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CYCLING MULTI-KINASE INHIBITORS IN IMATINIB-RESISTANT GASTROINTESTINAL STROMAL TUMORS TO MAXIMIZE DISEASE CONTROL: PRECLINICAL AND CLINICAL RATIONALE César.

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Presentation on theme: "CYCLING MULTI-KINASE INHIBITORS IN IMATINIB-RESISTANT GASTROINTESTINAL STROMAL TUMORS TO MAXIMIZE DISEASE CONTROL: PRECLINICAL AND CLINICAL RATIONALE César."— Presentation transcript:

1 CYCLING MULTI-KINASE INHIBITORS IN IMATINIB-RESISTANT GASTROINTESTINAL STROMAL TUMORS TO MAXIMIZE DISEASE CONTROL: PRECLINICAL AND CLINICAL RATIONALE César Serrano, Grant Eilers, Meijun Zhu, Anu Gupta, George D. Demetri, Suzanne George, Sebastian Bauer, Brian P. Rubin, Jonathan A. Fletcher Brigham and Women’s Hospital; Dana-Farber Cancer Institute; Harvard Medical School, Boston, MA, USA; Lerner Research Institute and Cleveland Clinic, Cleveland, OH; West German Cancer Center, Essen, Germany Paper 037 CTOS 18 th Annual Meeting Oct 30 - Nov 2, 2013 New York

2 KIT and PDGFRA are primary drivers of oncogenic signaling in GISTs. KIT inhibition with tyrosine-kinase inhibitors (TKIs)improves outcomes in most GIST patients. Resistance to TKIs eventually emerges in virtually all GIST patients. KIT secondary resistance mutations are the main mechanism of TKI failure. Background

3 Exon 13 Exon 14 Exon 17 Exon 11 Exon 9 SECONDARY MUTATIONS V654 D816 D820 N822 ATP- binding pocket Activation Loop Y823 40% 30% FREQUENCY Debiec-Rychter M, 2005 Antonescu CR, 2005 Wardelmann E, 2006 Heinrich MC, 2008 Liegl B, 2008 Secondary resistance in GIST

4 Exon 13 Exon 14 Exon 17 Exon 11 Exon 9 SECONDARY MUTATIONS V654 D816 D820 N822 ATP- binding pocket Activation Loop Y823 40% 30% FREQUENCY Debiec-Rychter M, 2005 Antonescu CR, 2005 Wardelmann E, 2006 Heinrich MC, 2008 Liegl B, 2008 Secondary resistance in GIST

5 Exon 13 Exon 14 Exon 17 Exon 11 Exon 9 SECONDARY MUTATIONS V654 D816 D820 N822 Y823 40% 30% FREQUENCY Debiec-Rychter M, 2005 Antonescu CR, 2005 Wardelmann E, 2006 Heinrich MC, 2008 Liegl B, 2008 Secondary resistance in GIST DRUG SENSITIVITY Imatinib Sunitinib Sensitive Resistant

6 Exon 13 Exon 14 Exon 17 Exon 11 Exon 9 SECONDARY MUTATIONS V654 D816 D820 N822 Y823 40% 30% FREQUENCY Debiec-Rychter M, 2005 Antonescu CR, 2005 Wardelmann E, 2006 Heinrich MC, 2008 Liegl B, 2008 Secondary resistance in GIST DRUG SENSITIVITY Imatinib Sunitinib Sensitive Resistant

7 Regorafenib (REGO) has recently obtained FDA- approval in GIST patients after failure of imatinib (IM) and sunitinib (SU). There is substantial heterogeneity of secondary KIT resistant mutations between and within metastases from individual patients after progression on TKIs. Progression-free survival after imatinib failure is 4 to 6 months irrespective of the second- or third-line TKI used. Second- and third-line treatment in GIST

8 We investigated novel strategies to overcome heterogeneity of resistant clones in TKI-resistant GIST patients. Aims

9 Imatinib, sunitinib and regorafenib are active against primary KIT exon 11 mutation nM DMSO REGO p-KIT (Y703) p-S6 (S235/236) Actin p-AKT S473 DMSO IM DMSO SU

10 Imatinib, sunitinib and regorafenib are active against primary KIT exon 11 mutation nM DMSO REGO p-KIT (Y703) p-S6 (S235/236) Actin p-AKT S473 DMSO IM DMSO SU

