Borad, Mitesh J.

3524 Background: In mCRC, induction combination chemotherapy with targeted agents is considered the mainstay of treatment. This is typically followed by maintenance therapy vs. observation which had been examined in various trials. However, it remains unclear how best optimize maintenance strategy. We aim to evaluate comparative effectiveness to support best maintenance strategy. Methods: We searched PubMed, Embase, and Cochrane CENTRAL for randomized controlled trials (RCT) evaluating different maintenance strategies in previously untreated mCRC patients (pts): observation (obs), bevacizumab (bev), fluoropyrimidine (FP), FP+bev, or continuing induction regimen (CTX). Outcomes of interest included OS and PFS. The overall effect was pooled using the DerSimonian random effects model. We conducted network meta-analysis based on White’s multivariate meta-regression to pool evidence from direct and indirect comparisons. Agents were ranked using surface under the cumulative ranking (SUCRA) probabilities. Higher SUCRA scores correspond to greater efficacy. Results: Twelve trials at low risk of bias (5540 pts) were included. Network meta-analysis shows no benefit of CTX over obs in terms of PFS (HR 0.7; 95% CI 0.46-1.09) and OS (HR 0.95; 95% CI 0.85-1.07). Compared to obs, maintenance therapy shows PFS benefit (HR 0.58; 95% CI 0.43-0.77) with only a trend in OS (HR 0.91; 95% CI 0.83-1.009). All maintenance strategies (FP, FP+bev, and bev) show significant improvement in PFS over obs. On SUCRA analysis, maintenance treatment (FP or FP+bev) has the highest likelihood of achieving better PFS (67.1% for FP and 99.8% for FP+bev) and OS (81.3% for FP and 73.2% for FP+bev). Conclusions: A maintenance strategy with at least a FP with or without the addition of bevacizumab is preferred. However, given the lack of a clear OS benefit, obs is an acceptable alternative. Optimal maintenance strategies should be dependent on factors including patient preferences, cost and toxicities. [Table: see text]

PURPOSE Recent advances in molecular diagnostic technologies have allowed for the evaluation of solid tumor malignancies via noninvasive blood sampling, including circulating tumor DNA (ctDNA) profiling. We sought to characterize the ctDNA genomic alteration landscape in patients with biliary tract cancers (BTCs). PATIENTS AND METHODS From January 2015 to February 2018, 124 patients with BTC at the Mayo Clinic Comprehensive Cancer Center underwent ctDNA testing using a clinically available assay. The majority of samples (n = 122) were tested using the 73-gene panel that includes somatic genomic targets, including complete or critical exon coverage in 30 and 40 genes, respectively, and in some, amplifications, fusions, and indels. RESULTS A total of 138 samples were included, with approximately 70% of patients having intrahepatic BTC. All patients had locally advanced or metastatic BTC. Samples with one or more alterations, when variants of unknown significance were excluded, numbered 105 (76%). Each sample contained, on average, three alterations with a median allelic fraction of 0.52%. The overall landscape of alterations is summarized in Figures 1 and 2. After excluding variants of unknown significance, therapeutically relevant alterations were observed in 76 patients (55%), including BRAF mutations, ERBB2 amplifications, FGFR2 fusions, FGFR2 mutations, and IDH1 mutations seen in 21% of patients. A different spectrum of alterations was observed in patients with early-onset BTC (younger than age 50 years) compared with older patients (older than age 50 years). CONCLUSION Data on ctDNA in BTC is currently limited. Our study, the largest cohort reported to date to our knowledge, demonstrates the feasibility of ctDNA testing in this disease. We provide a foundation upon which the field can continue to grow.

Abstract Summary We present MetaMarker, a pipeline for discovering metagenomic biomarkers from whole-metagenome sequencing samples. Different from existing methods, MetaMarker is based on a de novo approach that does not require mapping raw reads to a reference database. We applied MetaMarker on whole-metagenome sequencing of colorectal cancer (CRC) stool samples from France to discover CRC specific metagenomic biomarkers. We showed robustness of the discovered biomarkers by validating in independent samples from Hong Kong, Austria, Germany and Denmark. We further demonstrated these biomarkers could be used to build a machine learning classifier for CRC prediction. Availability and implementation MetaMarker is freely available at https://bitbucket.org/mkoohim/metamarker under GPLv3 license. Supplementary information Supplementary data are available at Bioinformatics online.

