Venetoclax and Obinutuzumab With/Without Ibrutinib Improves Efficacy in CLL

Barbara Eichhorst, MD

The combination of venetoclax (Venclexta) and obinutuzumab (Gazyva) with or without ibrutinib (Imbruvica) showed superiority compared with chemoimmunotherapy as first-line treatment in fit patients with previously untreated, advanced chronic lymphocytic leukemia (CLL), according to findings from the phase 3 GAIA–CLL13 trial (NCT02950051).¹

There was a higher percentage of patients with undetectable minimal residual disease (MRD) at month 15 who received venetoclax and obinutuzumab (86.5%; 97.5% CI, 80.6-91.1) and the venetoclax, obinutuzumab, and ibrutinib group (92.2%; 97.5% CI, 87.3-95.7) compared with 52.0% in the chemoimmunotherapy group (97.5% CI, 44.4-59.5; P < .001).

“The clinical trial compared 4 different treatment options in frontline therapy of fit patients requiring treatment because of their advanced CLL. Patients were randomized to receive chemo immunotherapy or 3 different targeted and time limited combinations: the BCL2 inhibitor venetoclax plus the CD20-antibody obinutuzumab or the same combination plus ibrutinib or venetoclax plus rituximab. The study showed that venetoclax plus obinutuzumab and venetoclax plus obinutuzumab plus ibrutinib are superior to chemoimmunotherapy with respect to progression-free survival and response rate, particularly undetectable minimal residual disease rates. The triple combination with venetoclax plus obinutuzumab plus ibrutinib was associated with more infections,” Barbara Eichhorst, MD, University Hospital Cologne, Cologne, Germany, told Targeted Oncology^TM.

The phase 3, multicenter, randomized, prospective, open-label trial randomized patients in a 1:1:1:1 ratio. Fit patients with CLL who did not have TP53 aberrations were given 6 cycles of chemoimmunotherapy, consisting of fludarabine, cyclophosphamide, and rituximab or bendamustine and rituximab, or 12 cycles of venetoclax and rituximab, venetoclax and obinutuzumab, or venetoclax, obinutuzumab, and ibrutinib. Treatment with ibrutinib was discontinued after 2 consecutive measurements of undetectable MRD or could be extended.

The primary end points of the trial were undetectable MRD as assessed by flow cytometry in peripheral blood at month 15 and progression-free survival (PFS). Secondary end points included MRD negativity rate in peripheral blood, PFS, overall survival, and rate of complete responses and complete responses with incomplete bone marrow recovery.²

A total of 926 patients were assigned to receive 1 of the 4 treatment regimens. There were 229 assigned to receive chemoimmunotherapy, 237 to venetoclax and rituximab (Rituxan), 229 to venetoclax and obinutuzumab, and 231 to venetoclax, obinutuzumab, and ibrutinib. Patients were aged 18 years and older with a life expectancy ≥ 6 months, adequate bone marrow function and liver function, and an ECOG performance status of 0-2.

Findings revealed that at month 15, there was a higher percentage of patients with undetectable MRD in the venetoclax and obinutuzumab group and the venetoclax, obinutuzumab, and ibrutinib group vs in the chemoimmunotherapy group.1 However, the rate was not significantly higher in the venetoclax and rituximab group (57.0%; 97.5% CI, 49.5-64.2; P = .32).

In the in the venetoclax, obinutuzumab, and ibrutinib group, the 3-year PFS rate was 90.5% vs 75.5% in the chemoimmunotherapy group (HR, 0.32; 97.5% CI, 0.19-0.54; P < .001). At 3 years, PFS rates were also higher in the venetoclax and obinutuzumab group at 87.7% (HR, 0.42; 97.5% CI, 0.26-0.68; P < .001), but were not higher with venetoclax and rituximab (80.8%; HR, 0.79; 97.5% CI, 0.53-1.18; P = .18).

Regarding safety, severe infections that were grade 3 or 4 were more frequent among patients given chemoimmunotherapy (18.5%) and venetoclax, obinutuzumab, and ibrutinib (21.2%) compared with those given treatment with venetoclax and rituximab (10.5%) or venetoclax and obinutuzumab (13.2%).

REFERENCES:

1. Eichhorst B, Niemann CU, Kater AP, et al. First-line venetoclax combinations in chronic lymphocytic leukemia. N Engl J Med. 2023;388(19):1739-1754. doi:10.1056/NEJMoa2213093

2. Standard chemoimmunotherapy (FCR/BR) versus rituximab + venetoclax (RVe) versus obinutuzumab (GA101) + venetoclax (GVe) versus obinutuzumab + ibrutinib + venetoclax (GIVe) in fit patients with previously untreated chronic lymphocytic leukemia (CLL) without del(17p) or TP53 mutation (GAIA). ClinicalTrials.gov. Updated October 19, 2022. Accessed May 15, 2023. https://clinicaltrials.gov/ct2/show/NCT02950051