Gastrointestinal stromal tumors (GIST)

Transcription

1 Gastrointestinal stromal tumors (GIST) JY Blay Professor of Medicine

2 GIST : standard of care Nosology : not a single disease Treatment of localized GIST Adjuvant treatment Treatment of advanced GIST First line Subsequent lines Next questions

3 Gastro-intestinal stromal tumors Precursors of interstitial cells of Cajal CD117+, CD34+ Resistance to cytotoxic agents Activating KIT and platelet-derived growth factor receptor (PDGFR) mutations in familial and sporadic forms HES CD117 3

4 Others OstéoS SFT Fibrosarcomas MPNST LG Fibromyxoid S Angiosarcomas Ewing Synovialosarcomas Rhabdomyosarcomas Myxofibrosarcomas MFH LMS (uterine) DermatofibroS Kaposi LMS (non uterine). Sarcomas NOS Liposarcomas GIST Incidence of sarcomas in 3 EU regions Incidence / 100,000 / yr

5 KIT KIT & PDGFRa are mutated in GIST Imatinib sensitive + Sunitinib sensitive Exon 9 (11%) Exon 11 (67.5%) Exon 13,14 (1%) Exon 17 (0.5%) PDGFRa KIT & PDGFRA : 85% Other genes: NF1, Raf, SDH, IGF1R Membrane Exon 12 (0.9%) Exon 14 (0.3%) Cytoplasm Exon 18 (6.3%) Heinrich et al. Hum Pathol. 2002;33:484; Science 2003, Corless et al. Proc AACR. 2003

6 NF1 GIST Rare molecular forms of GISTs 2% of GIST, 7% of NF1 patients, multiple, small bowel No mutations on KIT or PDGFRA SDHA,B, C, D mutated GIST Gastric, young women, multifocal Adjuvant treatment B Raf mutated GIST Pediatric GIST Carney s triad

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8 KIT Exon 11 PDGFRA Exon 12 KIT Exon 13 KIT Exon 17 From Corless C, Heinrich M. KIT and PDGFRA Mutations in GIST are Associated with Site of Origin and Treatment Response KIT Exon 9 NF1 PDGFRA Exon 18 D842V SDH mutated 8

9 Localized phase

10 Localized phase : ESMO Guidelines Biopsy first Debate on transparietal, data SSG XVIII reassuring Complete en-bloc resection of the primary tumor R0 margins on the gut/ gastric wall Often R1 in the peritoneal space Resection of the adjacent invaded organs Neo-adjuvant treatment? Pathology review. Molecular characterisation

11 Adjuvant imatinib Adjuvant treatment: Z9001, SSGXVIII & EORTC How long to treat with adjuvant imatinib? Whom to treat with adjuvant imatinib? Impact of mutational analysis on treatment decision What to do after 3-years of adjuvant imatinib treatment follow-up or continued treatment? IM reintroduction in case of relapse

12 GIST Evolution of histo-prognostic classifications? Author De Matteo Fletcher Miettinen Joensuu Criteria Size Size + mitosis Size + mitosis + site Size + mitosis + site + rupture Size + mitosis + site + rupture + mutation

13 Tumor Parameters Size 2 cm Risk stratification (2006 AFIP criteria) Mitotic Count % Patients with Disease Recurrence or Metastases Stomach Duodenum Jejunum / Ileum Rectum > 2, 5 cm 5 per > 5, 10 cm HPFs } 34 } 57 > 10 cm cm * * * 54 > 2, 5 cm > 5 per HPF > 5, 10 cm } 86 } 71 > 10 cm * Too few cases Miettinen & Lasota. Semin Diagn Pathol., 2006; 23:70-83.

