Dr Fürstenau on the Efficacy of Frontline Venetoclax-Based Combinations in CLL

Moritz Fürstenau MD, Division of Haematology, Immunology, Infectiology, Intensive Care, and Oncology, University of Cologne, discusses 4-year follow-up findings from the phase 3 GAIA/CLL13 trial (NCT02950051) investigating venetoclax (Venclexta) plus obinutuzumab (Gazyva) with or without ibrutinib (Imbruvica) vs chemoimmunotherapy in previously untreated, fit patients with chronic lymphocytic leukemia (CLL).

The GAIA trial’s primary end point analysis, which was published in 2023, evaluated differences in undetectable minimal residual disease rates and progression-free survival (PFS) between the venetoclax-based doublet and triplet and chemoimmunotherapy. The trial protocol initially allowed comparisons between the venetoclax arms and chemoimmunotherapy arm. Both venetoclax-based combinations generated superior PFS outcomes compared with chemoimmunotherapy. However, direct comparisons between the venetoclax-containing arms were not permitted in the primary analysis.

The 4-year follow-up analysis compared these venetoclax-containing arms. At a median follow-up of 50.7 months (interquartile range, 44.6-57.9) the doublet yielded a significantly longer median PFS than chemoimmunotherapy (HR, 0.47; 97.5% CI, 0.32-0.69; P < .0001), as did the triplet (HR, 0.30; 97.5% CI, 0.19-0.47; P < .0001). This analysis also showed that the doublet had superior PFS outcomes compared with venetoclax plus rituximab (Rituxan; HR, 0.57 [97.5% CI, 0.38-0.84; P = .0011]), as did the triplet (HR, 0.38; 97.5% CI, 0.24-0.59; P < .0001). The estimated 4-year PFS rates in the triplet and doublet arms were 85.5% (97.5% CI, 79.9%-91.1%) and 81.8% (97.5% CI, 75.8%-87.8%), respectively. These rates were 70.1% (97.5% CI, 63.0%-77.3%) and 62.0% (97.5% CI, 54.4%-69.7%) in the venetoclax/rituximab and chemoimmunotherapy arms, respectively.

Although there was no significant PFS difference between the venetoclax/obinutuzumab and venetoclax/obinutuzumab/ibrutinib arms, the survival curves for these arms were distinctly separated, Fürstenau says. Furthermore, in the largest subgroup of patients with unmutated IGHV, the addition of ibrutinib to venetoclax and obinutuzumab provided a significant PFS benefit. This is a higher-risk group with more dynamic disease, Fürstenau noted.