Chabner Symposium October 30, 2017 Lipika Goyal, MD, MPhil Massachusetts General Hospital Cancer Center Instructor, Harvard Medical School Is FGFR an Effective Target in Cholangiocarcinoma?
Disclosures • Consultant – DebioPharm • Consultant – Ribon Therapeutics
Cholangiocarcinoma (Bile Duct Cancer) Intrahepatic Cholangiocarcinoma Extrahepatic Cholangiocarcinoma
Valle, J, et al. NEJM 2010
Frequent Targetable Mutations in ICC Riener, et al. Genes Chromosomes Cancer 2008 Desphande, et al. BMC Cancer, 2011 Borger, et al. The Oncologist, 2012 Wang, et al. Oncogene 2012 Voss, et al. Human Pathology, 2013 Sia, et al. Gastroenterology, 2013 Jiao, et al. Nature Genetics, 2013 Chan-on, et al. Nature Genetics, 2013 Wu, et al. Cancer Discovery, 2013 Ross,et al. The Oncologist, 2014 Graham, et al. Human Pathology 2014 Arai, et al. Hepatology 2014 Sia, et al. Nature Communications, 2015 Slide courtesy Shoop Saha
FGFR2 fusions in cancer Yi-Mi Wu, et al. Cancer Discovery, 2013
FGFR Pathway FGFR FGFR Ligand Trap Anti-FGFR Monoclonal Antibody Small Molecule TKI Adapted from Turner & Grose, Nature Reviews Cancer 2010
FGFR Signaling in Cancer Babina & Turner, Nature Reviews 2017
Clinical development of FGFR inhibitors Lung Cancer Breast Cancer • NSCLC: 17% FGFR1 • Hormone receptor positive: 15% amplification FGFR1 amplification • SCLC: 6% FGFR1 amplification • TNBC: 5% FGFR1 amplification • NSCLC & SCLC: ~5% FGFR1- • Rare FGFR1 mutations 3 fusions and FGFR1-4 mutations Intrahepatic Cholangiocarcinoma • 10-15% FGFR2 fusions • ~5% FGFR1-3 mutations or INCB54828 amplification Touat, etal, CCR, 2015
Evidence of Oncogene Addiction to FGFR2 fusions in ICC BGJ398 ARQ087 INCB54828 FGFR2 IC50 = 1.4nM FGFR2 IC50 = 1.8nM FGFR2 IC50 = 3-50nM
Phase 2 Study of BGJ-398 in refractory FGFR-altered cholangiocarcinoma (n=61) n/N = 58/61 (95.1%)* 1 0 0 Best Change From Baseline (%) FGFR status 8 0 FGFR2 fusion FGFR2 amplification 6 0 FGFR2 mutation 4 0 FGFR2 mutation + fusion FGFR2 amplification + mutation 2 0 FGFR3 amplification 0 - 2 0 - 4 0 - 6 0 ORR = 14.8% (18.8% FGFR2 fusions only) DCR = 75.4% (83.3% FGFR2 fusions only) - 8 0 - - 1 0 0 1 0 0 Patients Javle, etal, JCO, 2017, in press
Phase 2 Study of BGJ-398 in refractory FGFR- altered cholangiocarcinoma (n=61) Median PFS was 5.8 months (95% CI, 4.3‒7.6 months) Javle, etal, JCO, 2017, in press
Phase I/II Trial of ARQ-087: Best % Change from Baseline in Target Lesions (n=35) Mazzaferro, etal, ASCO 2017
Phase I/II Trial of ARQ-087: Duration on Treatment and Best Overall Response (n=35) Mazzaferro, etal, ASCO 2017
Phase I/II Trial of INCB54828: Best % Change from Baseline in Target Lesions Saleh, etal, AACR 2017
Phase I/II Trial of INCB54828: Duration on Treatment and Best Overall Response Saleh, etal, AACR 2017
Unpacking Trial Results from FGFR inhibitors in Intrahepatic Cholangiocarcinoma 1. Why is the ORR only 15-20%? 2. Why is the PFS<6 months? 3. What drug combinations might deepen and prolong responses?
