A Randomized, Double-Blind, Placebo-Controlled, Phase III Noninferiority Study of the Long-Term Safety and Efficacy of Darbepoetin Alfa for Chemotherapy-Induced Anemia in Patients With Advanced NSCLC

Abstract

Introduction: This study evaluated noninferiority of darbepoetin alfa versus placebo for overall survival (OS) and progression-free survival (PFS) in anemic patients with NSCLC treated to a 12.0-g/dL hemoglobin (Hb) ceiling. Methods: Adults with stage IV NSCLC expected to receive two or more cycles of myelosuppressive chemotherapy and Hb less than or equal to 11.0 g/dL were randomized 2:1 to blinded 500 mg darbepoetin alfa or placebo every 3 weeks. The primary endpoint was OS; a stratified Cox proportional hazards model was used to evaluate noninferiority (upper confidence limit for hazard ratio [HR] < 1.15). Secondary endpoints were PFS and incidence of transfusions or Hb less than or equal to 8.0 g/dL from week 5 to end of the efficacy treatment period. Results: The primary analysis set included 2516 patients: 1680 were randomized to darbepoetin alfa; 836 to placebo. The study was stopped early per independent Data Monitoring Committee recommendation after the primary endpoint was met with no new safety concerns. Darbepoetin alfa was noninferior to placebo for OS (stratified HR ¼ 0.92; 95% confidence interval [CI]: 0.83-1.01) and PFS (stratified HR ¼ 0.95; 95% CI: 0.87-1.04). Darbepoetin alfa was superior to placebo for transfusion or Hb less than or equal to 8.0 g/dL from week 5 to end of the efficacy treatment period (stratified odds ratio ¼ 0.70; 95% CI: 0.57-0.86; p < 0.001). Objective tumor response was similar between the groups (darbepoetin alfa, 36.4%; placebo, 32.6%). Incidence of serious adverse events was 31.1% in both groups. No unexpected adverse events were observed. Conclusions: Darbepoetin alfa dosed to a 12.0-g/dL Hb ceiling was noninferior to placebo for OS and PFS and significantly reduced odds of transfusion or Hb less than or equal to 8.0 g/dL in anemic patients with NSCLC receiving myelosuppressive chemotherapy.

Baseline anemia and anemia grade are independent prognostic factors for stage IV non‑small cell lung cancer

“…The patients with anemia grade 0 had the longest OS (median OS: 28.0 months), followed by patients with anemia grades 1 and 2 (median OS: 17.5 months). The patients with anemia grades 3 (21). The early treatment of anemia is very important.…”

Recognition of thrombotic risk of thrombocytosis in iron deficiency

“…Without stratifying for iron deficiency or its successful abatement by intravenous iron, the observation of a marked increment in thromboses in erythropoiesis stimulating agent-treated patients with cancer and chemotherapy-induced anemia and anemia associated with both non-dialysis and dialysis-dependent chronic kidney disease led to the near proscription of the use of a treatment which unqualifiedly leads to improvements in energy, activity and quality of life in a cohort with debilitating chronic illness. Despite a litany of prospective, randomized, placebo-controlled studies failing to show harm with the use of erythropoiesis-stimulating agents, especially in cancer and chemotherapy-induced anemia, 6 extreme caution with their use remains the order of the day.…”

How I treat cancer-associated anemia

“…The results of recently published pharmacovigilance trials conducted in certain cancer subtypes, including lung cancer, have demonstrating that ESAs may be safely used in carefully selected patient populations such as the one presented in case 2. [75][76][77][78] ESA-induced tumor progression Investigation of the mechanisms responsible for poorer ESA-related outcomes gave rise to myriad hypotheses 79 including tumor-expressing EPO receptors, 78 hyperviscosity, 80 and VTE events owing to increasing hematocrit. After determining that EPO receptor expression did not correlate with decreased survival, further investigation led to the ephrin-B2 ligand and ephrin-B4 receptor hypothesis.…”