Is FGFR an Effective Target in Cholangiocarcinoma?

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1 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?

2 Disclosures Consultant DebioPharm Consultant Ribon Therapeutics

3 Cholangiocarcinoma (Bile Duct Cancer) Intrahepatic Cholangiocarcinoma Extrahepatic Cholangiocarcinoma

4 Valle, J, et al. NEJM 2010

5 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

6 FGFR2 fusions in cancer Yi-Mi Wu, et al. Cancer Discovery, 2013

7 Adapted from Turner & Grose, Nature Reviews Cancer 2010 FGFR Pathway FGFR Ligand Trap FGFR Anti-FGFR Monoclonal Antibody Small Molecule TKI

8 FGFR Signaling in Cancer Babina & Turner, Nature Reviews 2017

Clinical development of FGFR inhibitors Lung Cancer NSCLC: 17% FGFR1 amplification SCLC: 6% FGFR1 amplification NSCLC & SCLC: ~5% FGFR1-3 fusions and FGFR1-4 mutations Breast Cancer Hormone receptor

9 Clinical development of FGFR inhibitors Lung Cancer NSCLC: 17% FGFR1 amplification SCLC: 6% FGFR1 amplification NSCLC & SCLC: ~5% FGFR1-3 fusions and FGFR1-4 mutations Breast Cancer Hormone receptor positive: 15% FGFR1 amplification TNBC: 5% FGFR1 amplification Rare FGFR1 mutations INCB54828 Intrahepatic Cholangiocarcinoma 10-15% FGFR2 fusions ~5% FGFR1-3 mutations or amplification Touat, etal, CCR, 2015

10 Evidence of Oncogene Addiction to FGFR2 fusions in ICC BGJ398 FGFR2 IC50 = 1.4nM ARQ087 FGFR2 IC50 = 1.8nM INCB54828 FGFR2 IC50 = 3-50nM

11 Phase 2 Study of BGJ-398 in refractory FGFR-altered cholangiocarcinoma (n=61) Javle, etal, JCO, 2017, in press Best Change From Baseline (%) n/n = 58/61 (95.1%)* ORR = 14.8% (18.8% FGFR2 fusions only) DCR = 75.4% (83.3% FGFR2 fusions only) Patients FGFR status FGFR2 fusion FGFR2 amplification FGFR2 mutation FGFR2 mutation + fusion FGFR2 amplification + mutation FGFR3 amplification

12 Phase 2 Study of BGJ-398 in refractory FGFRaltered cholangiocarcinoma (n=61) Median PFS was 5.8 months (95% CI, months) Javle, etal, JCO, 2017, in press

13 Phase I/II Trial of ARQ-087: Best % Change from Baseline in Target Lesions (n=35) Mazzaferro, etal, ASCO 2017

14 Phase I/II Trial of ARQ-087: Duration on Treatment and Best Overall Response (n=35) Mazzaferro, etal, ASCO 2017

15 Phase I/II Trial of INCB54828: Best % Change from Baseline in Target Lesions Saleh, etal, AACR 2017

16 Phase I/II Trial of INCB54828: Duration on Treatment and Best Overall Response Saleh, etal, AACR 2017

17 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?

18 Javle, etal, JCO, 2017, in press 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.

19 BGJ398 Trial in CCA: Concurrent Genetic Alteration FGFR2 BAP1 TP53 CDKN2 A PIK3C A CDKN2B PBRM1 FGFR3 ARID1 A ARID2 A TM CDK6 FRS2 KMT2D MDM2 MET MYC TE R T TSC1 FGFR1 81% 34% 22% 16% 16% 9% 9% 9% 6% 6% 6% 6% 6% 6% 6% 6% 6% 6% 6% 3% Known structural variant Likely structural variant Known rearrangement Known amplification Known detection Javle, etal, JCO, 2017, in press

20 Adverse Events associated with FGFR inhibition Touat, etal, CCR, 2015

21 Acquired Resistance to FGFR inhibition in ICC Acquired resistance to BGJ398 Overcoming BGJ398 resistance with TAS120 Acquired resistance to TAS120 Published Unpublished

