Integrated Analysis Shows Denosumab Superiority Over Zometa(R) In Delaying Or Preventing Skeletal Related Events In Broad Population With Advanced Cancer
Additional Analyses Demonstrate Denosumab Significantly Delays Onset And Worsening Of Bone Pain Over Zometa
Exploratory Analysis Shows Denosumab Superior To Zometa In Delaying Time To First Skeletal Related Event Or Hypercalcemia Of Malignancy
THOUSAND OAKS, CA, USA | June 5, 2010 | Amgen (Nasdaq: AMGN) today announced positive results from several new analyses of two Phase 3 trials studying denosumab compared with Zometa(R) (zoledronic acid), the current standard of care, for the treatment of bone metastases in patients with advanced breast cancer ("136 study") and solid tumors or multiple myeloma ("244 study"). Results from these trials reinforce denosumab’s consistent ability to delay the complications of bone metastases in patients with advanced cancer. These results are being presented during the 2010 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago.
Integrated Analysis Shows Denosumab Superiority in Delaying or Preventing Skeletal Related Events in a Broad Population with Advanced Cancer(Oral Presentation 9015)
An integrated analysis of the 136 and 244 studies was performed to further evaluate the efficacy of denosumab and understand treatment effects in key sub-groups. The analysis demonstrated that denosumab was superior to Zometa in delaying or preventing skeletal related events (SREs). Denosumab delayed the time to first on-study SRE over Zometa (hazard ratio 0.83, 95 percent CI: 0.74, 0.92; P=0.001), and delayed the time to first-and-subsequent SREs (hazard ratio 0.82, 95 percent CI: 0.74, 0.91; P=0.001). Denosumab also reduced the mean skeletal morbidity rate (number of SREs per year) versus Zometa (0.64 versus 0.80; P=0.0006).
"Bone metastases are a major clinical concern and cause significant suffering to our advanced cancer patients. Since these two large head-to-head studies were identically designed, we were able to combine the data to obtain a broader view of denosumab’s effect compared to the current standard of care in a diverse group of patients with advanced cancer," said Allan Lipton, M.D., professor of Medicine & Oncology, M.S. Hershey Medical Center of the Pennsylvania State University. "Due to its strong efficacy profile, no need for renal monitoring, and convenient subcutaneous dosing, denosumab provides a significant improvement over the standard of care for preventing skeletal related events."
Overall, adverse events (AEs; 96 percent denosumab, 97 percent Zometa), and serious AEs (53 percent denosumab, 56 percent Zometa) were similar in both groups and consistent with what has previously been reported for these two agents. Osteonecrosis of the jaw (ONJ) occurred in 30 (1.6 percent) denosumab patients and 25 (1.3 percent) Zometa patients. In addition, Zometa-treated patients had increased rates of AEs potentially associated with renal toxicity (6.5 percent denosumab, 9.6 percent Zometa) and with acute phase reactions (8.8 percent denosumab, 21.4 percent Zometa). As with previous studies in advanced cancer patients, hypocalcemia was more frequent in the denosumab arm. Both overall survival (hazard ratio 0.95, 95 percent CI: 0.86, 1.05; P=0.35) and the time to cancer progression (hazard ratio 1.00, 95 percent CI: 0.92, 1.08; P=0.90) were balanced between treatment arms. The most common AEs for denosumab were nausea, fatigue and dyspnea, and the most common AEs for Zometa were nausea, fatigue, and anemia.
Sub-Analysis Shows Denosumab Superior to Zometa in Solid Tumor Subset of the 244 Study (Abstract 9133)
A post-hoc subset analysis of the 244 study evaluated patients with solid tumors only. This analysis showed that denosumab was superior to Zometa in delaying the time to the first on-study SRE (hazard ratio 0.81, 95 percent CI: 0.68, 0.96; P<0.02); and for delaying the time to first and subsequent SREs (multiple events) (hazard ratio 0.85, 95 percent CI: 0.72, 1.00; P<0.05). Both treatment groups had similar rates of overall survival (hazard ratio 0.92, 95 percent CI: 0.81, 1.05; P=0.21), disease progression (hazard ratio 0.96, 95 percent CI: 0.85, 1.08; P<0.5), and overall AEs (denosumab 95.6 percent, Zometa 95.5 percent). Zometa-treated patients reported higher rates of AEs potentially associated with renal toxicity (denosumab 7.1 percent, Zometa 10.3 percent) and acute phase reactions (denosumab 7.1 percent, Zometa 14.8 percent). Denosumab-treated patients had higher rates of hypocalcemia of grades 3 or 4 (denosumab 4 percent, Zometa 2 percent). Both treatment groups reported similarly low rates of ONJ (denosumab 0.8 percent, Zometa 1.1 percent).