11 Imatinib, sunitinib and regorafenib are active against primary KIT exon 11 mutation nM DMSO REGO p-KIT (Y703) p-S6 (S235/236) Actin p-AKT S473 DMSO IM DMSO SU

12 KIT MutationIC50 (nM) Cell linePrimarySecondarySUREGO GIST430/654Ex 11Ex 13 (V654A)1943,341 GIST-T1/816Ex 11Ex 17 (D816E)3, GIST-T1/820Ex 11Ex 17 (D820A)2, Sunitinib and regorafenib have complementary activity against imatinib-resistant GIST cell lines * IC50s: Green = predictive of clinical efficacy Red = predictive of clinical resistance

13 KIT MutationIC50 (nM) Cell linePrimarySecondarySUREGO GIST430/654Ex 11Ex 13 (V654A)1943,341 GIST-T1/816Ex 11Ex 17 (D816E)3, GIST-T1/820Ex 11Ex 17 (D820A)2, Sunitinib and regorafenib have complementary activity against imatinib-resistant GIST cell lines * IC50s: Green = predictive of clinical efficacy Red = predictive of clinical resistance

14 KIT MutationIC50 (nM) Cell linePrimarySecondarySUREGO GIST430/654Ex 11Ex 13 (V654A)1943,341 GIST-T1/816Ex 11Ex 17 (D816E)3, GIST-T1/820Ex 11Ex 17 (D820A)2, Sunitinib and regorafenib have complementary activity against imatinib-resistant GIST cell lines * IC50s: Green = predictive of clinical efficacy Red = predictive of clinical resistance

15 Progression of KIT Exon 13 imatinib-resistant subclone on regorafenib Baseline C12D21 exon 11 + exon 13 (V654A) KIT exon 13 (V654A). Radiographic and metabolic progression on regorafenib Resection biopsy

16 Response of KIT Exon 17 imatinib-resistant subclone on regorafenib Baseline C4D21 exon 11 + exon 17 (D820Y) Pre-regorafenib KIT exon 17 (D820Y). Radiographic and metabolic response on regorafenib

17 KIT MutationActivity PrimarySecondaryIMSUREGO Ex 11 Sensitive Ex 11 Sensitive Ex 11Ex 13 (V654A) ResistantSensitiveResistant Ex 11Ex 17 (D816) Resistant Sensitive Ex 11Ex 17 (D820) Resistant Sensitive Sunitinib and regorafenib have complementary activity against IM-resistant KIT mutations

18 ATP-binding pocket Activation Loop Activation Loop SUNITINIB REGORAFENIB Cycling sunitinib and regorafenib might suppress a broader spectrum of imatinib-resistant GIST clones and achieve prolonged long-term disease control Targeting TKI-resistance heterogeneity in GIST

19  Phosphorylation of KIT  Phosphorylation of downstream signal intermediates (AKT and ERK)  Increase of Cyclin A expression  Increase of Ki-67 expression  Mitotic activity TKI withdrawal Time-frame for restoration of kinase signaling and proliferation after TKI withdrawal

20 pAKT S473 pKIT Y703 DAY 0 DAY 1 DAY 3 DAY 7 SU 500nM pRB S795 Cyclin A Actin Sunitinib washout: reactivation of KIT, downstream pathways, and cell cycle GIST430/654 exon 11 + exon 13 Sunitinib treatment Days of drug withdrawal

21 pAKT S473 pKIT Y703 DAY 0 DAY 1 DAY 3 DAY 7 SU 500nM pRB S795 Cyclin A Actin Sunitinib washout: reactivation of KIT, downstream pathways, and cell cycle Days of drug withdrawal GIST430/654 exon 11 + exon 13 Sunitinib treatment

22 pAKT S473 pKIT Y703 DAY 0 DAY 1 DAY 3 DAY 7 SU 500nM pRB S795 Cyclin A Actin Sunitinib washout: reactivation of KIT, downstream pathways, and cell cycle Days of drug withdrawal GIST430/654 exon 11 + exon 13 Sunitinib treatment

23 UntreatedSU 100nMSU 500nM Day 0 Day 1 Day 3 Day 7 KI-67 expression Sunitinib washout: reactivation of proliferation Mitotic Count (per 5 mm 2 ) UT100nM500nM Day Day Day Day GIST430/654 exon 11 + exon 13 Sunitinib treatment

