Chemotherapy-Free Fixed-Duration Imbruvica Plus Venclexta Achieves 56% Complete Response Rate in First-Line CLL Treatment

Chronic lymphocytic leukemia (CLL, Image source: dxline.info)

June 08, 2021 /BIOON/ -- AbbVie recently announced new data from the Phase 2 CAPTIVATE (PCYC-1142) study. The study is being conducted in patients aged 18-70 years with previously untreated (treatment-naive) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), and is evaluatingImbruvica (Chinese trade name: Yike®, generic name: ibrutinib, Ibrutinib) in combination withVenclexta (Chinese brand name: Weikelai®, generic name: venetoclax, venetoclax)As an all-oral, once-daily, chemotherapy-free, fixed-duration (FD) regimen，For first-line treatmentefficacy and safety.

In the fixed-duration (FD) cohort, 159 patients received 3 cycles of ibrutinib lead-in therapy, followed by 12 cycles of ibrutinib + venetoclax combination therapy (ibrutinib 420 mg/day, venetoclax ramped up to 400 mg/day). After completing 12 cycles of ibrutinib + venetoclax treatment, patients confirmed to have undetectable measurable residual disease (uMRD, i.e., MRD-negative)—defined as uMRD in both peripheral blood [PB] and bone marrow [BM] for >3 consecutive cycles—were randomized 1:1 to receive double-blind treatment with placebo or ibrutinib. Patients who did not meet the uMRD criteria were randomized 1:1 to open-label treatment with ibrutinib or ibrutinib + venetoclax. uMRD (MRD-negative) indicates the absence of detectable cancer cells following treatment using a specialized and highly sensitive assay, defined as <1 cancer cell per 10,000 white blood cells.

The results showed that the FD cohort met the primary endpoint: with a median follow-up of 27.9 months,In patients without del(17p) aged 70 years or younger, the complete response rate (CR) was 56%.（95%CI:48-64），This rate substantially exceeds the 37% minimum clinically meaningful rate hypothesized in the study.（p＜0.0001）。In the overall study population, CR was 55%, and was consistent across all high-risk subgroups.. In addition,The 24-month progression-free survival (PFS) and overall survival (OS) rates were 95% and 98%, respectively.. In addition,77% of patients in peripheral blood (PB), 60% in bone marrow (BM)achieved undetectable minimal residual disease (uMRD, i.e., MRD-negative）。

These data build upon the MRD cohort results previously reported at the ASH 2020 annual meeting: more than two-thirds of patients achieved undetectable minimal residual disease (uMRD) after 12 cycles of treatment with ibrutinib plus venetoclax, with a 30-month progression-free survival (PFS) rate of ≥95%, regardless of subsequent randomized treatment.

In the study, the most common Grade 3/4 adverse events (AEs) were neutropenia (33%), hypertension (6%), and decreased neutrophil count (5%). AEs led to discontinuation of ibrutinib in 4% of patients and venetoclax in 2%. The safety profile of the combination therapy was consistent with the known AEs of each individual drug, with no new safety signals identified.

Dr. Paolo Ghia, a member of the CAPTIVATE Steering Committee and study investigator, said: “We are encouraged by these promising results, which indicate that ibrutinib + venetoclax has the potential to be an important chemotherapy-free, fixed-duration treatment option for patients with CLL.”

Ibrutinib is the world's first marketed BTK inhibitor, initially approved in November 2013. The drug was jointly developed and commercialized by Pharmacyclics, an AbbVie company, and Janssen Pharmaceuticals, a Johnson & Johnson company, with AbbVie holding commercialization rights for the US market and Johnson & Johnson holding rights for markets outside the US. BTK is a kinase essential for B-cell survival. By blocking BTK, ibrutinib helps force malignant B cells to leave their growth and proliferation environments, such as lymph nodes, and prevents them from returning. The action of ibrutinib, combined with other effects of BTK inhibition, reduces the survival capacity of malignant B cells.

Ibrutinib has been approved in over 100 countries and has treated more than 230,000 patients worldwide to date. Ibrutinib is the only BTK inhibitor to demonstrate an overall survival (OS) benefit across three CLL clinical trials, with durable responses lasting up to 8 years and 70% of patients remaining alive and progression-free at 5 years. Furthermore, ibrutinib is the only BTK inhibitor proven to modulate both short- and long-term immune recovery.

In China, ibrutinib (Imbruvica®) was first approved in August 2017 as a monotherapy for the treatment of: (1) patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who have received at least one prior therapy; and (2) patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. In November 2018, Imbruvica® was approved for new indications: (1) as monotherapy for patients with Waldenström's macroglobulinemia (WM) who have received at least one prior therapy, or as first-line treatment for patients who are not candidates for chemoimmunotherapy; and (2) in combination with rituximab for the treatment of patients with WM.

Venetoclax is a first-in-class, oral, selective B-cell lymphoma 2 (BCL-2) inhibitor developed collaboratively by AbbVie and Roche. The two companies jointly commercialize the drug in the US market under the brand name Venclexta, while AbbVie is responsible for commercialization in markets outside the US under the brand name Venclyxto. The BCL-2 protein plays a critical role in apoptosis (programmed cell death) by preventing the apoptosis of certain cells, including lymphocytes. It is overexpressed in certain types of cancer and is associated with the development of drug resistance. Venetoclax is designed to selectively inhibit the function of BCL-2, restoring cellular apoptotic signaling pathways, enabling cancer cells to undergo self-destruction, and thereby achieving antitumor therapeutic efficacy.

Venetoclax has been approved in over 80 countries worldwide for the treatment of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and acute myeloid leukemia (AML). In the United States, venetoclax has been granted five Breakthrough Therapy Designations (BTDs) by the FDA: one for first-line treatment of CLL, two for relapsed or refractory CLL, and two for first-line treatment of acute myeloid leukemia (AML).

In China, venetoclax (Venclexta®) was approved in December 2020 in combination with azacitidine for the treatment of newly diagnosed adult patients with acute myeloid leukemia (AML) who are ineligible for intensive induction chemotherapy due to comorbidities, or who are 75 years of age or older. Venetoclax (Venclexta®) is the first approved B-cell lymphoma-2 (BCL-2) inhibitor in China, marking the entry of the AML field in China into the era of targeted therapy. (Bioon.com)

Original Source: CAPTIVATE Study Shows an IMBRUVICA® (ibrutinib) Plus VENCLEXTA®/VENCLYXTO® (venetoclax) Chemotherapy-Free Combination Has Potential to Provide Remission After Fixed-Duration Treatment for Chronic Lymphocytic Leukemia (CLL)