Ibrutinib/venetoclax combination outperforms ibrutinib and FCR alone in long-term CLL

Compared with ibrutinib/ibrutinib (Ibrutinib) treatment or fludarabine-cyclophosphamide-rituximab (FCR), ibrutinib combined with venetoclax( Undetectable measurable residual disease (MRD) and prolonged progression-free survival (PFS) were more common in patients with chronic lymphocytic leukemia (CLL) treated with venetoclax). Data from this study (ISRCTN01844152) have been published.

Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor approved for a variety of cancers outside of CLL, including B-cell malignancies, mantle cell lymphoma, and Waldenström's macroglobulinemia. The drug was initially approved for CLL in 2014 as a monotherapy and subsequently in combination with other drugs over the past decade. Ibrutinib in combination with venetoclax is not approved for CLL in the United States but is approved in Europe.

Although not yet approved, ibrutinib combined with venetoclax showed clinically meaningful benefits in clinical trials. For example, according to the phase 2 CAPTIVATE study (NCT02910583), fixed-duration first-line ibrutinib plus venetoclax showed comparable survival outcomes in patients with CLL, even those with high-risk cytogenetics. In this UK study, the benefits of this combination are further elucidated.

This Phase 3, multicenter, open-label trial consisted of patients with CLL who were randomly assigned to receive ibrutinib and venetoclax, ibrutinib alone, or FCR. Doses and durations were as follows: FCR (fludarabine, cyclophosphamide, rituximab; n=263):

Fludarabine and cyclophosphamide are administered orally on days 1 to 5.

Intravenous Rituximab: 375 mg/m² on day 1 of cycle then 500 mg/m² on day 1 of cycles 2 to 6.

Each cycle repeats every 28 days for a total of 6 cycles.

I (ibrutinib monotherapy; n=263):

Ibrutinib is administered orally at 420 mg daily for 6 years.

I+V (ibrutinib plus venetoclax;n=260):

Ibrutinib is administered orally at 420 mg daily for 6 years.

Starting at week 9, the weekly dose of venetoclax is increased (20→50→100→200→400 mg) and then maintained at 400 mg daily for 6 years.

The study's primary endpoints were bone marrow MRD over 2 years in the ibrutinib plus veneclase group compared with ibrutinib monotherapy, and PFS in the ibrutinib plus venetoclax group compared with FCR. Secondary endpoints included PFS and overall survival (OS) in the ibrutinib plus venetoclax group compared with ibrutinib alone.

In the ibrutinib plus venetoclax group, 66.2% of patients (172 of 260) had undetectable MRD in their bone marrow within 2 years. Patients in the ibrutinibmonotherapy andFCR groups showed poorer responses. Compared with FCR, ibrutinib alone had the worst effect, with no patient reaching undetectable MRD, and FCR's results were better than the former (48.3% had undetectable MRD).

With a median follow-up of just over 62 months, 6.9% of patients treated with ibrutinib plus venetoclax experienced disease progression or death, compared with 6.9% of patients treated with ibrutinib alone 22.4% (HR, 0.29; 95%CI, 0.17-0.49; P<0.001), and 42.6% (HR, 0.13; 95%CI: 0.08-0.21; P<0.001) in FCR. At 5 years, the progression-free survival rate of ibrutinib plus venetoclax was 93.9%, compared with 79.0% for ibrutinib alone, and the FCR was 58.1%.

4.2% of patients who received ibrutinib plus venetoclax died compared with 9.9% of patients who received ibrutinib alone (HR, 0.41; 95% CI, 0.20-0.83) and 14.8% who received FCR (HR, 0.26; 95% CI, 0.13-0.50). Sudden death was reported in 3 patients in the ibrutinib and venetoclax group, 8 in the ibrutinib alone group, and 4 in the FCR group.

With longer follow-up and increased enrollment, the trial showed that ibrutinib-venetoclax was more likely to develop undetectable MRD and prolonged PFS than ibrutinib or FCR alone. The [OS] results were also consistent with the benefit of ibrutinib-venetoclax.

References:https://www.pharmacytimes.com/view/ibrutinib-venetoclax-outperforms-ibrutinib-alone-and-fcr-in-long-term-cll