Additional Analyses Show Denosumab Significantly Delays Onset and Worsening of Bone Pain Over Zometa (Abstracts 1024 and 9053)
Two additional pre-specified exploratory analyses presented at the meeting show denosumab treatment significantly delayed the onset or worsening of bone pain in both the 136 and 244 studies. These are the most comprehensive analyses of pain measures from the denosumab trial program in SREs to be presented to date.
Bone pain is one of the first signs that metastatic disease has spread to the skeleton and affects approximately 70 percent of patients with metastatic disease.[i] Bone pain dominates the daily lives of patients with metastatic disease and is often characterized as severe or intolerable.[ii]
In the 136 study, denosumab significantly extended the time breast cancer patients had no or mild pain, when compared to Zometa. In addition, fewer denosumab patients experienced worsening of pain. Patients with scores of no or mild pain at baseline (n=1042) experienced a prolonged median time to development of moderate to severe pain with denosumab (295 days) compared with Zometa (176 days) (hazard ratio 0.78, 95 percent CI: 0.67, 0.92; P=0.0024) (Abstract 1024).
In the 244 trial of patients with advanced solid tumors (excluding breast and prostate) or multiple myeloma, denosumab-treated patients also experienced a delay in clinically significant worsening of pain compared with patients on Zometa (median 169 days: denosumab, 143 days: Zometa; hazard ratio 0.85, 95 percent CI: 0.73, 0.98; P=0.02). In addition, among patients with no or mild pain at baseline, fewer denosumab-treated patients reported moderate to severe pain than Zometa-treated patients (Abstract 9053).
Exploratory Analysis Shows Denosumab Superior to Zometa in Delaying Time to First SRE or Hypercalcemia of Malignancy (Abstract 9042)
A pre-specified exploratory analysis of the 244 trial found that patients receiving denosumab also experienced a significantly longer time to first SRE or hypercalcemia of malignancy, a severe and sudden increase of calcium in the bones that has a very poor prognosis[iii] (19.0 months denosumab versus 14.4 months Zometa, hazard ratio 0.83, 95 percent CI: 0.71, 0.97; P=0.02). In another pre-specified exploratory analysis, denosumab also delayed the need to administer radiation to bone, a treatment for bone metastasis (hazard ratio 0.78, 95 percent CI: 0.63, 0.97; P=0.03). This poster was selected as "Best of ASCO" for 2010.
Adverse Events in Study 136
Overall, the incidence of AEs (96 percent denosumab, 97 percent Zometa) and serious AEs (44 percent denosumab, 46 percent Zometa) was consistent with what has previously been reported for these two agents. AEs potentially associated with renal toxicity occurred in 4.9 percent of patients treated with denosumab compared to 8.5 percent in patients treated with Zometa. ONJ was seen infrequently in both treatment groups (20 patients receiving denosumab (2.0 percent) as compared with 14 patients (1.4 percent) receiving Zometa). There was no statistically significant difference in the rate of ONJ between the two treatment arms. Infectious AEs were balanced between the two treatment arms. Overall survival (hazard ratio 0.95, 95 percent CI: 0.81, 1.11; P=0.49) and time to cancer progression (hazard ratio 1.00, 95 percent CI: 0.89, 1.11; P=0.93) were balanced between treatment arms.
Adverse Events in Study 244
AEs rates (96 percent denosumab, 96 percent Zometa) and serious AEs (63 percent denosumab, 66 percent Zometa) were similar between groups and were consistent with what has previously been reported for these two agents. Rates of ONJ were balanced and infrequent in both treatment groups (10 patients receiving denosumab as compared with 11 patients receiving Zometa). Infectious AEs were balanced between the two treatment arms (hazard ratio 0.95, 95 percent CI: 0.83, 1.08; P=0.43), as were the time to cancer progression (hazard ratio 1.00, 95 percent CI: 0.89, 1.12; P=1.0) and overall survival (hazard ratio 0.95, 95 percent CI: 0.83, 1.08; P=0.43). In an ad-hoc analysis, there was a difference in overall survival that favored denosumab in non-small cell lung cancer and a difference in overall survival that favored Zometa in multiple myeloma, which were both nominally statistically significant.
