VHL Systemic Therapy Eric Jonasch, MD UT MD Anderson Cancer Center - - PowerPoint PPT Presentation

VHL Systemic Therapy

Eric Jonasch, MD UT MD Anderson Cancer Center

Disclosures

Research funding: Exelixis, Merck, Novartis, Pfizer Consulting: Aravive, Aveo, Eisai, Exelixis, Merck, Novartis, Pfizer

Regulates how the cell sees its surroundings

Ohh et al, Mol Cell, Vol 1, 959-968, 1998 Kurban et al, Cancer Res 2006; 66: (3).

Regulates p53 Impacts blood vessel formation Controls the primary cilium

Thoma et al Nature Cell Biology Aug 2009 Pugh et al Narture Medicine 2003 Kuehn et al Ca Res May 15, 2007

Kerbel NEJM May 2008

Elongin C

α β

Elongin B

Cul 2

Roe and Youn Mol Cell May 2006

VHL- A Regulatory Hub

Other substrates

Qing Zhang

Transcription of: VEGF Other angiogenic factors HIF-α Nucleus HIF-β VHL

VEGF = vascular endothelial growth factor; HIF = hypoxia-inducible factor.

VHL Mutation Increases Growth Factors including VEGF

Tumor cells VHL-/- VHL-/-

VEGF

VHL-/-

VHL Loss Results Highly Angiogenic Lesions

Stromal cells

VEGF VEGF VEGF VEGF

Can We Block The Consequences of VHL Loss?

Tumor cells

VHL HIF

VEGF

Therapeutic Opportunities in the VHL-HIF-VEGF Pathway

Tumor cells

VHL HIF

VEGF

VEGFR inhibitors

Therapeutic Opportunities in the VHL-HIF-VEGF Pathway

Tumor cells

VHL HIF

VEGF

VEGF inhibitors VEGFR inhibitors

Therapeutic Opportunities in the VHL-HIF-VEGF Pathway

Tumor cells

VHL HIF

VEGF

VEGF inhibitors VEGFR inhibitors HIF inhibitors

Therapeutic Opportunities in the VHL-HIF-VEGF Pathway

Tumor cells

VHL HIF

VEGF

VEGF inhibitors VEGFR inhibitors HIF inhibitors VHL stabilizers/surrogates

Therapeutic Opportunities in the VHL-HIF-VEGF Pathway

Moving Towards Better Therapies for VHL Disease

Tumor cells

VHL HIF

VEGF

VEGFR inhibitors

VEGF and VEGFR inhibitors

VEGF inhibitors

Not all TKIs are created equal

14

Fabian, M., Biggs, W., Treiber, D. et al. A small molecule–kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 23, 329–336 (2005)

Tumor cells

VHL HIF

VEGF

VEGFR inhibitors

Sunitinib

Sunitinib is an oral, small molecule inhibitor of VEGFR 1-3, PDGFR, KIT and other kinases

Germline VHL RCC or Clinical VHL Sunitinib 50mg PO 4/2 Schedule RECIST 1.1 in all lesions at 6 months

Sunitinib Pilot Study

Jonasch and Matin, Annals of Oncology 2011 15 Patients Accrued

Lesion site Lesion number PR (%) SD (%) PD (%) Hemangioblastoma*

21 19(91) 2(9)

Renal cell carcinoma*

18 6 (33) 10(67) 2(10)

Renal cyst

9 9 (100)

Retinal angiomas

7 7 (100)

Pancreatic NET

5 5 (100)

Pancreatic cyst

3 3 (100)

Sunitinib Study: Efficacy

*(P=0.014) Jonasch and Matin, Annals of Oncology 2011

Nine out of 15 patients completed study- most came off study due to poor tolerability

Lesion site Lesion number PR (%) SD (%) PD (%) Hemangioblastoma*

21 19(91) 2(9)

Renal cell carcinoma*

18 6 (33) 10(67) 2(10)

Renal cyst

9 9 (100)

Retinal angiomas

7 7 (100)

Pancreatic NET

5 5 (100)

Pancreatic cyst

3 3 (100)

Sunitinib Study: Efficacy

*(P=0.014) Jonasch and Matin, Annals of Oncology 2011

Nine out of 15 patients completed study- most came off study due to poor tolerability

Lesion site Lesion number PR (%) SD (%) PD (%) Hemangioblastoma*

21 19(91) 2(9)

Renal cell carcinoma*

18 6 (33) 10(67) 2(10)

Renal cyst

9 9 (100)

Retinal angiomas

7 7 (100)

Pancreatic NET

5 5 (100)

Pancreatic cyst

3 3 (100)

Sunitinib Study: Efficacy

*(P=0.014) Jonasch and Matin, Annals of Oncology 2011

Nine out of 15 patients completed study- most came off study due to poor tolerability

Pancreatic NETs Responded

Jonasch and Matin, Annals of Oncology 2011

Renal Masses Responded

Baseline 12 Weeks 24 Weeks Jonasch and Matin, Annals of Oncology 2011

Hemangioblastomas Did Not Respond

Jonasch and Matin, Annals of Oncology 2011

VHL Related Tumors

Tumor cells VHL-/-

VHL-/-

Stromal cells

VEGFR EGFR PDGFR VEGFR

VEGF VEGF

VHL-/-

Are Endothelial Cells in RCC and Hemangioblastomas Driven by Same Growth Factors?

