FDA Breakthrough Therapy Designation Granted to Venetoclax/Azacitidine for Treatment-Naïve MDS

The FDA has granted breakthrough therapy designation (BTD) to the combination of venetoclax (Venclexta) and azacitidine (Vidaza) for the treatment of adult patients with previously untreated intermediate-, high- and very high-risk myelodysplastic syndromes (MDS) per the revised International Prognostic Scoring System (IPSS-R), according to a press release issued by Roche.¹

Results from the phase 1b M15-531 study (NCT02942290) supported the BTD. M15-531 is an ongoing study investigating the safety and pharmacokinetics of venetoclax plus azacitidine in approximately 137 patients with treatment-naïve higher-risk MDS. The study was initiated to address the short median survival of the population, which is about 18 months. The co-primary end points being explored include area under the curve for both agents, maximum plasma concentration, time of maximum plasma concentration, half-life for azacitidine, clearance for azacitidine, and the recommended phase 2 dose (RP2D) of the combination of venetoclax and azacitidine. The secondary end points include duration of response, rate of red blood cell transfusion independence, progression-free survival (PFS), overall survival (OS), hematologic improvement rate, and other efficacy end points.

“Higher-risk MDS is associated with poor prognosis, reduced quality of life, and limited treatment options,” said Levi Garraway, MD, PhD, Roche’s chief medical officer and head of Global Product Development. “We are pleased that the FDA has granted Venclexta its sixth Breakthrough Therapy Designation in recognition of its potential to improve outcomes for people with MDS in combination with azacitidine.”

Results from the M15-531 study, presented during the 2020 American Hematology Association Annual Meeting and Exposition, showed that venetoclax plus azacitidine has promising efficacy with response durability and a tolerable safety profile.²

The analysis included 57 patients followed-up for a median of 13.0 months (95% CI, 11.3-15.6). The population was largely male (75%) and had a median age of 71 years (range, 26-85 years). Also, 89% of the patients had an ECOG performance status of 0 or 1.

Treatment with venetoclax plus azacitidine led to an objective response rate of 77%, which included complete responses in 42% and marrow CRs in 35%. Of the patients who achieved a CR, 40% had CR with hematological improvement. Responses lasted for a median duration of 14.8 months (95% CI, 12.9 to not estimable [NE])

In terms of survival, the median OS was not reached (95% CI, 16.2 to NE). The median PFS was 17.5 months (95% CI, 14.5 months to NE).

At least 1 adverse event (AE) was observed in all patients treated. The most common AEs observed were constipation (54%), neutropenia (51%), and nausea (51%). Grade ≥3 AEs were experienced by 97% of patients, with neutropenia (51%), febrile neutropenia (46%), and thrombocytopenia (30%). Of the serious AEs observed, febrile neutropenia was the most common. The patients also had a 2% 30-day mortality rate.

Quality of life measurement were also assessed during the analysis. It was shown that of those who received the RP2D venetoclax (400 mg for 14 days per every 28-day cycle) combined with azacitidine, physical functioning was maintained through 48 weeks. Further, clinically meaningful improvement in dyspnea and fatigue were seen within the firs 48 weeks of treatment.

The BTD granted for treatment-naïve MDS is the 6th BTD for venetoclax. The agent also has BTDs for previously untreated chronic lymphocytic leukemia (CLL), 2 for relapsed or refractory CLL, 2 for patients with previously untreated acute myeloid leukemia, and 1 for those with myelodysplastic syndromes.

_References:

_{1. FDA grants breakthrough therapy designation for Venclexta in combination with azacitidine for the treatment of patients with myelodysplastic syndromes. News release. July 21, 2021. Accessed July 21, 2021. https://bit.ly/3eGvlF2}

_{2. Garcia JS, Wei AH, Borate U, et al. 656 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}