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Venetoclax, obinutuzumab regimen appears safe, effective for chronic lymphocytic leukemia
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The combination of venetoclax and obinutuzumab conferred high response rates with deep remissions among patients with previously untreated or relapsed/refractory chronic lymphocytic leukemia, according to results of a single-arm, phase 1b trial published in Blood.
The regimen also appeared safe, results showed.
“The standard of care for frontline CLL has shifted from chemoimmunotherapy to ibrutinib [Imbruvica; Pharmacyclics, Janssen], which is a fantastic drug for these patients and patients with relapsed or refractory CLL,” Ian W. Flinn, MD, PhD, oncologist at Sarah Cannon Research Institute/Tennessee Oncology, and lead study author, told HemOnc Today. “One of the downsides of it is that it has to be given for as long as it is helping patients. The advantage of [the venetoclax-obinutuzumab] regimen is that you can get people off of treatment in over a year. That’s really exciting for patients because now they won’t have to stay on treatment indefinitely.”
Flinn and colleagues sought to define the maximum tolerated dose of venetoclax (Venclexta; AbbVie, Genentech) — an oral BCL-2 inhibitor — when used in combination with obinutuzumab (Gazyva, Genentech), a type II anti-CD20 antibody.
The analysis included 46 patients with relapsed/refractory CLL — 24 of whom were in the study’s dose-finding cohort and 22 in the safety expansion cohort — and 32 patients with untreated CLL — including 12 in the dose-finding cohort and 20 in the safety expansion cohort.
Patients in the dose-finding cohort had been scheduled to receive venetoclax doses ranging from 100 mg to 600 mg with standard-dose obinutuzumab for six 28-day cycles.
The maximum tolerated dose of venetoclax when combined with obinutuzumab, as well as safety/tolerability of the regimen in all patients, served as the study’s primary endpoints.
About 80% (n = 36) of patients with relapsed/refractory CLL and all 32 patients with untreated CLL received venetoclax at 400 mg per day — after reviewing emerging data on venetoclax dosing, researchers decided not to test the 600-mg dose. More than 90% (n = 42) of patients with relapsed/refractory CLL and all 32 patients with untreated CLL completed six cycles of the regimen.
Median treatment time with venetoclax was 789 days (range, 8-1,516) among relapsed/refractory patients and 371 days (range, 314-883) for previously untreated patients.
Median relative dose intensity for venetoclax was 100% in both patient groups.
After median follow-up of 29.3 months (range, 3-55), 85.4% (95% CI, 74.5-96.2) of patients with relapsed/refractory disease achieved 24-month PFS.
After median follow-up of 26.7 months (range, 16-39), 90.6% (95% CI, 80.5-100) of patients with previously untreated disease achieved 24-month PFS.
Overall response rate reached 95% (95% CI, 84-99) in patients with relapsed/refractory disease and 100% (95% CI, 89-100) in patients with previously untreated disease.
Complete response with incomplete marrow recovery occurred in 37% (95% CI, 25-53) of patients with relapsed/refractory disease and 78% (95% CI, 60-91) of patients with previously untreated disease.
Median duration of response was 40.9 months (range, 39.9-51.8) in patients with relapsed/refractory disease and not reached in treatment-naive patients.
Results were similar among different cytogenetic groups.
Three patients with relapsed/refractory disease experienced fatal adverse events associated with treatment. These included acute respiratory failure in one patient with suspected Richter’s transformation, pneumonia in the context of metastatic squamous cell carcinoma of the lung, and pneumonia reported 3 months after the last venetoclax dose.
Venetoclax was discontinued in seven patients with relapsed/refractory disease and one previously untreated patient due to adverse events.
Common adverse events included diarrhea, infusion-related reactions, neutropenia, fatigue, nausea, cough, pyrexia and anemia.
Maximum tolerated dose was not reached, establishing 400 mg venetoclax as the recommended dose for future study.
The regimen, overall, was well-tolerated and could lead to a new standard of care for patients with CLL, Flinn said.
“I believe the safety data show that this combination can be given in the average community physicians office,” Flinn said. “It opens up new options for treatment for patients in both the frontline and relapsed or refractory settings. Ultimately, I think this will lead to the FDA approval of this regimen for frontline therapy in patients with CLL.”– by John DeRosier
For more information:
Ian W. Flinn , MD, PhD, can be reached at iflinn@tnonc.com
Disclosures: Flinn reports research funding from AbbVie, Acerta, Agios, ArQule, Beigene, Calithera, Celgene, Constellation, Curis, Forma, Forty Seven, Genentech, Gilead, Incyte, Infinity, Janssen, KITE, Merck, Novartis, Pfizer, Pharmacyclics, Portola, Seattle Genetics, Takeda, TG Therapeutics, Trillium and Verastem. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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Kanti R. Rai, MD
In this important study, Dr. Flinn and colleagues used a combination of venetoclax and obinutuzumab in patients with CLL who were either previously untreated or had relapsed or refractory disease. The authors initiated the combination by sequencing these agents in two ways, starting obinutuzumab first or venetoclax first. They eventually came to their recommended method of obinutuzumab first and then adding venetoclax. Their plan was to try to find the maximum tolerated dose for venetoclax in this combination, using the dose range of 100 mg a day to 600 mg a day. However, without reaching 600 mg a day, they chose 400 mg a day as their recommended venetoclax dose. A maximum tolerable dose for venetoclax was not determined in this combination study.
Although this study used the doublet of venetoclax and obinutuzumab, the authors mentioned that recently Seymour and colleagues demonstrated the effectiveness of venetoclax with rituximab (Rituxan; Genentech, Biogen) in relapsed or refractory CLL. In addition, the authors cite a currently ongoing (CLL13; NCT 02950051) study in which researchers are comparing venetoclax plus obinutuzumab with the triplet therapy that includes ibrutinib. At this time, we do not know whether the doublet or the triplet regimen will emerge as the new standard for CLL. If, however, the triplet regimen becomes the choice, then Dr. John Byrd’s words of advice and caution, published this year in Blood, become very relevant: ibrutinib may decrease CD20 expression on CLL cells and may have the potential to antagonize antibody-directed cellular cytotoxicity, which is one of the mechanisms of action of anti-CD20 antibodies.
In my opinion the study by Flinn and colleagues is important. Their results make us think of future evolution of the therapy for CLL. Such studies, indeed, are likely to help us find the new standard therapy for this disease.
References:
Byrd JC. Blood. 2019;doi:10.1182/blood-2019-01-892695.
Seymour JF, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1713976.
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