Introduction: The anti-PD-1 checkpoint inhibitor NIVO provides favorable safety and efficacy when administered at 3 mg/kg Q2W across multiple tumor types. Alternative dosing schedules would provide flexibility and offer benefits to patients and prescribers. A well-established understanding of NIVO clinical pharmacology, robust clinical data across multiple tumor types and well characterized, relatively flat E-R relationships for efficacy and safety support the use of model-based approaches to qualify other potential NIVO doses and schedules.

Methods: The feasibility of extending the dosing interval of NIVO from Q2W to Q4W was investigated using a combination of quantitative clinical pharmacology analyses and safety assessments. The predicted benefit-risk profile of NIVO 480 mg Q4W relative to 3 mg/kg Q2W was assessed by the following analyses: (1) comparison of NIVO exposures produced by 3 mg/kg Q2W and 480 mg Q4W across tumor types; (2) evaluation of NIVO exposure margins for safety relative to the well-tolerated dose of 10 mg/kg Q2W; (3) comparison of predicted risk of experiencing adverse events (Gr3+ AEs, immune-mediated AEs) with 480 mg Q4W relative to 3 mg/kg Q2W across indications of melanoma, NSCLC, RCC, UC, H&N and cHL; and (4) comparison of predicted objective tumor response (OR) and overall survival with NIVO 480 mg Q4W relative to 3 mg/kg Q2W in patients with melanoma, NSCLC, and RCC.

Results: Steady-state peak, time-averaged, and trough NIVO concentrations predicted with 480 mg Q4W were approximately 44% higher, 4% higher, and 18% lower, respectively, compared with 3 mg/kg Q2W. The aggregate of safety data accumulated for NIVO up to a dose level of 10 mg/kg Q2W in multiple tumor types provides a wide safety margin for the maximum concentration values expected with 480 mg Q4W. The steady-state exposures produced by 480 mg Q4W were lower than the corresponding exposures with 10 mg/kg Q2W, which has been shown to have acceptable safety and tolerability. The predicted probabilities of achieving an OR with NIVO 480 mg Q4W were similar to those with 3 mg/kg Q2W (<1% difference) across tumor types. Predicted 1- and 2-year survival probabilities were also similar to that of NIVO 3 mg/kg Q2W (differences ranging between 0%-4.6% at year 1, and 1.9%-6.9% at year 2) across tumor types.

Conclusion: With a well-established understanding of NIVO clinical pharmacology, robust clinical data across multiple tumor types and well-characterized E-R relationships for efficacy and safety, the differences in exposures produced by a NIVO schedule of 480 mg Q4W relative to 3 mg/kg Q2W dosing schedule are not expected to result in clinically meaningful differences in the safety and efficacy of NIVO. The proposed 480 mg Q4W schedule has been incorporated into NIVO clinical trials (NCT02713867, NCT02714218) across multiple tumor types.

Citation Format: Xiaochen Zhao, Vijay Ivaturi, Mathangi Gopalakrishnan, Jun Shen, Yan Feng, Paul Statkevich, Eric Richards, Michelle Rashford, Vicki Goodman, Joga Gobburu, Akintunde Bello, Amit Roy, Shruti Agrawal. A model-based exposure-response (E-R) assessment of a nivolumab (NIVO) 4-weekly (Q4W) dosing schedule across multiple tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT101. doi:10.1158/1538-7445.AM2017-CT101