Sitravatinib in combination with nivolumab plus ipilimumab in patients with advanced clear cell renal cell carcinoma: a phase 1 trial
Abstract We conducted a phase I trial to determine the optimal dose of triplet therapy with the tyrosine kinase inhibitor sitravatinib plus nivolumab plus ipilimumab in 22 previously untreated patients with advanced clear cell renal cell carcinoma. The primary endpoint was safety. Secondary endpoint...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55642-8 |
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| author | Pavlos Msaouel Kai Yu Ying Yuan Jianfeng Chen Xinmiao Yan Menuka Karki Fei Duan Rahul A. Sheth Priya Rao Kanishka Sircar Amishi Y. Shah Amado J. Zurita Giannicola Genovese Min Li Chih-Chen Yeh Minghao Dang Guangchun Han Yanshuo Chu Max Hallin Peter Olson Rui Yang Daniela Slavin Hirak Der-Torossian Curtis D. Chin Nizar M. Tannir Linghua Wang Jianjun Gao |
| author_facet | Pavlos Msaouel Kai Yu Ying Yuan Jianfeng Chen Xinmiao Yan Menuka Karki Fei Duan Rahul A. Sheth Priya Rao Kanishka Sircar Amishi Y. Shah Amado J. Zurita Giannicola Genovese Min Li Chih-Chen Yeh Minghao Dang Guangchun Han Yanshuo Chu Max Hallin Peter Olson Rui Yang Daniela Slavin Hirak Der-Torossian Curtis D. Chin Nizar M. Tannir Linghua Wang Jianjun Gao |
| author_sort | Pavlos Msaouel |
| collection | DOAJ |
| description | Abstract We conducted a phase I trial to determine the optimal dose of triplet therapy with the tyrosine kinase inhibitor sitravatinib plus nivolumab plus ipilimumab in 22 previously untreated patients with advanced clear cell renal cell carcinoma. The primary endpoint was safety. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), 1-year survival probability, and sitravatinib pharmacokinetics. Sitravatinib dose of 35 mg daily plus nivolumab 3 mg/kg and ipilimumab 1 mg/kg resulted in high frequency of immune-related adverse events. Subsequent dose reduction of ipilimumab to 0.7 mg/kg allowed safe escalation of sitravatinib up to 100 mg daily. Overall, the triplet combination achieved ORR 45.5%, DCR 86.4%, median PFS 14.5 months, and 1-year survival 80.8%. Median OS and DOR were not reached. Sitravatinib exposure increased dose-dependently. Single-cell RNA-seq of longitudinally collected tumor biopsies from 12 patients identified a tumor cell-specific epithelial-mesenchymal transition-like program associated with treatment resistance and poor outcomes. Treatment resistance was characterized by a transition from cytotoxic to exhausted T cell state and enrichment for M2-like myeloid cells. The observed hypothesis-generating changes in gene expression dynamics and cellular states may help inform future strategies to optimize immunotherapy efficacy. Clinical Trials.gov identifier: NCT04518046 |
| format | Article |
| id | doaj-art-3d7215b77310495a922a3e08ad74dabf |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-3d7215b77310495a922a3e08ad74dabf2025-01-12T12:31:23ZengNature PortfolioNature Communications2041-17232025-01-0116111810.1038/s41467-024-55642-8Sitravatinib in combination with nivolumab plus ipilimumab in patients with advanced clear cell renal cell carcinoma: a phase 1 trialPavlos Msaouel0Kai Yu1Ying Yuan2Jianfeng Chen3Xinmiao Yan4Menuka Karki5Fei Duan6Rahul A. Sheth7Priya Rao8Kanishka Sircar9Amishi Y. Shah10Amado J. Zurita11Giannicola Genovese12Min Li13Chih-Chen Yeh14Minghao Dang15Guangchun Han16Yanshuo Chu17Max Hallin18Peter Olson19Rui Yang20Daniela Slavin21Hirak Der-Torossian22Curtis D. Chin23Nizar M. Tannir24Linghua Wang25Jianjun Gao26Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer CenterDepartment of Biostatistics, The University of Texas MD Anderson Cancer CenterDepartment of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer CenterDepartment