FIXED‐DURATION VENETOCLAX PLUS OBINUTUZUMAB IMPROVES PFS AND MINIMAL RESIDUAL DISEASE NEGATIVITY IN PATIENTS WITH PREVIOUSLY UNTREATED CLL AND COMORBIDITIES

Introduction: The multinational, open-label, phase 3 CLL14 trial (NCT02242942) compared fixed-duration targeted venetoclax plus obinutuzumab (VenG) treatment with chlorambucil-obinutuzumab (ClbG) treatment in previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) and comorbidities. We present endpoint analyses with particular emphasis on progression-free survival (PFS) and minimal residual disease (MRD)-negativity. Methods: Pts with a CIRS score >6 and/or an estimated creatinine clearance <70 mL/min were randomized 1:1 to receive equal duration treatment with 12 cycles of standard Clb or Ven 400 mg daily in combination with G for the first 6 cycles. The primary endpoint was PFS. MRD-negativity in peripheral blood (PB) or bone marrow (BM) 3 months after treatment completion was a key secondary endpoint. MRD was analyzed serially from Cycle 4 every 3 months by an allele-specific oligonucleotide polymerase chain reaction assay (ASO-PCR; cut-off, 10-4) and by next generation sequencing (NGS; cut-offs, 10-4, 10-5, 10-6). Results: 432 pts were enrolled (216 in each treatment group; intent-to-treat population). Median age, total CIRS score, and CrCl at baseline were 72 years, 8, and 66.4 mL/min respectively. After 29 months’ median follow-up, superior PFS was observed with VenG vs ClbG (Figure 1a). Median PFS was not reached in either group: at Month 24, PFS rates were 88% with VenG and 64% with ClbG (hazard ratio [HR] 0.35; 95% confidence interval [CI] 0.23–0.53; P<0.0001). MRD-negativity by ASO-PCR was significantly higher with VenG vs ClbG in both PB (76% vs 35% [P<0.0001]) and BM (57% vs 17% [P<0.0001]) 3 months after treatment completion. Overall, 75% of VenG MRD-negative pts in PB were also MRD-negative in BM vs 49% in the ClbG group. Landmark analysis for this timepoint by PB MRD status showed that MRD-negativity was associated with longer PFS. MRD-negativity rates were more sustainable with VenG: 81% (VenG) vs 27% (ClbG) of pts were MRD-negative 12 months after treatment completion (Figure 1b). MRD-negativity rates by NGS confirmed these results; 78% (VenG) vs 34% (ClbG) of pts had MRD-negative status at <10-4, 35% vs 15% at ≥10-6–<10-5 and 31% vs 4% at <10-6, respectively. Conclusions: Fixed-duration VenG induced deep, high (<10-4 in 3/4 of pts and <10-6 in 1/3 of pts), and long lasting MRD-negativity rates (with a low rate of conversion to MRD-positive status 1 year after treatment) in previously untreated pts with CLL and comorbidities, translating into improved PFS. Funding: This study was funded by F. Hoffmann-La Roche Ltd and Abbvie Inc. Third-party editing and administrative support was provided by Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd. This abstract has been previously submitted in part to ASCO 2019 and EHA 2019. Keywords: chronic lymphocytic leukemia (CLL); obinutuzumab; venetoclax. Disclosures: Fischer, K: Other Remuneration: Expenses: Roche. Porro Lurà, M: Employment Leadership Position: Roche; Stock Ownership: Roche. Al-Sawaf, O: Other Remuneration: Other relationship: AbbVie, Roche, Gilead, Janssen. Bahlo, J: Honoraria: Roche; Other Remuneration: Expenses: Roche. Fink, A: Consultant Advisory Role: Janssen. Tandon, M: Employment Leadership Position: Roche. Dixon, M: Employment Leadership Position: Roche; Stock Ownership: Roche. Warburton, S: Employment Leadership Position: Roche. Humphrey, K: Employment Leadership Position: Roche; Stock