22 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

24 Radiological Outcomes on BGJ-398 Pre-treatment Nadir Progression Patient #1 FGFR2-ZMYM4-49.9% 6 months Patient #2 FGFR2-OPTN -28.0% 4 months Patient #3 FGFR-BICC1-36.9% 8 months Goyal, Saha, etal, Cancer Discov, 2016

25 Clinical Sample Acquisition Protocol Pre-treatment On Treatment Post- Progression Autopsy Biopsy: Whole Exome Seq RNA-Seq Targeted Sequencing Biopsy: Whole Exome Seq RNA-Seq Targeted Sequencing Targeted sequencing of multiple metastases Tissue to Bardeesy Lab for PDX Generation Tissue to Bardeesy Lab for PDX Generation Tissue to Bardeesy Lab for PDX Generation ctdna analysis: Targeted Sequencing & Corcoran Lab ctdna analysis: Targeted Sequencing & Corcoran Lab ctdna analysis: Targeted Sequencing & Corcoran Lab Ryan Corcoran, Nabeel Bardeesy, Leah Liu, David Ting, Dejan Juric, Andrew Zhu, Lipika Goyal

26 Patient #2: FGFR2 Mutations detected in post-progression Pre-treatment Nadir (-28%) Progression Tumor biopsy Fusion: FGFR2-OPTN Mutations: None detected Plasma (cell-free DNA) Mutations: None detected FGFR2-Related Genetic Events Tumor biopsy Fusion: FGFR2-OPTN Mutations: FGFR2 K641R Plasma (cell-free DNA) Mutations: FGFR2 V564F FGFR2 N549H FGFR2 K641R FGFR2 E565A FGFR2 L617V Goyal, Saha, etal, Cancer Discov, 2016

27 Rapid autopsy Program: Dissecting Tumoral heterogeneity of resistance A CT scan Rapid autopsy Goyal, Saha, etal, Cancer Discov, 2016

28 Intratumoral heterogeneity of resistance

Mechanisms of FGFR Resistance Patient 1 V564F N549H/K

molecular brake Strengthening of the hydrophobic spine

of the FGFR2 activation loop Patient 2 V564F N549H

29 Mechanisms of FGFR Resistance Patient 1 V564F N549H/K E565A K659M Gate Keeper Mutation Disengagement of the molecular brake Strengthening of the hydrophobic spine of the 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

30 Effect of resistance mutations on sensitivity to FGFR inhibitors BGJ398 Ponatinib Dovitinib AZD-4547 Debio-1347 FIIN-2 LY IC50 (nm) IC50 (nm) IC50 (nm) IC50 (nm) IC50 (nm) IC50 (nm) IC50 (nm) foldδ foldδ foldδ foldδ foldδ foldδ SD (n) SD (n) SD (n) SD (n) SD (n) SD (n) SD (n) foldδ BaF (3) 446 (4) 515 (3) 2526 (3) 2850 (3) 4139 (3) 11 (3) TEL-FGFR (4) 4 (4) 35 (4) 3.5 (4) 39 (4) 0.3 (3) 0.04 (5) TEL-FGFR3 (L608V) (4) 29 (4) 266 (4) 98 (4) 921 (4) 2.5 (4) 0.2 (4) TEL-FGFR3 (V555M) (4) 123 (4) 65 (4) 404 (4) 2305 (4) 31 (4) 0.01 (4) TEL-FGFR3 (N540K) (4) 12 (4) 351 (4) 317 (4) 2037 (4) 49 (4) 1.7 (6) TEL-FGFR3 (K650E) (4) 59 (4) 156 (4) 37 (4) 377 (4) 1.3 (4) 0.13 (4) Goyal, Saha, etal, Cancer Discov, 2016

31 Acquired Resistance to FGFR inhibition in ICC Acquired resistance to FGFR inhibitors Overcoming BGJ398 resistance with TAS120 Acquired resistance to TAS120 Published Unpublished

