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Clinical Trial
. 2025 Mar 22;16(1):2825.
doi: 10.1038/s41467-025-58186-7.

Serum VEGF-A as a biomarker for the addition of bevacizumab to chemo-immunotherapy in metastatic NSCLC

Kentaro Tanaka  1   2   2 , Jun Sugisaka  3 , Yoshimasa Shiraishi  4 , Yasutaka Watanabe  5 , Haruko Daga  6 , Koichi Azuma  7 , Kazumi Nishino  8 , Masahide Mori  9 , Takayo Ota  10 , Haruhiro Saito  11 , Akito Hata  12 , Tadashi Sakaguchi  13 , Toshiyuki Kozuki  14 , Hiroaki Akamatsu  15 , Hirotaka Matsumoto  16 , Motoko Tachihara  17 , Kazushige Wakuda  18 , Yuki Sato  19 , Tomohiro Ozaki  20 , Yuko Tsuchiya-Kawano  21 , Nobuyuki Yamamoto  14 , Kazuhiko Nakagawa  22 , Isamu Okamoto  4
Affiliations
Clinical Trial

Serum VEGF-A as a biomarker for the addition of bevacizumab to chemo-immunotherapy in metastatic NSCLC

Kentaro Tanaka et al. Nat Commun. .

Abstract

Anti-vascular endothelial growth factor (VEGF) agents in combination with immunotherapies have improved outcomes for cancer patients, but predictive biomarkers have not been elucidated. We report here a preplanned analysis in the previously reported APPLE study, a phase 3 trial evaluating the efficacy of the bevacizumab in combination with atezolizumab, plus platinum chemotherapy in metastatic, nonsquamous non-small cell lung cancer (NSCLC). We investigated the correlation of serum VEGF-A and its isoforms at baseline with treatment response by using an enzyme-linked immunosorbent assay. We reveal that the addition of bevacizumab significantly improves the progression-free survival in patients with the low VEGF-A level. Our results demonstrate that measuring serum VEGF-A or its isoforms may identify NSCLC patients who are likely to benefit from the addition of bevacizumab to immunotherapy. These assays are easy to measure and have significant potential for further clinical development.

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Conflict of interest statement

