New and Emerging Therapies for Soft Tissue Sarcomas and GIST: Recent Clinical Data and Expert Recommendations George D. Demetri, M.D. Director, Center for Sarcoma and Bone Oncology Dana-Farber Cancer Institute Director, Ludwig Center at Harvard Professor of Medicine, Harvard Medical School Boston, Massachusetts gdemetri@dfci.harvard.edu 2018 Oncology Master Class Course @DrSarcoma
DISCLOSURES FOR GEORGE D. DEMETRI, MD Scientific consultant: Bayer, Pfizer, Novartis, Lilly, EMD-Serono, GlaxoSmithKline, Sanofi, Janssen, PharmaMar, ZioPharm, Daiichi-Sankyo, Polaris, Eisai, AdaptImmune, Ignyta, Mirati Consultant/SAB member with minor equity holding: G1 Therapeutics, Caris Life Sciences, Champions Biotechnology Independent Member of Board of Directors and Scientific Advisory Board Consultant with minor equity holding: Blueprint Medicines and Merrimack Pharmaceuticals Off Label/Investigational Discussion In accordance with Annenberg Center policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. 2
Two Broad Clinical Groups of Sarcomas Soft Tissue Sarcomas (90%) Bone Sarcomas (10%)
Soft Tissue Sarcoma is not a single disease Unclassifiable GIST Leiomyo- Sarcomas Liposarcomas
Soft Tissue Sarcomas represent a very heterogeneous set of diseases Unclassifiable GIST Leiomyo- Sarcomas Liposarcomas Ducimetiere et al. PLoS ONE 6(8): e20294. doi:10.1371/journal.pone.0020294.
Gastrointestinal Stromal Tumor (GIST) Most common form of soft tissue sarcoma 1 Dominant Mutationally-Activated Receptor Tyrosine Kinase in each individual patient drives 90% of metastatic GIST Stomach 60% Eso / Duodenum 5% KIT (80%) 9 Exons PDGFRA (10%) Extracellular Domain Small intestine 30% 11 12 TM Domain JM Domain Colon / rectum 5% 13 Kinase Domain-1 Malignant precursors of the GI pacemaker interstitial cells of Cajal Primary generally in stomach or small intestine Metastases in liver, abdomen, elsewhere Completely resistant to cytotoxic chemotherapy Barnett & Heinrich (2012) Am Soc Clin Oncol Educ Book; 663-8 Nowain et al (2005) J Gastroen Heptol;20:818-24 Dematteo et al (2000) Ann Surg;231(1):51-8 Plumb et al (2013) Clin Radiol;68:770-5 17 18 Primary mutational hotpots KIT Exon 11 or 9 Kinase Domain-2 (activation loop) PDGFRα Exon 18 or 12 TKI Resistance mutations KIT Exons 13 and 17 PDGFRα Exon 18
Precision Cancer Medicine for GIST: Gene Mutations Matter SPECIFIC MUTATIONS impact patient outcomes GIST KIT mutation (80%) PDGFRA mutation (10% in met, 25% in gastric primary) SDH mutation or deficiency (either SDHA, SDHB, or SDHC) (approx. 10%) BRAF or NF1 mutations; TRK fusions (<2%) KIT exon 11 point mutations confer overall favorable prognosis KIT exon 9 mutations associated with worse prognosis PDGFRA mutation = good risk in primary GIST BUT worse outcomes in metastatic GIST Corless CL, et al. Nat Rev Cancer. 2011;11(12):865-878.
