1417PD - Phase 2 study of ponatinib in patients (pts) with advanced gastrointestinal stromal tumors (GIST) after failure of tyrosine kinase inhibitor (TKI)...

Date 27 September 2014
Event ESMO 2014
Session Sarcoma
Topics Anti-Cancer Agents & Biologic Therapy
GIST
Presenter Michael Heinrich
Citation Annals of Oncology (2014) 25 (suppl_4): iv494-iv510. 10.1093/annonc/mdu354
Authors M.C. Heinrich1, M. von Mehren2, G.D. Demetri3, J. Fletcher4, J. Sun5, J.G. Hodgson6, V. Rivera7, C.D. Turner8, S. George9
  • 1Portland Va Medical Center, Oregon Helath & Science University and OHSU Knight Cancer Institute, 97239 - Portland/US
  • 2Medical Oncology, Fox Chase Cancer Center, 19111 - Philadelphia/US
  • 3Ludwig Center At Dana-farber/harvard Cancer Center And Sarcoma Center, Dana-Farber Cancer Institute, 02215 - Boston/US
  • 4Pathology, Brigham and Women's Hospital, 02115 - Boston/US
  • 5Biostatistics, ARIAD Pharmaceuticals, 02139 - Cambridge/US
  • 6Biomarkers Translational Biology, ARIAD Pharmaceuticals, 02139 - Cambridge/US
  • 7Preclinical & Translational Research, ARIAD Pharmaceuticals, 02139 - Cambridge/US
  • 8Clinical Research, ARIAD Pharmaceuticals, 02139 - Cambridge/US
  • 9Center For Sarcoma And Bone Oncology, Dana Farber Cancer Institute, 02115 - Boston/US

 

Abstract

Aim

Ponatinib is an oral multi-targeted TKI with potent preclinical activity against mutant oncoproteins KIT and PDGFRα, including a broad range of clinically-relevant primary (especially KIT exon 11) and secondary (including KIT exon 17) resistance mutants. This in vitro activity suggests it may be effective in GIST pts with failure of prior TKI therapies.

Methods

This phase 2 single arm trial evaluated efficacy and safety of ponatinib at 45 mg qd in advanced GIST pts after failure of prior TKI therapies. Pts were enrolled in Cohorts based on the presence (A) or absence (B) of KIT exon 11 mutations. Primary end point: clinical benefit rate (CBR=CR+PR+SD at 16 wks) by modified RECIST 1.1 in Cohort A. Secondary end points: CBR in Cohort B and total; ORR, PFS, OS, safety/tolerability in each cohort and total. New pt enrollment was held due to safety observations in other ponatinib trials; enrollment criteria are being revised to include only pts with failure of all 3 GIST-approved TKI. NCT01874665.

Results

From Jun to Oct 2013, 35 pts were enrolled (Cohorts A: 24, B: 11). Median age: 58 yrs; 46% had 2 prior approved TKIs, 46% had 3 prior approved TKIs. 74% pts had ≥4 prior cancer regimens. Median time since diagnosis: 6 yrs. Median follow-up as of Apr 7 2014: Cohorts A: 7 mos, B: 4 mos. 14 pts on study, 21 discontinued: 10 PD, 7 AE, 4 other. Cohort A CBR: 50% (11/22 pts); ORR: 9% (2/22); Best Response: 2 PR and 14 SD. All 5 Cohort A pts with matched PET scans (BL v. C1) had decreased FDG uptake in active lesions, 3 remain on study with SD or better. Cohort B CBR: 27% (3/11); ORR: 0%. Most common (≥30%) treatment-emergent AE (TEAE): rash (57%), fatigue (49%), myalgia (46%), dry skin (43%), headache (43%), constipation (40%), abdominal pain (37%), hypertension (34%) and increased serum alkaline phosphatase (31%). Serious TEAE (≥2 pts): abdominal pain (11%), nausea (6%), vomiting (6%), and fatigue (6%). One pt had myocardial ischemia and 1 pt had right ventricular dysfunction. There was 1 death (pneumonia) that was possibly ponatinib-related.

Conclusions

Initial analysis of this ongoing trial suggests that ponatinib has clinical activity in advanced GIST pts after failure of prior TKI therapies.

Disclosure

M.C. Heinrich: Compensated consultant and/or advisor for Novartis, ARIAD, Pfizer, MolecularMD. Stock or other ownership interests in MolecularMD. I received honoraria directly from Novartis, Pfizer and Onyx. Conducted research funded by ARIAD; M. von Mehren: I am a compensated consultant and/or advisor for Novartis, ARIAD and GSK I have received honoraria directly from Novartis; G.D. Demetri: Compensated consultant/advisor for ARIAD, Novartis, Pfizer, Bayer & Blueprint Medicines, stock /other ownership in Blueprint Medcine. Received research funding from Novartis, Bayer and Pfizer; provided compensated expert testimony for ARIAD and Bayer; J. Fletcher: I am a compensated consultant and/or advisor for ARIAD, and received honoraria directly from Novartis; J. Sun: I have an employment /leadership role with ARIAD Pharmaceuticals – Senior Biostatistician. I have stock or other ownership interest in ARIAD Pharmaceuticals; J.G. Hodgson: I have an employment/leadership role with ARIAD Pharmaceuticals: Associate Director. I have stock or other ownership interest in ARIAD Pharmaceuticals; V.M. Rivera: I have an employment/leadership role with ARIAD Pharmaceuticals - Vice President, Preclinical and Translational Research. I have stock or other ownership interest in ARIAD Pharmaceuticals; C.D. Turner: I have an employment /leadership role with ARIAD Pharmaceuticals – Senior Medical Director. I have stock or other ownership interest in ARIAD Pharmaceuticals; S. George: I am a compensated consultant and/or advisor for Novartis, Bayer, Pfizer, ARIAD. I have received honoraria directly from Novartis. I have conducted research funded by Bayer, Novartis, and ARIAD