Venetoclax-obinutuzumab ± ibrutinib induces PFS benefit in CLL

A time-limited regimen of venetoclax plus obinutuzumab with or without ibrutinib improved progression-free survival (PFS) in fit, treatment-naïve patients with chronic lymphocytic leukaemia (CLL), according to results of the phase III GAIA/CLL13 trial presented at EHA 2022.

Study participants were 926 fit*, treatment-naïve patients (median age 61 years, median CIRS score 2) with CLL without TP53 or del(17p) mutations. Fifty-six and 41 percent of patients had unmutated and mutated IGHV status, respectively. They were randomized 1:1:1:1 to receive venetoclax (standard ramp-up from day 22 of cycle 1, 400 mg/day for cycles 2–12) plus rituximab (375/500 mg/m² on day 1 for cycles 1–6; VR), venetoclax plus obinutuzumab (1,000 mg/m² on days 1, 8, and 15 for cycle 1 and day 1 for cycles 2–6), venetoclax plus obinutuzumab plus ibrutinib (420 mg/day for cycles 1–12 and continued until cycle 36 if minimal residual disease [MRD] detected; triple regimen), or six cycles of chemoimmunotherapy** (CIT; fludarabine-cyclophosphamide-rituximab [FRC] for patients aged ≤65 years, bendamustine-rituximab [BR] for patients aged >65 years).

After a median 38.8 months of follow up, PFS was significantly improved in patients who received the triple regimen compared with CIT (median not reached [NR] vs 52.0 months; hazard ratio [HR], 0.32, 97.5 percent confidence interval [CI], 0.19–0.54; p<0.000001). [EHA 2022, abstract LB2365]

PFS was also significantly improved in the venetoclax-obinutuzumab vs CIT group (median NR vs 52.0 months; HR, 0.42, 97.5 percent CI, 0.26–0.68; p<0.0001), but not with VR vs CIT (median 52.3 months vs 52.0 months; HR, 0.79, 97.5 percent CI, 0.53–1.18; p=0.183). 

At 3 years, PFS rates were 90.5, 87.7, 80.8, and 75.5 percent in the triple regimen, venetoclax-obinutuzumab, VR, and CIT groups, respectively.

The benefits were particularly evident in patients with unmutated IGHV status, with 3-year PFS rates of 86.6, 82.9, 76.4, and 65.5 percent in the triple regimen, venetoclax-obinutuzumab, VR, and CIT groups, respectively, while PFS rates were comparable between groups in those with mutated IGHV status (96.0, 93.6, 87.0, and 89.9 percent, respectively). Among patients aged ≤65 years with IGHV mutation, 3-year PFS rates were similar between those on venetoclax-obinutuzumab and CIT (95.3 percent vs 95.0 percent).

At 3 years, 98.3, 94.1, 92.9, and 87.2 percent of patients in the triple regimen, venetoclax-obinutuzumab, VR, and CIT groups, respectively, were not on subsequent treatment. The short observational time precluded estimation of overall survival outcomes with 3-year rates of 95.3, 96.3, 96.5, and 95.0 percent, respectively.

These findings follow previous results presented at ASH 2021 that showed that at month 15, the rate of undetectable MRD (<10^-4) by flow cytometry in peripheral blood was greater among patients who received venetoclax plus obinutuzumab (86.5 percent) or the triple regimen (92.2 percent) compared with CIT (52.0 percent; p<0.0001 for both). Again, there was no significant difference between VR (57.0 percent) and CIT pertaining to this outcome (p=0.317).

Grade ≥3 adverse events occurred at a comparable rate across the triple regimen, venetoclax-obinutuzumab, VR, and CIT arms (83.5, 84.2, 73.0, and 81.5 percent, respectively). Severe infections and infestations occurred more often with the triple regimen and CIT (22.1 and 20.4 percent, respectively) than with venetoclax-obinutuzumab or VR (14.9 and 11.4 percent, respectively). Similar findings were noted for febrile neutropenia incidence (7.8, 3.1, 4.2, and 11.1 percent in the triple regimen, venetoclax-obinutuzumab, VR, and CIT arms, respectively). Hypertension occurred more often with the triple regimen (5.6 percent) than venetoclax-obinutuzumab, VR, or CIT (1.8, 2.1, and 1.4 percent, respectively).

Second primary malignancies were more common with CIT (n=49), primarily due to solid tumours and non-melanoma skin cancer, than with the triple regimen, venetoclax-obinutuzumab, or VR (n=29, 27, and 24, respectively).

“In fit patients with advanced CLL of favourable genetic risk, CIT with FCR or BR is still standard treatment,” said study author Associate Professor Barbara Eichhorst from the University of Cologne, Cologne, Germany. This is especially so in countries where continuous treatment with approved BTK*** inhibitors may not be reimbursed.

This study showed superior PFS with both venetoclax-obinutuzumab regimens vs CIT, but not the VR regimen, she added.