Exposure-Response Analyses of Tremelimumab Monotherapy or in Combination with Durvalumab in Patients with Unresectable Hepatocellular Carcinoma
©2022 The Authors; Published by the American Association for Cancer Research..
PURPOSE: A novel single-dose regimen of 300 mg tremelimumab in combination with durvalumab [Single Tremelimumab Regular Interval Durvalumab (STRIDE)] has demonstrated a favorable benefit-risk profile in the phase I/II Study 22 (NCT02519348) and phase III HIMALAYA study (NCT03298451). This study evaluated the pharmacokinetics, exposure-response, and exposure-pharmacodynamics relationships of tremelimumab in patients with unresectable hepatocellular carcinoma (uHCC).
PATIENTS AND METHODS: A previous tremelimumab population pharmacokinetic model was validated using data from parts 2 and 3 of Study 22. Exposure-response analyses explored relationships of tremelimumab exposure with efficacy and safety. Pharmacokinetics and pharmacodynamics relationships were evaluated using linear and nonlinear regression models.
RESULTS: The observed pharmacokinetics of tremelimumab in uHCC were consistent with predictions; no significant covariates were identified. Tremelimumab exposure was not significantly associated with adverse events, objective response rate, or progression-free survival. Overall survival (OS) was longer for patients with tremelimumab exposure, minimum serum drug concentration (Cmin1) ≥ median versus Cmin1 < median (18.99 months vs. 10.97 months), but this exposure-survival analysis might be confounded with baseline characteristics of albumin level and neutrophil to lymphocyte ratio, which had a significant impact on OS (P = 0.0004 and 0.0001, respectively). The predicted Cmin1 of tremelimumab in STRIDE regimen (12.9 μg/mL) was greater than the estimated concentration of tremelimumab eliciting half-maximal increases (EC50 = 5.24 μg/mL) in CD8+Ki67+ T-cell counts.
CONCLUSIONS: Our findings support novel insights into tremelimumab pharmacokinetics and exposure-response relationships in HCC and support the clinical utility of the STRIDE regimen in patients with uHCC.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:29 |
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| Enthalten in: |
Clinical cancer research : an official journal of the American Association for Cancer Research - 29(2023), 4 vom: 16. Feb., Seite 754-763 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Song, Xuyang [VerfasserIn] |
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| Links: |
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| Themen: |
28X28X9OKV |
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| Anmerkungen: |
Date Completed 17.02.2023 Date Revised 05.04.2023 published: Print Citation Status MEDLINE |
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| doi: |
10.1158/1078-0432.CCR-22-1983 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM349899525 |
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| 100 | 1 | |a Song, Xuyang |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Exposure-Response Analyses of Tremelimumab Monotherapy or in Combination with Durvalumab in Patients with Unresectable Hepatocellular Carcinoma |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Completed 17.02.2023 | ||
| 500 | |a Date Revised 05.04.2023 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2022 The Authors; Published by the American Association for Cancer Research. | ||
| 520 | |a PURPOSE: A novel single-dose regimen of 300 mg tremelimumab in combination with durvalumab [Single Tremelimumab Regular Interval Durvalumab (STRIDE)] has demonstrated a favorable benefit-risk profile in the phase I/II Study 22 (NCT02519348) and phase III HIMALAYA study (NCT03298451). This study evaluated the pharmacokinetics, exposure-response, and exposure-pharmacodynamics relationships of tremelimumab in patients with unresectable hepatocellular carcinoma (uHCC) | ||
| 520 | |a PATIENTS AND METHODS: A previous tremelimumab population pharmacokinetic model was validated using data from parts 2 and 3 of Study 22. Exposure-response analyses explored relationships of tremelimumab exposure with efficacy and safety. Pharmacokinetics and pharmacodynamics relationships were evaluated using linear and nonlinear regression models | ||
| 520 | |a RESULTS: The observed pharmacokinetics of tremelimumab in uHCC were consistent with predictions; no significant covariates were identified. Tremelimumab exposure was not significantly associated with adverse events, objective response rate, or progression-free survival. Overall survival (OS) was longer for patients with tremelimumab exposure, minimum serum drug concentration (Cmin1) ≥ median versus Cmin1 < median (18.99 months vs. 10.97 months), but this exposure-survival analysis might be confounded with baseline characteristics of albumin level and neutrophil to lymphocyte ratio, which had a significant impact on OS (P = 0.0004 and 0.0001, respectively). The predicted Cmin1 of tremelimumab in STRIDE regimen (12.9 μg/mL) was greater than the estimated concentration of tremelimumab eliciting half-maximal increases (EC50 = 5.24 μg/mL) in CD8+Ki67+ T-cell counts | ||
| 520 | |a CONCLUSIONS: Our findings support novel insights into tremelimumab pharmacokinetics and exposure-response relationships in HCC and support the clinical utility of the STRIDE regimen in patients with uHCC | ||
| 650 | 4 | |a Clinical Trial, Phase II | |
| 650 | 4 | |a Clinical Trial, Phase I | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 700 | 1 | |a Khan, Anis A |e verfasserin |4 aut | |
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| 700 | 1 | |a Zhou, Diansong |e verfasserin |4 aut | |
| 700 | 1 | |a Lim, KyoungSoo |e verfasserin |4 aut | |
| 700 | 1 | |a Krishna, Rajesh |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Lu |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Kun |e verfasserin |4 aut | |
| 700 | 1 | |a McCoon, Patricia |e verfasserin |4 aut | |
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| 700 | 1 | |a Gibbs, Megan |e verfasserin |4 aut | |
| 700 | 1 | |a Kurland, John F |e verfasserin |4 aut | |
| 700 | 1 | |a Abou-Alfa, Ghassan K |e verfasserin |4 aut | |
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