1100P - Ipilimumab (IPI) exposure-response (E-R) and meta-analysis of overall survival (OS) of advanced melanoma patients (pts)

Date 28 September 2014
Event ESMO 2014
Session Poster Display session
Topics Cancer Immunology and Immunotherapy
Melanoma and other Skin Tumours
Presenter Yan Feng
Citation Annals of Oncology (2014) 25 (suppl_4): iv374-iv393. 10.1093/annonc/mdu344
Authors Y. Feng1, D. Berman2, T. Chen3, E. Masson4, A. Roy5
  • 1Exploratory Clinical & Translational Research, Bristol-Myers Squibb Company, 08543 - Lawrenceville/US
  • 2Exploratory Clinical & Translational Research, Bristol-Myers Squibb, Princeton/US
  • 3Global Biometric Sciences, Bristol-Myers Squibb, Wallingford/US
  • 4Exploratory Clinical And Translational Research/clinical Pharmacology & Pharmacometrics, Bristol-Myers Squibb, Princeton/US
  • 5Clinical Pharmacology & Pharmacometrics, Bristol-Myers Squibb, Princeton/US

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Abstract

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 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.