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5.2 Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients With Cancer

ESAs resulted in decreased locoregional control/progression-free survival (PFS) and/or overall survival (OS) (see Table 2).

Adverse effects on PFS and/or OS were observed in studies of patients receiving chemotherapy for breast cancer (Studies 1, 2, and 4), lymphoid malignancy (Study 3), and cervical cancer (Study 5); in patients with advanced head and neck cancer receiving radiation therapy (Studies 6 and 7); and in patients with non-small cell lung cancer or various malignancies who were not receiving chemotherapy or radiotherapy (Studies 8 and 9).

Table 2: Randomized, Controlled Studies With Decreased Survival and/or Decreased Locoregional Control
Study/Tumor/(n) Hemoglobin Target Achieved Hemoglobin(Median; Q1, Q3*) Primary Efficacy Outcome Adverse Outcome for ESA- containing Arm
Q1=25th percentile,Q3=75th percentile
This study did not include a defined hemoglobin target. Doses were titrated to achieve and maintain the lowest hemoglobin level sufficient to avoid transfusion and not to exceed 12 g/dL.
Study 1 Metastatic breast cancer(n=2098) ≤12 g/dL 11.6 g/dL10.7, 12.1 g/dL Progression-free survival (PFS) Decreased progression-free and overall survival
Study 2 Metastatic breast cancer(n=939) 12–14 g/dL 12.9 g/dL;12.2, 13.3 g/dL 12-month overall survival Decreased 12-month survival
Study 3 Lymphoid malignancy(n=344) 13–15 g/dL (M)13–14 g/dL (F) 11 g/dL;9.8, 12.1 g/dL Proportion of patients achieving a hemoglobin response Decreased overall survival
Study 4 Early breast cancer(n=733) 12.5–13 g/dL 13.1 g/dL;12.5, 13.7 g/dL Relapse-free and overall survival Decreased 3-year relapse-free and overall survival
Study 5 Cervical cancer(n=114) 12–14 g/dL 12.7 g/dL;12.1, 13.3 g/dL Progression-free and overall survival and locoregional control Decreased 3-year progression-free and overall survival and locoregional control
Radiotherapy Alone
Study 6 Head and neck cancer(n=351) ≥ 15 g/dL (M)≥ 14 g/dL (F) Not available Locoregional progression-free survival Decreased 5-year locoregional progression-free and overall survival
Study 7 Head and neck cancer(n=522) 14–15.5 g/dL Not available Locoregional disease control Decreased locoregional disease control
No Chemotherapy or Radiotherapy
Study 8 Non-small cell lung cancer(n=70) 12–14 g/dL Not available Quality of life Decreased overall survival
Study 9 Non-myeloid malignancy(n=989) 12–13 g/dL 10.6 g/dL;9.4, 11.8 g/dL RBC transfusions Decreased overall survival

Decreased Overall Survival

Study 2 was described in the previous section [see Warnings and Precautions (5.1)]. Mortality at 4 months (8.7% vs. 3.4%) was significantly higher in the epoetin alfa arm. The most common investigator-attributed cause of death within the first 4 months was disease progression; 28 of 41 deaths in the epoetin alfa arm and 13 of 16 deaths in the placebo arm were attributed to disease progression. Investigator-assessed time to tumor progression was not different between the 2 groups. Survival at 12 months was significantly lower in the epoetin alfa arm (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; p=0.012).

Study 3 was a randomized, double-blind study (darbepoetin alfa vs. placebo) conducted in 344 anemic patients with lymphoid malignancy receiving chemotherapy. With a median follow-up of 29 months, overall mortality rates were significantly higher among patients randomized to darbepoetin alfa as compared to placebo (HR 1.36, 95% CI: 1.02, 1.82).

Study 8 was a multicenter, randomized, double-blind study (epoetin alfa vs. placebo) in which patients with advanced non-small cell lung cancer receiving only palliative radiotherapy or no active therapy were treated with epoetin alfa to achieve and maintain hemoglobin levels between 12 and 14 g/dL. Following an interim analysis of 70 patients (planned accrual 300 patients), a significant difference in survival in favor of the patients in the placebo arm of the study was observed (median survival 63 vs. 129 days; HR 1.84; p=0.04).

