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ALPINE

Zanubrutinib versus ibrutinib in relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma

Phase 3N = 652NCT03734016

Population
Relapsed or refractory CLL or SLL after at least one previous course of therapy
Design
Global randomised open-label phase 3 trial; 652 patients with relapsed or refractory CLL or SLL (at least one previous course of therapy) randomly assigned 1:1 to zanubrutinib or ibrutinib until progression or unacceptable toxicity. Primary endpoint: investigator-assessed overall response rate; interim analysis in the first 415 enrolled patients (207 zanubrutinib, 208 ibrutinib). PFS was a key secondary endpoint tested hierarchically (noninferiority, then superiority) in the final analysis.
Primary endpoint
ORR
Arms
  • Zanubrutinib (experimental): Zanubrutinib until disease progression or unacceptable toxic effects
  • Ibrutinib (control): Ibrutinib until disease progression or unacceptable toxic effects
People
Hillmen P
Δ ORR+15.8 pointsPFSHR 0.40 (95% CI 0.23–0.69)Δ 12-month PFS+10.9 pointsPFSHR 0.65 (95% CI 0.49–0.86)Δ 24-month PFS+12.5 points
Show the numbers
Results reported for ALPINE
EndpointAnalysisZanubrutinibIbrutinibEffect
ORRFirst 415 enrolled patients (zanubrutinib n=207, ibrutinib n=208), prespecified interim analysisinterimmedian follow-up 15 monthsHillmen 202378.3% (72.0–83.7%)62.5% (55.5–69.1%)P<.001Primary endpoint, investigator-assessed; two-sided P.
PFSFirst 415 enrolled patients, prespecified interim analysisinterimmedian follow-up 15 monthsHillmen 202394.9% at 12 mo84% at 12 moHR 0.40 (95% CI 0.23–0.69)Secondary analysis at the interim cut-off; PFS at 12 months in all patients of the interim population.
PFSAll randomly assigned patients (n=652); investigator-assessedfinalmedian follow-up 29.6 monthsBrown 202378.4% at 2 y65.9% at 2 yHR 0.65 (95% CI 0.49–0.86)P=0.002Key secondary endpoint (PFS), final analysis; results were similar by independent review committee. In patients with a 17p deletion, a TP53 mutation, or both, the PFS hazard ratio was 0.53 (95% CI 0.31 to 0.88).
Results reported for ALPINE
EndpointAnalysisZanubrutinibIbrutinibEffect
ORRFirst 415 enrolled patients (zanubrutinib n=207, ibrutinib n=208), prespecified interim analysisinterimmedian follow-up 15 monthsHillmen 202378.3% (72.0–83.7%)62.5% (55.5–69.1%)P<.001Primary endpoint, investigator-assessed; two-sided P.
PFSFirst 415 enrolled patients, prespecified interim analysisinterimmedian follow-up 15 monthsHillmen 202394.9% at 12 mo84% at 12 moHR 0.40 (95% CI 0.23–0.69)Secondary analysis at the interim cut-off; PFS at 12 months in all patients of the interim population.
PFSAll randomly assigned patients (n=652); investigator-assessedfinalmedian follow-up 29.6 monthsBrown 202378.4% at 2 y65.9% at 2 yHR 0.65 (95% CI 0.49–0.86)P=0.002Key secondary endpoint (PFS), final analysis; results were similar by independent review committee. In patients with a 17p deletion, a TP53 mutation, or both, the PFS hazard ratio was 0.53 (95% CI 0.31 to 0.88).
Hazard ratio (95% CI) by endpoint. Values below 1 favour the experimental arm.
PFSPFS0.512◀ experimentalcontrol ▶
Data table
EndpointHR95% CI
PFS0.40.23–0.69
PFS0.650.49–0.86
Primary publication: Hillmen P, Eichhorst B, Brown JR, Lamanna N, O'Brien SM, Tam CS, et al. Zanubrutinib Versus Ibrutinib in Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: Interim Analysis of a Randomized Phase III Trial. J Clin Oncol. 2023;41(5):1035-1045. PubMedDOI

Appears in

Sources

  1. Hillmen P, Eichhorst B, Brown JR, Lamanna N, O'Brien SM, Tam CS, et al. Zanubrutinib Versus Ibrutinib in Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: Interim Analysis of a Randomized Phase III Trial. J Clin Oncol. 2023;41(5):1035-1045.

    PubMedDOI

  2. Brown JR, Eichhorst B, Hillmen P, Jurczak W, Kaźmierczak M, Lamanna N, et al. Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med. 2023;388(4):319-332.

    PubMedDOI