PMID- 33569303
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220420
IS  - 2218-6751 (Print)
IS  - 2226-4477 (Electronic)
IS  - 2218-6751 (Linking)
VI  - 10
IP  - 1
DP  - 2021 Jan
TI  - Phase I study of afatinib plus bevacizumab in patients with advanced non-squamous 
      non-small cell lung cancer harboring EGFR mutations.
PG  - 183-192
LID - 10.21037/tlcr-20-824 [doi]
AB  - 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-naive 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.
CI  - 2021 Translational Lung Cancer Research. All rights reserved.
FAU - Ko, Ryo
AU  - Ko R
AD  - Department of Respiratory Medicine, Juntendo University Graduate School of 
      Medicine, Tokyo, Japan.
FAU - Shukuya, Takehito
AU  - Shukuya T
AD  - Department of Respiratory Medicine, Juntendo University Graduate School of 
      Medicine, Tokyo, Japan.
FAU - Imamura, Chiyo K
AU  - Imamura CK
AD  - Department of Clinical Pharmacokinetics and Pharmacodynamics, Keio University 
      School of Medicine, Tokyo, Japan.
AD  - Advanced Cancer Translational Research Institute, Showa University, Tokyo, Japan.
FAU - Tokito, Takaaki
AU  - Tokito T
AD  - Division of Respiratory, Neurology, and Rheumatology, Department of Internal 
      Medicine, Kurume University School of Medicine, Kurume, Japan.
FAU - Shimada, Naoko
AU  - Shimada N
AD  - Department of Respiratory Medicine, Juntendo University Graduate School of 
      Medicine, Tokyo, Japan.
FAU - Koyama, Ryo
AU  - Koyama R
AD  - Department of Respiratory Medicine, Juntendo University Graduate School of 
      Medicine, Tokyo, Japan.
FAU - Yamada, Kazuhiko
AU  - Yamada K
AD  - Division of Respiratory, Neurology, and Rheumatology, Department of Internal 
      Medicine, Kurume University School of Medicine, Kurume, Japan.
FAU - Ishii, Hidenobu
AU  - Ishii H
AD  - Division of Respiratory, Neurology, and Rheumatology, Department of Internal 
      Medicine, Kurume University School of Medicine, Kurume, Japan.
FAU - Azuma, Koichi
AU  - Azuma K
AD  - Division of Respiratory, Neurology, and Rheumatology, Department of Internal 
      Medicine, Kurume University School of Medicine, Kurume, Japan.
FAU - Takahashi, Kazuhisa
AU  - Takahashi K
AD  - Department of Respiratory Medicine, Juntendo University Graduate School of 
      Medicine, Tokyo, Japan.
LA  - eng
PT  - Journal Article
PL  - China
TA  - Transl Lung Cancer Res
JT  - Translational lung cancer research
JID - 101646875
PMC - PMC7867760
OTO - NOTNLM
OT  - Afatinib
OT  - EGFR mutation
OT  - bevacizumab
OT  - non-small cell lung cancer (NSCLC)
COIS- Conflicts of Interest: All authors have completed the ICMJE uniform disclosure 
      form (available at http://dx.doi.org/10.21037/tlcr-20-824). RK reports grants and 
      personal fees from Boehringer Ingelheim and AstraZeneca, personal fees from Taiho 
      Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical, and Pfizer, outside 
      the submitted work. TS reports grants and personal fee from MSD and Boehringer 
      Ingelheim, personal fees from Nichi-Iko Pharmaceutical Co., Daiichi Sankyo, Ono 
      Pharmaceutical, Bristol-Myers Squibb, Eli Lilly, Novartis, and Taiho 
      Pharmaceutical, outside the submitted work. CKI reports personal fees from Chugai 
      Pharmaceutical and Ono Pharmaceutical, outside the submitted work. TT reports 
      personal fees from AstraZeneca, Chugai Pharmaceutical, MSD and Boehringer 
      Ingelheim, outside the submitted work. KY reports personal fees from Chugai 
      Pharmaceutical, outside the submitted work. HI reports grants and personal fees 
      from Boehringer Ingelheim, personal fees from Ono Pharmaceutical, Chugai 
      Pharmaceutical, AstraZeneca and MSD, outside the submitted work. KA reports 
      personal fees from Chugai Pharmaceutical, AstraZeneca, Merck Sharp and Dohme, 
      Bristol-Myers Squibb, and Ono Pharmaceutical, outside the submitted work. KT 
      reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, and 
      Chugai Pharmaceutical, grants from MSD, and Bristol-Myers Squibb, personal fees 
      from Eli Lilly, Astellas, Ono Pharmaceutical, Taiho Pharmaceutical, Shionogi, 
      Novartis, Pfizer, Glaxo Smith Kline, and Actelion, outside the submitted work. 
      The other authors have no conflicts of interest to declare.
EDAT- 2021/02/12 06:00
MHDA- 2021/02/12 06:01
PMCR- 2021/01/01
CRDT- 2021/02/11 05:54
PHST- 2021/02/11 05:54 [entrez]
PHST- 2021/02/12 06:00 [pubmed]
PHST- 2021/02/12 06:01 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - tlcr-10-01-183 [pii]
AID - 10.21037/tlcr-20-824 [doi]
PST - ppublish
SO  - Transl Lung Cancer Res. 2021 Jan;10(1):183-192. doi: 10.21037/tlcr-20-824.