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Exposure–Response Analysis of Nivolumab in Patients With Previously Treated or Untreated Advanced Melanoma
Author(s) -
Bajaj Gaurav,
Gupta Manish,
Feng Yan,
Statkevich Paul,
Roy Amit
Publication year - 2017
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.962
Subject(s) - nivolumab , melanoma , medicine , oncology , pharmacology , dermatology , cancer research , cancer , immunotherapy
Nivolumab is a fully human immunoglobulin-G4 monoclonal antibody that selectively binds to the programmed death-1 (PD-1) membrane receptor, blocking the interaction of PD-1 with its 2 known ligands, PD-L1 and PD-L2.1 Blockade of PD-1 is believed to promote antitumor immune responses by preventing downregulation of T-cell activation and proliferation within the tumor microenvironment.1 Nivolumab has demonstrated clinical activity as monotherapy or in combination with ipilimumab (anti–cytotoxic Tlymphocyte antigen 4 [anti-CTLA-4]) in several tumor types, including melanoma,2,3 non–small cell lung cancer (NSCLC),4–6 and renal cell carcinoma (RCC).7,8 In addition, nivolumab monotherapy is shown to be well tolerated up to a dose of 10 mg/kg in patients with solid tumors.9 Nivolumab 240 mg every 2 weeks is approved for the treatment of patients with unresectable or metastatic melanoma, previously treated metastatic NSCLC, advanced RCC, and urothelial cancer, and 3 mg/kg every 2 weeks is approved for classical Hodgkin lymphoma and recurrent or metastatic squamous cell carcinoma of the head and neck.10 Nivolumab 1 mg/kg in combination with ipilimumab every 3 weeks for 4 doses followed by nivolumab 240 mg every 2 weeks is also approved for the treatment of unresectable or metastatic melanoma.10 Durable responses, overall survival benefit, and improved progression-free survival have been documented in patients with previously untreated melanoma who received nivolumab.2 The pharmacokinetics (PK) of nivolumab have been previously characterized and described by a linear 2-compartment model with time-varying clearance (CL).11 The PK of nivolumab has been found to be linear in the range of 0.1 to 10 mg/kg, and both elimination and distribution of nivolumab appeared to be independent of dose in the dose range studied.12 The end of infusion and minimum serum concentration (Cmin) after the first dose were approximately doseproportional. Exposure-response (E-R) of efficacy and safety has been characterized in previously treated patients with advanced melanoma receiving nivolumab 3 mg/kg (studies CA209003 and CA209037).13 The purpose of the current study was to extend the earlier characterization of nivolumab E-R of overall survival to patients with previously untreated advanced melanoma. In previous E-R analyses,13 nivolumab exposure (time averaged concentration after first dose [Cavg1]) was not a significant predictor of Response Evaluation Criteria In Solid Tumors v1.1 objective response or overall survival over the exposure range tested, and higher baseline tumor burden in melanoma was associated with a lower probability of response. The E-R safety analysis found that nivolumab exposure (Cavg1) was not a significant predictor of the risk of grade 3 drug-related adverse events and adverse events leading to drug discontinuation or death.