Goyal, Lipika

TPS545 Background: Advanced cholangiocarcinoma (CC) is a life-threatening disease with limited effective chemotherapy options. Mutations in isocitrate dehydrogenase 1 (mIDH1) occur in 13–15% of CC cases, and up to 25% of intrahepatic CC cases, leading to epigenetic and genetic changes that promote oncogenesis via production of the oncometabolite 2-hydroxyglutarate (2-HG). AG-120 (ivosidenib), a first-in-class oral mIDH1 inhibitor, displayed a favorable safety profile and clinical activity in a phase 1 study enrolling 73 mIDH1 CC patients who had received ≥1 prior systemic regimen. As of 10 Mar 2017, 4/73 (5%) had a partial response and 41/73 (56%) stable disease. Progression free survival (PFS) rates at 6 months and 12 months were 38.5% and 20.7%, respectively. The 500 mg once daily dose level of AG-120 was selected for further development in mIDH1 CC. Methods: ClarIDHy is a global, phase 3, multicenter, double-blind, randomized (2:1) study of AG-120 (500 mg once daily) vs. matched placebo in 186 mIDH1 CC patients (ClinicalTrials.gov NCT02989857). Key eligibility criteria: non-resectable or metastatic CC, documented mIDH1 by central laboratory testing, ECOG performance status 0–1, measurable disease (RECIST v1.1), documented disease progression after ≤2 prior systemic therapies in the advanced setting including at least 1 gemcitabine- or 5-fluorouracil-containing regimen, and no prior mIDH inhibitor therapy. Crossover from placebo to AG-120 will be allowed at time of radiographic disease progression. Primary endpoint: PFS assessed by independent radiologists. Secondary endpoints: safety, tolerability, overall response rate (RECIST 1.1), overall survival, pharmacokinetic/pharmacodynamic analyses, and quality of life (EORTC QLQ-C30 and QLQ-BIL21 scales). An independent data monitoring committee will monitor the data during study conduct. The ClarIDHy study is currently activated at participating sites in the US, UK, EU, and S. Korea. R eused with permission from the American Society of Clinical Oncology (ASCO). This abstract was accepted and previously presented at the 2017 ASCO Annual Meeting. All rights reserved. Clinical trial information: NCT02989857.

TPS4142 Background: Advanced cholangiocarcinoma (CC) is a life-threatening disease for which there are limited therapeutic options. Mutations in isocitrate dehydrogenase 1 (mIDH1) occur in up to 25% of intrahepatic CC cases. mIDH1 lead to epigenetic and genetic changes that promote oncogenesis via production of the oncometabolite, D-2-hydroxyglutarate (2-HG). AG-120 is a first-in-class oral inhibitor of the mIDH1 enzyme, and is being tested in a phase 1 study that enrolled 73 patients (pts) with mIDH1 CC who had received a median of 2 prior therapies (range 1–5). AG-120 has demonstrated a favorable safety profile and clinical activity in this study. Among the 72 efficacy evaluable pts (≥1 post-baseline response assessment or discontinued prematurely), 6% (n = 4) had a confirmed partial response and 56% (n = 40) had stable disease. Progression-free survival (PFS) rate at 6 months was 40% as of Dec 16, 2016. The 500 mg once daily (QD) dose of AG-120 was selected for the ongoing phase 3 study in mIDH1 CC described here. Methods: ClarIDHy is a global, phase 3, multicenter, double-blind study randomizing 186 pts with mIDH1 CC in a 2:1 ratio to AG-120 (500 mg QD) or matched placebo (NCT02989857). Key eligibility criteria: nonresectable or metastatic CC; documented mIDH1 based on central laboratory testing; ECOG 0–1; measurable disease (RECIST v1.1); documented disease progression following ≤2 prior systemic therapies in the advanced setting, including at least 1 gemcitabine- or 5-fluorouracil-containing regimen; and no prior mIDH inhibitor therapy. Crossover from the placebo arm to the AG-120 arm will be permitted. The primary endpoint is PFS as assessed by an independent review. Secondary endpoints include safety, tolerability, overall response rate, overall survival, pharmacokinetic and pharmacodynamic analyses on plasma, and quality of life as assessed by the EORTC QLQ-C30, EORTC QLQ-BIL21, and EQ-5D-5L instruments. An independent data monitoring committee will monitor the data throughout the study. The ClarIDHy study is currently activated at participating sites in the US and will be activated in centers throughout Europe and in South Korea. Clinical trial information: NCT02989857.

