PII-061 - MODEL INFORMED DRUG DEVELOPMENT (MIDD) TO SUPPORT AN ALTERNATIVE NIVOLUMAB DOSE AND SCHEDULE FOR ADVANCED MELANOMA.

S. Liu¹, Y. Zhao¹, S. Boyanapalli², A. Roy¹, P. Statkevich¹; ¹Bristol Myers Squibb, Lawrenceville, NJ, USA, ²Rutgers University, New Brunswick, NJ, USA.

Background: The initially approved nivolumab (NIVO) dosing regimen for melanoma, NSCLC, and RCC indications was changed from 3 mg/kg Q2W to flat doses of 240 mg Q2W and 480 mg Q4W based on pharmacometric (PMx) analyses demonstrating similar benefit-risk [1]. An additional flat dosing regimen of 360 mg Q3W would provide further flexibility and offer benefits to patients and prescribers especially in combination with therapies administered Q3W.

Methods: The predicted benefit-risk profile of NIVO 360 mg Q3W relative to 240 mg Q2W and 480 mg Q4W regimens was assessed by the following PMx analyses: (1) comparison of popPK model predicted NIVO exposures; (2) comparison of predicted risk of experiencing Gr2+ IMAEs; and (3) comparison of predicted objective tumor response (OR) and overall survival (OS) in advanced melanoma (advMEL) across the three regimens. Cavg on day 84 was selected as the exposure measure for the primary E-R analyses as it represents the overall drug concentration over a 12 week duration, representative of a common dosing interval from Q2W, Q3W and Q4W regimens.

Results: For the advMEL population, the geometric mean of the key NIVO exposure metrics (Cavg, Cmax, and Cmin at day 1, day 84, and steady-state) achieved with the 360 mg Q3W regimen were in between those achieved with 240 mg Q2W and 480 mg Q4W. Model predicted mean cumulative probabilities of Gr2+ IMAE were similar for NIVO 240 mg Q2W, 360 mg Q3W, and 480 mg Q4W. The predicted OR and OS for NIVO 360 mg Q3W were similar to 240 mg Q2W and 480 mg Q4W.

Conclusion: The PMx analyses demonstrated that the benefit-risk of the NIVO 360 mg Q3W regimen would be similar to that of the approved NIVO 240 mg Q2W and 480 mg Q4W regimens in advMEL to support development of potential combination therapies with NIVO Q3W.

Zhao, X. et al. Model-based evaluation of the efficacy and safety of nivolumab once every 4 weeks across multiple tumor types. Ann Oncol. 2020 Feb;31(2):302-309.