FDA Approves Venetoclax as a Chemotherapy-Free Combination in Previously Untreated CLL

Child embracing ill mother
Small caring child embracing her ill mother.

The U.S. Food and Drug Administration (FDA) has approved venetoclax (Venclexta®; AbbVie/Genentech), a first-in-class medicine that selectively binds and inhibits the B-cell lymphoma-2 (BCL-2) protein, in combination with obinutuzumab (Gazyva®) for previously untreated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). [1]  

CLL is typically a slow-progressing cancer of the bone marrow and blood in which types of white blood cells called B lymphocytes become cancerous and multiply abnormally. [7]  In the U.S., CLL accounts for more than 20,000 newly diagnosed cases of leukemia each year. [7]

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 FDA granted Breakthrough Therapy designation for this combination therapy, and early submission of the data was provided under the Real-Time Oncology Review (RTOR) pilot program, which led to approval in just over two months, following submission of the complete application. 

“This FDA approval provides a new chemotherapy-free combination treatment option for patients, and underscores the growing utility of venetoclax in CLL,” said Michael Severino, M.D., vice chairman and president, AbbVie.

“The approval is based on findings from the CLL14 trial in which patients received a 12-month treatment regimen. The majority of patients receiving venetoclax in the trial remained progression-free at two years,” Severino added.

Data from the CLL14 trial is expected to be presented at an upcoming medical meeting and published in a journal this year.

“Patients never treated for their CLL have had to rely largely on chemotherapy as their initial treatment,” said Michael Hallek, M.D., lead investigator of the CLL14 study, Department of Internal Medicine and Center of Integrated Oncology at the University Hospital Cologne in Germany, and Head of the German CLL Study Group.

“The approval of the venetoclax combination means that patients with previously untreated CLL now have a finite duration, chemotherapy-free treatment option that can allow them to live longer without disease progression, induce high rates of minimal residual disease (MRD) negativity and, importantly, allow them to complete their course of therapy within 12 months. This is a major step forward in how previously untreated CLL is managed and further supports the growing benefits offered by venetoclax in CLL,” Hallek further noted.

Progression free Survival

The CLL14 trial demonstrated superior progression-free survival as assessed by an independent review committee (PFS; the time from initiation of treatment until disease progression or death) in patients treated with venetoclax plus obinutuzumab compared to patients who received chlorambucil plus obinutuzumab, a commonly used standard of care. With a median follow-up of 28 months (range: 0.1 to 36 months), venetoclax plus obinutuzumab reduced the risk of progression or death by 67% compared with chlorambucil plus obinutuzumab (hazard ratio: 0.33, 95% confidence interval [CI]: 0.22, 0.51; p<0.0001). [1] Median PFS was not reached in either treatment arm. [1]  

Minimal residual disease (MRD) negativity (undetectable disease in the blood or bone marrow) was assessed as a secondary endpoint and occurs when less than one CLL cell per 10,000 leukocytes can be detected using sensitive analytical methods.  Higher rates of MRD negativity were observed with venetoclax plus obinutuzumab compared to obinutuzumab plus chlorambucil in both bone marrow (57% versus 17%, p<0.0001) and peripheral blood (76% versus 35%, p<0.0001) three months after treatment completion .[1]

Adverse events

In the CLL14 trial, adverse events (AEs) were consistent with the known safety profiles of venetoclax and obinutuzumab alone. Serious adverse reactions (ARs) were reported in 49% of patients in the venetoclax plus obinutuzumab arm, most often due to febrile neutropenia and pneumonia (5% each). The most common ARs (≥15%) of any grade were neutropenia (60%), diarrhea (28%), fatigue (21%), nausea (19%), anemia (17%), and upper respiratory tract infection (17%).[1]

Venetoclax , an oral B-cell lymphoma-2 (BCL-2) inhibitor, has been granted five Breakthrough Therapy designations from the FDA.[2][3][4][5][6]

