Fixed-Duration Ibrutinib Plus Venetoclax Earns Approval in Canada for Previously Untreated CLL

Canada Health 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), including those with 17p deletion.¹

The regulatory decision was supported by data from the phase 3 GLOW trial (NCT03462719) and the fixed-duration cohort of the phase 2 CAPTIVATE trial (NCT02910583).

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

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

“This authorization is significant in providing patients a much-needed additional treatment option that combines the complementary mechanisms of action of both ibrutinib and venetoclax,” Christine Chen, MMEd, MD, FRCPC, clinician investigator, Princess Margaret Cancer Centre, stated in a news release. “This combination regimen presents a new therapeutic option through an all oral, fixed duration of ibrutinib plus venetoclax for patients with previously untreated CLL, marking a positive shift in how we approach first-line treatment of this disease.”

The open-label GLOW trial evaluated 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.

Investigators randomly assigned patients 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 aged 70 years or younger, including those 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).

Those in the fixed-duration cohort were administered 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, the most common any-grade adverse effects (AEs) in the ibrutinib/venetoclax arm were diarrhea (51%) and neutropenia (42%).1 In the chlorambucil/obinutuzumab arm, the most common AEs of any grade were neutropenia (59%) and thrombocytopenia (28%). Grade 3 or higher AEs included neutropenia (35%), diarrhea (10%), pneumonia (9%), and hypertension (9%) in the ibrutinib/venetoclax group, and neutropenia (51%), thrombocytopenia (21%) and pneumonia (6%) in the chlorambucil/obinutuzumab group.

In CAPTIVATE, the most common any-grade AE included diarrhea (67%), neutropenia (48%), bruising (47%), nausea (44%) and musculoskeletal pain (41%). Grade 3 or higher AEs consisted of neutropenia (38%), hypertension (7%), thrombocytopenia (4%), and diarrhea (4%).

References

1. Health Canada authorizes Imbruvica® (ibrutinib) in a fixed-duration combination with venetoclax for adult patients with previously untreated chronic lymphocytic leukemia (CLL). News release. Janssen Pharmaceuticals. March 23, 2023. Accessed March 28, 2023. https://www.janssen.com/health-canada-authorizes-imbruvicar-ibrutinib
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.