The randomized phase II CAPTIVATE trial showed that a fixed-duration treatment approach with 12 cycles of ibrutinib and venetoclax as first-line therapy for chronic lymphocytic leukemia (CLL) achieved a 30-month progression-free survival of more than 95% in patients with undetectable minimal residual disease (MRD; also known as measurable residual disease).¹ Adverse events generally decreased over the first 6 months of this combination regimen, and no new safety signals were evident.

“The 30-month progression-free survival rates of more than 95% across all treatment arms compare favorably to other first-line fixed-duration regimens, including FCR (fludarabine, cyclophosphamide, rituximab) and venetoclax plus obinutuzumab. 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,” said William Wierda, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston, speaking at the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition.¹

“The 30-month progression-free survival rates of more than 95% across all treatment arms [with ibrutinib plus venetoclax] compare favorably to other first-line fixed-duration regimens.”

— William Wierda, MD, PhD

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One of the major take-away messages from the trial is that 1 year of treatment with fixed-duration ibrutininb/venetoclax achieves remission and time off treatment. “These results show the ibrutinib-plus-venetoclax combination provides continued disease-free survival for patients with CLL 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 stated.

Ibrutinib is a once-daily Bruton’s tyrosine kinase (BTK) inhibitor and is the only targeted therapy to demonstrate a significant survival benefit as first-line therapy for CLL in randomized phase III studies.^2,3 Ibrutinib and venetoclax are synergistic and have complementary antitumor activity, enabling clearance of CLL from disease compartments beyond blood and bone marrow. The phase II CAPTIVATE trial is an international study evaluating first-line treatment with 12 cycles of ibrutinib plus venetoclax.

At the ASH Annual Meeting, Dr. Wierda presented the primary analysis results of 1-year disease-free survival rates from the MRD cohort, evaluating whether this regimen allows for treatment-free remission in the setting of confirmed undetectable MRD.

Study Details

CAPTIVATE enrolled 164 patients with previously untreated CLL or small lymphocytic lymphoma. They had active disease requiring treatment and were given three cycles of lead-in ibrutinib followed by 12 cycles of ibrutinib plus venetoclax. Then, patients with confirmed undetectable MRD (84 of 149, 58%) were randomly assigned 1:1 to placebo or ibrutinib (double-blinded). Those with undetectable MRD not confirmed (63 of 149, 42%) were randomly assigned to open-label ibrutinib vs ibrutinib plus venetoclax. Dr. Wierda reported on the undetectable MRD cohort.

At baseline, the median patient age was 58; 32% had Rai stage III or IV disease; 36% had any cytopenia; and a lymph node diameter of at least 5 cm was seen in 31%. High-risk features were present in the following percentages: del(17p)/TP53 mutation in 36%; del(11q) in 17%; complex karyotype in 19%; and unmutated IGHV in 50%.

Three cycles of lead-in ibrutinib reduced the risk of tumor-lysis syndrome in 90% of high-risk patients at baseline and reduced the risk of hospitalization. Among 77 patients who would have had to be hospitalized for venetoclax initiation, it was no longer indicated in 51 patients (66%) after lead-in ibrutinib. Overall, 131 of 159 patients (82%) were able to initiate venetoclax without hospitalization.

Undetectable MRD Rates: In Peripheral Blood and Bone Marrow

Twelve cycles of ibrutinib plus venetoclax led to undetectable MRD as best response in the peripheral blood in 75% of evaluable patients (n = 163) and in the bone marrow in 72% (n = 155 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 164 treated patients, the undetectable MRD rate was 75% in peripheral blood and 68% in bone marrow.

After randomization in patients with confirmed undetectable MRD, at a median follow-up of 16.6 months, 1-year-disease-free survival was 95.3% for the placebo group and 100% for the ibrutinib group, which was not statistically different.

At a median follow-up of 31.3 months for the overall MRD cohort, 30-month progression-free survival was more than 95% for all four treatment arms. In patients without confirmed undetectable MRD after 12 cycles of combined ibrutinib and venetoclax, increases in undetectable MRD were greater with continued ibrutinib plus venetoclax vs ibrutinib alone. In the bone marrow, the rates of undetectable MRD were 66% with the combination vs 42% with ibrutinib alone and in the peripheral blood, 45% and 69%, respectively.

Safety

The rates of adverse events leading to dose reductions and discontinuations after randomization were low in both cohorts. The prevalence of adverse events was generally higher during the first 6 months before randomization and decreased over time, irrespective of subsequent treatment.

“Grade 3 and higher adverse events were infrequent across all randomized treatment arms,” Dr. Wierda said. 

DISCLOSURE: Dr. Wierda has served as a consultant or advisor to Sanofi and has received research funding from AbbVie, Acerta Pharma, Cyclacel, Emergent BioSolutions, Genentech, Gilead Sciences, GlaxoSmithKline/Novartis, Janssen, Juno Therapeutics, Karyopharm Therapeutics, Kite Pharma, Loxo, miRagen, Oncternal Therapeutics, Pharmacyclics, Sunesis Pharmaceuticals, and Xencor.

REFERENCES

1. Wierda WS, Tam CS, Allan JN, et al. Ibrutinib plus venetoclax for first-line treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma: 1-year disease-free survival results from the MRD cohort of the phase 2 CAPTIVATE study. 2020 American Society of Hematology (ASH) Annual Meeting and Exposition. Abstract 123. Presented Saturday, December 5, 2020.

2. Burger JA, Barr PM, Robak T, et al: Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia 34:787-798, 2020.

3. Shanafelt TD, Wang XV, Kay NE, et al: Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med 381:432-443, 2019.