The clinical value of drugs under development in hematological malignancies 55 3♣ Table 2: Magnitude of clinical benefit of FDA-approved targeted agents for the treatment of acute myeloid leukemia (AML). Treatment regimen & FDA approval date OS/EFS Control Group OS/EFS gain or ORR Other outcome measures (exp vs control or exp arm) Toxicity ESMO-MCBS v1.1 Score Magnitude of Clinical Benefit SOC +/- Gemtuzumab Ozogamicin September 2017 EFS: 17.1% 2 y EFS 23.7%, HR 0.58 (0.43 - 0.78) CR+CRp: 81% vs 75% OS: 34.0 mo vs 19.2 mo Increased A Major LD Decitabine +/- GlasdegiB November 2018 OS: 4.9 mo OS: 3.9 mo 0.51; 80% CI, 0.39–0.67 CR: 17.0% vs 2.3% ORR: 26.9% vs 5.3% Duration of CR: 6.5 mo Duration of ORR: 9.9 mo. Slightly increased 4 Substantial SOC +/- Midostaurin April 2017 OS: 25.6 mo OS: 49.1 mo, HR 0.78 (0.63 - 0.96) CR: 58.9% vs 53.5% EFS: 8.2 mo vs 3.0 mo Similar A Major Tagraxofusp December 2018 N/A CR + CCR: 72% ORR: 90% N/A 3 Moderate Venetoclax + decitabine or azacitidine October 2020 N/A 68% ORR CR+CRi: 67% Duration of CR+CRi: 11.3 mo Median OS: 17.5 mo N/A 2 N/A AZACITIDINE +/- VENETOCLAX October 2020 OS: 9.6 mo OS: 5.1 mo CR+CRi: 66.4% vs 28.3% Duration of CR+CRi: 17.5 mo vs 13.5 mo. Increased 4 Substantial Enasidenib August 2017 N/A ORR 40.3% CR: 20.2% vs 19.3% N/A 2 N/A Gilteritinib or Salvage Therapy November 2018 OS: 5.6 mo OS: 3.7 mo, HR 0.64 (0.49-0.83) CR+CRp: 34.0% vs 15.3% ORR: 67.5% vs 25.8% Slightly decreased 4 Substantial Ivosidenib July 2018 N/A 22% CR, ORR 42% Duration of CR: 8.2 mo Duration of ORR: 6.5 mo. N/A 2 N/A Overview of pivotal trials for the FDA-approval of targeted agents for the treatment of AML. ESMO-MCBS scores for midostaurin, gemtuzumab ozogamicin and enasidenib were adopted from Kiesewetter et al.10. The highest grades of the ESMO-MCBS in the curative setting are A and B. A indicates a major, and B indicates an important benefit. In the non-curative setting, scores 4 and 5 indicate a substantial benefit. 3 indicates a moderate benefit. The endpoint used for EMSOMCBS classification is printed italic. EXP experimental, SHh sonic hedgehog, OS overall survival, EFS event free survival, CR complete remission, CRp complete remission with incomplete platelet recovery, CRi complete remission with incomplete hematologic recovery, ORR overall response rate, R/R relapsed/refractory, LD low-dose, SOC standard of care, REF reference, HR hazard ratio, mos. months, y/o years old, N/A not applicable/no measure of magnitude of clinical benefit based on ESMO-MCBS v.1.1 CI confidence interval, ESMO-MCBS v1.1 European Society for Medical Oncology—Magnitude of Clinical Benefit Scale version 1.1.
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