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Thursday, June 11, 2020

Fixed-Duration Venetoclax-Obinutuzumab for Untreated Patients With CLL

By Sarah LaCorte

Treatment with fixed-duration venetoclax and obinutuzumab resulted in superior effectiveness and deeper remission than chlorambucil and obinutuzumab for patients with previously untreated chronic lymphocytic leukemia (CLL), according to a study presented during the 2020 ASCO Annual Meeting (Abstract 8027).

The study was a follow-up of results from the multicenter, open-label, randomized, phase III CLL14 trial (NCT02242942) in which investigators compare the efficacy and safety of a combined regimen of obinutuzumab and venetoclax versus obinutuzumab + chlorambucil in participants with CLL and coexisting medical conditions. The CLL14 trial demonstrated significant improvement of progression-free survival (PFS) with fixed-duration venetoclax-obinutuzumab (VenG) as compared to chlorambucil-obinutuzumab (ClbG).

In the follow-up study, the primary endpoint was investigator-assessed PFS. Secondary outcomes included response rates, rates of minimal residual disease (measured every 6 months and up to 5 years after last patient enrollment), and overall survival (OS). The authors noted that although follow-up is ongoing, all patients are off study treatment.

The study enrolled 432 patients, then 216 were randomly assigned to receive VenG and 216 to receive ClbG. Patients with previously untreated CLL 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.

After a median follow-up of 39.6 months, PFS continued to be superior for VenG compared to ClbG (median not reached vs. 35.6 months; hazard ratio [HR] 0.31 [0.22-0.44], p < 0.001). At 3 years, the estimated PFS rate was 81.9 percent in the VenG arm and 49.5 percent 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.

The researchers assessed minimal residual disease 18 months after end of treatment, which showed that 47.2 percent of patients in the VenG arm had undetectable (u) uMRD ( < 10−4), 13 percent had low (L)-MRD (≥ 10−4 and < 10−2) and 7.9 percent high (H)-MRD (≥ 10−2), compared to 7.4 percent uMRD, 17.1 percent L-MRD, and 26.9 percent H-MRD in the ClbG arm. OS rates were not significantly different for either group (HR 1.027, 95% CI 0.602-1.753, p = 0.921), and median OS was not reached in either group.

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.

The authors concluded by stating "The results suggest that the superior efficacy and deep remissions after fixed-duration VenG are maintained during extended follow-up, and show the long-term benefits of 12 cycles of VenG across all known risk categories."

Sarah LaCorte is a contributing writer.