In 4-Year Follow-Up, Venetoclax Combinations Outperform Chemo in CLL

Blood smear of chronic lymphocytic leukemia (CLL), analyzed by microscope: © jarun011 - stock.adobe.com

A 4-year follow-up of the phase 3 GAIA/CLL13 study (NCT02950051) sought to directly compare venetoclax (Venclexta)-based combinations for the treatment of patients with chronic lymphocytic leukemia (CLL). These included venetoclax with obinutuzumab (Gazvya), venetoclax/obinutuzumab/ibrutinib (Imbruvica), and venetoclax/rituximab (Rituxan). 

The study found that patients receiving venetoclax/obinutuzumab (85.5%; 97.5% CI, 79.9%-91.1%) or venetoclax/obinutuzumab/ibrutinib (81.8%; 75.8%-87.8%) had significantly longer progression-free survival (PFS) vs patients receiving venetoclax/rituximab (70.1%; 63.0%-77.3%) or chemoimmunotherapy (62.0%; 54.4%-69.7%). While there was no significant PFS difference between venetoclax and obinutuzumab with or without ibrutinib, there were more adverse events associated with the triplet regimen. 

This study suggests that venetoclax combined with obinutuzumab demonstrated a significant advantage in terms of PFS in previously untreated patients with CLL compared with standard chemoimmunotherapy or venetoclax with rituximab. However, the potential benefits of adding ibrutinib need to be weighed against the increased toxicity.

In an interview with Targeted Oncology^TM, Moritz Fürstenau, MD, University of Cologne, discussed the findings and implications of this follow-up study.

Targeted Oncology: What is the current standard-of-care in CLL?

Fürstenau: The population we looked at were rather young and fit patients with CLL, so fit for chemoimmunotherapy. At the time when we did the study, 1 of the standards of care was still chemoimmunotherapy with with [fludarabine, cyclophosphamide, and rituximab (FCR)] and in Germany, it was [bendamustine and rituximab (BR)] for older patients.

Now, the whole paradigm has shifted a bit more towards continuous therapies with [Bruton tyrosine kinase (BTK)] inhibitors, which is the standard first-line treatment, or venetoclax, or obinutuzumab as a time-limited option for a year. Now, in Europe, we also have venetoclax/ibrutinib available, which is approved by the by the [European Medicines Agency (EMA)] for the first-line treatment of patients with CLL.

What was the original GAIA/CLL13 study evaluating?

The GAIA/CLL13 trial is a phase 3, multicenter trial with approximately 1000 patients included. It was done across Europe and in Israel. We tested different venetoclax-based, time-limited combinations against chemoimmunotherapy in the first-line treatment of patients with CLL. The main primary endpoint analysis was already published about a year ago. What we found in the primary endpoint analysis was that venetoclax/obinitizumab and venetoclax/obinutuzumab/ibrutinib, a triplet treatment that is not approved at the moment, were both superior in terms of progression-free survival compared with chemoimmunotherapy. Now, with a little bit more follow-up, we were able to also compare the venetoclax arms against each other.

Can you summarize the findings of this follow-up?

We had a 4-year follow-up of all the primary efficacy outcomes of the GAIA trial. What we found now was that not only were the venetoclax/obinutuzumab groups, either with or without ibrutinib, associated with longer progression-free survival, compared with the chemoimmunotherapy arm, but they were also superior, in terms of PFS, compared with the third venetoclax arm, which was venetoclax/rituximab.

What we were also looking at was, how does the triplet combination compare with the doublet of venetoclax/obinutuzumab? Does the addition of ibrutinib add something to this combination? In terms of PFS for the whole study population, we did not see a significant difference. However, the curve separated quite clearly. We broke it down a little bit more and looked at the large subgroup of patients, so 60% of all patients in this study who had a nonmutated IGHV [immunoglobulin heavy chain variable], so patients with higher-risk CLL, and in this subgroup, the triplet combination was associated with a significantly longer progression-free survival compared with venetoclax/obinutuzumab. However, what we also found out was that the triplet combination was also associated with more toxicities, infectious adverse events, and cardiac adverse events, which is what we had anticipated by adding ibrutinib.

Could you discuss the safety profiles and adverse events associated with the triplet vs the doublet?

What we saw were mostly hematological toxicities, like neutropenia, thrombocytopenia and so on, and some infectious adverse events that are expected when you add a CD20 antibody. What came as an additional effect of adding ibrutinib, at least when we compare it in this randomized fashion, was a surplus of cardiac adverse events, not all very high grades, but we did see more atrial fibrillation, we did see more bruising, and we did see more hypertension. We also saw more infectious adverse events, and also some atypical infections, like fungal infections. 

Based on these findings, what do you think the implications are? How do you see these findings affecting treatment recommendations going forward?

I think the first conclusion we could draw from this study is that the doublet is safe and efficacious in this patient population and easily beats FCR and BR. For it, it proved that it is a good standard-of-care in this patient population. With regards to the triplet, I would be cautious to recommend it to anyone at this time, because the PFS benefit we see is only in a subgroup, and it is not a big difference compared to venetoclax/obinutuzumab. It is, at the moment, a rather small difference, and it comes with additional toxicities. Adding to that, we did not see any differences in the overall survival, which should be the parameter we look at when it comes to what we recommend in the long run. For the time being, I would say venetoclax/obinutuzumab is a good standard-of-care for this patient population.

REFERENCE:

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 Jul;25(7):e284. doi: 10.1016/S1470-2045(24)00329-2]. Lancet Oncol. 2024;25(6):744-759. doi:10.1016/S1470-2045(24)00196-7