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

TPS279 Background: Amivantamab, a fully human EGFR and MET bispecific antibody, has shown clinical activity against tumors with primary activating EGFR mutations, EGFR resistance mutations, or MET pathway activation. Amivantamab has demonstrated activity in both EGFR- and MET-driven non-small cell lung cancer, with preclinical evidence demonstrating its ability to recruit immune effector cells. While two anti-EGFR antibodies are incorporated as part of the standard of care (SoC) for metastatic colorectal cancer (mCRC) patients, MET is highly expressed or amplified in subsets of mCRC and additionally plays a role in mediating resistance to anti-EGFR therapies; therefore, amivantamab may provide benefit in this setting. Methods: This open-label, multicenter, global Ph1b/2 study will assess the safety and anti-tumor activity of amivantamab as a monotherapy and characterize the safety and tolerability of amivantamab in addition to SoC chemotherapy in KRAS, NRAS, BRAF, and EGFR ectodomain wild type participants with advanced or metastatic CRC. The Ph2 amivantamab monotherapy Cohorts A and B will assess the anti-tumor activity in participants with left-sided CRC who have progressed on or after SoC fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and an anti-VEGF treatment, without (Cohort A) or with (Cohort B) prior exposure to anti-EGFR treatment. The Ph2 amivantamab monotherapy Cohort C will assess the antitumor activity in participants with right-sided CRC who have progressed on or after SoC fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and an anti-VEGF treatment, with or without an anti-EGFR treatment. The Ph1b dose confirmation cohorts (Ph1b-D and Ph1b-E) will assess the safety and confirm the recommended Ph2 combination dose (RP2CD) of amivantamab in addition to SoC chemotherapy regimens (mFOLFOX6 or FOLFIRI). Upon confirmation of the RP2CD, the Ph2 Cohorts D and E, which are distinct cohorts from Ph1b-D or Ph1b-E, will further characterize the safety, tolerability, and preliminary anti-tumor activity of amivantamab in addition to SoC mFOLFOX6 or FOLFIRI in mCRC patients who have progressed after front-line therapy. The primary objectives are to assess the anti-tumor activity of amivantamab as a monotherapy and characterize the safety of amivantamab when added to SoC chemotherapy in participants with mCRC (Ph2 cohorts), as well as to assess the RP2CD of amivantamab when added to SoC chemotherapy (Ph1b). The key secondary objectives are to characterize the safety of amivantamab as a monotherapy and to assess the anti-tumor activity of amivantamab when added to SoC chemotherapy in participants with mCRC. This study is currently enrolling (NCT05379595) as of August 2022 in 12 countries, with goal enrollment of 225 participants. Clinical trial information: NCT05379595 .

TPS263 Background: The objective of this Phase 2, open-label, multicenter study is to investigate the antitumor activity of navicixizumab monotherapy or in combination with chemotherapy in patients with advanced solid tumors (NCT05453825). Cohort A will enroll colorectal cancer (CRC) patients. Navicixizumab is a bispecific humanized monoclonal immunoglobulin G2 kappa antibody directed against human delta-like ligand 4, a critical ligand of the NOTCH pathway, and human vascular endothelial growth factor (VEGF). Aggressive CRC remains difficult to treat owing to the aberrant activation of oncogenic signaling pathways including the NOTCH pathway. Preclinical data show that co-inhibition of NOTCH and angiogenesis have superior antitumor activity compared to individual pathway inhibition. We postulate that navicixizumab will demonstrate anticancer efficacy against CRC. Methods: Eligible CRC patients will have locally advanced or metastatic disease and have received at least 2 and no more than 3 prior lines of standard therapy for metastatic disease, including an anti-VEGF monoclonal