW)-MRI pre- and post-treatment was used to evaluate in vivo tumor cellularity. Results The MTD of vorinostat was 400mg. Dose limiting toxicities occurred in one patient each at dose levels 100mg, 300mg, and 400mg: 2 gastrointestinal toxicities and one thrombocytopenia. The most common adverse events were lymphopenia (76%) and nausea (14%). The apparent diffusion coefficient (ADC) increased in most tumors. Nineteen (90%) patients had stable disease, and two (10%) had progressive disease at time of surgery. Eleven patients underwent surgical exploration with four R0 resections and one R1 resection. Median overall survival was 1.1years (95% confidence interval 0.78–1.35). Conclusions The combination of vorinostat 400mg daily M–F and capecitabine 1000mg q12 M–F with radiation (30Gy in 10 fractions) was well tolerated with encouraging median overall survival.

Colorectal cancer (CRC) is the second leading cause of cancer death in the United States, and research advances over the past 20 years have allowed us to better understand the molecular mechanisms underlying both tumorigenesis and resistance to therapy. As a result, there are a wide range of novel agents currently under development that we anticipate will enter the clinical arena within the coming years. This review seeks to discuss a spectrum of key pathways and agents that may be particularly relevant to the treatment of CRC in the near future, as well as briefly discuss some of the challenges we face in this new era of drug discovery.

Pancreas cancer is a significant cause of cancer mortality; therefore, the development of early diagnostic strategies and effective treatment is essential. Improvements in imaging technology, as well as use of biomarkers such as CA 19-9, are changing the way that pancreas cancer is diagnosed and staged. Although progress in treatment for pancreas cancer has been incremental, development of combination therapies involving both chemotherapeutic and biologic agents is ongoing. This article reviews current strategies in the diagnosis and treatment of resectable and advanced pancreas cancer.

574 Background: Epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) are approved in RAS WT mCRC; however, patients (pts) will develop resistance to these agents. Alterations in glutamine (Gln) metabolism play a critical role in cancer cell growth. In cancers such as CRC, EGFR and Gln cooperate to provide signals and fuel for mitogen activated protein kinase-dependent cell growth. Our in vitro data show that Gln abrogates EGFR inhibition, and blockade of Gln transport restores sensitivity. We also observed a greater antitumor response in vivo with EGFR mAb plus CB-839, an inhibitor of a rate-limiting enzyme of Gln metabolism, than either agent alone. We designed a phase I/II study (NCT03263429) to evaluate CB-839 + panitumumab + irinotecan in anti-EGFR refractory RAS WT mCRC. Methods: Dose escalation used a Bayesian continual reassessment method targeting a 25% toxicity probability. CB-839 (600 mg or 800 mg twice daily [BID]) were evaluated with panitumumab (6 mg/kg) and irinotecan (180 mg/m2). Irinotecan was included in phase I to establish a future phase II dose of the triplet. Prior EGFR mAb treatment (tx) was not required for phase I. Dose-limiting toxicity (DLT) was any tx-related non-hematologic ≥Gr 3 toxicity (except fatigue, rash, or elevated liver enzymes) or ≥Gr 4 hematologic toxicity during the first 28 days. Results: Nine pts have been enrolled; 2 were not evaluable for DLT and replaced. Zero DLTs were observed at dose level 1 (n = 3) or 2 (n = 4); 2 more pts are needed to confirm the maximum tolerated dose (MTD). Most frequent toxicities were anemia and hypomagnesemia (88%) and elevated alkaline phosphatase, nausea, and rash (75%), most ≤Gr 2. One of 7 evaluable pts (14%) has an ongoing partial response, and 5 pts had stable disease (SD; 71%). Three pts have been on tx > 6 months, and 3 pts with prior EGFR mAb tx achieved SD. Conclusions: Triplet combination was tolerable at full doses of each drug, and preliminary antitumor activity was observed in a majority of pts. Phase II will begin after phase I completion and will evaluate efficacy of CB-839 (800 mg BID) and panitumumab (6 mg/kg). Imaging studies using investigational PET tracers to evaluate Gln metabolism as a function of tumor response are planned. Clinical trial information: NCT03263429.

