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Phase I study of afatinib plus bevacizumab in patients with advanced non-squamous non-small cell lung cancer harboring EGFR mutations
BACKGROUND: Afatinib is a second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Combination therapies with first-generation EGFR-TKIs and bevacizumab have been reported to prolong progression-free survival (PFS). However, there are few data on the combination of...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
AME Publishing Company
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867760/ https://www.ncbi.nlm.nih.gov/pubmed/33569303 http://dx.doi.org/10.21037/tlcr-20-824 |
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author | Ko, Ryo Shukuya, Takehito Imamura, Chiyo K. Tokito, Takaaki Shimada, Naoko Koyama, Ryo Yamada, Kazuhiko Ishii, Hidenobu Azuma, Koichi Takahashi, Kazuhisa |
author_facet | Ko, Ryo Shukuya, Takehito Imamura, Chiyo K. Tokito, Takaaki Shimada, Naoko Koyama, Ryo Yamada, Kazuhiko Ishii, Hidenobu Azuma, Koichi Takahashi, Kazuhisa |
author_sort | Ko, Ryo |
collection | PubMed |
description | BACKGROUND: Afatinib is a second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Combination therapies with first-generation EGFR-TKIs and bevacizumab have been reported to prolong progression-free survival (PFS). However, there are few data on the combination of afatinib and bevacizumab. METHODS: In this phase I trial, we evaluated the safety of afatinib plus bevacizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC) harboring EGFR mutations. This study consisted of two cohorts. In the dose-finding cohort, enrolled patients were treated with afatinib at a dose of 20, 30, or 40 mg/day (days 1–21) plus bevacizumab at a dose of 15 mg/kg (day 1) in 21-day cycles. This cohort was performed according to a 3 + 3 manner. In the expansion cohort, enrolled patients received the recommended dose (RD) based on the results of the dose-finding cohort. The serum trough concentration of afatinib was determined at the steady state. RESULTS: Seventeen patients were enrolled in this study (6 patients in the dose-finding cohort and 11 patients in the expansion cohort). There were no dose-limiting toxicities (DLTs) with afatinib at a dose of 30 mg/day. With afatinib at a dose of 40 mg/day, two of two patients experienced DLTs (grade 3 diarrhea) in cycle 1. With these results, afatinib at a dose of 30 mg/day plus bevacizumab at a dose of 15 mg/kg was determined as the RD. Eleven patients in the expansion cohort were treated with the RD. Common treatment-related adverse events (AEs) with the RD were diarrhea (79%), rash (71%), perionychia (64%), and stomatitis (50%). Grade 3 AEs with the RD were diarrhea (7%), perionychia (7%), and hypertension (7%). There were no grade 4/5 AEs or cases of interstitial lung disease. Dose-proportional increases in serum afatinib trough concentrations at steady state were not observed. The response rates (RRs) and disease control rates were 55% and 100% in EGFR-TKI-naïve patients. Re-biopsy was performed in eight patients after progressive disease following the study treatment, and three patients acquired a T790M mutation. CONCLUSIONS: Afatinib at a dose of 30 mg/day plus bevacizumab at a dose of 15 mg/kg q3w is well tolerated. |
format | Online Article Text |
id | pubmed-7867760 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | AME Publishing Company |
record_format | MEDLINE/PubMed |
spelling | pubmed-78677602021-02-09 Phase I study of afatinib plus bevacizumab in patients with advanced non-squamous non-small cell lung cancer harboring EGFR mutations Ko, Ryo Shukuya, Takehito Imamura, Chiyo K. Tokito, Takaaki Shimada, Naoko Koyama, Ryo Yamada, Kazuhiko Ishii, Hidenobu Azuma, Koichi Takahashi, Kazuhisa Transl Lung Cancer Res Original Article BACKGROUND: Afatinib is a second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Combination therapies with first-generation EGFR-TKIs and bevacizumab have been reported to prolong progression-free survival (PFS). However, there are few data on the combination of afatinib and bevacizumab. METHODS: In this phase I trial, we evaluated the safety of afatinib plus bevacizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC) harboring EGFR mutations. This study consisted of two cohorts. In the dose-finding cohort, enrolled patients were treated with afatinib at a dose of 20, 30, or 40 mg/day (days 1–21) plus bevacizumab at a dose of 15 mg/kg (day 1) in 21-day cycles. This cohort was performed according to a 3 + 3 manner. In the expansion cohort, enrolled patients received the recommended dose (RD) based on the results of the dose-finding cohort. The serum trough concentration of afatinib was determined at the steady state. RESULTS: Seventeen patients were enrolled in this study (6 patients in the dose-finding cohort and 11 patients in the expansion cohort). There were no dose-limiting toxicities (DLTs) with afatinib at a dose of 30 mg/day. With afatinib at a dose of 40 mg/day, two of two patients experienced DLTs (grade 3 diarrhea) in cycle 1. With these results, afatinib at a dose of 30 mg/day plus bevacizumab at a dose of 15 mg/kg was determined as the RD. Eleven patients in the expansion cohort were treated with the RD. Common treatment-related adverse events (AEs) with the RD were diarrhea (79%), rash (71%), perionychia (64%), and stomatitis (50%). Grade 3 AEs with the RD were diarrhea (7%), perionychia (7%), and hypertension (7%). There were no grade 4/5 AEs or cases of interstitial lung disease. Dose-proportional increases in serum afatinib trough concentrations at steady state were not observed. The response rates (RRs) and disease control rates were 55% and 100% in EGFR-TKI-naïve patients. Re-biopsy was performed in eight patients after progressive disease following the study treatment, and three patients acquired a T790M mutation. CONCLUSIONS: Afatinib at a dose of 30 mg/day plus bevacizumab at a dose of 15 mg/kg q3w is well tolerated. AME Publishing Company 2021-01 /pmc/articles/PMC7867760/ /pubmed/33569303 http://dx.doi.org/10.21037/tlcr-20-824 Text en 2021 Translational Lung Cancer Research. All rights reserved. https://creativecommons.org/licenses/by-nc-nd/4.0/Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Original Article Ko, Ryo Shukuya, Takehito Imamura, Chiyo K. Tokito, Takaaki Shimada, Naoko Koyama, Ryo Yamada, Kazuhiko Ishii, Hidenobu Azuma, Koichi Takahashi, Kazuhisa Phase I study of afatinib plus bevacizumab in patients with advanced non-squamous non-small cell lung cancer harboring EGFR mutations |
title | Phase I study of afatinib plus bevacizumab in patients with advanced non-squamous non-small cell lung cancer harboring EGFR mutations |
title_full | Phase I study of afatinib plus bevacizumab in patients with advanced non-squamous non-small cell lung cancer harboring EGFR mutations |
title_fullStr | Phase I study of afatinib plus bevacizumab in patients with advanced non-squamous non-small cell lung cancer harboring EGFR mutations |
title_full_unstemmed | Phase I study of afatinib plus bevacizumab in patients with advanced non-squamous non-small cell lung cancer harboring EGFR mutations |
title_short | Phase I study of afatinib plus bevacizumab in patients with advanced non-squamous non-small cell lung cancer harboring EGFR mutations |
title_sort | phase i study of afatinib plus bevacizumab in patients with advanced non-squamous non-small cell lung cancer harboring egfr mutations |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867760/ https://www.ncbi.nlm.nih.gov/pubmed/33569303 http://dx.doi.org/10.21037/tlcr-20-824 |
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