Nuevos avances en el tratamiento de los GIST Dr Javier Martin Broto Oncología Médica HospitalSon Espases Palma de Mallorca www.cotmes.com
AGENDA Enfermedad localizada SSG AIO Enfermedad diseminada Sorafenib Regorafenib Dasatinib Conclusiones
ADJUVANT IMATINIB TRIAL DESIGN RISK GROUP TIME AIM ACOSOG Imatinib 400 Low-Intermediate-High 1 year RFS Placebo EORTC- Imatinib 400 Intermediate-High 2 years OS RFS ISG-GEIS- FSG Control SSG-AIO Imatinib 400 High- Very High(m1 ned) 1 year RFS Imatinib 400 3 years
ACOSOG Z9001: Phase III 713 patients randomized Imatinib (n=359) 337 received treatment 22 did not receive treatment 32 ineligible patients Placebo (n=354) 345 received treatment 9 did not receive treatment 33 ineligible patients 97 (27.0%) discontinued treatment early 87 (24.6%) discontinued treatmentearlyearly 57 (15.9%) for adverse events 11 (3.1%) for adverse events 1 (<1%) for disease recurrence 41 (11.6%) for disease recurrence 15 (4.2%) for patient withdrawal 20 (5.6%) for patient withdrawal 24 (6.7%) for other/missing reasons 15 (4.2%) for other/missing i reasons Grade 3 or 4 AEs: 31.0% (n=104) Grade 3 or 4 AEs: 18.0% (n=63) Dose reducction/int t14.5% Dose reduction/int. 28% 2.8% thelancet.com online March 19, 2009
ACOSOG Z9001 The Lancet, 373,P 1097-1104, 28 March 2009
ACOSOG Z9001 Mediana de seguimiento para vivos: 19,7 meses Estratificados sólo por tamaño Sorprende un 16% de efectos secundarios G3 en placebo
SSGXVIII: Study design An open-label Phase III study Random assignment 1:1 Imatinib for 12 months Follow-up Stratification: 1) R0 resection, no tumor rupture 2) R1 resection or tumor rupture Imatinib for 36 months Follow-up
SSGXVIII: Objectives Primary: RFS Time from randomization to GIST recurrence or death Secondary objectives included: Safety Overall survival
SSGXIII: Key inclusion criteria Histologically confirmed GIST, KIT-positive High risk of recurrence according to the modified Consensus Criteria*: Tumor diameter >10 cm or Tumor mitosis i count >10/50 HPF** or Size >5 cm and mitosis count >5/50 HPFs or Tumor rupture spontaneously or at surgery *Fletcher CD et al. Hum Pathol 2002; 33:459-65 **HPF, High Power Field of the microscope
Baseline characteristics (ITT) Characteristic ti 12-Mo group 36-Mo group Median age (range) - years 62 (23-84) 60 (22-81) Male - (%) 52 49 ECOG performance status 0 - (%) 85 86 Gastric primary tumor - (%) 49 53 Median tumor size (range) - cm 9 (2-35) 10 (2-40) Median mitosis count - /50 HPFs 10 (0-250) 8 (0-165) Tumor rupture - (%) 18 22 GIST gene mutation site - (%)* - KIT exon 9 6 7 - KIT exon 11 69 71 - KIT exon 13 2 1 - PDGFRA (D842V) 13 (10) 12 (8) - wild type 10 8 *Available for 366 (92%) out of the 397 tumors
RFS events and deaths* (ITT) (n=199) No. (%) Event 12- Month group 36- Month group (n=198) No. (%) RFS events (recurrences or deaths) 84 (42) 50 (25) Cause of death** 25 (13) 12 (6) - GIST 14 (7) 7 (4) - Another cause, with recurred GIST 6 (3) 3 (2) - Another cause, no GIST recurrence 5 (3) 2 (1) *Median follow-up time 54 months ** As reported by investigators
SSGXVIII: Recurrence-free survival (ITT) % 100 80 86.6% 36 Months 65.6% 12 Months 60 60.1% No. at risk (n=397) 47.9% 40 Hazard ratio 0.46 Median follow-up (95% CI, 0.32-0.65) time 54 months 20 P <.0001 0 0 1 2 3 4 5 6 7 Years 36 Months of imatinib 198 184 173 133 82 39 8 0 12 Months of imatinib 199 177 137 88 49 27 10 0
SSGXVIII: Overall survival (ITT) % 100 80 96.3% 92.0% 94.0% 81.7% 60 40 20 Hazard ratio 0.45 (95% CI, 0.22-0.89) 0.89) P =.019 36 Months 12 Months 0 No. at risk (n=397) 0 1 2 3 4 5 6 7 Years 36 Months of imatinib 198 192 184 152 100 56 13 0 12 Months of imatinib 199 188 176 140 87 46 20 0
