- Email: [email protected]
Ipilimumab (Ipi) Exposure-Response (E-R) and Meta-Analysis of Overall Survival (Os) of Advanced Melanoma Patients (Pts)
Annals of Oncology 25 (Supplement 4): iv374–iv393, 2014 doi:10.1093/annonc/mdu344.16
melanoma and other skin tumours 1100P
IPILIMUMAB (IPI) EXPOSURE-RESPONSE (E-R) AND META-ANALYSIS OF OVERALL SURVIVAL (OS) OF ADVANCED MELANOMA PATIENTS (PTS)
abstracts
Aim: We report on two analyses that were used to support the European Medicines Agency approval of 3-mg/kg IPI for previously untreated ( puTx) advanced melanoma pts. A published meta-analysis model (Korn model) was employed to control for factors prognostic for OS and assess the potential OS benefit of IPI. In addition, an E-R analysis was employed to provide supportive evidence that OS of advanced melanoma pts is independent of prior treatment status. Methods: The Korn model was first validated with OS data from the dacarbazine (DTIC)-only arm of CA184-024 (a phase 3 clinical trial of OS in puTx pts). The effect
© European Society for Medical Oncology 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from https://academic.oup.com/annonc/article-abstract/25/suppl_4/iv381/2241803 by guest on 24 October 2019
Y. Feng1, D. Berman2, T. Chen3, E. Masson4, A. Roy5 1 Exploratory Clinical & Translational Research, Bristol-Myers Squibb Company, Lawrenceville, NJ, USA 2 Exploratory Clinical & Translational Research, Bristol-Myers Squibb, Princeton, NJ, USA 3 Global Biometric Sciences, Bristol-Myers Squibb, Wallingford, CT, USA 4 Exploratory Clinical and Translational Research/clinical Pharmacology & Pharmacometrics, Bristol-Myers Squibb, Princeton, NJ, USA 5 Clinical Pharmacology & Pharmacometrics, Bristol-Myers Squibb, Princeton, NJ, USA
of 3-mg/kg IPI monotherapy (mTx) on the OS of puTx pts was then assessed by comparing the Kaplan-Meier (K-M) of observed OS in 2 observational single-arm studies with the corresponding Korn model-predicted OS. Finally, the E-R relationship between IPI steady-state trough concentration (Cminss) and OS was assessed by a Cox proportional-hazards model of pooled data from 4 phase 2 clinical trials of IPI (0.3, 3, and 10 mg/kg) and CA184-024 (DTIC + 10-mg/kg IPI or placebo). Results: The Korn model-predicted OS of pts in the DTIC-only arm of CA184-024 was contained within the 95% confidence interval (CI) of the observed K-M OS curve, and the curves were largely overlapped, demonstrating that the model is appropriate to describe the OS of puTx advanced melanoma pts. In contrast, the K-M (95% CI) of observed OS of pts in each of the 2 single-arm observational studies was superior to the Korn model-predicted OS of these pts (representing virtual control arms that account for effect of prognostic factors). The E-R analysis of pooled data from clinical trials of IPI-treated pts indicates that OS improved with increasing Cminss. For all Cminss in 3-mg/kg IPI-treated pts, the hazard ratio (95% CI) was <1. The E-R analysis also confirmed that prior treatment status is not prognostic for OS and that the benefit of IPI is independent of prior treatment status. Conclusions: The OS of advanced melanoma pts is independent of prior treatment status based on the E-R analysis. The Korn model was independently validated and demonstrated that the OS of puTx pts receiving 3-mg/kg IPI mTx appears markedly superior to historical data. Disclosure: Y. Feng: is employed by Bristol-Myers Squibb and owns stock in this company; D. Berman: is employed by Bristol-Myers Squibb and owns stock in this company; T. Chen: is employed by Bristol-Myers Squibb (BMS) and owns stock in this company. He also participates in BMS-sponsored research; E. Masson: is employed by Bristol-Myers Squibb (BMS) and owns stock in this company. He also participates in BMS-sponsored research; A. Roy: is employed by Bristol-Myers Squibb and owns stock in this company.