antibody. Formalin-fixed paraffin-embedded tissue from an archival or a core tumor sample must be available for biomarker analysis. Samples will be tested using Oncomap ExTra with the Xerna TME Panel where patient samples will be classified into one of four tumor microenviroment (TME) subtypes based on angiogenic and immune gene expression signatures. Up to 30 patients will be enrolled to each CRC cohort from approximately 8 sites in the US and will receive 3 mg/kg navicixizumab alone (Cohort A1) or in combination with irinotecan (180 mg/m2 on Days 1 and 15 of a 28-day cycle, Cohort A2). Patients will have radiologic tumor assessments every 8 weeks and will continue to receive treatment until disease progression per RECIST v1.1 (as assessed by the investigator), unacceptable toxicity, withdrawal of consent, another protocol-defined discontinuation criterion is met, or the sponsor terminates the study, whichever occurs first. The primary endpoints of the study are objective response rate (ORR) and progression-free survival (PFS). The historical benchmarks for this patient population are estimated at an ORR of

209 Background: Metastatic colorectal (CRC), pancreatic (PANC), and gastroesophageal cancers are the leading causes of GI cancer–related mortality (5-y survival: 15%, 3%, and 5%-6%, respectively) (ACS 2022). HLA LOH is a recurrent mechanism of immune escape observed in 15%-20% of GI cancers (Hecht R., ASCO GI 2022). The Tmod platform is a logic-gated chimeric antigen receptor (CAR) T-cell modular system, comprising a carcinoembryonic antigen (CEA)- or mesothelin (MSLN)-targeting CAR activator and a separate HLA-A*02-targeting blocker receptor. Both in vitro/in vivo, Tmod CAR T therapy kills cells with HLA-A*02 LOH (tumor) without harming cells with retained HLA-A*02 expression (normal). However, HLA-A*02 LOH can only be therapeutically exploited if patients are identifiable through a feasible and timely clinical workflow. Methods: We established a biobanking protocol (BASECAMP-1, NCT04981119) to determine whether HLA-A*02 LOH patients can be prospectively identified. Patients with CRC, PANC, or non-small cell lung cancer (NSCLC), and a high risk for incurable relapse, were screened first using a standard HLA assay. Heterozygous HLA-A*02 positive tumor samples were then assessed for LOH using a bioinformatic algorithm applied via the Tempus xT platform. Results: As of Sep 1, 2022, 83 patients were consented at 4 institutions. HLA status was obtained from 70 patients and 28 were identified as HLA-A*02:01 heterozygous (40%; expected frequency based on USA NMDP data, 27.6%). LOH results were available for 16 patients; 4 LOH-positive patients were identified (25%, 2 PANC, 2 NSCLC). The LOH assay sensitivity declines below a tumor purity of 40% (Hecht R., ASCO GI 2022). Six patients had a tumor purity of 20% (all with PANC, a tumor known for high stromal content), limiting possible LOH detection. The impact of tumor purity on LOH sensitivity was highlighted in a patient with a low initial sample tumor purity (30%) that resulted in a 41% probability of HLA-A*02:01 LOH (below positive threshold). A second sample with a higher tumor purity (70%), obtained from formalin-fixed, paraffin-embedded sections, resulted in a 92% probability of HLA-A*02:01 LOH (positive). Conclusions: BASECAMP-1 prospective identification of HLA-A*02 LOH is feasible in the real-world setting. The frequencies of the HLA-A*02 allele and of HLA-A*02 LOH in this cohort mirrored expected population frequencies. LOH results can be obtained within a clinically feasible workflow and timeframe, although samples with a < 40% tumor purity have a reduced sensitivity for LOH detection, an issue recurrently observed in patients with PANC. The BASECAMP-1 strategy enables prospective identification of appropriate patients for future therapeutic clinical trials using Tmod CEA and MSLN logic-gated CAR T cells. Clinical trial information: NCT04981119 .

