GEINO TRIALS. RESULTS IN 2015

Transcription

1 VII Symposium Educacional GEINO Madrid, 3-4 diciembre 2015 GEINO TRIALS. RESULTS IN 2015 Juan M Sepúlveda Sánchez Unidad Multidisciplinar de Neurooncología Hospital 12 de Octubre

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6 GEINO-11: A Prospective Multicenter, Open Label, Phase II Pilot Clinical Trial To Evaluate Safety And Efficacy Of Dacomitinib, A Pan-her Irreversible Inhibitor, In Patients With Recurrent Glioblastoma With EGFR Amplification With Or Without EGFRvIII Mutation Sepúlveda JM, Vaz MA, Gil M, Reynés G, Gallego O, Bolos MV, Hernandez Lain A, Sanchez P, Martinez M, Vicente E, Quindos M, Luque R, Ramos A, Ruano Y, Manneh RA, Benavides M, Balaña C. Clinical Trial Information: EudraCT: ; NCT

7 EGFR as a target in GBM 40% of GBM have Epidermal Growth Factor Receptor gene amplification Predictor of poor prognosis % of EGFR amplified tumours have EGFRvIII mutation But, activity with EGFR TKIs has been modest to date in GBM. Gefitinib and Erlotinib have been tested without any patient selection based on EGFR alterations.

8 DACOMITINIB DACOMITINIB is a highly selective, pan-her irreversible small molecule inhibitor of HER family tyrosine kinases HER1 (EGFR): IC50 6 nm HER2 (ErbB2): IC50 46 nm HER4 (ErbB4): IC50 74 nm Active in erlotinib-resistant NSCLC preclinical models No activity against panel of other tyrosine or serine threonine kinases Unlikely to interfere with enzyme-inducing antiepileptic drug therapy

9 Dacomitinib in GBM. Preclinical Studies Dacomitinib inhibits growth in EGFR amplified GBM xengrafts models Zahonero C, et al. Molecular Cancer Therapeutics 2015

10 Dacomitinib in GBM. Preclinical Studies Dacomitinib inhibits growth in GBM EGFR amplified / EGFR viii xenografts models Zahonero C, et al. Molecular Cancer Therapeutics 2015

11 Dacomitinib in GBM. Preclinical Studies Zahonero C, et al. Molecular Cancer Therapeutics 2015

12 Dacomitinib in GBM. Preclinical Studies Zahonero C, et al. Molecular Cancer Therapeutics 2015

13 STUDY AIM To determine the efficacy and safety of dacomitinib in recurrent GBM with EGFR amplification with or without viii mutation.

14 TRIAL DESIGN -GBM at first recurrence -Documented PD following prior combined chemorradiotherapy - >12 weeks after completion of RT -ECOG PS0-2

15 ENDPOINTS AND STUDY CONDUCT Primary Endpoint 6 months Progression-Free Survival rate according to RANO criteria Secondary Endpoints: Tumor response rate according to RANO criteria, PFS, OS and safety Cohort A (EGFRamp+/EGFRvIII-) and Cohort B (EGFRamp+/EGFRvIII+) were analysed independently

16 Statistical methods/sample size estimate Sample size of each cohort was estimated according to the Simon 2-stage phase II design P0 = 15% progression-free survival rate at 6 months P1=35% progression-free survival rate at 6 months Ho SLP= P0 H1 SLP = P1 To achieve an (a, b) error of (0.1, 0.1), a total of 32 patients for each cohort is required. FIRST STAGE (17 Patients per cohort). Primary endpoint not reached if only 2 or less patients were progressionfree at 6 months. SECOND STAGE (32 Patients per cohort) Primary endpoint not reached if less than 8 patients were progressionfree at 6 months.