Ownership: Roche. Liberati, A: Other Remuneration: Personal Fees: Abbvie. Pinilla-Ibarz, J: Consultant Advisory Role: Janssen, Gilead, Abbvie, Pharmacyclics, Millenium Pharmaceuticals/Takeda, TEVA, TG Therapeutics; Research Funding: TG Therapeutics; Other Remuneration: Speakers' Bureau: Janssen, Gilead, Abbvie, Pharmacyclics, Millenium Pharmaceuticals/Takeda, TEVA, Bayer. Opat, S: Consultant Advisory Role: Roche, AbbVie; Honoraria: Roche, AbbVie; Research Funding: Roche; Other Remuneration: Speakers' Bureau: Roche. Utoft Niemann, C: Consultant Advisory Role: Abbvie, Janssen, Gilead, AstraZeneca, Sunesis, Acerta, CSL Behring, Roche; Research Funding: Abbvie, Janssen; Other Remuneration: Expenses: Novartis, Gilead, Roche; Other relationship: Roche - Payment for trial enrollment/patient management of the trial, indirectly through GCLLSG. Weinkove, R: Consultant Advisory Role: Abbvie; Honoraria: Abbvie; Other Remuneration: Other relationship: Capital & Coast District Health Board - Institution received reimbursement of the costs of conducting trial-related clinical procedures. Robinson, S: Consultant Advisory Role: Roche, AbbVie. Kipps, T: Employment Leadership Position: UC, San Diego Health, Moores Cancer Center; Consultant Advisory Role: AbbVie, Genentech-Roche, Gilead, Pharmacyclics, Celgene; Honoraria: Gilead, AbbVie, Pharmacyclics, Janssen, Verastem; Research Funding: AbbVie, Genentech-Roche, Pharmacyclics, Oncternal; Other Remuneration: Membership on an entity's board of directors, speaker's bureau, or its advisory committees: AbbVie, Pharmacyclics, Janssen, Verastem. Boettcher, S: Honoraria: Roche, AbbVie, Janssen; Research Funding: Celgene, Roche, AbbVie, Janssen; Other Remuneration: Personal Fees: Janssen, Abbvie. Tausch, E: Consultant Advisory Role: Roche; Other Remuneration: Speakers' Bureau: Roche; Expert testimony: Abbvie; Expenses: Abbvie. Schary, W: Employment Leadership Position: AbbVie; Stock Ownership: AbbVie. Eichhorst, B: Consultant Advisory Role: Abbvie, Roche; Honoraria: Abbvie, Roche; Research Funding: Abbvie, Roche; Other Remuneration: Speakers' Bureau and expenses: Abbvie, Roche. Wendtner, C: Honoraria: F. Hoffmann La-Roche Ltd, Abbvie, Janssen-Cilag, Gilead, MorphoSys, Mundipharma, Novartis; Research Funding: F. Hoffmann La-Roche Ltd, Abbvie, Janssen-Cilag, Gilead, MorphoSys, Mundipharma, Novartis. Langerak, A: Consultant Advisory Role: AbbVie; Research Funding: Roche-Genentech, Gilead. Kreuzer, K: Consultant Advisory Role: Roche, Abbvie; Other Remuneration: Expert Testimony: Roche, Abbvie. Goede, V: Consultant Advisory Role: Roche, Janssen, Gilead, AbbVie; Other Remuneration: Speakers’ Bureau: Roche, Janssen, Gilead. Stilgenbauer, S: Research Funding: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann La-Roche, Janssen, Novartis, Pharmacyclics, Sunesis; Other Remuneration: Personal Fees: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann La-Roche, Janssen, Novartis, Pharmacyclics, Sunesis. Mobasher, M: Employment Leadership Position: Genentech/F. Hoffmann-La Roche Ltd, Corvus; Stock Ownership: Genentech/F. Hoffmann-La Roche Ltd, Corvus; Other Remuneration: Expenses: Genentech/F. Hoffmann-La Roche Ltd, Corvus. Ritgen, M: Consultant Advisory Role: Roche, Abbvie; Research Funding: Roche, Abbvie; Other Remuneration: Personal Fees – Roche. Hallek, M: Consultant Advisory Role: Roche, Abbvie; Honoraria: Roche, Abbvie, Gilead, Janssen, Celgene, Boehringer Ingelheim; Research Funding: Roche, Abbvie; Other Remuneration: Speakers’ Bureau: Roche, Abbvie.

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