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AbbVie issued the following announcement on Nov. 21.
- Acute myeloid leukemia (AML) is one of the most aggressive blood cancers, with a very low survival rate and few options for patients who are ineligible for intensive chemotherapy[1,2]
- VENCLEXTA is now approved in the U.S. for use in two different blood cancers: newly-diagnosed AML and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)
- The approval in AML is the third provided under priority review by the U.S. Food and Drug Administration (FDA) for VENCLEXTA, an oral B-cell lymphoma-2 (BCL-2) inhibitor, which has been granted four Breakthrough Therapy Designations (BTDs) by the FDA[3,4,5,6]
Intensive chemotherapy may not be appropriate for all patients diagnosed with AML.8 An analysis of 446 older (≥70 years of age) AML patients concluded that intensive chemotherapy can be delivered but may not be beneficial to most.8 There are a number of factors why AML patients may be unable to tolerate intensive chemotherapy, such as age, performance status and comorbidities.8 Median survival in patients not eligible for intensive chemotherapy is five to 10 months.1
"AML is an extremely aggressive and debilitating blood cancer, and outcomes for patients ineligible for intensive chemotherapy are very poor," said Michael Severino, M.D., executive vice president of research and development and chief scientific officer, AbbVie. "This new approval for VENCLEXTA marks a significant milestone for AbbVie and, more importantly, for patients diagnosed with this deadly disease. We look forward to continuing our work developing VENCLEXTA and advancing treatment options in other aggressive cancers."
The FDA accelerated approval is based on two open-label non-randomized trials in patients with newly-diagnosed AML who were age 75 years or older, or had comorbidities that precluded the use of intensive induction chemotherapy: M14-358, a trial evaluating VENCLEXTA in combination with azacitidine (n=67) or decitabine (n=13), and M14-387, a trial of VENCLEXTA and LDAC (n=61).7Efficacy was established based on the rate of complete remission (CR) and duration of CR.7
The M14-358 trial showed that VENCLEXTA in combination with azacitidine resulted in a CR rate of 37 percent and a CR with partial hematologic recovery (CRh) rate of 24 percent. The median follow-up of patients included in the study was 7.9 months (range: 0.4 to 36 months). At the time of analysis, for patients who achieved a CR, the median observed time in remission was 5.5 months (range: 0.4 to 30 months), with patients achieving a first CR or CRh at a median of 1 month (range: 0.7 to 8.9 months). For patients taking VENCLEXTA in combination with decitabine, the CR rate was 54 percent and the CRh rate was 7.7 percent. The median follow-up of patients taking this combination was 11 months (range: 0.7 to 21 months). At the time of analysis, for patients who achieved a CR, the median observed time in remission was 4.7 months (range: 1 to 18 months), with patients achieving a first CR or CRh at a median of 1.9 months (range: 0.8 to 4.2 months).7
The M14-387 trial showed that patients receiving VENCLEXTA in combination with LDAC achieved a CR rate of 21 percent and a CRh rate of 21 percent. The median follow-up of patients was 6.5 months (range: 0.3 to 34 months). At the time of analysis, for patients who achieved a CR, the median observed time in remission was six months (range: 0.03 to 25 months), with patients achieving a first CR or CRh at a median of 1 month (range: 0.8 to 9.4 months).7
For patients taking VENCLEXTA in combination with azacitidine, serious ARs were reported in 75 percent of patients. The most frequent serious adverse reactions (ARs; ≥5 percent) were febrile neutropenia, pneumonia (excluding fungal), sepsis (excluding fungal), respiratory failure and multiple organ dysfunction syndrome. For those taking VENCLEXTA and decitabine, serious ARs were reported in 85 percent of patients. The most frequent serious ARs (≥5 percent) were febrile neutropenia, sepsis (excluding fungal), pneumonia (excluding fungal), diarrhea, fatigue, cellulitis and localized infection.7
For patients taking VENCLEXTA in combination with LDAC, serious ARs were reported in 95 percent of patients. The most frequent serious adverse reactions (ARs; ≥5 percent) were febrile neutropenia, sepsis (excluding fungal), hemorrhage, pneumonia (excluding fungal) and device-related infection.7
The challenges of treating AML, including in older adults who are more likely to be ineligible for intensive chemotherapy, are an ongoing topic of discussion among the medical community. Dr. Daniel Pollyea, clinical director of leukemia services at University of Colorado Hospital reflected on his experience treating patients with AML here: "A Physicians View: Facing the Challenges of Treating AML in Older Adults."
"Many of my patients are ineligible for the intensive treatment for AML, which typically involves intensive chemotherapy. Only a minority of AML patients older than 60 are able to tolerate the standard chemotherapy required to achieve optimal results," said Dr. Pollyea. "Having a new medicine to treat AML is encouraging for my patients and their families. VENCLEXTA's approval is a true breakthrough for AML patients ineligible for intensive chemotherapy."
