KEY TAKEAWAYS
- The study is a randomized, placebo-controlled, phase 3 trial, QUAZAR AML-001, conducted in patients with AML in remission.
- The trial’s primary aim was to evaluate the effect of oral azacitidine (CC-486) on OS compared to PBO.
- Patients were randomly assigned to receive oral azacitidine 300 mg or PBO for 14 days/28-day treatment cycles within 4 months after complete remission.
- The trial found that oral azacitidine significantly prolonged OS compared to PBO, with a median OS of 24.7 months for Oral-AZA and 14.8 months for PBO, respectively.
- The long-term follow-up study showed further separation between the Oral-AZA and PBO KM OS curves compared to the primary analysis, suggesting a long-term OS benefit with Oral-AZA.
- The study demonstrated that oral azacitidine significantly prolonged overall survival in patients with AML.
In patients (pts) with AML in remission after intensive chemotherapy (IC) and ineligible for stem cell transplant, the randomized, placebo-controlled, phase 3 QUAZAR AML-001 trial of Oral-AZA (CC-486) significantly prolonged overall survival (OS) vs. PBO: 24.7 months vs. 14.8 months (mo), respectively (P <0.001) (Wei, 2020). After 48 months, the Oral-AZA and PBO Kaplan-Meier (KM) OS curves converged. Of the 472 patients included in the original analysis, 125 (26.5%; n = 45) were either currently receiving Oral-AZA (n = 26) or PBO (n = 28) or were alive in survival follow-up at the time of the analysis’s July 2019 cutoff. After over a year of extra follow-up, researchers evaluated longer-term OS for pts in QUAZAR AML-001. Patients who met the inclusion criteria (age 55 years, newly diagnosed AML, intermediate/poor-risk cytogenetics at AML diagnosis [Dx], ECOG PS 3) were randomly assigned (1:1) to receive either Oral-AZA 300 mg or PBO QD for 14 days/28-day Tx cycle within 4 months after CR/CRi. Trial unblinding for oral-AZA patients occurred in July 2019. Those still benefiting from treatment might continue on Tx in an extension phase; individuals receiving placebo had Tx withdrawn and were monitored for OS.
Time to death, withdrawal of consent, or loss of follow-up (log-rank test) was used to determine KM estimated OS. Patients who were alive (on-Tx and in survival follow-up) for more than three years after randomization were deemed Long-term (LT) Survivors, and those who died or were censored before this time were considered Short-term (ST) Survivors. At trial unblinding, 39 (or 16%) of the initial 472 patients assigned to Oral-AZA (n = 238) or PBO (n = 234) had progressed to the extension phase. Overall, 31.4% of patients on Oral-AZA and 15.5% on PBO were treated for longer than 24 months. A total of 165 patients (69%) had died at the time of the September 2020 follow-up; 31 patients (13% of the total) were still taking Oral-AZA in the extension phase; and 19 patients (8%) had withdrawn consent or been lost to follow-up. In the PBO group, 23 participants started their permission or were lost to follow-up, while 176 patients died.
At a median follow-up of 51.7 months, there was no difference between the two groups regarding median OS from the primary cutoff date (24.7 months for Oral-AZA and 14.8 months for PBO, respectively; P = 0.0008). Three-year projected survival rates for the Oral-AZA and PBO arms were 37.4% and 27.9%, respectively ( +9.5% on the KM OS curves, showing larger separation at long-term follow-up. [95% CI 0.9%, 18.1%]). The LT Survivors cohort included 140 patients (29.7%), 83 in the Oral-AZA arm and 57 in the PBO arm. A higher proportion of LT Survivors had intermediate-risk cytogenetics (95% vs. 82%) and NPM1 mutation (45% vs. 22.5%) at AML Dx, while a lower proportion was MRD+ at BL (33% vs 52%). Seventy-one percent (34/48) of LT Survivors with post-IC MRD+ at BL attained MRD negative on-study, but only 15% (26/172) of the 3-year cohort did so (P<0.0001). The further separation between the Oral-AZA and PBO KM OS curves at later time points was observed in the follow-up study compared to the primary analysis, suggesting a long-term OS benefit with Oral-AZA. Long-term survival in QUAZAR AML-001 was associated with intermediate-risk cytogenetics and NPM1 mutations at AML Dx and a lack of detectable MRD post-IC.
Source:https://onlinelibrary.wiley.com/doi/10.1111/bjh.18134
Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT03110562
Andrew Wei, Hartmut Döhner, Hamid Sayar, Farhad Ravandi, Pau Montesinos, Hervé Dombret, Dominik Selleslag, Kimmo Porkka, Jun Ho Jang, Barry Skikne, C. L. Beach, Yu (Olivia) Tian, Timothy Chevassut, Gail Roboz/Oral Azacitidine (Oral-AZA) in Patients with Acute Myeloid Leukaemia (AML) in First Remission after Intensive Chemotherapy (IC): Long-Term Overall Survival (OS) Results from the Phase 3 QUAZAR AML-001 Trial/ALL, AML MDS & Bone Marrow Failure. (2022). British Journal of Haematology, 197(S1), 54–170. https://doi.org/10.1111/bjh.18134
