Combination Therapy With Ibrutinib and Venetoclax Bests Chlorambucil/Obinutuzumab for CLL

Fixed-duration ibrutinib (Imbruvica) and venetoclax (Venclexta) for patients with first-line chronic lymphocytic leukemia (CLL) led to better progression-free survival (PFS) outcomes than chlorambucil plus obinutuzumab, according to data from the phase 3 GLOW (NCT03462719) study presented at the European Hematology Association (EHA) 2021 Virtual Congress.

In particular, ibrutinib is an oral BTK inhibitor administered once per day and has shown to provide a survival benefit in patients with previously untreated CLL. Venetoclax is an oral BCL-2 inhibitor given once per day with demonstrated PFS benefit in patients with previously untreated CLL when given with an anti-CD20 antibody during a 12-week regimen.

“The expectation [was] that combining ibrutinib with venetoclax will lead to deeper, durable responses and enable treatment-free periods,” Arnon P. Kater, MD, PhD, leader of tumor immunology at the Cancer Center Amsterdam, said during the presentation.

In this study, researchers aimed to evaluate the efficacy and safety of fixed-duration ibrutinib plus venetoclax compared with chlorambucil plus obinutuzumab in patients with previously untreated CLL. Researchers enrolled 211 patients with previously untreated CLL who were 65 years or older or between ages 18 to 64. Moreover, these patients had a cumulative illness rating scale (CIRS) score greater than 6 or creatinine clearance less than 70 mL/min. Exclusion criteria included del(17p) or known TP53 mutations.

After stratification by IGHV mutational status and the presence of del(11q), patients were randomized 1:1 to one of the following treatments:

• 420 mg daily of ibrutinib for a 3-cycle lead-in followed by ibrutinib plus venetoclax for 12 cycles (venetoclax was ramped up for 20 mg to 400 mg over 5 weeks beginning with cycle 4), or
• 0.5 mg/kg of chlorambucil on days 1 and 15 for 6 six cycles plus 1,000 mg of obinutuzumab on days 1, 2, 8 and 15 of the first cycle and day 1 of cycles 2 through 6.

The primary endpoint for this study was PFS assessed by independent review committee (IRC). Key secondary endpoints included undetectable minimal residual disease (MRD) in bone marrow, the rate of complete response (CR) assessed by IRC, overall response rate (ORR) assessed by IRC, overall survival (OS) and safety.

In total, 106 patients were randomized to ibrutinib plus venetoclax (median age, 71 years; 55.7% men) and 105 were randomized to chlorambucil plus obinutuzumab (median age, 71 years; 60% men).

“Overall, [the] study population was elderly and unfit,” Kater said. “The majority of patients had a CIRS score greater than 6, and thereby, the study population was unfit than other ibrutinib first-line studies including RESONATE 2 and ILLUMINATE.”

After a median follow-up of 28 months, the combination of ibrutinib plus venetoclax significantly improved PFS compared with chlorambucil plus obinutuzumab. Therefore, ibrutinub plus venetoclax was superior to chlorambucil plus obinutuzumab and reduced the risk for progression or death by 78% (HR, 0.216; 95% CI, 0.131-0.357). This benefit was consistent across subgroups including comorbidities, age and underlying biology such as IGHV and del(11q) status.

Patients who were treated with ibrutinub plus venetoclax had deeper and more durable responses compared with chlorambucil plus obinutuzumab.

“This is likely related to the synergistic mechanism of action of [ibrutinub plus venetoclax],” Kater said.

The rate of CR was significantly higher in patients treated with ibrutinub plus venetoclax compared with chlorambucil plus obinutuzumab (38.7% vs. 11.4%; P < .0001). Most responders to ibrutinub plus venetoclax (90%) had a maintained response after 2 years compared with 41% in patients who responded to chlorambucil plus obinutuzumab.

Treatment with ibrutinub plus venetoclax also led to significantly higher undetectable MRD rates compared with chlorambucil plus obinutuzumab as assessed in bone marrow (51.9% vs. 17.1%: P < .0001) and peripheral blood (54.7% vs. 39.0%; P = .0259). At 1 year after end of treatment, 85% of patients with undetectable MRD at the end of treatment with ibrutinub plus venetoclax sustained their undetectable MRD status.

The median exposure to ibrutinub plus venetoclax was 13.8 months (range, 0.7-19.5) compared with 5.1 months (range, 1.8-7.9) for chlorambucil plus obinutuzumab.

“Safety profiles for both arms were as expected given the known safety profiles of ibrutinib, venetoclax and chlorambucil plus obinutuzumab when used to treat [an] older comorbid CLL patient population,” Kater said.

Data on OS are immature, Kater said, with 11 deaths occurring in the ibrutinub plus venetoclax arm and 12 deaths in the chlorambucil plus obinutuzumab arm (HR, 1.048; 95% CI, 0.454-2.419). Causes of deaths in both study arms were similar, with the most common causes being infections and cardiac events.

“If you take this GLOW data together with CAPTIVATE in the unfit population, we now experienced across a broad spectrum more than 400 CLL patients treated with [ibrutinub plus venetoclax] in this first-line setting,” Kater said.

“This is going to be the new standard of care, isn’t it,” Elizabeth Macintyre, MD, head of the biological hematology department at Institut Necker Enfants-Malades in Paris, said during the press briefing.

In response, Kater said, “Well, hopefully. I think it is a choice now. … Indeed, you have a good choice option for I think both fit and unfit patients now.”

Reference

Kater A, Owen C, Moreno C, et al. Fixed duration ibrutinib and venetoclax (I+V) versus chlorambucil plus obinutuzumab (CLB+O) for first-line (1L) chronic lymphocytic leukemia (CLL): primary analysis of the phase 3 GLOW study. Presented at: European Hematology Association 2021 Virtual Congress; June 9-19, 2021; virtual. Abstract LB1902.