TPS468 Background: Intrahepatic cholangiocarcinoma (iCCA) is a cancer arising from the intrahepatic bile duct. Standard treatment of unresectable, recurrent, or metastatic iCCA is with cytotoxic chemotherapy. FGFR2 gene fusions have been identified as oncogenic drivers in 10–20% of iCCA tumors, but no targeted agents have been established to date. TAS-120 is an investigational irreversible FGFR1–4 inhibitor in development as a once-daily oral treatment for iCCA. Based on initial studies in multiple tumor types expressing FGFR abnormalities, iCCA was identified as a tumor type with potential susceptibility to FGFR inhibition and high unmet need. A phase I portion of the trial with an iCCA expansion cohort demonstrated tolerability and preliminary evidence of clinical efficacy with TAS-120 as a continuous, once-daily oral treatment in patients with iCCA. The most common AEs in the phase I portion of the trial were hyperphosphatemia, a mechanism-based on-target side effect, cutaneous AEs, and gastrointestinal AEs. The phase I portion of the study is continuing to enroll, and final results are anticipated in early 2019. Based on preliminary findings, a phase II portion of the study (FOENIX-101; clinicaltrials.gov registration NCT02052778) has been initiated. Methods: The phase II portion of the trial is a global, single-arm study of TAS-120 in patients with iCCA harboring FGFR2 gene rearrangements. The study will enroll approximately 100 adult patients with locally advanced or metastatic iCCA that progressed after ≥ 1 systemic therapies and with an ECOG PS of 0 or 1. Prior systemic therapy must include gemcitabine plus platinum-based chemotherapy. Screening for FGFR2 gene rearrangements will be performed at a central laboratory. The primary endpoint is objective response rate based on RECIST v1.1. Secondary endpoints include duration of response, disease control rate, overall survival, progression-free survival, safety, and health-related quality of life. Clinical trial information: NCT02052778.

TPS462 Background: Dysregulation of fibroblast growth factor receptor (FGFR) signaling by FGFR genetic alterations is implicated in many cancers, including cholangiocarcinoma (CCA). FGFR2 translocations with fusion partners occur in ≈10% to 20% of intrahepatic CCA tumors. Pemigatinib is a selective oral inhibitor of FGFR-1, 2, 3. Preliminary data from the ongoing phase 2 study show efficacy and tolerable safety in patients (pts) with CCA with FGFR2 translocations. We present the design for a phase 3, open-label, randomized trial investigating pemigatinib monotherapy versus gemcitabine plus cisplatin chemotherapy in the first-line treatment of pts with advanced/metastatic or unresectable CCA with FGFR2 rearrangement. Methods: Eligible pts (target, N = 432) are ≥ 18 years (≥ 20 years for Japanese pts) and have ECOG performance status ≤ 1 and histologically confirmed advanced (locally advanced, metastatic, or recurrent) CCA with a documented FGFR2 rearrangement. Key exclusion criteria include prior systemic therapy, excluding adjuvant/neoadjuvant treatment completed ≥ 6 months before enrollment; current evidence of clinically significant corneal or retinal disorder; history of calcium and phosphate homeostasis disorder or systemic mineral imbalance with ectopic calcification of soft tissues; and known, untreated CNS metastases or history of uncontrolled seizures. Pts are randomized 1:1 and stratified by geographic region and tumor burden into 2 treatment groups: pemigatinib starting dose 13.5 mg once daily continuously on a 3-week cycle; or gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) administered intravenously on days 1 and 8 of every 3-week cycle for up to 8 cycles until disease progression or unacceptable toxicity. Crossover to pemigatinib may be allowed once progressive disease is confirmed. The primary endpoint is progression-free survival (based on independent central review using RECIST v1.1). Secondary endpoints include overall response rate, overall survival, duration of response, disease control rate, safety and tolerability, and impact on quality of life. Clinical trial information: NCT03656536.