14 Risk of recurrence of GIST after surgery: An analysis of pooled population-based cohorts Joensuu et al. Lancet Oncol. 2012; 13:

15 Overview of adjuvant trials ACOSOG Z9001 SSG/AIO XVIII EORTC Treatment 0 vs 12 months 12 vs 36 months 0 vs 24 months Patients Size > 3cm Size > 10cm OR Mitotic count >10/50 HPF OR Size > 5cm and Mitotic count >5/50 HPF OR Tumour rupture Primary Outcome Recurrence-free survival High risk patients (Modified NIH criteria) Recurrence-free survival Intermediate OR High risk (NIH criteria) Imatinib failurefree survival

16 North American Intergroup Phase III trial ACOSOG Z9001: Recurrence-free survival % Recurrence-Free and Alive Placebo 354 Imatinib From 6 months Imatinib : 99.3% RFS Placebo : 90.7% RFS Time in Months Number at Risk At 12 months Imatinib : 97.7% RFS Placebo : 82.3% RFS Imatinib Placebo At 30 months Imatinib : 84.2% RFS Placebo : 69.6% RFS RFS ITT (Kaplan Meier) P< HR ( ) 8 6 DeMatteo et al. Lancet 2009; 373:

17 Number at risk SSG XVIII: RFS 1yr vs 3yrs 36-Mo of imatinib Mo of imatinib Joensuu et al., JAMA. 2012; 307:

18 Number at risk SSG XVIII: Overall survival 36-Mo of imatinib Mo of imatinib Joensuu et al., JAMA. 2012; 307:

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20 INTEGRATING GENOTYPE IN RISK CLASSIFICATION FOR GIST RECURRENCE. A Spanish Group for Sarcoma Research (GEIS) Study

21 Actuarial RFS Curves according to del 557 and/or 558 mutation P = No Del 557 and/or 558 Del 557 and/or % 38%

22 P= % 93% 90% LOW RISK 7-year Actuarial RFS in Miettinen classification According to prognostic genotype INTERMED RISK P= % 26 % 64 % PDGFRa mut Del 557/558 mut Other P= % HIGH RISK 28 % 21 % Deletion involving 557 and/or 558 codons of KIT gene carries a significant worse prognosis in localized IR according to Miettinen classification. These patient should be advised for adjuvant imatinib. No conclusion for PDGFRa mutants (low number of PDGFRa in this series)

23 GIST Evolution of histo-prognostic classifications? Author De Matteo Fletcher Miettinen Joensuu Criteria Size Size + mitosis Size + mitosis + site Size + mitosis + site + rupture Size + mitosis + site + rupture + mutation

24 KIT exon 9 mutants (10% of patients) Median PFS (months) 3-year estimate (%) P value (logrank test) KIT exon 9 mutants: 400 mg / 800 mg Other patients: 400 mg / 800 mg GIST Are at Least 10 Diseases 6 / 19 5 / Years Blay JY, et al. Discov Med. 2012;13: Dose Adjuvant KIT exon 11 Im KIT exon 9 Im (dose?) PDGFRA Non-D842V Im D842V: 0 0 KIT/PDGFR WT Im 400 +/? NF1?/Im 400 +/? SDH mutation?/im 400 +/? SDH epimutations?/im 400? Raf??

25 Ongoing Trials: PERSIST-5 Post-resection Evaluation of Recurrence-free Survival for GastroIntestinal Stromal Tumours with Adjuvant Imatinib Phase II nonrandomised, open-label, multi-centre Imatinib (400 mg/day for 5 years) Follow-up (2 years) Primary Endpoint: RFS following the complete resection of significant-risk primary GIST in patients who are treated with adjuvant imatinib for 5 years Secondary Endpoint: OS Safety and tolerability of 5 years of adjuvant imatinib therapy Study specifics 85 patients enrolled at 21 centres 5-year treatment with adjuvant imatinib (follow-up 2 years)

26 Ongoing trials: ImadGIST & SSG XXII An open-label phase III study in high risk patient in CR after 3 years of adjuvant imatinib Random Assignment 1:1 Stratification: 1) Tumour rupture 2) Risk <80% STOP Imatinib Follow-up Imatinib for 36 / 24 months Follow-up