Long Term Overall Survival (OS) in Metastatic GIST Patients treated with imatinib as first-line tyrosine kinase inhibitor (TKI) ALL PATIENTS PATIENTS BY GIST PRIMARY KIT MUTATION From: Correlation of Long-term Results of Imatinib in Advanced Gastrointestinal Stromal Tumors With Next-Generation Sequencing Results - Analysis of Phase 3 SWOG Intergroup Trial S0033 JAMA Oncol. Published online February 09, 2017. doi:10.1001/jamaoncol.2016.6728
Different PDGFRA mutations induce different clinical outcomes in metastatic GIST Progression-Free Survival Overall Survival Philippe A. Cassier et al. Clin Cancer Res 2012;18:4458-4464 2012 by American Association for Cancer Research
Does adjuvant TKI therapy benefit patients with early stage, localized primary GIST? Which GIST patients need adjuvant therapy? (and which patients do not benefit)?
Quantifying the Risk of Recurrence for Primary Localized GIST (resected without prior imatinib) Tumor Parameters % RISK OF RELAPSE or METASTASIS Size Mitotic Count Stomach Duodenum Jejunum / Ileum Rectum 2 cm 0 0 0 0 > 2, 5 cm 2 8 4 9 5 per 50 > 5, 10 cm HPFs 4 24 } > 10 cm 12 34 52 2 cm 0* * 50* 54 > 2, 5 cm 16 50 73 52 > 5 per 50 > 5, 10 cm HPF 55 } 85 > 10 cm 86 86 90 * Too few cases Adapted from Miettinen and Lasota. Sem Diag Pathol. 2006; 23(2):70-83. See also Joensuu H et al. Lancet Oncol 2012; 13: 265 74 Adapted from Miettinen and Lasota. Sem Diag Pathol. 2006; 23(2):70-83. } 57 } 71
Improved Overall Survival with 3 yrs vs. 1 yr of Adjuvant Imatinib in GIST % 100 80 96.3% 92.0% 94.0% 81.7% 3 Years IM 1 Year IM 60 Hazard ratio 0.45 40 (95% CI 0.22-0.89) 20 P = 0.019 No. at risk (n=397) 0 0 1 2 3 4 5 6 7 Years 36 Months of imatinib 198 192 184 152 100 56 13 0 12 Months of imatinib 199 188 176 140 87 46 20 0 Joensuu H, et al
GIST genotype impacts whether adjuvant imatinib has any benefit following resection of primary localized GIST % Recurrence-Free and Alive 100 90 80 70 60 50 40 30 20 10 0 NO benefit with adjuvant imatinib therapy for GIST with no mutations in KIT or PDGFRA ( Wild Type GIST) Imatinib Rx p=0.6126 at 24 months 0 6 12 18 24 30 36 42 48 54 60 Time in Months Placebo (n=32) Imatinib (n=32) Corless et al ASCO 2010
% Recurrence-Free and Alive GIST genotype impacts whether adjuvant imatinib has any benefit following resection of primary localized GIST 100 90 80 70 60 50 40 30 20 10 NO benefit with adjuvant imatinib therapy for GIST with the PDGFRA Mutation Imatinib Rx Imatinib (n=15) Placebo (n=13) p=0.9984 Also note the very good prognosis of patients with primary localized GIST harboring this mutation 0 0 6 12 18 24 30 36 42 48 54 Time in Months Corless et al ASCO 2010
Understanding TKI Resistance in GIST to Overcome It: Differential resistance to current TKI Rx with KIT resistance mutations Predicted sensitivity profiles of imatinib, sunitinib, and regorafenib Resistant Sensitive PRIMARY MUTATIONS KIT Exon 9: 12% KIT Cell membrane SECONDARY MUTATIONS Exon 13 V654A Exon 14 T670I Imatinib DRUG SENSITIVITY Sunitinib Regorafenib Exon 11: 70% ATP-binding pocket Exon 17 D816E D820A/Y Activation loop Exon 18 N822K Adapted from Serrano-García C, et al. ASCO 2013. Abstract 10510.