59 Background: 5-Fluorouracil (5-FU) is a component of first-line treatment regimens for metastatic colorectal cancer (mCRC). Historically, 5-FU is administered as a bolus followed by an infusion. However, the bolus dose adds substantial toxicity and is often withheld in patients with limited functional status or high-risk comorbidities, but its impact on treatment outcomes remains unclear. Small studies suggest that it may be omitted. The aim of this study was to determine whether omission of the 5-FU bolus is associated with a difference in overall survival (OS). Methods: An electronic health record-derived national multicenter oncology database from Flatiron Health was queried to select patients with mCRC who received a first-line 5-FU-containing regimen. Demographics, relevant labs, treatment details, and survival outcomes were collected. Propensity score (PrS) matching and OS analysis were performed incorporating age, race, sex, ECOG score, combination drug regimen, and baseline creatinine and bilirubin. Variables with p < 0.10 in univariable Cox proportional hazards models were included in the multivariable analysis. Results: We included 9741 patients with mCRC who received 5-FU-based regimens. All individuals received a 5-FU infusion, and 7901 (81%) also received a 5-FU bolus. Among our entire cohort, 43% were female, 23% were > 70 years, 66% were white, and 89% had ECOG ≤ 1. Over a median follow-up time of 19 months, 5847 patients (60%) died. In the unmatched univariable (HR 0.94, 95% CI 0.88-1.00, p = 0.06) and multivariable (aHR 0.85, 95% CI 0.93-1.06, p = 0.85) analyses, there was no association between the use of bolus 5-FU and OS. A number of factors were associated with an increased risk of death, including older age, high ECOG scores, and elevated bilirubin or creatinine levels. Similarly, in our PrS-matched dataset (n = 6126), the use of a 5-FU bolus was not associated with OS (HR 0.98; 95% CI 0.91-1.06; p = 0.64). Conclusions: The findings of our PrS-matched multicenter cohort study indicate that, after adjusting for host and treatment factors, 5-FU bolus dosing was not associated with an overall survival benefit among patients with mCRC. These results suggest that, in mCRC, the addition of a 5-FU bolus does not appear to add efficacy to regimens utilizing infusional 5-FU. Future work is necessary to determine the role of bolus dosing in the adjuvant setting and its impact on other clinically-relevant outcomes.

TPS3635 Background: Treatment options for most patients with metastatic colorectal cancer (mCRC) are largely limited to cytotoxic chemotherapy, with little advancement in the last decade. Encouragingly, a small subset of patients deficient in mismatch repair (dMMR/MSI-hi) benefit from checkpoint inhibitors (CPI) whereas those proficient in mismatch repair (pMMR/MSS) do not. The absence of clinical benefit in patients with pMMR/MSS mCRC may relate to a lack of neoantigen-specific T cells and immune infiltration. An individualized neoantigen vaccine that induces CD8 T cells capable of tumor lysis has the potential to expand the number of patients with mCRC who may benefit from immunotherapy. Data from a Phase 1/2 study evaluating neoantigen vaccines in combination with CPIs in patients with previously treated mCRC demonstrated a 44% molecular response (MR) rate (≥50% decrease in ctDNA relative to baseline) in 4/9 patients; this correlated with improvement in OS relative to those without a MR. To further investigate neoantigen vaccines in earlier lines of treatment, a Phase 2/3 study in the1L maintenance setting in mCRC was initiated. Methods: GO-010 is a Phase 2/3, randomized, open-label, multi-center study evaluating the efficacy and safety of 2 neoantigen-containing vectors (GRT-C901-adenoviral vector plus GRT-R902-self-amplifying mRNA vector) as prime/boost in combination with CPIs as an add-on to fluoropyrimidine/bevacizumab (bev) following 1L therapy with FOLFOX/bev in patients with mCRC. During Phase 2, up to 90 patients will be randomized 1:1 to the vaccine or control arm with a primary objective of assessing efficacy by MR. During Phase 3, up to 226 patients will be randomized with a primary objective of assessing PFS per iRECIST in a blinded, independent manner. There are two stages to the study. In the vaccine production stage, while patients receive FOLFOX/bev 1L therapy, neoantigen prediction is performed using a tumor biopsy and Gritstone’s EDGE™ neoantigen prediction model. For patients in the vaccine arm the top 20 predicted neoantigens are included in the vaccine vectors. After completing oxaliplatin, patients will enter the study treatment stage. Patients in the control arm will continue with maintenance therapy whereas patients in the vaccine arm will add the vaccine regimen to maintenance therapy. The vaccine regimen consists of GRT-C901/GRT-R902 as well as SC ipilimumab (30 mg) and IV atezolizumab (1680 mg). Over the first year of treatment, 6 vaccinations will occur. Ipilimumab will be administered SC with the first doses of GRT-C901 and GRT-R902. Atezolizumab will be administered every 4 weeks for up to 2 years. Study assessments include imaging, ctDNA, safety, immunogenicity and exploratory biomarker analysis. Clinical trial information: NCT05141721.

