VENETOCLAX‐OBINUTUZUMAB FOR PREVIOUSLY UNTREATED CHRONIC LYMPHOCYTIC LEUKEMIA: 4‐YEAR FOLLOW‐UP ANALYSIS OF THE RANDOMIZED CLL14 STUDY

Abstract

Introduction: The CLL14 study showed significant improvement of progression-free survival (PFS) and rates of undetectable minimal residual disease (uMRD) with venetoclax-obinutuzumab (Ven-Obi) as compared to chlorambucil-obinutuzumab (Clb-Obi) in patients (pts) with previously untreated chronic lymphocytic leukemia (CLL) and coexisting conditions. The aim of this report is to provide updated efficacy and safety data from the ongoing follow-up of the CLL14 study with now all pts being off study treatment for at least 3 years. Methods: Pts with previously untreated CLL and coexisting conditions were randomized 1:1 to receive 12 cycles of Ven with 6 cycles of Obi or 12 cycles of Clb with 6 cycles of Obi. Primary endpoint was investigator-assessed PFS. Key secondary endpoints were safety, response rates, rates of minimal residual disease (MRD) and overall survival. Results: Of the 432 enrolled pts, 216 were randomly assigned to receive Ven-Obi and 216 to receive Clb-Obi. After a median follow-up of 52.4 months (interquartile range 49.5-56.2), PFS continued to be superior for Ven-Obi as compared to Clb-Obi (median not reached (nr) vs. 36.4 months; HR 0.33 [95% CI 0.25-0.45], p < 0.0001)(Fig A). At 4 years after randomization, the estimated PFS rate was 74.0% in the Ven-Obi arm and 35.4% in the Clb-Obi arm. This improvement was observed across all clinical and biological risk groups, including pts with TP53 mutation/deletion (4-year PFS 53.0% vs 20.8%) and unmutated IGHV status (4-year PFS 68.0% vs 19.8%)(Fig B,C). Overall, 35 disease progressions in the Ven-Obi arm have been observed, compared to 122 in the Clb-Obi arm. Time to next treatment was significantly longer in the Ven-Obi arm (4-year TTNT 81.1% vs 59.9%; HR 0.46, 95% CI [0.32-0.65], p < 0.0001)(Fig D). The majority of pts received and responded to BTK inhibitor monotherapy as a second-line treatment after progressive disease in both arms (57.1% in Ven-Obi arm, 55.6% in Clb-Obi arm). Assessment of MRD by NGS in peripheral blood 30 months after the end of treatment showed that 26.9% of pts in the Ven-Obi arm had uMRD (<10‒4), 21.8% had low (L)-MRD (≥10‒4 and <10‒2) and 13.4% high (H)-MRD (≥10‒2), compared to 3.2% uMRD, 8.8%% L-MRD, 28.2% H-MRD in the Clb-Obi arm. No difference in overall survival has been observed between the Ven-Obi and Clb-Obi arm; at 4 years 85.4% pts were alive in the Ven-Obi arm and 83.1% in the Clb-Obi arm (HR 0.85 [0.54-1.35], p = 0.49)(Fig E). Second primary malignancies were reported in 40 (18.9%) pts in the Ven-Obi arm and 30 (14.0%) in the Clb-Obi arm. No new safety signals were observed. Conclusion: The 4-year follow-up confirms the superior efficacy with longer PFS and deep remissions after fixed-duration Ven-Obi compared to Clb-Obi. The majority of pts remains without relapse three years after completing Ven-Obi therapy. Fixed-duration Ven-Obi continues to be an effective treatment for all pts with CLL and coexisting conditions. EA – previously submitted to EHA 2021. The research was funded by: Hoffmann-La Roche Ltd.; AbbVie Inc. Keywords: Combination Therapies, Chronic Lymphocytic Leukemia (CLL) Conflicts of interests pertinent to the abstract O. Al-Sawaf Honoraria: Roche, AbbVie, Janssen, Gilead, AstraZeneca Research funding: Roche, AbbVie, Janssen, Beigene Educational grants: Roche, AbbVie, Janssen, Gilead, AstraZeneca M. Tandon Employment or leadership position: Roche Products Ltd Stock ownership: Roche Products Ltd. A. Panchal Employment or leadership position: Roche Products Ltd. A.-M. Fink Honoraria: Celgene, Janssen, Hoffmann-LaRoche E. Tausch Honoraria: Roche, AbbVie M. Ritgen Honoraria: Hoffmann-LaRoche, AbbVie Research funding: Hoffman-LaRoche K.-A. Kreuzer Honoraria: Hoffmann-LaRoche, AbbVie Research funding: Roche, AbbVie S. Kim Employment or leadership position: AbbVie C. Wendtner Honoraria: Hoffmann-LaRoche, AbbVie, Janssen-Cilag, Gilead, MorphoSys B. Eichhorst Honoraria: Hoffmann-LaRoche, AbbVie, Celgene, Bovartis, ArQule, BeiGene, Gilead, AstraZeneca, Oxford Biomedica (UK), Adaptive Biotechnologies Research funding: Hoffmann-LaRoche, AbbVie, Janssen S. Stilgenbauer Honoraria: AbbVie, AstraZeneca, Celgene, Gilead, GSK, Hoffmann La-Roche, Janssen, Novartis, Pharmacyclics, Sunesis, Verastem Research funding: AbbVie, AstraZeneca, Celgene, Gilead, GSK, Hoffmann La-Roche, Janssen, Novartis, Pharmacyclics, Sunesis, Verastem Y. Jiang Employment or leadership position: Genentec Inc. M. Hallek Honoraria: Roche, Gilead, Mundipharma, Janssen, Celgene, Pharmacyclics, AbbVie, Boehringer Ingelheim Research funding: Roche, Gilead, Mundipharma, Janssen, Celgene, Pharmacyclics, AbbVie K. Fischer Honoraria: AbbVie, Hoffmann-LaRoche