Guadecitabine Fails to Improve OS Over Physician’s Choice of Treatment in MDS and CMML

Guadecitabine (SGI-11) did not result in a statistically significant improvement in overall survival (OS) compared with physician’s choice of treatment in patients with relapsed/refractory myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML), according to data from the phase 3 ASTRAL-3 trial (NCT02907359) presented at the 2022 EHA Congress.

Patients treated with guadecitabine experienced a median OS of 9.11 months (95% CI, 7.99-10.29) vs 8.28 months (95% CI, 6.58-10.68) in patients who received physician’s choice of treatment (HR, 0.94; 95% CI, 0.74-1.19; P =.61). Moreover, all-cause mortality was found to be marginally higher in those who received guadecitabine vs those who received physician’s choice of treatment.

“There were no clinically meaningful differences between guadecitabine and physician’s choice of treatment for the secondary end points of 8-week transfusion independence, 12-month survival, leukemia-free survival, or duration of response [DOR] in subjects with complete response,” Guillermo Garcia-Manero, MD, lead study author, chief of the Section of Myelodysplastic Syndromes, deputy chair of Translational Research, and professor in the Department of Leukemia and Division of Cancer Medicine at The University of Texas MD Anderson, and colleagues, wrote in the poster on the data. “Treatment for patients [with] MDS who are never or no longer responsive to hypomethylating agents [HMAs] remains a major challenge and unmet need.”

Guadecitabine, a next-generation HMA, is designed to be resistant to deamination by cytidine deaminase, thus prolonging in vivo exposure to active metabolite decitabine. The agent is hypothesized to be able overcome the pharmacokinetic resistance to first-generation HMAs. Data from a phase 2 trial (NCT01261312) showed that treatment with guadecitabine led to a median OS of almost 12 months in patients with relapsed/refractory MDS.

Based on those data, investigators launched the open-label, global, randomized ASTRAL-3 study. Here, they sought to evaluate the benefit of guadecitabine compared with physician’s choice of treatment, which included low-dose cytarabine, intensive chemotherapy, or best supportive care in patients who were previously treated with a HMA like azacitidine, decitabine, or both.

To be eligible for enrollment, patients needed to have a confirmed diagnosed with MDS or CMML and have failed or progressed on a full course of prior treatment with a HMA and any other prior active anticancer therapy.

A total of 417 participants were randomized 2:1 to receive 60 mg/mg² of subcutaneous guadecitabine per day for 5 days of every 28-day cycle and best supportive care (BSC) for at least 6 cycles (n = 277), or physician’s treatment choice, which included low-dose cytarabine, intensive chemotherapy, or BSC (n = 140). All patients were assigned a treatment choice prior to randomization.

Stratification factors included disease (MDS vs CMML), preselected treatment of choice (low-dose cytarabine vs intensive chemotherapy vs BSC), geographic region (North America vs rest of world), and bone marrow blasts (greater than 10% or less than or equal to 10%).

The primary end point of the trial was OS. Specifically, the trial aimed to detect a HR of 0.68, or an approximate 2.8 median OS improvement, with guadecitabine vs physician’s treatment choice. Secondary end points included transfusion independence, bone marrow complete response (mCR), 1-year survival rate, leukemia-free survival, number of days alive outside of hospital, overall response rate, DOR, number of red blood cell (RBC)/platelet transfusions, health-related quality of life, and adverse effects, as well as 30- and 60-day mortality.

The median age of all patients was 74.0 years (range, 44-91). Most of the patients on the trial were male (69.5%), were treated outside North America (64%), had an ECOG performance status of 1 (56.1%), better-risk cytogenetics (35.5%), were dependent on RBC/platelet transfusions (83%), and had bone marrow blasts of 10% or less (63.5%).

In terms of preselected treatment choice options, 59.0% of all patients received low-dose cytarabine, 37.4% had BSC only, and 3.6% received standard intensive chemotherapy.

Additional data showed that the 12-month OS rate with guadecitabine was 39% (95% CI, 34%-45%) vs 39% (95% CI, 30%-47%) with physician’s choice of treatment. The 24-month OS rates were 16% (95% CI, 11%-21%) and 17% (10%-25%), respectively. Additionally, leukemia-free survival events occurred in 83% of patients in the guadecitabine arm vs 81.4% of those in the control arm.

The complete response (CR) rate was 1.4% (95% CI, 0%-2.8%) in the guadecitabine group, compared with 0.7% (95% CI, 0%-2.1%) in the control group. No partial responses were observed in either arm. The mCR rate was 17.3% (95% CI, 12.9%-21.8%) in the guadecitabine arm vs 8.6% (95% CI, 3.9%-13.2%) in the control arm.

At 8 weeks, transfusion independence was achieved by 15.9% and 15.7% of patients in the guadecitabine and control arms, respectively. The mean number of days alive and out of the hospital in the first 6 months was 130.6 days in the guadecitabine arm and 134.6 days in the control arm.

Grade 3 or higher adverse effects (AEs) were reported in 92.2% and 70.5% of patients in the guadecitabine and control arms, respectively. The most common grade 3 or higher AEs included febrile neutropenia (38.5% and 18.9%, respectively), pneumonia (29.6% and 16.4%), neutropenia (33.0% and 14.8%), thrombocytopenia (30.0% and 18.9%), anemia (21.5% and 16.4%), leukopenia (11.9% and 9.8%), sepsis (10.4% and 3.3%), cellulitis (6.7% and 1.6%), and septic shock (5.9% and 1.6%).

“The safety profiles of guadecitabine and treatment choice were generally similar,” the study authors concluded. “However, AEs were generally more common in the guadecitabine group.”

Reference

Garcia-Manero G, Bart S, McCloskey JK, et al. Guadecitabine (SGI-110) vs treatment choice (TC) in relapsed/refractory (R/R) myelodysplastic syndrome (MDS), results of a global, randomized, phase 3 study. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract P768.