Guadecitabine vs treatment of choice in AML

The phase 3 ASTRAL-1 study compared the use of guadecitabine to treatment of choice (ToC) in patients with acute myeloid leukaemia (AML) who had not received prior treatment and who were not eligible for intensive chemotherapy.

This study failed to meet the primary endpoint of a statistical difference in complete response (CR) and overall survival (OS) between guadecitabine and ToC. However, Prof. Pierre Fenaux (Hôpital Saint-Louis, France) presented data that a benefit was observed in patients who received >4 cycles, indicating that treatment duration is crucial to response. Around 40% of patients in both arms did not receive the minimum of 4 cycles to see the maximum treatment benefit [1].

Guadecitabine is a next-generation hypomethylating agent designed to be resistant to degradation by cytidine deaminase and prolong the exposure of tumour cells to the active metabolite decitabine. For this phase 3 study, the largest trial in treatment-naïve patients with AML, participants were randomised 1:1 to either guadecitabine (n=401, 60mg/m² dose subcutaneously administered over 5 days) or ToC (n=392). In the ToC arm, the investigators could choose between decitabine, azacitidine, or low-dose cytosine arabinoside. Most patients were unfit and 75 years or older. In the subgroup analysis, there were no differences between treatment arms based on age, sex, cytogenetic risk, ECOG score, or race. The exception was that TP53 mutations were more common in the control arm (ToC).

Primary endpoint analysis in the intention-to-treat (ITT) population demonstrated no difference in median OS at 12 or 24 months (P=0.73; HR 0.97; 95% CI 0.83-1.14) or complete response (P=0.48). However, the survival analysis (see Table) shows improved outcome for patients responding to ≥4 cycles or ≥6 cycles guadecitabine compared with ToC. This superior survival was more pronounced when patients received >6 cycles (P=0.002) compared with >4 cycles (P=0.02) of guadecitabine. These results indicate that prolonged exposure to guadecitabine is necessary to observe clinical benefit. Approximately 41% and 54% of patients did receive less than 4, or 6 cycles, respectively.

Table: Subgroup analysis of ASTRAL-1. Survival of patients with a response who received ≥4 cycles and ≥6 cycles of guadecitabine vs treatment of choice. Data derived from [1]
CI, confidence interval; G, guadecitabine; HR, hazard ratio; ToC, treatment of choice.

The most common grade 3 and 4 adverse events occurring in ≥20% of patients in either group were febrile neutropenia, pneumonia, thrombocytopenia, neutropenia, and anaemia. In relation to safety, both guadecitabine and all 3 ToC options were comparable, though higher rates of febrile neutropenia and pneumonia were noted in the guadecitabine arm. Adverse events leading to discontinuation of treatment were higher in the guadecitabine arm (10.2%) versus the ToC arm (6.6%).

1. 
   
   1. Fenaux P. et al. Abstract S879, 24th Congress of the EHA. June 13-16, Amsterdam, the Netherlands.

 



Posted on 9 August 201922 February 2024