of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Interventional Radiology, The University of Texas MD Anderson Cancer CenterDepartment of Pathology, The University of Texas MD Anderson Cancer CenterDepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer CenterDepartment of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer CenterDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer CenterDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer CenterMirati Therapeutics, IncMirati Therapeutics, IncMirati Therapeutics, IncMirati Therapeutics, IncMirati Therapeutics, IncMirati Therapeutics, IncDepartment of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Genomic Medicine, The University of Texas MD Anderson Cancer CenterDepartment of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer CenterAbstract We conducted a phase I trial to determine the optimal dose of triplet therapy with the tyrosine kinase inhibitor sitravatinib plus nivolumab plus ipilimumab in 22 previously untreated patients with advanced clear cell renal cell carcinoma. The primary endpoint was safety. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), 1-year survival probability, and sitravatinib pharmacokinetics. Sitravatinib dose of 35 mg daily plus nivolumab 3 mg/kg and ipilimumab 1 mg/kg resulted in high frequency of immune-related adverse events. Subsequent dose reduction of ipilimumab to 0.7 mg/kg allowed safe escalation of sitravatinib up to 100 mg daily. Overall, the triplet combination achieved ORR 45.5%, DCR 86.4%, median PFS 14.5 months, and 1-year survival 80.8%. Median OS and DOR were not reached. Sitravatinib exposure increased dose-dependently. Single-cell RNA-seq of longitudinally collected tumor biopsies from 12 patients identified a tumor cell-specific epithelial-mesenchymal transition-like program associated with treatment resistance and poor outcomes. Treatment resistance was characterized by a transition from cytotoxic to exhausted T cell state and enrichment for M2-like myeloid cells. The observed hypothesis-generating changes in gene expression dynamics and cellular states may help inform future strategies to optimize immunotherapy efficacy. Clinical Trials.gov identifier: NCT04518046https://doi.org/10.1038/s41467-024-55642-8 |
| spellingShingle | Pavlos Msaouel Kai Yu Ying Yuan Jianfeng Chen Xinmiao Yan Menuka Karki Fei Duan Rahul A. Sheth Priya Rao Kanishka Sircar Amishi Y. Shah Amado J. Zurita Giannicola Genovese Min Li Chih-Chen Yeh Minghao Dang Guangchun Han Yanshuo Chu Max Hallin Peter Olson Rui Yang Daniela Slavin Hirak Der-Torossian Curtis D. Chin Nizar M. Tannir Linghua Wang Jianjun Gao Sitravatinib in combination with nivolumab plus ipilimumab in patients with advanced clear cell renal cell carcinoma: a phase 1 trial Nature Communications |
| title | Sitravatinib in combination with nivolumab plus ipilimumab in patients with advanced clear cell renal cell carcinoma: a phase 1 trial |
| title_full | Sitravatinib in combination with nivolumab plus ipilimumab in patients with advanced clear cell renal cell carcinoma: a phase 1 trial |
| title_fullStr | Sitravatinib in combination with nivolumab plus ipilimumab in patients with advanced clear cell renal cell carcinoma: a phase 1 trial |
| title_full_unstemmed | Sitravatinib in combination with nivolumab plus ipilimumab in patients with advanced clear cell renal cell carcinoma: a phase 1 trial |
| title_short | Sitravatinib in combination with nivolumab plus ipilimumab in patients with advanced clear cell renal cell carcinoma: a phase 1 trial |
| title_sort | sitravatinib in combination with nivolumab plus ipilimumab in patients with advanced clear cell renal cell carcinoma a phase 1 trial |
| url | https://doi.org/10.1038/s41467-024-55642-8 |
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