4140 Background: Pancreatic cancer remains the third-leading cause of cancer-related death in the US. Average overall survival is only one year, and no standard therapies exist beyond second line. Chemotherapy resistance is one reason for the poor outcomes in pancreatic cancer, which can be caused by, among other factors, excess tumor expression of the glucocorticoid receptor (GR). Nonclinical and clinical data indicate that GR antagonism may enhance or restore chemotherapy sensitivity. Here, we report the interim analysis of RELIANT, a trial evaluating the efficacy and safety of relacorilant, a selective GR modulator, with nab-paclitaxel in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). Methods: RELIANT (NCT04329949) was a single-arm, open-label, multicenter study of relacorilant (100 mg QD) + nab-paclitaxel (80 mg/m2 on days 1, 8, and 15 of each 28-day cycle) in patients with histologically confirmed mPDAC. Based on tolerability, relacorilant doses were escalated up to 150 mg. Patients with 2+ prior lines of therapy, including prior gemcitabine- and fluoropyrimidine-based therapy, were enrolled. Planned enrollment was 80 patients. The study included a planned interim analysis after approximately 40 patients had completed 12 weeks of treatment or discontinued study treatment due to disease progression or toxicity. Objective response rate (ORR) by blinded independent central review was the primary endpoint. At the interim analysis, ORR was assessed by the investigator. Results: At the interim analysis, 43 heavily pretreated patients with a median age of 64 years (range: 43–78; 56% male) had been enrolled. 27/43 (63%) patients had received ≥2 prior lines of therapy (range: 2–5), and all but 3 patients had received prior treatment with nab-paclitaxel. Twelve patients (28%) did not have a post-baseline radiographic tumor assessment and were hence not efficacy evaluable. Most common reasons for discontinuation from relacorilant were disease progression (n = 16), adverse event (AE, n = 8), and patient decision (n = 9). Relacorilant + nab-paclitaxel demonstrated antitumor activity with 15/43 (35%) patients showing decreases in target lesion size, 10/43 (23%) achieving disease control for at least 12 weeks, and 17/43 (40%) having decreases in CA 19-9. Of note, one patient has been on study treatment for > 15 months. No confirmed responses by RECIST (CR or PR) were observed, and enrollment was thus stopped after the interim analysis. No new safety signals were identified. The most common AEs were fatigue, nausea, and decreased appetite. Suppression of GR target genes was also observed. Conclusions: Modest antitumor activity of relacorilant + nab-paclitaxel was observed in this heavily pretreated patient population, with a safety profile similar to that observed for relacorilant in other oncology studies. Clinical trial information: NCT04329949.