New agents can be designed as potent, highly selective inhibitors of KIT and PDGFRα mutants resistant to imatinib and other TKIs Approved Standard of Care Drugs for GIST in 2018 Non-selective Type I inhibitors Avapritinib (BLU-285) imatinib sunitinib regorafenib crenolanib Kinome screening at 3 µm Kinome illustration reproduced courtesy of Cell Signaling Technology, Inc. (www.cellsignal.com) Adapted from Evans E, et al. AACR 2017 16
New agents can be designed as potent, highly selective inhibitors of KIT and PDGFRα mutants resistant to imatinib and other TKIs TKI resistance Mutants in Kinase Activation loop DOUBLE MUTANTS In both kinase JM domain and activation loop Compound Exon 18 PDGFRα IC 50 nm Exon 17 Exon 11/17 KIT KIT D816V V560G/D816V IC 50 nm IC 50 nm BLU-285 0.24 0.27 0.10 imatinib 759 8150 6145 sunitinib 120 207 97.2 regorafenib 810 3640 1685 midostaurin 4.9 2.8 1.4 crenolanib 0.2 1.5 1.2 New Agent inhibits mutant kinases Standard Drugs (Type II inhibitors) Are INACTIVE Non-selective Type I inhibitors Approved Standard of Care Drugs for GIST in 2018 Avapritinib (BLU-285) imatinib sunitinib regorafenib crenolanib midostaurin Kinome screening at 3 µm Kinome illustration reproduced courtesy of Cell Signaling Technology, Inc. (www.cellsignal.com) Adapted from Evans E, et al. AACR 2017 17
Antitumor activity of Avapritinib (BLU-285) in PDGFRA D842-mutant GIST Maximum reduction: sum of diameter change from baseline (%) 100 80 60 40 0-20 -40-60 -80 31 of 31 (100%) patients with tumor shrinkage by central radiology review D842-843V D842-H845V 20 PD 400 400 200 90 30 600 400 60 200 60 135 400 300 90 400 90 60 400 60 400 30 30 135 135 300 300 300 90 400 Mutation status* SD PR -100 Numbers under bars indicate dose level 400 200 CR * per archival tumor and ctdna Adapted from Heinrich, M., et al. CTOS 2017
DCC-2618, a novel pan-kit and PDGFRA Kinase Switch Control Inhibitor: Best Response in Advanced GIST patients per RECIST (n = 37) Somaiah N, et al. CTOS Annual Meeting 2017
How to Avoid or Overcome TKI Resistance in GIST Several trials designed to overcome resistance Combinations of drugs or other new agents PLX-9486 Crenolanib Immuno-Oncology Checkpoint inhibitors have been negative to date in GIST (but new combinations are being studied) Clinical trial participation is key to improving outcomes
Update on Managing Sarcomas other than GIST
Physicians (and patients) have lots of systemic therapy options for management of advanced Soft Tissue Sarcomas
Dose-Intense Combination Chemotherapy has marginal additional benefit over single-agent doxorubicin for unselected metastatic soft tissue sarcomas
Doxorubicin + ifosfamide Combination Chemotherapy vs. Doxorubicin alone for Metastatic Soft Tissue Sarcomas: EORTC 62012 Eligibility: High grade STS (2-3) Age 18-60 No previous chemo for advanced/metastatic disease WHO PS < 2 Stratification: Age (<50 vs 50) PS (0 vs 1) Liver metastases (0 vs +) Histological grade (2 vs 3) Single-agent Doxorubicin (75 mg/m 2 bolus or as a 72 hour continous i.v. infusion) R New Treatment: Doxorubicin B 25 mg/m 2 d 1-3 + Ifosfamide 2.5 g/m 2 d 1-4 + PEG-Filgrastim 6 mg s.c. d5 Judson I, et al. ESMO 2012 and Lancet Oncol. 2014 Mar 4.