RISK STRATIFICATION Size Mitotic Count (50 hpf) Very Low Risk < 2 cm 5 mitoses 50 HPF= 10-12 mm 2 FLETCHER Low Risk 2-5 cm 5 mitoses Intermediate Risk 5 cm 5-10 cm 6-10 mitoses 5 mitoses High Risk > 5 cm > 10 cm > 5 mitoses Any mitotic count Any size > 10mitosis Fletcher CD et al. Hum Pathol. 2002;33:459 65 Size Mitotic count (50 hpf) Location Very Low Risk 2-5cm 5 mitoses gastric 50 HPF= 5 mm 2 MIETTINEN- LASOTA Low Risk >5 10 cm 5 mitoses gastric 2-5 cm 5 mitoses intestinal Intermediate Risk >10 cm 5 mitoses gastric >5 y 10 cm 5 mitoses intestinal 2-5 cm > 5 mitoses gastric Miettinen M, Lasota J. Semin Diagn Pathol. 2006 May;23(2):70 83 High Risk 2-5 cm > 5 mitoses intestinal > 10 cm 5 mitoses intestinal >5 y 10 cm > 5 mitoses gastric > 10 cm > 5 mitoses gastric >5 y 10 cm > 5 mitoses intestinal > 10 cm > 5 mitoses intestinal
RISK STRATIFICATION Lancet Oncol 2009; 10: 1045 52
RISK STRATIFICATION
J Martin et al, J Clin Oncol. 2005;23(25):6190-8
J Clin Oncol 28:15s, 2010 (suppl; abstr 10006)
>5 MIT > 5 CM FLETCHER NIH MIETTINEN AFIP MODIFIED JOENSUU 50% RFS 50 months 45% RFS 50 months 21% RFS 50 months >10 MIT 50% RFS 50 months 45% RFS 50 months 21% RFS 50 months >10 CM 5 MIT GASTR 5 MIT >5 CM NO GAST 50% RFS 50 months 77% RFS 50 months (88 % RFS) 85% RFS 50 months 45% RFS 50 months (75% RFS) 5 CM 85% RFS 50 months 45% RFS 50 months >5 MIT (50% RFS) NO GAST T Rupture 21% RFS 50 months 21% RFS 50 months 21% RFS 50 months 21% RFS 50 months (17% RFS) Ann Oncol 2010;21(7):1552 7 Ann Oncol. 2010;21(7):1552-7 Semin Diagn Pathol. 2006;23(2):91-102 Eur J Surg Oncol. 2011;37(10):890-6.
CONCLUSIONS Compared to 1 year of adjuvant imatinib, 3 years of imatinib improves RFS and Overall Survival as treatment of GIST patients who have a high estimated risk of recurrence after surgery. Adjuvant Imatinib is reletively well tolerated; severe adverse effects are infrequent. Gareful with long-lasting ggrade II toxicity We need to identify uniquivocaly high risk populations with a unique risk stratification tifi ti method. Genotype should be integrated into the decision making
Clinical Trials Advanced GIST
Clinical lessons: Radiologic response (Tissue changes) RECIST correlates poorly with survival: PR similar with SD Sometimes myxoid degeneration causes increase in size CHOI criteria better correlate with survival - Decrease of > 15% (UH) and/or decrease of 10% in size
Clinical lessons: Radiologic Progression
Overall Survival According to Best Response
Clinical Lessons From Imatinib Trials The role of maintenance N randomized (interrupted) pts at 1 year: 58 Stop imatinib arm: 32 imatinib arm: 26 BFR14 : Survie sans progression des randomisés à 1 an BFR14 : Survie globale des randomisés à 1 an Probabilité de survie 1.0 0.9 0.8 07 0.7 0.6 0.5 0.4 0.3 0.2 0.1 CONT group 10 evts / 26 patients 0.6 STOP group Médiane SSP: 28.3 mois 0.5 28 evts / 32 patients Médiane SSP : 6.1 mois 0.4 Log-rank test : p < 0.0001 robabilité de survie P 1.0 0.9 0.8 0.7 0.3 0.2 0.1 STOP group 3 décès / 32 patients 5 décès / 58 patients CONT group 2 décès / 26 patients Médiane de suivi : 17.9 mois ; IC95 = [15.2 ; 19.4] Log-rank test : p = 0.70 0.0 0 6 12 18 24 30 36 42 Délai depuis randomisation à 1 an (mois) 0.0 0 6 12 18 24 30 36 42 Délai depuis randomisation à 1 an (mois) Median time to IM reintroduction 5.7 (2-15) months after randomization BFR14 PFS Randomization at 1 yr Blay JY, Le Cesne A et al. JCO 2007