BGJ398 Trial in CCA: FGFR2 Rearrangements and Fusions FGFR2 fusion partners and rearrangements a (n = 38) BICC1 (n = 9) NOL4 (n = 1) Intron 17 rearrangement (n = 6) PARK2 (n = 1) AHCYL1 (n = 1) PCMI (n = 1) AFF4, R678G (n = 1) RASAL2 (n = 1) C7 (n = 1) SLMAP2 (n = 1) CCDC6 (n = 1) STK3 (n = 1) CELF2 (n = 1) TFEC (n = 1) DNAJC12 (n = 1) UBQLN1 (n = 1) HOOK1 (n = 1) WAC (n = 1) KCTD1 (n = 1) ZMY4 (n = 1) KIAA1217 (n = 1) Unknown fusion partner (n = 3) KIAA1598 (n = 1) a Most genetic alterations were detected locally using next-generation sequencing. Javle, etal, JCO, 2017, in press
BGJ398 Trial in CCA: Concurrent Genetic Alteration FGFR2 FGFR2 81% BAP1 BAP1 34% TP53 TP53 22% CDKN2 A CDKN2 A 16% PIK3C A PIK3C A 16% CDKN2B CDKN2B 9% PBRM1 PBRM1 9% FGFR3 FGFR3 9% ARID1 A ARID1 A 6% ARID2 ARID2 6% A A TM TM 6% CDK6 CDK6 6% FRS2 FRS2 6% KMT2D KMT2D 6% MDM2 MDM2 6% MET MET 6% MYC MYC 6% TE R T TE R T 6% TSC1 TSC1 6% FGFR1 FGFR1 3% Known structural variant Likely structural variant Known rearrangement Known amplification Known detection Javle, etal, JCO, 2017, in press
Adverse Events associated with FGFR inhibition Touat, etal, CCR, 2015
Acquired Resistance to FGFR inhibition in ICC Overcoming Acquired Acquired Acquired BGJ398 resistance to resistance to resistance to resistance with TAS120 BGJ398 BGJ398 TAS120 Published Unpublished
MGH Team:FGFR Resistance in Cholangiocarcinoma Ryan B. Corcoran, MD, PhD Nabeel M. Bardeesy, PhD Andrew X. Zhu, MD, PhD Dejan Juric, MD Cyril Benes, PhD Leah Y. Liu, PhD Shoop Saha, MD, PhD David Ting, MD, PhD
Radiological Outcomes on BGJ-398 Progression Pre-treatment Nadir Patient #1 FGFR2-ZMYM4 6 months -49.9% Patient #2 FGFR2-OPTN -28.0% 4 months Patient #3 FGFR-BICC1 8 months -36.9% Goyal, Saha, etal, Cancer Discov , 2016
Clinical Sample Acquisition Protocol Post- Pre-treatment On Treatment Autopsy Progression Biopsy: Biopsy: Targeted Whole Exome Seq Whole Exome Seq sequencing of RNA-Seq RNA-Seq multiple metastases Targeted Sequencing Targeted Sequencing Tissue to Bardeesy Tissue to Bardeesy Tissue to Bardeesy Lab for PDX Lab for PDX Lab for PDX Generation Generation Generation ctDNA analysis: ctDNA analysis: ctDNA analysis: Targeted Sequencing Targeted Sequencing Targeted Sequencing & Corcoran Lab & Corcoran Lab & Corcoran Lab Ryan Corcoran, Nabeel Bardeesy, Leah Liu, David Ting, Dejan Juric, Andrew Zhu, Lipika Goyal
Patient #2: FGFR2 Mutations detected in post-progression Pre-treatment Progression Nadir (-28%) Tumor biopsy FGFR2-Related Genetic Events Tumor biopsy Fusion: FGFR2-OPTN Fusion: FGFR2-OPTN Mutations: None detected Mutations: FGFR2 K641R Plasma (cell-free DNA) Plasma (cell-free DNA) Mutations: None detected Mutations: FGFR2 V564F FGFR2 N549H FGFR2 K641R FGFR2 E565A FGFR2 L617V Goyal, Saha, etal, Cancer Discov , 2016
Rapid autopsy Program: Dissecting Tumoral heterogeneity of resistance A 4 3 5 CT scan 1 3 4 Rapid autopsy 1 5 Goyal, Saha, etal, Cancer Discov , 2016
