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A phase I trial of afatinib and bevacizumab in chemo-naïve patients with advanced non-small-cell lung cancer harboring EGFR mutations: Okayama Lung Cancer Study Group Trial 1404.
Lung Cancer 2018; 115:103-108LC

Abstract

OBJECTIVE

In advanced epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC), treatment with afatinib, a second-generation EGFR-tyrosine kinase inhibitor (TKI), confers a significant survival benefit over platinum-based chemotherapy. The first-generation EGFR-TKIs gefitinib and erlotinib in combination with bevacizumab have improved progression-free survival. We hypothesized that the combination of afatinib with bevacizumab would further improve efficacy, and conducted a phase I trial to test this hypothesis.

MATERIALS AND METHODS

Untreated patients with advanced EGFR-mutant NSCLC were enrolled. The primary endpoint was safety. Two doses of afatinib, 40mg/day (level 0) and 30mg/day (level -1), were evaluated in combination with 15mg/kg bevacizumab every 3 weeks. Optimal dosing was determined by dose-limiting toxicity (DLT), with the concentration at which ≤4 of 12 patients experienced toxicity considered the recommended dose.

RESULTS

Nineteen patients were enrolled (level 0:5, level -1:14). Three of the five patients at level 0 experienced a DLT, which indicated that this dose was unfeasible. Three patients at level -1 developed a DLT of grade 3 non-hematological toxicity, which was soon resolved. Grade 3 or worse adverse events were experienced by all five patients at dose level 0 (diarrhea in 2, skin rash in 1, hypoxia in 1, and paronychia in 1), and by three patients at level -1 (diarrhea in 2 and anorexia in 1). Among 16 evaluable patients, 1 had a complete response, 12 had partial responses, and 0 had progressive disease.

CONCLUSION

Afatinib plus bevacizumab (level -1) was well tolerated and showed evidence of favorable disease control. This combination therapy may represent a potent therapeutic option for patients with EGFR-mutant NSCLC.

Authors+Show Affiliations

Department of Respiratory Medicine and Allergy, Okayama University Hospital, 2-5-1, Shikata-cho, Okayama, Japan. Electronic address: tninomiya5@okayama-u.ac.jp.Department of Thoracic Oncology and Medicine, National Hospital Organization, Shikoku Cancer Center, 160, Minamiumemoto-ko, Matsuyama, Japan.Department of Thoracic Oncology and Medicine, National Hospital Organization, Shikoku Cancer Center, 160, Minamiumemoto-ko, Matsuyama, Japan.Department of Thoracic Oncology and Medicine, National Hospital Organization, Shikoku Cancer Center, 160, Minamiumemoto-ko, Matsuyama, Japan.Department of Respiratory Medicine and Allergy, Okayama University Hospital, 2-5-1, Shikata-cho, Okayama, Japan; Center for Oncology, Okayama University Hospital, 2-5-1, Shikata-cho, Okayama, Japan.Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Okayama, Japan.Department of Respiratory Medicine, Iwakuni Clinical Center, 1-1-1, Atago-cho, Iwakuni, Japan.Department of Respiratory Medicine, Iwakuni Clinical Center, 1-1-1, Atago-cho, Iwakuni, Japan.Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital, 2-1-1, Aoe, Okayama, Japan.Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital, 2-1-1, Aoe, Okayama, Japan.Department of Medical Oncology, Okayama Rosai Hospital, 1-10-25, Chikkomidorimachi, Okayama, Japan.Department of Medical Oncology, National Hospital Organization, Yamaguchi-Ube Medical Center, 685, Higashikiwa, Ube, Japan.Department of Respiratory Medicine, National Hospital Organization, Okayama Medical Center, 1711-1, Tamasu, Okayama, Japan.Department of Respiratory Medicine, Japanese Red Cross Kobe Hospital, 1-3-1, Wakihamakaigann-dori, Chuo-ku, Kobe, Japan.Department of General Internal Medicine 4, Kawasaki Medical School, 2-6-1, Nakasange, Okayama, Japan.Center for Innovative Clinical Medicine, Okayama University Hospital, 2-5-1, Shikata-cho, Okayama, Japan.Department of Respiratory Medicine and Allergy, Okayama University Hospital, 2-5-1, Shikata-cho, Okayama, Japan.

