The U.S. Food and Drug Administration (FDA) has provided full approval to venetoclax (Venclexta®; AbbVie/Genentech) in combination with azacitidine (Vidaza®; Celgene/BMS), or decitabine, or low-dose cytarabine (LDAC; Pfizer/Hospira) for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude the use of intensive induction chemotherapy.
Venetoclax is a first-in-class medicine that selectively binds and inhibits the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers, BCL-2 prevents cancer cells from undergoing their natural death or self-destruction process, called apoptosis. Venetoclax targets the BCL-2 protein and works to help restore the process of apoptosis.
The approval is supported by data from the Phase III VIALE-A (M15-656) and VIALE-C (M16-043) studies and updated data from the Phase Ib M14-358 and the Phase I/II M14-387 studies.
Venetoclax is being developed by AbbVie and Roche and It is jointly commercialized by AbbVie and Genentech in the U.S. and by AbbVie outside of the U.S.
The FDA previously granted accelerated approval to venetoclax for this indication in 2018.
The Phase III VIALE-A trial showed that significantly more patients diagnosed with AML, one of the most aggressive and difficult-to-treat blood cancers with a very low survival rate, treated with venetoclax, in combination with azacitidine achieved complete remission and lived longer versus patients treated with azacitidine alone. Based on these results, the National Comprehensive Cancer Network (NCCN) guidelines recommend the venetoclax and azacitidine combination as a Category 1 Preferred AML treatment regimen for patients ineligible for intensive chemotherapy.
“AML is a complex and challenging disease with generally low survival rates. This approval is significant because data from our VIALE-A trial has shown that newly-diagnosed patients, who cannot undergo intensive chemotherapy, lived longer when treated with venetoclax plus azacitidine than those treated with azacitidine alone,” said Mohamed Zaki, M.D., Ph.D., vice president and global head of oncology development, AbbVie.
“This trial also provides physicians more information for managing patients – from treatment initiation, to assessing response and management post disease remission,” Zaki added.
A total of 431 patients were randomized in the double-blind, placebo-controlled, multicenter, Phase III VIALE-A trial, which evaluated the efficacy and safety of venetoclax in combination with azacitidine (n=286) in patients with AML who are ineligible for standard induction therapy versus azacitidine in combination with placebo (n=145). The primary endpoint was Overall Survival (OS).
Positive OS data seen at an interim analysis of the VIALE-A trial led to an early submission supporting the FDA approval of venetoclax in AML. The trial results demonstrated patients on the active regimen of venetoclax plus azacitidine achieved a 34% reduction in the risk of death compared to azacitidine in combination with placebo (Hazard Ratio [HR]=0.66 [95% CI: 0.52-0.85], p<0.001).
The median OS for patients in the venetoclax arm was 14.7 months (95% CI: 11.9, 18.7) versus 9.6 months in patients treated with azacitidine in combinationthe placebo (95% CI: 7.4, 12.7).
Additionally, patients in the venetoclax plus azacitidine arm achieved a complete remission (CR) rate of 37% (95% CI: 31%, 43%) with a median duration of CR of 18.0 months (95% CI: 15.3, -) compared with patients in the placebo plus azacitidine arm with a CR rate of 18% (95% CI: 12%, 25%) with a median duration of CR of 13.4 months (95% CI: 8.7, 17.6). The observed safety profile was generally consistent with the known safety profile of venetoclax in combination with azacitidine.
The median duration of treatment was 7.6 months (range: <0.1 to 30.7 months) in the venetoclax arm.
For patients taking venetoclax in combination with azacitidine, the most frequent serious adverse reactions (ARs; ≥5%) at first use were febrile neutropenia (30%), pneumonia (22%), sepsis (excluding fungal; 19%) and hemorrhage (6%).
Data from VIALE-A was presented for the first time as a late-breaking abstract at the 25th European Hematology Association (EHA) Annual Congress in June 2020 and recently published in the New England Journal of Medicine.
“For far too long, people with AML had very few treatment options, aside from very intense chemotherapy. Today’s news continues the progress of bringing more treatment options to patients with this devastating disease,” said Lee Greenberger, Ph.D., chief scientific officer of The Leukemia & Lymphoma Society.
“The results of the VIALE-A study reinforce the clinically meaningful benefit of Venclexta plus azacitidine for people newly diagnosed with AML,” explained Courtney DiNardo, M.D., Associate Professor of the Department of Leukemia, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center.
“Based on the results of this study, this treatment regimen represents a significant advance for older AML patients, including higher response rates, greater transfusion independence, longer durations of remission, and ultimately significantly improved overall survival compared to azacitidine alone,” DiNardo added.
A total of 211 patients were enrolled and treated in the randomized, double-blind, placebo-controlled, multicenter, Phase III VIALE-C trial, which evaluated the efficacy and safety of venetoclax in combination with LDAC (n=143) versus placebo with LDAC (n=68).
