Exposure‐safety and exposure‐efficacy analyses for tisotumab vedotin for patients with locally advanced or metastatic solid tumors
Abstract The antibody‐drug conjugate (ADC) tisotumab vedotin (TV) received accelerated approval from the US Food and Drug Administration for treatment of adults with recurrent or metastatic cervical cancer (r/mCC) with disease progression on or after chemotherapy. A population pharmacokinetic (PK) m...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-09-01
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| Series: | CPT: Pharmacometrics & Systems Pharmacology |
| Online Access: | https://doi.org/10.1002/psp4.13007 |
| _version_ | 1797681064155545600 |
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| author | Chaitali Passey Jenna Voellinger Leonid Gibiansky Rudy Gunawan Leonardo Nicacio Ibrahima Soumaoro William D. Hanley Helen Winter Manish Gupta |
| author_facet | Chaitali Passey Jenna Voellinger Leonid Gibiansky Rudy Gunawan Leonardo Nicacio Ibrahima Soumaoro William D. Hanley Helen Winter Manish Gupta |
| author_sort | Chaitali Passey |
| collection | DOAJ |
| description | Abstract The antibody‐drug conjugate (ADC) tisotumab vedotin (TV) received accelerated approval from the US Food and Drug Administration for treatment of adults with recurrent or metastatic cervical cancer (r/mCC) with disease progression on or after chemotherapy. A population pharmacokinetic (PK) model, developed using dosing data from four clinical TV studies, was used to estimate individual exposure and explore safety and efficacy exposure‐response (ER) relationships. Because PK analysis showed no appreciable accumulation of TV and monomethyl auristatin E (MMAE) with repeated dosing, cycle 1 exposure metrics and predicted average concentrations from time zero until end of the cycle in which an event occurred (CavgLast) were used for ER analyses. The probability of achieving objective response increased significantly as the ADC cycle 1 maximum serum concentration (Cmax) increased. The probability of treatment‐related adverse events (AEs) leading to dose modification increased significantly as ADC cycle 1 area under the concentration‐time curve (AUC) increased. Number of grade 2+ ocular AEs increased significantly as ADC cycle 1 AUC, Cmax, and ADC CavgLast increased. MMAE cycle 1 AUC predicted risk of serious treatment‐related AEs. The relationship between ADC exposure and efficacy end points suggests ADC treatment was associated with clinically meaningful response across the observed exposures; greater exposure was associated with increased efficacy. The relationship between ADC and MMAE exposure and safety end points suggests increased exposure was associated with increased AE risk. These results align with clinical findings showing TV 2 mg/kg (≤200 mg for patients ≥100 kg) every 3 weeks is efficacious and tolerable for patients with r/mCC. |
| first_indexed | 2024-03-11T23:39:28Z |
| format | Article |
| id | doaj.art-f763cc3c5c194c33bd0453c17ee0e64a |
| institution | Directory Open Access Journal |
| issn | 2163-8306 |
| language | English |
| last_indexed | 2024-03-11T23:39:28Z |
| publishDate | 2023-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | CPT: Pharmacometrics & Systems Pharmacology |
| spelling | doaj.art-f763cc3c5c194c33bd0453c17ee0e64a2023-09-19T16:40:33ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062023-09-011291262127310.1002/psp4.13007Exposure‐safety and exposure‐efficacy analyses for tisotumab vedotin for patients with locally advanced or metastatic solid tumorsChaitali Passey0Jenna Voellinger1Leonid Gibiansky2Rudy Gunawan3Leonardo Nicacio4Ibrahima Soumaoro5William D. Hanley6Helen Winter7Manish Gupta8Genmab US, Inc. Princeton New Jersey USASeagen Inc. Bothell Washington USAQuantPharm LLC North Potomac Maryland USASeagen Inc. Bothell Washington USASeagen Inc. Bothell Washington USAGenmab US, Inc. Princeton New Jersey USASeagen Inc. Bothell Washington USAGilead Sciences, Inc. Foster City California USAGenmab US, Inc. Princeton New Jersey USAAbstract The antibody‐drug conjugate (ADC) tisotumab vedotin (TV) received accelerated approval from the US Food and Drug Administration for treatment of adults with recurrent or metastatic cervical cancer (r/mCC) with disease progression on or after chemotherapy. A population pharmacokinetic (PK) model, developed using dosing data from four clinical TV studies, was used to estimate individual exposure and explore safety and efficacy exposure‐response (ER) relationships. Because PK analysis showed no appreciable accumulation of TV and monomethyl auristatin E (MMAE) with repeated dosing, cycle 1 exposure metrics and predicted average concentrations from time zero until end of the cycle in which an event occurred (CavgLast) were used for ER analyses. The probability of achieving objective response increased significantly as the ADC cycle 1 maximum serum concentration (Cmax) increased. The probability of treatment‐related adverse events (AEs) leading to dose modification increased significantly as ADC cycle 1 area under the concentration‐time curve (AUC) increased. Number of grade 2+ ocular AEs increased significantly as ADC cycle 1 AUC, Cmax, and ADC CavgLast increased. MMAE cycle 1 AUC predicted risk of serious treatment‐related AEs. The relationship between ADC exposure and efficacy end points suggests ADC treatment was associated with clinically meaningful response across the observed exposures; greater exposure was associated with increased efficacy. The relationship between ADC and MMAE exposure and safety end points suggests increased exposure was associated with increased AE risk. These results align with clinical findings showing TV 2 mg/kg (≤200 mg for patients ≥100 kg) every 3 weeks is efficacious and tolerable for patients with r/mCC.https://doi.org/10.1002/psp4.13007 |
| spellingShingle | Chaitali Passey Jenna Voellinger Leonid Gibiansky Rudy Gunawan Leonardo Nicacio Ibrahima Soumaoro William D. Hanley Helen Winter Manish Gupta Exposure‐safety and exposure‐efficacy analyses for tisotumab vedotin for patients with locally advanced or metastatic solid tumors CPT: Pharmacometrics & Systems Pharmacology |
| title | Exposure‐safety and exposure‐efficacy analyses for tisotumab vedotin for patients with locally advanced or metastatic solid tumors |
| title_full | Exposure‐safety and exposure‐efficacy analyses for tisotumab vedotin for patients with locally advanced or metastatic solid tumors |
| title_fullStr | Exposure‐safety and exposure‐efficacy analyses for tisotumab vedotin for patients with locally advanced or metastatic solid tumors |
| title_full_unstemmed | Exposure‐safety and exposure‐efficacy analyses for tisotumab vedotin for patients with locally advanced or metastatic solid tumors |
| title_short | Exposure‐safety and exposure‐efficacy analyses for tisotumab vedotin for patients with locally advanced or metastatic solid tumors |
| title_sort | exposure safety and exposure efficacy analyses for tisotumab vedotin for patients with locally advanced or metastatic solid tumors |
| url | https://doi.org/10.1002/psp4.13007 |
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