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.

Purpose No standard treatment exists for patients with cholangiocarcinoma for whom first-line gemcitabine-based therapy fails. Fibroblast growth factor receptor 2 ( FGFR2) fusions/translocations are present in 13% to 17% of intrahepatic cholangiocarcinomas. BGJ398, an orally bioavailable, selective pan-FGFR kinase inhibitor, has shown preliminary clinical activity against tumors with FGFR alterations. Methods A multicenter, open-label, phase II study ( ClinicalTrials.gov identifier: NCT02150967) evaluated BGJ398 antitumor activity in patients age ≥ 18 years with advanced or metastatic cholangiocarcinoma containing FGFR2 fusions or other FGFR alterations whose disease had progressed while receiving prior therapy. Patients received BGJ398 125 mg once daily for 21 days, then 7 days off (28-day cycles). The primary end point was investigator-assessed overall response rate. Results Sixty-one patients (35 women; median age, 57 years) with FGFR2 fusion (n = 48), mutation (n = 8), or amplification (n = 3) participated. At the prespecified data cutoff (June 30, 2016), 50 patients had discontinued treatment. All responsive tumors contained FGFR2 fusions. The overall response rate was 14.8% (18.8% FGFR2 fusions only), disease control rate was 75.4% (83.3% FGFR2 fusions only), and estimated median progression-free survival was 5.8 months (95% CI, 4.3 to 7.6 months). Adverse events included hyperphosphatemia (72.1% all grade), fatigue (36.1%), stomatitis (29.5%), and alopecia (26.2%). Grade 3 or 4 treatment-related adverse events occurred in 25 patients (41%) and included hyperphosphatemia (16.4%), stomatitis (6.6%), and palmar-plantar erythrodysesthesia (4.9%). Conclusion BGJ398 is a first-in-class FGFR kinase inhibitor with manageable toxicities that shows meaningful clinical activity against chemotherapy-refractory cholangiocarcinoma containing FGFR2 fusions. This promising antitumor activity supports continued development of BGJ398 in this highly selected patient population.

4076 Background: Gallbladder carcinoma (GBC) is commonly diagnosed at an advanced, unresectable disease stage and has a poor prognosis. Comprehensive genomic profiling (CGP) has a developing role in guiding systemic, precision anti-cancer therapy. Methods: We performed hybrid capture-based CGP on FFPE samples for 491 consecutive advanced GBCs. Mean coverage depth was >550X for up to 315 cancer-related genes plus 37 introns from 28 genes frequently rearranged in cancer. All 4 classes of genomic alterations (GA) were detected. Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA. Results: Median age was 64 (range 25-88) and 69% (337/491) of patients were female. 96% (470), 2.9% (14), and 1.4% (7) of GBC patients had the diagnosis of adenocarcinoma, adenosquamous, or carcinoma not specified (NOS), respectively. Commonly altered genes were TP53 (62%), CDNK2A (31%), ARID1A (18%), and SMAD4 (15%), and most of the genetic aberrations (GA) were short variants. Potentially targetable SCNAs (including ERBB genes, MET, FGFRs, and the CCND1-FGF3/4/19 11q13 amplicon) were identified in 21% of cases (Table). Oncogenic BRAF, ALK, or FGFR2/3 rearrangements were found in 7 cases (1.4%). Moreover, 7.8% of cases had BRCA2 or ATM GA, and 0.8% had INI1loss suggesting benefit from PARP or EZH2 inhibitors, respectively. TMB was low; the 25th, 50th, and 75th percentiles were 2.5, 3.8 and 6.3 mutations/Mb, respectively. Less than 1% of cases had microsatellite instability. Radiological response to TKIs and immunotherapy was noted. Conclusions: In addition to the significant opportunity for anti-HER targeted therapies, other subsets of GBC cases harbored kinase GA (particularly SCNA), the 11q13 amplicon, or BRCA2/ ATM/ INI1mutations that are linked to therapeutic benefit. How the frequency of both driver SCNA and DNA repair alterations in GBC can be linked with inflammation awaits additional investigation. [Table: see text]