Is FGFR an Effective Target in Cholangiocarcinoma? Disclosures - - PowerPoint PPT Presentation

Is FGFR an Effective Target in Cholangiocarcinoma?

Lipika Goyal, MD, MPhil Massachusetts General Hospital Cancer Center Instructor, Harvard Medical School

Chabner Symposium October 30, 2017

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

Adapted from Turner & Grose, Nature Reviews Cancer 2010

Ligand Trap

FGFR FGFR

Anti-FGFR Monoclonal Antibody Small Molecule TKI

FGFR Signaling in Cancer

Babina & Turner, Nature Reviews 2017

Clinical development of FGFR inhibitors

Touat, etal, CCR, 2015

INCB54828

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

Intrahepatic Cholangiocarcinoma

• 10-15% FGFR2 fusions
• ~5% FGFR1-3 mutations or

amplification

Evidence of Oncogene Addiction to FGFR2 fusions in ICC

BGJ398 FGFR2 IC50 = 1.4nM ARQ087 FGFR2 IC50 = 1.8nM INCB54828 FGFR2 IC50 = 3-50nM

• 1 0 0
• 1 0 0
• 8 0
• 6 0
• 4 0
• 2 0

2 0 4 0 6 0 8 0 1 0 0

n/N = 58/61 (95.1%)*

Best Change From Baseline (%) Patients

FGFR status

FGFR2 mutation + fusion FGFR2 amplification FGFR2 amplification + mutation FGFR2 mutation FGFR2 fusion FGFR3 amplification

Phase 2 Study of BGJ-398 in refractory FGFR-altered cholangiocarcinoma (n=61)

ORR = 14.8% (18.8% FGFR2 fusions only) DCR = 75.4% (83.3% FGFR2 fusions only) Javle, etal, JCO, 2017, in press

Median PFS was 5.8 months (95% CI, 4.3‒7.6 months)

Phase 2 Study of BGJ-398 in refractory FGFR- altered cholangiocarcinoma (n=61)

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 rearrangementsa (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

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 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%

Likely structural variant Known rearrangement Known structural variant Known amplification Known detection

BGJ398 Trial in CCA: Concurrent Genetic Alteration

Javle, etal, JCO, 2017, in press

Adverse Events associated with FGFR inhibition

Touat, etal, CCR, 2015

Acquired resistance to BGJ398

Acquired Resistance to FGFR inhibition in ICC

Acquired resistance to BGJ398 Published Unpublished Overcoming BGJ398 resistance with TAS120 Acquired resistance to TAS120

MGH Team:FGFR Resistance in Cholangiocarcinoma

Ryan B. Corcoran, MD, PhD Andrew X. Zhu, MD, PhD Dejan Juric, MD Nabeel M. Bardeesy, PhD Leah Y. Liu, PhD Cyril Benes, PhD Shoop Saha, MD, PhD David Ting, MD, PhD

Radiological Outcomes on BGJ-398

Pre-treatment Nadir Progression Patient #1 FGFR2-ZMYM4 Patient #2 FGFR2-OPTN Patient #3 FGFR-BICC1

Goyal, Saha, etal, Cancer Discov, 2016

• 49.9%
• 28.0%
• 36.9%

6 months 4 months 8 months

Biopsy: Whole Exome Seq RNA-Seq Targeted Sequencing

Clinical Sample Acquisition Protocol

On Treatment Autopsy Biopsy: Whole Exome Seq RNA-Seq Targeted Sequencing Targeted sequencing of multiple metastases Pre-treatment Post- Progression ctDNA analysis: Targeted Sequencing & Corcoran Lab Ryan Corcoran, Nabeel Bardeesy, Leah Liu, David Ting, Dejan Juric, Andrew Zhu, Lipika Goyal 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

Patient #2: FGFR2 Mutations detected in post-progression

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

Rapid autopsy Program: Dissecting Tumoral heterogeneity of resistance

1 3 4 5 1 3 4 5 CT scan Rapid autopsy A

Goyal, Saha, etal, Cancer Discov, 2016

Intratumoral heterogeneity of resistance

1 3 4 5 1 3 4 5

Mechanisms of FGFR Resistance

V564F N549H/K E565A V564F N549H E565A K641R

Gate Keeper Mutation Disengagement of the molecular brake Strengthening of the hydrophobic spine of the kinase