Tumor cells VHL-/-

VHL-/-

Stromal cells

VEGFR EGFR PDGFR VEGFR

VEGF VEGF

VHL-/-

Hemangioblastomas

Densely packed, seemingly normal blood vessel channels of varying sizes, separated by stromal cells.

20 Hemangioblastomas Evaluate Status of Different Receptor Types in Blood Vessels Using Laser Scanning Cytometry 20 Renal Cell Carcinomas Determine Differences Between Hb and RCC

Jonasch and Matin Annals of Oncology 2011

log(Hb) log(RCC) t-test Wilcoxon’s rank test

N mean SD N mean SD p-value p-value pVEGFR2 in CD31 Cells 20 11.268 0.498 20 11.752 0.378 0.001 0.003 tVEGFR in CD31 Cell 20 12.977 0.478 20 13.081 0.859 0.639 0.192 pPDGFR in CD31 Cells 20 10.952 0.654 20 10.805 0.839 0.539 0.82 tPDGFR in CD31 Cells 20 13.078 0.659 20 12.842 0.851 0.333 0.947 VEGFR.ratio 20 0.206 0.122 20 0.372 0.431 0.105 0.043 PDGFR.ratio 20 0.145 0.067 20 0.157 0.077 0.608 0.602

VEGF receptor activation state is higher in kidney tumors compared to hemangioblastomas.

Jonasch and Matin Annals of Oncology 2011

log(Hb) log(RCC) t-test Wilcoxon’s rank test

N mean SD N mean SD p-value p-value Tie2 in CD31 Positive Cells 20 12.654 0.455 20 12.63 0.817 0.909 0.883 Tie2 in Tumor Tissue 20 11.598 0.321 20 11.614 0.303 0.866 0.947 FGFR3 in CD31 Positive Cells 20 12.265 0.448 20 12.29 0.961 0.914 0.495 FGFR3 in Tumor Tissue 20 11.439 0.224 20 11.338 0.106 0.075 0.174 pFRS2 in CD31 Positive Cells 20 12.495 0.492 20 11.91 0.989 0.023 0.059 pFRS2 in Tumor Tissue 20 11.452 0.258 20 11.258 0.089 0.003 0.003

pFRS2 (a marker for FGF receptor activation) is higher in hemangioblastomas compared to ccRCC

Jonasch and Matin Annals of Oncology 2011

Tumor cells

VHL HIF

VEGF

VEGFR inhibitors

Pazopanib

Sunitinib is an oral, small molecule inhibitor of VEGFR 1-3, PDGFR, FGFR and other kinases

Pazopanib- Case Study: Response in Hemangioblastoma

Kim Jonasch and McCutcheon Targ Oncol 2012

Germline VHL RCC or Clinical VHL Pazopanib 800mg PO Daily RECIST 1.1 in all lesions at 6 months

Pazopanib Phase 2 Study

Jonasch and Matin The Lancet Oncology 2018

32 Jonasch and Matin The Lancet Oncology 2018

Pazopanib Phase 2 Study

33

Pazopanib Phase 2 Study

Jonasch and Matin The Lancet Oncology 2018

RCC Pancreatic Lesions Hemangioblastomas Jonasch and Matin The Lancet Oncology 2018

Pazopanib Phase 2 Study

Pazopanib: Tumor Response

Jonasch and Matin The Lancet Oncology 2018

Tumor cells

VHL HIF

VEGF

HIF inhibitors

PT2977/MK6482

PT

HIF-α Nucleus HIF-β VHL

PT2977

VEGF

HIF 2 Alpha Blockade

HIF-2α HIF-1β

Scheuermann et al. PNAS 2009, 106:450 Key et al. JACS 2009, 131:17647 Scheuermann et al. Nature Chem Biol 2013, 9:271

UT Southwestern (UTSW) research on HIF- 2α biology

• Identified small molecule binding

pocket in PAS-B domain

• Established that small molecule

binding led to inhibition of transcriptional activity

Development of a Small Molecule HIF2a Inhibitor

Slide courtesy of Naseem Zojwalla

Atlas of Genetics and Cytogenetics in Oncology and Haematology

HIF-2α HIF-1β

Scheuermann et al. PNAS 2009, 106:450 Key et al. JACS 2009, 131:17647 Scheuermann et al. Nature Chem Biol 2013, 9:271 Rogers et al. J Med Chem 2013, 56:1739