About Studies 136 and 244
Studies 136 and 244 were international, Phase 3, randomized, double-blind studies comparing denosumab with Zometa in the treatment of bone metastases in patients with advanced breast cancer (study 136) and advanced cancer (excluding breast and prostate cancer) or multiple myeloma (study 244). Patients enrolled in the studies were randomized in a one-to-one ratio to receive either 120 mg of denosumab subcutaneously every four weeks (Q4W) or Zometa administered intravenously at a dose of 4 mg in a 15 minute infusion every four weeks as per the label instructions.
In clinical trials testing new medications for bone metastases, treatment success has been measured by whether the bone complications, or SREs, caused by the tumor are reduced or delayed. The primary and secondary endpoints of both 136 and 244 use a composite endpoint of four SREs – fracture, the need for radiation to bone, the need for bone surgery, and spinal cord compression – to measure the effectiveness of denosumab versus Zometa.
The primary endpoint of the studies was to evaluate if denosumab is non-inferior to Zometa with respect to the first, on-study SRE in patients with advanced breast cancer and bone metastases. Secondary endpoints were to evaluate if denosumab was superior to Zometa with respect to the first, on-study SRE, as well as the first-and-subsequent on-study SREs, and to assess the safety and tolerability of denosumab compared with Zometa.
Bone Metastases: Prevalence and Impact
Bone metastases occur in more than 1.5 million patients with cancer worldwide and are most commonly associated with cancers of the prostate, lung, and breast, with incidence rates as high as 75 percent of patients with metastatic disease.[iv]
The economic burden of United States (U.S.) patients with bone metastases is significant and is estimated to be $12.6 billion annually[v]. Patients with bone metastases who experience an SRE incur significantly higher medical costs compared with those who do not experience an SRE[vi].
About Denosumab and Amgen’s Research in Bone Biology
Denosumab is the first fully human monoclonal antibody in late stage clinical development that specifically targets RANK Ligand, the essential regulator of osteoclasts (the cells that break down bone). The denosumab development program is the largest ever initiated by Amgen. This broad and deep development program demonstrates Amgen’s commitment to researching and delivering pioneering medicines to patients with unmet medical needs. Amgen is studying denosumab in numerous tumor types across the spectrum of cancer-related bone diseases. Over 11,000 patients have been enrolled in the denosumab oncology clinical trials, testing the drug for the reduction of SREs in patients with breast and prostate cancer, as well as other solid tumors and multiple myeloma, for the amelioration of treatment-induced bone loss in patients with non-metastatic breast or prostate cancers, and for its potential to delay bone metastases in prostate cancer.
About Amgen
Amgen discovers, develops, manufactures and delivers innovative human therapeutics. A biotechnology pioneer since 1980, Amgen was one of the first companies to realize the new science’s promise by bringing safe and effective medicines from lab, to manufacturing plant, to patient. Amgen therapeutics have changed the practice of medicine, helping millions of people around the world in the fight against cancer, kidney disease, rheumatoid arthritis, and other serious illnesses. With a deep and broad pipeline of potential new medicines, Amgen remains committed to advancing science to dramatically improve people’s lives. To learn more about our pioneering science and our vital medicines, visit www.amgen.com.
[i] Cleeland CS, et al.Pain and its treatment in outpatients with metastatic cancer.N Eng J Med. 1994: 330:592-596.
[ii] Diel IJ.Effectiveness of bisphosphonates on bone pain and quality of life in breast cancer patients with metastatic bone disease: A review.Support Care Cancer.2007: 15:1243-1249.
[iii] Grill V, Martin TJ. Hypercalcemia of malignancy. Rev Endocr Metab Disord. 2000 Nov;1(4):253-63.
[iv] Coleman RE. Skeletal complications of malignancy.Cancer Suppl.1997: 80(8):1588
[v] Schulman K and Kohles J. Cancer. 2007;109:2334-2342.
[vi] GVD/Barber ISPOR 2008 Poster; Schulman 2007; Delea et al. 2006.
