Randomized Phase 2 Placebo-Controlled Trial of Nintedanib for the Treatment of Radiation Pneumonitis

Rimner, Andreas; Moore, Zachary; Lobaugh, Stephanie; Geyer, Alexander; Gelblum, D.; Abdulnour, Raja-Elie E.; Shepherd, Annemarie F.; Shaverdian, Narek; Wu, Abraham J.; Cuaron, John; Chaft, Jamie E.; Zauderer, Marjorie G.; Eng, Juliana; Riely, Gregory J.; Rudin, Charles M.; Vander, Nicholas; Chawla, Mohit; McCune, Megan; Li, Henry; Jones, David R.; Sopka, Dennis M.; Simone, Charles B.; Mak, Raymond H.; Weinhouse, Gerald L.; Liao, Zhongxing; Gomez, Daniel R.; Zhang, Zhigang; Paik, Paul K.

doi:10.1016/j.ijrobp.2023.02.030

Cited by 7 publications

(5 citation statements)

References 33 publications

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“…This suggests that nintedanib may influence M1 polarization in macrophages via the MAPK and/or PI3K-AKT pathways. It has also been reported that nintedanib reduces the phosphorylation of AKT and p38 in hypoxia-induced macrophages, 32,43 further corroborating our experimental results. There are some limitations in this study, we only used in vivo and in vitro mouse models for the study, and a large sample of clinical trials is highly warranted.…”

Section: Nintedanib Inhibited Lps-induced Phosphorylation Of Mapk And...supporting

confidence: 92%

“…Nintedanib has been extensively investigated in the pathological fibrosis of lung tissue 32–34 and has also been reported in extrapulmonary tissues, such as repair after urethral injury, 35 scar formation after glaucoma surgery, 36 and pulmonary sarcoidosis combined with rheumatoid arthritis 37 . A recent report showed that nintedanib antagonizes pathological CHON‐001 chondrocyte injury in vitro 23 .…”

Section: Discussionmentioning

confidence: 99%

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Nintedanib ameliorates osteoarthritis in mice by inhibiting synovial inflammation and fibrosis caused by M1 polarization of synovial macrophages via the MAPK/PI3K‐AKT pathway

Yan,

Feng,

Yang

et al. 2023

The FASEB Journal

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Synovial inflammation and fibrosis are important pathological changes associated with osteoarthritis (OA). Herein, we investigated if nintedanib, a drug specific for pulmonary fibrosis, plays a positive role in osteoarthritic synovial inflammation and fibrosis. We assessed the effect of nintedanib on osteoarthritic synovial inflammation and fibrosis in a mouse model of OA created by destabilization of the medial meniscus and a macrophage M1 polarization model created by stimulating RAW264.7 cells with lipopolysaccharide. Histological staining showed that daily gavage administration of nintedanib significantly alleviated articular cartilage degeneration, reduced the OARSI score, upregulated matrix metalloproteinase‐13 and downregulated collagen II expression, and significantly reduced the synovial score and synovial fibrosis in a mouse OA model. In addition, immunofluorescence staining showed that nintedanib significantly decreased the number of M1 macrophages in the synovium of a mouse model of OA. In vitro results showed that nintedanib downregulated the phosphorylation levels of ERK, JNK, p38, PI3K, and AKT while inhibiting the expression of macrophage M1 polarization marker proteins (CD86, CD80, and iNOS). In conclusion, this study suggests that nintedanib is a potential candidate for OA treatment. The mechanisms of action of nintedanib include the inhibition of M1 polarization in OA synovial macrophages via the MAPK/PI3K‐AKT pathway, inhibition of synovial inflammation and fibrosis, and reduction of articular cartilage degeneration.

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Section: Nintedanib Inhibited Lps-induced Phosphorylation Of Mapk And...supporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Nintedanib ameliorates osteoarthritis in mice by inhibiting synovial inflammation and fibrosis caused by M1 polarization of synovial macrophages via the MAPK/PI3K‐AKT pathway

Yan,

Feng,

Yang

et al. 2023

The FASEB Journal

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“…Nintedanib inhibits fibrosis in the RILI model in vivo [ 10 ]. Clinical trials are currently underway to evaluate the efficacy of nintedanib in RILI [ 11 , 12 ]. In a study by Dy GK, nintedanib for patients with non-small-cell lung cancer (NSCLC) after concurrent chemoradiation therapy was terminated owing to accrual logistics; therefore, efficacy could not be evaluated with a small sample size [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