Background: FTD/TPI combines a thymidine-based nucleoside analog, FTD, and a thymidine phosphorylase inhibitor, TPI, and is approved for previously treated patients with metastatic colorectal cancer (mCRC). Preclinical results with FTD/TPI indicated additive antitumor activity with IRI. The primary objectives of this Phase I study were to determine the safety, maximum tolerated dose (MTD), and dose-limiting toxicity (DLT) of combined FTD/TPI and IRI treatment in patients with advanced GI tumors. Methods: Patients aged ≥18 years with advanced GI tumors who were refractory to ≥1 line of chemotherapy were included. Patients were excluded if they had received any prior IRI dose reductions, dose delay, or growth factor support in the first 8 weeks of treatment with IRI. Escalating doses of FTD/TPI (20, 25, 30, or 35 mg/m2/dose BID p.o.) and IRI (30-minute i.v. infusion of 120, 150, or 180 mg/m2/dose) were administered using a standard 3+3 design. FTD/TPI was given on days 1-5 of 14-day cycles; IRI on day 1 of each cycle. DLT was assessed during the first 28 days. Results: 26 patients were enrolled and assigned to 6 treatment cohorts consisting of 3-6 patients per cohort. The most common cancer types were colon (54%) and rectal (27%). All patients initiated treatment but 3 patients were not evaluable for DLT (2 patients had disease-related complications and 1 was ineligible). The majority (65%) of patients had received ≥4 lines of prior systemic therapies and 25/26 patients initiated cycle 3. Two patients in the dose-escalation phase were IRI-naïve. Mean relative dose intensities (ratio to planned) for FTD/TPI and IRI during the first 2 cycles were 92% and 93%, respectively. Two DLTs (grade 3 fatigue and grade 2 neutropenia resulting in a >2-week delay to cycle 3) were observed in the FTD/TPI 30 mg/m2 and IRI 180 mg/m2 cohort. Thus, the MTD was FTD/TPI 25 mg/m2 and IRI 180 mg/m2. Based on a data cut-off point for the dose-escalation phase (March 22, 2016), grade ≥3 adverse events were reported in 15 patients (58%); the most common were fatigue (15%), nausea (11%), and vomiting (11%). Of 25 patients (data missing for 1 patient due to early discontinuation), the most common laboratory abnormalities that worsened from baseline were leukocytes (28%), neutrophils (24%), lymphocytes (20%), hemoglobin (16%), and hypokalemia (12%). Conclusions: In patients with advanced GI tumors, the safety findings of FTD/TPI in combination with IRI were consistent with the existing safety profiles of these drugs. The MTD was declared as FTD/TPI 25 mg/m2 and IRI 180 mg/m2. Further safety, pharmacokinetic, and efficacy (with bevacizumab) analyses in patients with mCRC are complete and will be presented at a later date. Citation Format: Anna M. Varghese, Dana B. Cardin, Jon Hersch, Al B. Benson, Howard S. Hochster, Robert Winkler, Fabio Benedetti, Kensuke Hamada, Jordan D. Berlin, Leonard Saltz. A phase I dose escalation study of trifluridine and tipiracil (FTD/TPI) in combination with irinotecan (IRI) in patients with advanced gastrointestinal (GI) tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT062.

TPS3616Background: Irinotecan plus panitumumab is active in RAS WT metastatic CRC (mCRC) patients who progress on 5-FU based regimens. Inevitably, patients develop resistance to EGFR inhibition; on...

