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2020 Master Class Course Best Practices and Expanding Treatment Options in Soft Tissue Sarcomas Including GIST George D

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2020 Master Class Course Best Practices and Expanding Treatment Options in Soft Tissue Sarcomas Including GIST George D 2020 Master Class Course Best Practices and Expanding Treatment Options in Soft Tissue Sarcomas including GIST George D. Demetri, MD FACP FASCO 1 George D. Demetri, MD Faculty Disclosure • Scientific consultant with sponsored research to Dana-Farber: Bayer, Pfizer, Novartis, Epizyme, Roche/Genentech, Epizyme, LOXO Oncology, AbbVie, GlaxoSmithKline, Janssen, PharmaMar, Daiichi-Sankyo, AdaptImmune • Scientific consultant: GlaxoSmithKline, EMD-Serono, Sanofi, ICON plc, MEDSCAPE, Mirati, WCG/Arsenal Capital, Polaris, MJ Hennessey/OncLive, C4 Therapeutics, Synlogic, McCann Health • Consultant/SAB member with minor equity holding: G1 Therapeutics, Caris Life Sciences, Erasca Pharmaceuticals, RELAY Therapeutics, Bessor Pharmaceuticals, Champions Biotechnology, Caprion/HistoGeneX • Board of Directors member and Scientific Advisory Board Consultant with minor equity holding: Blueprint Medicines, Translate BIO • Patents/Royalties: Novartis royalty to Dana-Farber for use patent of imatinib in GIST • Non-Financial Interests: AACR Science Policy and Government Affairs Committee Chair, Alexandria Real Estate Equities, Faculty of this CE activity may include discussions of products or devices that are not currently labeled for use by the FDA. The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off label or investigational uses (any uses not approved by the FDA) of products or devices. 2 Soft Tissue Sarcomas: Approximate Anatomic Distribution Head and Neck 10% Upper extremities 15% Trunk 10% Retroperitoneal, pelvic and visceral Lower extremities 15% 50% (includes GIST and GYN sarcomas) Modified from Clark MA et al. NEJM 2005;353:701-11 3 Sarcomas represent an exceedingly diverse set of diseases Bone Sarcomas 10% GIST Un- differentiated Liposarcomas Leiomyo- Sarcomas 4 Ducimetiere et al. PLoS ONE 6(8): e20294. doi:10.1371/journal.pone.0020294. What’s New in GIST? Necessity to Test for Tumor Mutations SPECIFIC MUTATIONS impact patient outcomes KIT mutation KIT exon 11 point mutations (80%) confer overall favorable prognosis KIT exon 9 mutations associated with worse prognosis GIST Adapted from Corless CL, et al. Nat Rev Cancer. 2011;11(12):865-878 What’s New in GIST? Necessity to Test for Tumor Mutations SPECIFIC MUTATIONS impact patient outcomes KIT mutation (80%) PDGFRA D842V mutation = PDGFRA mutation good risk in primary GIST. (10% in met, 25% in gastric primary) GIST Imatinib not effective. 2020 FDA approved new selective inhibitor avapritinib Adapted from Corless CL, et al. Nat Rev Cancer. 2011;11(12):865-878 Activity of Avapritinib in PDGFRA D842-mutant GIST 49 of 56 (88%) patients with confirmed objective response by central radiology review Heinrich M. et al. 7 What’s New in GIST? Necessity to Test for Tumor Mutations SPECIFIC MUTATIONS impact patient outcomes KIT mutation (80%) PDGFRA mutation (10% in met, 25% in gastric primary) Most common pediatric type SDH GIST mutation or deficiency by IHC Epithelioid+spindle cells (either SDHA, SDHB, or SDHC) (approx. 10%) Gastric primaries, often multifocal DIFFERENT MOLECULAR MECHANISM! Adapted from Corless CL, et al. Nat Rev Cancer. 