Intratumoral heterogeneity of resistance 3 4 4 3 5 1 5 1
Mechanisms of FGFR Resistance V564F N549H/K E565A Patient 1 K659M Strengthening of the hydrophobic Gate Keeper Disengagement of the spine of the Mutation molecular brake kinase Stabilization of the active conformatio n of the FGFR2 activation loop Patient 2 V564F N549H E565A K641R L617V Patient 3 V564F Byron, et al., Neoplasia 2013
Effect of resistance mutations on sensitivity to FGFR inhibitors BGJ398 Ponatinib Dovitinib AZD-4547 Debio-1347 FIIN-2 LY2874455 IC50 (nM) IC50 (nM) IC50 (nM) IC50 (nM) IC50 (nM) IC50 (nM) IC50 (nM) fold Δ fold Δ fold Δ fold Δ fold Δ fold Δ fold Δ SD (n) SD (n) SD (n) SD (n) SD (n) SD (n) SD (n) 3960 1478 1474 7854 8355 5865 71 BaF3 1427 13 21 683 113 12304 533 2421 (3) 446 (4) 515 (3) 2526 (3) 2850 (3) 4139 (3) 11 (3) 2.8 45 69 12 74 0.48 0.13 TEL-FGFR3 1 1 1 1 1 1 1 1.34 (4) 4 (4) 35 (4) 3.5 (4) 39 (4) 0.3 (3) 0.04 (5) 167 444 915 485 3236 6.7 0.72 TEL-FGFR3 (L608V) 60 10 13 42 44 14 5 33 (4) 29 (4) 266 (4) 98 (4) 921 (4) 2.5 (4) 0.2 (4) 1540 637 164 1891 8236 90 0.32 TEL-FGFR3 (V555M) 555 13 2 164 111 189 2 606 (4) 123 (4) 65 (4) 404 (4) 2305 (4) 31 (4) 0.01 (4) 600 81 1315 3454 6179 83 5.1 TEL-FGFR3 (N540K) 216 2 19 300 83 174 39 141 (4) 12 (4) 351 (4) 317 (4) 2037 (4) 49 (4) 1.7 (6) 41 309 991 230 1489 5.9 0.90 TEL-FGFR3 (K650E) 15 7 14 20 20 12 7 10 (4) 59 (4) 156 (4) 37 (4) 377 (4) 1.3 (4) 0.13 (4) Goyal, Saha, etal, Cancer Discov , 2016
Acquired Resistance to FGFR inhibition in ICC Acquired Acquired Overcoming resistance to resistance to BGJ398 TAS120 FGFR inhibitors resistance with TAS120 Published Unpublished
Tan, et al., PNAS 2014
TAS-120: Highly selective covalent-binding pan-FGFR inhibitor TAS-120 inhibits FGFR1-4 Strong antitumor efficacy of TAS-120 exhibited similar IC 50 for TAS-120 in OCUM-2MD3 nude mice FGFR2 wild type and key mutants xenograft model-bearing gastic (e.g. gatekeeper mutant V565I) tumors with FGFR2 amplification 1 FGFR2 amplified gastric cancer pFGFR2 inhibition IC 50 (nM) Enzyme IC 50 (nM ) 2.5 Relative tumor volume FGFR2 WT 0.9 FGFR1 3.9 2.0 FGFR2 V565I 1.3 FGFR2 1.3 1.5 FGFR2 N550H 3.6 FGFR3 1.6 1.0 FGFR2 E566G 2.3 FGFR4 8.3 0.5 FGFR2 K660M 5.2 0.0 0 2 4 6 8 10 12 14 16 Days Vehicle TAS-120 0.15 mg/kg/day TAS-120 1.5 mg/kg/day TAS-120 0.50 mg/kg/day TAS-120 5 mg/kg/day 1. Nakatsuru Y et al. AACR-NCI-EORTC International Conference, 2013; abstract A272
TAS-120: Waterfall plot in FGF/FGFR aberrant CCA 100 Change from baseline in longest diameter (%) 50 * 0 uPR uPR cPR cPR -50 FGFR2 fusion * Other FGF/FGFR alteration * Prior treatment with FGFR inhibitor -100 uPR = unconfirmed PR, cPR = confirmed PR Goyal, etal, GI ESMO, 2017 4 of the 23 patients are not included as they have no scans available yet; of these, 3 had prior FGFRi; Cut-off date: May 12, 2017
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