ORLANDO-A new analysis of the MRD cohort in the CAPTIVATE clinical trial evaluating ibrutinib fixed-duration therapy in combination with venetoclax was revealed at the 2019 ASH Annual Meeting (Abstract 35).

New data from the phase II study shows the drug combination has a synergistic anti-tumor effect as a first-line treatment in an all-oral, once daily, chemotherapy-free regimen that provides high rates of undetectable minimal residual disease (uMRD) in both peripheral blood (PB) and bone marrow (BM) in patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

Constantine Tam, MD, Hematologist and Disease Group Lead, Low Grade Lymphoma and CLL, Peter MacCallum Cancer Centre, Victoria, Australia, shared the results from the CAPTIVATE cohort following 12 cycles of ibrutinib + venetoclax prior to MRD-guided randomized treatment discontinuation.

In the abstract of the ASH presentation, researchers noted that ibrutinib is the only once-daily inhibitor of Bruton tyrosine kinase and venetoclax is an oral inhibitor of BCL2, both of which are separately FDA-approved for the treatment of CLL/SLL in the U.S.

The anti-tumor activity that may occur when the drugs are combined, according to the researchers, stems from "the capacity of ibrutinib to mobilize CLL cells from protected niches within lymphoid tissue to the blood where they may have a greater dependence on BCL2 for survival."

In an interview with Oncology Times, Tam noted that previous studies have shown ibrutinib and venetoclax are the two best drugs for treating CLL/SLL, which was a large part of what made combining them appealing from a research perspective. "What we have shown is that ibrutinib and venetoclax can be combined and that they have synergistic, anti-tumor effect," in patients with CLL/SLL, he noted.

Another motivation for the study, Tam said, was to find out if targeted therapy using the new drug combination would yield high rates of uMRD and potentially allow patients with CLL to have a drug holiday. "The key goal is to get patients with CLL off the therapy when they show undetectable MRD. And what we have shown is that the best drug combination for doing that is ibrutinib + venetoclax," he said.

Study Details

The analysis of the MRD cohort in the phase II CAPTIVATE study included 164 patients with previously untreated CLL/SLL and requiring therapy. The cohort received a single-agent ibrutinib lead-in (420 mg/day PO) for 3 cycles followed by ibrutinib + venetoclax (5-week ramp-up to 400 mg/day PO) for 12 cycles, according to the abstract of the presentation.

The key endpoints prior to MRD-guided randomization included uMRD (<10-4 by 8-color flow cytometry), venetoclax-related tumor lysis syndrome (TLS) risk, pharmacokinetics, and adverse events (AEs). MRD status was evaluated in peripheral blood after 6, 9, and 12 cycles of ibrutinib + venetoclax combination, and in bone marrow after 12 cycles of ibrutinib + venetoclax, the researchers report.

In total, 151 pts (92%) in the MRD cohort completed ibrutinib lead-in and all 12 cycles of ibrutinib + venetoclax. uMRD was achieved at any time after baseline in 75 percent of patients (122/163) in PB and 72 percent (111/155) in BM. The proportion of patients who had uMRD in PB increased over time, from 57 percent after 6 cycles of combined ibrutinib + venetoclax to 68 percent after 9 cycles and 73 percent after 12 cycles of ibrutinib + venetoclax.

The high rates of uMRD were consistent across high-risk subgroups, according to the researchers, including in patients with del(17p) (75%), del(17p) or TP53 mutation (70%), del(11q) (84%), complex karyotype (83%), and unmutated IGHV status (81%). In patients with uMRD in PB with matched BM samples, 93 percent had uMRD in both PB and BM. Response by iwCLL criteria was achieved in 97 percent of patients.

From a safety perspective, researchers found that 3 cycles of ibrutinib lead-in reduced TLS risk and need for hospitalization in patients included in the study. Hospitalization was avoided in 76 percent of at-risk patients after 3 cycles of ibrutinib initiation. Among patients with high baseline TLS risk, 90 percent shifted to medium or low risk and 74 percent avoided hospitalization for venetoclax initiation. Among patients with medium baseline TLS risk plus CrCl <80 mL/min, 19 percent shifted to low risk while 78 percent avoided hospitalization for venetoclax initiation. Meanwhile, no medium- or low-risk patients shifted to high risk.

With median follow-up of 14.7 months (range, 0.5-19.9) only three patients (2%) had disease progression (one Richter's transformation during single-agent ibrutinib lead-in; one after discontinuation of ibrutinib lead-in due to an AE; and one during treatment with ibrutinib + venetoclax), and no patients died.

The most common AEs of any grade occurred in less than 20 percent of patients, according to the researchers, and included diarrhea (31%) and arthralgia (22%) during single-agent ibrutinib; and diarrhea (60%), neutropenia (40%), nausea (34%), upper respiratory tract infection (24%), and fatigue (20%) with ibrutinib + venetoclax. Overall, AEs leading to dose reductions occurred in 20 percent of patients (ibrutinib: 14%; venetoclax: 9%). While AEs leading to discontinuation of treatment were infrequent, occurring in 7 percent of patients.

One of the key takeaways from the study's findings is how well patients in the phase II study tolerated the combination of the two drugs, Tam noted. Another important finding is that combining the drugs had equally high response rates among the patients in the study irrespective of the acuity of their disease, he emphasized. "After 12 cycles of treatment, we saw a clearing of minimum residual disease, including 75 percent from the peripheral blood and 72 percent from the bone marrow," he said.

There were no unexpected results in the study findings, Tam said, explaining, "We knew most of the information about the drugs going in, and we also knew from previous studies that they were associated with high MRD clearance rates."

Because the drug combination has not yet been approved for CLL/SLL, however, it is too soon to say what the clinical implications of the study results may be, Tam explained. "It's important to note that this regimen is paving the way for future regimens that will become frontline treatments for CLL/SLL."

Toward that end, Tam said future research will focus on finding the best way to deliver the combined ibrutinib + venetoclax targeted therapy to patients, how to identify patients with an incurable level disease who will not respond, and, finally, why 25 percent of the patients in the analysis did not achieve MRD negativity. "We need to know ahead of time what the optimal stage is for delivering the targeted therapy to patients with CLL/SLL," he concluded.

Chuck Holt is a contributing writer.