CLL14 Trial

The prospective, multicenter, open-label, randomized Phase III CLL14 trial, which was conducted in close collaboration with the German CLL Study Group (DCLLSG), evaluated the efficacy and safety of a combined regimen of VENCLEXTA and obinutuzumab (n=216) versus obinutuzumab and chlorambucil (n=216) in previously untreated patients with CLL and coexisting medical conditions (total Cumulative Illness Rating Scale [CIRS] score >6 or creatinine clearance <70 mL/min). The therapies were administered for a fixed duration of 12 months for VENCLEXTA in combination with six cycles of obinutuzumab. The trial enrolled 432 patients, all of whom were previously untreated according to the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria. Efficacy was based on progression-free survival (PFS) as assessed by an Independent Review Committee (IRC).[1][8]

Key secondary endpoints were MRD negativity in peripheral blood and bone marrow, overall and complete response rates, MRD negativity in complete response in peripheral blood and bone marrow, and overall survival.[8]

VENCLEXTA is being developed by AbbVie and Roche. In the United States the drug is jointly commercialized by AbbVie and Genentech. Outside the United States AbbVie is responsible commercialization of the drug.

Together, the companies are committed to BCL-2 research and to studying venetoclax in clinical trials across several blood and other cancers. Venetoclax is being studied in several other hematologic malignancies including acute myeloid leukemia (AML), multiple myeloma (MM), non-Hodgkin lymphoma (NHL) and myelodysplastic syndrome (MDS). [9][10][11][12[13]

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. [1]

In November 2018, VENCLEXTA was approved in combination with azacitidine, or decitabine, or low-dose cytarabine to treat adults with newly-diagnosed acute myeloid leukemia (AML) who are 75 years of age or older, or have other medical conditions that prevent the use of standard chemotherapy.[15]

References

[1] VENCLEXTA (venetoclax) [Package Insert]. North Chicago, Ill.: AbbVie Inc.
[2] American Cancer Society (2018). Chronic Lymphocytic Leukemia
(CLL). Accessed May 2019.
[3] Farrell A. Grant-Breakthrough Therapy Designation (CLL). Department of Health and Human Services. 2015:1-3.
[4] Farrell A. Grant-Breakthrough Therapy Designation (CLL). Department of Health and Human Services. 2015:1-3.
[5] Farrell A. Grant-Breakthrough Therapy Designation (AML). Department of Health and Human Services. 2016:1-3.
[6] Farrell A. Grant-Breakthrough Therapy Designation (AML). Department of Health and Human Services. 2017:1-3.
[7] Farrell A. Grant-Breakthrough Therapy Designation (CLL). Department of Health and Human Services. 2019:1-3.
[8] A Prospective, Open-Label, Multicenter Randomized Phase III Trial to Compare The Efficacy and Safety of A Combined Regimen of Obinutuzumab and Venetoclax (GDC-0199/ABT-199) Versus Obinutuzumab and Chlorambucil in Previously Untreated Patients With CLL and Coexisting Medical Conditions. NCT02242942. Last Accessed February 2019.
[9] A study of venetoclax in combination with azacytidine versus azacytidine in treatment naïve subjects with acute myeloid leukemia who are ineligible for standard induction therapy. NCT02993523 Last accessed January 2019.
[10] A study of venetoclax in combination with low dose cytarabine versus low dose cytarabine alone in treatment naïve patients with acute myeloid leukemia who are ineligible for intensive chemotherapy. NCT03069352 Last accessed January 2019.
[11] Study evaluating ABT-199 in subjects with relapsed or refractory Multiple Myeloma. NCT01794520. Last accessed January 2019.
[12] A Phase 1 study evaluating the safety and pharmacokinetics of ABT-199 in subjects with relapsed or refractory Chronic Lymphocytic Leukemia and Non-Hodgkin Lymphoma. NCT01328626. Last accessed January 2019.
[13] A study evaluating venetoclax in combination with azacytidine in subjects with treatment-naïve higher-risk myelodysplastic syndromes (MDS). NCT02942290. Last accessed January 2019.
[14] U.S. Food and Drug Administration (2016). News and Events: FDA approves new drug for chronic lymphocytic leukemia in patients with a specific chromosomal abnormality. Last accessed January 2019.
[15] U.S. Food and Drug Administration (2018). Approved Drugs: FDA approves venetoclax in combination for AML in adults. Accessed January 2019.