Citations

Abstract Background: Focal adhesion kinase (FAK) is consistently hyperactivated in multiple tumor types including PDAC. Our preclinical work showed that FAK and PD-1 inhibitors elicit significant tumor regression, and that combining FAK and PD-1 inhibitors with gemcitabine achieves a maximal response. This suggests the need for a cytotoxic agent to bolster antigen presentation. Defactinib is an orally available, well-tolerated, potent FAK inhibitor. Methods: This study included a dose escalation phase (all solid tumors) and dose expansion phase (metastatic PDAC). A 3+3 design with five dose levels was used in the dose escalation phase. For the expansion phase, 10 PDAC patients with stable disease on front-line gemcitabine/nab-paclitaxel were enrolled in the Maintenance cohort (A), while 10 patients who progressed on at least one line of therapy were enrolled in the Refractory cohort (B). Pre and on-treatment biopsied were collected from all PDAC patients. The primary endpoint was to determine the recommended phase 2 dose (RP2D). Secondary endpoints included safety, toxicity, objective response rate, progression-free survival (PFS) and overall survival (OS). The exploratory endpoints included developing a molecular and immune profile for treatment response. Results: In dose escalation, the common low grade (G1/2) treatment-emergent adverse events included fatigue, anorexia, nausea and vomiting. No DLTs were seen. The RP2D was defactinib 400mg twice daily, gemcitabine 1000 mg/m2 days 1, 8 and pembrolizumab 200mg day 1 of a 21-day cycle. Safety and toxicity results in the escalation cohort were reported at the 2018 ASCO Annual Meeting. Among 8 evaluable PDAC patients enrolled on the dose escalation phase, we observed 1 (13%) partial response (PR), 3 (38%) stable disease (SD), 4 (50%) progressive disease (PD). In the Maintenance cohort, 1 (10%) PR, 6 (60%) SD, and 3 (30%) PD were observed. Two patients in the Maintenance cohort remain on study, and the median time on treatment was 4.6 months. In the Refractory cohort, 5 (50%) had SD, 4 (40%) PD, 1 not evaluable; median PFS was 2.9 months and median OS was 7.6 months. Interestingly, two confirmed PR patients both have MSS disease. Paired biopsies in PDAC patients show increased proliferating CD8+ T cells, while Tregs, macrophages, and stromal density decrease with treatment. Conclusions: The combination regimen was well tolerated. Encouraging efficacy signals were observed in both Maintenance and Refractory cohorts. Updated outcomes and correlative analyses are forthcoming. Citation Format: Andrea Wang-Gillam, Robert McWilliams, A. Craig Lockhart, Benjamin R Tan, Rama Suresh, Kian-Huat Lim, Katrina S. Pedersen, Nikolaos Trikalinos, Olivia Aranha, Haeseong Park, Lee Ratner, Nicholas Boice, David G. Denardo. Phase I study of defactinib combined with pembrolizumab and gemcitabine in patients with advanced cancer: Experiences of pancreatic ductal adenocarcinoma (PDAC) patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT118.

4003 Background: Aspirin and cyclooxygenase-2 (COX-2) inhibitors have been associated with a reduced risk of colorectal polyps and cancer in observational and randomized studies. CALGB/SWOG 80702 tested the effect of celecoxib, a COX-2 inhibitor, on reducing the risk of recurrence in stage III CC. Methods: CALGB/SWOG 80702 is a 2x2 randomized controlled phase III trial of 3 v 6 months of adjuvant FOLFOX (data previously reported as part of the IDEA collaboration) with concurrent celecoxib (400 mg daily) v placebo x 3 yrs for patients (pts) with resected stage III CC. The primary endpoint of the trial is disease-free survival (DFS), defined as time from randomization to recurrence or death from any cause. The trial was designed to provide 91% power to detect a hazard ratio (HR) of 0.79 in favor of celecoxib with 2-sided alpha = 0.05 (775 events required); due to slowing accumulation of events 4 years after complete accrual, power was lowered to 85% with same HR and alpha assumptions (696 events required). The DSMB released data on February 24, 2020 at median f/u of 5.6 yrs with 689 DFS events. Results: Between June 2010 and November 2015, 2,526 pts were consented and randomized to the trial. Treatment arms were well balanced by patient and tumor prognostic features, as well as low-dose aspirin use. Baseline characteristics included 45% female, 18% non-White, 8% Hispanic, 15% T4, 26% N2. 3-yr DFS for celecoxib was 76.3% v 73.3% for placebo (HR 0.89 [95% CI 0.77-1.04]; P = 0.14). 5-yr overall survival (OS) was 83.9% for celecoxib v 81.7% for placebo (HR 0.87 [95% CI 0.72-1.05]; P = 0.14). When considering the 4 treatment arms separately, 3-yr DFS was 77.0% for 12 months FOLFOX + celecoxib, 74.9% for 12 months FOLFOX + placebo, 75.5% for 6 months FOLFOX + celecoxib, and 71.9% for 6 months FOLFOX + placebo (log rank P = 0.22; P interaction = 0.64). There were no significant differences in grade 3-4 toxicity with celecoxib v placebo. Compliance with protocol celecoxib treatment, defined as 3 yrs of therapy completion or recurrence/death while on treatment, was 58.1% pts on celecoxib and 60.2% pts on placebo. Conclusions: The addition of celecoxib to standard chemotherapy did not significantly improve DFS or OS. Clinical trial information: NCT01150045 .

