Guadecitabine Fails to Significantly Improve OS in Previously Treated AML and MDS/CMML

Guadecitabine (SGI-110) failed to result in a statistically significant improvement in overall survival (OS) compared with physician’s choice of alternative therapy in previously treated adult patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (MDS/CMML), failing to meet the primary end points of the phase 3 ASTRAL-2 (NCT02920008) and ASTRAL-3 (NCT02907359) trials, respectively.¹

Investigators will continue to examine the prospective subgroups in the studies and evaluation of secondary end points is ongoing, according to Astex Pharmaceuticals, Inc. With regard to safety, the agent exhibited a toxicity profile determined to be comparable to that observed in previous studies. Full data from the trials will be presented at an upcoming medical meeting.

“We are disappointed in the outcome of the ASTRAL-2 and ASTRAL-3 studies,” said Mohammad Azab, president and chief medical officer at Astex Pharmaceuticals, Inc.¹ “The ASTRAL series of studies were designed to deliver a new therapeutic option to patients with AML or MDS/CMML, and although guadecitabine is an active drug, the studies failed to demonstrate a statistically superior survival outcome compared with current therapeutic alternatives.”

Patients with relapsed/refractory AML have limited options available to them, especially those who are ineligible for hematopoietic cell transplant or do not have actionable mutations. Those with MDS or CMML are often administered hypomethylating agents (HMAs), but many will relapse following this treatment.

Guadecitabine is a next-generation DNA HMA that was developed to be resistant to cytidine deaminase–induced degradation; the agent extends the exposure of tumor cells to decitabine, which ensures greater uptake of the active metabolite into the DNA of rapidly-dividing cancer cells.

Through the action of decitabine, the agent is able to hinder DNA methyl transferase or reverse aberrant DNA methylation to potentially restore the expression of silenced tumor suppression genes and antigens. It is hypothesized that by restoring expression to silenced genes, guadecitabine may be able to sensitize tumor cells to other anticancer drugs, according to Astex Pharmaceuticals, Inc.

In the phase 3 ASTRAL-2 trial, investigators compared the outcomes of patients who received guadecitabine versus physician’s choice of therapy which included a high-intensity regimen comprised of intermediate- or high-dose cytarabine; mitoxantrone, etoposide, and cytarabine; or fludarabine, cytarabine, granulocyte colony stimulating factor (G-CSF), with or without idarubicin (FLAG/FLAG-ida); a low-intensity regimen comprised of low-dose cytarabine or azacitidine or decitabine; or best supportive care only. 

To be eligible for participation, patients had to have AML and received prior treatment with initial induction therapy comprised of a standard intensive chemotherapy regimen that included cytarabine and an anthracycline; they also needed to be refractory to initial induction therapy or in relapsed following initial treatment. 

The primary end point was OS, and key secondary end points included event-free survival, long-term survival, number of days alive and out of the hospital, transfusion independence rate, complete response (CR) rate, composite complete response, hematopoietic cell transplant rate, duration of CR, quality of life (QoL), incidence and severity of adverse effects (AEs), as well as 30- and 60-day all-cause mortality.²

A total of 302 patients from 98 investigator sites across 15 countries were randomized 1:1 to receive 28-day cycles of either subcutaneous guadecitabine for 10 days in cycle 1 followed by 10 or 5 days in cycle 2, and 5 days in cycle 3 onward, or physician’s choice.

In the phase 3 ASTRAL-3 trial, investigators also compared the use of guadecitabine with physician’s choice of therapy, although the control regimens differed from those evaluated in ASTRAL-2. Here, physician’s choice of therapy included low-dose cytarabine; a standard intensive chemotherapy 7+3 regimen comprised of cytarabine and an anthracycline or mitoxantrone; or best supportive care.

Patients had to have MDS or CMML and have received previous treatment with at least 1 HMA to be eligible for inclusion on the trial. The primary end point of the trial was OS, while key secondary objectives were comprised of transfusion independence, marrow CR, survival rate, leukemia-free survival, number of days alive and out of the hospital, disease response, duration of response, number of transfusions, health-related QoL, incidence and severity of AEs, as well as 30- and 60-day all-cause mortality.³

A total of 417 patients from 91 investigator sites spanning 14 countries were randomized 2:1 to receive 28-day cycles of either subcutaneous guadecitabine for 5 days or physician’s choice.

“The ASTRAL studies generated for the medical community one of the largest bodies of clinical and genetic data from prospective randomized studies using HMA treatment,” Azab added.¹ “Guadecitabine was associated with improved outcomes in certain subgroups, but that needs to be validated by additional studies.”

Previous research efforts have shown that guadecitabine is safe and well tolerated in treatment-naïve and refractory patients with AML or MDS. For example, data from a randomized phase 1/2 trial (NCT01261312) evaluated 3 doses/schedules of the agent: 60 mg/m² or 90 mg/m² on the first 5 days of a 28-day cycle or 60 mg/m² on days 1 to 5 and 8 to 12 of a 28-day cycle.⁴

All participants were examined for responses, and no statistically significant difference was observed with regard to CR rate across the 3 dosing/schedule cohorts evaluated: 38%, 41%, and 33%, respectively. Moreover, median OS proved to be comparable among the 5-day cohorts (316 days; 95% CI, 160-420; 44 patients died) and the 10-day cohort (284 days; 95% CI, 140-478; 42 patients died. Investigators determined that the 60-mg/m² dose on the 5-day schedule would be the recommended regimen for patients with treatment-naïve or relapsed/refractory AML. As such, that is the dose that is being utilized in the ASTRAL trials.

Guadecitabine is also under exploration in more than 20 investigator-sponsored clinical trials in other hematologic malignancies and in solid tumors, as a monotherapy and in combination with either immunotherapy or chemotherapy.

References:

1. Astex and Otsuka announce results of phase 3 ASTRAL-2 and ASTRAL-3 studies of guadecitabine (SGI-110) in patients with previously treated acute myeloid leukemia (AML) and myelodysplastic syndromes or chronic myelomonocytic leukemia (MDS/CMML). News release. Astex Pharmaceuticals, Inc. October 14, 2020. Accessed October 15, 2020. https://bit.ly/37aOYSE.
2. Phase 3 randomized, open-label study of guadecitabine vs treatment choice in previously treated acute myeloid leukemia. ClinicalTrials.gov. Updated August 18, 2020. Accessed October 15, 2020. https://www.clinicaltrials.gov/ct2/show/NCT02920008.
3. Guadecitabine (SGI-110) vs treatment choice in adults with MDS or CMML previously treated with HMAs. ClinicalTrials.gov. Updated August 18, 2020. Accessed October 15, 2020. https://www.clinicaltrials.gov/ct2/show/NCT02907359.
4. Kantarjian HM, Roboz GJ, Kropf PL, et al. Guadecitabine (SGI-110) in treatment-naive patients with acute myeloid leukaemia: phase 2 results from a multicentre, randomised, phase 1/2 trial. Lancet Oncol. 2017;18(10):1317-1326. doi:10.1016/S1470-2045(17)30576-4