GLOW: Ibrutinib + venetoclax showed superior PFS as first-line CLL treatment

Fixed-duration ibrutinib + venetoclax showed superior efficacy in older or unfit patients with chronic lymphocytic leukaemia (CLL) compared with chlorambucil + obinutuzumab in the phase 3 GLOW study. These results support the positive clinical profile of all-oral, once-daily, fixed-duration ibrutinib + venetoclax as first-line treatment.

Prof. Arnon Kater (Amsterdam University Medical Centres, the Netherlands) presented the primary results of the randomised, open-label, phase 3 GLOW study (NCT03462719) [1]. The once-daily, all-oral, fixed-duration therapy induced deep remissions in young or fit patients in the phase 2 CAPTIVATE study (NCT02910583), with 2-year progression-free survival (PFS) of 95% [2].

A total of 211 patients ≥65 years of age or <65 years with cumulative illness rating scale (CIRS) >6 or creatinine clearance <70 mL/min were randomised 1:1 to receive 420 mg ibrutinib daily for a 3-cycle lead-in followed by ibrutinib + venetoclax for 12 cycles (n=106), or chlorambucil + obinutuzumab for 6 cycles (n=105). Primary endpoint was PFS, and secondary endpoints included undetectable minimal residual disease (MRD) in bone marrow (<1 CLL cell/10,000 leukocytes), complete response rate, overall response rate, overall survival, and safety.

With a median follow-up of 27.7 months, PFS for ibrutinib + venetoclax was superior to chlorambucil + obinutuzumab (P<0.0001); ibrutinib + venetoclax reduced the risk of progression or death by 78% (HR 0.216; 95% CI 0.131–0.357). Median PFS was not reached with ibrutinib + venetoclax, while median PFS was 21.0 months with chlorambucil + obinutuzumab (see Figure). PFS analysis in pre-specified subgroups consistently favoured ibrutinib + venetoclax.

Figure: Progression-free survival was significantly improved with ibrutinib + venetoclax [1]

Clb+O, chlorambucil + obinutuzumab; I+V, ibrutinib + venetoclax; PFS, progression-free survival.

Complete response rates were significantly higher for ibrutinib + venetoclax versus chlorambucil + obinutuzumab (38.7% vs 11.4%; P<0.0001) and responses to ibrutinib + venetoclax were more durable, with 90% versus 41% of responders sustaining response 24 months after initial response. Undetectable MRD rate was also significantly higher in ibrutinib + venetoclax-treated patients (bone marrow P<0.0001; peripheral blood P=0.0259) and sustained by the majority of ibrutinib + venetoclax-treated patients at 12 months post-treatment. The risk of needing second-line therapy was reduced by 86% with first-line ibrutinib + venetoclax versus chlorambucil + obinutuzumab.

In the ibrutinib + venetoclax arm, 11 deaths occurred compared with 12 in the chlorambucil + obinutuzumab arm. Causes of death were similar, with infections and cardiac events being most common. Hazard ratio for overall survival was 1.048 (95% CI 0.454–2.419) in ibrutinib + venetoclax versus chlorambucil + obinutuzumab.

Median exposure was 13.8 months with ibrutinib + venetoclax and 5.1 months with chlorambucil + obinutuzumab. Interim safety results showed serious adverse events in ≥5% of patients (infections 12.3% vs 8.6%; atrial fibrillation 6.6% vs 0%, respectively). Two patients (1.9%) in the ibrutinib + venetoclax arm discontinued ibrutinib due to atrial fibrillation.

In summary, fixed-duration ibrutinib + venetoclax as first-line treatment for older or unfit adults with CLL demonstrated superior efficacy in the primary endpoint PFS as well as in key secondary endpoints. Tolerability profiles were consistent with CLL treatment in elderly comorbid patients.

1. 
   
   1. Kater A, et al. Fixed duration ibrutinib and venetoclax (I+V) versus chlorambucil plus obinutuzumab (Clb+O) for first-line (1L) chronic lymphocytic leukemia (CLL): primary analysis of the phase 3 GLOW study. P205-2, EHA 2021 Congress, 09–17 June.
   2. Ghia P, et al. Abstract 7501, ASCO 2021, 4–8 June.

 

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Posted on 5 August, 202125 March, 2024