The following article features coverage from the American Society of Hematology 2019 meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.

Preliminary results of a phase 2 study showed promising activity and tolerability for the combination of acalabrutinib, obinutuzumab, and venetoclax in the setting of treatment-naive chronic lymphocytic leukemia (CLL). These findings were presented at the 61st American Society of Hematology (ASH) Annual Meeting and Exposition in Orlando, Florida.1

Results of a recent, open-label, randomized phase 3 study of the combination of the BCL2 inhibitor venetoclax and the CD20-directed antibody obinutuzumab, compared with obinutuzumab plus chlorambucil, an alkylating agent, in patients with untreated CLL and comorbid conditions (ClinicalTrials.gov Identifier: NCT02242942), showed higher rates of 2-year progression-free survival in the former compared with the latter treatment group, with similar rates of grade 3/4 neutropenia and infection in the 2 study arms following 6 monthly cycles of obinutuzumab and 12 monthly cycles of venetoclax or chlorambucil.2  Notably, more than 50% of the patients receiving venetoclax plus obinutuzumab achieved a status of no detectable residual disease in the bone marrow.

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While a study of the triplet combination of venetoclax, obinutuzumab, and the Bruton tyrosine kinase (BTK) ibrutinib (ClinicalTrials.gov Identifier: NCT02427451), demonstrated a high overall response rate, including deep responses in a phase 1b study of patients with relapsed/refractory CLL — rates of diarrhea, bruising, infusion-related reactions, hypertension, and neutropenia were also high.3  

This ongoing, open-label, single-arm phase 2 study is evaluating the triplet combination of venetoclax, obinutuzumab, and the selective BTK inhibitor, acalabrutinb, in treatment-naive adult patients with high-risk CLL who require treatment according to criteria established by the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) (ClinicalTrial.gov Identifier: NCT03580928).  


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Treatment is initiated in monthly cycles with cycle 1 including acalabrutinib only, followed by the combination of acalabrutinib and obinutuzumab in cycles 2 and 3, and then introduction of venetoclax in cycle 4. Triplet therapy is administered through cycle 7, followed by acalabrutinib and obinutuzumab combination therapy through cycle 15.

The primary study end point is rate of undetectable bone marrow minimal residual disease (MRD) complete response (CR) at 15 monthly cycles; those achieving this end point were given the option of treatment cessation with continued monitoring. Those achieving a partial response or CR with MRD-positive disease would continue acalabrutinib plus venetoclax for another 8 months, with reassessment after that time.

According to results of an interim analysis, the median age of the 37 patients enrolled in the study was 63 years, and had a high rate of  adverse prognostic features.

Of the 32 patients restaged at cycle 8, the overall response rate was 100%, with 75% and 25% achieving a partial response (PR) and a complete response (CR) to treatment, respectively.  

Minimal residual disease (MRD) was undetectable in the peripheral blood and bone marrow of 67.8% and 48.3% of these patients, respectively. Furthermore, a CR characterized by no detectable MRD in the bone marrow was observed in 16.7% of patients.

At cycle 4, prior to addition of venetoclax, all responses were PRs, which were observed in 97% of patients.

Notably, based on limited long-term data, (8 individuals at cycle 16), responses appeared to deepen over time.

For the 10 patients with disease characterized by aberrations in TP53, the spectrum of responses were similar to those seen in the overall study population. For thosewho had received 8 cycles of treatment, rates of PR, CR, and undetectable MRD in the bone marrow were 67%, 33%, and 33%, respectively.

Common adverse effects included fatigue, bruising, and headache, although almost all of these events were classified as grade 1/2. Infusion-related reactions occurred in 22% of patients, with grade 3/4 events seen in 3% of patients. Grade 3 or higher neutropenia was observed in approximately one-third of patients, with grade 3 tumor lysis syndrome occurring in 2 patients (5%) immediately after initiation of obinutuzumab, but prior to the start of venetoclax. Atrial fibrillation occurred in 1 patient.

Study presenter Benjamin L. Lampson, MD, PhD, department of medical oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, commented that this triplet therapy is highly active as a frontline therapy, and can be safely administered.

He further noted that an expansion cohort has been opened to further characterize the efficacy and safety of acalabrutinib-obinutuzumab-venetoclax in patients with TP53-aberrant disease (ClinicalTrials.gov Identifier: NCT03580928). In addition, this drug combination will be compared directly with chemoimmunotherapy and acalabrutinb-venetoclax in an upcoming phase 3 trial (ClinicalTrials.gov Identifier: NCT03836261).

Disclosure: Some of the authors disclosed financial relationships with the pharmaceutical industry. For a full list of disclosures, please refer to the original abstract.

Read more of Cancer Therapy Advisor‘s coverage of ASH’s annual meeting by visiting the conference page.

References

  1. Lampson BL, Tyekucheva S, Crombie JL, et al. Preliminary safety and efficacy results from a phase 2 study of acalabrutinib, venetoclax and obinutuzumab in patients with previously untreated chronic lymphocytic leukemia (CLL). Presented at: 61st American Society of Hematology (ASH) Annual Meeting and Exposition 2019; December 7-10, 2019: Orlando, FL. Abstract 32.
  2. Fischer K, Al-Sawaf O, Bahlo J, et al.  Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380:2225-2236.
  3. Rogers KA, Huang Y,  Ruppert AS, et al. Phase 1b study of obinutuzumab, ibrutinib, and venetoclax in relapsed and refractory chronic lymphocytic leukemia. Blood. 2018;132:1568-1572.