Results from a large phase III trial of the hypomethylating agent (HMA) guadecitabine in patients with treatment-naïve acute myeloid leukemia (AML) suggest that this next-generation agent outperforms other HMAs in prolonging overall survival (OS) and improving complete response (CR) rates, according to results presented at the 24th Congress of the European Hematology Association. However, the trial did not meet its primary endpoint for superiority.
“Guadecitabine is a next-generation HMA given subcutaneously, which provides prolonged in vivo exposure to its active metabolite decitabine,” the investigators explained, “thus offering potential clinical advantages over current HMAs.”
To test this hypothesis, the researchers, led by Pierre Fenaux, MD, PhD, from Hôpital Saint Louis in Paris, conducted a multicenter, randomized phase III trial comparing guadecitabine with a preselected treatment choice of azacitidine, decitabine, or low-dose cytarabine.
ASTRAL-1 was based on results from a previous phase II study, in which a five-day regimen of guadecitabine demonstrated a CR rate of 38% in patients with treatment-naïve AML who were not eligible for intensive chemotherapy.
The present study enrolled 815 patients who were deemed ineligible for intensive chemotherapy because of age (≥75 years) or comorbidities. Participants were randomized 1:1 to either:
- guadecitabine 60 mg/m2 per day for five days of a 28-day treatment cycle (n=408)
- preselected treatment choice of azacitidine, decitabine, or low-dose cytarabine administered in standard regimens (n=407)
The researchers reported that baseline variables were balanced across the two arms: Participants’ median age was 76 years in each group (range not provided), and most patients in each group (62%) were older than 75 years. Approximately one-third of patients had poor-risk cytogenetics (34.3% in the guadecitabine arm and 34.6% in the preselected group).
In the preselected group, decitabine was the most commonly used treatment (43%), followed by azacitidine (42%) and low-dose cytarabine (15%).
After a median follow-up of 25.5 months and a median of five treatment cycles in each arm (ranges not provided), a high percentage of patients (41.6%) in the study had discontinued treatment within the first three treatment cycles due to early death or progression. Discontinuation rates were similar between the two arms (42.4% for guadecitabine and 40.8% for preselected therapy).
In the intent-to-treat analysis, the CR rate (assessed by an independent central pathologist blinded to randomization) was 19.4% in the guadecitabine group versus 17.4% in the preselected group (p=0.48).
Median OS was similar between the two treatment groups, with no statistically significant differences in survival at one or two years (TABLE).
Though the analysis for the primary endpoints did not reach statistical significance, Dr. Fenaux and colleagues reported that landmark survival analyses showed potential OS benefit with guadecitabine in patients who received at least three treatment cycles: 15.6 months vs. 13 months (hazard ratio [HR] = 0.78; 95% CI 0.64-0.96; p=0.02).
Other OS endpoints also appeared to be higher with the guadecitabine arm (p values not provided):
- 1-year OS: 60% vs. 52%
- 2-year OS: 29% vs. 20%
Patients who achieved a CR or CR with incomplete hematologic recovery also appeared to have longer OS with guadecitabine than with other HMAs or cytarabine (HR=0.72; 95% CI 0.50-1.05; p values not provided).
Subgroup analyses according to predefined clinical, cytogenetic, and molecular genetic variables also failed to show any significant differences in outcomes, except that patients with TP53 mutations experienced worse outcomes on guadecitabine. The authors noted that this is an area that needs to be explored further.
In terms of safety, both treatment groups showed similar safety profiles, though the researchers observed “slightly higher but not significant” rates of serious adverse events (AEs) and grade ≥3 AEs with guadecitabine (81% vs. 75.5% for serious AEs; 91.5% vs 87.5% for grade ≥3 AEs; p values not reported). Overall, there was no difference in AEs leading to death (28.7% for guadecitabine vs. 29.8% for preselected therapy; p value not reported).
Although the trial did not achieve its primary endpoints of statistically significant superiority of guadecitabine versus treatment choice for CR or OS, the authors concluded, “due to the large sample size and narrow 95% confidence interval for OS difference, the trial suggests that guadecitabine is an active drug with an overall similar efficacy and safety profile to standard therapy.”
The study’s findings are potentially limited by bias in preselected treatment, as well as the high percentage of treatment discontinuations within the first three treatment cycles.
Fenaux P, Gobbi M, Kropf PL, et al. Results of ASTRAL-1 study, a phase 3 randomized trial of guadecitabine (G) vs treatment choice (TC) in treatment naïve acute myeloid leukemia (TN-AML) not eligible for intensive chemotherapy (IC). Abstract #S879. Presented at the 24th European Hematology Association Annual Congress, June 15, 2019; Amsterdam, The Netherlands.
TABLE. Survival With Guadecitabine and Preselected Therapy Choice
|Preselected Therapy Choice (n=407)|
|Median OS||7.10 months||8.47 months|
|Hazard ratio (95% CI)||0.97 (0.83-1.14; p=0.73)|
|OS = overall survival|