Venetoclax Combos Improve Survival, MRD Outcomes Vs Chemo in Advanced CLL

“Although the data in the [triplet] group in the current trial confirm phase 2 trial results with respect to the efficacy of triple-combination regimens, whether the triple combination is even more beneficial than other regimens such as continuous [Bruton tyrosine kinase] inhibitor therapy or double combinations that include BCL2 inhibitors cannot be answered by our trial,” according to the study authors.

Frontline venetoclax (Venclexta), when combined with obinutuzumab (Gazyva) alone or with ibrutinib (Imbruvica), yielded longer survival and better minimal residual disease (MRD) outcomes than chemoimmunotherapy among fit patients with advanced chronic lymphocytic leukemia (CLL), according to findings from the phase 3 GAIA-CLL13 trial (NCT02950051) published recently in The New England Journal of Medicine.

The proportion of patients with undetectable minimal residual disease (MRD) at 15 months was 86.5% (97.5% CI, 80.6%-91.1%) in the venetoclax plus obinutuzumab group and 92.2% (97.5% CI, 87.3%-95.7%) in the venetoclax plus obinutuzumab and ibrutinib group compared with 52.0% in the chemoimmunotherapy group (97.5% CI, 44.4%-59.5%; P <.001 for both). The corresponding figure was 57.0% in the venetoclax plus rituximab (Rituxan) group (97.5% CI, 49.5%-64.2%), translating to no significant improvement over chemoimmunotherapy (P = 0.32).

The progression-free survival (PFS) rate at 3 years was 90.5% in the triplet group vs 75.5% in the chemoimmunotherapy group (hazard ratio [HR], 0.32; 97.5% CI, 0.19-0.54; P <.001). Venetoclax plus obinutuzumab similarly yielded a significantly higher 3-year PFS rate (87.7%) than the control regimen (HR, 0.42; 97.5% CI, 0.26-0.68; P <.001), whereas venetoclax plus rituximab did not (80.8%; HR, 0.79; 97.5% CI, 0.53-1.18; P = 0.18).

Complete responses occurred in 31.0% of patients in the chemoimmunotherapy group, 49.4% of those in the venetoclax plus rituximab group, 56.8% of those in the venetoclax plus obinutuzumab group, and 61.9% of those in the triplet group.

“Although the data in the [triplet] group in the current trial confirm phase 2 trial results with respect to the efficacy of triple-combination regimens, whether the triple combination is even more beneficial than other regimens such as continuous [Bruton tyrosine kinase] inhibitor therapy or double combinations that include BCL2 inhibitors cannot be answered by our trial,” the investigators wrote. “Some of the benefits of the triplet therapy are neutralized by the need for dose reductions and early treatment discontinuation owing to adverse events [AEs].”

In total, 926 patients constituted the intention-to-treat population of this prospective, open-label trial conducted by the German CLL Study Group, the Hemato-Oncology Foundation for Adults in the Netherlands Study Group, and the Nordic CLL Study Group. Screening occurred between December 2016 and October 2019, and 159 sites participated in the trial.

Patients were randomly assigned 1:1:1:1 to the 4 treatment regimens. Those in the chemoimmunotherapy group (n = 229) received 6 cycles of treatment lasting 28 days each. Patients 65 years old or younger received intravenous fludarabine at a dose of 25 mg/m² and cyclophosphamide at a dose of 250 mg/m2 on days 1 to 3 of each cycle. Patients older than 65 years received intravenous bendamustine (Bendeka) at a dose of 90 mg/m² on the first and second day of each cycle. Rituximab was added intravenously to chemotherapy at a dose of 375 mg/m² on the first day of the first cycle and 500 mg/m² on the first day of the next 5 cycles.

All 3 experimental regimens included oral venetoclax at a dose of 400 mg daily for 10 cycles of 28 days each. This dosage followed a 5-week ramp-up phase lasting from day 22 of cycle 1 to the end of cycle 2.

In the venetoclax plus rituximab group (n = 237), intravenous rituximab was administered at a dose of 375 mg/m2 on the first day of cycle 1, and then at a dose of 500 mg/m2 on the first day of the next 5 cycles.

In both the venetoclax/obinutuzumab (n = 229) and triplet (n = 231) groups, intravenous obinutuzumab was administered at a dose of 100 mg on day 1, 900 mg on day 2, and then 1000 mg on days 8 and 15 of the first cycle. It was then administered at a dose of 1000 mg on the first day of the following 5 cycles.

As part of the triplet regimen, oral ibrutinib was administered at a dose of 420 mg daily together with the first obinutuzumab infusion on the first day of cycle 1 and was thereafter continued during the 12 treatment cycles. Patients discontinued ibrutinib if MRD became undetectable in peripheral blood in 2 consecutive local measurements or in peripheral blood and consecutive bone marrow aspirations. Otherwise, treatment continued until cycle 36, except in the case of unacceptable toxicity.

The primary end points were the proportion of patients with undetectable MRD at 15 months and PFS. Secondary end points included the proportion with undetectable MRD at 2, 9, and 12 months, overall and complete response rates, and safety.

Patient characteristics were similar across all 4 subgroups. Median ages ranged from 60 to 62 years, and more than 70% of each group had an ECOG performance status of 0. Male patients made up anywhere from 68.4% to 74.7% of the 4 groups. Most patients in all groups had an unmutated immunoglobulin heavy-chain variable region (IGHV), and the proportion of patients without any cytogenetic abnormalities ranged from 19.0% to 25.5%.

The most common reason for early treatment discontinuation was AEs in 9.8% of the total population. Early discontinuation resulting from AEs occurred in 15.3% of patients in the chemoimmunotherapy group, 5.9% of patients in the venetoclax/rituximab group, 5.7% of those in the venetoclax/obinutuzumab group, and 12.6% of those in the triplet group.

The most frequent grade 3/4 AEs in the overall population were cytopenia and infections. Serious AEs affected 47.7%, 40.1%, 44.7%, and 50.2% of patients in the chemoimmunotherapy, venetoclax plus rituximab, venetoclax plus obinutuzumab, and triplet groups, respectively.

“In this trial involving patients with CLL and a low burden of coexisting conditions, time-limited combinations of targeted agents such as [venetoclax plus obinutuzumab] and [venetoclax plus obinutuzumab and ibrutinib] led to longer and deeper responses than the current first-line chemoimmunotherapy standard,” the investigators concluded.

Reference

Eichhorst B, Niemann CU, Kater AP, et al. First-line venetoclax combinations in chronic lymphocytic leukemia. N Engl J Med. 2023;388(19):1739-1754. doi:10.