Chet Bohac

Safety and efficacy outcomes with erythropoiesis-stimulating agents in patients with breast cancer: a meta-analysis

BACKGROUND New data on erythropoiesis-stimulating agents (ESAs) regarding overall survival and disease progression-related outcomes in patients with breast cancer receiving chemotherapy are presented in a meta-analysis of controlled trials of ESA use (epoetin α, epoetin β, darbepoetin α, biosimilars). PATIENTS AND METHODS A literature search identified reports from January 1997 through March 2014. We used company databases for Amgen, Inc., or Janssen studies and published data for other studies. Random-effects odds ratios (ORs) were calculated to compare results for patients randomized to ESA with those randomized to control. RESULTS Deaths were reported for 571 of 2346 patients (24%) in the ESA groups and 523 of 2367 patients (22%) in the control groups [OR, 1.20; 95% confidence interval (CI) 1.03-1.40]. Sensitivity analyses were conducted to explore the effects of individual studies and exclusion of one study (BEST) resulted in an OR for death of 1.12 (95% CI 0.94-1.34). In seven studies reporting progression-related end points (N = 4197; ESA n = 2088; control n = 2109), the OR was 1.01 (95% CI 0.87-1.16) for ESA compared with control. CONCLUSIONS After incorporating recent results of ESA use in patients with breast cancer, risks of survival and progression-free survival remain consistent with previously published data.

Effects of erythropoiesis-stimulating agents on survival and other outcomes in patients with lymphoproliferative malignancies: a study-level meta-analysis

Abstract Erythropoiesis-stimulating agents (ESAs) are approved to treat anemia in patients with non-myeloid malignancies receiving myelosuppressive chemotherapy. ESAs reduce transfusion rates, but some clinical studies suggest that ESAs may reduce survival or increase disease progression. This study-level meta-analysis examined the effects of darbepoetin alfa, epoetin alfa or epoetin beta on mortality, disease progression and transfusion incidence in patients with lymphoproliferative malignancies, using randomized, controlled trials of patients receiving chemotherapy and ESAs or standard of care. The odds ratio (OR) for mortality was 1.04 (95% confidence interval [CI], 0.81–1.34, random-effects model, 10 studies); the risk difference was − 0.01 (95% CI, − 0.03–0.02). The OR for disease progression was 1.02 (95% CI 0.81–1.30, random-effects model, five studies). A lower proportion of ESA-treated patients than controls received transfusions (seven studies). In this meta-analysis, ESAs reduced transfusions with no clear effect on mortality or disease progression in patients with lymphoproliferative malignancies receiving chemotherapy.

Dermatologic Toxicity Occurring During Anti-EGFR Monoclonal Inhibitor Therapy in Patients With Metastatic Colorectal Cancer: A Systematic Review

Abstract Monoclonal antibody inhibitors of the epidermal growth factor receptor (EGFR) have been shown to improve outcomes for patients with metastatic colorectal cancer (mCRC) without RAS gene mutations. However, treatment with anti‐EGFR agents can be associated with toxicities of the skin, nails, hair, and eyes. Because these dermatologic toxicities can result in treatment discontinuation and affect patient quality of life, their management is an important focus when administering anti‐EGFR monoclonal antibodies. The present systematic review describes the current data reporting the nature and incidence of, and management and treatment options for, dermatologic toxicities occurring during anti‐EGFR treatment of mCRC. A search of the National Library of Medicine PubMed database from January 1, 2009, to August 18, 2016, identified relevant reports discussing dermatologic toxicity management among patients with mCRC receiving anti‐EGFR therapy. The studies were grouped by type and rated by level of evidence using the GRADE approach developed by the Agency for Healthcare Research and Quality. Overall, 269 reports were reviewed (nonrandomized trials, n = 120; randomized trials, n = 31; retrospective studies, n = 15; reviews, n = 39). Dermatologic toxicity of any grade occurs in most patients who receive anti‐EGFR therapy; approximately 10% to 20% of patients experienced grade 3/4 toxicity. The most common dermatologic toxicities include papulopustular/acneiform rash, xerosis, and pruritus; however, nail changes, hair abnormalities, and ocular conditions also occur. Guidance for managing these toxicities includes the use of inexpensive emollient ointments and moisturizers, avoidance of sun exposure, avoidance of irritants, and the use of short showers. Several studies also found that preemptive treatment was more effective than reactive treatment at limiting the incidence and severity of skin toxicity. With appropriate treatment, the dermatologic toxicities associated with anti‐EGFR monoclonal antibody therapy can be managed, minimizing patient discomfort and the need for therapy interruption and/or discontinuation. Additionally, preemptive treatment can reduce dermatologic toxicity severity, ultimately yielding better quality of life.