17 Study Conduct 12 centres in Spain Opened to enrolment in March 2012 Closed to enrolment in December 2014

18 Demographics Age, median (range) [years] Gender Cohort A (EGFRamp/EGFRvIII- ) N=30 62,5 (41-81) 52 (39-72) Males, N (%) 20 (66) 12 (63) Females, N (%) 10 (34) 7 (27) ECOG PS 0 3 (10) 2 (11) 1 19 (63) 13 (68) 2 8 (27) 4 (21) Cohort B (EGFRamp/EGFRvIII +) N=19

19 RESULTS Primary Endpoint: PFS6m COHORT A. EGFRamp/EGFRvIII- 6 month PFS rate: 13.3% (95% CI: ). Patients without progression at 6 months: 3/30 Median PFS: 2.7 months (95% CI: )

20 RESULTS Primary Endpoint COHORT B. EGFRamp/EGFRvIII+ Recruitment was closed after the planned interim analysis (First Stage). Only 1 patient did not progress after 6 months of treatment after the inclusion of the first 17 evaluable patients. 6 PFS rate: 6% (95% CI: 0-18) Median PFS: 2.6 months CI 95%:

21 Best Overall Response A (EGFRamp+/EGFRvII I-) N=30 n (%) COHORT B (EGFRamp+/EGFRv III+) N=19 n (%) TOTAL N=49 N (%) CR 1 (3.3) 0 1 (2) PR 1 (3.3) 1 (5.3) 2 (4.1) SD 8 (26.7) 4 (21) 12 (24) PD 17 (56.7) 13 (68.4) 30 (61.2) Not Evaluable 3 (10) 1 (5.3) 4 (8.2)

22 Overall Survival Cohort A -Median OS: 7.8 months (CI 95%: ) Cohort B -Median OS: 6.7 months (CI 95%: )

23 Partial Response after 6 months of treatment. EGFR amp without VIII mutation

24 Drug-related Adverse events in >5% AE by CTAE 4.0 All Grades N (%) Grade 3 N(%) Total with AE 47 (96%) 20 (40%) Rash 40 (82%) 11 (22%) Diarrhea 33 (67%) 3 (6%) Asthenia 11 (22%) 2 (4.1%) Nausea/Vomiting 4 (22%) 0

25 CONCLUSION The administration of dacomitinib in EGFR amplified rgbm did not meet the prespecified threshold for 6mPFS rate, neither in cases with viii mutation nor in cases without this mutation 4 patients had significant benefit: 4 progression-free after 6 months 3 progression-free after 12 months 1 patient still on treatment after 31 months Translational study is currently ongoing

26 Acknowledgments Investigators: MA Vaz, C Balañá, M Gil, G Reynés, O Gallego, M Martinez, E Vicente, M Quindos, R Luque, RA Manneh, M Benavides. Neuropathologist Aurelio Hernández Lain Molecular Assessment Pilar Sánchez Gómez, Yolanda Ruano Radiologist Ana Ramos Thanks to the patients and their families MFAR (Marketing Farmacéutico & Investigación clínica) Staff Pfizer Pfizer provided a grant to conduct the trial and provided Dacomitinib

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28 FOTEGEINO Retrospective study. HGG treated with Fotemustine 2nd, 3th or further lines Whatever scheme (Standard, Addeo ) Follow-up according to clinical protocols. 114 patients analized.

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31 Response Rate & Toxicity Overall Response Rate: 8% 6% PR 2% CR Toxicity No treatment delays in 64% 3-4 toxicity: 27% Most Common: Neutropenia 3-4 and thrombocytopenia

32 PFS. GBM cases

33 OS. GBM cases

34 PFS. Non-GBM cases

35 OS. Non GBM cases

36 FOTEGEINO CONCLUSIONS FOTEMUSTINE is safe in HGG patients Addeo scheme is the most used among all centers Results in terms of OS and PFS are similar to other publications.

37 Next Steps: FOTEGEINO II Retrospective study Inclusion Criteria: GBM, 1st recurrence Addeo Schme only

38 VII Symposium Educacional GEINO Madrid, 3-4 diciembre 2015 Muchas Gracias Por su Atención