According to the United States Food and Drug Administration (FDA), approximately half of adults diagnosed with acute myeloid leukemia (AML) are not treated with intensive chemotherapy due to comorbidities and chemotherapy-related toxicities.1 Glasdegib, a selective, small‐molecule hedgehog signaling inhibitor, has now received the first-in-class approval to be used in combination with low-dose cytarabine (LDAC) for the treatment of newly diagnosed AML in adults who are 75 years of age or older or with comorbidities that may preclude the use of intensive chemotherapy.2,3 The approval is based on the positive results shown in the phase 2 BRIGHT 1003 trial.2,3
On top of its essential role in embryogenesis, the hedgehog signaling pathway has recently received much attention for its implications in the development and persistence of cancer stem cells.4,5 Preclinical studies have shown that the inhibition of the smoothened (SMO) receptor by glasdegib disrupted the hedgehog pathway, and thus reduced the leukemic stem cell burden in xenograft models.4,5
The efficacy and safety of glasdegib was assessed in the pivotal, randomized, international phase 2 BRIGHT 1003 trial, which randomized 115 patients with newly diagnosed AML in a 2:1 ratio to receive either glasdegib plus LDAC or LDAC alone.1,3 “The randomized phase 2 study, which formed the basis for today’s approval, included patients with cardiac disease or mild to moderate kidney disease, who are often excluded from clinical trials,” said Dr. Jorge Cortes, deputy chair and professor of medicine in the Department of Leukemia, University of Texas, MD Anderson Cancer Center, United States.3
Amongst 77 patients who received glasdegib plus LDAC, 39 (51%) of them had secondary AML, or AML that develops as a result of prior blood/bone marrow conditions or previous anticancer therapy.3 Moreover, 11 (28%) out of these 39 patients had received prior treatment with a hypomethylating agent – the prognosis for these patients has historically been poor, with treatment options being limited to palliative care or enrollment to clinical trials.3
With a median follow-up of approximately 20 months, BRIGHT 1003 found that median overall survival (OS) was significantly longer at 8.3 months with glasdegib plus LDAC as compared to 4.3 months with LDAC alone, which represents 54% reduction in the risk of death for patients who were treated with glasdegib plus LDAC (HR=0.46; 95% CI: 0.30-0.71; one-sided p-value: 0.0002).1,3
Patients were initially stratified by cytogenetic risk (good/intermediate or poor), and OS improvement was found to be consistent across these prespecified cytogenetic risk subgroups.1,3 Complete response (CR) was achieved by 14 (18.2%) of 77 patients in the glasdegib plus LDAC arm and 1 (2.6%) of 38 patients in the LDAC alone arm.6
Commenting on the considerable survival benefit that was shown in the study, Dr. Cortes said that “[glasdegib plus LDAC provide] a much-needed treatment for those patients for whom intensive chemotherapy is not an option.”3
As listed by the FDA, the most frequently (≥20% of patients) reported adverse events (AEs) in patients treated with glasdegib plus LDAC as compared to LDAC alone in the first 90 days of therapy were anemia, fatigue, hemorrhage, febrile neutropenia, muscle pain, nausea, edema, thrombocytopenia, dyspnea, decreased appetite, dysgeusia, mucositis, constipation, and rash.1,3 Of note, the U.S. prescribing information also includes a boxed warning for embryo-fetal toxicity.1,3
“Intensive chemotherapy is usually used to control AML, but many adults with AML are unable to have intensive chemotherapy because of its toxicities. Today’s approval gives health care providers another tool to use in the treatment of AML patients with various, unique needs,” said Dr. Richard Pazdur, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.1
1. FDA approves new treatment for patients with acute myeloid leukemia. FDA News Release. 2018 (Accessed December 24, 2018, at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm626443.htm).
2. FDA Approves Glasdegib for Patients With Newly Diagnosed AML Who Cannot Undergo Intensive Chemotherapy. The ASCO Post. 2018 (Accessed December 24, 2018, at http://www.ascopost.com/News/59497).
3. U.S. FDA APPROVES DAURISMO™ (GLASDEGIB) FOR ADULT PATIENTS WITH NEWLY-DIAGNOSED ACUTE MYELOID LEUKEMIA (AML) FOR WHOM INTENSIVE CHEMOTHERAPY IS NOT AN OPTION. Pfizer Press Release. 2018 (Accessed December 24, 2018, at https://www.pfizer.com/news/press-release/press-release-detail/u_s_fda_approves_daurismo_glasdegib_for_adult_patients_with_newly_
4. Minami Y, Minami H, Miyamoto T, et al. Phase I study of glasdegib (PF-04449913), an oral smoothened inhibitor, in Japanese patients with select hematologic malignancies. Cancer Sci. 2017;108(8):1628-1633.
5. Glasdegib (PF-04449913) Fact Sheet. Pfizer Oncology. May 2018 (Accessed December 24, 2018, at https://www.pfizer.com/files/news/asco/Glasdegib-Fact-Sheet-6JUNE2018.pdf).
6. FDA Approves Glasdegib for Frontline AML. OncLive. 2018 (Accessed December 28, 2018, at https://www.onclive.com/web-exclusives/fda-approves-glasdegib-for-frontline-aml).