Pub Type(s)

Clinical Trial, Phase I
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29290249

Citation

Ninomiya, Takashi, et al. "A Phase I Trial of Afatinib and Bevacizumab in Chemo-naïve Patients With Advanced Non-small-cell Lung Cancer Harboring EGFR Mutations: Okayama Lung Cancer Study Group Trial 1404." Lung Cancer (Amsterdam, Netherlands), vol. 115, 2018, pp. 103-108.
Ninomiya T, Nogami N, Kozuki T, et al. A phase I trial of afatinib and bevacizumab in chemo-naïve patients with advanced non-small-cell lung cancer harboring EGFR mutations: Okayama Lung Cancer Study Group Trial 1404. Lung Cancer. 2018;115:103-108.
Ninomiya, T., Nogami, N., Kozuki, T., Harada, D., Kubo, T., Ohashi, K., ... Kiura, K. (2018). A phase I trial of afatinib and bevacizumab in chemo-naïve patients with advanced non-small-cell lung cancer harboring EGFR mutations: Okayama Lung Cancer Study Group Trial 1404. Lung Cancer (Amsterdam, Netherlands), 115, pp. 103-108. doi:10.1016/j.lungcan.2017.11.025.
Ninomiya T, et al. A Phase I Trial of Afatinib and Bevacizumab in Chemo-naïve Patients With Advanced Non-small-cell Lung Cancer Harboring EGFR Mutations: Okayama Lung Cancer Study Group Trial 1404. Lung Cancer. 2018;115:103-108. PubMed PMID: 29290249.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A phase I trial of afatinib and bevacizumab in chemo-naïve patients with advanced non-small-cell lung cancer harboring EGFR mutations: Okayama Lung Cancer Study Group Trial 1404. AU - Ninomiya,Takashi, AU - Nogami,Naoyuki, AU - Kozuki,Toshiyuki, AU - Harada,Daijiro, AU - Kubo,Toshio, AU - Ohashi,Kadoaki, AU - Kuyama,Shoichi, AU - Kudo,Kenichiro, AU - Bessho,Akihiro, AU - Fukamatsu,Nobuaki, AU - Fujimoto,Nobukazu, AU - Aoe,Keisuke, AU - Shibayama,Takuo, AU - Sugimoto,Keisuke, AU - Takigawa,Nagio, AU - Hotta,Katsuyuki, AU - Kiura,Katsuyuki, Y1 - 2017/11/28/ PY - 2017/10/12/received PY - 2017/11/22/revised PY - 2017/11/27/accepted PY - 2018/1/2/entrez PY - 2018/1/2/pubmed PY - 2018/12/18/medline KW - Afatinib KW - Bevacizumab KW - EGFR KW - EGFR-TKI KW - Non-small-cell lung cancer KW - Phase Ib SP - 103 EP - 108 JF - Lung cancer (Amsterdam, Netherlands) JO - Lung Cancer VL - 115 N2 - OBJECTIVE: In advanced epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC), treatment with afatinib, a second-generation EGFR-tyrosine kinase inhibitor (TKI), confers a significant survival benefit over platinum-based chemotherapy. The first-generation EGFR-TKIs gefitinib and erlotinib in combination with bevacizumab have improved progression-free survival. We hypothesized that the combination of afatinib with bevacizumab would further improve efficacy, and conducted a phase I trial to test this hypothesis. MATERIALS AND METHODS: Untreated patients with advanced EGFR-mutant NSCLC were enrolled. The primary endpoint was safety. Two doses of afatinib, 40mg/day (level 0) and 30mg/day (level -1), were evaluated in combination with 15mg/kg bevacizumab every 3 weeks. Optimal dosing was determined by dose-limiting toxicity (DLT), with the concentration at which ≤4 of 12 patients experienced toxicity considered the recommended dose. RESULTS: Nineteen patients were enrolled (level 0:5, level -1:14). Three of the five patients at level 0 experienced a DLT, which indicated that this dose was unfeasible. Three patients at level -1 developed a DLT of grade 3 non-hematological toxicity, which was soon resolved. Grade 3 or worse adverse events were experienced by all five patients at dose level 0 (diarrhea in 2, skin rash in 1, hypoxia in 1, and paronychia in 1), and by three patients at level -1 (diarrhea in 2 and anorexia in 1). Among 16 evaluable patients, 1 had a complete response, 12 had partial responses, and 0 had progressive disease. CONCLUSION: Afatinib plus bevacizumab (level -1) was well tolerated and showed evidence of favorable disease control. This combination therapy may represent a potent therapeutic option for patients with EGFR-mutant NSCLC. SN - 1872-8332 UR - https://www.unboundmedicine.com/medline/citation/29290249/A_phase_I_trial_of_afatinib_and_bevacizumab_in_chemo_naïve_patients_with_advanced_non_small_cell_lung_cancer_harboring_EGFR_mutations:_Okayama_Lung_Cancer_Study_Group_Trial_1404_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0169-5002(17)30594-9 DB - PRIME DP - Unbound Medicine ER -