PowerPoint Presentation1
2021 Master Class Course Best Practices and Expanding Treatment Options in Soft Tissue Sarcomas including GIST George D. Demetri, MD FACP FASCO
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• 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, Synlogic, WCG/Arsenal Capital, MJ Hennessey/OncLive, C4 Therapeutics, McCann Health, Rain Therapeutics
• Consultant/SAB member with minor equity holding: G1 Therapeutics, Caris Life Sciences, Erasca Pharmaceuticals, RELAY Therapeutics, Bessor Pharmaceuticals, Champions Biotechnology, CellCarta, ikena Oncology, Kojin Therapeutics
• Board of Directors member and Scientific Advisory Board Consultant with minor equity holding: Blueprint Medicines
• 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.
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Upper extremities 15%
Lower extremities 15% Retroperitoneal, pelvic and visceral 50% (includes GIST and GYN sarcomas) Modified from Clark MA et al.
NEJM 2005;353:701-11
Trunk 10%
Bone Sarcomas
7%
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What’s New in GIST? Necessity to Test for Tumor Mutations
GIST
NTRK fusions; BRAF or NF1 mutations; (<2%)
SDH mutation or deficiency by IHC (either SDHA, SDHB, or SDHC)
(approx. 10%)
Require therapy with specific Rx: TRK-fusion inhibitor,
BRAF inhibitor, MEK pathway inhibitor
Adapted from Corless CL, et al. Nat Rev Cancer. 2011;11(12):865-878
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49 of 56 (88%) patients with confirmed objective response
by central radiology review
Heinrich M. et al.
Flavahan W. et al, Nature 2019
Genetic Epigenetic
Oncogene Activation
Brad Bernstein MD PhD
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Interactive Response Question: choose the best answer Which of the following is FALSE about adjuvant therapy after complete surgical resection of primary localized GIST?
1. The duration of adjuvant imatinib therapy is often 3 years, based on randomized data
2. The risk of recurrence decreases in the first 2 years after discontinuation of adjuvant imatinib therapy
3. There is no time limit on the duration of adjuvant imatinib therapy in the formal FDA approval for this indication
4. Adjuvant imatinib therapy is associated with significantly longer recurrence-free survival
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Adjuvant therapy after resection of PRIMARY LOCALIZED GIST at moderate to high risk of recurrence
• Standard is post-operative adjuvant imatinib for at least 3 years
• For high risk of recurrence, adjuvant imatinib may continue for > 5 years since risk of recurrence increases once imatinib therapy is stopped
• AVOID A KEY ERROR: if the patient stops adjuvant imatinib, increase the frequency of surveillance scans (since risk of recurrence rises). Restarting imatinib is usually effective to control recurrence.
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• Lifelong kinase inhibition therapy • Standard sequence Rx for KIT-mutant GIST:
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
ripretinib
Ripretinib is superior to placebo for PFS in > 4th Line GIST (after failure of imatinib, sunitinib, and regorafenib)
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PFS 6 months, % (95% CI)
51.0% (39.4– 61.4)
3.2% (0.2–13.8)
Months
Number of patients at risk:
Ripretinib 150 mg QD PlaceboCensored
Median PFS 6.3 months vs 1.0 month* HR=0.15 (95% CI, 0.09–0.25) P<0.0001
Blay JY, et al. Lancet Oncology 2020;21: 923-34
OS Benefit of Ripretinib vs.Placebo in > 4th Line GIST (after failure of imatinib, sunitinib, and regorafenib)
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*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.
Ripretinib (n=85)
Placebo (n=44)
Events, n (%) 26 (30.6%) 26 (59.1%) Censored, n (%) 59 (69.4%) 18 (40.9%) OS 6 months, % (95% CI) 84.3% (74.5–
90.6) 55.9% (39.9–69.2)
25.9% (7.2–49.9)
Median OS 15.1 vs 6.6 months HR=0.36 (95% CI, 0.20–0.62) Nominal P = 0.0004*100
80
60
40
20
Months
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Blay JY, et al. Lancet Oncology 2020;21: 923-34
Failure of avapritinib to demonstrate superiority in PFS compared to regorafenib in 3rd Line GIST
(after resistance to imatinib and then sunitinib)
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Kang Y-K, George S, et al. J Clin Onc 2021 ascopubs.org/journal/jco, August 3,2021: DOI https://doi.org/10.1200/JCO.21.00217
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Failure of avapritinib to demonstrate superiority in Duration of Response over regorafenib in 3rd Line GIST
(after resistance to imatinib and then sunitinib) Regorafenib
Kang Y-K, George S, et al. J Clin Onc 2021 ascopubs.org/journal/jco, August 3,2021: DOI https://doi.org/10.1200/JCO.21.00217
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4/10 Undiff Pleomorphic Sarcs
2/9 Liposarcomas (De-Diff)
Other clinical trials demonstrate benefit of PD1 or PDL1 inhibitors in • Alveolar Soft Part Sarcomas • Angiosarcoma of Scalp • Rare other types
• New combination Rx in trials
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Interactive Response Question: choose the best answer NTRK gene fusions are… (choose one)
1. reliably diagnosed by an expert histopathologist in nearly all cancers when present
2. always noted to contain the same chimeric fusion partner gene across patients
3. proven drivers of GIST without activating kinase mutations
4. often found in GIST which also harbor KIT or PDGFRA mutations
NTRK gene fusions are rare but relevant to sarcomas in both adults and children
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.
