The randomized phase 2 CAPTIVATE clinical trial showed that first-line therapy with ibrutinib (Imbruvica) and venetoclax (Venclexta) for a fixed duration (ie, 12 cycles) led to a 30-month progression-free survival (PFS) in more than 95% of patients with chronic lymphocytic leukemia (CLL) and undetectable minimal residual disease (MRD). The results of the MRD cohort of the study were presented at ASH 2020.
Adverse events occurred mainly during the first few months with the chemotherapy-free combination, and no new safety signals emerged during the trial, according to lead investigator William G. Wierda, MD, PhD, Section Chief, Chronic Lymphocytic Leukemia, Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX, who presented the results.
“The 30-month progression-free survival rates of more than 95% across all treatment arms compare favorably to other first-line fixed-duration regimens,” said Dr Wierda. “Ibrutinib plus venetoclax is an all-oral, once-daily, chemotherapy-free, fixed-duration regimen that provides highly concordant, deep MRD remissions in the bone marrow [72%] and peripheral blood [75%] as first-line treatment of CLL,” he added.
An important finding of the CAPTIVATE study is that this 1-year fixed-duration regimen of ibrutinib plus venetoclax allows patients a break from treatment.
“These results show the ibrutinib plus venetoclax combination providing continued disease-free survival for CLL patients once treatment is complete. It will be really exciting for patients to have a potential option in the future that can put them into remission and time off treatment,” Dr Wierda continued.
The Bruton tyrosine kinase inhibitor ibrutinib is the only targeted therapy that demonstrated a significant survival benefit as a first-line treatment for patients with CLL in 2 previous randomized phase 3 clinical trials, according to Dr Wierda. Ibrutinib and venetoclax are synergistic and complementary, he said, allowing clearance of CLL cells from blood and bone marrow, as well as from other areas.
The CAPTIVATE Study
The international phase 2 CAPTIVATE study included 164 treatment-naïve patients with CLL or with small lymphocytic lymphoma who had active disease that required treatment. All patients received 3 cycles of lead-in ibrutinib alone, followed by 12 cycles of ibrutinib plus venetoclax.
Of 147 patients with undetectable MRD, 86 (58%) patients with confirmed undetectable MRD were randomized in a 1:1 double-blind fashion to placebo or to ibrutinib. The 63 (42%) patients whose status of undetectable MRD was not confirmed were randomized to an open-label group of ibrutinib versus ibrutinib plus venetoclax.
At baseline, the patients’ median age was 58 years, 32% had Rai stage III/IV, 36% had any cytopenia, and lymph-node diameter of ≥5 cm was seen in 31% of the patients. High-risk features included deletion (del) 17p or TP53 mutation in 36% of patients, del 11q in 17% of patients, complex karyotype in 19% of patients, and 50% of patients had no IGHV mutation.
The use of 3 cycles of lead-in ibrutinib reduced the risk for tumor lysis syndrome in 90% of high-risk patients at baseline, as well as the risk for hospitalization. Of the 77 patients who would have needed to be hospitalized for the initiation of venetoclax therapy, 51 (66%) of them no longer required the use of venetoclax after lead-in ibrutinib therapy. Overall, 131 of 159 (82%) patients were able to start venetoclax therapy without hospitalization.
Twelve cycles of ibrutinib plus venetoclax led to undetectable MRD as best response in peripheral blood in 75% of evaluable patients and in the bone marrow in 72% of evaluable patients.
“At cycle 16, in patients with undetectable MRD in peripheral blood with matched bone marrow samples, 93% had undetectable MRD in both blood and bone marrow. In all treated patients, undetectable MRD rate was 75% in peripheral blood and 68% in bone marrow,” Dr Wierda said.
At a median follow-up of 16.6 months postrandomization of patients with confirmed undetectable MRD, the 1-year disease-free survival rate was 95.3% in the placebo group and 100% in the ibrutinib group, a not significant difference.
At a median follow-up of 31.3 months for the overall MRD cohort, 30-month PFS was more than 95% for all 4 treatment arms.
In patients without confirmed undetectable MRD after 12 cycles of combined ibrutinib plus venetoclax, increases in undetectable MRD were greater in those who continued ibrutinib plus venetoclax therapy versus ibrutinib alone. In bone marrow, the rates of undetectable MRD were 66% with the combination arm versus 42% with ibrutinib monotherapy, and in peripheral blood, the rates were 45% and 69%, respectively.
Safe Combination Therapy
The 2 MRD cohorts had low rates of adverse events leading to dose reductions and discontinuations after randomization. After the lead-in phase, most adverse events decreased over time, regardless of any subsequent treatment.
“Grade 3 and higher adverse events were infrequent across all randomized treatment arms,” Dr Wierda said.