Nintedanib promotes antitumour immunity and shows antitumour activity in combination with PD-1 blockade in mice: potential role of cancer-associated fibroblasts

Kato, Ryuichi; Haratani, Koji; Hayashi, Hidetoshi; Sakai, Kazuko; Sakai, Hitomi; Kawakami, Hisato; Tanaka, Kaoru; Takeda, Masayuki; Yonesaka, Kimio; Nishio, Kazuto; Nakagawa, Kazuhiko

doi:10.1038/s41416-020-01201-z

Cited by 45 publications

(46 citation statements)

References 36 publications

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“…Nintedanib also promotes antitumor immunity and antitumor activity in combination with PD-1 blockade in mice. 9 In conclusion, we encountered a patient with NSCLC and IPF who responded well to nintedanib. Further research is warranted for identifying predictive factors that may help in the selection of appropriate treatments for individual patients with lung cancer complicated by IPF.…”

Section: Discussionmentioning

confidence: 89%

Remarkable response of non‐small cell lung cancer to nintedanib treatment in a patient with idiopathic pulmonary fibrosis

Kai

Matsuda

Fukuoka³

et al. 2021

Thoracic Cancer

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Nintedanib is a multi‐target receptor tyrosine kinase inhibitor that reduces the decline in forced vital capacity (FVC) and prevents acute exacerbations in idiopathic pulmonary fibrosis (IPF), which is a risk factor for lung cancer. However, it remains unclear whether nintedanib is an effective treatment for lung cancer in patients with IPF. Here, we describe an 82‐year‐old man with non‐small cell lung carcinoma complicated by IPF who was treated with nintedanib. High‐resolution computed tomography (HRCT) showed a subpleural basal‐predominant reticular shadow and traction bronchiectasis with a honeycomb pattern. His FVC decreased over time, and his 6‐min walk test showed oxygen desaturation. Furthermore, an enlarged nodular lesion was detected after 6 months of referral. Biopsy confirmed non‐small cell carcinoma. Because of the risk of acute exacerbation of IPF by chemotherapy, supportive care was selected. Nintedanib was started as treatment for the IPF. Nine months later, HRCT revealed partial remission without exacerbation of IPF. This case indicates the possibility of nintedanib monotherapy in suppressing lung cancer complicated by IPF. Patients with lung cancer complicated by IPF in whom treatment is effective remain unknown. Additional research is needed to identify effective therapy for lung cancer with IPF.

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Section: Discussionmentioning

confidence: 89%

Remarkable response of non‐small cell lung cancer to nintedanib treatment in a patient with idiopathic pulmonary fibrosis

Kai

Matsuda

Fukuoka³

et al. 2021

Thoracic Cancer

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“…VEGF also exerts direct immunosuppressive effects on numerous cell types; for example, by inhibiting dendritic cell maturation and promoting the expansion of regulatory T cells, myeloid-derived suppressor cells and tumour-associated macrophages [9,23]. The 'angio-immunogenic switch' hypothesis proposes that anti-angiogenic treatment could reverse the immunosuppressive TME that contributed initially to the failure of ICI therapy [8e10], and this is supported by preclinical data [22,25], the efficacy results observed in this latest analysis of VARGADO cohort B and in patients treated with nintedanib plus docetaxel in the second line, following first-line chemotherapy plus ICIs in VARGADO cohort C [26,27].…”

Section: Discussionmentioning

confidence: 99%

“…A more recent retrospective analysis investigated the efficacy of third-line ramucirumab plus docetaxel after failure of first-line chemotherapy and second-line ICI therapy (n ¼ 67); ORR was 36%, DCR was 69%, median PFS was 6.8 months and median overall survival was 11.0 months after the start of third-line treatment [6]. Preclinical data indicate potential synergies stemming from the combination of ICIs with antiangiogenic agents [25]. Many clinical trials are underway investigating such combinations in NSCLC, and early data are encouraging [28].…”

Section: Discussionmentioning

confidence: 99%

Real-World Efficacy of Nintedanib Plus Docetaxel After Progression on Immune Checkpoint Inhibitors: Results From the Ongoing, Non-interventional VARGADO Study

