Venetoclax Plus Obinutuzumab With or Without Ibrutinib Extends PFS in First-Line CLL

Combination therapy with venetoclax (Venclexta) plus obinutuzumab (Gazyva) or venetoclax plus obinutuzumab and ibrutinib (Imbruvica) demonstrated a significant improvement in progression-free survival (PFS) vs standard chemoimmunotherapy and vs venetoclax plus rituximab (Rituxan) in patients with previously untreated chronic lymphocytic leukemia (CLL), according to findings from the phase 3 GAIA/CLL13 trial (NCT02950051) published in The Lancet Oncology.¹

Updated 4-year PFS data from a post-hoc exploratory analysis of GAIA revealed that, at a median follow-up of 50.7 months (IQR, 44.6-57.9), patients achieved 4-year PFS rates of 85.5% (97.5% CI, 79.9%-91.1%) in the venetoclax plus obinutuzumab and ibrutinib arm (n = 231), 81.8% (97.5% CI, 75.8%-87.8%) in the venetoclax plus obinutuzumab arm (n = 229), 70.1% (97.5% CI, 63.0%-77.3%) in the venetoclax plus rituximab arm (n = 237), and 62.0% (97.5% CI, 54.4%-69.7%) in the chemoimmunotherapy arm (n = 229).

The benefit observed with the triplet was significant compared with chemoimmunotherapy (HR, 0.30; 97.5% CI, 0.19-0.47; log-rank P < .0001) and vs venetoclax plus rituximab (HR, 0.38; 97.5% CI, 0.24-0.59; log-rank P < .0001). Investigators noted there was no difference in PFS with the triplet vs venetoclax plus obinutuzumab (HR, 0.63; 97.5% CI, 0.39-1.02; log-rank P = .031). Additionally, patients experienced a significant PFS benefit when treated with venetoclax plus obinutuzumab vs chemoimmunotherapy (HR, 0.47; 97.5% CI, 0.32-0.69; log-rank P < .0001) and venetoclax plus obinutuzumab vs venetoclax plus rituximab (HR, 0.57; 97.5% CI, 0.38-0.84; log-rank P = .0011).

“With more than 4 years of follow-up, venetoclax [plus] obinutuzumab and venetoclax [plus] obinutuzumab [and] ibrutinib significantly extended PFS compared with both chemoimmunotherapy and venetoclax [plus] rituximab in previously untreated, fit patients with CLL, thereby supporting their use and further evaluation in this patient group, while still considering the higher toxicities observed with the triple combination,” Moritz Fürstenau, MD, of the University of Cologne in Germany, and coauthors wrote.

Adult patients with CLL and a life expectancy of at least 6 months were enrolled in the open-label GAIA trial, which was conducted at 159 sites in 10 countries in Europe and the Middle East. Patients needed to have an ECOG performance status of up to 2 and adequate bone marrow and liver function. Additionally, patients could not have TP53 aberrations.^1,2

Following 1:1:1:1 random assignment, stratification took place by age (≤ 65 vs > 65 years), Binet stage at screening (A vs B vs C), and regional study group (German CLL Study Group vs Stichting Hemato-Oncologie voor Volwassenen Nederland vs Nordic CLL Study Group vs Cancer Trials Ireland vs Israeli CLL Study Group vs Swiss Group for Clinical Cancer Research). All patients received treatment in 28-day cycles. In the chemoimmunotherapy arm, patients received 6 cycles of intravenous bendamustine 90 mg/m² on days 1-2 if older than 65 years or intravenous fludarabine 25 mg/m² on days 1-3 as well as intravenous cyclophosphamide 250 mg/m² on days 1-3 if younger than 65 years old; intravenous rituximab 375 mg/m² was administered on day 1 of cycle 1, then the agent was given at a dose of 500 mg/m² on day 1 of cycles 2-6.¹

In the venetoclax plus rituximab arm, oral venetoclax 400 mg was administered daily for 10 cycles following a 5-week ramp-up phase starting on day 22 of cycle 1 with the same dosing of rituximab patients in the chemoimmunotherapy arm received, for 12 cycles. Obinutuzumab was administered at 100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15 of cycle 1 and at 1000 mg on day 1 of cycles 2-6 in combination with venetoclax (for 12 cycles) with or without ibrutinib (for between 12 and 36 cycles). Patients in the triplet arm received oral ibrutinib 420 mg daily from day 1 of cycle 1 until cycle 36 or undetectable minimal residual disease (MRD) was achieved in 2 consecutive measurements 3 months apart.

The coprimary end points in the intention-to-treat population were undetectable MRD rate in the peripheral blood at month 15 with venetoclax plus obinutuzumab vs standard chemoimmunotherapy and investigator-assessed PFS for venetoclax plus obinutuzumab and ibrutinib vs standard chemoimmunotherapy. Secondary end points included overall survival (OS), overall response rate, and duration of response for all comparisons.

Baseline characteristics were generally well balanced between the 4 arms. The mean age of the overall population (n = 926) was 60.8 years (SD, 10.2); most patients were male (72.0%), had less than 3 complex karyotype aberrations (82.9%), and had high CLL-international prognostic index risk group stage disease (51.0%). The median time between first diagnosis and random assignment was 29.0 months (IQR, 9.1-59.9) and the median Cumulative Illness Rating Scale score was 2 (IQR, 1-4). Patients had Binet stage A (26.5%), B (37.9%), or C (35.6%) disease as well as IGHV unmutated (56.0%) or mutated (41.1%) disease.

“In an exploratory subgroup analysis, unmutated IGHV was associated with shorter PFS across all treatment groups than was mutated IGHV and similar between-treatment group hazards were found for most comparisons,” study authors noted.

Additional data revealed that OS did not differ significantly between any of the groups. At the data cutoff, 7% of patients in the chemoimmunotherapy arm, 4% in the venetoclax plus rituximab arm, 5% in the venetoclax plus obinutuzumab arm, and 5% in the venetoclax plus obinutuzumab and ibrutinib arm had died. Regarding safety, the most common grade 3 or higher treatment-related adverse effect was neutropenia occurring in 53% vs 46% vs 56% vs 48% of patients, respectively.

Deaths related to study treatment as determined by the investigator occurred in 3 patients in the chemoimmunotherapy group due to sepsis, metastatic squamous cell carcinoma, and Richter’s syndrome. Further, 4 patients in the triplet group died due to acute myeloid leukemia, fungal encephalitis, small cell lung cancer, and toxic leukoencephalopathy.

References

1. Fürstenau M, Kater AP, Robrecht S, et al. First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2024;25(6):744-759. doi:10.1016/S1470-2045(24)00196-7
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 March 6, 2024. Accessed June 11, 2024. https://clinicaltrials.gov/study/NCT02950051