SAN ANTONIO — Over the last decade, the U.S. Food and Drug Administration has approved 19 new drugs or combinations to treat chronic lymphocytic leukemia. The therapies have given veterans with CLL more effective options for treating the blood disorder, and new combinations and studies provide even more hope for the future.
The 2021 virtual American Society of Clinical Oncologists conference highlighted a number of the more-promising therapies currently being studied for CLL. Two particularly stood out: the ELEVATE-RR trial of acalabrutinib and the CAPTIVATE study of venetoclax with ibrutinib. BRUIN, another significant study appeared in The Lancet in March, evaluating pirtobrutinib as a second-line therapy for CLL.
The VA has been quick to adopt new treatments for CLL as they have been released. A study presented at the 2020 ASCO conference found that uptake of new therapies grew rapidly between October 2013 and March 2018 and traditional chemotherapy and chemoimmunotherapy dropping steadily. “Novel agents are becoming the treatment of choice in all but a very small percentage of patients in first and relapsed or recurring setting,” study lead author Zohra Nooruddin, MD, a staff hematologist at the South Texas Veterans Health Care System in San Antonio previously told U.S. Medicine.1,
Acalabrutinib vs. Ibrutinib
An international team of researchers led by John C. Byrd, MD, co-leader of the Leukemia Research Program at The Ohio State University Comprehensive Cancer Center—Arthur G. James Cancer Hospital conducted the phase 3 ELEVATE-RR trial to evaluate the performance of acalabrutinib compared to ibrutinib in patients with previously treated CLL. Both acalabrutinib and ibrutinib are targeted therapies that irreversibly inhibit the action of Bruton’s tyrosine kinase (BTK), effectively blocking the growth of the malignant B-cells that drive CLL.2
In the first head-to-head trial of the two drugs, the investigators enrolled 533 patients who were randomized to acalabrutinib (268) or ibrutinib (265). Patients were a median age of 66 years old and had received a median of two prior therapies. Among the participants, 45.2% had del(17p) and 64.2% del(11q). At a median of 40.9 months, both groups had the same progression-free survival (38.4%). The acalabrutinib group, however, experienced significantly lower rates of cardiac events
“Acalabrutinib is a more-selective inhibitor of BTK and has been known to have less adverse events (AEs) when compared across trials,” Byrd said in his ASCO presentation. Previously, “no clinical trial has directly compared ibrutinib to acalabrutinib in previously treated CLL. Our trial presented here does this.”
Atrial fibrillation occurred at lower rates in the acalabrutinib arm compared to ibrutinib arm (9.4% vs 16.0%, P=0.23). Among patients who developed atrial fibrillation and flutter in the acalabrutinib arm, prior history of cardiac events were more common. “When considering de-novo atrial fibrillation flutter occurring in patients who had never had this before, the difference between ibrutinib and acalabrutinib was greater,” Byrd added. In this subset, those in the acalabrutinib group had a 6.2% incidence of atrial fibrillation, while those in the ibrutinib group had an incidence of 14.9%.
Neither group reached average overall survival. The two drugs had similar rates of Grade 3 or higher infection and Richter transformation. In the acalabrutinib arm, 63 (23.5%) participants died, while there were 73 (27.5%) deaths in ibrutinib. While both groups had similar progression-free survival “survival nonstatistically favored acalabrutinib with 10 fewer deaths,” Byrd said. “These results demonstrate that acalabrutinib is better tolerated and safer than ibrutinib,” with similar efficacy in patients with previously treated CLL.
Venetoclax With Ibrutinib
The Phase 2 CAPTIVATE trial tested an all-oral, once-daily, regime that combined venetoclax with ibrutinib in patients with treatment-naive CLL or small lymphocytic lymphoma (SLL). The researchers enrolled 159 patients under age 70 who received three months of oral ibrutinib as a monotherapy, then received 12 months of ibrutinib and oral venetoclax. Less than 10% of patients failed to complete both cycles.3
At a median follow-up of 27.9 months, the overall response rate was 96%. And 56% achieved a complete response, of which 89% maintained for at least one year. Complete response occurred a similar rates, even in patients with high-risk genomic features such as del(17p) or TP53 mutations. The estimated rate of 24-month progression-free survival was 97% for patients with mutated immunoglobulin and 93% for those without mutated immunoglobulin heavy chain variable. Overall survival at 24 months was 98%.
Undetectable minimal residual disease was achieved in 77% of patients in peripheral blood and 60% of patients in the bone marrow.
“The use of continuous treatment with IMBRUVICA in CLL has well been established as the standard-of-care for patients, including those with high-risk disease,” said Paolo Ghia, MD, PhD, professor of medical oncology, Università Vita-Salute San Raffaele, Italy, and principal study investigator. “The latest data from the CAPTIVATE study underscore that [ibrutinib] in an all-oral fixed-duration combination with venetoclax also delivers a high rate of progression-free survival at two years while enabling treatment-free remission for patients.”
All but 6% of patients at high risk of tumor-lysis at the study start became medium or low risk following treatment. The most common Grade 3 or 4 adverse events were neutropenia (33%), hypertension (6%) and decreased neutrophil counts (5%). Discontinuation of treatment as a result of adverse events was associated with ibrutinib in 4% of patient and with venetoclax in 2%.
The results of the study offer some hope that the 15-month regimen could provide a break from treatment for patients.
Pirtobrutinib
Pirtobrutinib (formerly LOXO-305), a third-generation BTK inhibitor, showed strong results in a Phase ½ study of heavily pretreated patients with B-cell malignancies. Of the 139 patients with CLL or SLL, the overall response rate for pirtobrutinib, at various doses, was 63%. The objective response rate remained between 60% and 65%, regardless of prior treatment exposure.4
The stability of objective response provides good news as treatment regimens increasingly employ multiple therapy classes. “Patients with B-cell malignancies who have been previously treated with the most commonly used regimens represent an area of growing and urgent unmet need,” said Anthony Mato, MD, director of the CLL Program at Memorial Sloan Kettering Cancer Center and lead author of The Lancet study. “These data establish that the third-generation BTK inhibitor pirtobrutinib possesses a compelling efficacy and safety profile with the potential to address this exact unmet need.”
- Nooruddin Z, et al. The shift in therapies for the treatment of chronic lymphocytic leukemia (CLL) patients in the US Veterans Health Administration (VHA) from 2013-2018. Clin Oncol 38: 2020 (suppl; abstr e19339)
- Byrd J, et al. First results of a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia. ASCO 2021; Abstract 7500.
- Wierda W, et al. Phase 2 CAPTIVATE results of ibrutinib (ibr) plus venetoclax (ven) in first-line chronic lymphocytic leukemia (CLL). ASCO 2021; Abstract 7501.
- Mato AR, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021 Mar 6;397(10277):892-901. doi: 10.1016/S0140-6736(21)00224-5. PMID: 33676628.