2011;11(12):865-878 Novel Epigenetic Mechanism for Oncogene Activation in SDH-Deficient GIST Brad Bernstein MD PhD Genetic Epigenetic TAD boundary FGF/KIT (disrupted) KIT mutation insulator losses GIST Oncogene Oncogene Suzanne George, MD Activation Flavahan W. et al, Nature 2019 CTEP 10411: Trial to Target FGFR in SDH-deficient GIST 9 What’s New in GIST? Necessity to Test for Tumor Mutations SPECIFIC MUTATIONS impact patient outcomes KIT mutation (80%) PDGFRA mutation (10% in met, 25% in gastric primary) GIST SDH mutation or deficiency by IHC (either SDHA, SDHB, or SDHC) Require therapy with specific Rx: (approx. 10%) TRK-fusion inhibitor, NTRK fusions; BRAF or NF1 mutations; BRAF inhibitor, (<2%) MEK pathway inhibitor Adapted from Corless CL, et al. Nat Rev Cancer. 2011;11(12):865-878 Adjuvant therapy after resection for PRIMARY localized GIST at moderate/high risk of recurrence • Standard is post-operative adjuvant imatinib for at least 3 years • For high risk of recurrence, 5 years or longer may be better if patient tolerates imatinib well since risk of recurrence increases once imatinib therapy is stopped 11 Managing Recurrent or Metastatic GIST • Standard sequence remains imatinib sunitinib regorafenib • At each point of progression, assess for potential to resect clonal site of solitary or limited progressive disease and continue same Rx • New option for unresectable metastatic disease after failure of all three of these standard kinase inhibitors = RIPRETINIB • FDA approved for > 4th line GIST therapy, May 2020 12 85% Risk Reduction of Disease Progression or Death with Ripretinib Compared to Placebo in > 4th Line GIST 100 Median PFS 6.3 months vs 1.0 month* HR=0.15 (95% CI, 0.09–0.25) Ripretinib Placebo (n=85) (n=44) P<0.0001 80 Events, n (%) 51 (60.0%) 37 (84.1%) Censored, n (%) 34 (40.0%) 7 (15.9%) 60 PFS 6 months, % (95% 51.0% (39.4– 3.2% (0.2–13.8) CI) 61.4) 40 20 Survival probability (%) probability Survival Ripretinib 150 mg QD Censored 0 Placebo 0 2 4 6 8 10 12 14 Months Number of patients at risk: Ripretinib 150 mg QD 85 64 52 37 18 8 1 0 Placebo 44 7 4 1 1 0 *Double-blind period. Blay JY, CTOS Presentation, Tokyo Nov 2019 13 OS Benefit: 64% Risk Reduction of Death with Ripretinib Compared to Placebo in > 4th Line GIST Median OS 15.1 vs 6.6 months HR=0.36 (95% CI, 0.20–0.62) Nominal Ripretinib Placebo (n=85) (n=44) 100 P=0.0004* Events, n (%) 26 (30.6%) 26 (59.1%) Censored, n (%) 59 (69.4%) 18 (40.9%) 80 OS 6 months, % (95% CI) 84.3% (74.5– 55.9% (39.9–69.2) 90.6) OS 12 months, % (95% CI) 65.4% (51.6– 25.9% (7.2–49.9) 60 76.1) 40 20 Survival probability (%) probability Survival Ripretinib 150 mg QD Censored 0 Placebo 0 2 4 6 8 10 12 14 16 Months Number of patients at risk: Ripretinib 150 mg QD 85 81 76 67 42 24 10 2 0 Placebo 44 34 29 24 14 8 1 1 0 *Due to hierarchal testing procedures of the end points, the OS end point could not be formally tested because the ORR was not statistically significant. Blay JY, CTOS Presentation, Tokyo Nov 2019 14 Advances in Management of Other Sarcoma Subtypes • Undifferentiated Pleomorphic Sarcoma • This term is pathologist-dependent, as many cancers can mistakenly be placed into this diagnostic rubric, including • Poorly differentiated sarcomatoid carcinomas • Many other sarcomas or even some melanomas 15 Immune Checkpoint Inhibitors: Activity in Sarcoma Subtypes Objective Responses 4/10 Undiff Pleomorphic Sarcs 2/9 Liposarcomas (De-Diff) 16 NTRK gene fusions are rare but relevant to sarcomas in both adults and children Brain tumors (glioma, GBM, astrocytoma) Salivary gland carcinoma (MASC) Thyroid cancer Lung cancer Breast carcinoma (secretory) Pancreatic Cholangiocarcinoma Gliomas Colon GIST with Thyroid cancer Infantile fibrosarcoma Melanoma normal KIT, PDGFRA, SDH, BRAF Congenital nephroma Spitz nevi Sarcomas (undifferentiated and Sarcoma (multiple subtypes) multiple other subtypes) Amatu. ESMO Open. 2016;1:e000023. Urano. Hum Pathol. 