3546Background: FTD/TPI is an oral antineoplastic agent that was developed to overcome resistance to fluoropyrimidines. FTD/TPI is approved for use in previously treated patients with mCRC. This Ph...

e15607 Background: Preclinical studies have shown synergy between everolimus, an mTOR inhibitor, radiation and platinum agents in EC. We conducted a multi-institutional phase IB trial to determine the recommended phase II dose (RP2D) of concurrent everolimus with carboplatin and radiation in non-metastatic EC pts. Methods: Patients with untreated, localized EC and ECOG performance status 0-1 were eligible. Following two cycles of induction Capecitabine/Oxaliplatin (XELOX), pts without evidence of disease progression, received concurrent chemoradiation (total dose: 50.4Gy in 28 fractions), weekly carboplatin (AUC = 2), and escalating doses of everolimus. A standard 3+3 dose escalation design was used. Results: Nineteen patients were enrolled. There were two screen failures (thrombocytopenia, metastases) and 4 pts were removed due to poor tolerance of XELOX (2 pts) or disease progression (2 pts). A total of 13 pts with stage II/III (6/7) EC completed concurrent therapy. Median age 58 (44-71yrs), 85% males; all had adenocarcinoma deemed resectable. One pt at dose level 1 (2.5 mg/QOD), was replaced due to ongoing anxiety. One of 6 pts had a DLT (bowel ischemia). At dose level 2 (2.5mg/QD), 2 out of 6 patients had a DLT (fever with neutropenia and nausea). The RP2D of everolimus was 2.5 mg QOD. Clinically relevant ≥ grade 3 toxicities included lymphopenia (25%), dehydration (12%), fatigue, leukopenia, hyponatremia, abdominal pain, vomiting (each 6%). R0 resection was achieved in 100%; a pathologic response rate (RR) of 40% and a pathologic complete response (pCR) rate of 23% were observed. The 2-year PFS and OS were 50% and 49.6% respectively. Conclusions: The RP2D of everolimus with concurrent weekly carboplatin and radiation is 2.5 mg QOD. Despite the 100% R0 resection rate, the pCR and OS rates were within the expected historical controls. (The study was funded by Novartis Pharmaceuticals) Clinical trial information: NCT01490749.

4122 Background: Although level 1 data supports the use of adjuvant chemotherapy (ACT) in resected pancreatic adenocarcinoma (PDAC), the role of adjuvant chemoradiation (ACRT) remains controversial. The objective of this study is to investigate the impact of adding ACRT to ACT on overall survival (OS), based on lymph node (LN) and margin status. Methods: Resected AJCC Stage I and II PDAC patients from 2004-2013 identified within the National Cancer Database were classified into groups based on treatment: surgery alone (SX), ACT alone, ACT+ACRT, and ACRT only. Kaplan-Meier analyses were performed to determine median OS. Multivariable (MV) Cox regression models with interactions of treatment with LN and margin status were constructed to examine the independent effects of ACT and ACT+ACRT in these subgroups. Results: Of 31,348 patients, 30% were treated with SX, 30% with ACT, 38% with ACT+ACRT, and 2% with ACRT alone. Median OS (mos.) for ACT (22.5, 95% CI 21.9-23.1) and ACT+ACRT (23.7, 23.3-24.2) were significantly longer than SX (14, 13.4-14.5) or ACRT (11.2, 9.8-12.9). MV analysis confirmed a significant OS benefit of both ACT and ACT+ACRT controlling for patient and tumor related factors. ACRT+ACT was associated with improved OS compared to ACT in patients with positive margins and/or LN. Those with negative margins and LN did not benefit from the additional use of ACRT (Table). Conclusions: This large hospital-based study demonstrates that ACT and ACRT are associated with improved OS when compared to SX. The addition of ACRT to ACT, however, was only beneficial in high-risk patients with positive margins and/or LN. ACT+ACRT in patients with both margin and LN negative disease may not be warranted. Future clinical trials should stratify patients based on LN and margin status in order to determine which patients are most likely to benefit from the use of ACRT. [Table: see text]

