2020 master class course best practices and expanding ...€¦ · 2 george d. demetri, md faculty...

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2020 Master Class CourseBest Practices and Expanding Treatment Options in Soft Tissue Sarcomas including GISTGeorge D. Demetri, MD FACP FASCO

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George D. Demetri, MDFaculty 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.

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Soft Tissue Sarcomas: Approximate Anatomic Distribution

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%

Head and Neck 10%

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GIST

Leiomyo-Sarcomas

Liposarcomas

Un-differentiated

Ducimetiere et al. PLoS ONE 6(8): e20294. doi:10.1371/journal.pone.0020294.

Sarcomas represent an exceedingly diverse set of diseases

BoneSarcomas

10%

Chart1

Bone Primary (Osteosarcoma/Chondrosarcoma/Ewing)

GIST

Liposarcoma

Soft-Tissue Ewing sarcoma/PNET

Kaposi sarcoma

Dermatofibrosarcoma

Unclassified sarcoma

Leiomyosarcoma

Rhabdomyosarcoma

Angiosarcoma

Myxofibrosarcoma

Synovial sarcoma

Endometrial stromal sarcoma

Other very rare subtypes

0.11

0.18

0.15

0.01

0.03

0.05

0.16

0.11

0.04

0.03

0.02

0.02

0.02

0.07

Sheet1

Bone Primary (Osteosarcoma/Chondrosarcoma/Ewing)11%

GIST18%

Liposarcoma15%

Soft-Tissue Ewing sarcoma/PNET1%

Kaposi sarcoma3%

Dermatofibrosarcoma5%

Unclassified sarcoma16%

Leiomyosarcoma11%

Rhabdomyosarcoma4%

Angiosarcoma3%

Myxofibrosarcoma2%

Synovial sarcoma2%

Endometrial stromal sarcoma2%

Other very rare subtypes7%

Sheet2

What’s New in GIST? Necessity to Test for Tumor Mutations

GIST

KIT mutation (80%)

SPECIFIC MUTATIONSimpact patient outcomes

KIT exon 11 point mutationsconfer overall favorable prognosis

KIT exon 9 mutationsassociated with worse prognosis

Adapted from Corless CL, et al. Nat Rev Cancer. 2011;11(12):865-878


GIST

KIT mutation (80%)

PDGFRA mutation(10% in met, 25% in gastric primary)


PDGFRA D842V mutation =good risk in primary GIST.

Imatinib not effective.2020 FDA approved

new selective inhibitor avapritinib


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Activity of Avapritinib in PDGFRA D842-mutant GIST

49 of 56 (88%) patientswith confirmed objective response

by central radiology review

Heinrich M. et al.


GIST

KIT mutation (80%)


SDH mutation or deficiency by IHC(either SDHA, SDHB, or SDHC)

(approx. 10%)


Most common pediatric typeEpithelioid+spindle cells

Gastric primaries, often multifocalDIFFERENT MOLECULAR MECHANISM!


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Novel Epigenetic Mechanism for Oncogene Activation inSDH-Deficient GIST

Flavahan W. et al, Nature 2019

Genetic Epigenetic

Oncogene Activation

KIT mutationFGF/KIT

insulator lossesGIST

TAD boundary(disrupted)

Oncogene

CTEP 10411: Trial toTarget FGFR inSDH-deficient GIST

Brad Bernstein MD PhD

Suzanne George, MD


GIST

KIT mutation (80%)


NTRK fusions; BRAF or NF1 mutations; (

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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

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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

85% Risk Reduction of Disease Progression or Death with Ripretinib Compared to Placebo in > 4th Line GIST

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*Double-blind period.

Ripretinib(n=85)

Placebo(n=44)

Events, n (%) 51 (60.0%) 37 (84.1%)

Censored, n (%) 34 (40.0%) 7 (15.9%)

PFS 6 months, % (95% CI)

51.0% (39.4–61.4)

3.2% (0.2–13.8)

100

80

60

40

20

00 2 4 6 8 10 12 14

Months

Surv

ival

pro

babi

lity

(%)

8544

647

524

371

181

80

1 0Ripretinib 150 mg QDPlacebo

Number of patients at risk:

Ripretinib 150 mg QDPlaceboCensored

Median PFS 6.3 months vs 1.0 month* HR=0.15 (95% CI, 0.09–0.25)P

OS Benefit: 64% Risk Reduction of Death with RipretinibCompared to Placebo in > 4th Line GIST