Competing interests: K.T. has received personal fees from Chugai Pharmaceutical, Ono Pharmaceutical, AstraZeneca, Daiichi Sankyo, Eli Lilly, Merck, Takeda Pharmaceutical, Pfizer, MSD, Novartis and Bristol Myers Squibb outside the submitted work. Y Shiraishi has received personal fees from Ono Pharmaceutical, Taiho Pharmaceutical, AstraZeneca, Ono Pharmaceutical and Bristol Myers Squibb outside the submitted work. H.D. has received personal fees from AstraZeneca outside the submitted work. K.A. has received personal fees from Chugai Pharmaceutical, Takeda Pharmaceutical, MSD, AstraZeneca, and Bristol Myers Squibb outside the submitted work. K.N. has received grants from Ono Pharmaceutical, Taiho Pharmaceutical, MSD, AbbVie, Daiichi Sankyo, Amgen, Eisai, Sanofi, Janssen Pharmaceutical, Novartis, Pfizer, Eli Lilly, Merck, Takeda Pharmaceutical, Chugai Pharmaceutical and AstraZeneca; and personal fees from AstraZeneca, Ono Pharmaceutical, Boehringer Ingelheim, Eli Lilly, Novartis, Pfizer, Merck, Janssen Pharmaceutical, Bristol Myers Squibb and Nihon Kayaku outside the submitted work. M M. has received personal fees from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, Daiichi-Sankyo, Eli Lilly, Kyowa Hakko Kirin, MSD, Nihon Kayaku, Pfizer, Taiho Pharmaceutical, Takeda Pharmaceutical and AbbVie outside the submitted work. H.S. has received grants from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical and Bristol Myers Squibb; and personal fees from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical and Bristol Myers Squibb, Boehringer Ingelheim and Pfizer outside the submitted work. A.H. has received grants from MSD, Eli Lilly, Chugai Pharmaceutical, Taiho Pharmaceutical, Boehringer Ingelheim and AstraZeneca; and personal fees from MSD, Eli Lilly, Chugai Pharmaceutical, Taiho Pharmaceutical, Boehringer Ingelheim, Pfizer and AstraZeneca outside the submitted work. T.S. has received personal fees from MSD, Eli Lilly, Chugai Pharmaceutical, Merck, Ono Pharmaceutical and AstraZeneca outside the submitted work. T.K. has received grants from Chugai Pharmaceutical, AstraZeneca, Eli Lilly, Taiho Pharmaceutical, Bristol Myers Squibb, Ono Pharmaceutical, MSD, Kyowa Hakko Kirin, Merck, Daiichi-Sankyo, Amgen, Abbvie, Sanofi, Labcorp development Japan, IQVIA Services Japan, Gilead Sciences, Pfizer and Bayer; consulting fees from Chugai Pharmaceutical, AstraZeneca, Ono Pharmaceutical, Pfizer, Daiichi-Sankyo, Bayer and Abbvie; and personal fees from Chugai Pharmaceutical, AstraZeneca, Eli Lilly, Taiho Pharmaceutical, Bristol Myers Squibb, Ono Pharmaceutical, MSD, Pfizer, Kyowa Hakko Kirin, Boehringer Ingelheim, Merck, Nihon Kayaku, Novartis, Daiichi-Sankyo, Takeda Pharmaceutical, Bayer, Sawai, Amgen and Eisai outside the submitted work. H.A. has received grants from Amgen, Boehringer Ingelheim; personal fees from Amgen, Chugai Pharmaceutical, AstraZeneca, Eli Lilly, Taiho Pharmaceutical, Bristol Myers Squibb, Ono Pharmaceutical, MSD, Pfizer, Boehringer Ingelheim, Merck, Nihon Kayaku, Novartis, Daiichi-Sankyo, Takeda Pharmaceutical; fees for membership of an advisory board for Amgen, Janssen Pharmaceutical, Sandoz and MSD outside the submitted work. H.M. has personal fees from AstraZeneca, Boehringer Ingelheim, Ono Pharmaceutical, Chugai Pharmaceutical, Taiho Pharmaceutical, Takeda Pharmaceutical and MSD outside the submitted work. M.T. has received grants from AstraZeneca, Chugai Pharmaceutical and Eli Lilly; personal fees from Eli Lilly, Ono Pharmaceutical, Bristol Myers Squibb, Chugai Pharmaceutical, AstraZeneca, MSD, Novartis pharmaceuticals, Takeda Pharmaceutical, Taiho Pharmaceutical, Boehringer Ingelheim, Daiichi Sankyo, Pfizer and Janssen Pharmaceutical outside the submitted work. K.W. has received grants from Chugai Pharmaceutical, AstraZeneca, Novartis, Abbvie, Amgen, MSD and Daiichi Sankyo; personal fees from Chugai Pharmaceutical, Taiho Pharmaceutical, Boehringer Ingelheim, Eli Lilly, Ono Pharmaceutical, MSD, AstraZeneca, Daiichi Sankyo, Janssen Pharmaceutical and Takeda Pharmaceutical outside the submitted work. Y Sato has received personal fees from AstraZeneca, MSD, Novartis, Chugai Pharmaceutical, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, Nihon Kayaku, Bristol Myers Squibb, Eli Lilly, Takeda, Kyowa Hakko Kirin and Daiichi Sankyo outside the submitted work. Y. T. K. has received personal fees from Bristol Myers Squibb, Taiho Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, Kyowa Hakko Kirin, MSD, Ono Pharmaceutical and Takeda Pharmaceutical outside the submitted work. N.Y. has received grants from Boehringer Ingelheim, Taiho Pharmaceutical, Chugai Pharmaceutical, Shionogi, Eli Lilly, Daiichi Sankyo, Tumura, Nihon Kayaku, Asahikasei-pharma, AstraZeneca, Janssen, Sanofi, Amgen, Novartis, Astellas, MSD, Esai, Bristol-Myers Squibb, Abbvie and Tosoh; and personal fees from MSD, AstraZeneca, Amgen, Ono Pharmaceutical, Otsuka, Guardant Health Japan, Tumura, Kyowa Hakko Kirin, Kyorin, GlaxoSmithKline, Sanofi, Daiichi Sankyo, Taiho Pharmaceutical, Takeda, Chugai Pharmaceutical, Eli Lilly, Nippon Kayaku, Boehringer Ingelheim, Novartis, Pfizer, Bristol Myers Squibb, Miyarisan, Merck and Janssen; and fees for membership of a data safety monitoring board or an advisory board from AstraZeneca, Eli Lilly, and Takeda outside the submitted work. K.N. has received grants from AstraZeneca, SD, Ono Pharmaceutical, Boehringer Ingelheim, Novartis, Pfizer, Bristol-Myers Squibb, Eli Lilly, Chugai Pharmaceutical, Daiichi Sankyo, Merck, PAREXEL International, PRA HEALTHSCIENCES, EPS Corporation., Kissei Pharmaceutical, EPS International, Taiho Pharmaceutical, PPD-SNBL, SymBio Pharmaceuticals, IQVIA Services JAPAN, SYNEOS HEALTH CLINICAL, Nihon Kayaku, EP-CRSU, Mebix, Janssen, AbbVie, Bayer, Eisai, Mochida Pharmaceutical, Covance Japan, Japan Clinical Research Operations, Takeda, GlaxoSmithKline, Sanofi, Sysmex, Medical Reserch Support, Otsuka Pharmaceutical, SRL, and Amgen; and consulting fees from Eli Lilly, Kyorin Pharmaceutical, Ono Pharmaceutical and Pfizer; and personal fees from Ono Pharmaceutical, Amgen, Nippon Kayaku, AstraZeneca, Chugai Pharmaceutical, Eli Lilly, MSD, Pfizer, Boehringer Ingelheim, Taiho Pharmaceutical, Bayer, CMIC ShiftZero, Life Technologies Japan, Neo Communication, Roche Diagnostics, AbbVie, Merck, Kyowa hakko Kirin, Takeda, 3H Clinical Trial, Care Net, Medical Review, Medical Mobile Communications, YODOSHA, Nikkei Business Publications, Japan Clinical Research Operations, CMIC, Novartis, TAIYO Pharma, Kyorin Pharmaceutical, and Bristol-Myers Squibb; and patents from Daiichi Sankyo outside submitted work. I.O. has received grants from Chugai Pharmaceutical, AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, MSD, Eli Lilly, Astellas, Bristol Myers Squibb, Novartis, Pfizer, and AbbVie; and consulting fee from AstraZeneca, Bristol Myers Squibb, and AbbVie; and personal fees from AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Chugai Pharmaceutical, Ono Pharmaceutical, MSD, Eli Lilly, Bristol-Myers Squibb, Novartis, and Pfizer outside the submitted work. J.S., T Ota and T Ozaki declare no competing interests.

