• Nivolumab Exposure-Response Analysis for Adjuvant Treatment of Melanoma Supporting a Change in Posology

      Sanghavi, Kinjal; Vuppala, Pradeep; Ivaturi, Vijay; Hamuro, Lora; Roy, Amit; Suryawanshi, Satyendra (Wiley-Blackwell, 2021-05-06)
      Nivolumab monotherapy is approved as adjuvant treatment for melanoma, based on results from the pivotal CheckMate 238 trial. We present a model-based benefit-risk assessment of nivolumab in adjuvant melanoma supporting a posology change from a weight-based to a less frequent, flat-dosing regimen. The exposure-response (E-R) relationship for efficacy was evaluated using recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) endpoints from the CheckMate 238 trial. The E-R for safety was evaluated using data from 14 studies across a broad range of doses in several tumor types, using grade 3+ adverse events (AEs) and grade 2+ immune-mediated AEs (IMAEs) endpoints. Nivolumab trough exposures were not significant predictors of RFS or DMFS. Covariates significantly associated with increased risk of disease recurrence or death were PD-L1 (< 5% cutoff), lower baseline lactate dehydrogenase, and higher age. Covariates associated with increased risk of distant metastasis or death were PD-L1 (< 5% cutoff) and higher age. Higher nivolumab Cmax1 (maximum concentration after first dose) was significantly associated with grade 2+ IMAEs, but not grade 3+ AEs. The risk of grade 3+ AEs was significantly lower in adjuvant versus advanced melanoma. PS > 0 was associated with higher incidences of grade 2+ IMAEs and grade 3+ AEs. Female patients had significantly higher incidence of grade 2+ IMAEs than male patients. Nivolumab monotherapy in adjuvant melanoma demonstrated a relatively flat E-R relationship over the range of exposures produced by 3 mg/kg every 2 weeks and predicted a comparable benefit-risk profile to flat-dosing regimens.