5P - Tisotumab vedotin (TV) dose schedule optimization in non-cervical populations

Background

TV, a tissue factor-directed antibody-drug conjugate, is approved under accelerated approval in the US at a dose of 2.0 mg/kg every 21 days (Q3W) for adult patients (pts) with recurrent or metastatic cervical cancer (r/mCC) who have progressed on or after chemotherapy. Based on TV pharmacokinetics (PK) and exposure-response relationships, we hypothesized that a higher dose intensity and optimized key PK parameters can lead to improvement in efficacy. Here, we report a pharmacometric approach to continuously optimize the TV dosing schedule in non-cervical solid tumors.

Methods

TV is being evaluated for pts with advanced solid tumors in 3 schedules: Q3W; Days 1, 8, and 15 of a 28-day cycle (3Q4W); and Days 1 and 15 of a 28-day cycle (Q2W). A population-PK-tumor growth inhibition (PPK-TGI) model was developed using available longitudinal tumor size data from 711 pts, using a wide range of doses and 3 schedules, to determine the effect of TV exposure on tumor dynamics. A Markov model was developed to characterize the occurrence, severity, and duration of ocular adverse events (OAEs). Alternate TV dosing regimen simulations were performed in non-cervical solid tumor populations.

Results

Compared with the approved 2.0 mg/kg Q3W regimen, the PPK model predicted a 26% increase in AUC_12wks at 1.2 mg/kg 3Q4W, but DLTs were observed in pts with ovarian cancer. At a lower dose of 0.9 mg/kg 3Q4W, AUC_12wks was predicted to decrease 12% and C_max to decrease 54%; this regimen had a tolerable safety profile but modest antitumor activity. Alternatively, 1.7 mg/kg Q2W predicted a 24% increase in AUC_12wks, 15% decrease in C_max, and a higher C_trough. PPK-TGI modeling predicted 1.7 mg/kg Q2W to result in more time above the predicted EC₅₀ and a greater reduction in tumor size, thus potentially better efficacy. Markov modeling predicted a potentially higher rate of Grade ≥2 OAEs for 1.7 mg/kg Q2W compared with 2.0 mg/kg Q3W.

Conclusions

TV demonstrated a favorable benefit-risk profile in r/mCC at the approved 2.0 mg/kg Q3W regimen. Along with available data, our modeling approach suggests that a Q2W schedule may lead to improvements in efficacy and potential risk of a higher rate of Grade ≥2 OAEs. Currently, TV is being evaluated at 1.7 mg/kg Q2W in advanced solid tumors in the enrolling innovaTV 207 study.

Clinical trial identification

Editorial acknowledgement

Writing and editorial assistance was provided by Kristoffer Myczek, PhD, and Stephanie Wamsley of Ashfield MedComms, an Inizio Company, and funded by Seagen, Inc.

Legal entity responsible for the study

Seagen, Inc. and Genmab.

Funding

Seagen, Inc. and Genmab.

Disclosure

J. Voellinger: Financial Interests, Personal, Full or part-time Employment: Seagen, Inc.; Financial Interests, Personal, Stocks/Shares: Seagen, Inc. C. Passey, Y.S. Feng, A. Gerritsen, I. Soumaoro, M. Gupta: Financial Interests, Personal, Full or part-time Employment: Genmab. R. Gunawan, C. O'Day, L. Nicacio, W. Hanley: Financial Interests, Personal, Full or part-time Employment: Seagen, Inc. L. Gibiansky: Financial Interests, Personal, Full or part-time Employment: QuantPharm Llc; Financial Interests, Personal, Other, Paid Consultant: Seagen, Inc., Genmab. D. Polhamus: Financial Interests, Personal, Full or part-time Employment: Metrum Research Group; Financial Interests, Personal, Other, Paid Consultant: Seagen, Inc., Genmab.