Figures

Fig. 1
Fig. 1. CONSORT diagram.
EGFR epidermal growth factor receptor gene, WT wild type, MT mutation.
Fig. 2
Fig. 2. Serum concentrations of total VEGF-A (tVEGF-A), VEGF121, and VEGF165 at baseline for all study patients according to treatment arm.
Horizontal bars indicate median values for Chemo/Atezo (n = 76) and Chemo/Atezo/Bev (n = 73) groups, and the statistical analysis was performed with two-sided Mann–Whitney U test. tVEGF-A total vascular endothelial growth factor–A, VEGF vascular endothelial growth factor, Chemo carboplatin-pemetrexed chemotherapy, Atezo atezolizumab, Bev bevacizumab.
Fig. 3
Fig. 3. Kaplan–Meier estimates of PFS according to treatment arm for patients with low or high serum concentrations of VEGF-A at baseline.
All study patients with low (left) or high (right) concentrations of tVEGF-A (A), VEGF121 (B), or VEGF165 (C) defined according to the corresponding median value were examined. The survival curve for Chemo/Atezo is shown in blue, and the survival curve for Chemo/Atezo/Bev is shown in red. PFS progression-free survival, tVEGF-A total vascular endothelial growth factor–A, VEGF vascular endothelial growth factor, Chemo carboplatin-pemetrexed chemotherapy, Atezo atezolizumab, Bev bevacizumab, HR hazard ratio, CI confidence interval.
Fig. 4
Fig. 4. Kaplan–Meier estimates of PFS according to treatment arm for patients with EGFR-WT tumors and either low or high concentrations of VEGF-A at baseline.
Patients with EGFR-WT tumors and either low (left) or high (right) concentrations of tVEGF-A (A), VEGF121 (B), or VEGF165 (C) defined according to the corresponding median value were examined. The survival curve for Chemo/Atezo is shown in blue, and the survival curve for Chemo/Atezo/Bev is shown in red. EGFR epidermal growth factor receptor gene, PFS progression-free survival, WT wild type, tVEGF-A total vascular endothelial growth factor–A, VEGF vascular endothelial growth factor, Chemo carboplatin-pemetrexed chemotherapy, Atezo atezolizumab, Bev bevacizumab, HR hazard ratio, CI confidence interval.
Fig. 5
Fig. 5. Kaplan–Meier estimates of PFS according to treatment arm for patients with EGFR-WT tumors and VEGF121 and VEGF165 measurement added to either low or high concentrations of VEGF-A at baseline.
Patients with EGFR-WT tumors and VEGF121 and VEGF165 measurement added to either low (left) or high (right) concentrations of tVEGF-A (A, D), VEGF121 (B, E), or VEGF165 (C, F) defined according to the corresponding median value were examined. The survival curve for Chemo/Atezo is shown in blue, and the survival curve for Chemo/Atezo/Bev is shown in red. EGFR epidermal growth factor receptor gene, PFS progression-free survival, WT wild type, tVEGF-A total vascular endothelial growth factor–A, VEGF vascular endothelial growth factor, Chemo carboplatin-pemetrexed chemotherapy, Atezo atezolizumab, Bev bevacizumab, HR hazard ratio, CI confidence interval.
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