442 Background: Neutrophil to lymphocyte ratio (NLR) has been used as an inflammation-based prognostic marker for various malignancies. The aim of our study was to determine whether NLR can independently predict the overall survival in patients with metastatic gallbladder cancer (GBC). Methods: We identified patients diagnosed with GBC who were treated at Mayo Clinic between the years 2000 and 2016. Patients who had nonmetastatic GBC were excluded along with the patients who did not have data for neutrophils and lymphocytes. Optimal cutoff point for NLR was identified by plotting martingale residuals against NLR and patients were divided into two groups, ≥ 5 or < 5. Demographic, follow-up data and outcomes were collected by retrospective review of electronic medical records. Fisher’s exact test was used to compare categorical variables, while The Mann- Whitney U test was used to compare continuous variables. Kaplan-Meier curves were plotted for NLR ≥ 5 and NLR < 5 and overall survival (OS) between the two groups were compared using log rank test. Multivariate survival analysis was performed using Cox-proportional hazard regression. Results: A total of 231 patients met our inclusion criteria, of which, 138 (60%) had NLR < 5 and 93 (40%) had NLR ≥ 5. Patients with NLR ≥ 5 were more likely to be older and have poor performance score, lower albumin level, higher alkaline phosphatase level, and higher platelet count. There were no significant differences noted in gender, race and administration of chemotherapy between the two groups. In univariate analysis, patients with NLR ≥ 5 at presentation had a significantly worse OS compared to those with NLR < 5 (Median survival: 3.6 vs. 8.8 months, p < 0.001). In multivariate analysis, adjusting for age, ECOG status, albumin, ALP, AST, ALT, bilirubin, platelet count and administration of chemotherapy, NLR of ≥ 5 was associated with a worse OS compared to NLR < 5 (HR: 1.70, 95% CI:1.20 – 2.39. p < 0.05). Conclusions: Our study demonstrates that NLR ≥ 5 is an independent predictor of poor prognosis in patients with metastatic gallbladder cancer.

408 Background: Standard of care for CCA/GBC is C-G therapy. MAbs (ATZ, pembrolizumab) targeting PD-L1 show promise in treating CCA/GBC. Hyaluronan (HA), which may impede drug and immune cell access, is high (67%) in CCA/GBC tumors. PEGPH20 enzymatically degrades HA. HALO 110-101 (NCT03267940) evaluates safety and activity of PEG-C-G-ATZ or PEG-C-G versus C-G in CCA/GBC pts. Methods: This study comprises two parts. In Run-In (RI) six pts were enrolled in PEG-C-G arm, then six pts in PEG-C-G-ATZ arm. Eight additional pts may be enrolled for tolerability. In Expansion (EX), up to 50 pts will be enrolled for efficacy. Treatment (Tx) cycle is 21 days (d). PEGPH20 dose is 3 μg/kg on d1, eight and 15 and ATZ dose is 1200 mg (one–three hours after PEGPH20) on d1 (PEG-C-G-ATZ only). C-G is dosed at 25 mg/m2 C and 1000 mg/m2 G on d2 and nine. In C-G arm (EX only), C-G is dosed on d1 and 8. Primary endpoints are ORR (RECIST v1.1), AEs (NCI CTCAE v4.03), laboratory/safety (RI only); secondary endpoints are PK; DOR, DCR, PFS; OS, OS by PD-L1 expression; ORR and DOR (imRECIST). Results: Eighteen pts have been enrolled (nine in each arm). The mean (SD) age is 57 (12.2) yrs in PEG-C-G and 69 (8.8) yrs in PEG-C-G-ATZ. 56% were men. All pts experienced ≥ 1 AE. The most common AEs are nausea, fatigue (50% each); decreased appetite (44%); anemia, constipation (39% each); thrombocytopenia, oedema peripheral, AST increased, myalgia (33% each). To date, there has been one dose-limiting toxicity (febrile neutropenia) in the PEG-C-G arm. There have been no deaths due to AEs. Conclusions: The overall safety profile of PEGPH20 + C + G ± ATZ is acceptable and consistent with safety observed for the individual components. There were no DLTs resulting in a dose reduction of PEGPH20, which is being dosed at 3 μg/kg in the EX phase. Clinical trial information: NCT03267940. [Table: see text]