Ibrutinib Plus Venetoclax Shows Promising Activity Against CLL

In CAPTIVATE, first-line ibrutinib plus venetoclax yielded a high rate of undetectable residual disease, without new safety signals, in chronic lymphocytic leukemia.

First-line ibrutinib plus venetoclax therapy for chronic lymphocytic leukemia (CLL) was associated with encouraging clinical responses, including a high rate of undetectable minimal residual disease (MRD), according to findings from the phase II CAPTIVATE (PCYC-1142) study (NCT02910583; abstract 7502) presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 1–5 in Chicago.

The study found a 77% rate of undetectable MRD in patients’ peripheral blood after 6 cycles of treatment, reported lead study author William G. Wierda, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston.

Early undetectable MRD status was maintained over time and subsequently confirmed in bone marrow, with an 86% undetectable MRD rate for bone marrow after 12 cycles of therapy.

Assessment of the durability of response is still needed, Wierda said.

“The spectrum of AEs [adverse events] was consistent with the historic safety profile of single-agent ibrutinib and AEs expected with venetoclax, with no new safety signals,” Wierda noted.

Ibrutinib is a first-in-class, once-daily oral Bruton tyrosine kinase (BTK ) inhibitor that is FDA-approved for treating CLL, including del17p disease. Venetoclax is an oral BCL-2 inhibitor. Both agents have high activity in CLL, but undetectable levels of residual disease are rare with ibrutinib monotherapy, Wierda noted.

Preclinical and ongoing clinical studies suggest that combination therapy with ibrutinib and venetoclax (I+V) offers antitumor synergies in combination, with the potential for deeper remission and lower risk of tumor lysis syndrome (TLS) with an ibrutinib lead-in regimen, he said.

The phase II CAPTIVATE trial evaluated I+V as a first-line treatment for CLL. Two cohorts of patients were enrolled. Wierda reported exposure and safety findings for the first group, an MRD cohort of 164 patients. Data from the second group, a Fixed Duration cohort of 159 patients, were not presented.

Eligibility criteria included a diagnosis of previously untreated CLL or small lymphocytic lymphoma (CLL/SLL), active disease requiring treatment, age younger than 70 years, and an ECOG (Eastern Cooperative Oncology Group) performance score of 0–1.

During the initial safety run-in stage of the study, patients received oral ibrutinib (420 mg/d) lead-in therapy for three 28-day cycles before an oral venetoclax ramp-up to 400 mg/d. MRD in peripheral blood was assessed after 12 cycles of I+V. Patients with confirmed-undetectable MRD were then randomly assigned (1:1, double-blind) to receive either ibrutinib or placebo. Patients for whom undetectable MRD could not be confirmed were randomly assigned (1:1) to continue I+V treatment or ibrutinib monotherapy.

No dose-limiting toxicities or clinical TLS were reported during the first 6 weeks of I+V.

The high activity levels support additional investigation of I+V as a fixed-duration regimen for first-line CLL therapy, Wierda said.