27 Metastatic phase

28 Survival probability BFR14 trial PFS first-line imatinib (400 mg/d) N = 434 Median PFS : 20 months EORTC Months 317 progressions or deaths / 434 patients 1-year PFS: 76% ; CI95 = [71-79] 3-years PFS: 43% ; CI95 = [39-48] 5-years PFS: 26% ; CI95 = [21-30] Median PFS : 29.7 months ; CI95 = [ ] New bases for hypothesis generating trials in front-line Perol et al. J Clin Oncol., 2012; 30: abstract

29 Survival probability Long-term OS advanced GIST first-line imatinib B2222 trial: N =147 Median OS: 58 months BFR14 trial: N = 434 patients Median OS: 75.9 months (6.4 yrs) Months Before imatinib era: median OS 18 months Perol et al., J Clin Oncol., 2012; 30: ; Blanke et al. J Clin Oncol. 2008; 26:

30 Imatinib interruption in advanced GIST - PFS 10 years +? Blay et al. J Clin Oncol. 2007; 25: ; Le Cesne et al. Lancet Oncol. 2010; 11: ; Bertucci et al. J Clin Oncol. 2012: 30 [abstract 10095]

31 PDGFRA GIST in the advanced phase Cumulative survival probability Probability of Progression-free survival Months Months Cassier et al. Clin Cancer Res. 2012; 18:

32 Exon 11 mutation Exon 9 mutation Wild Type Nb events (%) 109/ % 17/ % 21/ % Median PFS [95% CI] 39.4 months [ ] 12.6 months [ ] 12.3 months [ ] Domont J, et al. J Clin Oncol. 2013;31(suppl). Abstract BFR14: Progression-free Survival 1-year PFS [95% CI] 87.20% [ ] 54.50% [ ] 57.00% [ ] 3-year PFS [95% CI] 30.50% [ ] 26.50% [ ] 30.50% [ ] 5-year PFS [95% CI] 37.00% [ ] 19.90% [ ] 15.20% [ ] variables Coding Survival rate (%) HR CI95% P value Gender Male (R) Female [ ] CD34 expression Yes (R) No [ ] Tumor size (mm) [ ] E11 mutation Yes (R) 45 <.0001 No [ ] Progression-free survival Months Log-rank test P = E9 mutation WT E11 mutation

33 GIST exon 11 Kit with Del : Favorable predictive factor? Patients having at least 5 yrs of fu, BFR14 trial (Blesius et al, ASCO 2011) P= 0.02 < /558 > 559 CR 30% 43.1% 23.5% PR 57.5% 40.3% 45.1% SD 10% 16.7% 31.4% JF Emile et al, ASCO 2013 B % of pts are always under IM at 9 yrs (Von Mehren et al, ASCO 2011) SWOG S % of pts are alive at 10 year. Half of them were still under IM at the time of the analysis (Demetri et al, ASCO 2014) The majority have a KIT exon 11 mutation: majority of del ?

34 KIT exon 9 mutants (10% of patients) Median PFS (months) 3-year estimate (%) P value (logrank test) KIT exon 9 mutants: 400 mg / 800 mg Other patients: 400 mg / 800 mg GIST Are at Least 10 Diseases 6 / 19 5 / Years Blay JY, et al. Discov Med. 2012;13: Dose Adjuvant KIT exon 11 Im KIT exon 9 Im (dose?) PDGFRA Non-D842V Im D842V: 0 0 KIT/PDGFR WT Im 400 +/? NF1?/Im 400 +/? SDH mutation?/im 400 +/? SDH epimutations?/im 400? Raf??