Clinical Lessons From Imatinib Trials The role of genomic profiles KIT PDGFRα Imatinib sensitive Overall mutation frequency: 87.2% Exon 9 (11%) Membrane Exon 11 (67.5%) Exon 12 (0.9%) Exon 13 (0.9%) Exon 14 (0.3%) Cytoplasm Exon 17 (0.5%) Exon 18 (6.3%) Heinrich et al. Hum Pathol. 2002;33:484; Science 2003, Corless et al. Proc AACR. 2003
Primary Resistance: - TTP <= 3 months (6 months?) - Generally multifocal - Wild type or exon 9 mutation (kit gene) - Exon 18 mutation D842V (pdgfr α gene) Secondary Resistance: R beyond 3-month period Partial Resistance: Nodule within a mass Increase of FDG uptake on PET scan (local) Multifocal Resistance
Sunitinib Phase III Study: TTP Blinded phase Blinded and open-label phases TTP Probabilit probabilit ty (%) 100 Sunitinib (N=243) 100 Median 28.9 weeks 90 90 Placebo (N=118) 80 Median 7.0 weeks 80 70 Hazard ratio = 0.28 95% CI (0.21, 0.39) 70 60 P<0.0001 0001 60 50 40 30 20 10 0 0 13 26 39 52 65 78 Time (weeks) TTP Probabilit probabilit ty (%) 50 40 30 20 10 0 Sunitinib (N=243) Median 28.4 weeks Placebo (N=118) Median 8.7 weeks Hazard ratio = 0.41 95% CI (0.31, 0.53) P<0.0001 0 13 26 39 52 65 78 Time (weeks) Casali et al., ASCO 2006, abstract 9513 Judson et al., ESMO 2006, abstract 506
P SRC P GRB-2 SOS RAS-GDP KIT or PDGFRA KIT inhibition P SHC DOK RAS-GAP P X RAS-GTP X PI3K P AKT P P P STAT1+3 MYC? P SAPK P MAPK P P MEK1/2 X RAF-1 mtor Inhibition P mtor BAD BAD BCLX L BCLX L 14-3-3 Mitochondria 14-3-3 3 P
Tumor heterogeneity Molecular heterogeneity at progression After imatinib Debiec Rychter et al, Heinrich et al 2006 After sunitinib Fletcher et al ECCO 2007 + Exon 13 + Exon 14 Exon 11 mutation + Exon 17
Drug # Patients RTKi BEYOND IMATINIB AND SUNITINB Phase Target PFS (m) Toxicity ii Doxo+IMAT 26 I II (2nd Kit, PDGFR, 3.2 < G3; Alopecia; 3rd line) BCR ABL Fatigue;Edema; Mucositis Nilotinib vs RTKi RAD001+ IMAT 248 III (3rd Kit, PDGFR, 3.1 vs Nausea, Abdominal pain, line) BCR ABL 3.1 Fatigue 117 I II (3rd line) mtor; Kit; PDGFRa 3.5 HypoK+; Fatigue; Vomiting Regorafenib 34 II (3rd line) VEGFR2 3, 10 Hypertension; Hand foot Kit, TIE2, PDGFRb; skin reaction; Hypophosphatemia FGFR1; RET; RAF; p38mapk Dasatinib 50 II (3rd line) Kit, PDGFR, ABL, SRC Sorafenib 29 II (2ª 3ª) Kit, VEGFR, PDGFRa 1.8 Fatigue, Gintestinal, Respiratory, Myelosupression 3.5 (2ª) 5.7 (3ª) Hypertension; Hand food; Rash
RTKi BEYOND IMATINIB AND SUNITINB SORAFENIB Inhibits KIT, VEGFR and PDGFR; RAS/RAF PRECLINICAL Ø KIT activity and cell growth of multiple IMresistant KIT mutants In a randomized, phase II discontinuated trial: 2 patients with Imatinib R GIST PR lasting 11 months Guo et al. Clin Ca Res, 2007
RTKi BEYOND IMATINIB AND SUNITINB SORAFENIB (400 mg po BID) Laurent Wiebe, ASCO 2008, 10502
REGORAFENIB Dose 160 mg/day d 1-21/28 d Dose reduction 120 mg/day (39%) Dose reduction 80 mg (30%)
CHOI criteria is not validated beyond 1rst line As for RECIST the figures are very encouraging J Clin Oncol 29: 2011 (suppl; abstr 10007)
The Best PFS of RTKi beyond second line J Clin Oncol 29: 2011 (suppl; abstr 10007)
DASATINIB Interesting CB Activity in Resistant genotype J Clin Oncol 29: 2011 (suppl; abstr 10006)
DASATINIB Poor PFS P-Src predictive biomarker
CLINICAL-RADIOLOGICAL EVALUATION IS CRUCIAL TO MAKE ADEQUATE DECISIONS IN ADVANCED GIST PATIENTS BEYOND IMATINIB-SUNITINIB: REGORAFEBID: The BEST PFS DASATINIB: In Resistant GIST (D842V) NILOTINIB: In true 3rd line could add DISEASE CONTROL DESIGN OF CLINICAL TRIALS No PLACEBO ARM The BEST Endpoint?