Efficacy and safety of darbepoetin alfa initiated at hemoglobin ≤10 g/dL in patients with stage IV cancer and chemotherapy-induced anemia

Data on efficacy and safety of darbepoetin alfa (DA) administered at hemoglobin (Hb) ≤10 g/dL are limited. In this analysis, we examined DAs efficacy and safety in patients with Stage IV cancers and chemotherapy‐induced anemia (CIA) initiated on DA at Hb ≤10 g/dL. Data for patients with Stage IV cancers and CIA and who initiated DA at Hb ≤10 g/dL were extracted from three phase 3 trials identified in a central database of Amgen‐sponsored DA studies in CIA. Efficacy outcomes were assessed by achievement of Hb increases of ≥1 g/dL and ≥2 g/dL and red blood cell (RBC) or whole blood transfusion requirements. Data were analyzed for all patients with baseline Hb ≤10 g/dL, and by the subgroups of patients with baseline Hb ≥9 to ≤10 g/dL versus <9 g/dL. Crude and Kaplan–Meier proportions of patients who experienced each outcome and time (days) to each outcome were summarized by treatment. Meta‐analysis (fixed‐effects inverse‐variance model) was performed to compare outcomes for DA versus placebo. Safety was assessed by occurrence of adverse events. Data from 213 patients were analyzed: DA, n = 115; placebo, n = 98. More patients in the DA versus the placebo subgroup achieved Hb increase of ≥1 g/dL (72% vs. 36%; HR: 2.92, 95% CI: 1.95, 4.39) and ≥2 g/dL (44% vs. 18%; HR: 2.98, 95% CI: 1.71, 5.21) during the first 12 treatment weeks. Median times to Hb increase of ≥1 g/dL and ≥2 g/dL were 36 days and 78 days for DA, respectively. RBC or whole blood transfusions were less common in patients in the DA versus the placebo subgroup (24% vs. 45%; HR: 0.44, 95% CI: 0.27, 0.73). No new safety issues were reported. Our results confirm that DA use in patients with Stage IV cancer and CIA is more effective than placebo at increasing Hb levels and at reducing transfusion needs when DA treatment is initiated at Hb ≤10 g/dL.

Abstract P5-15-18: Hemoglobin levels and quality of life in patients with breast cancer and symptomatic chemotherapy-induced anemia enrolled in the eAQUA study

