Gastrointestinal Stromal Tumor GEIS Symposium 2018 Jon Trent, MD, PhD Professor of Medicine Director, Bone and Soft-tissue Program Associate Director, Clinical Research Sylvester Comprehensive Cancer Center
@JTrentMDPhD Background GIST Overview
• Most common GI sarcoma – 0.2% of all GI tumors, but 80% of GI sarcomas • Distinct clinical and histopathologic entity – Highest incidence in the 40-60 year age group – Similar male/female incidence • About 5,000 newly diagnosed GIST patients per year in the US • Clinical presentation is variable – pain, hemorrhage, anemia, anorexia, nausea, bleeding • High recurrence rate after surgery (>50%) • Metastatic sites: Liver and peritoneum GIST Subtypes – Kit exon 11 – Kit exon 9 – PDGFR D842V – SDH deficiency – Raf V600E – NF-1, Ras – PI3K – IGF-1R expressing – TRK fusion – KIT resistance mutations • Exon 13 (ATP binding site) • Exon 17 (A-loop)
Personal Communication Jon Trent, MD, PhD (Sylvester Comprehensive Cancer Center) Kit Receptor Structure
Extracellular Domain (exon 9, 10.2%)
Juxtamembrane Domain (exon 11, 66.1%) ATP
Tyrosine Kinase Domain I (exon 13/14, 1.2%)
Tyrosine Kinase Domain II (exon 17, 0.6%)
= common mutation site Kit Receptor Phenotype
ATP
Proliferation Survival Adhesion Invasion Metastasis Angiogenesis = imanitib contact point EORTC Phase III Imatinib for Advanced GIST Survival Benefit
Verweij, et al 2004 2nd Line Therapy And Beyond Vascular Endothelial Growth Factor Correlates With Survival
Low VEGF Expression
High VEGF Expression
KIT and VEGFR inhibition: Sunitinib, Regorafenib
McAuliffe, Trent 2008 Randomized, Phase III Sunitinib v Placebo Time to Tumor Progression
100 Sunitinib (N=207) 90 Placebo (N=105) 80 Hazard ratio = 0.335 P<0.00001 70 60 50 Median (95% CI) 6.3 (3.7, 7.6) 40 1.5 (1.0, 2.3) 30 20
Estimated TTP probability (%) 10 0 0 3 6 9 12 Time (Months) Phase III Regorafenib vs Placebo Progression-free survival Regorafenib (investigator assessment) Regorafenib (central review) Placebo (investigator assessment) 1.00 Placebo (central review)
0.75
0.50
0.25 Survival distribution function Survival distribution
0 0 50 100 150 200 250 300 350 Days from randomization Reichardt, ESMO 2012. Clinical Trials…...
Jon Trent, MD, PhD GIST Subtypes – Kit exon 11 – Kit exon 9 – PDGFR D842V – SDH deficiency – Raf V600E – NF-1, Ras – PI3K – IGF-1R expressing – TRK fusion – KIT resistance mutations • Exon 13 (ATP binding site) • Exon 17 (A-loop)
Personal Communication Jon Trent, MD, PhD (Sylvester Comprehensive Cancer Center) KIT-mutant, Advanced GIST
• Phase I NAVIGATOR Study of Avapritinib (International) – 2nd line • Phase I PLX9486 Alone or With PLX3397 or Sunitinib (US) • Phase I MEK162 in Combination With Imatinib (MSK)
• Phase II study of single-agent Cabozantinib (EORTC) • Phase II POETIG-POnatinib After rEsisTance to Imatinib (Germany)
• Phase III Imatinib Alternating With Regorafenib Vs. Imatinib Alone for 1st Line Treatment (Australia) • Phase III VOYAGER Avapritinib vs Regorafenib (international) • Phase III DCC-2618 vs Placebo > 4th line (International)
