• Andreas Hochhaus, Jianxiang Wang, Dong-Wook Kim, Dennis Dong Hwan Kim, Jiri Mayer, Yeow-Tee Goh, le CoutrePhilippPFrom Klinik für Innere Medizin II, Hematology/Oncology, Universitätsklinikum Jena and Comprehensive Cancer Center Central Germany, Campus Jena, Jena (A.H.), and the Department of Oncology and Hematology, Charité-Universitätsmedizin Berlin, Naoto Takahashi, Inho Kim, Gabriel Etienne, David Andorsky, Ghayas C Issa, Richard A Larson, Felice Bombaci, Shruti Kapoor, Tracey McCulloch, Kamel Malek, Lillian Yau, Sophie Ifrah, Matthias Hoch, Jorge E Cortes, Timothy P Hughes, and ASC4FIRST Investigators.
• From Klinik für Innere Medizin II, Hematology/Oncology, Universitätsklinikum Jena and Comprehensive Cancer Center Central Germany, Campus Jena, Jena (A.H.), and the Department of Oncology and Hematology, Charité-Universitätsmedizin Berlin, Berlin (P.C.) - both in Germany; State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (J.W.); Uijeongbu Eulji Medical Center, Geumo-dong, Uijeongbu-si (D.-W.K.), and the Department of Internal Medicine, Seoul National University Hospital, Biomedical Research Institute, Cancer Research Institute, Seoul National University College of Medicine, Seoul (I.K.) - both in South Korea; Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto (D.D.H.K.); the Department of Internal Medicine, Hematology and Oncology, University Hospital Brno, and Masaryk University - both in Brno, Czech Republic (J.M.); the Department of Hematology, Singapore General Hospital, Singapore (Y.-T.G.); the Department of Hematology, Akita University, Akita City, Japan (N.T.); the Hematology Department, Institut Bergonié, Bordeaux (G.E.), and Novartis Pharma, Paris (S.I.) - both in France; Rocky Mountain Cancer Centers, Boulder, CO (D.A.); the Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston (G.C.I.); the University of Chicago, Chicago (R.A.L.); CML Patients Group, CML Advocates Network, Turin, Italy (F.B.); Novartis Pharmaceuticals, East Hanover, NJ (S.K.); Novartis Pharma, Basel, Switzerland (T.M., K.M., L.Y., M.H.); Georgia Cancer Center at Augusta University, Augusta (J.E.C.); and the South Australian Health and Medical Research Institute and University of Adelaide, Adelaide, SA, Australia (T.P.H.).
• N. Engl. J. Med. 2024 Sep 12; 391 (10): 885898885-898.

BackgroundPatients with newly diagnosed chronic myeloid leukemia (CML) need long-term therapy with high efficacy and safety. Asciminib, a BCR::ABL1 inhibitor specifically targeting the ABL myristoyl pocket, may offer better efficacy and safety and fewer side effects than currently available frontline ATP-competitive tyrosine kinase inhibitors (TKIs).MethodsIn a phase 3 trial, patients with newly diagnosed CML were randomly assigned in a 1:1 ratio to receive either asciminib (80 mg once daily) or an investigator-selected TKI, with randomization stratified by European Treatment and Outcome Study long-term survival score category (low, intermediate, or high risk) and by TKI selected by investigators before randomization (including imatinib and second-generation TKIs). The primary end points were major molecular response (defined as BCR::ABL1 transcript levels ≤0.1% on the International Scale [IS]) at week 48, for comparisons between asciminib and investigator-selected TKIs and between asciminib and investigator-selected TKIs in the prerandomization-selected imatinib stratum.ResultsA total of 201 patients were assigned to receive asciminib and 204 to receive investigator-selected TKIs. The median follow-up was 16.3 months in the asciminib group and 15.7 months in the investigator-selected TKI group. A major molecular response at week 48 occurred in 67.7% of patients in the asciminib group, as compared with 49.0% in the investigator-selected TKI group (difference, 18.9 percentage points; 95% confidence interval [CI], 9.6 to 28.2; adjusted two-sided P<0.001]), and in 69.3% of patients in the asciminib group as compared with 40.2% in the imatinib group within the imatinib stratum (difference, 29.6 percentage points; 95% CI, 16.9 to 42.2; adjusted two-sided P<0.001). The percentage of patients with a major molecular response at week 48 was 66.0% with asciminib and 57.8% with TKIs in the second-generation TKI stratum (difference, 8.2 percentage points; 95% CI, -5.1 to 21.5). Adverse events of grade 3 or higher and events leading to discontinuation of the trial regimen were less frequent with asciminib (38.0% and 4.5%, respectively) than with imatinib (44.4% and 11.1%) and second-generation TKIs (54.9% and 9.8%).ConclusionsIn this trial comparing asciminib with investigator-selected TKIs and imatinib, asciminib showed superior efficacy and a favorable safety profile in patients with newly diagnosed chronic-phase CML. Direct comparison between asciminib and second-generation TKIs was not a primary objective. (Funded by Novartis; ASC4FIRST ClinicalTrials.gov number, NCT04971226).Copyright © 2024 Massachusetts Medical Society.

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