FDA Approval: Gemtuzumab Ozogamicin for the Treatment of Adults with Newly Diagnosed CD33-Positive Acute Myeloid Leukemia

Abstract

On September 1, 2017, the FDA granted approval for gemtuzumab ozogamicin (Mylotarg; Pfizer Inc.) in combination with daunorubicin and cytarabine and as a monotherapy for the treatment of adult patients with newly diagnosed CD33-positive acute myeloid leukemia (AML). Gemtuzumab ozogamicin is a CD33-targeted antibody-drug conjugate joined to calicheamicin. Approval of gemtuzumab ozogamicin combination treatment was based on a randomized trial of 271 patients with newly diagnosed AML treated with daunorubicin and cytarabine with or without 3 mg/m fractionated gemtuzumab ozogamicin, which resulted in an event-free survival (EFS) of 13.6 months for gemtuzumab ozogamicin + daunorubicin and cytarabine and 8.8 months for daunorubicin and cytarabine alone [HR = 0.68 (95% confidence interval (CI), 0.51-0.91)]. Hemorrhage, prolonged thrombocytopenia, and veno-occlusive disease were serious toxicities that were more common in patients treated with gemtuzumab ozogamicin + daunorubicin and cytarabine. Approval of gemtuzumab ozogamicin monotherapy was based on a randomized trial of 237 patients with newly diagnosed AML treated without curative intent. Median overall survival (OS) was 4.9 months with gemtuzumab ozogamicin versus 3.6 months on best supportive care [HR = 0.69 (95% CI, 0.53-0.90)]. Adverse events were similar on both arms. Postapproval, several studies are required including evaluation of fractionated gemtuzumab ozogamicin pharmacokinetics, safety of combination gemtuzumab ozogamicin in the pediatric population, immunogenicity, and the effects of gemtuzumab ozogamicin on platelet function. .

Antibody–Drug Conjugates: Future Directions in Clinical and Translational Strategies to Improve the Therapeutic Index

“…10,11). In 2017, gemtuzumab ozogamicin was reapproved for relapsed/refractory acute myeloid leukemia after a phase III trial with a fractionated dosing schedule lowered the peak serum concentration and improved the safety profile, with a complete response rate of 26% (12). These clinical data demonstrate the importance of understanding the relationship between the exposure, safety, and efficacy of ADCs in clinical development.…”

“…ADCs have been shown to be effective in hematologyoncology indications, including three of the four approved ADCs (gemtuzumab ozogamicin, brentuximab vedotin, and inotuzumab ozogamicin; refs. [10][11][12][13][14]; establishing a means of monitoring the changes in tumor burden in bone marrow without invasive sampling could help make development in these indications more efficient and less burdensome for patients.…”

Gemtuzumab ozogamicin and novel antibody-drug conjugates in clinical trials for acute myeloid leukemia

“…Over the past decade, several investigational studies using fractionated dosing schedule of GO were completed and were able to improve the safety profiles without compromising the clinical efficacy [21,40,41]. Based on these promising results, GO gained re-approval from FDA in September 2017 as monotherapy or in combination with conventional chemotherapy for the treatment of newly-diagnosed CD33+ AML and relapsed or refractory (R/R) CD33+ AML in adults [35,42].…”

A Phase 1B Clinical Study of Combretastatin A1 Diphosphate (OXi4503) and Cytarabine (ARA-C) in Combination (OXA) for Patients with Relapsed or Refractory Acute Myeloid Leukemia

“…There is an urgent need for effective new treatment strategies for relapsed AML [9][10][11][12][13][14][15][16]. Therefore, clinical development of new targeted medicines, as well as biologics and cellular therapies, has been the focal point of AML research over the last decade, as reflected by several new drug approvals since 2017 [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27].…”