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GAIA Trial Shows Venetoclax Combo as Superior in CLL
Co-primary endpoint analysis results from the phase 3 GAIA CLL13 trial were presented at the 2021 American Society of Hematology (ASH) Annual Meeting to share novel investigative data of 3 venetoclax plus CD20 antibody-based regimens in comparison to chemoimmunotherapy (CIT) as a frontline treatment for fit patients with chronic lymphocytic leukemia (CLL) who do not have a TP53 mutation or deletion.
“For fit CLL patients, continuous BTK inhibitor treatment is replacing CIT as the standard of care in frontline settings. The time limited combinations venetoclax plus obinutuzumab, and venetoclax plus rituximab, have produced high rates of undetectable minimal residual disease (uMRD), which strongly associates with long progression-free survival (PFS) both in frontline and relapsed settings,” explained Barbara Eichhorst, MD, University Hospital of Cologne, Germany, and co-investigators.
Researchers of the international trial sought to evaluate a fit CLL cohort, as data are not yet available for this respective patient population. However, frontline venetoclax plus obinutuzumab therapy is approved from the CLL14 trial for unfit CLL populations.
In total, 926 treatment-naïve patients with CLL were enrolled to the trial and were randomized to a 1:1:1:1 ratio to receive 6 courses of CIT (for patients less than 65 years: fludrabine 25 mg/m2 d1-3, cyclophosphamide 250 mg/m2 d1-3, rituximab 375 mg/m2 d1 cycle 1 and 500 mg/m1 d1 cycle 2-6; for patients older than 65: bendamustine 90 mg/m2 d1-2, rituximab).
Other therapies included either 1 of 3 venetoclax combinations (standard ramp-up from cycle 1 d22, 400 mg/d cycle 2-12): venetoclax and rituximab (375/500 mg/m2 d1 cycle 1-6; venetoclax and obinutuzumab (1000 mg d1, 8, 15 cycle 1 and d1 cycle 2-6), or venetoclax plus obinutuzumab and ibrutinib (420 mg/d cycle 1-12, if MRD-detectable continued until cycle 36.
The co-primary endpoints are the rate uMRD (<10-4) by flow in peripheral blood (PB) at month 15 (MO15, venetoclax plus obinutuzumab vs CIT) and PFS (venetoclax, obinutuzumab, and ibrutinib vs CIT), each with a significance level at 2.5 percent. Secondary endpoints were investigator-assessed responses according to iwCLL 2008 guidelines and safety.
In all, 229 patients with CLL were assigned to CIT (150 to fludrabine, cyclophosphamide, and rituximab and 79 to bendamustine and rituximab), 237 to venetoclax plus rituximab, 229 to venetoclax plus obinutuzumab, and 331 to venetoclax plus obinutuzumab and ibrutinib for a total of 926 patients with a median age of 61 years (range, 27-84). Most patients were in advanced Binet stage (73.4%) and unmutated immunoglobin heavy chain gene status was present in 56 percent. The median observation time was 27.9 months.
“The co-primary endpoint uMRD in PB at MO15 was met as the rate of uMRD in the intention-to-treat population was significantly higher in venetoclax plus obinutuzumab compared to CIT, 86.5 percent (97.5% CI, 80.6-91.1) versus 52 percent (CI, 44.4-59.5; P<0.0001), respectively,” continued Dr Eichhorst and co-authors.
Further, venetoclax plus obinutuzumab and ibrutinib demonstrated a superior uMRD rate of 92.2 percent (CI 87.3-95.7) compared to CIT (P <0.0001), while venetoclax plus rituximab (57.0%, CI 49.5-64.2) did not (p=0.317). Corresponding BM uMRD rates were 37.1 percent (CIT), 43 percent (venetoclax plus rituximab), 72.5 percent (venetoclax plus obinutuzumab), and 77.9 percent (venetoclax plus obinutuzumab and ibrutinib), respectively.
The most common grade 3 to 5 treatment-emergent adverse events (TEAEs) of all patients were neutropenia (50.5%), thrombocytopenia (12.2%), tumor lysis syndrome (7.5%), infusion-related reaction (7.2%), febrile neutropenia (6.5%), and pneumonia (5.3%). Fatal AEs occurred in 27 patients.
“The time-limited therapies of venetoclax plus obinutuzumab and venetoclax plus obinutuzumab and ibrutinib provided superior uMRD rates in PB at MO15 compared to CIT. In addition, uMRD rates in BM complete response rates were higher in venetoclax plus obinutuzumab and venetoclax plus obintuzumab and ibrutinib in particular than in CIT. All arms showed a good safety profile in this fit population,” concluded Dr Eichhorst, et al. –Alexa Stoia
Eichhorst B, Niemann C, Kater A, et al. A Randomized Phase III Study of Venetoclax-Based Time-Limited Combination Treatments (RVe, GVe, GIVe) Vs Standard Chemoimmunotherapy (CIT: FCR/BR) in Frontline Chronic Lymphocytic Leukemia of Fit Patients: First Co-Primary Endpoint Analysis of the International Intergroup GAIA (CLL13) Trial. Presented at: the 2021 ASH Annual Meeting; Dec. 11-14; 2021; Abstract 71.
