Fixed-Duration Ibrutinib Plus Venetoclax Wins EU Approval in Previously Untreated CLL

The European Commission has approved the fixed-duration, all-oral combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) for the frontline treatment of adult patients with chronic lymphocytic leukemia (CLL).¹

The approval was based on findings from the pivotal phase 3 GLOW trial (NCT03462719) and the fixed-duration cohort of the phase 2 CAPTIVATE trial (NCT02910583).^2,3

At a median follow-up of 27.7 months (range, 1.7-33.8), data from GLOW showed that the median progression-free survival (PFS) was not reached (NR; 95% CI, 31.2-NR) with ibrutinib plus venetoclax vs 21.0 months (95% CI, 16.6-24.7) with chlorambucil plus obinutuzumab (Gazyva), per independent review committee (IRC) assessment (HR, 0.216; 95% CI, 0.131-0.357; P < .001).²

Additionally, data from CAPTIVATE demonstrated that ibrutinib plus venetoclax resulted in a 24-month PFS rate of 94% (95% CI, 88%-97%) and 97% (95% CI, 89%-99%) in patients with CLL or small lymphocytic lymphoma (SLL) with high-risk features and patients without high-risk features, respectively.³

“Developing innovative therapies remains vitally important in CLL, to ensure we have the option and ability to best tailor treatment to meet individual patient needs and preferences,” Edmond Chan, MBChB, MD, EMEA Therapeutic Area Lead of Hematology at Janssen-Cilag Limited, stated in a press release. “Over the past 11 years, the efficacy and safety profile of ibrutinib has been established in clinical trials and real-world settings. With this approval, health care professionals will now have the flexibility to use ibrutinib either in a fixed-duration combination with venetoclax or as a continuous monotherapy in first-line CLL.”

GLOW was an open-label trial comparing ibrutinib plus venetoclax vs chlorambucil plus obinutuzumab in patients with CLL or SLL who were at least 65 years of age or between the ages of 18 and 64 years with a Cumulative Illness Rating Scale score of more than 6, a creatinine clearance of less than 70 mL/min, and without deletion 17p or TP53 mutations.

Patients in the GLOW study were randomized to receive 3 cycles of ibrutinib lead-in, followed by 12 cycles of ibrutinib plus venetoclax (n = 106), or 6 cycles of chlorambucil plus obinutuzumab (n = 105). The primary end point of the GLOW trial was PFS per IRC.

CAPTIVATE enrolled patients with previously untreated CLL who were 70 years or younger, including patients with high-risk disease. Patients were enrolled into 2 cohorts: the minimal residual disease–guided cohort (n = 164) and the fixed-duration cohort (n = 159).

Patients in the fixed-duration cohort received 3 cycles of ibrutinib lead-in followed by 12 cycles of ibrutinib plus venetoclax. Ibrutinib was administered at 420 mg per day, and venetoclax was ramped up to 400 mg per day over 5 weeks. The primary end point of CAPTIVATE was complete response rate.

Regarding safety, updated data showed the safety profile of the fixed-duration combination was consistent across the 2 studies. The most common adverse effects (AEs) of any grade reported in the ibrutinib plus venetoclax arm in GLOW included diarrhea (50.9%) and neutropenia (41.5%). AEs of grade 3 or higher were reported in 75.5% of patients in the ibrutinib plus venetoclax arm compared with 69.5% in the chlorambucil plus obinutuzumab arm.

In CAPTIVATE, the most common any-grade AEs included diarrhea (62%), nausea (43%), neutropenia (42%), and arthralgia (33%). The most common grade 3/4 AEs consisted of neutropenia (33%), hypertension (6%), and neutrophil count decrease (5%). Serious AEs occurred in 23% of patients, and one patient experienced a fatal AE.

“The distinct and complementary mechanisms of action of ibrutinib and venetoclax, and the potential of this combination regimen to provide treatment-free remissions, mark important progress for how we approach first-line CLL therapy,” Arnon Kater, MD, PhD, deputy head of Hematology at Amsterdam University Medical Centers and the principal investigator of GLOW, said.

“These highly active blood cancer treatments not only combine to deliver superior progression-free survival versus chlorambucil plus obinutuzumab, but also demonstrate robust disease clearance in lymphoid tissue, blood and bone marrow, and early sustainability of those responses after stopping treatment.”

References

1. European Commission approves IMBRUVICA® (ibrutinib) in a fixed-duration combination regimen for adult patients with previously untreated chronic lymphocytic leukaemia (CLL). News release. Johnson & Johnson. August 4, 2022. Accessed August 25, 2022. https://bit.ly/3AMP4yh
2. Kater AP, Owen C, Moreno C, et al. Fixed-duration ibrutinib-venetoclax in patients with chronic lymphocytic leukemia and comorbidities. NEJM Evid. 2022;1(7). doi:10.1056/EVIDoa2200006
3. Allan JN, Flinn IW, Siddiqi T, et al. Fixed-duration ibrutinib + venetoclax for first-line treatment of chronic lymphocytic leukemia in patients with high-risk features: phase 2 CAPTIVATE study. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Accessed August 25, 2022. Abstract CT028.