melanoma and other skin tumours 1100P
IPILIMUMAB (IPI) EXPOSURE-RESPONSE (E-R) AND META-ANALYSIS OF OVERALL SURVIVAL (OS) OF ADVANCED MELANOMA PATIENTS (PTS)
abstracts
Aim: We report on two analyses that were used to support the European Medicines Agency approval of 3-mg/kg IPI for previously untreated ( puTx) advanced melanoma pts. A published meta-analysis model (Korn model) was employed to control for factors prognostic for OS and assess the potential OS benefit of IPI. In addition, an E-R analysis was employed to provide supportive evidence that OS of advanced melanoma pts is independent of prior treatment status. Methods: The Korn model was first validated with OS data from the dacarbazine (DTIC)-only arm of CA184-024 (a phase 3 clinical trial of OS in puTx pts). The effect
© European Society for Medical Oncology 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from https://academic.oup.com/annonc/article-abstract/25/suppl_4/iv381/2241803 by guest on 24 October 2019
Y. Feng1, D. Berman2, T. Chen3, E. Masson4, A. Roy5 1 Exploratory Clinical & Translational Research, Bristol-Myers Squibb Company, Lawrenceville, NJ, USA 2 Exploratory Clinical & Translational Research, Bristol-Myers Squibb, Princeton, NJ, USA 3 Global Biometric Sciences, Bristol-Myers Squibb, Wallingford, CT, USA 4 Exploratory Clinical and Translational Research/clinical Pharmacology & Pharmacometrics, Bristol-Myers Squibb, Princeton, NJ, USA 5 Clinical Pharmacology & Pharmacometrics, Bristol-Myers Squibb, Princeton, NJ, USA
of 3-mg/kg IPI monotherapy (mTx) on the OS of puTx pts was then assessed by comparing the Kaplan-Meier (K-M) of observed OS in 2 observational single-arm studies with the corresponding Korn model-predicted OS. Finally, the E-R relationship between IPI steady-state trough concentration (Cminss) and OS was assessed by a Cox proportional-hazards model of pooled data from 4 phase 2 clinical trials of IPI (0.3, 3, and 10 mg/kg) and CA184-024 (DTIC + 10-mg/kg IPI or placebo). Results: The Korn model-predicted OS of pts in the DTIC-only arm of CA184-024 was contained within the 95% confidence interval (CI) of the observed K-M OS curve, and the curves were largely overlapped, demonstrating that the model is appropriate to describe the OS of puTx advanced melanoma pts. In contrast, the K-M (95% CI) of observed OS of pts in each of the 2 single-arm observational studies was superior to the Korn model-predicted OS of these pts (representing virtual control arms that account for effect of prognostic factors). The E-R analysis of pooled data from clinical trials of IPI-treated pts indicates that OS improved with increasing Cminss. For all Cminss in 3-mg/kg IPI-treated pts, the hazard ratio (95% CI) was <1. The E-R analysis also confirmed that prior treatment status is not prognostic for OS and that the benefit of IPI is independent of prior treatment status. Conclusions: The OS of advanced melanoma pts is independent of prior treatment status based on the E-R analysis. The Korn model was independently validated and demonstrated that the OS of puTx pts receiving 3-mg/kg IPI mTx appears markedly superior to historical data. Disclosure: Y. Feng: is employed by Bristol-Myers Squibb and owns stock in this company; D. Berman: is employed by Bristol-Myers Squibb and owns stock in this company; T. Chen: is employed by Bristol-Myers Squibb (BMS) and owns stock in this company. He also participates in BMS-sponsored research; E. Masson: is employed by Bristol-Myers Squibb (BMS) and owns stock in this company. He also participates in BMS-sponsored research; A. Roy: is employed by Bristol-Myers Squibb and owns stock in this company.