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. 2023 Oct;14(29):2909-2923.
doi: 10.1111/1759-7714.15077. Epub 2023 Aug 24.

Exploratory analysis to predict pneumonitis during durvalumab consolidation therapy for patients with locally advanced non-small cell lung cancer from proteomic profiling of circulating extracellular vesicles

Masahiro Torasawa  1   2 , Hidehito Horinouchi  1 , Shigehiro Yagishita  3 , Hirofumi Utsumi  4 , Keitaro Okuda  4 , Daisuke Takekoshi  4 , Saburo Ito  4 , Hiroshi Wakui  4 , Saori Murata  1 , Sawako Kaku  5 , Kae Okuma  6 , Yuji Matsumoto  1 , Yuki Shinno  1 , Yusuke Okuma  1 , Tatsuya Yoshida  1   7 , Yasushi Goto  1 , Noboru Yamamoto  1   7 , Jun Araya  4 , Yuichiro Ohe  1 , Yu Fujita  4   8
Affiliations

Exploratory analysis to predict pneumonitis during durvalumab consolidation therapy for patients with locally advanced non-small cell lung cancer from proteomic profiling of circulating extracellular vesicles

Masahiro Torasawa et al. Thorac Cancer. 2023 Oct.

Abstract

Background: Risk factors for predicting pneumonitis during durvalumab consolidation after chemoradiotherapy (CRT) in locally advanced non-small cell lung cancer (LA-NSCLC) are still lacking. Extracellular vesicles (EVs) play a crucial role in intercellular communication and are potential diagnostic tools for various diseases.

Methods: We retrospectively collected predurvalumab treatment serum samples from patients treated with durvalumab for LA-NSCLC, isolated EVs using anti-CD9 and anti-CD63 antibodies, and performed proteomic analyses. We examined EV proteins that could predict the development of symptomatic pneumonitis (SP) during durvalumab treatment. Potential EV-protein biomarkers were validated in an independent cohort.

Results: In the discovery cohort, 73 patients were included, 49 with asymptomatic pneumonitis (AP) and 24 with SP. Of the 5797 proteins detected in circulating EVs, 33 were significantly elevated (fold change [FC] > 1.5, p < 0.05) in the SP group, indicating enrichment of the nuclear factor kappa B (NF-κB) pathway. Patients with high levels of EV-RELA, an NF-κB subunit, had a higher incidence of SP than those with low levels of EV-RELA (53.8% vs. 13.4%, p = 0.0017). In the receiver operating characteristic analysis, EV-RELA demonstrated a higher area under the curve (AUC) than lung V20 (0.76 vs. 0.62) and was identified as an independent risk factor in the multivariate logistic regression analysis (p = 0.008, odds ratio 7.72). Moreover, high EV-RELA was also a predictor of SP in the validation cohort comprising 43 patients (AUC of 0.80).

Conclusions: Circulating EV-RELA may be a predictive marker for symptomatic pneumonitis in patients with LA-NSCLC treated with durvalumab.

Keywords: chemoradiotherapy; durvalumab; extracellular vesicles; pneumonitis.

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Conflict of interest statement

Dr Torasawa has nothing to disclose. Dr. Horinouchi reports receiving personal fees from AstraZeneca.K.K during the conduct of the study; grants and personal fees from Chugai, Merck Sharp & Dohme, Novartis, Ono, and Roche; grants from AbbVie, Bristol‐Myers Squibb, Daiichi Sankyo, Genomic Health, Janssen, Merck Biopharma; and personal fees from Eli Lilly and Kyowa‐Kirin, outside of the submitted work. Dr Yagishita reports receiving grants from Nippon Boehringer Ingelheim, outside of the submitted work. Dr Utsumi has nothing to disclose. Dr Okuda has nothing to disclose. Dr Takekoshi has nothing to disclose. Dr Ito has nothing to disclose. Dr Wakui reports receiving personal fees from AstraZeneca.K.K during the conduct of the study.