32 Tan, et al., PNAS 2014

33 TAS-120: Highly selective covalent-binding pan-fgfr inhibitor TAS-120 inhibits FGFR1-4 Strong antitumor efficacy of TAS-120 in OCUM-2MD3 nude mice xenograft model-bearing gastic TAS-120 exhibited similar IC 50 for FGFR2 wild type and key mutants (e.g. gatekeeper mutant V565I) tumors with FGFR2 amplification 1 Enzyme IC 50 (nm) FGFR1 3.9 FGFR2 1.3 FGFR3 1.6 FGFR4 8.3 Relative tumor volume FGFR2 amplified gastric cancer Days Vehicle pfgfr2 inhibition IC 50 (nm) FGFR2 WT 0.9 FGFR2 V565I 1.3 FGFR2 N550H 3.6 FGFR2 E566G 2.3 FGFR2 K660M 5.2 TAS mg/kg/day TAS mg/kg/day TAS mg/kg/day TAS mg/kg/day 1. Nakatsuru Y et al. AACR-NCI-EORTC International Conference, 2013; abstract A272

34 TAS-120: Waterfall plot in FGF/FGFR aberrant CCA 100 Change from baseline in longest diameter (%) * FGFR2 fusion Other FGF/FGFR alteration upr upr cpr cpr * -100 *Prior treatment with FGFR inhibitor upr = unconfirmed PR, cpr = confirmed PR 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 Goyal, etal, GI ESMO, 2017

35 TAS-120: Efficacy after prior FGFR inhibitor 73yo F with FGFR2-SORBS1 fusion+ ICC who progressed on Gemcitabine/Cisplatin and FOLFOX Goyal, etal, AACR-NCI-EORTC Conference 2017

36 Acquired Resistance to FGFR inhibition in ICC Acquired resistance to FGFR inhibitors Overcoming BGJ398 resistance with TAS120 Acquired resistance to TAS120 Published Unpublished

37 Acquired resistance to TAS120 56yoF w/ FGFR2-BICC1 fusion+ ICC Treated with Gem/Cis FOLFOX TAS120 Concurrent mutations in Tissue: Baseline : FGFR2-BICC1 fusion (SFA) Post-progression: FGFR2-BICC1 fusion, and PIK3C2B Amplification among others *FGFR2 and RAS mutations were not found Pre TAS-120 Nadir -46.4% Post TAS-120 Bone Lesion PFS 7.2 months Progression in Spine

38 Acquired Resistance to TAS120 Why were no FGFR2 or RAS mutations found on biopsy? Is FGFR2 C491F the primary driver of acquired resistance? Why did the gatekeeper mutation arise? What is the relevance of the KRAS and NRAS mutations? Why did she progress in her bones? Post-TAS 120 Biopsy FGFR2-BICC1 fusion MDM4 amplification BAP1 A606fs*11 PIK3C2B amplification *CDKN2B p. D86N *IGF1R p. N135Y *KDM5A p. Q1197P *LRP1B p. N2336H *MAGI2 p. A899T *NF1 p. L2439V *NTRK1 p. G18E *PIK3C2B p. V213G *PLCG2 p. L209R ZNF703 p. H402_D403>PTHLGGSSCSTCSAHD

39 FGFRi in ICC: Conclusions and Future Directions 1. FGFR alterations are present in 15-20% of ICCs and in multiple tumor types. Why is there primary resistance in many patients with FGFR2 fusions? Which FGFR mutations and amplifications are druggable? 2. Acquired BGJ398 resistance can occur through FGFR2 kinase mutations. Which ones emerge first and are clinically relevant? What FGFR-independent mechanisms of resistance exist? What non-genomic mechanisms of resistance exist? What drugs and drug combinations can delay or overcome resistance? Will more specific and more potent FGFR2 inhibitors lead to higher ORR&PFS? 3. BGJ398 resistance can be overcome, in some cases, by TAS120. Which other drugs and drug combinations can delay or overcome resistance? What is the drug development strategy for Taiho and PrincipioBio? 4. TAS120 Resistance may develop via mutation of the P-Loop cysteine and/or upregulation by bypass tracks. Same questions as #2 Do tumors need a double hit to become resistant?