• Modest cell activity
• Poor pharmacokinetic properties
• Metabolic liabilities
• Electrophilic -- Potential for non-

specific covalent protein modification

Initial UTSW HIF-2α hit not viable lead

Slide courtesy of Naseem Zojwalla

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Development of a Small Molecule HIF2a Inhibitor

HIF-2α HIF-1β

Further iteration of molecule

HIF-2α antagonist bound to HIF-2α PAS-B* domain

HIF-2α PAS-B* (R247E mutant) domain (green) HIF-1β PAS-B* (E362R mutant) domain (blue) PT2385 (magenta)Wallace et al. Cancer Res 2016, 76:5491 Cho et al. Nature 2016, 539:107 Chen et al. Nature 2016, 539:112 Courtney et al. J Clin Oncol 2018

Slide courtesy of Naseem Zojwalla

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Development of a Small Molecule HIF2a Inhibitor

HIF-2α HIF-1β

PT2385

Slide courtesy of Naseem Zojwalla

Further iteration of molecule

HIF-2α antagonist bound to HIF-2α PAS-B* domain

Wallace et al. Cancer Res 2016, 76:5491 Cho et al. Nature 2016, 539:107 Chen et al. Nature 2016, 539:112 Courtney et al. J Clin Oncol 2018

Development of a Small Molecule HIF2a Inhibitor

Phase 2 Study of the Oral HIF-2α Inhibitor MK-6482 for Von Hippel-Lindau Disease–Associated Clear Cell Renal Cell Carcinoma: Update on RCC and Non-RCC Disease

1Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; 2Aarhus University Hospital, Aarhus, Denmark; 3Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA; 4Vanderbilt University Medical

Center, Nashville, TN, USA; 5University of Pennsylvania, Philadelphia, PA, USA; 6University of Utah, Salt Lake City, UT, USA;

7Hôpital Européen Georges-Pompidou, University of Paris, Paris, France; 8University of Michigan, Ann Arbor, MI, USA; 9University of Pittsburgh, Pittsburgh, PA, USA; 10Cambridge University Hospitals NHS Foundation Trust, Cambridge, United

Kingdom; 11Merck & Co., Inc., Kenilworth, NJ, USA; 12The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Ramaprasad Srinivasan,1 Frede Donskov,2 Othon IIiopoulos,3 W. Kimryn Rathmell,4 Vivek K. Narayan,5 Benjamin L. Maughan,6 Stephane Oudard,7 Tobias Else,8 Jodi K. Maranchie,9 Sarah J. Welsh,10 Sanjay Thamake,11 Rodolfo F. Perini,11 Eric K. Park,11 W. Marston Linehan,1 Eric Jonasch12

Phase 2 Study: MK-6482 for VHL-Associated RCC (NCT03401788)

MK-6482 120 mg orally once daily Key Eligibility Criteria

• Diagnosis of VHL

disease, based on germline mutation

• ≥1 measurable RCC

tumor

• No prior systemic

anticancer therapy

• No metastatic

disease

• ECOG PS 0 or 1

Primary End Points

• ORR in VHL-associated

RCC tumors per RECIST v1.1 by independent central review Secondary End Points

• ORR in non-RCC lesions
• DOR in RCC and

non-RCC lesions

• Safety

Tumor evaluation performed at screening and every 12 weeks thereafter

N = 61 Primary Objective

• To evaluate efficacy of MK-6482 for the treatment of VHL disease–associated RCC

Baseline Characteristics

aA waiver was requested by the investigator and approved by the IRB before enrollment. bAs evaluable by independent radiology committee. cIncludes pancreatic neuroendocrine tumors

and serous cystadenomas. Data cutoff: June 1, 2020.

Characteristic All Patients N = 61 Age, median (range), years 41 (19-66) Sex, n (%) Male 32 (52.5) Female 29 (47.5) ECOG PS, n (%) 50 (82.0) 1 10 (16.4) 2a 1 (1.6) Non-renal cell carcinoma tumor typeb Pancreatic lesionsc 61 (100) CNS hemangioblastoma 43 (70.5) Retinal lesions 16 (26.2)

• Fifty-six patients (91.8%) ongoing

treatment

• Minimum of 60 weeks’ follow-up
• Median (range) follow-up:

68.7 weeks (18.3-104.7)

Response in Target RCC Lesions by Independent Central Review

aDocumented at 1 time point and to be confirmed at subsequent time point. Data cutoff: June 1, 2020.

