• Timothy P Hughes, Michael J Mauro, Jorge E Cortes, Hironobu Minami, Delphine Rea, Daniel J DeAngelo, Massimo Breccia, Yeow-Tee Goh, Moshe Talpaz, Andreas Hochhaus, le CoutrePhilippPFrom the South Australian Health and Medical Research Institute and the University of Adelaide, Adelaide, SA, Australia (T.P.H., D.Y., D.M.R.); Memorial Sloan Kettering Cancer Center, New York (M.J.M., M.S.T., J.H.P.); University of Texas, Oliver Ottmann, Michael C Heinrich, Juan L Steegmann, DeiningerMichael W NMWNFrom the South Australian Health and Medical Research Institute and the University of Adelaide, Adelaide, SA, Australia (T.P.H., D.Y., D.M.R.); Memorial Sloan Kettering Cancer Center, New York (M.J.M., M.S.T., J.H.P.); University of, JanssenJeroen J W MJJWMFrom the South Australian Health and Medical Research Institute and the University of Adelaide, Adelaide, SA, Australia (T.P.H., D.Y., D.M.R.); Memorial Sloan Kettering Cancer Center, New York (M.J.M., M.S.T., J.H.P.); University of, Francois-Xavier Mahon, Yosuke Minami, David Yeung, David M Ross, Martin S Tallman, Jae H Park, Brian J Druker, David Hynds, Yuyan Duan, Christophe Meille, Florence Hourcade-Potelleret, K Gary Vanasse, Fabian Lang, and Dong-Wook Kim.
• From the South Australian Health and Medical Research Institute and the University of Adelaide, Adelaide, SA, Australia (T.P.H., D.Y., D.M.R.); Memorial Sloan Kettering Cancer Center, New York (M.J.M., M.S.T., J.H.P.); University of Texas M.D. Anderson Cancer Center, Houston (J.E.C.); Kobe University Graduate School of Medicine, Kobe (H.M.), and the National Cancer Center Hospital East, Chiba (Y.M.) - both in Japan; Hôpital Saint-Louis, Paris (D.R.), and the University of Bordeaux, Bordeaux (F.-X.M.) - both in France; Dana-Farber Cancer Institute, Boston (D.J.D.); Sapienza University, Rome (M.B.); Singapore General Hospital, Singapore (Y.-T.G.); University of Michigan Comprehensive Cancer Center, Ann Arbor (M.T.); Universitätsklinikum Jena, Jena (A.H.), Charité Hospital, Berlin (P.C.), and the Department for Hematology-Oncology, Goethe University Hospital, Frankfurt am Main (F.L.) - all in Germany; University of Cardiff, Cardiff, United Kingdom (O.O.); Veterans Affairs Portland Health Care System (M.C.H.) and Oregon Health and Science University Knight Cancer Institute (M.C.H., B.J.D.), Portland; Hospital de la Princesa and Instituto de Investigación Sanitaria Princesa, Madrid (J.L.S.); Huntsman Cancer Institute, University of Utah, Salt Lake City (M.W.N.D.); Amsterdam University Medical Centers, VU University Medical Center, Amsterdam (J.J.W.M.J.); Novartis Pharma, Basel, Switzerland (D.H., Y.D., C.M., F.H.-P., K.G.V.); and Seoul St. Mary's Hematology Hospital, Catholic University of Korea, Seoul, South Korea (D.-W.K.).
• N. Engl. J. Med. 2019 Dec 12; 381 (24): 231523262315-2326.

BackgroundAsciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein, locking BCR-ABL1 into an inactive conformation through a mechanism distinct from those for all other ABL kinase inhibitors. Asciminib targets both native and mutated BCR-ABL1, including the gatekeeper T315I mutant. The safety and antileukemic activity of asciminib in patients with Philadelphia chromosome-positive leukemia are unknown.MethodsIn this phase 1, dose-escalation study, we enrolled 141 patients with chronic-phase and 9 with accelerated-phase chronic myeloid leukemia (CML) who had resistance to or unacceptable side effects from at least two previous ATP-competitive tyrosine kinase inhibitors (TKIs). The primary objective was to determine the maximum tolerated dose or the recommended dose (or both) of asciminib. Asciminib was administered once or twice daily (at doses of 10 to 200 mg). The median follow-up was 14 months.ResultsPatients were heavily pretreated; 70% (105 of 150 patients) had received at least three TKIs. The maximum tolerated dose of asciminib was not reached. Among patients with chronic-phase CML, 34 (92%) with a hematologic relapse had a complete hematologic response; 31 (54%) without a complete cytogenetic response at baseline had a complete cytogenetic response. A major molecular response was achieved or maintained by 12 months in 48% of patients who could be evaluated, including 8 of 14 (57%) deemed to have resistance to or unacceptable side effects from ponatinib. A major molecular response was achieved or maintained by 12 months in 5 patients (28%) with a T315I mutation at baseline. Clinical responses were durable; a major molecular response was maintained in 40 of 44 patients. Dose-limiting toxic effects included asymptomatic elevations in the lipase level and clinical pancreatitis. Common adverse events included fatigue, headache, arthralgia, hypertension, and thrombocytopenia.ConclusionsAsciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom ponatinib had failed and those with a T315I mutation. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02081378.).Copyright © 2019 Massachusetts Medical Society.

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