Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), such as erlotinib, are standard-of-care for patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC), but most patients progress within 1 year. Previously, we demonstrated that erlotinib plus bevacizumab (EB) improved progression-free survival (PFS) in patients with EGFR -positive non-squamous NSCLC in the randomized JO25567 study. To understand this effect, we conducted comprehensive exploratory biomarker analyses.
Methods: Using blood and tissue specimens from patients enrolled in the JO25567 study, angiogenesis-related serum factors, plasma vascular endothelial growth factor-A (pVEGFA), angiogenesis-related gene polymorphisms, and messenger RNAs (mRNAs) in tumor tissue were analyzed. Interactions between potential predictors and treatment effect on PFS were analyzed in a Cox model. Continuous variable predictors were evaluated by multivariate fractional polynomial interaction methodology and subpopulation treatment effect pattern plotting (STEPP).
Results: Overall, 152 patients treated with EB or erlotinib alone (E) were included in the analysis. Among 26 factors analyzed in 134 baseline serum samples, high follistatin and low leptin were identified as potential biomarkers for worse and better outcomes with EB, with interaction P values of 0.0168 and 0.0049, respectively. Serum concentrations of 12 angiogenic factors were significantly higher in patients with high follistatin. Low pVEGFA levels related to better outcomes with EB, interaction P=0.033. VEGF-A165a was the only predictive tissue mRNA, showing a similar trend to pVEGFA. No valid results were obtained in 13 polymorphisms of eight genes.
Conclusions: EB treatment showed better treatment outcomes in patients with low pVEGFA and serum leptin, and limited efficacy in patients with high serum follistatin.
Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-632/coif). TH serves as an unpaid editorial board member of Translational Lung Cancer Research from January 2022 to December 2023. MN reports receiving grants and personal fees from AstraZeneca, Amgen, MSD, Taiho Pharmaceutical, Takeda Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Novartis, Pfizer, Bristol-Myers Squibb, and Merck Biopharma; personal fees from Ono Pharmaceutical, Boehringer Ingelheim, and Janssen Pharmaceutical; and grants from Daiichi-Sankyo. SA reports grants from AstraZeneca, Eli Lilly, Ono, Taiho Pharmaceutical, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, MSD, Chugai Pharmaceutical, Merck, and F. Hoffmann-La Roche; and honoraria from Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, Sawai Pharmaceutical, Novartis Pharma, AstraZeneca, Ono, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, Hisamitsu, MSD, Kyowa Hakko Kirin, Merck, and Thermo Fisher Scientific. KG reports receiving research grants from Amgen Astellas BioPharma, Amgen, AstraZeneca, Bayer Yakuhin, Ltd., Bristol-Myers Squibb K.K., Boehringer Ingelheim Japan, Inc., Blueprint Medicines Corporation, Daiichi-Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Haihe Biopharma Co., Ltd., Ignyta, Inc., Janssen Pharmaceutical K.K., Kissei Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Life Technologies Japan Ltd., Loxo Oncology, Inc., Medical & Biological Laboratories Co., Ltd., Merck Biopharma Co., Ltd., Merus N.V., MSD K.K., NEC Corporation, Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sumitomo Dainippon Pharma Co., Ltd., Spectrum Pharmaceuticals, Inc., Sysmex Corporation, Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Turning Point Therapeutics, Inc.; honoraria from Amgen Inc., AstraZeneca K.K., Bayer HealthCare Pharmaceuticals Inc., Boehringer Ingelheim Japan, Inc., Bristol-Myers Squibb K.K., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Guardant Health Inc., Janssen Pharmaceutical K.K., Kyowa Kirin Co., Ltd., Life Technologies Japan Ltd., Medpace Japan K.K., Merck Biopharma Co., Ltd., MSD K.K., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Taiho Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd. YH reports receiving payment/honoraria from Chugai Pharmaceutical, AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical, Bristol-Myers Squibb, Kyowa Kirin, and Ono Pharmaceutical. TS reports receiving institutional funding from AbbVie, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Kissei