Dr Murata has nothing to disclose. Dr Kaku has nothing to disclose. Dr Okuma has nothing to disclose. Dr Sinnno reports receiving personal fees from AstraZeneca.K.K during the conduct of the study; personal fees from Bristol‐Myers Squibb, Chugai, and Eli Lilly; grants and personal fees from Ono; and grants from Janssen and Japan Clinical Research Operations K.K. outside of the submitted work. Dr Matsumoto reports receiving personal fees from AstraZeneca.K.K during the conduct of the study; grants from Grant‐in‐Aid for Scientific Research on Innovative Areas, Hitachi, Ltd., and the National Cancer Center Research and Development Fund; grants and personal fees from Olympus; and personal fees from AMCO Inc., Chugai, COOK, Eli Lilly, Erbe Elektromedizin GmbH, Fujifilm, Novartis, and Thermo Fisher Scientific outside of the submitted work. Dr Okuma reports receiving personal fees from AstraZeneca.K.K during the conduct of the study; grants from AbbVie K.K. and Roche; and personal fees from Nippon Boehringer Ingelheim, Bristol‐Myers Squibb, Chugai Pharma Co. Ltd., Ely Lilly K.K., Ono Pharma Co. Ltd., Pfizer Taiho Pharma Co. Ltd., and Taiho Pharma Co. Ltd. outside of the submitted work. Dr Yoshida reports receiving personal fees from AstraZeneca.K.K during the conduct of the study; grants and personal fees from Amgen, Bristol‐Myers Squibb, Chugai, Merck Sharp & Dohme, Novartis, and Ono; grants from AbbVie, Daiichi Sankyo, and Takeda; and personal fees from ArcherDX, Eli Lilly, Roche, and Taiho outside of the submitted work. Dr Goto reports receiving personal fees from AstraZeneca.K.K during the conduct of the study; grants from AbbVie, AZK, Kyorin, and Preferred Network; grants and personal fees from Bristol‐Myers Squibb, Daiichi Sankyo, Eli Lilly, Novartis, Ono, and Pfizer; and personal fees from Boehringer Ingelheim, Chugai, Guardant Health Inc., Illumina, Merck Sharp & Dohme, Taiho, and Thermo Fisher outside of the submitted work. Dr. Yamamoto reports receiving personal fees from AstraZeneca.K.K during the conduct of the study; grants from Astellas, Bayer, Boehringer Ingelheim, Bristol‐Myers Squibb, Carna Biosciences, Chugai, Chiome Bioscience Inc., Daiichi Sankyo, Eisai, Eli Lilly, Genmab, GlaxoSmithKline, Janssen Pharma, Kyowa‐Hakko Kirin, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical Co., Ltd., Otsuka, Pfizer, Quintiles, Shionogi, Sumitomo Dainippon, Takeda, and Taiho; and personal fees from Boehringer Ingelheim, Bristol‐Myers Squibb, Chugai, Cimic, Eisai, Lilly, Ono Pharmaceutical Co., Ltd., Otsuka, Pfizer, Sysmex, and Takeda, outside of the submitted work. Dr Araya receiving grants from Japanese Respiratory Foundation and Kowa company, LTD (campany x) outside of the submitted work. Dr Ohe reports receiving grants, personal fees, and nonfinancial support from AstraZeneca.K.K during the conduct of the study; personal fees from Amgen, AnHeeart Therapeutics Inc., Bayer, Boehringer Ingelheim, Bristol‐Myers Squibb, Celltrion, Chugai, Kyowa‐Hakko Kirin, Merck Sharp & Dohme, Nippon Kayaku, Ono Pharmaceutical Co., Ltd., Pfizer, and Taiho; grants and personal fees from Eli Lilly; grants and nonfinancial support from Kyorin; grants from Daiichi Sankyo, Dainippon‐Sumitomo, Janssen, Kissei, LOXO, Novartis, Takeda, and Taiho, outside of the submitted work. Dr Fujita reports receiving grants from AstraZeneca.K.K during the conduct of the study; grants from Preferred networks, Showa Denko Materials Co. Ltd., SHIBUYA Cooperation, H.U. Group Holdings, Inc., Merck Sharp & Dohme outside of the submitted work.

Figures

FIGURE 1
FIGURE 1
(a) Overview of the study. If the patient developed pneumonitis requiring corticosteroids before four doses of durvalumab, the timing of the “before‐steroid” blood collection is before the “on‐durva” samples. (b) Consort diagram and patient classification for this study. Durva, durvalumab; IP, immunoprecipitation; LC–MS, liquid chromatography–tandem mass spectrometry.
FIGURE 2
FIGURE 2
(a) Procedure for narrowing down candidate EV proteins in the discovery cohort. (b) Volcano plot representing EV‐proteins with elevated expression in patients with symptomatic and asymptomatic pneumonitis in serum samples before durvalumab administration in the discovery cohort. Annotated proteins involved in NF‐κB signaling. (c) Pathways enriched in EV‐proteins significantly elevated in patients with symptomatic pneumonitis in the discovery cohort. Pathways underlined in red are those related to NF‐κB. (d) A hierarchical clustering tree summarizes the correlation among enriched pathways in patients with symptomatic pneumonitis in the discovery cohort. (e) Network plot visualizing pathways enriched in patients with symptomatic pneumonitis in the discovery cohort. (f) Protein–protein interaction plot of EV proteins elevated in patients with symptomatic pneumonitis in the discovery cohort. RELA is highlighted with a red circle. EV, extracellular vesicle; NF‐κB, nuclear factor kappa B; PPI, protein–protein interaction.
FIGURE 3
FIGURE 3
(a) Boxplot showing symptoms of pneumonitis and expression of EV‐RELA in the discovery cohort. (b) Receiver operating characteristic plot of risk factors for symptomatic pneumonitis development in the discovery cohort. (c) Percentage of asymptomatic and symptomatic pneumonitis in low and high RELA groups in the discovery cohort. (d) Kaplan–Meier plots showing the cumulative incidence of symptomatic pneumonitis in EV‐RELA subgroups in the discovery cohort.
FIGURE 4
FIGURE 4
Swimmer plot showing the clinical course after durvalumab initiation in patients (n = 52) in whom EV‐RELA was measured in the discovery cohort. Patients are listed from top to bottom in order of EV‐RELA levels.
FIGURE 5
FIGURE 5
(a) Box plot showing symptoms of pneumonitis and expression of EV‐RELA in the validation cohort. (b) Receiver operating characteristic plot of EV‐RELA for symptomatic pneumonitis development in the validation cohort.
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