Although the introduction of reversible Bruton’s tyrosine kinase (BTK) inhibitors, such as first-generation ibrutinib (Imbruvica), represents a major advancement in the treatment of chronic lymphocytic leukemia (CLL), ibrutinib also irreversibly inhibits other kinase agents that may compromise its therapeutic index; side effects are the most common reason that patients discontinue ibrutinib. This finding led researchers to evaluate the safety and efficacy of acalabrutinib. It is a second-generation, more selective, irreversible BTK inhibitor with improved pharmacologic features that was specifically designed to improve on the safety and efficacy of first-generation BTK inhibitors (Byrd JC, et al. N Engl J Med. 2016;374:323-332).
The uncontrolled, multicenter, phase 1/2 study was designed to determine the recommended dose, safety, efficacy, pharmacokinetics, and pharmacodynamics of acalabrutinib in 61 patients with relapsed CLL. The median age of the patients was 62 years, and the patients had received a median of 3 previous therapies for CLL. In the phase 1 dose-escalation portion of the trial, patients received 100 mg to 400 mg of acalabrutinib once daily, followed by 100 mg twice daily in the phase 2 expansion of the trial.
At a median follow-up of 14.3 months, the overall response rate was 95%, including 85% with a partial response and 10% with a partial response with lymphocytosis; the remaining 5% of patients had stable disease. In patients with 17p13.1 deletion (31%), the overall response rate was 100%. The researchers noted there were no patients with Richter’s transformation and only 1 patient with progression of CLL.
Acalabrutinib demonstrated robust clinical activity, with 98% of patients achieving a reduction in lymphadenopathy. The safety profile of acalabrutinib was also favorable. Most adverse events (AEs) were grade 1 or 2 and resolved over time. The most common grade 1 or 2 AEs were headache (43%), diarrhea (39%), increased weight (26%), and upper respiratory infection (23%). Severe diarrhea, rash, arthralgia or myalgia, bruising, and bleeding events each occurred in ≤2% of patients. There were no reported cases of major hemorrhage or atrial fibrillation.
In an accompanying editorial (Wilson WH. N Engl J Med. 2016;374:386-388), Wilson commented that the findings on acalabrutinib “provide compelling evidence of decreased toxicity. In addition, acalabrutinib showed durable activity across molecular prognostic groups, confirming the importance of selective BTK inhibition.” He noted that a comparison study of acalabrutinib and ibrutinib is needed to assess meaningful differences.
RETURN TO TOP
Targeted therapies have improved the outcomes for patients with relapsed chronic lymphocytic leukemia (CLL), but achieving complete remission remains uncommon. Venetoclax is an investigational inhibitor of B-cell lymphoma-2 (BCL2), which is a protein that is central to the survival of CLL cells. In a recent study, researchers reported the results of a first-in-human, phase 1, dose-escalation study of daily oral venetoclax in patients with CLL or small lymphocytic lymphoma (Roberts AW, et al. N Engl J Med. 2016;374:311-322).
A total of 116 patients were enrolled in the study; 56 patients in the dose-escalation cohort received active treatment in 1 of 8 dose groups that ranged from 150 mg to 1200 mg daily; in an expansion cohort, 60 patients were treated with venetoclax in a weekly stepwise ramp-up dosing of up to 400 mg daily. The majority of patients had received multiple previous treatments, and 89% had poor prognostic clinical or genetic features.
Patients receiving venetoclax had an overall response rate of 79% and a complete response rate in 20% of patients, including 5% who had no minimal residual disease by flow cytometry. Venetoclax was active at all dose levels, and no maximum tolerated dose was identified. Among patients with an adverse prognosis, the response rates ranged from 71% to 79% depending on the subgroup, including those with resistance to fludarabine (79%), chromosome 17p deletions (71%), and those with unmutated IGHV (76%). The researchers also estimated the 15-month progression-free survival rate to be 69% with the expansion dose.
In terms of safety, tumor lysis syndrome occurred in 10 patients in the dose-escalation group, but clinically important sequelae occurred in only 3 of those patients, 2 of whom had severe sequelae. After adjustments were made to the dosing schedule, no incidences of tumor lysis syndrome occurred in the expansion cohort. Other adverse events included mild diarrhea, upper respiratory tract infection, nausea, and grade 3 or 4 neutropenia, which occurred in 41% to 52% of patients.
This first trial of venetoclax demonstrates the potential of BCL2 antagonism as an additional therapy for patients with relapsed CLL, including those with poor prognostic features. Furthermore, the overall response rate in patients provides support for investigating venetoclax as a treatment option for patients with heavily pretreated relapsed or refractory small lymphocytic lymphoma, concluded the researchers.
