Fixed-duration venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: Follow-up of efficacy and safety results from the multicenter, open-label, randomized phase 3 CLL14 trial.

Abstract

Background: The CLL14 trial demonstrated significant improvement of progression-free survival (PFS) with fixed-duration venetoclax-obinutuzumab (VenG) as compared to chlorambucil-obinutuzumab (ClbG) in patients with previously untreated CLL and coexisting conditions. Aim(s): The aim of this report is to provide efficacy and safety data from follow-up of the CLL14 trial with now all patients being off treatment for at least 2 years. Method(s): Patients with previously untreated chronic lymphocytic leukaemia and coexisting conditions were randomized 1:1 to receive 12 cycles of venetoclax with 6 cycles of obinutuzumab or 12 cycles of chlorambucil with 6 cycles of obinutuzumab. Primary endpoint was investigator- assessed PFS. Key secondary endpoints were response rates, rates of minimal residual disease (measured every 6 months up to 5 years after last patient enrolment) and overall survival. Follow-up is ongoing but all patients are off study treatment. This trial was registered with ClinicalTrials.gov, number NCT02242942. Result(s): Of the 432 enrolled patients, 216 were randomly assigned to receive VenG and 216 to receive ClbG. After a median follow-up of 39.6 months (interquartile range 36.8 - 43.0), progression-free survival continued to be superior for VenG as compared to ClbG (median not reached vs 35.6 months; hazard ratio [HR] 0.31 [0.22-0.44], p<0.001)(Figure A). At 3 years, the estimated PFS rate was 81.9% in the VenG arm and 49.5% in the ClbG arm. This benefit was consistently observed across all clinical and biological risk groups, including patients with TP53 mutation/deletion and unmutated IGHV status. Of note, PFS was also significantly longer for VenG treated patients with mutated IGHV status compared to ClbG (HR 0.33 [0.16-0.70] p = 0.004). Overall, 21 disease progressions after VenG treatment have been observed. Assessment of minimal residual disease in peripheral blood 18 months after the end of treatment showed that 47.2% of patients in the VenG arm still had undetectable (u) uMRD (< 10-4), 13.0% had low (L)-MRD (>= 10-4 and < 10-2) and 7.9% high (H)-MRD (>= 10-2), compared to 7.4% uMRD, 17.1% L-MRD, 26.9% H-MRD in the ClbG arm. Median time to MRD conversion (i.e. increase to >=10-4) was not reached in the VenG arm and was 6 months in the ClbG arm. In landmark analysis, twenty patients in the VenG arm, who either had L-MRD or H-MRD, had a median PFS of 17.7 months after last treatment exposure, whereas the median was not reached in patients with uMRD (Figure B). Further landmark analysis showed similar PFS for patients with uMRD and partial remission (PR) or complete remission (CR); patients with uMRD/PR had a longer PFS than patients with detectable MRD and CR. MRD assessment by next generation sequencing (NGS) indicated levels below 10-6 in 90 patients (41.7%) treated with VenG, in contrast to 14 (6.5%) in the ClbG arm (Figure D). For VenG, median time to MRD conversion (i.e. >=10-6) in patients with uMRD by NGS (<10-6) was 12.0 months and only one case of disease progression was reported. No difference has been observed for overall survival; at 36 months 88.9% pts were alive in the VenG arm and 88.0% in the ClbG arm (HR 1.03, 95% CI 0.60-1.75, p = 0.921). Second primary malignancies were reported in 36 (17%) patients in the VenG arm and 22 (10.3%) in the ClbG arm. No new safety signals were observed. Summary/Conclusion: The results confirm the superior efficacy with longer progression-free survival and deep remissions after fixed-duration VenG compared to ClbG. This suggests that longterm benefits are maintained for over two years after completing 12 cycles of VenG. (Figure Presented) .