Brain tumors (glioma, GBM, astrocytoma)
Thyroid cancer Salivary gland carcinoma (MASC)
Lung cancer Breast carcinoma (secretory)
Pancreatic Cholangiocarcinoma
Colon Melanoma
Gliomas
Sarcoma (multiple subtypes)
Frequent and Durable Responses in TRK-FUSION+ Sarcomas and other cancers with either Larotrectinib vs Entrectinib
Lassen. ESMO 2018. Abstr 279. Drilon. NEJM. 2018;378:731. Demetri. ESMO 2018. Abstr LBA17. Doebele. Lancet Oncol. 2020;21:271.
Larotrectinib Entrectinib
EZH2-inhibitor Tazemetostat in Epithelioid Sarcoma Patients (INI-1 deficient): FDA accelerated approval, Jan 2020
Best percent change in sum of diameters of target lesions Durability of disease control
Gounder M. et al. Lancet Oncology (online October 6, 2020)
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CSF-1R inhibitor Pexidartinib for Tenosynovial Giant Cell Tumor: Phase 3 placebo-controlled trial (FDA approval Aug 2019)
Tap WD, et al.
Durable Responses: Median still not reached after 22 months of follow-up
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Synovial Sarcoma is driven by a fusion which alters the BAF (SWI/SNF) chromatin remodeling complex
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Figure adapted from Varga J, et al.
New Phase I Clinical Trial of BRD9 targeted Protein Degrader FHD-609
ClinicalTrials.gov NCT04965753
Synovial Sarcomas and High Grade Myxoid/Round Cell Liposarcoma can uniquely overexpress cancer-germline antigens
- NY-ESO-1 - MAGE-A4
Autologous T-cells can be genetically engineered to express a new optimized T-cell receptor to make the immune cells act as “living drugs” against these sarcomas
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
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Durable Responses in Metastatic Synovial Sarcoma Patients with MAGE-A4 Targeted Engineered T-Cells
Modified from Van Tine et al. CTOS 2020
https://www.ctos.org/Meeting/2020On-DemandLibrary.aspx
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Impact of MDM2 inhibitor Milademetan
Gounder M, et al.
PHASE 3 TRIAL OF MILADEMETAN OPENED FOR ACCRUAL SEPTEMBER 2021
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Evolving Management of 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
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Summary: New Approaches to Sarcomas and GIST
• Best care starts with the most accurate diagnosis: expert pathology review and consideration of genomic profiling
• New trials and new approaches are rapidly changing management
• It is hard to keep up – lots of new studies and therapies!
• Expert centers are here to help you care for your patients
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George D. Demetri, M.D. Sarcoma Center
Dana-Farber Cancer Institute
gdemetri@dfci.harvard.edu @DrSarcoma
2021 Master Class CourseBest Practices and Expanding Treatment Options in Soft Tissue Sarcomas including GIST
George D. Demetri, MDFaculty Disclosure
Sarcomas can occur in any anatomic site
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Interactive Response Question: choose the best answer
Adjuvant therapy after resection of PRIMARY LOCALIZED GIST at moderate to high risk of recurrence
Managing metastatic (or recurrent) GIST
Ripretinib is superior to placebo for PFS in > 4th Line GIST(after failure of imatinib, sunitinib, and regorafenib)
OS Benefit of Ripretinib vs.Placebo in > 4th Line GIST(after failure of imatinib, sunitinib, and regorafenib)
Failure of avapritinib to demonstrate superiority in PFS compared to regorafenib in 3rd Line GIST (after resistance to imatinib and then sunitinib)
Failure of avapritinib to demonstrate superiority in Duration of Response over regorafenib in 3rd Line GIST(after resistance to imatinib and then sunitinib)
Advances in Management of Other Sarcoma Subtypes
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Interactive Response Question: choose the best answer
NTRK gene fusions are rare butrelevant to sarcomas in both adults and children
Frequent and Durable Responses in TRK-FUSION+ Sarcomas and other cancers with either Larotrectinib vs Entrectinib
EZH2-inhibitor Tazemetostat in Epithelioid Sarcoma Patients (INI-1 deficient): FDA accelerated approval, Jan 2020
CSF-1R inhibitor Pexidartinib for Tenosynovial Giant Cell Tumor: Phase 3 placebo-controlled trial (FDA approval Aug 2019)
Synovial Sarcoma is driven by a fusion which alters the BAF (SWI/SNF) chromatin remodeling complex
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Evolving Management of Desmoid Tumor
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