e16287 Background: Pancreatic ductal adenocarcinoma (PDA) has been refractory to therapeutic targeting of the immune microenvironment. In preclinical work, IL-1β was upregulated in PDA tumors, and in mouse models, IL-1β expression led to activation of pancreatic stellate cells and immunosuppression. We hypothesize that blockade of IL-1β and PD-1 will result in significant alterations in immune and fibroblast subsets within the PDA microenvironment. Methods: We conducted an open-label multicenter Phase Ib study evaluating gemcitabine and nab-paclitaxel with canakinumab (ACZ885), a high-affinity human anti-interleukin-1β (IL-1β) mAb, and spartalizumab (PDR001), a mAb directed against human PD-1. 10 subjects with untreated metastatic PDA and RECIST measurable disease were enrolled. The primary objective was to identify a recommended phase II/III dose by evaluating the incidence of DLTs in the first 56 days. All subjects underwent baseline and on-study tissue and blood collection for extensive exploratory correlative studies. Secondary objectives including safety and tolerability and preliminary assessment of clinical activity. Results: 10 subjects were enrolled between November 2020 and March 2021. 6 out of 10 were evaluable for the dose confirmation. In the dose confirmation analysis there were no dose limiting toxicities (DLTs) and the recommended Phase II/III dose was established as; gemcitabine (1000 mg/m2 IV) and nab-paclitaxel (125 mg/m2 IV) on day 1,8,15; canakinumab (250 mg via subcutaneous injection) and spartalizumab (400 mg IV) on day 1; of each 28 day cycle. Adverse events were consistent with those seen with chemotherapy and were predominately hematologic. A preliminary efficacy analysis confirms 1 PR and 7 pts with SD. Two of the 7 pts have been treated for 11 and 12 cycles, respectively, without progression. Activation of CD8 T cells in peripheral blood and increased serum levels of IFN-induced chemokines CXCL9/10 were observed in patient samples. Using an in vitro suppression assay, we showed that baseline serum, from patients deriving clinical benefit, could induce myeloid derived suppressor cells, but that this effect was abrogated with treatment. Single cell transcriptional profiling also revealed treatment-dependent shifts in T cell activation state and myeloid cells in the tumors of patients experiencing clinical benefit. Conclusions: In this Phase Ib study, we established the Phase II/III dose of canakinumab and spartalizumab with chemotherapy in first line metastatic PDA. Translational studies suggest putative biomarkers that may help identify responding pts. This novel combination is being evaluated in a randomized Phase II/III study through the Precision Promise clinical trial network. Clinical trial information: NCT04581343.

4136 Background: Mesothelin (MSLN) is overexpressed in 80-85% of pancreatic adenocarcinomas (PDAC). Anetumab ravtansine (AR) is a fully human anti-MSLN immunoglobulin G1 antibody conjugated to the anti-tubulin maytansinoid DM4. Through NCI-ETCTN, the North American Star Consortium conducted a phase I study to evaluate the safety/tolerability of AR in various combinations in patients (pts) with PDAC. Here, we report preliminary results of the escalation part. Methods: Pts with advanced PDAC after at least one line of treatment were included. AR was combined with nivolumab (ARM1), nivolumab/ipilimumab (ARM 2), or nivolumab plus gemcitabine (Gem) (ARM3), using an integrated biomarker analysis. Two dose levels (DL) of AR were evaluated, DL1=5.5mg/kg and DL2=6.5mg/kg (established RP2D). Key eligibility criterion was MSLN expression in >5% of tumor cells by immunohistochemistry. Pts with prior anti-PD1/anti-CTLA4 treatment were excluded but treatment with prior Gem was allowed. Mandatory blood and paired tumor samples were collected