Early-Phase Study Finds Venetoclax Plus Obinutuzumab Safe and Effective in Patients with Untreated CLL

Venetoclax – a highly selective, potent BCL2 inhibitor – demonstrated significant anti-tumor activity in patients with chronic lymphocytic leukemia (CLL), both as monotherapy and in combination with obinutuzumab, in preliminary results from a phase Ib study. Ian W. Flinn, MD, PhD, from the Sarah Cannon Center for Blood Cancer in Nashville, Tennessee, and co-authors reported updated safety, efficacy, and minimal residual disease (MRD) negativity data in patients with previously treated CLL at the 2017 ASH Annual Meeting.

“This combination of venetoclax and obinutuzumab achieved high overall and complete remission rates,” Dr. Flinn said during his presentation. This included “high rates of undetectable bone marrow (BM) MRD, irrespective of response status.”

The trial enrolled patients with previously treated CLL; patients were eligible if they had an Eastern Cooperative Oncology Group performance status score of ≤1 and adequate organ function.

Treatment was administered by one of two schedules during the first cycle: In schedule A, patients received venetoclax first; in schedule B, patients received obinutuzumab first.

The recommended target dose for the safety-expansion cohorts was venetoclax 400 mg, which was determined from an earlier dose-finding cohort. Obinutuzumab was administered according to the approved dosing schedule (cycle 1: 100 mg day 1, 900 mg day 2, 1,000 mg days 8 and 15; cycle 2-6: 1,000 mg day 1, based on a 28-day cycle).

Thirty-two patients (median age = 63 years; range not provided) received six cycles of venetoclax plus obinutuzumab, followed by an additional six cycles of venetoclax alone. Depending on CLL disease status, venetoclax could be extended after one year of treatment.

The primary endpoints were safety and tolerability of venetoclax plus obinutuzumab, as well as efficacy and MRD negativity.

During the first cycle of treatment, six patients received schedule A and 26 received schedule B. All 32 patients completed six cycles of venetoclax plus obinutuzumab; follow-up continued for at least nine months from treatment onset. Twelve patients were followed for longer than 15 months.

Median time on study was 11.3 months (range not provided). All patients experienced at least one adverse event (AE); the most commonly reported AEs were neutropenia, febrile neutropenia, and thrombocytopenia. No cases of tumor lysis syndrome were reported on either schedule, and there were no treatment discontinuations related to AEs. There were no deaths as of data cutoff (date not reported).

All 32 patients in the study responded to treatment (overall response rate = 100%), including 17 patients with complete response (CR), one with CR with incomplete hematologic recovery (56.3%), and 14 with partial response (43.8%).

The rate of progression-free survival at one year was 100 percent. At 437 and 451 days after treatment initiation, two patients (6.3%) had disease progression, both of whom had del17p mutation at screening.

MRD negativity in peripheral blood occurred in all participants, and 20 patients (62.5% in intention-to-treat population; 74% in patients with samples available) achieved MRD negativity in BM.

Dr. Flinn called the rates of MRD negativity “unprecedented,” compared with other chemo-immunotherapy regimens or chemotherapy-free approaches. These results suggest “that [venetoclax plus obinutuzumab] may be administered with a favorable benefit-risk profile,” the authors concluded.

This combination is being tested in a phase III trial, and Dr. Flinn noted that questions remain about the optimal venetoclax-based combination.

The authors report financial relationships with Roche, AbbVie, and Genentech.


Flinn IW, Gribben JG, Dyer MJS, et al. Safety, efficacy and MRD negativity of a combination of venetoclax and obinutuzumab in patients with previously untreated chronic lymphocytic leukemia—results from a phase 1b study (GP28331). Abstract #430. Presented at the 2017 ASH Annual Meeting, December 10, 2017; Atlanta, GA.