VENCLEXTA, an oral B-cell lymphoma-2 (BCL-2) inhibitor, has been granted four Breakthrough Therapy Designations (BTDs) from the FDA.3,4,5,6The FDA approved VENCLEXTA in combination with azacitidine, or decitabine, or low-dose cytarabine for the treatment of newly-diagnosed AML in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. This indication is approved under accelerated approval based on response rates. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.7
The approval of VENCLEXTA in AML marks the third approval granted under priority review by the FDA for VENCLEXTA.7 VENCLEXTA is being studied in two ongoing Phase 3 studies in the AML patient population ineligible for intensive chemotherapy.9,10
Venetoclax is being studied in several other hematologic malignancies including chronic lymphocytic leukemia (CLL), multiple myeloma (MM), non-Hodgkin lymphoma (NHL) and myelodysplastic syndrome (MDS).11,12,13Venetoclax is being developed by AbbVie and Roche and is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S.
About the Clinical Trials that Supported Accelerated Approval in AML
The FDA accelerated approval is based on two open-label non-randomized trials in patients with newly-diagnosed AML who were age 75 years or older, or had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline Eastern Cooperative Oncology Group (ECOG) performance status of 2-3, severe cardiac or pulmonary comorbidity, moderate hepatic impairment, or CLcr <45 mL/min or other comorbidity. Efficacy was established based on the rate of complete remission (CR) and duration of CR.7
Study M14-358 was a non-randomized, open-label clinical trial of VENCLEXTA in combination with azacitidine (N=84) or decitabine (N=31) in patients with newly-diagnosed AML. Of those patients, 67 who received azacitidine combination and 13 who received decitabine combination were age 75 or older or had comorbidities that precluded the use of intensive induction chemotherapy. Patients received VENCLEXTA via a daily ramp-up to a final 400 mg once daily dose.7
Azacitidine (N=67):
The CR rate was 37 percent (95% confidence interval [CI]: 26, 50), and the CRh rate was 24 percent (95% CI: 14, 36). The median follow-up was 7.9 months (range: 0.4 to 36 months) for VENCLEXTA in combination with azacitidine. At the time of analysis, for patients who achieved a CR, the median observed time in remission was 5.5 months (range: 0.4 to 30 months). The observed time in remission is the time from the start of CR to the time of data cut-off date or relapse from CR. Median time to first CR or CRh was 1.0 month (range: 0.7 to 8.9 months).7
Of patients treated with VENCLEXTA in combination with azacitidine, 7.5 percent (5/67) subsequently received stem cell transplant.7
The study enrolled 17 additional patients who did not have known comorbidities that preclude the use of intensive induction chemotherapy. For those patients, the CR rate was 35 percent (95% CI: 14, 62) and the CRh rate was 41 percent (95% CI: 18, 67). Seven patients subsequently received stem cell transplant.7
The most common ARs (≥30 percent) of any grade were nausea, diarrhea, constipation, neutropenia, thrombocytopenia, hemorrhage, peripheral edema, vomiting, fatigue, febrile neutropenia, rash and anemia.7 Serious ARs were reported in 75 percent of patients.7 The most frequent serious adverse reactions (ARs; ≥5 percent) were febrile neutropenia, pneumonia (excluding fungal), sepsis (excluding fungal), respiratory failure and multiple organ dysfunction syndrome.7
Decitabine (N=13):
The CR rate was 54 percent (95% CI: 25, 81), and the CRh rate was 7.7 percent (95% CI: 0.2, 36). The median follow-up was 11 months (range: 0.7 to 21 months) for VENCLEXTA in combination with decitabine. At the time of analysis, for patients who achieved a CR, the median observed time in remission was 4.7 months (range: 1.0 to 18 months). The observed time in remission is the time from the start of CR to the time of data cut-off date or relapse from CR. Median time to first CR or CRh was 1.9 months (range: 0.8 to 4.2 months).7
The study enrolled 18 additional patients who did not have known comorbidities that preclude the use of intensive induction chemotherapy. For those patients, the CR rate was 56 percent (95% CI: 31, 79) and the CRh rate was 22 percent (95% CI: 6.4, 48). Three patients subsequently received stem cell transplant.7
The most common ARs (≥30 percent) of any grade were febrile neutropenia, constipation, fatigue, thrombocytopenia, abdominal pain, dizziness, hemorrhage, nausea, pneumonia (excluding fungal), sepsis (excluding fungal), cough, diarrhea, neutropenia, back pain, hypotension, myalgia, oropharyngeal pain, peripheral edema, pyrexia and rash. Serious ARs were reported in 85 percent of patients.7 The most frequent serious ARs (≥5 percent) were febrile neutropenia, sepsis (excluding fungal), pneumonia (excluding fungal), diarrhea, fatigue, cellulitis and localized infection.7
Low-dose cytarabine (N=61):
Study M14-387 was a non-randomized, open-label clinical trial of VENCLEXTA in combination with low dose cytarabine (N=82) in patients with newly-diagnosed AML, including patients with previous exposure to a hypomethylating agent for an antecedent hematologic disorder. Of those patients, 61 were age 75 or older or had comorbidities that precluded the use of intensive induction chemotherapy. Patients initiated VENCLEXTA via daily ramp-up to a final 600 mg once-daily dose.7
The CR rate was 21 percent (95% CI: 12, 34), and the CRh rate was 21 percent (95% CI: 12, 34). The median follow-up was 6.5 months (range: 0.3 to 34 months). At the time of analysis, for patients who achieved a CR, the median observed time in remission was 6.0 months (range: 0.03 to 25 months). The observed time in remission is the time from the start of CR to the time of data cut-off date or relapse from CR. Median time to first CR or CRh was 1.0 month (range: 0.8 to 9.4 months).7
The study enrolled 21 additional patients who did not have known comorbidities that preclude the use of intensive induction chemotherapy. For those patients, the CR rate was 33 percent (95% CI:15, 57) and the CRh rate was 24 percent (95% CI: 8.2, 47). One patient subsequently received stem cell transplant.7
The most common ARs (≥30 percent) of any grade were nausea, thrombocytopenia, hemorrhage, febrile neutropenia, neutropenia, diarrhea, fatigue, constipation and dyspnea. Serious ARs were reported in 95 percent of patients. The most frequent serious adverse reactions (ARs; ≥5 percent) were febrile neutropenia, sepsis (excluding fungal), hemorrhage, pneumonia (excluding fungal) and device-related infection.7
About VENCLEXTA® (venetoclax) (US)
VENCLEXTA® 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. VENCLEXTA targets the BCL-2 protein and works to help restore the process of apoptosis.7
VENCLEXTA is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S. Together, the companies are committed to BCL-2 research and to studying venetoclax in clinical trials across several blood and other cancers.