for investigation of the immune microenvironment, genomic/transcriptomic changes and for an in-depth description of AR pharmacokinetics. Results: Data cut-off date was 22/01/2022. A total of n=33 pts were enrolled, n=11 (ARM 1), n=13 (ARM 2) and n=9 (ARM3). Median age of pts was 66 (40-83), 33% of PS=0 and 66% of PS=1. Twenty-six pts (79%) had previously been exposed to Gem. Median number of prior lines of treatment was 3 (1-7). Twenty-eight patients were evaluable for DLT. Grade (G)3/4 TRAEs: 0% in ARM1DL1, 5.3% in ARM1DL2, 0% in ARM2DL1, 16.9% in ARM2DL2, 8.6% in ARM3DL1 and 19.5% in ARM3DL2. There were 2 dose-limiting toxicities in ARM2DL2, one G3 upper gastrointestinal haemorrhage, possibly related to AR, and one G3 thrombocytopenia and G3 anaemia, definitely related to AR. Ocular toxicity events were G1/2 blurred vision in 5/33 (15%) and G1 xerophthalmia in 1/33 (3%), related to both AR and anti-PD1; G2 keratitis in 1/33 (3%), related to AR only. Only G1 peripheral neuropathy was observed in 4/33 (12%) pts. Efficacy data is presented in the table. In ARM3, the range of tumor measurement (ΤΜ) change was ΔTM=–16.8% to +16.2% and 3/8 (36%) pts with SD had previously been exposed to Gem. Conclusions: Based on the observed disease control rate and acceptable toleratbility, ARM3 (both DL1 and DL2) will be tested in the expansion part. A further 20 patients will be recruited for dose confirmation and comprehensive biomarker evaluation. Pharmacokinetic/pharmacodynamic analysis is under way. Clinical trial information: NCT03816358. [Table: see text]

4023 Background: Metastatic pancreatic cancer (mPC) remains a deadly disease with very limited treatment options. FFX is a standard first-line therapy for mPC with a median overall survival (mOS) of 11.1 months. CPI-613 is a stable intermediate of a lipoate analog that inhibits pyruvate dehydrogenase and α-ketoglutarate dehydrogenase enzymes of the tricarboxylic cycle preferentially within the mitochondria of cancer cells. In a phase I study, CPI-613+mFFX was safe and exhibited promising signal of efficacy. Methods: A global, randomized phase 3 trial was conducted across 73 sites to investigate the efficacy and safety of CPI-613 in combination with mFFX compared to standard dose FFX in treatment-naïve patients with mPC. Treatment was administered in 2-weekly cycles until progression or intolerable toxicity. In the experimental arm, CPI-613 at 500 mg/m2 was given intravenously on days 1 and 3. The doses of irinotecan, oxaliplatin, and 5-fluorouracil in the experimental arm were 65 mg/m2, 140 mg/m2, and 2,400 mg/2, respectively. Primary endpoint was OS. Secondary endpoints were progression-free survival (PFS), overall response rate (ORR), duration of response, pharmacokinetics, patient reported outcomes and safety. Results: 528 patients were randomly assigned (266 in test and 262 in control arm). There were 362 deaths, with a mOS of 11.1 months for CPI-613+mFFX vs. 11.7 months for FFX [hazard ratio (HR), 0.95; 95% CI, 0.77 to 1.18; P = 0.655]; mPFS was 7.8 months vs. 8.0 months respectively [HR, 0.99; 95% CI, 0.76 to 1.29; P = 0.94]; ORR was 39% in the test arm vs. 34% in the control arm [ORR ratio, 1.23 (95% CI, 0.86 to 1.75)]. Grade ≥ 3 treatment-emergent adverse events with ≥ 10% frequency in CPI-613 plus mFFX vs. FFX arm were diarrhea (11.2% vs. 19.6%), hypokalemia (13.1% vs. 14.9%), anemia (13.9% vs. 13.6%), neutropenia (11.2% vs. 14.0%), thrombocytopenia (11.6% vs. 13.6%) and fatigue (10.8% vs. 11.5%). Conclusions: The addition of CPI-613 to mFFX failed to show significant improvements of ORR, PFS or OS. The mFFX in the test arm that had the lowest prospectively tested doses of FFX was without compromise on PFS or OS and may be considered as a reference for future FFX administration. Clinical trial information: NCT03504423.