The primary endpoint was OS.Trial data from the VIALE-C trial was presented at both the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting and the EHA Annual Congress and previously published in Blood.
Venetoclax in combination with LDAC did not significantly improve OS versus placebo in combination with LDAC. The HR for OS was 0.75 (95% CI: 0.52, 1.07); p-value 0.114.
The median OS for venetoclax in combination with LDAC was 7.2 months (95% CI: 5.6, 10.1) and 4.1 months for LDAC in combination with placebo (95% CI: 3.1, 8.8). The HR for the primary endpoint of OS was 0.75 (95% CI: 0.52-1.07; p=0.114).
The trial did not meet its primary endpoint of statistically significant improvement of OS for patients with AML who are ineligible for intensive chemotherapy at the time of the planned analysis. Efficacy was based on the rate of CR and duration of CR with supportive evidence of rate of CR + complete remission with partial hematologic recovery (CR+CRh), duration of CR+CRh, and the rate of conversion from transfusion dependence to transfusion independence.
Efficacy was based on the rate of CR and duration of CR with supportive evidence of rate of CR+CRh, duration of CR+CRh, and the rate of conversion from transfusion dependence to transfusion independence. The CR rate in the venetoclax in combination with LDAC arm was 27% (95% CI: 20%, 35%) with a median duration of CR of 11.1 months (95% CI: 6.1, -), and the CR rate in the placebo arm was 7.4% (95% CI: 2.4%, 16%) with a median duration of CR of 8.3 months (95% CI: 3.1, – ).
The CR+CRh rate in the venetoclax in combination with LDAC arm was 47% (95% CI: 39%, 55%) and in the placebo arm was 15% (95% CI: 7.3%, 25%) with a median duration of CR+CRh of 11.1 months with venetoclax in combination with LDAC and 6.2 months with LDAC in combination with placebo. The median time to first response of CR or CRh was 1.0 month (range: 0.7 to 5.8 months) with venetoclax in combination with LDAC.
In the venetoclax arm, the most frequent serious ARs were (≥10%) pneumonia (17%), febrile neutropenia (16%) and sepsis (excluding fungal; 12%).
An agressive hematological malignancy
AML is an aggressive and difficult-to-treat blood cancer with a low survival rate. Despite recent advances in available therapies, the five-year survival rate for patients diagnosed with AML remains approximately 29%. AML typically worsens quickly, and due to age or comorbidities, not all patients are eligible to receive intensive chemotherapy.
This is the second time that the FDA reviewed the clinical data for venetoclax under the FDA’s new Real-Time Oncology Review (RTOR) pilot program and Project Orbis initiative, which led to approval in the U.S. in October 2020.
The RTOR pilot programme explores a more efficient review process to ensure safe and effective treatments are available to patients as early as possible.
Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. The U.S. FDA, the Australian Therapeutic Goods Administration, Swissmedic, Health Canada and ANVISA (Agência Nacional de Vigilância Sanitária) collaborated on this review based on the marketing applications submitted in their respective countries.
“This full approval is supported by the significant results that showed that venetoclax in combination with azacitidine extended overall survival for people with newly diagnosed acute myeloid leukaemia who cannot tolerate intensive induction chemotherapy,” noted Levi Garraway, M.D., Ph.D., Roche’s Chief Medical Officer and Head of Global Product Development.
“We are very pleased that this application was reviewed under the FDA’s Real-Time Oncology Review pilot and Project Orbis initiative, helping to bring this treatment option more rapidly to patients in the United States and other countries,” Garraway concluded.
A Study of Venetoclax in Combination With Azacitidine Versus Azacitidine in Treatment Naïve Subjects With Acute Myeloid Leukemia Who Are Ineligible for Standard Induction Therapy – NCT02993523
A Study of Venetoclax in Combination With Low Dose Cytarabine Versus Low Dose Cytarabine Alone in Treatment Naive Patients With Acute Myeloid Leukemia Who Are Ineligible for Intensive Chemotherapy – NCT03069352
Highlights of Prescription information
Venetoclax (Venclexta®; AbbVie/Genentech) [Prescribing Information]
Azacitidine (Vidaza®; Celgene/Bristol/Meyers Squibb)[Prescribing Information]
Decitabine (Dacogen®; Otsuka America Pharmaceutical/Astex Pharmaceuticals) [Prescribing Information]
Cytarabine; Pfizer/Hospira [Prescribing Information]
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 AbbVie Receives US FDA Accelerated Approval for VENCLEXTA® (venetoclax) for Treatment of Newly-Diagnosed Acute Myeloid Leukemia Patients Ineligible for Intensive Chemotherapy. AbbVie. Online. Last accessed on October 16, 2020.
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Featured image: AbbVie booth at the 2019 annual meeting of the American Society of Clinical Oncology (ASCO) held June 1 – 4, 2019 in Chicago, Ill. Photo courtesy: © Sunvalley Communication. used with permission.