SOURCE Amgen
Post Views: 731
Integrated Analysis Shows Denosumab Superiority Over Zometa(R) In Delaying Or Preventing Skeletal Related Events In Broad Population With Advanced Cancer
Additional Analyses Demonstrate Denosumab Significantly Delays Onset And Worsening Of Bone Pain Over Zometa
Exploratory Analysis Shows Denosumab Superior To Zometa In Delaying Time To First Skeletal Related Event Or Hypercalcemia Of Malignancy
THOUSAND OAKS, CA, USA | June 5, 2010 | Amgen (Nasdaq: AMGN) today announced positive results from several new analyses of two Phase 3 trials studying denosumab compared with Zometa(R) (zoledronic acid), the current standard of care, for the treatment of bone metastases in patients with advanced breast cancer ("136 study") and solid tumors or multiple myeloma ("244 study"). Results from these trials reinforce denosumab’s consistent ability to delay the complications of bone metastases in patients with advanced cancer. These results are being presented during the 2010 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago.
Integrated Analysis Shows Denosumab Superiority in Delaying or Preventing Skeletal Related Events in a Broad Population with Advanced Cancer(Oral Presentation 9015)
An integrated analysis of the 136 and 244 studies was performed to further evaluate the efficacy of denosumab and understand treatment effects in key sub-groups. The analysis demonstrated that denosumab was superior to Zometa in delaying or preventing skeletal related events (SREs). Denosumab delayed the time to first on-study SRE over Zometa (hazard ratio 0.83, 95 percent CI: 0.74, 0.92; P=0.001), and delayed the time to first-and-subsequent SREs (hazard ratio 0.82, 95 percent CI: 0.74, 0.91; P=0.001). Denosumab also reduced the mean skeletal morbidity rate (number of SREs per year) versus Zometa (0.64 versus 0.80; P=0.0006).
"Bone metastases are a major clinical concern and cause significant suffering to our advanced cancer patients. Since these two large head-to-head studies were identically designed, we were able to combine the data to obtain a broader view of denosumab’s effect compared to the current standard of care in a diverse group of patients with advanced cancer," said Allan Lipton, M.D., professor of Medicine & Oncology, M.S. Hershey Medical Center of the Pennsylvania State University. "Due to its strong efficacy profile, no need for renal monitoring, and convenient subcutaneous dosing, denosumab provides a significant improvement over the standard of care for preventing skeletal related events."
Overall, adverse events (AEs; 96 percent denosumab, 97 percent Zometa), and serious AEs (53 percent denosumab, 56 percent Zometa) were similar in both groups and consistent with what has previously been reported for these two agents. Osteonecrosis of the jaw (ONJ) occurred in 30 (1.6 percent) denosumab patients and 25 (1.3 percent) Zometa patients. In addition, Zometa-treated patients had increased rates of AEs potentially associated with renal toxicity (6.5 percent denosumab, 9.6 percent Zometa) and with acute phase reactions (8.8 percent denosumab, 21.4 percent Zometa). As with previous studies in advanced cancer patients, hypocalcemia was more frequent in the denosumab arm. Both overall survival (hazard ratio 0.95, 95 percent CI: 0.86, 1.05; P=0.35) and the time to cancer progression (hazard ratio 1.00, 95 percent CI: 0.92, 1.08; P=0.90) were balanced between treatment arms. The most common AEs for denosumab were nausea, fatigue and dyspnea, and the most common AEs for Zometa were nausea, fatigue, and anemia.
Sub-Analysis Shows Denosumab Superior to Zometa in Solid Tumor Subset of the 244 Study (Abstract 9133)
A post-hoc subset analysis of the 244 study evaluated patients with solid tumors only. This analysis showed that denosumab was superior to Zometa in delaying the time to the first on-study SRE (hazard ratio 0.81, 95 percent CI: 0.68, 0.96; P<0.02); and for delaying the time to first and subsequent SREs (multiple events) (hazard ratio 0.85, 95 percent CI: 0.72, 1.00; P<0.05). Both treatment groups had similar rates of overall survival (hazard ratio 0.92, 95 percent CI: 0.81, 1.05; P=0.21), disease progression (hazard ratio 0.96, 95 percent CI: 0.85, 1.08; P<0.5), and overall AEs (denosumab 95.6 percent, Zometa 95.5 percent). Zometa-treated patients reported higher rates of AEs potentially associated with renal toxicity (denosumab 7.1 percent, Zometa 10.3 percent) and acute phase reactions (denosumab 7.1 percent, Zometa 14.8 percent). Denosumab-treated patients had higher rates of hypocalcemia of grades 3 or 4 (denosumab 4 percent, Zometa 2 percent). Both treatment groups reported similarly low rates of ONJ (denosumab 0.8 percent, Zometa 1.1 percent).