Pharmaceutical, MSD, Novartis Pharma, Pfizer Japan, Takeda Pharmaceutical; honoraria from AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, Covidien Japan, Daiichi Sankyo, Eli Lilly Japan, Kyowa Hakko Kirin, MSD, Mochida Pharmaceutical, Nippon Boehringer Ingelheim, Novartis Pharma, Ono Pharmaceutical, Pfizer Japan, Taiho Pharmaceutical, Takeda Pharmaceutical, and Towa Pharmaceutical; and is an employee of Precision Medicine Asia. TH reports receiving research grants from Chugai Pharmaceutical, AstraZeneca, Nippon Boehringer Ingelheim, Pfizer, Eli Lilly, Takeda Bio, Novartis Pharma, Ono Pharmaceutical, Daiichi-Sankyo, Merck Serono, Dainippon Sumitomo Pharma, Bristol-Myers Squibb, and Eisai. Kazuhiko Nakagawa reports receiving honoraria from Chugai Pharmaceutical, AstraZeneca, Nippon Boehringer Ingelheim, and Eli Lilly. HY reports research grants from Chugai Pharmaceutical, Boehringer Ingelheim, and Nippon Kayaku; consulting fees from Delta Fly Pharma; honoraria from Eli Lilly, Chugai Pharmaceutical, Boehringer Ingelheim, Delta Fly Pharma, AstraZeneca, BMS, MSD, Ono Pharmaceutical, Merck Biopharma, Nippon Kayaku, Taiho Pharmaceutical, Otsuka Pharmaceutical, Takeda Pharmaceutical, Novartis Pharmaceutical, Amgen, Nipro Pharma, Kyowa Kirin, and Pfizer. NN reports receiving honoraria from Chugai Pharmaceutical, Pfizer Japan, Taiho Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, AstraZeneca, and Nippon Boehringer Ingelheim. MM reports receiving honoraria from Chugai Pharmaceutical and AstraZeneca; research grants and honoraria from Nippon Boehringer Ingelheim. IO reports receiving payment/honoraria from Chugai Pharmaceutical. Noboru Yamamoto reports receiving research grants from Chugai Pharmaceutical, Taiho Pharmaceutical, Eisai, Eli Lilly, Quintiles, Astellas Pharma, Bristol-Myers Squibb, Novartis, Daiichi-Sankyo, Pfizer, Boehringer Ingelheim, Kyowa-Hakko Kirin, Bayer, Ono Pharmaceutical Co., Ltd., Takeda, Janssen Pharma, MSD, Merck, GSK, Sumitomo Dainippon, Chiome Bioscience Inc, Otsuka, Carna Bioscienes, Genmab, and Shionogi; honoraria from Ono Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, Pfizer, Eli Lilly, Bristol-Myers Squibb, Sysmex, and Eisai; and consulting fees from Eisai, Otsuka, Takeda, Boehringer Ingelheim, and Cimic. YI and KT are employees of Chugai Pharmaceutical. MF reports receiving honoraria from Eisai and Chugai Pharmaceutical. Nobuyuki Yamamoto reports receiving grants from MSD K.K., AstraZeneca, Ono Pharmaceutical Co., Ltd., Daiichi-Sankyo Co., Ltd., Taiho Pharmaceutical., Takeda, Chugai Pharmaceutical Co., Ltd., Pfizer, Amgen, Janssen Pharmaceutical K.K., Toppan Printing, Terumo, and Boehringer Ingelheim; consulting fees from AstraZeneca, Daiichi-Sankyo, Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Boehringer Ingelheim, Novartis, Bristol-Myers Squibb, Nippon Kayaku, Life Technologies Japan, Ltd., Amgen, Guardant Health Japan, and Janssen Pharmaceutical K.K.; honoraria from MSD, AstraZeneca, Ono Pharmaceutical, Thermo Fisher Scientific, Daiichi-Sankyo, Taiho Pharmaceutical, Takeda, Chugai Pharmaceutical, Eli Lilly Japan K.K., Boehringer Ingelheim, Novartis, Pfizer, Bristol-Myers Squibb, Nippon Kayaku, GSK K.K., Sanofi K.K., Hisamitsu Pharmaceutical, and Merck Biopharma; and participated on a data safety monitoring board/advisory board for MSD K.K., AstraZeneca, Ono Pharmaceutical, Takeda Pharmaceutical, Chugai Pharmaceutical, Eli Lilly Japan K.K., Boehringer Ingelheim, and Pfizer. Kazuto Nishio reports receiving grants from Nippon Boehringer Ingelheim, West Japan Oncology Group, Thoracic Oncology Research Group, North East Japan Study Group, Clinical Research Support Center Kyushu, Nichirei Biosciences Inc., and Eli Lilly Japan; consulting fees from SymBio Pharmaceuticals, Solasia Pharma, Eli Lilly Japan, and Otsuka Pharmaceutical; honoraria for lectures from Boehringer Ingelheim Japan, AstraZeneca, Chugai, Novartis Pharma, Eisai, MSD, Bristol-Myers Squibb, Ono Pharmaceutical, Pfizer, Sanofi, Guardant Health, Eli Lilly Japan, Amgen, Merck Biopharma, Roche Diagnostics, Yakult Honsha, Takeda Pharmaceutical, Fujirebio, and Janssen Pharmaceutical. All authors report receiving funding from Chugai Pharmaceutical Co., Ltd. The authors have no other conflicts of interest to declare.
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