The GAIA trial raises some important points, according to Susan M. O’Brien, MD, Associate Director for Clinical Research at the UCI Chao Family Comprehensive Cancer Center in Irvine, California. Dr. O’Brien co-moderated the session where Dr. Eichhorst presented study results.
Susan M. O’Brien, MD
“The CLL14 trial investigators compared venetoclax plus obinutuzumab vs chlorambucil plus obinutuzumab, which is obviously not a very good regimen. We don’t use it much in the United States, but it is used in Europe for older, frail patients. Better regimens in this setting are BR [bendamustine and rituximab] and FCR [fludarabine, cyclophosphamide, rituximab]. GAIA is the first study to compare venetoclax plus obinutuzumab to a more effective chemoimmunotherapy [BR or FCR],” Dr. O’Brien said.
The numbers were slightly higher for undetectable measurable residucal disease [MRD] with venetoclax/obinutuzumab/ibrutinib than with venetoclax/obinutuzumab in the GAIA study. “Probably it was a bit hard to know how much difference the antibody makes with venetoclax. In the MURANO trial, which compared venetoclax plus rituximab vs BR in relapsed CLL, the median number of prior regimens was one. The CLL14 trial was the only randomized comparison of front-line venetoclax plus obinutuzumab vs chlorambucil plus obinutuzumab, and this led to the front-line approval of venetoclax plus obinutuzumab. In the GAIA trial, we see that venetoclax plus obinutuzmab is better than chemoimmunotherapy with FCR or CR,” Dr. O’Brien continued. “If you look at the data from the MURANO and CLL14 trials, the CLL14 data looks better, but the former trial was in relapsed CLL, and the latter was as front-line therapy, so different patient populations,” she explained. GAIA is a head-to-head comparison of venetoclax with two different antibodies: rituximab and obinutuzumab.”
So, does ibrutinib add much to venetoclax/obinutuzumab? In Dr. O’Brien’s opinion, possibly. “Results were not that much better when ibrutinib was added. The numbers are a bit higher for undetectable MRD [the co-primary endpoint]…. The MRD undetectability numbers are 86% for [venetoclax/obinutuzumab] and 92.2% for [venetoclax/obinutuzumab/ibrutinib], but the comparison in the study was not between these two regimens—they were each compared with chemoimmunotherapy. My bet is they may not be significantly different from each other. Both regimens were significantly superior to chemoimmunotherapy [FCR or BR],” she commented. “Are the differences between [the two regimens] significant? The authors didn’t compare them directly, but my guess is probably not.”
“The take-home message from the GAIA study is that I am not sure the three-drug regimen is better than the two-drug regimen. We need longer follow-up to see whether the progression-free survival curves start to show a difference. These patients are fit, and they can live a long time,” Dr. O’Brien noted.
More Impactful in Europe
“The three-drugregimen is not approved in the United States. GLOW is a randomized registration trial presented at the European Hematology Association meeting and updated at the 2021 ASH meeting. The study was highly positive for ibrutinib/venetoclax (vs chlorambucil/obinutuzumab), and the data will be submitted to the FDA for approval,” she said.
“The GAIA trial won’t change much in the United States, since most physicians don’t use chemoimmunotherapy as front-line therapy anymore. Arguably, it could have more impact in Europe, where chemoimmunotherapy is the gold standard. The value of GAIA is that it allows us to compare five different regimens and gives us a lot of information in one trial,” she stated.
DISCLOSURE: 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 consulted 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.
Administering time-limitedcombination regimens of venetoclax plus obinutuzumab or venetoclax plus obinutuzumab and ibrutinib was superior to chemoimmunotherapy in achieving undetectable measurable residual disease (MRD) in the peripheral blood at month 15 in fit patients with chronic lymphocytic...