Additional Analyses Show Denosumab Significantly Delays Onset and Worsening of Bone Pain Over Zometa (Abstracts 1024 and 9053)
Two additional pre-specified exploratory analyses presented at the meeting show denosumab treatment significantly delayed the onset or worsening of bone pain in both the 136 and 244 studies. These are the most comprehensive analyses of pain measures from the denosumab trial program in SREs to be presented to date.
Bone pain is one of the first signs that metastatic disease has spread to the skeleton and affects approximately 70 percent of patients with metastatic disease.[i] Bone pain dominates the daily lives of patients with metastatic disease and is often characterized as severe or intolerable.[ii]
In the 136 study, denosumab significantly extended the time breast cancer patients had no or mild pain, when compared to Zometa. In addition, fewer denosumab patients experienced worsening of pain. Patients with scores of no or mild pain at baseline (n=1042) experienced a prolonged median time to development of moderate to severe pain with denosumab (295 days) compared with Zometa (176 days) (hazard ratio 0.78, 95 percent CI: 0.67, 0.92; P=0.0024) (Abstract 1024).
In the 244 trial of patients with advanced solid tumors (excluding breast and prostate) or multiple myeloma, denosumab-treated patients also experienced a delay in clinically significant worsening of pain compared with patients on Zometa (median 169 days: denosumab, 143 days: Zometa; hazard ratio 0.85, 95 percent CI: 0.73, 0.98; P=0.02). In addition, among patients with no or mild pain at baseline, fewer denosumab-treated patients reported moderate to severe pain than Zometa-treated patients (Abstract 9053).
Exploratory Analysis Shows Denosumab Superior to Zometa in Delaying Time to First SRE or Hypercalcemia of Malignancy (Abstract 9042)
A pre-specified exploratory analysis of the 244 trial found that patients receiving denosumab also experienced a significantly longer time to first SRE or hypercalcemia of malignancy, a severe and sudden increase of calcium in the bones that has a very poor prognosis[iii] (19.0 months denosumab versus 14.4 months Zometa, hazard ratio 0.83, 95 percent CI: 0.71, 0.97; P=0.02). In another pre-specified exploratory analysis, denosumab also delayed the need to administer radiation to bone, a treatment for bone metastasis (hazard ratio 0.78, 95 percent CI: 0.63, 0.97; P=0.03). This poster was selected as "Best of ASCO" for 2010.
Adverse Events in Study 136
Overall, the incidence of AEs (96 percent denosumab, 97 percent Zometa) and serious AEs (44 percent denosumab, 46 percent Zometa) was consistent with what has previously been reported for these two agents. AEs potentially associated with renal toxicity occurred in 4.9 percent of patients treated with denosumab compared to 8.5 percent in patients treated with Zometa. ONJ was seen infrequently in both treatment groups (20 patients receiving denosumab (2.0 percent) as compared with 14 patients (1.4 percent) receiving Zometa). There was no statistically significant difference in the rate of ONJ between the two treatment arms. Infectious AEs were balanced between the two treatment arms. Overall survival (hazard ratio 0.95, 95 percent CI: 0.81, 1.11; P=0.49) and time to cancer progression (hazard ratio 1.00, 95 percent CI: 0.89, 1.11; P=0.93) were balanced between treatment arms.
Adverse Events in Study 244
AEs rates (96 percent denosumab, 96 percent Zometa) and serious AEs (63 percent denosumab, 66 percent Zometa) were similar between groups and were consistent with what has previously been reported for these two agents. Rates of ONJ were balanced and infrequent in both treatment groups (10 patients receiving denosumab as compared with 11 patients receiving Zometa). Infectious AEs were balanced between the two treatment arms (hazard ratio 0.95, 95 percent CI: 0.83, 1.08; P=0.43), as were the time to cancer progression (hazard ratio 1.00, 95 percent CI: 0.89, 1.12; P=1.0) and overall survival (hazard ratio 0.95, 95 percent CI: 0.83, 1.08; P=0.43). In an ad-hoc analysis, there was a difference in overall survival that favored denosumab in non-small cell lung cancer and a difference in overall survival that favored Zometa in multiple myeloma, which were both nominally statistically significant.