In April 2016, the U.S. FDA first granted accelerated approval of VENCLEXTA for the treatment of patients with CLL with 17p deletion, as detected by an FDA-approved test, who have received at least one prior therapy.14 The FDA approved this indication under accelerated approval based on overall response rate.14 Based on the results of the MURANO study, VENCLEXTA was approved in June 2018 for the treatment of patients with CLL or SLL, with or without 17p deletion, who have received at least one prior therapy in combination with rituximab or as monotherapy.7
Venetoclax is approved in more than 50 countries, including the U.S. AbbVie, in collaboration with Roche, is currently working with regulatory agencies around the world to bring this medicine to additional eligible patients in need.
Use and Important Safety Information (US)
What is VENCLEXTA® (venetoclax)?
VENCLEXTA is a prescription medicine used:
Important Safety Information
What is the most important information I should know about VENCLEXTA?
VENCLEXTA can cause serious side effects, including:
Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure, the need for dialysis treatment, and may lead to death. Your healthcare provider will do tests to check your risk of getting TLS before you start taking VENCLEXTA. You will receive other medicines before starting and during treatment with VENCLEXTA to help reduce your risk of TLS .You may also need to receive intravenous (IV) fluids into your vein. Your healthcare provider will do blood tests to check for TLS when you first start treatment and during treatment with VENCLEXTA.
It is important to keep your appointments for blood tests. Tell your healthcare provider right away if you have any symptoms of TLS during treatment with VENCLEXTA, including fever, chills, nausea, vomiting, confusion, shortness of breath, seizures, irregular heartbeat, dark or cloudy urine, unusual tiredness, or muscle or joint pain.
Drink plenty of water when taking VENCLEXTA to help reduce your risk of getting TLS.
Drink 6 to 8 glasses (about 56 ounces total) of water each day, starting 2 days before your first dose, on the day of your first dose of VENCLEXTA, and each time your dose is increased.
Your healthcare provider may delay, decrease your dose, or stop treatment with VENCLEXTA if you have side effects.
Who should not take VENCLEXTA?
Certain medicines must not be taken when you first start taking VENCLEXTA and while your dose is being slowly increased because of the risk of increased tumor lysis syndrome (TLS).
You should not drink grapefruit juice, eat grapefruit, Seville oranges (often used in marmalades), or starfruit while you are taking VENCLEXTA. These products may increase the amount of VENCLEXTA in your blood.
What are the possible side effects of VENCLEXTA?
VENCLEXTA can cause serious side effects, including:
The most common side effects of VENCLEXTA when used alone in people with CLL/SLL include low white blood cell counts; diarrhea; nausea; upper respiratory tract infection; low red blood cell counts; tiredness; low platelet counts; muscle and joint pain; swelling of your arms, legs, hands, and feet; and cough.
The most common side effects of VENCLEXTA in combination with azacitidine, or decitabine, or low-dose cytarabine in people with AML include low white blood cell counts; nausea; diarrhea; low platelet counts; constipation; fever with low white blood cell counts; low red blood cell counts, infection in blood; rash; dizziness; low blood pressure; fever; swelling of your arms, legs, hands, and feet; vomiting; tiredness; shortness of breath; bleeding; infection in lung; stomach (abdominal) pain; pain in muscles or back; cough; and sore throat.
VENCLEXTA may cause fertility problems in males. This may affect your ability to father a child. Talk to your healthcare provider if you have concerns about fertility.
These are not all the possible side effects of VENCLEXTA. For more information, ask your healthcare provider or pharmacist.
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit http://www.fda.gov/medwatch or call 1-800-FDA-1088.
If you cannot afford your medication, contact: www.pparx.org for assistance.