4158 Background: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death with a 5-year survival rate of 10%. Novel strategies for advanced PDAC are a critical need. A DNA hypomethylating agent (HMA) increased tumor-infiltrating effector T cells and significantly prolonged survival in combination with immune checkpoint blockade (ICB) in a PDAC mouse model (Gonda et al 2020). We hypothesized that combining HMA with ICB will lead to therapeutic benefit in pts with advanced PDAC. Methods: This is an open-label, single-arm, single-center, Phase 2 trial of AZA plus pembro in pts with unresectable or metastatic PDAC. Pts were treated with AZA 50 mg/m2 subcutaneous daily for 5 days Q4W beginning week 1 day 1 followed by pembro 200 mg IV Q3W starting week 3 day 1. Key eligibility criteria included documented progression on or following first-line systemic treatment, ECOG PS 0-1, and adequate organ function. The primary objective was progression-free survival (PFS). Thirty-one evaluable pts were required to detect an improvement in PFS from 2 mo to 4 mo with a one-sided p-value of 0.05 and 80% power. Secondary endpoints included safety and tolerability, overall response rate (ORR), disease control rate (DCR), and overall survival (OS). Data cutoff was February 10, 2022. Results: Between Oct 2017 and Sept 2021, 36 pts were enrolled (median age 62.5, 75% white, 72% male). At data cutoff, 34 and 31 pts received at least 1 dose of AZA and pembro, respectively. Median PFS for ≥1 dose of AZA was 1.48 mo (95% CI: 1.35, 1.74) and for ≥1 dose of pembro was 1.51 mo (95% CI, 1.38, 3.42). The median OS was 4.67 months. Among the 34 pts, 3 (8.8%) experienced a partial response (PR) by RECIST with a DCR of 32.4%. Of the 3 pts with PR, 2 received 35 doses of pembro and continued beyond 2 years with an ongoing PR. One pt remains on pembro 20 months after study completion. None of the pts with a PR were microsatellite instability-high or tumor mutation burden high, and next-generation sequencing of the 3 cancers identified a BRCA1 variant and POLE variant. Treatment-related AEs (TRAEs) occurred in 20/34 pts (59%), the most common of which were diarrhea and fatigue. Grade ≥3 occurred in 7/34 (21%) including 1 immune-related grade 5 event (encephalitis). Conclusions: AZA plus pembro demonstrated a tolerable safety profile but no PFS benefit compared to historical controls. Our data suggests combined epigenetic therapy and ICB may expand therapeutic options in a subset of pts with PDAC. Further investigation is needed to identify biomarkers to predict response and elucidate effective timing, sequencing, and combination of epigenetic agents. Follow-up for OS is ongoing. Correlative analysis of epigenetic effects and characterization of the tumor immune microenvironment will be reported. Clinical trial information: NCT03264404.

Neuroendocrine tumors (NETs) describe a heterogeneous group of tumors with a wide range of morphologic, functional, and behavioral characteristics. These tumors are often indolent but they have the potential to cause symptoms through release of hormones and through local or distant spread. Pancreatic neuroendocrine tumors (pNET) represent a subset of NETs and they have a unique pattern of symptoms and disease progression. Due to the heterogeneity of this disease it is important to identify reliable markers to help guide prognosis and predict response to therapy. The recent approval of two new agents in the treatment of advanced pNET has raised additional interest in the significance of molecular markers in this disease. At the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting, several investigators reported on collaborative efforts to develop clinically useful biomarkers for this disease. Choti et al. (Abstract #4126) reported data about the functional characteristics of NETs and pNETs among a multi-institutional cohort finding that a substantial minority of patients have functional symptoms even when the disease is localized. Faggiano et al. (Abstract #1604) looked at a wide spectrum of NETs in several referral centers and reported on predictors of both short term and long term survival in this setting. Yao et al. (Abstract #4014) reported analysis of predictive biomarkers among patients in the RADIANT-2 trial which looked at the role of the mTOR inhibitor, everolimus compared to placebo in NET. Fischer et al. (Abstract #4128) looked at a novel biomarker, placental growth factor (PlGF) and evaluated the role of serum and tissue levels of this protein as a predictive marker. Finally, Khan et al. (Abstract #4123) investigated the role of circulating tumor cells in NET (and pNET) and found that this may have potential as a prognostic marker and an early marker of response to therapy. The authors review and summarize these abstracts in this article., JOP. Journal of the Pancreas, Vol 13, N° 4 (2012): July - p. 330-469