2015;46:94. Knezevich. Nat Gen. 1998;18:184. Watanabe. Cancer Genet Cytogenet. 2002;136:10. Hyman. ASCO 2017. Abstr LBA2501. Gatalica. AACR-NCI-EORTC 2017. Abstr A047. Frequent and Durable Responses in TRK-FUSION+ Sarcomas and other cancers with either Larotrectinib vs Entrectinib Larotrectinib Entrectinib Lassen. ESMO 2018. Abstr 279. Drilon. NEJM. 2018;378:731. Demetri. ESMO 2018. Abstr LBA17. Doebele. Lancet Oncol. 2020;21:271. Epithelioid Sarcoma is characterized by loss of INI1 LOSS OF INI1 CREATES AN ONCOGENIC Tazemetostat: first-in-class, DEPENDENCY ON EZH2 selective oral inhibitor of EZH2 SWI/SNF SWI/SNF NORMAL PRC2 INI1 PRC2 INI1 loss EZH2 EZH2 • Coordinated gene transcription Enhanced EZH2 activity • Appropriate cell differentiation and growth Repressed cell differentiation • Tumor suppression Promotion of tumor growth Adapted from Stacciotti S, et al. ASCO June 2019 19 Tazemetostat (FDA accelerated approval, Jan 2020): Activity in Epithelioid Sarcoma Patients Best percent change in sum of diameters of target lesions Durability of disease control Gounder M. et al. Lancet Oncology (online October 6, 2020) 20 Pexidartinib for Tenosynovial Giant Cell Tumor: Phase 3 placebo-controlled trial. (FDA approval Aug 2019) Durable Responses: Median Duration still not met after median 22 months of follow-up Tap WD, et al. 21 Variable Efficacy of Genetically Engineered Autologous T-cells with an optimized T-Cell Receptor Targeting NY-ESO1 (and different pre-cell-infusion chemotherapy regimen intensity) 50% Response Rate 27% Response Rate Modified from Van Tine et al. ESMO 2019 presentation, 2019 Clinical Responses in MAGE-A4+ Sarcomas with ADP-A2M4 Genetically Engineered Autologous T-Cells Modified from Van Tine et al. ESMO 2019 presentation, 2019 Changes in Management Approach to Desmoid Tumor • Up to 1500 cases per year in USA • FAP associated (15%) with loss of function of APC gene product and subsequent accumulation of β-cateinin • Sporadic (85%): point mutations in the β-cateinin gene with aberrant stability and accumulation • Least aggressive surgical intervention is advised • Medical therapies preferred (e.g. anti-inflammatory agents, low dose anthracyclines, vinca alkaloids, methotrexate, or TKI) 25 Sorafenib improves PFS in Desmoid – but responses are seen with placebo as well as sorafenib Changes from baseline in Tumor Size Placebo Sorafenib Gounder MM, et al. 26 Summary: New Approaches to Sarcomas and GIST • The most expert and detailed diagnosis is key to management • Referral to centers with expertise in all disciplines is helpful • New trials and new approaches change management • It is hard to keep up – lots of new therapies! • Expert centers are here to help you care for your patients 27 THANK YOU for your attention George D. Demetri, M.D. Sarcoma Center Dana-Farber Cancer Institute Professor of Medicine, Harvard Medical School Boston, Massachusetts [email protected] @DrSarcoma 28.
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