Time-limited venetoclax-obinutuzumab with or without ibrutinib superior to chemo-immunotherapy in frontline CLL

In fit patients with advanced chronic lymphocytic leukaemia (CLL) of favourable genetic risk, chemo-immunotherapy (CIT) with FCR or BR is still standard treatment. In less fit patients, fixed-duration venetoclax plus obinutuzumab (GV) is superior to chlorambucil plus obinutuzumab with respect to progression-free survival. In addition, triple combinations adding BTK inhibitors have shown promising results within phase II trials. Data comparing GV to GV plus ibrutinib (GIV) in fit, previously untreated patients with CLL are not yet available. The GAIA/CLL13 trial evaluated the efficacy and safety of three time-limited venetoclax-based first-line regimens in comparison to CIT in fit patients with CLL. At EHA 2022, a pre-planned interim analysis of progression-free survival (PFS) was presented.

Study design

Treatment-naïve fit (CIRS ≤6, creatinine clearance ≥70 ml/min) CLL patients without presence of TP53 aberrations who required therapy were eligible. Patients were randomised in a 1:1:1:1 ratio to receive six courses of CIT (FCR for patients ≤65 years; BR for patients >65 years) or one of three venetoclax (V) combinations (standard ramp-up from cycle 1 day 22, 400 mg/day cycle 2-12): V and rituximab (375/500 mg/m² d1 cycle 1-6) [RV], V and obinutuzumab (1000 mg d1, 8, 15 cycle 1 and d1 cycle 2-6) [GV], or V plus obinutuzumab and ibrutinib (420 mg/d cycle 1-12, if MRD-detectable continued until cycle 36) [GIV]. Co-primary endpoints were the rate of undetectable MRD (uMRD, <10^-4) by flow cytometry in peripheral blood (PB) at month 15 (GV vs. CIT) and PFS (GIV vs. CIT), each with a significance level of 2.5%. Key secondary endpoints were PFS and uMRD comparisons between other treatment arms using a pre-specified hierarchical test sequence, overall survival (OS) and safety.

Results

In total, 926 patients were enrolled in the trial; 229 in CIT (FCR, N= 150 and BR, N= 79), 237 in RV, 229 in GV and 231 in GIV. The median age was relatively young at 61 years and 56% of patients were IGHV un-mutated. The MRD analysis as one of two co-primary endpoints of the GAIA/CLL13 trial previously showed high rates of uMRD in PB for patients treated with GV (86.5%) or GIV (92.2%) in comparison to CIT (52.0%; p<0.0001 for both comparisons).

With a median follow-up of 38.8 months, results of the coprimary endpoint of PFS are now also available. GIV showed superior PFS compared to CIT (HR[97.5%CI]: 0.32[0.19-0.54], p< 0.000001). While superior PFS was also observed for GV vs. CIT (HR[97.5%CI]: 0.42[0.26-0.68], p< 0.0001), PFS was not significantly different between RV and CIT (HR[97.5%CI]: 0.79[0.53-1.18], p= 0.183). The median PFS was 52.0 months for CIT, 52.3 months for RV and not reached for GV and GIV. Three-year PFS rates were respectively, 75.5%, 80.8%, 87.7% and 90.5%. Particularly the patients with un-mutated IGHV benefitted from targeted therapy, with 3-year PFS rates of 86.6% (GIV), 82.9% (GV), 76.4% (RV) and 65.5% (CIT). In contrast, for patients with mutated IGHV, the 3-year PFS rates were not very different among the various treatment arms (96.0%, 93.6%, 87.0% and 89.9%, respectively). Patients without new treatment at three years were 98.3% for GIV, 94.1% for GV, 92.9% for RV and 87.2% for CIT. Thus far, no difference in overall survival among the four treatment arms could be observed.

No  major differences in side effects between all four arms were observed. Infections and febrile neutropenia of grade ≥3 occurred more frequently in the CIT and GIV arms. Hypertension occurred in 5.6% of the patients receiving GIV. Second primary malignancies occurred more frequently with CIT (49 patients) than with the arms GV, GIV and RV (27, 29, 24 patients).

Conclusion

The phase III GAIA/CLL13 study, evaluating time-limited therapy in fit, previously untreated patients with CLL meets both coprimary endpoints for GV and GIV respectively versus CIT. A superior PFS for both GV-based regimens versus CIT was observed. Furthermore, RV is not superior to CIT in terms of PFS.

Reference

Eichhorst B, et al. Time-limited venetoclax-obinutuzumab +/- ibrutinib is superior to chemoimmunotherapy in frontline chronic lymphocytic leukemia (CLL): PFS co-primary endpoint of the randomized phase 3 GAIA/CLL13 trial. Presented at EHA 2022; Abstract LB2365.