40 Clinical team: Andrew X. Zhu David P. Ryan Avinash Kambadakone Vikram Deshpande Rapid Autopsy Program Dejan Juric James R. Stone Translational Research Laboratory (TRL): A. John Iafrate Jochen Lennerz Darrell Borger Ting Laboratory: David Ting Acknowledgements Patients and their families who generously participated in research Bardeesy Lab: Nabeel Bardeesy Leah Y. Liu Phuong Vu Supriya K. Saha Corcoran Lab: Ryan B. Corcoran Leanne G. Ahronian Bardelli Lab: Alberto Bardelli Giulia Siravegna Benedetta Mussolin Broad Institute: Ignaty Leshchiner Gad Getz Benes Lab: Cyril Benes Novartis: Diana Graus Porta Ralph Tiedt Sabrina Baltschukat Barbara Schacher-Engstler Louise Barys Christelle Stamm Pascal Furet Research Assistants: Jordan Maurer Chandler Shapiro Stephanie Reyes Emily E. Van Seventer Funding support for this project: NIH GI SPORE, ECOR Fund for Medical Discovery, Jonathan Kraft Translational Research Award, MGH American Cancer Society Grant, Cholangiocarcinoma Foundation

41 BGJX2204 Trial: Time to Response Investigator-Assessed Response Partial response Stable disease Progressive disease Patients BGJ398 dose (mg) 125 mg 100 mg 75 mg 50 mg 25 mg Treatment Duration (days)

2 months and ORR is 5-11% 1 FGFR2 fusions: ~15% of intrahepatic CCAs 2-4 1. Brieau B et al. Cancer 2015;121:3290-3297; 2.

43 Cholangiocarcinoma and FGFR pathway Cholangiocarcinoma (CCA) FGFR gene abnrmalities 5 Intrahepatic CCA Extrahepatic CCA CCA has poor prognosis and limited treatment options In previously treated CCA, median PFS is 3.2 months and ORR is 5-11% 1 FGFR2 fusions: ~15% of intrahepatic CCAs Brieau B et al. Cancer 2015;121: ; 2. Wu YM et al. Cancer Discov 2013;3(6): , 3. Graham RP et al. Hum Pathol. 2014;45(8): ; 4. Ross JS et al. Oncologist 2014;19(3): ; 5.Turner N et al. Nat Rev Can 2010;10:

44 Cholangiocarcinoma Mutational Spectrum (TCGA)

45 Phase 2 Study of BGJ-398 in refractory FGFRaltered cholangiocarcinoma -28% -37% -50% Javle, et al. GI ASCO 2015

46 Mutation in P-loop Cysteine Confers Resistance FIIN-2 and TAS120 covalently bind to Cysteine residues in the kinase domain receptor of FGFR Mutation of FGFR kinase domain cysteine residue (C491F) in cholangiocarcinoma is associated with disease progression

47 MGH Efforts to study FGFR inhibition and resistance Clinical Efforts: Andrew Zhu, Lipika Goyal Rapid Autopsy: Dejan Juric Breast: 18 Lung: 13 Epithelial: 2 Cholangio: 6 Pancreatic: 2 Colorectal: 3 Melanoma: 2 Laboratory Efforts: Corcoran, Bardeesy, Benes, and Ting Labs Corcoran Lab Patient-derived Xenograft (PDX) Bardeesy Lab Benes Lab Ting Lab Digest & Culture ICC Cell Lines 15 FGFR WT ICC Lines ctdna ddpcr Genetically-Engineered Mouse Models (GEMMs) ICC Organoid 2 FGFR Altered ICC Lines CTC analysis RNA Seq

$Phase 2 Study of BGJ-398 in refractory FGFR-altered$

48 Phase 2 Study of BGJ-398 in refractory FGFR-altered cholangiocarcinoma 3.6 months 5.6 months 7.4 months Javle, et al. GI ASCO 2015

49 ARQ-087: Most Common Adverse Events - All Grades in 20% of Patients and Grade 3 in 2 or More Patients Mazzaferro, etal, ASCO 2017

Gatekeeper mutations and intra-tumoural heterogeneity in FGFR2-translocated

Gatekeeper mutations and intra-tumoural heterogeneity in FGFR2-translocated cholangiocarcinoma. Elizabeth C. Smyth 1, Irina S. Babina 2, Nicholas C. Turner 2,3*. 1 GI Unit, The Royal Marsden Hospital,