About Studies 136 and 244
Studies 136 and 244 were international, Phase 3, randomized, double-blind studies comparing denosumab with Zometa in the treatment of bone metastases in patients with advanced breast cancer (study 136) and advanced cancer (excluding breast and prostate cancer) or multiple myeloma (study 244). Patients enrolled in the studies were randomized in a one-to-one ratio to receive either 120 mg of denosumab subcutaneously every four weeks (Q4W) or Zometa administered intravenously at a dose of 4 mg in a 15 minute infusion every four weeks as per the label instructions.
In clinical trials testing new medications for bone metastases, treatment success has been measured by whether the bone complications, or SREs, caused by the tumor are reduced or delayed. The primary and secondary endpoints of both 136 and 244 use a composite endpoint of four SREs – fracture, the need for radiation to bone, the need for bone surgery, and spinal cord compression – to measure the effectiveness of denosumab versus Zometa.
The primary endpoint of the studies was to evaluate if denosumab is non-inferior to Zometa with respect to the first, on-study SRE in patients with advanced breast cancer and bone metastases. Secondary endpoints were to evaluate if denosumab was superior to Zometa with respect to the first, on-study SRE, as well as the first-and-subsequent on-study SREs, and to assess the safety and tolerability of denosumab compared with Zometa.
Bone Metastases: Prevalence and Impact
Bone metastases occur in more than 1.5 million patients with cancer worldwide and are most commonly associated with cancers of the prostate, lung, and breast, with incidence rates as high as 75 percent of patients with metastatic disease.[iv]
The economic burden of United States (U.S.) patients with bone metastases is significant and is estimated to be $12.6 billion annually[v]. Patients with bone metastases who experience an SRE incur significantly higher medical costs compared with those who do not experience an SRE[vi].
About Denosumab and Amgen’s Research in Bone Biology
Denosumab is the first fully human monoclonal antibody in late stage clinical development that specifically targets RANK Ligand, the essential regulator of osteoclasts (the cells that break down bone). The denosumab development program is the largest ever initiated by Amgen. This broad and deep development program demonstrates Amgen’s commitment to researching and delivering pioneering medicines to patients with unmet medical needs. Amgen is studying denosumab in numerous tumor types across the spectrum of cancer-related bone diseases. Over 11,000 patients have been enrolled in the denosumab oncology clinical trials, testing the drug for the reduction of SREs in patients with breast and prostate cancer, as well as other solid tumors and multiple myeloma, for the amelioration of treatment-induced bone loss in patients with non-metastatic breast or prostate cancers, and for its potential to delay bone metastases in prostate cancer.
About Amgen
Amgen discovers, develops, manufactures and delivers innovative human therapeutics. A biotechnology pioneer since 1980, Amgen was one of the first companies to realize the new science’s promise by bringing safe and effective medicines from lab, to manufacturing plant, to patient. Amgen therapeutics have changed the practice of medicine, helping millions of people around the world in the fight against cancer, kidney disease, rheumatoid arthritis, and other serious illnesses. With a deep and broad pipeline of potential new medicines, Amgen remains committed to advancing science to dramatically improve people’s lives. To learn more about our pioneering science and our vital medicines, visit www.amgen.com.
[i] Cleeland CS, et al.Pain and its treatment in outpatients with metastatic cancer.N Eng J Med. 1994: 330:592-596.
[ii] Diel IJ.Effectiveness of bisphosphonates on bone pain and quality of life in breast cancer patients with metastatic bone disease: A review.Support Care Cancer.2007: 15:1243-1249.
[iii] Grill V, Martin TJ. Hypercalcemia of malignancy. Rev Endocr Metab Disord. 2000 Nov;1(4):253-63.
[iv] Coleman RE. Skeletal complications of malignancy.Cancer Suppl.1997: 80(8):1588
[v] Schulman K and Kohles J. Cancer. 2007;109:2334-2342.
[vi] GVD/Barber ISPOR 2008 Poster; Schulman 2007; Delea et al. 2006.
SOURCE Amgen
Post Views: 731
