Patients with untreated chronic lymphocytic leukaemia given ibrutinib–venetoclax in a phase 3 study had significantly better four-year progression-free survival rates compared to those given chemoimmunotherapy, an analysis of long-term data shows.
Furthermore, the data demonstrated for the first time an overall survival advantage in patients given fixed-duration ibrutinib–venetoclax compared to those who received chlorambucil–obinutuzumab after four years’ follow-up, according to the paper published in The Lancet Oncology (link here).
“Ibrutinib–venetoclax provides long-lasting remission and is feasible for older patients or patients with comorbidities without TP53 mutations,” noted Dr Anna Fink from the University of Cologne in an accompanying editorial.
Results of the Phase 3 study (GLOW) led to ibrutinib–venetoclax combination therapy being approved for first-line treatment of CLL: after a median 27.7 months, the primary endpoint of PFS was significantly longer in the ibrutinib–venetoclax treatment group than in the chemoimmunotherapy chlorambucil–obinutuzumab group (p<0.001).
Now, an analysis of long-term follow-up data undertaken by GLOW investigators Dr Carsten Niemann from Copenhagen University Hospital and colleagues confirms the durability of the results: after a median 46 months’ follow-up, PFS remained superior in the ibrutinib–venetoclax group (hazard ratio [HR] 0.214, 95% CI 0.138–0.334; p<0·0001).
“Several key questions have arisen in the context of [ibrutinib–venetoclax] therapy, including the durability of remission achieved with the combination,” noted Dr Fink. “The [long-term] data presented by Dr Niemann and colleagues confirm the results of the primary endpoint analysis. The efficacy of the fixed-duration treatment remains robust.”
In the original GLOW study, investigators enrolled previously untreated CLL patients (with an Eastern Cooperative Oncology Group performance status of two or less) either aged at least 65 years, or 18-64 years with comorbidities rated at least six on a cumulative rating scale and/or creatinine clearance <70 mL/min. 106 patients were randomly assigned to combination therapy comprising the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib plus the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax for 12 cycles, and 105 patients to chlorambucil–obinutuzumab for six cycles.
Survival advantage
In the follow-up analysis, PFS rates at 42 months were 74.6% (95% CI 65.0–82.0) in the ibrutinib–venetoclax group and 24.8% (16.5–34.1) in the chlorambucil–obinutuzumab group.
The estimated 42-month overall survival rate was 87.5% (95% CI 79·4–92·5) for the ibrutinib–venetoclax group and 77.6% (68·2–84·5) for those taking chlorambucil–obinutuzumab group, the investigators noted.
Also of note, ibrutinib–venetoclax maintained MRD clearance in most patients through 2 years after treatment, with a 17 percentage-point fall from 3 months to 27 months post treatment.
“Although MRD clearance was better maintained after treatment for patients with mutated IGHV, on-treatment MRD clearance was more frequent and faster in patients with unmutated IGHV. As such, MRD kinetics varied for different molecular subgroups,” the authors noted.
To conclude, Dr Niemann and co-authors said their long-term analysis showed that “ibrutinib–venetoclax continued to significantly prolong PFS versus chemoimmunotherapy” and that the findings “supported the use of ibrutinib–venetoclax as a first-line option for patients with previously untreated CLL.”
Dr Fink also highlighted the need for “evidence that ibrutinib–venetoclax might yield an efficacy similar to other standard regimens, such as continuous treatment with BTK inhibitors alone, or in combination with obinutuzumab, or the combination of venetoclax and obinutuzumab.” However, she also acknowledged that “ibrutinib–venetoclax represents yet another milestone on the path towards personalised therapeutic approaches for patients with CLL.”
The study was funded by Janssen Research & Development and Pharmacyclics.