Importance KRASmutations are common in pancreatic cancer, but directly targeting the KRAS protein has thus far been unsuccessful. The aim of this trial was to block the MEK and PI3K/AKT pathways downstream of the KRAS protein as an alternate treatment strategy to slow cancer growth and prolong survival. This was the first cooperative group trial to evaluate this strategy using molecularly targeted oral combination therapy for the treatment of chemotherapy-refractory pancreatic cancer. Objective To compare selumetinib and MK-2206 vs modified FOLFOX (mFOLFOX) in patients with metastatic pancreatic cancer for whom gemcitabine-based therapy had failed. Design, Setting, and Participants SWOG S1115 was a randomized phase 2 clinical trial. Between September 2012 and May 2014, 137 patients with metastatic pancreatic adenocarcinoma for whom gemcitabine-based chemotherapy had failed were randomized to selumetinib plus MK-2206 or mFOLFOX. Patients were randomized in a 1:1 fashion and stratified according to duration of prior systemic therapy and presence of liver metastases. Interventions Patients received selumetinib 100 mg orally per day plus MK-2206 135 mg orally once per week or mFOLFOX (oxaliplatin, 85 mg/m2intravenous, and fluorouracil, 2400 mg/m2intravenous infusion over 46-48 hours) on days 1 and 15 of a 28-day cycle. Main Outcomes and Measures The primary end point of the study was overall survival. Secondary objectives included evaluating toxic effects, objective tumor response, and progression-free survival. Results There were 58 patients in the selumetinib plus MK-2206 (experimental) arm (60% male; median [range] age, 69 [54-88] years) and 62 patients in the mFOLFOX arm (35% male; median [range] age, 65 [34-82] years). In the experimental arm, median overall survival was shorter (3.9 vs 6.7 months; HR, 1.37; 95% CI, 0.90-2.08;P = .15), as was median progression-free survival (1.9 vs 2.0 months; HR, 1.61; 95% CI, 1.07-2.43;P = .02). One vs 5 patients had a partial response and 12 vs 14 patients had stable disease in the experimental arm vs mFOLFOX arm. Grade 3 or higher toxic effects were observed in 39 patients treated with selumetinib and MK-2206 vs 23 patients treated with mFOLFOX. More patients in the experimental arm discontinued therapy due to adverse events (13 vs 7 patients). Conclusions and Relevance Dual targeting of the MEK and PI3K/AKT pathways downstream of KRAS by selumetinib plus MK-2206 did not improve overall survival in patients with metastatic pancreatic adenocarcinoma for whom gemcitabine-based chemotherapy had failed. This was the first randomized prospective evaluation of mFOLFOX in the US population that showed comparable results to CONKO-003 and PANCREOX. Trial Registration clinicaltrials.gov Identifier:NCT01658943

TPS477 Background: In pts with LAPC, more effective systemic therapies may be associated with improved local control, delay of metastasis, and overall survival (OS). The phase III MPACT trial in pts with metastatic PC demonstrated longer OS (median, 8.7 vs 6.6 mos; HR, 0.72; P < 0.001) and an ≈ 3-fold greater shrinkage of primary tumors with nab-P + Gem vs Gem alone (−22.15% vs −7.02%), raising the possibility of improved local PC control with nab-P + Gem. LAPACT will assess the efficacy and safety of nab-P + Gem in LAPC. Methods: LAPACT will enroll treatment-naive pts (planned n ≈ 110) in the United States, Canada, and Europe with Eastern Cooperative Oncology Group performance status ≤ 1, confirmed unresectable LAPC, no distant metastases, and adequate organ function. Pts with mixed-origin tumors, any other malignancy within 5 years, peripheral neuropathy grade > 1, or clinically significant ascites are ineligible. Pts will receive nab-P 125 mg/m2 + Gem 1000 mg/m2 on days 1, 8, and 15 of each 28-day cycle. Pts without progressive disease (PD) or unacceptable toxicity after 6 cycles will receive investigator’s choice of surgery, chemoradiotherapy, or continued nab-P + Gem. If a major response is observed, surgery may occur prior to completing 6 cycles of nab-P + Gem. The primary endpoint is time to treatment failure (TTF; time from first therapy dose to discontinuation due to PD, start of a new non–protocol-defined anti-cancer therapy, or death). The study design allows for 80% power at a 1-sided α of 0.05 to detect a 30% increase over the 5.1-month median TTF observed for nab-P + Gem in the MPACT study. The secondary endpoints are disease control rate (DCR) after 6 cycles, overall response rate, progression-free survival, OS, safety, and quality of life. The exploratory endpoint is correlation of changes in circulating nucleic acids with PD and treatment response. An interim DCR analysis will occur after all pts have completed 6 cycles of nab-P + Gem, discontinued therapy due to PD, died, or started a new non–protocol-defined therapy before completing 6 cycles of therapy. Enrollment is ongoing (first pt enrolled in April 2015). Clinical trial information: NCT02301143.

