In results from a phase II study published in The New England Journal of Medicine, the combination of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and the BCL2 inhibitor venetoclax was associated with high response rates in patients with relapsed/refractory and treatment-naive mantle cell lymphoma (MCL).
Both agents have demonstrated clinical activity alone, explained the authors, led by Constantine S. Tam, MD. “These findings confirm the high activity of ibrutinib and venetoclax in combination in patients with MCL,” Dr. Tam, of St. Vincent’s Hospital and the Peter MacCallum Cancer Center in Melbourne, Australia, told ASH Clinical News. “In particular, the achievement of deep, minimal residual disease (MRD)–negative remission may translate to longer-duration remissions, and the possibility of therapy interruption, which we are exploring in trials.”
The open-label, single-arm ABT-199 and Ibrutinib in Mantle Cell Lymphoma (AIM) study included 23 patients with relapsed or refractory MCL and one patient with previously untreated MCL (median age = 68 years; range = 47-81 years). Eligible participants were not suitable candidates for cytotoxic chemotherapy and were required to have a neutrophil count of ≥750/mm3, platelet count of ≥50,000/mm3, and Eastern Cooperative Oncology Group performance status score ≤2. Twelve patients (50%) had aberrations of TP53, and 75 percent had a high-risk prognostic score.
Treatment consisted of a starting dose of single-agent ibrutinib 560 mg/day for four weeks to reduce the risk of tumor lysis syndrome. Following this phase, venetoclax was introduced at 50 mg/day and increased each week to a maximum dose of 400 mg/day. However, after another trial reported that the recommended phase II dose in MCL was 800 mg/day, the study protocol was amended to allow escalation to venetoclax 800 mg/day after week 16 if a complete response (CR) had not occurred. Treatment continued until disease progression or unacceptable toxicity.
Investigators assessed disease response via CT and PET imaging, as well as MRD (measured via flow cytometry or polymerase chain reaction) in the bone marrow and peripheral blood, at four, 16, 28, 40, and 56 weeks of treatment.
At 16 weeks, the CR rate assessed by CT imaging (primary endpoint) was 42 percent (n=10), “which was higher than the historical result of 9 percent at this time point with ibrutinib monotherapy (p<0.001),” the authors reported. When the investigators included PET assessments, the CR rate at week 16 was 62 percent (n=15), and two patients achieved partial response (8%). The latter two patients subsequently achieved a CR, one of which occurred after escalation to venetoclax 800 mg/day, the researchers noted.
Of the 19 patients assessed with CT and 16 assessed with PET who were evaluable for MRD in bone marrow samples via flow cytometry, 16 (84%) and 9 (56%), respectively, were MRD-negative. Most patients with a CR were also MRD-negative (93% in bone marrow; 82% in peripheral blood).
After a median follow-up of 15.9 months (range = 1.4-26.2 months), the median duration of response and median progression-free survival (PFS) had not been reached, with an estimated 12-month PFS rate of 75 percent and an estimated 18-month PFS rate of 57 percent in the entire population. Among the 17 patients who responded to ibrutinib-venetoclax treatment, 78 percent remained progression-free at 15 months.
Rates of 12- and 18-month overall survival were 79 percent and 74 percent, respectively.
The most common adverse events (AEs) reported in this population “were predominantly of grade 1 or 2 in severity” and included:
- diarrhea (n=20; 83%)
- fatigue (n=18; 75%)
- nausea or vomiting (n=17; 71%)
- bleeding, bruising, or postoperative hemorrhage (n=13; 54%)
- musculoskeletal or connective-tissue pain (n=12; 50%)
Two patients experienced tumor lysis syndrome during the study. Other serious AEs included:
- diarrhea (n=3; 12%)
- atrial fibrillation (n=2; 8%)
- pyrexia (n=2; 8%)
- pleural effusion (n=2; 8%)
- cardiac failure (n=1; 4%)
- soft-tissue infection (n=1; 4%)
Based on the findings of this phase II trial, the investigators initiated a phase III study comparing single-agent ibrutinib with the ibrutinib-venetoclax combination. “The global phase III study will provide an objective evaluation of [this combination’s] efficacy,” Dr. Tam explained. “Locally, we have identified genomic markers of resistance of ibrutinib-venetoclax therapy, which we would like to use to identify a priori patients who are likely to have a poor response for risk-stratified therapy in a planned follow-up study.”
Limitations of the phase II study include its small number of participants, the lack of a comparator arm, and the relatively short follow-up period. The authors report financial relationships with Janssen, AbbVie, the Victorian Cancer Agency, the Leukemia & Lymphoma Society, and the Peter MacCallum Cancer Foundation.
Tam CS, Anderson MA, Pott C, et al. Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma. N Engl J Med. 2018;378:1211-23.