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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)

OS 12 months, % (95% CI) 65.4% (51.6–76.1)

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

00 2 4 6 8 10 12 16

Months

Surv

ival

pro

babi

lity

(%)

8544

Ripretinib 150 mg QDPlacebo

Number of patients at risk:

Ripretinib 150 mg QDPlacebo

14

8134

7629

6724

4214

248

101

00

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Censored

Blay JY, CTOS Presentation, Tokyo Nov 2019

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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

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Immune Checkpoint Inhibitors:Activity in Sarcoma Subtypes

4/10 Undiff Pleomorphic Sarcs

Objective Responses

2/9 Liposarcomas (De-Diff)

NTRK gene fusions are rare butrelevant 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 cancerSalivary gland carcinoma (MASC)

Lung cancerBreast carcinoma (secretory)

PancreaticCholangiocarcinoma

GIST withnormal KIT, PDGFRA, SDH, BRAF

ColonMelanoma

Sarcomas (undifferentiated andmultiple other subtypes)

Gliomas

Infantile fibrosarcomaThyroid cancer

Congenital nephromaSpitz nevi

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

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Epithelioid Sarcoma is characterized by loss of INI1

Tazemetostat: first-in-class, selective oral inhibitor of EZH2

LOSS OF INI1 CREATES AN ONCOGENIC DEPENDENCY ON EZH2

• Coordinated gene transcription• Appropriate cell differentiation and growth• Tumor suppression

Enhanced EZH2 activity Repressed cell differentiation Promotion of tumor growth

INI1lossINI1

SWI/SNFSWI/SNF

EZH2 EZH2

PRC2PRC2

NORMAL

Adapted from Stacciotti S, et al. ASCO June 2019

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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)

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Pexidartinib for Tenosynovial Giant Cell Tumor: Phase 3 placebo-controlled trial. (FDA approval Aug 2019)

Tap WD, et al.

Durable Responses: Median Duration stillnot met after median 22 months of follow-up

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

Modified from Van Tine et al. ESMO 2019 presentation, 2019

Clinical Responses in MAGE-A4+ Sarcomas with ADP-A2M4 Genetically Engineered Autologous T-Cells

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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)

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Sorafenib improves PFS in Desmoid –but responses are seen with placebo as well as sorafenib

Gounder MM, et al.

Placebo Sorafenib

Changes from baseline in Tumor Size

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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

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THANK YOU for your attention

George D. Demetri, M.D.Sarcoma Center

Dana-Farber Cancer Institute

Professor of Medicine, Harvard Medical SchoolBoston, Massachusetts

[email protected]@DrSarcoma

2020 Master Class Course�Best Practices and Expanding Treatment Options in Soft Tissue Sarcomas including GIST George D. Demetri, MD�Faculty DisclosureSoft Tissue Sarcomas: Approximate Anatomic DistributionSlide Number 4Slide Number 5Slide Number 6Activity of Avapritinib in PDGFRA D842-mutant GISTSlide Number 8Slide Number 9Slide Number 10Adjuvant therapy after resection for PRIMARY localized GIST at moderate/high risk of recurrenceManaging Recurrent or Metastatic GIST85% Risk Reduction of Disease Progression or Death with Ripretinib Compared to Placebo in > 4th Line GISTOS Benefit: 64% Risk Reduction of Death with Ripretinib Compared to Placebo in > 4th Line GISTAdvances in Management of Other Sarcoma SubtypesSlide Number 16NTRK gene fusions are rare but�relevant to sarcomas in both adults and childrenFrequent and Durable Responses in TRK-FUSION+ Sarcomas and other cancers with either Larotrectinib vs EntrectinibEpithelioid Sarcoma is characterized by loss of INI1Tazemetostat (FDA accelerated approval, Jan 2020): Activity in Epithelioid Sarcoma PatientsPexidartinib for Tenosynovial Giant Cell Tumor: �Phase 3 placebo-controlled trial. (FDA approval Aug 2019)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)Slide Number 23Slide Number 24Changes in Management Approach to Desmoid TumorSorafenib improves PFS in Desmoid – �but responses are seen with placebo as well as sorafenibSlide Number 27THANK YOU for your attention

2020 master class course best practices and expanding ...€¦ · 2 george d. demetri, md faculty...

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