Fixed-Duration Venetoclax-Based Combos Maintain Benefit in Frontline CLL

Moritz Fürstenau, MD

Additional follow-up from the phase 3 GAIA/CLL13 trial (NCT02950051) demonstrated that fixed-duration treatment with venetoclax (Venclexta) plus obinutuzumab (Gazyva) with or without ibrutinib (Imbruvica) continued to improve progression-free survival (PFS) vs chemoimmunotherapy in previously untreated, fit patients with chronic lymphocytic leukemia (CLL), and further analyses could help better identify patients most likely to benefit from the addition of ibrutinib to this regimen, according to Moritz Fürstenau, MD.

“We need to better define the patient population that really benefits from the triplet combination. We already saw that the patients with genetically higher-risk CLL benefit more from this triplet combination,” Fürstenau said.

Finding from a 4-year follow-up analysis published in Lancet Oncology showed that at median follow-up of 50.7 months (interquartile range, 44.6-57.9), PFS improvements were observed vs the chemoimmunotherapy regimen (n = 229) for both venetoclax plus obinutuzumab (n = 229; HR, 0.47; 97.5% CI, 0.32-0.69; P < .0001) and venetoclax plus obinutuzumab and ibrutinib (n = 231; HR, 0.30; 97.5% CI, 0.19-0.47; P < .0001).

In the overall population, 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%) for patients treated with venetoclax plus rituximab (Rituxan; n = 237) and 62.0% (97.5% CI, 54.4%-69.7%) for those given chemoimmunotherapy.

Notably, in patients with unmutated IGHV, venetoclax plus obinutuzumab (n = 130; HR, 0.45; 95% CI, 0.31-0.66; P < .001) and venetoclax plus obinutuzumab and ibrutinib (n = 123; HR, 0.27; 95% CI, 0.17-0.42; P < .0001) both demonstrated improved PFS vs chemoimmunotherapy (n = 131).

In an interview with OncLive®, Fürstenau, a physician in the Division of Haematology, Immunology, Infectiology, Intensive Care, and Oncology at the University of Cologne in Germany, expanded on updated findings from GAIA and detailed ongoing research using fixed-duration venetoclax-based combinations in patients with treatment-naive CLL.

OncLive: What was the rationale for examining these venetoclax-based combinations in the GAIA trial?

Fürstenau: We examined 3 different time-limited venetoclax combinations in the GAIA trial. For 1 of the combinations—venetoclax plus obinutuzumab, which is also already approved in the first-line setting [for patients with CLL]—we knew from [data from] phase 2 and 3 trials that it was very efficacious in certain patient populations, especially older patients. Therefore, we wanted to know whether venetoclax plus obinutuzumab would also be more efficacious than, for example, FCR [fludarabine, cyclophosphamide, and rituximab] in the first-line setting in a fitter patient population, and that’s that we looked at in the GAIA trial.

Regarding the other combinations, we added venetoclax plus rituximab because we wanted to have a very clean comparison of the 2 CD20 antibodies that are being used in CLL and see whether we need to give obinutuzumab to all patients or if rituximab comes with the same efficacy. That's why we added the venetoclax plus rituximab arm.

The third combination, which is the triplet of venetoclax, obinutuzumab, and ibrutinib, was a logical next step to try to increase efficacy even more by adding another agent to see how the toxicity profile looks.

What were the key efficacy findings of the trial?

In the primary end point analysis that was published more than a year ago for the GAIA trial, we examined undetectable minimal residual disease rates and PFS differences between arms. These were the 2 primary end points. In the primary analysis, we were only allowed per protocol to compare venetoclax plus obinutuzumab and venetoclax plus obinutuzumab and ibrutinib with the chemoimmunotherapy arm, and both [combinations] were more efficacious in terms of PFS compared with chemoimmunotherapy. However, we didn't have any information or any statistical tests to look at the differences between the venetoclax-containing arms.

With the follow-up analysis, we analyzed differences between the venetoclax-containing arms, and we found that venetoclax plus obinutuzumab and venetoclax plus obinutuzumab and ibrutinib were both more efficacious or superior in terms of PFS compared with the chemoimmunotherapy arm and the venetoclax plus rituximab arm.