Jon Trent, MD, PhD DCC-2618 ACTIVITY IN GIST PATIENTS
Dose Mutant Investigator CT Scan Level Patient ID Gene Review C3D1 mg BID 30 KIT 01.001 PMR SD 50 KIT 01.003 PMR PD 50 KIT 03.003 PMR SD 50 KIT 03.004 PMR SD 50 KIT 04.008 PMR SD 100 KIT 04.009 PMR PR 100 KIT 01.004 PMR SD 100 KIT 04.010 PMR SD 100 KIT 01.005 PMR SD 150 KIT 01.007 PMR SD Baseline Cycle 1 150 KIT 02.002 PMR SD 150 KIT 03.005 PMR SD 150 KIT 01.006 PMR PD • 93% (14/15) PMR in KIT-mutant 150 KIT 04.012 PMR Too early GIST 150 KIT 03.007 PMD SD 100 PDGFRA 04.011 SMD SD • 87% (13/15) PMR in KIT-mutant 100 SDHA 03.006 SMD PD GIST by central review (EORTC PET response criteria)
Janku et al EORTC-NCI-AACR, 2016 DCC-2618: DIMENSIONAL RESPONSE
Baseline CT CT after cycle 2
. Widely metastatic GIST with KIT Exon 11 deletion, who received 6 different prior KIT inhibitors . RECIST: partial response (-37%) maintained for 5+ cycles on DL4 100mg BID
Janku et al EORTC-NCI-AACR, 2016 PLX-9486 KIT INHIBITOR ACTIVITY
Primary Mutations Secondary Mutations Exon 8 Exon 9 Exon Exon Exon Exon Exon PLX-9486 + Sunitinib 11 13 14 17 18
Imatinib 1st Line
Sunitinib PLX-9486 + 3397 2nd Line
Regorafenib 3rd Line PLX9486
Pexidartinib
PLX9486 + Sunitinib
PLX9486 + Pexidartinib PDGFR D842V mutant GIST
• Randomized Trial of Crenolanib in Subjects With D842V Mutated GIST • Inhibitors of downstream pathways (RAF, MEK, mTOR, etc)
Jon Trent, MD, PhD Clinical activity of Avapritinib in PDGFR D842V advanced GIST
ASCO 2017. Abstract no: 11011 SDH-deficient GIST
• Phase II Temozolomide In Advanced Succinate Dehydrogenase (SDH)-Mutant or Deficient GIST (UCSD) • A Phase II Trial of the DNA Methyl Transferase Inhibitor, Guadecitabine (NCI-US) • Phase I/II PT2977 HIF2-alpha inhibitor (Sylvester) • Phase II Regorafenib in First-line for KIT/PDGFR Wild Type GIST (GEIS + ISG)
SDH Increase Increase Increase loss HIF DNA methylation VEGF
Jon Trent, MD, PhD ACTIVITY OF LAROTRECTINIB GIST Patient Initial Therapy RAF V600E Mutation
Treatment with RAF inhibitor Vemurafenib
Falchook, Trent, Heinrich Oncotarget. 2013 Feb;4(2):310-5. Advanced GIST
• Phase II Study of AUY922, Novel HSP Inhibitor (China) • A Phase I Intratumorally Administered Ilixadencel (Sweden) • Phase I Epacadostat and Pembrolizumab (UM + Columbia) • Phase II Nivolumab With or Without Ipilimumab (UCLA) • A Study of XmAb18087 in Subjects With NET and GIST (US)
Caution: No KIT/PDGFR Inhibition
Jon Trent, MD, PhD KIT INHIBITOR RESISTANCE
Jon Trent, MD, PhD Secondary Mutations in KIT
ATP/ADP Binding Site (V654)
Gate Keeper (T670)
Activation Loop (D820)
Chen, Trent, et al. Cancer Res 2004;64:5913-5919 Primary Secondary Drug Protein Mutations Mutations Sensitivity Domain IM REG KIT SU PON Receptor
Exon 13 V654A
Ligand binding Exon 14 T670I Exon 9 : 12%
Exon 11: 70% JM D816A/G/H/V Exon 13: 1% ATP binding K642E D820A/E/G/Y Exon 17 N822H/K