35 Does the physical reduction of tumor cell mass enables to reduce the risk of progression? Metastatic GIST in response on IM Imatinib PD Imatinib + surgery at best response (within 1 yr) Follow for PFS & OS

36 A randomized trial of surgery in metastatic GIST Shi et al Eur J Cancer 2014

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38 Sunitinib and regorafenib Second and Third line agents

39 N Imatinib, sunitinib and regorafenib TKI profiles H H N N N N H 3 C O Imatinib N N CH 3 N N H O NH O Sunitinib N H F Regorafenib Wilhelm SM, et al. Int J Cancer. 2011;129: ; Murphy EA, et al. PNAS. 2010;107: ; Fabian M, et al. Nat Biotechnol. 2005;23: ; Sutent (sunitinib malate) [prescribing information] New York, NY: Pfizer, Inc; F Cl F F N H O N H F O N O N H Inhibit: KIT PDGFRs VEGFRs RAF RET TIE-2 FGFR1

40 Primary Mutations Exon 9 : 12% Exon 11: 70% Exon 13: 1% K642E Exon 17: 1% N822H/K, D820Y Protein Domain Ligand binding JM ATP binding Activation Loop Gramza et al, Clinical Cancer Research 15:7510, 2009 Heinrich et al, ASCO 2013 Poster/Abstract Exon 13 Exon 14 Exon 17 Exon 18 Secondary Mutations V654A T670I D816A/G/H/V D820A/E/G/Y N822H/K Y823D A829P Drugs IM SU REGPON NR

41 Secondary GIST Mutations in Patients Progressing on Imatinib or Sunitinib Exon 11 deletions P-loop K623 V654 T A I H G Y Y K D P Distribution of secondary mutations (n = 27) DHPLC 829 V T D D D N N Y A Exon 13 Exon 14 Exon 17 Exon 18 Drug/ATP binding pocket 42.9% KIT Kinase Domain - Catalytic loop Kinase activation loop 57.1% Activation loop Exon 11 Exon 9 Exon 13 Primary KIT Mutation DHPLC, denaturing high-pressure liquid chromatography. Liegl B, et al. J Pathol. 2008;216(1):64-74; Wilhelm S. 2006; Patent #WO A2, C KIT Cytoplasmic Domain figure.

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45 Mutational Analysis of DNA from Plasma (via BEAMing) and Tumor Tissue (via sequencing) Plasma (BEAMing) Tumor Tissue Patients with data, n (%) 163 (82) 102 (51) Any KIT mutation (primary or secondary) detected, % of samples Primary KIT mutations, % of samples Exon Exon 11 12* 43 Secondary KIT mutations, % of samples Other mutations detected, % of samples PDGFR 1 3 KRAS (1 of 2 samples) 2 BRAF 0 0 *BEAMing assays were not designed to detect most primary KIT exon 11 deletions. Since KIT secondary mutations were detected, these samples likely harbor primary KIT exon 11 deletions. Demetri GD, et al. J Clin Oncol. 2013;31(suppl):abstract

46 Regorafenib Shows Benefit Over Placebo in Patients With and Without Secondary KIT Mutations (BEAMing of plasma DNA) PFS Probability Days from Randomization Secondary KIT mutation absent Placebo (n = 25) HR 0.27 ( ) Regorafenib (n = 61) P <.001 Secondary KIT mutation present Placebo (n = 27) HR 0.22 ( ) Regorafenib (n = 50) P <.001 Demetri GD, et al. J Clin Oncol. 2013;31(suppl):abstract

47 Proportion progression-free Long-Term Survival with Regorafenib in Pretreated GIST Progression-free survival Median PFS = 13.2 months Number at risk Time (months) Ben-Ami E, et al. Ann Oncol Jul 1. [Epub ahead of print].

48 Study Design: RIGHT (Rechallenge of Imatinib in GIST Having no effective Treatment) Patients with: 1) prior clinical benefit from first line imatinib, and 2) progression with both first line imatinib and second line sunitinib, (prior use of third line TKI is permitted) Placebo PD Cross over to Imatinib Randomization 1:1 Imatinib C min at 2 weeks for compliance check Judged by treating investigators Imatinib Stop or continue Imatinib Stratification 1) ECOG PS: 0-1 vs 2-3 2) Use of 3 rd line TKI: yes vs no PD Kang Y-K, et al. J Clin Oncol. 2013;31(suppl):abstract LBA10502.