A phase 1 study of atezolizumab, which is an engineered humanized immunoglobulin G1 monoclonal antibody that binds selectively to programmed death ligand 1 (PD-L1), has shown durable response in patients with metastatic bladder cancer. To confirm the antitumor activity of the investigational drug in patients with advanced urothelial carcinoma whose disease progressed after platinum-based chemotherapy, the researchers conducted a phase 2 study to assess the efficacy and safety of atezolizumab (Rosenberg JE, et al. Lancet. 2016 Mar 4. Epub ahead of print).
The global, multicenter, single-arm, phase 2 trial included 310 patients aged ≥18 years who had inoperable locally advanced or metastatic urothelial carcinoma that progressed after platinum-based chemotherapy. The group received 1200 mg of atezolizumab intravenously every 3 weeks. PD-L1 expression on tumor-infiltrating immune cells was defined by the percentage of PD-L1 positive immune cells IC0, IC1, and IC2/3. The coprimary end points were objective response rate on independent review according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and investigator-assessed objective response rate according to immune-modified RECIST in the intention-to-treat population.
The study demonstrated that targeting PD-L1 with atezolizumab in heavily pretreated patients (40% had received at least 1 systemic regimen in the metastatic setting) induced durable antitumor response. The primary analysis showed that compared with a historical control of overall response rate of 10%, treatment with atezolizumab resulted in a significantly improved RECIST v1.1 objective response for each prespecified immune cell group, with rates of 27% in the IC2/3 group, 18% in the IC1/2/3 group, and 15% in all patients. On independent review, with longer follow-up, the objective response rates were 26% in the IC2/3 group, 18% in the IC1/2/3 group, and 15% among all patients. After a median follow-up of 11.7 months, ongoing responses were observed in 38 (84%) of the 45 responding patients. The median time to response was 2.1 months. In an exploratory analysis of 195 patients, The Cancer Genome Atlas (TCGA) subtypes and mutation load were independently predictive for response to atezolizumab.
Most treatment-related adverse events (AEs) were mild to moderate. The incidence of grade 3 or 4 treatment-related AEs was low, with fatigue being most common, occurring in 5 (2%) patients.
“This report is the first to show the association of TCGA subtypes with response to immune checkpoint inhibition and to show the importance of mutation load as a biomarker of response to this class of agents in advanced urothelial carcinoma,” the investigators concluded.
Chlorambucil has been a standard first-line therapy for chronic lymphocytic leukemia (CLL) in individuals who cannot tolerate strong chemotherapy, especially for older patients or those with coexisting conditions. To determine the role of an alternative single agent as first-line treatment in older patients with CLL, researchers compared ibrutinib (Imbruvica)—a Bruton’s tyrosine kinase inhibitor—and chlorambucil in older patients with previously untreated CLL or with small lymphocytic lymphoma (Burger JA, et al. N Engl J Med. 2015;373:2425-2437).
The multicenter, open-label, randomized, phase 3 trial included 269 treatment-naïve patients aged ≥65 years (median age, 73 years). The patients were randomized to ibrutinib 420 mg once daily until disease progression or until unacceptable toxicity or to chlorambucil given in up to 12 cycles at a dose of 0.5 mg/kg on days 1 and 15 of each 28-day cycle, which was increased to a maximum of 0.8 mg/kg if there was no unacceptable toxicity. The median follow-up was 18.4 months, with 87% of patients continuing to take ibrutinib. The primary end point was progression-free survival (PFS). The key secondary end points included overall survival (OS), rate of sustained hematologic variables, and safety.
Ibrutinib was superior to chlorambucil in PFS, OS, and in improvement in hematologic variables. The patients receiving ibrutinib had significantly longer PFS than patients receiving chlorambucil (median not reached vs 18.9 months, respectively); the risk for progression or death was 84% lower with ibrutinib than with chlorambucil. The rate of PFS at 18 months was 90% in the ibrutinib group and 52% in the chlorambucil group. At 24 months, the estimated OS was significantly prolonged with ibrutinib than with chlorambucil (98% vs 85%, respectively); the relative risk for death was 84% lower with ibrutinib than with chlorambucil. Ibrutinib also resulted in significantly higher sustained improvements in hematologic variables than chlorambucil.
The safety of ibrutinib in this patient population was consistent with previous studies. Exposure to treatment and adverse event (AE) follow-up was nearly 2.5 times as long with ibrutinib than with chlorambucil (17.4 vs 7.1 months, respectively). The most common AE of any grade with ibrutinib was diarrhea (42%). Grade 3 hemorrhage occurred in 4% of patients receiving ibrutinib and led to treatment discontinuation in 3 patients.
This study provides evidence of the potential role of ibrutinib as a first-line alternative to traditional chemotherapy in older patients with CLL or small lymphocytic lymphoma.