Significantly Better Objective Response Rate for Combination Dox + Ifos Treatment Doxo (n=228) Doxo-Ifos (n=227) Total (n=455) n (%) n (%) n (%) Complete Response 1 (0.4) 4 (1.8) 5 (1.1) Partial Response 30 (13.2) 56 (24.7) 86 (18.9) Overall RESPONSE RATE 13.6 26.5 ** No Change 105 (46.1) 114 (50.2) 219 (48.1) Progressive Disease 74 (32.5) 30 (13.2) 104 (22.9) Early Death - Progression 4 (1.8) 5 (2.2) 9 (2.0) Early Death Other cause 3 (1.3) 2 (0.9) 5 (1.1) Not evaluable 11 (4.8) 16 (7.0) 27 (5.9) ** Significant difference between the two arms: p < 0.001 Judson I, et al. ESMO 2012 and Lancet Oncol. 2014 Mar 4. 25
Progression-Free Survival: Statistically Different (p=0.003) Favoring Dox+Ifos Dox + Ifos Median PFS: 7.4 months (ORR 27%) Dox Median PFS 4.6 months (ORR 14%) (year) Judson I, et al. ESMO 2012 and Lancet Oncol. 2014 Mar 4. 26
Overall survival: Dox+Ifos = Dox alone 100 90 80 70 60 50 40 HR = 0.83 (95.5% CI 0.67 1.03) Stratified logrank test, p = 0.076 No difference statistically 30 20 10 0 0 1 2 3 4 5 6 7 8 (years) O N Number of patients at risk : Treatment 188 228 113 54 29 19 14 9 2 Doxo 184 227 130 64 30 20 13 7 3 DxIf Judson I, et al. ESMO 2012 and Lancet Oncol. 2014 Mar 4. 27
No Significant Improvement in Clinical Outcomes with Adjuvant Combination Chemotherapy (doxorubicin+ifos) vs. observation for Unselected Soft-Tissue Sarcoma Patients Following Resection Minor Benefit in Relapse-Free Survival only in first 3 years Woll PJ et al. Lancet Oncology, 2012 Oct;13(10):1045-54
Improving on chemotherapy alone with addition of Olaratumab, a Monoclonal Ab targeting PDGFRA Fully human monoclonal antibody of immunoglobin G class 1 (IgG1) that selectively binds PDGFRα 1 Blocks PDGF binding and PDGF-induced signalling 1 Demonstrated activity in both in vitro and in vivo cancer models known to be driven by a PDGF-PDGFRα autocrine loop 2 Demonstrated antitumor activity alone 1 or in combination with doxorubicin in human sarcoma xenograft models 1. Loizos N et al. Mol Cancer Ther. 2005;4:369-379. 2. Gerber DE et al. Mol Cancer Ther. 2012;11:2473-2482.
Doxorubicin +/- Olaratumab Open-Label, Multicenter, Phase 1b/2 Trial Phase 2 Advanced STS Stratification: PDGFRα expression by IHC # Lines of prior treatment ECOG PS Histology (leiomyosarcoma, synovial sarcoma, other STS) R A N D O M I Z A T I O N Olaratumab 15 mg/kg d 1 and 8 + Dox 75 mg/m 2 d 1 x 8 cycles (21 d) a Doxorubicin alone 75 mg/m 2 d 1 x 8 cycles Olaratumab monotherapy until progression Olaratumab monotherapy after progression (optional) Primary endpoint: PFS (predefined statistical significance: 2-sided alpha = 0.2) Secondary endpoints: OS, ORR, PFS at 3 mo Biomarker: PDGFRα (IHC) and related ligands a During cycles 5-8, patients receiving Dox could receive dexrazoxane, at the investigator s discretion. Tap W et al. ASCO 2015. Abstract 10501 and Lancet 2016; 388: 488 97
Doxorubicin +/- Olaratumab Open-Label, Multicenter, Phase 1b/2 Trial PFS Median 6.6 vs 4.1 months (N.S.) OS Median 26.5 vs 14.7 months (p = 0.0003) U.S. FDA and European Medicines Agency Accelerated Approval and Conditional Approval in November 2016 Tap W et al. ASCO 2015. Abstract 10501 and Lancet 2016; 388: 488 97