49 Other agents in advanced phase Median (months) PFS OS Imatinib NR Sunitinib Valatanib NR Sorafenib 4 4 NR Regorafenib Dovitinib Pazopanib 3.8 NE Ponatinib 4 NE Imatinib Gastrointestinal Stromal Tumor Meta-Analysis Group. J Clin Oncol. 2010; 28: Demetri et al. Lancet 2006; 368: Joensuu et al. Br J Cancer. 2011; 104: Montemurro et al. Eur J Cancer. 2013; 49: Demetri et al. Lancet 2013; 381: Kang et al. Ann Oncol. 2012; 23: abstract # 1481PD.

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51 PAZOGIST A randomized multicenter phase II study evaluating the efficacy of pazopanib plus best supportive care (BSC) versus BSC alone in unresectable metastatic and/or locally advanced GastroIntestinal Stromal Tumors (GIST), resistant to imatinib and sunitinib. Jean-Yves BLAY, Julien DOMONT, Claire CROPET, Binh BUI N GUYEN, Emmanuelle BOMPAS, Philippe CASSIER, Isabelle RAY- COQUARD, Maria RIOS, Antoine ADENIS, Antoine ITALIANO, Axel LE CESNE, Olivier BOUCHE, Olivier MIR, Florence DUFFAUD, François BERTUCCI, Nicolas ISAMBERT, Emilie REMIR, Aurélie BELLEVILLE, Julien GAUTIER, David PEROL

52 Progression-Free Survival (investigator-assessed progression) 4-month PFS rate [95% CI] P+BSC N= % [29.1; 60.0] HR [95% CI] 0.59 [0.37; 0.96] Stratified Log-rank test p=0.03 BSC alone N= % [7.8; 30.8]

53 Exploratory objectives Progression-free survival and gastrectomy (all patients, N=81) Cox Model for PFS on 81 patients: - Treatment arm and treatment arm*gastrectomy independent predictors (p=0.002 and p=0.08 respectively).

54 M1 TAM have anti-tumor activities CSF1 dependent Shift to M2 in pts responding to IM Switch back to M1 in progressive pts

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56 Masitinib L1 L2 Studies ongoing Palbociclib L3 phase II (p16 deficient) Crenolanib in D842V BRAF inhibitors in BRAF mutants BLU285 DC2618 PD1/L1 Abs Regorafenib alternated with imatinib L1

57 Stratify by: Prior adjuvant therapy (Y/N) Site Commenced imatinib for metastatic disease <21 days prior (Y/N) R A N D O M I Z A T I O N Study Schema: ALT-GIST A randomized phase II trial of imatinib ALTernating with regorafenib compared with imatinib alone for the first-line treatment of advanced gastrointestinal stromal tumor (GIST) ARM A ARM B Imatinib for between 21 and 25 days* Continuous Imatinib 3-7 day gap Cycle 1 28 days in total 28 days in total Cycle 1 Regorafenib for 21 days 7 day ga p Imatinib for between 21 and 25 days Continuous Imatinib Cycle 2 and ongoing 3-7 day gap Regorafenib for 21 days 7 da y ga p Cycle 2 and ongoing Accessed at

58 Investigational Plan Overview of Study Design Dosing will be continuous until disease progression, unacceptable toxicity or willingness to stop. Metastatic GIST w/ D842V Mutation Crenolanib in D842V PD R Arm 1: crenolanib (100 mg TID daily) Randomization: 2:1 Ratio # Patients: 120 Arm 2: placebo (100 mg TID daily) 58

59 ENA 2016 Blueprint : BLU285 Deciphera : DC 2618

60 Conclusions GIST 2016 >10 different diseases Optimal local treatment Adjuvant: molecular typing in the decision? Advanced phase : adapt to disease nosology Many novel agents Surgery in advanced phase New concepts for clinical trial Molecular monitoring?