TPS473 Background: Gem therapy improves outcomes in pts with resected PC. However, disease recurrence is common, prompting a need for improved regimens. nab-P + Gem was superior to Gem alone in MPACT, a phase III trial of pts with metastatic PC (mPC) for all endpoints, including overall survival (OS; median, 8.7 vs 6.6 months; hazard ratio [HR] 0.72; P < 0.001). Toxicities were manageable and consistent with prior studies. The APACT trial will compare adjuvant nab-P + Gem vs Gem alone in pts with resected PC. Methods: Pts (≈ 800) with confirmed PC (R0 or R1 resection); stage T1 - 3, N0 - 1, M0; Eastern Cooperative Oncology Group performance status ≤ 1; adequate organ function; and CA19-9 < 100 U/mL within 14 days of randomization are eligible. Pts with mixed-origin tumors; present or previous mPC; any other malignancy within 5 years of randomization; HIV or hepatitis B or C infection; or prior neoadjuvant treatment or radiotherapy for PC are ineligible. Randomization should occur once pts adequately recover from surgery but ≤ 12 weeks after surgery. Pts will receive 6 cycles of either nab-P 125 mg/m2 plus Gem 1000 mg/m2 or Gem 1000 mg/m2 on days 1, 8, and 15 of a 28-day cycle. Stratification factors are resection (R0 vs R1) and nodal (LN+ vs LN−) status and geographic region (North America vs Europe vs Australia vs Asia Pacific). Pts with > 2 dose reductions will be discontinued. The primary endpoint is independently assessed disease-free survival (DFS). Secondary endpoints are OS and safety. Quality of life and correlation of tumor heterogeneity with clinical outcome are exploratory outcomes. At least 489 DFS events from 800 pts will allow 90% power to detect an HR for DFS of 0.74 at a 2-sided significance level of 0.05. Interim analyses, 1 for safety (after 100 pts are treated for ≥ 2 cycles) and 2 for efficacy (the first for futility and the second for futility and superiority), will be performed. As of July 2015, > 400 pts were enrolled, and 80% of all activated study sites (n = 141) randomized ≥ 1 pt. Of the 674 screened pts, ≈ 25% were ineligible, mainly due to postsurgical disease recurrence identified at screening. Pt enrollment is ongoing. ClinicalTrials.gov: NCT01964430. Clinical trial information: NCT01964430.

TPS4153 Background: Adjuvant chemotherapy for resected PC has been shown to decrease recurrence and increase survival. Gem alone is a standard adjuvant therapy option. nab-P + Gem was superior to G...

4008 Background: Infusional 5-FU, oxaliplatin, leucovorin and irinotecan (FOLFIRINOX) is effective for metastatic PDAC. The tolerability and efficacy of neoadjuvant FOLFIRINOX and CRT for BLR PDAC ...