Abstract Purpose: Patients with metastatic colorectal cancer refractory to chemotherapy have limited treatment options. Ensituximab (NEO-102) is a novel chimeric mAb targeting a variant of MUC5AC with specificity to colorectal cancer. Patients and Methods: Single-arm, phase II trial assessed the efficacy and safety of ensituximab in patients with advanced, refractory cancer who expressed MUC5AC antigen in tumor tissue. Ensituximab was administered intravenously every 2 weeks with 3 mg/kg as recommended phase II dose (RP2D). A minimum sample size of 43 patients was required on the basis of the assumption that ensituximab would improve median overall survival (OS) by 7 months using a one-sided significance level of 10% and 80% power. Written informed consent was obtained from all patients. Results: Sixty-three patients with advanced, refractory colorectal cancer were enrolled and 53 subjects were treated in phase II arm. Median age was 58 years and 46% of the patients were female. Among 57 evaluable patients, median OS was 6.8 months. No responses were observed, and stable disease was achieved in 21% of the patients. The most common treatment-related adverse events (AE) at RP2D included fatigue (38%), anemia (30%), nausea (15%), vomiting (11%), increased bilirubin (9%), constipation (8%), decreased appetite (6%), and diarrhea (6%). Serious AEs at least possibly related to ensituximab occurred in 4 patients and included anemia, nausea, increased bilirubin, and hypoxia. No patients discontinued treatment due to drug-related AEs. Conclusions: Ensituximab was well tolerated and demonstrated modest antitumor activity in patients with heavily pretreated refractory colorectal cancer.

Abstract Background: Targeted therapies are increasingly under evaluation in clinical trials for the treatment of biliary tract cancer (BTC), and cell-free tumor DNA assays are an emerging technology for the detection of actionable alterations. Methods: ctDNA analysis was performed in patients with BTC using the CLIA-certified Guardant360 liquid biopsy assay as part of routine clinical care. The assay screens up to 73 genes for single-nucleotide variants (SNVs), 23 for insertions or deletions (INDELs), 18 for copy number variations (CNVs), and 6 for fusions. Results: 855 samples were analyzed from 751 unique BTC patients. Median age was 64 years (range, 29-89), 53% were female, and 631 (84%) had at least one alteration in their first sample. In the 751 patients, the most common genes altered were TP53 (39%), KRAS (15%), PIK3CA (13%), ARID1A (13%), EGFR (11%), FGFR2 (11%), ERBB2 (11%), NF1 (10%), IDH1 (10%), APC (9%), BRAF (9%), MYC (8%), MET (7%), CCNE1 (7%), and FGFR1 (7%). Alterations in DNA damage response genes were also seen, including BRCA2 (6%), BRCA1 (5%), ATM (4%), and MLH1 (1%). The median number of alterations per sample was 3 (range, 0-40). In a clinically annotated dataset from the Massachusetts General Hospital Cancer Center, 112 samples were obtained from 61 unique patients. Among these, 52 (85%) had intrahepatic cholangiocarcinoma (ICC), 3 (5%) had extrahepatic cholangiocarcinoma, and 6 (10%) had gallbladder cancer. 20/61 (33%) patients were treated with targeted therapy. Among 20 patients with both ctDNA and tumor sequencing results, the targetable mutation was found in both ctDNA and tumor tissue in 7/20 (35%), solely in ctDNA in 1/20 (5%), and solely in tissue in 12/20 (60%) patients. The patient with the alteration detected solely in ctDNA had insufficient tissue for analysis; she was found to have an FGFR2 F276C mutation and benefited for 8.5 months from an FGFR inhibitor on a clinical trial. Of the 12 patients whose targetable mutation was not detected in plasma, 10 (83%) had an FGFR2 fusion, 1 had an INDEL in FGFR2 (Leu262_Ala266delinsAsp), and 1 had an FGFR3 splice site mutation. 15/20 (75%) patients treated with targeted therapy were followed with serial ctDNA analysis, and a potential resistance mechanism was identified in 5/15 (33%). All 5 patients had FGFR2-fusion positive ICC and developed mutations in the FGFR2 kinase domain as a potential resistance mechanism to FGFR inhibition, including the FGFR2 V564F gatekeeper mutation in 4/5 patients. Conclusions: In patients with BTC, ctDNA-based genomic profiling can detect alterations in IDH, FGFR, PIK3CA, ERBB2, BRAF, and MET. The technology is still evolving for the detection of FGFR2 fusions, which is hindered in capture-based methods in plasma by the large number of unique breakpoints and fusion partners. ctDNA analysis may also provide a noninvasive mechanism to study resistance to targeted therapy and clonal dynamics in BTC. Citation Format: Lipika Goyal, Robin Kate Kelley, Lesli Kiedrowski, Daniel Catenacci, Kabir Mody, Rachna Shroff, Aparna Parikh, Stephanie Reyes, Jordan R. Maurer, Ryan B. Corcoran, Paul Fanta, Mike Cusnir, Becky Nagy, Richard Lanman, Michael Morse, Benjamin Tan, Milind Javle, Andrew Zhu. Blood-based genomic profiling of cell-free tumor DNA (ctDNA) in patients with biliary tract cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A183.