New Imbruvica data in fixed-duration combination regimen ( + venetoclax) presented at EHA 2022 shows deep, durable response at three years in untreated chronic lymphocytic leukemia.- Janssen

Updated data from the FD cohort with three years of follow-up shows that I+V continues to demonstrate deep and durable responses and clinically meaningful progression-free survival (PFS) and overall survival (OS) in the first-line treatment setting.

New data will be presented from the minimal residual disease (MRD) cohort, which suggests immune restoration with this combination. These data will be presented during the 2022 European Hematology Association (EHA) Annual Congress taking place in Vienna, Austria June 9-12 (Abstracts #S144 and #P669).

“These promising data highlight the complementary mechanism of action between ibrutinib and venetoclax in a fixed-duration combination regimen,” said Carol Moreno, M.D., Ph.D., Consultant Hematologist, Hospital de la Santa Creu Sant Pau, Autonomous University of Barcelona, Barcelona, Spain, and study investigator. “The CAPTIVATE study suggests that this combination may have the potential to provide treatment-free remissions for patients and effectively eradicate CLL cells and help to restore normal B cells to healthy donor levels in patients with previously untreated CLL/SLL.”

The Phase II CAPTIVATE (PCYC-1142) study (NCT02910583) – sponsored by Pharmacyclics LLC, an AbbVie Company, and Janssen Biotech, Inc. – enrolled 323 patients with previously untreated CLL/SLL who were younger than 70 years, including patients with high-risk disease, in two cohorts: an FD cohort where all patients stopped therapy after 12 cycles of the combination, regardless of MRD status; and an MRD-guided cohort where treatment duration was guided by the patients’ MRD status after 12 cycles of I+V combination (patients who met criteria for confirmed undetectable minimal residual disease [uMRD] were randomized 1:1 to placebo or Imbruvica; patients who did not meet uMRD criteria were randomized to Imbruvica or I+V.

Three-Year Follow-Up Data from the FD Cohort of the Phase II CAPTIVATE (PCYC-1142) Study of Imbruvica-Based Combination Regimen in Previously Untreated Patients with CLL/SLL (Abstract #P669): After an additional year of follow-up data from the FD cohort of CAPTIVATE, I+V continues to demonstrate deep, durable responses and clinically meaningful PFS, including in patients with del(17p)/TP53 mutated or unmutated immunoglobulin heavy chain gene (IGHV). The clinical data underscore the distinct and complementary modes of action of Imbruvica and venetoclax (a BCL-2 inhibitor). Imbruvica has been shown to mobilize CLL cells out of lymph nodes and other lymphoid niches and into peripheral blood where they are more susceptible to venetoclax-induced apoptosis, eliminating dividing and resting CLL cells.

Key findings from the Phase II CAPTIVATE FD cohort study include : i. At a median follow-up of 38.7 months, the 36-month PFS rate was 88 percent for all treated patients, 80 percent for patients with del(17p)/TP53 mutated and 86 percent for unmutated IGHV patients (95 percent Confidence Interval [CI]). ii. With an additional year of follow-up, no additional OS events occurred. The 36-month OS rate was 98 percent, overall (95 percent CI).

The 36-month OS rates were similar in patients with del(17p)/TP53 mutated (96 percent) or unmutated IGHV (97 percent).: i. The complete response (CR) rate was 57 percent (n=159; 95 percent CI, 50-65) and consistent across high-risk subgroups. ii. Median duration of CR was not reached (n=91); the 24-month landmark estimate for duration of CR was 94 percent. Median duration of response was not reached for responding patients (n=153). iii. Seventy-nine percent of patients (n=125) achieved undetectable uMRD at any time in the peripheral blood (PB) and/or bone marrow. iv. Of patients with uMRD in PB at three months post treatment, 78 percent (66/85) of evaluable patients maintained uMRD through 12 months post treatment. v. All patients are currently off treatment. Frequently occurring treatment-emergent adverse events (TEAEs) (period from first dose until 30 days after the last dose of study treatment) were primarily Grade 1/2 in severity with the exception of neutropenia. Median time to onset of frequently occurring TEAEs generally occurred within four months (87-100 percent). The median time to resolution or improvement ranged from 16.5 days (diarrhea) to 42.5 days (arthralgia). No new serious adverse events or secondary malignancies have been reported since the primary analysis. vi. Twelve patients who progressed after FD treatment with I+V have been retreated with single-agent Imbruvica; 11 of the 12 patients were evaluable for response, with 10 responding.

New Data from the MRD-Guided Cohort of the Phase II CAPTIVATE (PCYC-1142) Study of Imbruvica-Based Combination Regimen Evaluating Immune Restoration in Previously Untreated Patients with CLL/SLL (Abstract #S144): Data on the changes over time in the cellular immune profile in patients with CLL/SLL treated with the I+V combination and age-matched healthy donors were featured in an oral presentation at EHA. The FD regimen of I+V in the confirmed uMRD placebo arm effectively eradicated CLL cells to healthy donor levels and enabled sustained regeneration of normal B cell counts.

Immune restoration was evaluated in 79 previously untreated patients with CLL/SLL enrolled in the MRD cohort by monitoring changes over time in the cellular immune profile of patients treated with I+V combination regimen and compared to 20 age-matched healthy donors.

Key findings from this analysis include : i. patients with confirmed uMRD (n=40) had a significantly more pronounced decrease in circulating CLL cell count than patients with uMRD not confirmed (n=39). At Cycles seven and 16 the p-value was <0.0001 with i+v combination therapy. i. from cycle 16 – 29, patients with confirmed umrd (n="40)" had cell counts similar to those of healthy donors (?0.8 cell ?l). ii. normalization of critical immune cells, including t-cell subsets, classical monocytes, and dendritic cell counts was observed in this population.></0.0001>

“These new clinical and immune results from the CAPTIVATE study add further evidence of the promise of Imbruvica in a fixed-duration regimen for previously untreated CLL patients,” said Craig Tendler, M.D., Vice President, Late Development and Global Medical Affairs, Janssen Research & Development, LLC. “Imbruvica has become a standard of care in CLL treatment, and we continue to explore novel combinations such as I+V which may offer the option of off-treatment, disease-free intervals for patients with B-cell malignancies.”

The CAPTIVATE study is part of a comprehensive development program exploring the potential of Imbruvica-based FD therapy. Janssen continues to evaluate the I+V combination regimen and its potential to provide a FD treatment option for patients living with CLL/SLL. Recently, The New England Journal of Medicine Evidence published the primary analysis from the Phase III GLOW study, which evaluated the safety and efficacy of the I+V combination in older or unfit patients with CLL/SLL, and showed that the combination demonstrated superior PFS and deeper sustained responses compared to chemoimmunotherapy in first-line CLL.

See-

"Fixed-Duration Ibrutinib-Venetoclax in Patients with Chronic Lymphocytic Leukemia and Comorbidities"- Arnon P. Kater, M.D., Ph.D., Carolyn Owen, M.D., Carol Moreno, M.D., George Follows, B.M.Bch., Ph.D., , ... ,for the GLOW Investigators. Published May 13, 2022 .DOI:https://doi.org/10.1056/EVIDoa2200006.