Background: Gem monotherapy after surgery improves both survival rates and disease-free survival (DFS) in patients with PC. However, disease recurrence is common, suggesting a need for improved regimens. nab-P + Gem demonstrated superior efficacy to Gem alone in a phase III metastatic PC trial, including the primary endpoint of overall survival (OS [8.7 vs 6.6 months; hazard ratio (HR) 0.72; P Trial design: Approximately 800 patients with histologically confirmed pancreatic cancer who undergo macroscopic complete resection (R0 or R1), with no evidence of metastasis, will be randomized 1:1 to receive 6 cycles of either nab-P 125 mg/m2 plus Gem 1000 mg/m2 or Gem alone 1000 mg/m2 days 1, 8, and 15 of each 28-day cycle. Other eligibility criteria include staging T1-3, N0-1, M0; ECOG PS 0 or 1; acceptable hematologic function; CA19-9 Disclosure: M.A. Tempero: Consultant or advisory role and research funding, Celgene; A. Biankin: Consultant or advisory role, Celgene; D. Goldstein: Consultant of advisory role unremunerated and research funding, Celgene; M. Moore: Consultant of advisory role and honoraria, Celgene; E.M. O'Reilly: Consultant or advisory role, Celgene; P.A. Philip: Consultant: BMS, Bayer/Onyx, SA, Curis, Lilly, Amgen, Clovis, BI, GHI, Roche, Gilead, NVS, TLOG; Honoraria: Amgen, NVS, GNE, Bayer/Onyx, Roche, SA, Celgene; Research funding: GNE, BMS, NVS, Genvec, Chugai, Nektar, Amgen, Lilly, Roche, Bayer, Incyte, SA; H. Riess: Consultant or advisory role, Celgene; L. Yung, X. Wei and B. Lu: Employment or leadership position and stock ownership, Celgene. All other authors have declared no conflicts of interest.

TPS4162^ Background: Resection is the only curative treatment for PDA. Adjuvant chemotherapy following resection is associated with improved disease-free survival (DFS), median overall survival (OS...

297 Background: Heat shock protein 90 (HSP90) regulates folding, stability and function of signaling proteins such as EGFR, IGF-1R, c-Met, ERBB4, PDGFRα and c-Ret, several of which are key pathways for MPC pathogenesis. G prevents Hsp90 binding to client proteins leading to inactivation and degradation, disrupting signaling that promotes cancer progression. This phase II study is designed to evaluate the efficacy of G in patients (pts) with refractory MPC. Methods: Pts with MPC in the 2nd or 3rd line setting, with PS 0-1, received G 175 mg/m2intravenously once weekly for 3 weeks out of a 4 week cycle. Primary endpoint was disease control rate (DCR) at 8 weeks, with a goal of 70% DCR. Secondary endpoints were response rate (RR), overall survival (OS), and safety. 43 pts were planned for initial accrual. Simon’s optimal two-stage design was used to assess 8 week DCR. G was considered inactive if 8 or fewer pts among the first 15 treated had disease control after 8 weeks of treatment (tx). Results: Seventeen pts were enrolled, and 14 received G. Median age was 65 (range 33-77), 4 female and 10 male. Eight received 1 prior line of therapy, and 6 received 2 prior lines of therapy. Grade 3 related toxicities include abdominal pain (4), fatigue (4), diarrhea (4), hyponatremia (9), nausea (1) and vomiting (1). There were no Grade 4-5 related events. DCR at 8 weeks was 21%, and OS was 2.5 months. Three pts didn’t complete tx; 1 due to disease progression after first cycle, 1 due to tx related toxicity, and 1 withdrew after 2 tx’s. Early stopping rules for lack of clinical efficacy led to study closure. Conclusions: Single agent G was tolerable with modest disease control when used as a single agent in refractory MPC. This disease is resistant to chemotherapy, and given the emerging data in both lung and breast cancer suggesting improved activity of G in combination with cytotoxic agents, studies combining this agent with chemotherapy in MPC are under development. Supported by Vanderbilt-Ingram Cancer Center CCSG (P30CA68485) and Synta. Clinical trial information: NCT01227018.