Histology-Specific Management of Soft Tissue Sarcomas
Phase III Study Design in chemo-refractory STS PAZOPANIB vs. PLACEBO R A N D O M I Z E 2:1 Pazopanib (800 mg QD) n=246 Placebo (Matching dose 800 mg) n=123 Primary Endpoint PFS by Independent Review Secondary Endpoints Overall Survival Overall Response Rate Quality of Life Safety N= 369 Soft Tissue Sarcomas (Excluding LIPOSARCOMA and GIST) after chemo failure Stratification Factors: Performance status # of Prior lines of systemic therapy for advanced disease NO cross-over of patients on placebo to pazopanib A 33
Pazopanib Significantly Improves Progression-Free Survival but not Overall Survival in Metastatic Soft Tissue Sarcomas progressing after standard chemotherapy Van der Graaf W, et al. Lancet 2012: 379; 1879-1886 A 34
Trabectedin is associated with better patient outcomes in leiomyosarcomas and liposarcomas than other subtypes of Soft Tissue Sarcomas: Expanded Access Trial Trabectedin, a marine-derived DNA minor groove binding drug Samuels BL et al. Annals of Oncology, Volume 24, Issue 6, 1 June 2013, Pages 1703 1709
Improved Disease Control (PFS) with Trabectedin vs. Dacarbazine in Leiomyosarcomas and Liposarcomas PFS events: 329 (63.5% of 518 patients) mpfs Trabectedin: 4.2 months mpfs Dacarbazine: 1.5 months HR (95% CI) = 0.55 (0.436,0.696) p<0.0001 Unstratified analysis Demetri GD et al. J Clin Oncol. 2016 Mar 10;34(8):786-93
PFS Improved for both Leios and Lipos with Trabectedin Demetri GD et al. J Clin Oncol. 2016 Mar 10;34(8):786-93
Overall Survival (Final Analysis): Trabectedin vs. Dacarbazine Phase 3 Trial in Leiomyosarcomas and Liposarcomas OS events: 381 median OS Trabectedin: 13.7 months median OS Dacarbazine: 13.1 months HR (95% CI)=0.927 (0.748, 1.150) p=0.4920 Patel S. et al. ESMO Vienna Sept 2015
Trabectedin: Histology-specific FDA approval October 2015 Trabectedin is FDA approved for leiomyosarcomas and liposarcomas after prior doxorubicin-based chemotherapy
Eribulin vs. Dacarbazine in Leiomyosarcomas and Liposarcomas: No Difference in PFS (Secondary Endpoint) for all patients Survival Probability 1.0 0.8 0.6 0.4 0.2 Eribulin, a marine-derived microtubule-targeting Eribulin drug Eribulin Dacarbazine Median (months) Dacarbazine 2.6 2.6 HR (95% CI) 0.877 (0.710, 1.085) Stratified P- value 0.2287 0.0 0 3 6 9 12 15 18 21 24 27 Survival Time (months) Patients at Risk: Eribulin 228 79 41 27 16 9 5 2 1 0 Dacarbazine 224 63 27 14 6 4 2 1 1 0 Schöffski P et al. Lancet. 2016;387:1629-1637
Eribulin vs. Dacarbazine in Leiomyosarcomas and Liposarcomas: Significantly better OS (primary endpoint) with eribulin Survival Probability 1.0 0.8 0.6 0.4 0.2 Eribulin Dacarbazine Eribulin Dacarbazine Median (months) 13.5 11.5 HR (95% CI) 0.768 (0.618, 0.954) Stratified P-value 0.0169 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Survival Time (months) Patients at Risk: Eribulin 228 197 162 138 120 97 88 64 45 34 25 14 7 1 1 0 Dacarbazine 224 190 158 130 103 81 64 45 32 24 16 8 3 0 0 0 Primary endpoint of OS was met, indicating a 2-month improvement in median OS with eribulin Schöffski P et al. Lancet. 2016;387:1629-1637
