Exposure-safety Markov modeling of ocular adverse events in patient populations treated with tisotumab vedotin.

Tisotumab vedotin (TV), a tissue factor-directed antibody-drug conjugate (ADC), is approved in the US at 2.0 mg/kg every 3 weeks (Q3W) for adult patients with recurrent or metastatic cervical cancer following disease progression on or after chemotherapy. Previous logistic regression analysis showed a positive association between TV exposure and ocular adverse events (OAEs), which were identified as prespecified AEs of interest in TV clinical studies. To further optimize TV dose from a safety perspective, we developed a discrete-time Markov model (DTMM) to characterize exposure-response (E-R) relationships of exposures of both ADC and the microtubule-disrupting agent monomethyl auristatin E to the incidence, severity, and longitudinal time course of grade ≥ 2 OAEs in patients with advanced solid tumors. A total of 757 patients who received TV as monotherapy or combination (with carboplatin, bevacizumab, or pembrolizumab) across seven clinical studies were included in this analysis. Of multiple covariates modeled, implementation of an eye care plan was the only covariate to significantly reduce risk of grade ≥ 2 OAEs. The DTMM suggested an association between ADC exposure and risk of grade ≥ 2 OAEs. Based on the totality of data from clinical outcomes, pharmacokinetics, and E-R analyses, as well as DTMM modeling results, TV 1.7 mg/kg every 2 weeks may provide higher efficacy with slightly increased risk of OAEs compared with 2.0 mg/kg Q3W, although these OAEs are manageable with an appropriate eye care plan. ClinicalTrials.gov ID (first submission): NCT03485209 (2018-03-08), NCT03657043 (2018-08-22), NCT03438396 (2018-02-08), NCT03786081 (2018-12-13), NCT03913741 (2019-03-29), NCT02001623 (2013-11-14), and NCT02552121 (2015-09-14).