Grohé¹,

Blau

Gleiber

et al. 2022

Clinical Oncology

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Aims: To evaluate the efficacy and safety of nintedanib plus docetaxel in patients with advanced adenocarcinoma non-small cell lung cancer (NSCLC) who progressed after chemotherapy and immune checkpoint inhibitor (ICI) therapy. Materials and methods: VARGADO (NCT02392455) is an ongoing, prospective, non-interventional, real-world study of nintedanib plus docetaxel after first-line chemotherapy in the routine clinical treatment of patients with locally advanced, metastatic or locally recurrent adenocarcinoma NSCLC. Data were collected during routine visits. We report the results from cohort B (n ¼ 80), who received third-line nintedanib plus docetaxel after first-line chemotherapy and secondline ICI therapy. Results: The median duration of follow-up was 12.4 months. Median progression-free survival from initiation of third-line nintedanib plus docetaxel was 6.4 months (95% confidence interval 4.8, 7.3); median overall survival was 12.1 months (95% confidence interval 9.4, 13.5). The 1-year overall survival rate after initiation of third-line nintedanib plus docetaxel treatment (primary end point) was 52% (95% confidence interval 38.0%, 64.4%). Among 64 patients with a documented response, the objective response rate was 50% (n ¼ 32; one complete response and 31 partial responses) and the disease control rate was 86% (n ¼ 55). There were no new safety signals or unexpected toxicities. Among all treated patients, 74% (n ¼ 59) experienced drug-related adverse events, most commonly (nintedanib-related/docetaxel-related) diarrhoea (34%/24%), a decreased white blood cell count (11%/19%) and nausea (13%/16%). Conclusions: Nintedanib plus docetaxel demonstrated a high response rate and disease stabilisation in the third-line setting after failure of prior chemotherapy and ICI treatment, with a manageable safety profile. These results suggest that nintedanib plus docetaxel represents an efficient treatment option after failure of prior ICIs. The ongoing VARGADO study provides valuable real-world data to inform clinical decision-making regarding treatment sequencing after chemotherapy and ICI failure in patients with adenocarcinoma NSCLC.

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“…In a study conducted by Haratani et al, the authors inoculated s.c. B16-F10 cells in C57BL/6 mice. They demonstrated that the oral administration of nintedanib markedly delayed tumor growth (around three-fold) and prolonged mice survival when compared to control [187]. Using the same tumor induction protocol, Ferreira and coworkers demonstrated that indomethacin incorporated in mesoporous silica nanoparticles inhibited tumor growth by up to 70%.…”

Section: Syngeneic Modelmentioning

confidence: 99%

The Challenging Melanoma Landscape: From Early Drug Discovery to Clinical Approval

Matias

Pinho

Penetra

et al. 2021

Cells

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Melanoma is recognized as the most dangerous type of skin cancer, with high mortality and resistance to currently used treatments. To overcome the limitations of the available therapeutic options, the discovery and development of new, more effective, and safer therapies is required. In this review, the different research steps involved in the process of antimelanoma drug evaluation and selection are explored, including information regarding in silico, in vitro, and in vivo experiments, as well as clinical trial phases. Details are given about the most used cell lines and assays to perform both two- and three-dimensional in vitro screening of drug candidates towards melanoma. For in vivo studies, murine models are, undoubtedly, the most widely used for assessing the therapeutic potential of new compounds and to study the underlying mechanisms of action. Here, the main melanoma murine models are described as well as other animal species. A section is dedicated to ongoing clinical studies, demonstrating the wide interest and successful efforts devoted to melanoma therapy, in particular at advanced stages of the disease, and a final section includes some considerations regarding approval for marketing by regulatory agencies. Overall, considerable commitment is being directed to the continuous development of optimized experimental models, important for the understanding of melanoma biology and for the evaluation and validation of novel therapeutic strategies.

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Nintedanib promotes antitumour immunity and shows antitumour activity in combination with PD-1 blockade in mice: potential role of cancer-associated fibroblasts

Cited by 45 publications

References 36 publications

Remarkable response of non‐small cell lung cancer to nintedanib treatment in a patient with idiopathic pulmonary fibrosis

Remarkable response of non‐small cell lung cancer to nintedanib treatment in a patient with idiopathic pulmonary fibrosis

Real-World Efficacy of Nintedanib Plus Docetaxel After Progression on Immune Checkpoint Inhibitors: Results From the Ongoing, Non-interventional VARGADO Study

The Challenging Melanoma Landscape: From Early Drug Discovery to Clinical Approval

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