Background: Fatigue associated with chemotherapy-induced anemia (CIA) is common in patients with breast cancer, and can have adverse effects on quality of life (QoL). Erythropoiesis-stimulating agents (ESAs) reduce the need for transfusions and may improve QoL in patients with symptomatic CIA. Information on hemoglobin (Hb) levels and effects of fatigue on QoL in patients with breast cancer and CIA in real-world clinical practice is limited. Methods: The Electronic Assessment of Quality of Life in Patients With Symptomatic CIA (eAQUA) study evaluated improvements in QoL for patients with CIA receiving ESAs who had an increase in Hb of ≥1 g/dL by week 9. This phase 4, international, longitudinal, prospective, observational study enrolled patients with solid tumors who received chemotherapy and had symptomatic anemia. Patients received ESA therapy for up to 13 weeks based on European indication. The primary outcome was the proportion of patients with increase in Hb ≥1 g/dL and improvement in fatigue-related QoL based on the Functional Assessment of Cancer Therapy-Fatigue (FACT-F; scale = 0 to 52 with lower scores indicating worse fatigue) subscale scores and fatigue Visual Analog Scale (VAS; scale = 0 to 100 with higher scores indicating worse fatigue) from baseline to week 9. FACT-F change scores were anchored to VAS change scores to determine the minimally important difference (MID) for improvements in QoL. Patients with a FACT-F change score that was ≥ the MID were considered to have an improvement in QoL. For Hb and QoL outcomes, week 9 data were those assessed closest to on-treatment day 57 (after initiation of ESA) and within on-treatment days 43 to 70 inclusive, to account for different ESA dosing schedules and the observational nature of the study. Secondary outcomes included rates of red blood cell (RBC) transfusions or iron supplementation during the study. Results: Of 1262 patients enrolled in eAQUA, 289 had breast cancer and were included in the full analysis set (FAS; had at least one ESA dose); of these, 152 patients were eligible to be included in the primary analysis set (PAS; had QoL and Hb data available at baseline and week 9). At baseline, mean (standard deviation [SD]) Hb was 9.4 (0.6) g/dL; mean (SD) FACT-F and VAS scores were 27.1 (10.5) and 52.7 (22.8), respectively, in the FAS. Mean (SD) change from baseline at week 9 was 1.3 (1.3) g/dL for Hb; 4.1 (10.8) score change for FACT-F; and 4.7 (25.9) score change for VAS in the FAS. A total of 54 (18.7%) patients in the FAS required an RBC transfusion and 79 (27.3%) received iron supplementation. At week 9, 77 of 152 patients in the PAS had achieved improvement in fatigue-related QoL (50.7%; 95% confidence interval [CI] = 42.7%, 58.6%); 93 patients had increased Hb ≥1 g/dL (61.2%; 95% CI = 53.4%, 68.9%); and 59 patients (38.8%; 95% CI = 31.1%, 46.6%) had achieved both improvement in fatigue-related QoL and increased Hb ≥1 g/dL. Conclusions: In this exploratory subgroup analysis, patients with breast cancer and symptomatic CIA treated with ESAs achieved clinically meaningful improvements in fatigue-related QoL and Hb levels. Citation Format: Mario Airoldi, Dominique Spaeth, Joan Van den Bosch, Charalambos Christofyllakis, Laura Belton, Chet Bohac, Jan-Henrik Terwey, Giuseppe Tonini. Hemoglobin levels and quality of life in patients with breast cancer and symptomatic chemotherapy-induced anemia enrolled in the eAQUA study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-15-18.

1508PHAEMOGLOBIN (HB) LEVELS AND QUALITY OF LIFE (QOL) IN PATIENTS (PTS) WITH SYMPTOMATIC CHEMOTHERAPY-INDUCED ANAEMIA (CIA): THE EAQUA STUDY

ABSTRACT Aim: Fatigue is common in pts with CIA and can adversely impact QoL. There are limited data related to improvements in Hb levels and fatigue-related QoL in routine clinical practice. Methods: eAQUA was a phase 4, prospective, observational study assessing Hb outcome and fatigue-related QoL (electronic assessment) in pts with solid tumours receiving chemotherapy who had symptomatic CIA and were receiving an erythropoiesis-stimulating agent according to European indications. The primary aim was to determine the proportion of pts receiving darbepoetin alfa (DA) with a Hb increase ≥1 g/dL and improved QoL between baseline and week (wk) 9. Pts receiving DA who had baseline and wk 9 Hb and QoL data represented the primary analysis set (PAS). QoL was measured in terms of Functional Assessment of Cancer Therapy-Fatigue (FACT-F) subscale scores and fatigue Visual Analogue Scale (VAS) scores (0=least fatigued). FACT-F change scores were anchored to VAS change scores to determine the minimally important difference (MID) for a perceived QoL improvement, based on a predefined algorithm. Pts who had a FACT-F change score ≥ the calculated MID were deemed to have improved QoL. Results: 1262 pts were enrolled; 510 pts were included in the PAS. At baseline, median age was 65 years, 30% had been diagnosed with breast cancer, 69% had stage IV disease and 96% were experiencing fatigue. At baseline, mean (SD) Hb was 9.4 (0.6) g/dL; mean (SD) FACT-F and VAS scores were 29.2 (10.3) and 49.2 (22.6), respectively. Mean (SD) change from baseline in Hb at wk 9 was 1.2 (1.4) g/dL; mean (SD) change in FACT-F and VAS scores were 3.5 (10.5) and 4.3 (24.7). The mean (SD) FACT-F change determined to be the MID for a QoL improvement was 3.5 (5.5). Overall, 32% (95% CI: 28-36%) of pts met the primary endpoint with both a Hb increase ≥1 g/dL and improved QoL at wk 9. The proportions of pts achieving either improvements in QoL or Hb ≥1 g/dL at wk 9 were 49% and 58%; 70% and 76% of pts had improvements in QoL or Hb levels at any time up to end of study. Conclusions: In our study, pts with solid tumours receiving DA per European indication for symptomatic CIA had a clinically meaningful improvement in both Hb levels and QoL. Disclosure: G. Tonini, J. Mouysset, B. Freier, J. van den Bosch, A. Bols and H.W. Tessen: Research funding from Amgen for eAQUA participation; C.B. Levache: is voluntary President of association called “association pour la recherche clinique de francheville”, which received a payment on behalf of AMGEN to realize the e-aqua study; L. Belton: Contractor funded by Amgen; C. Bohac: Amgen Inc. employee and stockholder; J. Terwey: Amgen (Europe) GmbH employee and stockholder.