Activation Loop Y823D NR Exon 17: 1% * N822H/K, D820Y A829P Exon 18 Resistant Trent, ASCO 2017 Intermediate Sensitive Gramza et al, Clinical Cancer Research 15:7510, 2009 Heinrich et al, ASCO 2013 Poster/Abstract 10509 NR Not reported Circulating Tumor DNA Mutation Testing From Blood (Liquid Biopsy)
Nurwidya et al, 2018 Ponatinib
Arshad et al, ASCO 2018 Conclusions
• GIST is a molecularly defined disease • Molecular characterization is necessary for optimal GIST therapy including clinical trials • Caution with patient selection for non- targeted trials • Circulating Tumor DNA is a promising modality to guide targeted therapy
Jon Trent, MD, PhD Sylvester Comprehensive Cancer Center Sarcoma and GIST Team • Interventional Radiology • Medical Oncology • Orthopedic Oncology – Shree Venkat – Jon Trent – Sheila Conway – Ivan Chaitowitz – Matteo Trucco (Pedi) – Frank Eismont – Evelyn Wempe – Warren Alperstein (Pedi) – Juan Pretell • Gynecologic • Pathology – Mo Al Maaieh Oncology – Andrew Rosenberg • Surgical Oncology – Brian Slomovitz – Darcy Kerr – Nipun Merchant – Marilyn Huang • Radiology – Alan Livingstone • Clinical Research – Ty Subhawong – Neha Goel – Tamara Leon – Jean Jose • Radiation Therapy – Liz Bornote – Raphael Yechieli • ARNP – Junet Alvarez – Aaron Wolfson – Morgan Smith • Lab Research – Ali Naveda • Head & Neck Surgery – Josie Eid – Zoukaa Sargi • Nursing – Joanna DeSalvo – Frank Civantos – Eryka Lacayo – Luyuan Li – Yolanda Roper • Thoracic Surgery – Karina Galoian • Social Work – Dao Nguyen – Shuchao Zhang – Marlene Morales – Nestor Villamizar Gastrointestinal Stromal Tumor GEIS Symposium 2018
Jon Trent, MD, PhD Professor of Medicine Director, Bone and Soft-tissue Program Associate Director, Clinical Research The University of Miami, Sylvester Cancer Center
@JTrentMDPhD GIST Subtypes and Treatment – Kit exon 11: Imatinib 400 mg – Kit exon 9: Imatinib 800mg (or tolerated dose) – PDGFR D842V: anti-PDGFR trial (avapritinib, crenolanib) – SDH deficiency: Sunitinib, Regorafenib, DNMTi, HIF2a-i – Raf V600E: Raf inhibitor – NF-1, Ras: Raf or Mek inhibitor – PI3K: mTOR inhibitor – IGF-1R expressing – IGF-1R inhibitor trial – TRK fusion – LOXO-101 NTRK inhibitor trial – KIT resistance mutations • Exon 13 (ATP binding site): Sunitinib 37.5 mg daily, trial • Exon 17 (A-loop): Regorafenib 120 mg daily, trial
Personal Communication Jon Trent, MD, PhD (Sylvester Comprehensive Cancer Center) Kit Receptor Phenotype
ADP + ATP P
Proliferation Survival Adhesion Invasion Metastasis Angiogenesis GIST Response
Pre-Imatinib Post-Imatinib (8 weeks therapy)
Courtesy Jon Trent and Alex Lazar GIST Precision Medicine
Advanced GIST Patient
Tissue Sent For NGS or NGS available
SCCC Weekly Targeted Trial Molecular Tumor Board SCCC O Immunotherapy NCI MATCH Trial p O t Actionable No actionable p mutation mutation i t External SCCC Non- o i Targeted Trial Targeted trial Targeted SDH n o Drug Expression s Loss n FDA Approved s External Non- (Off-Label) Sunitinib Targeted trial Regorafenib DNMTi