FDA Grants Breakthrough Therapy Designation to Venetoclax/Azacitidine for MDS

Levi Garraway, MD, PhD

The FDA has granted a breakthrough therapy designation to the combination of venetoclax (Venclexta) plus azacitidine for use in the treatment of adult patients with previously untreated, intermediate-, high-, and very high–risk myelodysplastic syndromes (MDS) based on the revised International Prognostic Scoring System (IPSS).¹

The decision was based on interim data from the phase 1b M15-531 study (NCT02942290), which demonstrated that the combination showcased encouraging efficacy, which included durable responses, and an acceptable safety profile in patients with higher-risk MDS.²

“Higher-risk MDS is associated with poor prognosis, reduced quality of life, and limited treatment options,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Genentech, stated in a press release. “We are pleased that the FDA has granted [venetoclax] its sixth breakthrough therapy designation in recognition of its potential to improve outcomes for people with MDS in combination with azacitidine.”

The open-label, non-randomized, multicenter, dose-finding phase 1b study examined venetoclax plus azacitidine in treatment-naïve patients with higher-risk MDS. To be eligible for enrollment, patients needed to be at least 18 years of age, be IPSS intermediate-2 or high risk, bone marrow blasts that were lower than 20% at baseline, and an ECOG performance status of 0 to 2.

Patients who had chronic myelomonocytic leukemia or therapy-related MDS and who were eligible to receive intensive chemotherapy or allogeneic hematopoietic stem cell transplantation, were excluded.

The trial was comprised of 2 parts: a dose-escalation portion and a safety expansion portion. Venetoclax was initially given at a dose of 400 mg or 800 mg for 28 days in a 28-day treatment cycle. Because of intolerance among patients with MDS, this was later amended to an escalating dose, which went from 100 mg to 200 mg to 400 mg for 14 days in a 28-day cycle. Azacitidine was given at a dose of 75 mg/m2 subcutaneously or intravenously on days 1 through 7 of each 28-day cycle.

The primary objectives of the study are to evaluate the safety profile, pharmacokinetics, and identify the recommended phase 2 dose (RP2D) and dosing schedule of venetoclax in combination with azacitidine.

The median age of study participants was 71 years (range, 26-85), 75% were male, and 89% had an ECOG performance status of 0 to 1. At a data cutoff of December 31, 2019, a total of 57 patients received treatment with venetoclax plus azacitidine.

Data indicated that a median follow-up of 13.0 months (95% CI, 11.3-15.6), the objective response rate achieved with the doublet was 77%; this was comprised of a complete remission (CR) rate of 42% and a marrow CR (mCR) rate of 35%. Of these patients, 40% achieved a mCR and hematological improvement. No patients experienced a partial remission to treatment.

Moreover, the median duration of response with the regimen was 14.8 months (95% CI, 12.9–not estimable [NE]). The median progression-free survival was 17.5 months (95% CI, 14.5–NE) with the venetoclax regimen, and the median overall survival had not yet been reached (95% CI, 16.2 months–NE).

Additional data indicated that of the participants who were given the RP2D of venetoclax at 400 mg for 14 days in each 28-day cycle plus azacitidine, physical functioning per EORTC QLQ-C30 was maintained through 48 weeks of treatment. Additionally, a clinically meaningful improvement was observed with regard to fatigue and dyspnea per EORTC QLQ-C30, and this was achieved by the start of cycle 5; it was maintained through week 48.

Regarding safety, all patients reported at least 1 adverse effect (AE) and the most common ones experienced included constipation (54%), neutropenia (51%), and nausea (51%). Grade 3 or higher toxicities were experienced by 97% of patients; these comprised neutropenia (51%), febrile neutropenia (46%), and thrombocytopenia (30%). The most frequently experienced serious AE was febrile neutropenia, and that was observed in 42% of patients. The 30-day mortality rate was 2%.

References

1. FDA grants breakthrough therapy designation for Venclexta in combination with azacitidine for the treatment of patients with myelodysplastic syndromes. News release. Genentech. July 21, 2021. Accessed July 21, 2021. https://bwnews.pr/3hUkhWX
2. Garcia JS, Wei AH, Borate U, et al. Safety, efficacy, and patient-reported outcomes of venetoclax in combination with azacitidine for the treatment of patients with higher-risk myelodysplastic syndrome: a phase 1b study. Blood. 2020;136(suppl 1):55-57. doi:10.1182/blood-2020-139492