Time-limited venetoclax-based regimens provide deeper and more durable remissions than chemoimmunotherapy combinations in patients with previously untreated chronic lymphocytic leukemia (CLL), regardless of patients’ fitness, according to late-breaking data presented during the European Hematology Association (EHA) 2022 Congress in Vienna.1
The preplanned interim analysis of the phase III GAIA/CLL13 trial showed improved rates of undetectable measurable residual disease (MRD) at 15 months and prolonged progression-free survival among fit patients randomly assigned to targeted therapy–based regimens with the BCL2 inhibitor vs standard chemoimmunotherapy. At 3 years, progression-free survival rates were 90.5% and 87.7% with venetoclax/obinutuzumab and venetoclax/obinutuzumab/ibrutinib, respectively, and 75.5% with chemoimmunotherapy.
“The interim analysis showed the triplet combination of venetoclax and obinutuzumab plus ibrutinib was clearly superior to chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab [FCR] for younger patients or bendamustine and rituximab [BR] for elderly patients who were fit,” said Barbara Eichhorst, MD, Associate Professor and Attending Physician at the University Hospital Cologne, Germany. “Venetoclax plus rituximab was not superior, so it depends on the antibody you combine with the venetoclax treatment.”
Barbara Eichhorst, MD
As Dr. Eichhorst explained, in fit patients with CLL of favorable genetic risk, chemoimmunotherapy, with either FCR or BR, is still the standard treatment in the front-line setting. In patients who are less fit, however, fixed-duration venetoclax plus obinutuzumab demonstrated superior progression-free survival vs chlorambucil plus obinutuzumab,2 and triplet combinations including Bruton’s tyrosine kinase inhibitors have shown activity in phase II trials.
Study Methods
The GAIA/CLL13 trial evaluated the efficacy and safety of three time-limited venetoclax-based first-line regimens in comparison to chemoimmunotherapy in treatment-naive, fit patients with CLL without the presence of TP53 aberrations.
Dr. Eichhorst and colleagues randomly assigned 926 patients to receive six courses of chemoimmunotherapy (FCR for patients up to age 65 and BR for patients aged 65 or older) or one of three venetoclax combinations: venetoclax and rituximab; venetoclax and obinutuzumab; or venetoclax, obinutuzumab, plus ibrutinib. Co-primary endpoints were the rate of undetectable MRD by flow cytometry in peripheral blood at month 15 and progression-free survival.
A preplanned interim analysis of progression-free survival was conducted at the fixed time point of month 61. On data review, an independent data monitoring committee recommended full analysis.
Outcomes and Toxicity
With a median follow-up of 38.8 months, median progression-free survival has not been reached with venetoclax, obinutuzumab, and ibrutinib (hazard ratio [HR] = 0.32) or venetoclax and obinutuzumab (HR = 0.42). For standard chemotherapy, the median progression-free survival was 52 months.
“Results showed superior progressive-free survival with venetoclax, obinutuzumab, and ibrutinib as well as venetoclax plus obinutuzumab, reducing the risk of CLL progression by 68% and 58%, respectively,” said Dr. Eichhorst. In addition, she noted that progression-free survival did not differ significantly between venetoclax plus rituximab and chemoimmunotherapy.
The rates of 3-year progression-free survival were 90.5% and 87.7% with venetoclax, obinutuzumab, and ibrutinib and venetoclax plus obinutuzumab, respectively.
Data from the interim analysis also supported previously reported findings of increased MRD negativity rates among patients treated with venetoclax-based regimens.
Researchers reported similar overall survival rates across all treatment arms.
Severe infections (grade 3 or higher) occurred more commonly with venetoclax, obinutuzumab, and ibrutinib (22.1%) and chemoimmunotherapy (20.4%) than with the venetoclax/rituximab (11.4%) and venetoclax/obinutuzumab (14.9%) combinations.
Subgroup Analysis: Focus on IGHV Status
Dr. Eichhorst and colleagues also presented a subgroup analysis of patients with IGHV-mutant disease. Patients with unmutated IGHV had 3-year progression-free survival rates of 86.6% with venetoclax, obinutuzumab, and ibrutinib, 82.9% with venetoclax plus obinutuzumab, 76.4% with venetoclax plus rituximab, and 65.5% with chemoimmunotherapy. Those with mutated IGHV had 3-year progression-free survival rates of 96% with venetoclax, obinutuzumab, and ibrutinib, 93.6% with venetoclax plus obinutuzumab, 87% with venetoclax plus rituximab, and 89.9% with chemoimmunotherapy.