All Patients N = 61 ORR, % (95% CI) 36.1 (24.2-49.4) Best response, n (%) CR PR 22 (36.1) SD 38 (62.3) Unconfirmed PRsa 7 (11.5) PD Not Evaluable 1 (1.6)

• 100
• 90
• 80
• 70
• 60
• 50
• 40
• 30
• 20
• 10

10 20 30 40 50 60 70 80 90 100

Confirmed PR Stable disease Unconfirmed PRa

• 91.8% (56/61) of patients had

decrease in size of target lesions

Percentage Change From Baseline

Duration of Treatment by Independent Central Review

aDocumented at 1 time point and to be confirmed at subsequent time point. Data cutoff: June 1, 2020.

• Time to response, median (range),

weeks

–

31.1 (11.9-62.3)

• Duration of response, median

(range), weeks

–

Not reached (11.9-62.3)

• PFS rate at 52 weeks

–

98.3%

12 24 36 48 60 72 84 96 108

Death Treatment ongoing

Patients Weeks

Confirmed PR Unconfirmed PRa Stable Disease Not Evaluable

Confirmed ORR in Pancreatic Lesions and CNS Hemangioblastomas by Independent Central Review

aIncludes both target and non-target lesions. Data cutoff: June 1, 2020.

Pancreatic Lesions N = 61 CNS Hemangioblastoma N = 43a ORR, % (95% CI) 63.9 (50.6-75.8) 30.2 (17.2-46.1) Best response, n (%) CR 4 (6.6) 5 (11.6) PR 35 (57.4) 8 (18.6) SD 21 (34.4) 28 (65.1) PD 1 (2.3) Not Evaluable 1 (1.6) 1 (2.3)

Best Response in Retinal Lesions by Independent Central Review

Data cutoff: June 1, 2020.

Best Response, n (%) Retinal Lesions N = 16 Improved + Stable 15 (93.8) Improved 11 (68.8) Stable 4 (25.0) Progressed Not Evaluable 1 (6.3)

Adverse Events

a1 patient was recorded as having hypoxia (grade 3; treatment-related). b1 patient was recorded with retinal detachment (grade 4; not treatment-related). c1 patient died from toxicity of

various agents (grade 5; not treatment-related). Data cutoff: June 1, 2020.

All cause AEs in ≥15% of patients , n (%) All Patients N = 61 Any Grade Grade 1/2 Grade 3a Grade 4/5b,c Any 61 (100) 46 (75.5) 13 (21.3) 2 (3.3) Anemia 55 (90.2) 51 (83.6) 4 (6.6) Fatigue 37 (60.7) 34 (55.7) 3 (4.9) Headache 23 (37.7) 23 (37.7) Dizziness 22 (36.1) 22 (36.1) Nausea 19 (31.1) 19 (31.1) Dyspnea 12 (19.7) 11 (18.0) 1 (1.6) Arthralgia 11 (18.0) 11 (18.0) Upper respiratory tract infection 11 (18.0) 11 (18.0) Alanine aminotransferase increased 10 (16.4) 10 (16.4) Myalgia 10 (16.4) 10 (16.4)

• Sixty patients (98.4%) had a

treatment-related AE – 8 patients (13.1%) had a grade 3 treatment-related AE – There were no grade 4/5 treatment-related AEs – One patient (1.6%) discontinued due to a treatment-related AE (grade 1 dizziness)

Tumor cells

VHL HIF

VEGF

Therapeutic Opportunities in the VHL-HIF-VEGF Pathway

VHL stabilizers/surrogates

Fixing Broken VHL- the Holy Grail

Tumor cells Gene Therapy Voretigene neparvovec (Luxturna) may be a model- AAV based delivery CRISPR/Cas9 technology

Fixing Broken VHL- the Holy Grail

Tumor cells Gene Therapy AAV based delivery CRISPR/Cas9 technology Tumor cells Stabilizing Point Mutated VHL Blocking chaperones like HSP90. Preventing proteasomal degradation. Inhibiting VHL cleavage.

Tumor cells

VHL HIF

VEGF

VEGFR Inhibitor: Sunitinib Pazopanib HIF2a Inhibitor: PT2977

Summary

Acknowledgements

Research Colleagues

• Bill Kaelin
• Ram Srinivasan
• Othon Iliopoulos
• Marston Linehan
• Surena Matin
• Ian McCutcheon
• Steven Waguespack
• Dan Gombos
• Greg Fuller
• Nancy Perrier
• Kamran Ahrar

MDACC Clinical Team

• Christine Robichaux
• Rudy Hernandez
• Mederbek Tatmusaev
• Cherie Perez
• Mercedes Villarreal
• Christine Robichaux
• Lacy Anderson

Lab Team

• Xiande Liu
• Zhiyong Ding
• Xuesong Zhang
• Truong Lam
• Patrick Pilie

Merck Team

• Eric Park
• Rodolfo Perini