Updated efficacy and safety data from the AGILE study in patients with newly diagnosed acute myeloid leukemia treated with ivosidenib + azacitidine compared to placebo + azacitidine.

Stéphane De Botton Institut Gustave Roussy, Paris, France info_outline Stéphane De Botton, Pau Montesinos, Susana Vives Polo, Ewa Zarzycka, Jianxiang Wang, Marta Riva, Michael Heuser, Rodrigo T. Calado, Andre C. Schuh, Su-Peng Yeh, Jianan Hui, Diego A. Gianolio, Prapti Arvind Patel, Christian Recher, Hartmut Dohner

Authors Stéphane De Botton Institut Gustave Roussy, Paris, France info_outline Stéphane De Botton, Pau Montesinos, Susana Vives Polo, Ewa Zarzycka, Jianxiang Wang, Marta Riva, Michael Heuser, Rodrigo T. Calado, Andre C. Schuh, Su-Peng Yeh, Jianan Hui, Diego A. Gianolio, Prapti Arvind Patel, Christian Recher, Hartmut Dohner Organizations Institut Gustave Roussy, Paris, France, Hospital Universitario y Politecnico La Fe, Valencia, Spain, ICO-Hospital Germans Trias i Pujol, Badalona, Spain, Medical University of Gdansk, Gdansk, Poland, Peking Union Medical College Hospital, Beijing, China, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy, Hannover Medical School, Hannover, Germany, Ribeirão Preto School of Medicine, University of São Paulo, São Paulo, Brazil, Princess Margaret Cancer Centre, Toronto, ON, Canada, China Medical University Hospital, Taichung, Taiwan, Servier Pharmaceuticals LLC, Boston, MA, Servier Pharmaceuticals, Boston, MA, CHU de Toulouse-Institut Universitaire du Cancer de Toulouse Oncople, Toulouse, France, Ulm University, Ulm, Germany Abstract Disclosures Research Funding Pharmaceutical/Biotech Company This study was supported by Agios Pharmaceuticals, Inc. Servier Pharmaceuticals LLC has completed the acquisition of Agios’ oncology business Background: Ivosidenib (IVO) is a potent oral targeted inhibitor of mutant IDH1 . In the AGILE study in patients (pts) with newly diagnosed IDH1 -mutated acute myeloid leukemia, IVO plus azacitidine (AZA) significantly improved event-free survival (EFS), overall survival (OS), complete remission (CR), and CR or CR with partial hematologic recovery (CR+CRh) rates v placebo (PBO) plus AZA. As of March 2021, median OS (mOS) was 24 months (IVO+AZA) v 7.9 months (PBO+AZA; HR: 0.44; p=0.0005). Long-term follow-up data are presented. Methods: In the double-blind AGILE study, pts were randomized 1:1 to IVO 500 mg QD + AZA 75 mg/m 2 SC or IV for 7 days in 28-day cycles, or PBO+AZA. Long-term follow-up data (June 2022) for OS, blood count recovery, transfusion independence and safety are described here. Results: 148 pts were randomized: 73 to IVO+AZA; 75 to PBO+AZA. Median treatment duration was 10.8 months (IVO+AZA) v 3.2 months (PBO+AZA). Five PBO+AZA pts crossed over to IVO+AZA after March 2021 (Table), and no adjustment was made for crossover in the updated OS analysis. At a median follow-up of 28.6 months, mOS was 29.3 months (95% CI 13.2, not reached) for IVO+AZA v 7.9 months (95% CI 4.1, 11.3) for PBO+AZA (HR 0.42 [0.27, 0.65]; p<0.0001). OS rates were 62.9% and 38.3% at 12 months and 53.1% and 17.4% at 24 months, with IVO+AZA and PBO+AZA, respectively. In the IVO+AZA arm, hemoglobin levels steadily increased from baseline (BL; 88.8 g/L) to cycle 8, and then stabilized; mean platelet count recovered from BL values (72.7 x 10 9 /L) as early as week 8 (171.9 x 10 9 /L) and remained stable; and mean neutrophil counts rapidly increased from BL (0.98 x 10 9 /L) to week 3 (3.99 x 10 9 /L) and week 4 (4.36 x 10 9 /L), and then stabilized to within the normal range. Conversion from BL transfusion dependence (red blood cell and/or platelet transfusion dependence) to post-BL transfusion independence was significantly higher with IVO+AZA than PBO+AZA (53.8% v 17.1%, respectively; p=0.0004). There were fewer neutropenic fever events (27.8% v 33.8%) and infections (34.7% v 51.4%) with IVO+AZA than with PBO+AZA. TEAEs led to discontinuation of IVO+AZA or PBO+AZA in 26.4% and 25.7% of pts, respectively. Conclusions: Updated data on OS (>5 months longer mOS and a greater risk reduction in deaths compared to the initial analysis), transfusion independence, blood count recovery and safety confirms the clinically and statistically robust benefit in favor of IVO+AZA at long-term follow up. Patient disposition. Clinical trial information: NCT03173248. Patients, n (%) IVO+AZA (n=73) PBO+AZA (n=75) Randomized but not treated 1 (1.4) 1 (1.3) On-treatment with IVO/PBO 21 (28.8) 0 On-treatment with AZA 19 (26.0) 3 (4.0) Crossed over to IVO+AZA - 5 (6.7) Discontinued IVO - 2 (2.7) Ongoing with IVO - 3 (4.0) Discontinued IVO/PBO 51 (69.9) 74 (98.7) Discontinued AZA 53 (72.6) 71 (94.7)

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