A special focus was also put on the comparison between the approved doublet of venetoclax plus obinutuzumab and the experimental triplet of venetoclax plus obinutuzumab and ibrutinib. In general, we didn't see a significant PFS difference [between these 2 arms], but the curves separated quite clearly [in favor of the triplet]. When we looked at the largest subgroup of patients—patients with unmutated IGHV, meaning higher-risk patients with more dynamic disease—they benefited from the addition of ibrutinib. We saw a significant PFS benefit with the triplet compared with venetoclax plus obinutuzumab.

What is the significance of the overall survival (OS) and time to next treatment (TTNT) data from this study?

When we look at the OS data at the moment, there is no significant difference between the arms. We do see that in the chemoimmunotherapy arm, the outcomes are a bit worse at the end of the curve, so we might see a difference in OS between the venetoclax-containing arms and the chemoimmunotherapy arm at the next update. However, we don’t currently see any of OS differences.

Regarding TTNT [data]—a more meaningful outcome parameter than PFS for patients with CLL, because it means that they will have to start a new treatment at that time point—we saw the same trends we saw with PFS. Venetoclax plus obinutuzumab and ibrutinib had the best [TTNT] outcomes, with only a handful of patients [4.0%] requiring a next line of treatment in this group [after 4 years].

What should be known about the toxicities with the doublet and triplet therapies that were examined?

With venetoclax plus obinutuzumab, we already have quite a lot of experience and a lot of safety data. What we observed in the GAIA trial was what we had expected. [We observed] hematological toxicities, neutropenia, low platelet counts, and infectious adverse effects [AEs], such as upper respiratory tract infections or pneumonia, but [these AEs] did not go above a degree of what we would expect with this combination.

The spectrum of AEs was a little bit different when we added ibrutinib. With the triplet, we did see more ibrutinib-associated AEs. We had significantly more cardiac AEs in this group. We saw more infectious AEs, and we also [observed] more atypical infections, such as fungal infections and invasive fungal infections, and we did see more bruising. This is what you would expect when adding a BTK inhibitor [to a treatment regimen].

Most of the toxicities are very well known, and most physicians would know how to manage them. It needs to be said that this patient population we [observed] does not necessarily represent a typical CLL population in the real-world setting. [In the GAIA trial], we had younger and rather fit patients with a low burden of comorbidities. That's why the safety outcomes were what we expected.

If you looked at the same combinations, especially the triplet combination, in patients who were older or more frail, you would need to pay more attention to comedication and comorbidities. When you add venetoclax, a BTK inhibitor, and a CD20 antibody to an already existing multi-drug regimen that a patient may take for their comorbidities, you need to be careful. However, in this fit patient population, there were hardly any surprises regarding toxicities, so most physicians would easily know what to do in these cases.

What are some next steps for research with these combination therapies?

What we are looking at the moment and what we think is an important outcome measure for patients is quality-of-life [QOL] data in the GAIA trial. We're currently preparing to submit an abstract to the 2024 ASH Annual Meeting to present some of the QOL data. I can already mention that there were some differences in patient-reported QOL outcomes between the venetoclax plus obinutuzumab arm and the venetoclax plus obinutuzumab and ibrutinib arm that will hopefully be able to show at this year's ASH Annual Meeting. [QOL data] need to be included when discussing which [regimen] is better. It's not only about PFS and OS. The patient-reported outcomes are very important in this discussion.

Furthermore, we're currently doing another trial, the [phase 3] CLL16 study [NCT05197192], in which we are comparing the combination of acalabrutinib [Calquence] venetoclax, and obinutuzumab against venetoclax plus obinutuzumab in patients with [previously untreated] high-risk CLL.

The ultimate question with all time-limited, venetoclax-based combinations is: can we retreat patients with the same regimen, say 5 or 6 years after they had stopped first-line treatment and had a good treatment-free remission? That's something we're looking at in the [phase 2] ReVenG trial [(NCT04895436), which is a study of venetoclax plus obinutuzumab retreatment in patients with CLL who previously received fixed-duration therapy with a venetoclax-based regimen].

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;25(6):744-759. doi:10.1016/S1470-2045(24)00196-7