1509PADDITIONAL HAEMOGLOBIN (HB) AND QUALITY OF LIFE (QOL) ANALYSES FROM EAQUA

ABSTRACT Aim: Erythropoiesis-stimulating agents (ESAs) such as darbepoetin alfa (DA) can be used to reduce the need for transfusions and improve QoL in patients (pts) with symptomatic chemotherapy-induced anaemia (CIA). eAQUA was a phase 4, prospective, observational study, assessing Hb outcome and fatigue-related QoL (electronic assessment) in pts with solid tumours who had symptomatic CIA and were receiving an ESA according to approved European indication. Primary data and detailed methodology from the eAQUA study are reported in the accompanying abstract (Tonini et al). Methods: Additional analyses for eAQUA included: median time from baseline to an increase in Hb ≥1 g/dL or a QoL improvement (Kaplan-Meier methodology); proportion of pts with both a QoL improvement and a Hb increase ≥1 g/dL at week (wk) 9, by tumour type, and red blood cell (RBC) transfusion/iron use during the course of the study. QoL was measured in terms of Functional Assessment of Cancer Therapy-Fatigue subscale scores and fatigue Visual Analogue Scale scores. Results: 1262 pts were enrolled; the primary analysis set reported here comprised pts who received DA and had baseline and wk 9 Hb and QoL data (n = 510). Overall, 65% of pts were female, 52% were ≥65 years and 56% had competed 1-3 chemotherapy cycles. By tumour type, the proportions of pts having both a Hb increase ≥1 g/dL and QoL improvement at wk 9 were: breast (n = 152) 39% (95% confidence intervals [CI]: 31-47%); ovarian (n = 79) 38% (95% CI: 27-49%); colorectal (n = 71) 31% (95% CI: 20-42%); NSCLC (n = 70) 29% (95% CI: 18-39%) and prostate (n = 39) 28% (95% CI: 14-42%). Median times to Hb increase ≥1 g/dL or QoL improvement were 37 (95% CI: 30-43) days and 40 (95% CI: 34-43) days, respectively. Overall, 82 pts (16%) required ≥1 RBC transfusion; median Hb in the 7 days prior to transfusion was 8.3 (range: 6-12) g/dL. Overall, 163 pts (32%) required iron supplementation. Conclusions: In our study, many pts treated with DA per current European indication for symptomatic CIA had Hb increases ≥1 g/dL and/or QoL improvements within 6 weeks of starting treatment. QoL/Hb improvements were observed across tumour types. Relatively few pts required transfusions or iron supplementation during the study. Disclosure: G. Tonini: received Research funding from Amgen for eAQUA participation; J. Mouysset, M. Rotarski, M. Airoldi, C. Toganel and C. Christofyllakis: has received research funding from Amgen for eAQUA participation; D. Spaeth: has received research funding from Amgen for eAQUA participation and honoraria for symposia participation from Amgen; L. Belton: is a contractor funded by Amgen; C. Bohac: is an Amgen Inc. employee and stockholder; J. Terwey: is an Amgen (Europe) GmbH employee and stockholder.