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'Future looks bright' for combination of venetoclax, obinutuzumab in chronic lymphocytic leukemia
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ATLANTA — Venetoclax with obinutuzumab induced a high level of deep and durable response with high minimal residual disease rates among patients with previously untreated chronic lymphocytic leukemia, according to results of a phase 1b study presented at the ASH Annual Meeting and Exposition.
“This combination of venetoclax [Venclexta; AbbVie, Genentech], and obinutuzumab [Gazyva, Genentech], achieved high overall and complete remission rates,” Ian W. Flinn, MD, PhD, director of hematology and oncology at Sarah Cannon Center for Blood Cancer, said during his presentation. “There are high rates of undetectable bone marrow minimal residual disease irrespective of response status. We also showed an acceptable and manageable safety profile.”
Preclinical data suggest that venetoclax — a potent BCL-2 inhibitor — in combination with obinutuzumab, a glycoengineered anti-CD20 antibody, may have synergistic activity among patients with CLL.
In a follow-up to their phase 1 study, Flinn and colleagues presented updated safety, efficacy and minimal residual disease (MRD) data from the first-line treatment of 32 patients (median age, 63 years; range, 47-73; 62.5% men) with CLL.
Patients had ECOG performance status of 1 or less, adequate organ function and were in need of treatment.
In the first of six cycles, patients received venetoclax first (schedule A; n = 6), or obinutuzumab first (schedule B; n = 26). Patients received a gradual increase in venetoclax to the final, 400-mg dose to mitigate risk for tumor lysis syndrome. The obinutuzumab regimen included 100 mg first on day 1, 900 mg on day 2, 1,000 mg on days 8 and day 15 in cycle 1. In cycles 2 through 6, patients received 1,000 mg day 1, based on a 28-day cycle.
After the first six cycles, patients received six cycles of venetoclax monotherapy and could extend monotherapy after 1 year depending on MRD positivity or partial remission.
Researchers assed risk for tumor lysis syndrome based on lymph node tumor burden and lymphocyte count. Seventy-five percent of patients had medium risk and 18.8% had high risk at screening.
Safety, tolerability and MRD negativity — defined as less than on CLL cell detectable per 10,000 leukocytes assessed by 5-color flow cytometry — served as primary endpoints.
Twenty-six patients had samples available for cytogenetic assessment at screening: five had del(17p), six had del(11q), six had 12 trisomy, 14 had (del)13 monosomy and four had del(13) nullisomy.
All 32 patients completed six cycles of venetoclax and obinutuzumab and were followed for least 9 months from the start of treatment.
Median time on the study was 11.3 months.
All 32 patients responded to treatment: 56.3% achieved complete remission and 43.8% achieved partial remission.
MRD negativity as best response in peripheral blood occurred among all patients, and twenty patients (62.5% in intention-to-treat population; 74% in patients with samples available) achieved MRD negativity in bone marrow.
All patients achieved 1-year PFS. Two patients (6.3%) had disease progression at study days 437 and 451, both of whom had del(17p) at screening. These patients maintained bone marrow MRD positivity at 1 year of treatment.
All patients experienced at least one adverse event. Neutropenia (40.6%), febrile neutropenia (12.5%) and thrombocytopenia (12.5%) represented the most common grade 3 or grade 4 adverse events.
Clinical tumor lysis syndrome did not occur among patients on either treatment schedule, and there were no infusion-related reactions, discontinuation of treatment due to adverse events, or death.
The combination of venetoclax and obinutuzumab currently is being tested in a phase 3 trial, according to Kurtz.
“My opinion is that obinutuzumab has greater efficacy among patients with CLL compared with rituximab (Rituxan; Genentech, Biogen) and our hypothesis is that it is a superior antibody to combine with venetoclax,” Kurtz said. “It’s up for further discussion upon which is the best combination — whether it’s two drugs or three drugs — but this regimen produced a very high MRD rate both in the blood and in the marrow and its future looks bright.”– by Chuck Gormley
Reference:
Flinn IW, et al. Abstract 430. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.
Disclosures: Flinn reports research funding from Genentech and AbbVie, among others. Please see the study for all other authors’ relevant financial disclosures.