Phase III trial of nilotinib in patients with advanced gastrointestinal stromal tumor (GIST): First results from ENEST g3.
Authors: P. Reichardt, J. Blay, H. Gelderblom, M. Schlemmer, G. D. Demetri, N. Bin Bui, G. A. McArthur, S. Yazji, Y. Hsu, P. Rutkowski
Journal: Journal of Clinical Oncology (2010)

10017^ Background: Nilotinib (N), a selective tyrosine kinase inhibitor (TKI) targeting KIT, PDGFRA, and BCR-ABL with activity against imatinib (IM)-sensitive and -resistant GIST cells, has shown efficacy in phase I and II trials. ENEST g3, a phase III, randomized, open-label, multicenter trial was performed to test N vs best supportive care (BSC) with physician choice to continue or stop IM or sunitinib (S) in patients (pts) with advanced/metastatic GIST who had failed IM and S. Methods: Pts were randomized 2:1 to N 400 mg bid or to the control arm (C = BSC, BSC+IM, or BSC+S, at physician discretion). Primary endpoint was progression-free survival (PFS) per RECIST assessed by blinded central radiology review (CRR). Results: 248 pts were included in the intent-to-treat (ITT) population: N=165, C=83 (BSC=6, BSC+IM=54, BSC+S=23). No significant difference in PFS between the N and C arms was observed based on CRR (p=0.5555; median PFS=109 vs. 111 days, respectively). There was major discordance in local investigator assessment of PFS in favor of N; median PFS for N=119 vs. C=70 (p=0.0007). Median overall survival (OS) was 332 vs. 280 days in the N and C arms, respectively (p=0.29; ns). 51 pts (21%) had >2 prior regimens of which 10 pts entered the study without clear documented progression. Exploratory analyses were done on "true 3rd-line" pts (n=197), defined as those who had objectively progressed after IM and S regimens given sequentially only once. A significant difference in median OS was observed: 405 vs. 280 days for N (n=132) vs. C (n=65), respectively (p=0.02). N was well tolerated, with no differences in adverse events between arms. Conclusions: No statistical differences in PFS or OS for N vs. BSC (usually with continuation of TKI therapy) were demonstrated in the ITT population. The mixed pt population entering the study (multiple lines of previous therapy, lack of documented failure to prior therapy) and investigator choice to include TKI continuation in the BSC control make the outcomes difficult to interpret. Given the almost 2-month improvement in median OS in the ITT population and 4-month improvement in true 3rd-line pts, further study of N activity in well-defined GIST patient populations is warranted. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Alnylam Pharmaceuticals, Amgen, ARIAD, Bayer, Champions Biotechnology, Daiichi Sankyo, EMD Serono, Genentech, Idera Pharmaceuticals, Infinity Pharmaceuticals, Johnson&Johnson, Kolltan Pharmaceuticals, Millennium, n-of-one, Novartis, PamGene, Pfizer, PharmaMar, ZIOPHARMOncology Champions Biotechnology, Kolltan Pharmaceuticals, n-of-one, Novartis, Plexxikon Novartis, Pfizer ARIAD, Bristol-Myers Squibb, Daiichi Sankyo, Infinity, Johnson&Johnson, Novartis, Pfizer ARIAD, Infinity In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519-521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2010 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest.