CHICAGO—Ibrutinib combined with venetoclax is showing promising clinical activity in the frontline treatment of patients with chronic lymphocytic leukemia (CLL), according to investigators for the CAPTIVATE study.

In the first 30 patients, 77% of treatment-naïve patients had undetected minimal residual disease (MRD; <10^-4 cells) in the blood and 86% showed a similar response in the bone marrow.

The overall response rate (ORR) was 100% in 11 evaluable patients. The investigators reported this initial data at the 2018 Annual Meeting of the American Society of Clinical Oncology (abstract 7502).

“These early results show a highly active and safe treatment with 12 cycles of combined treatment with ibrutinib and venetoclax,” said William G. Wierda, MD, PhD, of the MD Anderson Cancer Center in Houston, Texas, who presented the findings at ASCO.

Ibrutinib, a Bruton-kinase inhibitor, has already been approved for the treatment of CLL and venetoclax, a Bcl-2 inhibitor, is currently used to treat relapsed del 17p CLL.

Venetoclax in combination with rituximab was recently approved by the US Food and Drug Administration to treat patients with CLL or small lymphocytic lymphoma whether or not patients have del 17p.

With complementary mechanisms of action and preclinical studies suggesting synergy with the combination, CAPTIVATE was designed to test the efficacy of the oral combination given for 12 cycles.

Study design

CAPTIVATE (NCT02910583) is an ongoing phase 2 study that enrolled 164 patients with treatment-naïve CLL. Patients first received 3 cycles of ibrutinib monotherapy at the standard dose. This was intended to debulk the disease and reduce risk for venetoclax-associated tumor lysis syndrome (TLS).

Venetoclax 400 mg was initiated at cycle 4. After 12 cycles of the combination, patients with confirmed MRD negativity were randomized to receive ibrutinib with a placebo or to continue with the combination therapy.

In this initial report, Dr Wierda highlighted safety data for all 164 enrolled patients and efficacy data for the first 30 patients who had 6 cycles of combination therapy (MRD assessment cohort).

Dr Wierda also reported bone marrow data for the first 14 patients, who received a total of 12 cycles of the combination and represent the safety run-in cohort.

Ibrutinib and venetoclax show promising activity

Median age of patients was 58 years; about 2/3 of patients had unmutated IGHV and 1/3 had a creatine clearance of <80 mL/min.

Of 164 patients, 95% remain on therapy, with discontinuations reported for adverse events; one patient had disease progression to Richter’s transformation.

For the MRD evaluation, all 30 patients had 6 months of combination therapy and continue on treatment.

As expected, lead-in with ibrutinib monotherapy debulked the disease.

Investigators observed a reduction in the proportion of patients at high risk for TLS (24% to 3%) and an increase in the proportion of patients at low risk for TLS (12% to 29%).

A similar picture emerged for debulking of lymph node disease. No patient developed clinical TLS.

Other adverse events were consistent with the safety profile of single-agent ibrutinib and venetoclax. No new safety signals were seen.

After 6 cycles of the combination, blood MRD negativity was reported in 77% of the patients in the MRD assessment cohort.

In the safety-run in cohort of 14 patients, blood MRD negativity was reported in 86% of patients after 12 cycles and 93% of patients after 15 cycles of the combination. In these patients, bone marrow MRD negativity was achieved in 86%.

After 12 cycles of combination therapy, the objective response rate was 100% for 11 of the 14 evaluable patients from the safety run-in cohort: 6 patients showed complete remission (CR) or CR with incomplete blood count recovery (CRi) for a CR/CRi of 55%. All patients had confirmed undetectable MRD.

Investigators considered these responses promising and an assessment of the full treatment plan and durability of response are awaited.

The study was sponsored by Pharmacyclics.

Ibrutinib and venetoclax combo promising in frontline CLL