TPS4145 Background: Pancreatic cancer remains a deadly disease and despite advances in chemotherapy treatment, survival for most patients is still less than one year. Over 80% of pancreatic cancers are KRAS mutant which activates the PI3K/AKT pathway and signals downstream to mTOR leading to cell growth, proliferation and survival. Recent data has shown that blocking both the PI3K/AKT and MEK pathways simultaneously is effective in KRASmutant tumors. Our trial is a novel, molecular targeted treatment approach for patients with metastatic pancreatic cancer that has the potential to establish a new treatment paradigm. Methods: S1115 was activated in SWOG in August 2012 and is currently IRB approved at 130 institutions within SWOG and the Clinical Trials Support Unit (CTSU). Patients (performance status 0 or 1) with metastatic pancreatic cancer failing standard gemcitabine chemotherapy are randomized to MK-2206 135 mg orally weekly plus selumetinib 100 mg orally daily or mFOLFOX IV every 2 weeks. Eligibility criteria allow metastatic patients who have progressed within 6 months of receiving adjuvant gemcitabine. Patients receiving prior 5-fluorouracil (excluding radiation-sensitizing doses), capecitabine, oxaliplatin, MEK or PI3K/AKT inhibitors are not eligible. Stratification factors include duration of prior systemic therapy and presence of liver metastases. The primary endpoint of this study is overall survival (OS) in patients treated with the combination of MK-2206 and selumetinib compared with those treated with mFOLFOX. Based on previous studies, median OS in the control group is approximately 6 months. Assuming a one-sided type 1 error of 10%, 80% power, approximately 2 years of accrual and 1.5 years of follow-up, 120 eligible patients will be accrued to detect an improvement in median survival from 6 to 9 months (corresponding to a 1.5 hazard ratio). Prospective tumoral tissue collection will be undertaken. ClinicalTrials.gov Identifier: NCT01658943. Support: NCI grants CA32102 & CA38926 Clinical trial information: NCT01658943.

191 Background: The MAP kinase pathway plays a central role in PC pathogenesis. Blockade of this pathway at multiple levels using S and E is attractive mechanistically. S also targets VEGF receptors. Evidence suggests that dual blockade of both EGFR and VEGF pathways has potential for additive, if not synergistic, effects. This phase II trial was designed to evaluate the efficacy of the combination of S and E in patients (pts) with UPC. An exploratory correlative study analyzing pre-treatment serum samples using a proteomic mass-spectrometry test (VeriStrat), previously shown to correlate with outcomes in lung cancer pts treated with E or the combination of E and S, was performed to evaluate the possible clinical utility of the test in pts with UPC. Methods: Pts with UPC received S 400mg daily along with E 150mg daily as primarily second-line therapy (first-line was allowed). Primary endpoint was 8-week progression free survival (PFS) rate. Pre-treatment serum sample analysis by proteomic test was done blinded to clinical and outcome data; the endpoints were PFS and overall survival (OS). Difference between groups was assessed using log-rank p values; hazard ratios (HR) were obtained from Cox proportional hazards models. Results: Thirty-seven pts received study drugs and were included in the survival analysis. Eight-week PFS rate 0.47 (95% CI 0.32-0.67) did not meet the primary endpoint of a rate of ≥ 0.70. Thirty two pts were included in the correlative analysis. VeriStrat “Good” pts had superior PFS and OS compared to VeriStrat “Poor” pts (Table). Conclusions: This study did not meet the primary endpoint and this drug combination will not be further pursued. In this small retrospective analysis the proteomic classification was significantly associated with clinical outcomes (PFS and OS), meriting further evaluation. This will include a companion study to an ongoing phase I study evaluating gemcitabine, erlotinib and dasatinib in UPC (NCT01660971). Clinical trial information: NCT00837876. [Table: see text]