24 UntreatedSU 100nMSU 500nM Day 0 Day 1 Day 3 Day 7 KI-67 expression Sunitinib washout: reactivation of proliferation Mitotic Count (per 5 mm 2 ) UT100nM500nM Day Day Day Day GIST430/654 exon 11 + exon 13 Sunitinib treatment

25 DAY 0 DAY 1 DAY 3 DAY 7 REGO 500nM pAKT S473 pKIT Y703 pRB S795 Cyclin A Actin Regorafenib washout: reactivation of KIT, downstream pathways, and cell cycle Days of drug withdrawal GIST48/820 exon 11 + exon 17 Regorafenib treatment

26 DAY 0 DAY 1 DAY 3 DAY 7 REGO 500nM GIST48/820 exon 11 + exon 17 Regorafenib treatment pAKT S473 pKIT Y703 pRB S795 Cyclin A Actin Days of drug withdrawal Regorafenib washout: reactivation of KIT, downstream pathways, and cell cycle

27 DAY 0 DAY 1 DAY 3 DAY 7 REGO 500nM pAKT S473 pKIT Y703 pRB S795 Cyclin A Actin Days of drug withdrawal GIST48/820 exon 11 + exon 17 Regorafenib treatment Regorafenib washout: reactivation of KIT, downstream pathways, and cell cycle

28 UntreatedREGO 100nMREGO 500nM Day 0 Day 1 Day 3 Day 7 Regorafenib washout: reactivation of proliferation GIST48/820 exon 11 + exon 17 Regorafenib treatment KI-67 expression Mitotic Count (per 5 mm 2 ) UT100nM500nM Day Day Day Day

29 UntreatedREGO 100nMREGO 500nM Day 0 Day 1 Day 3 Day 7 Regorafenib washout: reactivation of proliferation GIST48/820 exon 11 + exon 17 Regorafenib treatment KI-67 expression Mitotic Count (per 5 mm 2 ) UT100nM500nM Day Day Day Day

30 Once a KIT inhibitor is withdrawn:  Phosphorylation of KIT  Phosphorylation of downstream signal intermediates (AKT and ERK)  Increase of Cyclin A expression  Increase of Ki-67 expression  Mitotic activity 2 days 4 days 7 days

31 Recovery of mitotic activity in GIST patients responding to TKI therapy after withdrawal of the KIT inhibitor PATIENTDRUG #DAYS after last TKI KIT MUTATION 2 ND MUTATIONMitosis 1aSU3Exon 11no0 1bSU3Exon 11Exon 13 (V654A)0 2aREGO9Exon 11Exon 17 (Y823D)13 2bREGO9Exon 11Exon 17 (D820Y)7

32 Rapid alternation regimen 3 days SU 4 days REGO3 days SU 4 days REGO Rapid alternation regimen might minimize toxic effects. Alternation of complementary drugs increases the spectrum of effective inhibition of IM-resistant clones.

33 2.After withdrawal of an effective KIT inhibitor, target re-activation occurs in 1 to 3 days. 3.Proliferation markers are re-activated between 3 to 7 days, and mitotic activation is observed in vitro and in clinical correlates between 4 to 7 days. 4.These observations define a rational schedule for alternation of sunitinib and regorafenib in a heterogeneous GIST population that will be shortly tested in a Phase Ib clinical trial. Conclusions 1.Sunitinib and regorafenib have complementary activity against secondary KIT mutations.

34 Brigham and Women’s Hospital Jonathan Fletcher Lab Jonathan A. Fletcher Grant Eilers Albert Ha Adrián Mariño-Enríquez Anna Quattrone Gloria Ravegnini Inga-Marie Schaefer Derrick Tao Yue-Xiang Wang Mei-Jun Zhu Pathology Department Christopher D.M. Fletcher Leona A. Doyle Jason Hornick Division of Surgical Oncology Chandrajit P. Raut Co-authors / Acknowledgments Ludwig Center at Dana-Farber Cancer Institute George D. Demetri James E. Butrynski David R. D’Adamo Suzanne George Jeffrey A. Morgan Andrew J. Wagner Lerner Research Institute and Cleveland Clinic Anu Gupta Brian P. Rubin West German Cancer Center Sebastian Bauer ASCO Young Investigator Award Spanish Society of Medical Oncology Translational Award Faculty from the 2013 Flims Workshop GIST Cancer Research Fund, The LifeRaft Group Virginia and Daniel K. Ludwig Trust for Cancer Research Vall d’Hebron University Hospital Joan Carles Galcerán


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