Study 9 was a randomized, double-blind study (darbepoetin alfa vs. placebo) in 989 anemic patients with active malignant disease, neither receiving nor planning to receive chemotherapy or radiation therapy. There was no evidence of a statistically significant reduction in proportion of patients receiving RBC transfusions. The median survival was shorter in the darbepoetin alfa treatment group than in the placebo group (8 months vs. 10.8 months; HR 1.30, 95% CI: 1.07, 1.57).

Decreased Progression-free Survival and Overall Survival

Study 1 was a randomized, open-label, multicenter study in 2,098 anemic women with metastatic breast cancer, who received first line or second line chemotherapy. This was a noninferiority study designed to rule out a 15% risk increase in tumor progression or death of epoetin alfa plus standard of care (SOC) as compared with SOC alone. At the time of clinical data cutoff, the median progression free survival (PFS) per investigator assessment of disease progression was 7.4 months in each arm (HR 1.09, 95% CI: 0.99, 1.20), indicating the study objective was not met. There were more deaths from disease progression in the epoetin alfa plus SOC arm (59% vs. 56%) and more thrombotic vascular events in the epoetin alfa plus SOC arm (3% vs. 1%). At the final analysis, 1653 deaths were reported (79.8% subjects in the epoetin alfa plus SOC group and 77.8% subjects in the SOC group). Median overall survival in the epoetin alfa plus SOC group was 17.8 months compared with 18.0 months in the SOC alone group (HR 1.07, 95% CI: 0.97, 1.18).

Study 4 was a randomized, open-label, controlled, factorial design study in which darbepoetin alfa was administered to prevent anemia in 733 women receiving neo-adjuvant breast cancer treatment. A final analysis was performed after a median follow-up of approximately 3 years. The 3-year survival rate was lower (86% vs. 90%; HR 1.42, 95% CI: 0.93, 2.18) and the 3-year relapse-free survival rate was lower (72% vs. 78%; HR 1.33, 95% CI: 0.99, 1.79) in the darbepoetin alfa-treated arm compared to the control arm.

Study 5 was a randomized, open-label, controlled study that enrolled 114 of a planned 460 cervical cancer patients receiving chemotherapy and radiotherapy. Patients were randomized to receive epoetin alfa to maintain hemoglobin between 12 and 14 g/dL or to RBC transfusion support as needed. The study was terminated prematurely due to an increase in thromboembolic adverse reactions in epoetin alfa-treated patients compared to control (19% vs. 9%). Both local recurrence (21% vs. 20%) and distant recurrence (12% vs. 7%) were more frequent in epoetin alfa-treated patients compared to control. Progression-free survival at 3 years was lower in the epoetin alfa-treated group compared to control (59% vs. 62%; HR 1.06, 95% CI: 0.58, 1.91). Overall survival at 3 years was lower in the epoetin alfa-treated group compared to control (61% vs. 71%; HR 1.28, 95% CI: 0.68, 2.42).

Study 6 was a randomized, placebo-controlled study in 351 head and neck cancer patients where epoetin beta or placebo was administered to achieve target hemoglobins ≥ 14 and ≥ 15 g/dL for women and men, respectively. Locoregional progression-free survival was significantly shorter in patients receiving epoetin beta (HR 1.62, 95% CI: 1.22, 2.14; p=0.0008) with medians of 406 days and 745 days in the epoetin beta and placebo arms, respectively. Overall survival was significantly shorter in patients receiving epoetin beta (HR 1.39, 95% CI: 1.05, 1.84; p=0.02).

Decreased Locoregional Control

Study 7 was a randomized, open-label, controlled study conducted in 522 patients with primary squamous cell carcinoma of the head and neck receiving radiation therapy alone (no chemotherapy) who were randomized to receive darbepoetin alfa to maintain hemoglobin levels of 14 to 15.5 g/dL or no darbepoetin alfa. An interim analysis performed on 484 patients demonstrated that locoregional control at 5 years was significantly shorter in patients receiving darbepoetin alfa (RR 1.44, 95% CI: 1.06, 1.96; p=0.02). Overall survival was shorter in patients receiving darbepoetin alfa (RR 1.28, 95% CI: 0.98, 1.68; p=0.08).

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