NO IMPROVEMENT with Eribulin over Dacarbazine for Leiomyosarcomas in the Preplanned OS subgroup analysis Events/n Group/Subgroup Eribulin Dacarb Histology LIPOSARCOMA LEIOMYOSARCOMA 52/71 124/15 7 63/72 118/15 2 HR (95% CI) 0.511 (0.346, 0.753) 0.927 (0.714, 1.203) Median (months) Eribulin Dacarb 15.6 12.7 8.4 13 Point of No Difference AJCC, American Joint Committee 0.25 1 4 16 on Cancer. Schöffski P et al. Lancet. 2016;387:1629-1637 Favors eribulin Favors dacarbazine
Eribulin improves Progression-free survival in Liposarcoma Patients vs. dacarbazine PFS significantly better with eribulin compared with dacarzabine (2.9 vs 1.7; HR: 0.521 [95% CI: 0.346 0.784]; nominal p = 0.0015). Demetri GD et al. J Clin Oncol. 2017 Oct 20;35(30):3433-3439
Eribulin improves Overall survival in Liposarcoma Patients vs. dacarbazine OS was longer with eribulin treatment compared with dacarbazine (15.6 vs 8.4 months; HR: 0.511; 95% CI: 0.346 0.753; nominal p = 0.0006). OS MEDIAN 15.6 vs. 8.4 months Demetri GD et al. J Clin Oncol. 2017 Oct 20;35(30):3433-3439
Eribulin: Histology-specific FDA approval January 2016 Eribulin is FDA approved only for liposarcomas after prior doxorubicin-based chemotherapy
What is the role for advanced molecular diagnostics with Next Generation Sequencing (NGS) Tests in choosing therapy for advanced Soft Tissue Sarcomas?
GIST Undifferentiated Sarcoma
Strong TRK expression by IHC
Large Gene Panel NGS Analysis of Undifferentiated Sarcoma (not GIST) Patient
Impact of TRK-inhibitor (Larotrectenib) on Patient with Undifferentiated Sarcoma (not GIST) with NTRK1-fusion Confirmed major Partial Remission after 2 cycles of larotrectinib Baseline Cycle 4
Progression on Larotrectenib after 7 months in Metastatic Undifferentiated Sarcoma 15002-155.001, LOXO-EXT-17007, Dana Farber New Baseline End of cycle 1 of 2 nd Generation TRK inhibitor
Disappointing Level of Activity of Immune Checkpoint Inhibitors in Sarcoma Patients Objective Responses 4/10 Undiff Pleomorphic Sarcomas 2/9 Liposarcomas (de-diff)
Disappointing Level of Activity of Immune Checkpoint Inhibitors in Sarcoma Patients Nivolumab Alone Nivolumab + Ipilimumab
Disappointing Level of Activity of Immune Checkpoint Inhibitors in Sarcoma Patients Nivolumab Alone PFS OS Nivolumab + Ipilimumab PFS OS
Efficacy of Autologous T-cells with Genetically Engineered to express an optimized T-Cell Receptor Targeting NY-ESO1: 60% Response Rate # ** ** * ** Modified from slide courtesy of Crystal McKall, Stanford
Other New Molecular Targeted Approaches for Therapy of Defined Subtypes of Soft Tissue Sarcomas
Epigenetic Next Generation Targets in Sarcomas Tazemetostat (EZH2 inhibitor) for INI-1 deficient malignant rhabdoid tumors and epithelioid sarcomas Tazemetostat Gounder et al. ASCO 2017 57
Summary: New Approaches to GIST and Sarcomas There are several recent therapeutic advances in practice and in clinical practice for patients with sarcomas The first monoclonal antibody used for sarcomas (Olaratumab) with doxorubicin may improve survival, but needs phase III data to confirm Several new drugs for TKI-resistant GIST are promising Sarcomas continue to prove that translational research can improve the outcomes of patients with well-defined and carefully studied subsets based great science and careful clinical investigation