“Prognosis was favorable for patients with mutated IGHV status,” said Dr. Eichhorst, who noted minimal difference between chemoimmunotherapy and targeted agents in this subgroup. “For patients with unmutated IGVH status, however, we see a huge difference.”
What Next?
According to Dr. Eichhorst, future research will include a direct comparison of venetoclax, obinutuzumab, and ibrutinib vs venetoclax plus obinutuzumab. A trial directly comparing venetoclax plus obinutuzumab with ibrutinib is ongoing.
“The study did not yet do a direct head-to-head comparison between venetoclax/obinutuzumab vs venetoclax/rituximab. However, with respect to MRD rates and 3-year progression-free survival rates, it’s clear that the antibody [combined with venetoclax] matters,” said Dr. Eichhorst.
Regarding the addition of ibrutinib to venetoclax and obinutuzumab, Dr. Eichhorst noted that longer follow-up is still needed. Furthermore, a head-to-head comparison between the triplet and doublet combinations starting next year should provide a definitive answer.
“Ibrutinib is adding more toxicity with respect to infections, but we also see a higher rate of undetectable MRD, and there is a trend of slightly higher median progression-free survival,” explained Dr. Eichhorst. “We will have to see what the direct comparison shows, but based on these data, I would not use the triplet combination in clinical practice.”
Expert Point of View
Susan M. O’Brien, MD
Susan M. O’Brien, MD, Professor of Medicine at the UCI Chao Family Comprehensive Cancer Center, Irvine, California, agreed with Dr. Eichhorst about not yet using the triplet combination in clinical practice. Additional data are needed to convince clinicians of the effectiveness of including ibrutinib given the added toxicity.
“At this time, the three-drug regimen (venetoclax, obinutuzumab, and ibrutinib) and the two-drug drug regimen (venetoclax and obinutuzumab) are producing similar rates of measurable residual disease undetectability and similar progression-free survival curves, so I don’t think there is any reason to prefer the three-drug regimen,” Dr. O’Brien told The ASCO Post. “However, given the expected excellent results with both regimens, it is too early to know whether one will prove to be better than the other.”
DISCLOSURE: Dr. Eichhorst has served as a consultant or advisor to AbbVie, BeiGene, AstraZeneca, Novartis, Celgene, ArQule, Oxford Biomedica (UK), MSD, F. Hoffmann–La Roche Ltd, Gilead, and Janssen; has received reimbursement for travel, accommodation, or expenses from AbbVie, Novartis, Celgene, F. Hoffmann–La Roche Ltd, Gilead, and Janssen; has received research funding from AbbVie, BeiGene, AstraZeneca, F. Hoffmann–La Roche Ltd, Gilead, and Janssen; and has served on a speakers bureau for AbbVie, BeiGene, AstraZeneca, Novartis, Celgene, Adaptive Biotechnologies, Hexal, F. Hoffmann–La Roche Ltd, Gilead, and Janssen. Dr. O’Brien has received honoraria from Celgene, Janssen, Pharmacyclics, Gilead Sciences, Pfizer, Amgen, Astellas Pharma, GlaxoSmithKline, Aptose Biosciences, Vaniam Group, AbbVie, Sunesis Pharmaceuticals, Alexion Pharmaceuticals, Eisai, TG Therapeutics, and Nova Research Company; has served as a consultant for Amgen, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences, Vaniam Group , AbbVie/Genentech, Sunesis Pharmaceuticals, Alexion Pharmaceuticals, Astellas Pharma, Gilead Sciences, Pharmacyclics, TG Therapeutics, and Pfizer; has received research funding from Acerta Pharma, Regeneron, Gilead Sciences, Pfizer, TG Therapeutics, Pharmacyclics, Kite, and Sunesis Pharmaceuticals; and has been reimbursed for travel or accommodations from Celgene, Janssen, Gilead Sciences, Regeneron, and Janssen Oncology.
REFERENCES
1. Eichhorst B, Niemann C, Kater A, et al: Time-limited venetoclax-obinutuzumab ± ibrutinib is superior to chemoimmunotherapy in frontline chronic lymphocytic leukemia: PFS co-primary endpoint of the randomized phase 3 GAIA/CLL13 trial. EHA 2022 Congress. Abstract LB2365. Presented June 11, 2022.
2. Al-Sawaf O, Zhang C, Robrecht S, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 5-year results of the randomized CLL14 study. EHA 2022 Congress. Abstract S148. Presented June 12, 2022.