Patient 1 Patient 2 L617V K659M

Stabilization

• f the active

conformatio n of the FGFR2 activation loop Byron, et al., Neoplasia 2013

Patient 3 V564F

Effect of resistance mutations on sensitivity to FGFR inhibitors

BGJ398 Ponatinib Dovitinib AZD-4547 Debio-1347 FIIN-2 LY2874455 IC50 (nM) foldΔ IC50 (nM) foldΔ IC50 (nM) foldΔ IC50 (nM) foldΔ IC50 (nM) foldΔ IC50 (nM) foldΔ IC50 (nM) foldΔ SD (n) SD (n) SD (n) SD (n) SD (n) SD (n) SD (n) BaF3 3960 1427 1478 13 1474 21 7854 683 8355 113 5865 12304 71 533 2421 (3) 446 (4) 515 (3) 2526 (3) 2850 (3) 4139 (3) 11 (3) TEL-FGFR3 2.8 1 45 1 69 1 12 1 74 1 0.48 1 0.13 1 1.34 (4) 4 (4) 35 (4) 3.5 (4) 39 (4) 0.3 (3) 0.04 (5) TEL-FGFR3 (L608V) 167 60 444 10 915 13 485 42 3236 44 6.7 14 0.72 5 33 (4) 29 (4) 266 (4) 98 (4) 921 (4) 2.5 (4) 0.2 (4) TEL-FGFR3 (V555M) 1540 555 637 13 164 2 1891 164 8236 111 90 189 0.32 2 606 (4) 123 (4) 65 (4) 404 (4) 2305 (4) 31 (4) 0.01 (4) TEL-FGFR3 (N540K) 600 216 81 2 1315 19 3454 300 6179 83 83 174 5.1 39 141 (4) 12 (4) 351 (4) 317 (4) 2037 (4) 49 (4) 1.7 (6) TEL-FGFR3 (K650E) 41 15 309 7 991 14 230 20 1489 20 5.9 12 0.90 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 resistance to FGFR inhibitors Overcoming BGJ398 resistance with TAS120 Acquired resistance to TAS120 Published Unpublished

Tan, et al., PNAS 2014

TAS-120 inhibits FGFR1-4 TAS-120 exhibited similar IC50 for FGFR2 wild type and key mutants (e.g. gatekeeper mutant V565I)

TAS-120: Highly selective covalent-binding pan-FGFR inhibitor

• 1. Nakatsuru Y et al. AACR-NCI-EORTC International Conference, 2013; abstract A272

pFGFR2 inhibition IC50 (nM) FGFR2 WT 0.9 FGFR2 V565I 1.3 FGFR2 N550H 3.6 FGFR2 E566G 2.3 FGFR2 K660M 5.2 Enzyme IC50 (nM) FGFR1 3.9 FGFR2 1.3 FGFR3 1.6 FGFR4 8.3

FGFR2 amplified gastric cancer Strong antitumor efficacy of TAS-120 in OCUM-2MD3 nude mice xenograft model-bearing gastic tumors with FGFR2 amplification1

TAS-120 0.15 mg/kg/day TAS-120 5 mg/kg/day TAS-120 0.50 mg/kg/day TAS-120 1.5 mg/kg/day Vehicle

2.5 2.0 1.5 1.0 0.5 0.0 2 4 6 8 Days Relative tumor volume 10 12 14 16

TAS-120: Waterfall plot in FGF/FGFR aberrant CCA

• 100
• 50

50 100

* *

Change from baseline in longest diameter (%)

FGFR2 fusion Other FGF/FGFR alteration

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

uPR cPR uPR cPR

*Prior treatment with FGFR inhibitor

Goyal, etal, GI ESMO, 2017

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

Acquired Resistance to FGFR inhibition in ICC

Acquired resistance to FGFR inhibitors Overcoming BGJ398 resistance with TAS120 Acquired resistance to TAS120 Published Unpublished

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 TAS-120 PFS 7.2 months Pre TAS-120 Nadir -46.4% Bone Lesion Progression in Spine Post-progression: FGFR2-BICC1 fusion, and PIK3C2B Amplification among others *FGFR2 and RAS mutations were not found

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

• 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?

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?

Acknowledgements

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 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

Patients and their families who generously participated in research

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

Patients

0 16 32 48 64 80 96 1 12 128 144 160 176 192 208 224 240 256 272 288 304 320 336 352 368 384 400 416

T reatment Duration (days)

Investigator-Assessed Response Partial response Stable disease Progressive disease BGJ398 dose (mg) 125 mg 100 mg 75 mg 50 mg 25 mg

BGJX2204 Trial: Time to Response

Cholangiocarcinoma and FGFR pathway

FGFR gene abnrmalities5

• 1. Brieau B et al. Cancer 2015;121:3290-3297; 2. Wu YM et al. Cancer Discov 2013;3(6):636-647, 3. Graham RP et al. Hum Pathol. 2014;45(8):1630-1638;
• 4. Ross JS et al. Oncologist 2014;19(3):235-242; 5.Turner N et al. Nat Rev Can 2010;10:116-129
• 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 CCAs2-4

Intrahepatic CCA Extrahepatic CCA

Cholangiocarcinoma (CCA)

Cholangiocarcinoma Mutational Spectrum (TCGA)

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

Javle, et al. GI ASCO 2015

• 50%
• 28%
• 37%

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

MGH Efforts to study FGFR inhibition and resistance

Clinical Efforts: Andrew Zhu, Lipika Goyal Laboratory Efforts: Corcoran, Bardeesy, Benes, and Ting Labs

Patient-derived

Xenograft (PDX)

Digest &

Culture

ICC Cell Lines

Genetically-Engineered Mouse Models (GEMMs)

ICC Organoid

ctDNA ddPCR

2 FGFR Altered ICC Lines 15 FGFR WT ICC Lines

Corcoran Lab Bardeesy Lab Benes Lab Ting Lab

CTC analysis RNA Seq

Rapid Autopsy: Dejan Juric

Breast: 18 Pancreatic: 2 Colorectal: 3 Melanoma: 2 Cholangio: 6 Lung: 13

Epithelial: 2

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

ARQ-087: Most Common Adverse Events - All Grades in ≥20% of Patients and Grade ≥3 in 2 or More Patients

Mazzaferro, etal, ASCO 2017