“…In a study by Dy GK, nintedanib for patients with non-small-cell lung cancer (NSCLC) after concurrent chemoradiation therapy was terminated owing to accrual logistics; therefore, efficacy could not be evaluated with a small sample size [ 11 ]. However, another study showed a significantly lower exacerbation-free rate in patients who added nintedanib to PSL (72%, 95% confidence interval [CI]: 54-96% vs. 42%, 95% CI: 20-82%; P = 0.037) [ 12 ]. The pathogenesis of RILI and these data suggest that nintedanib affected the RILI with progressive fibrotic change.…”

Section: Discussionmentioning

confidence: 99%

Radiation-Induced Lung Injury With Lung Cancer Treated With the Combination Therapy of Nintedanib and Dexamethasone

Itano,

Kimura,

Ninomiya

et al. 2023

Cureus

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Radiation-induced lung injury (RILI) associated with lung cancer becomes refractory. Nintedanib is a multi-kinase inhibitor that suppresses the development of pulmonary fibrosis. Herein, we report a case of RILI with progressive pulmonary fibrosis after stereotactic body radiation therapy in a 70-year-old man with lung cancer. The patient responded well to the initial prednisolone therapy but became resistant during tapering. The combination therapy of nintedanib and dexamethasone resulted in a temporary improvement in RILI. Nintedanib is not a standard therapy for RILI, and further investigation is needed to evaluate the effects of nintedanib on RILI complicated by lung cancer.

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“…Steroids are empirically given to treat pneumonitis, and early studies suggest some benefit with pentoxyfiline and ACE inhibitors in humans and animals 16, 17, 18 . A recent trial evaluating nintedanib in RILI failed to show benefit 19 . The most successful strategies for RILI have come with advances in limiting the radiation dose and volume of irradiated lung with techniques such as stereotactic ablative body radiotherapy (SABR) and intensity modulated radiation therapy (IMRT), as well as through careful risk stratification of patients with known factors such as age, concomitant pulmonary fibrosis, and chemotherapy making RILI more likely 5 .…”

Section: Introductionmentioning

confidence: 99%

Noninvasive Quantification of Radiation-Induced Lung Injury using a Targeted Molecular Imaging Probe

Abston,

Zhou,

Saenger

et al. 2023

Preprint

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RationaleRadiation-induced lung injury (RILI) is a progressive inflammatory process commonly seen following irradiation for lung cancer. The disease can be insidious, often characterized by acute pneumonitis followed by chronic fibrosis with significant associated morbidity. No therapies are approved for RILI, and accurate disease quantification is a major barrier to improved management.ObjectiveTo noninvasively quantify RILI, utilizing a molecular imaging probe that specifically targets type 1 collagen in mouse models and patients with confirmed RILI.MethodsUsing a murine model of lung radiation, mice were imaged with EP-3533, a type 1 collagen probe to characterize the development of RILI and to assess disease mitigation following losartan treatment. The human analog probe targeted against type 1 collagen,68Ga-CBP8, was tested on excised human lung tissue containing RILI and quantified via autoradiography. Finally,68Ga-CBP8 PET was used to assess RILIin vivoin six human subjects.ResultsMurine models demonstrated that probe signal correlated with progressive RILI severity over six-months. The probe was sensitive to mitigation of RILI by losartan. Excised human lung tissue with RILI had increased binding vs unirradiated control tissue and68Ga-CBP8 uptake correlated with collagen proportional area. Human imaging revealed significant68Ga-CBP8 uptake in areas of RILI and minimal background uptake.ConclusionsThese findings support the ability of a molecular imaging probe targeted at type 1 collagen to detect RILI in preclinical models and human disease, suggesting a role for targeted molecular imaging of collagen in the assessment of RILI.Clinical trial registered withwww.clinicaltrials.gov(NCT04485286,NCT03535545)

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Randomized Phase 2 Placebo-Controlled Trial of Nintedanib for the Treatment of Radiation Pneumonitis

Cited by 7 publications

References 33 publications

Nintedanib ameliorates osteoarthritis in mice by inhibiting synovial inflammation and fibrosis caused by M1 polarization of synovial macrophages via the MAPK/PI3K‐AKT pathway

Nintedanib ameliorates osteoarthritis in mice by inhibiting synovial inflammation and fibrosis caused by M1 polarization of synovial macrophages via the MAPK/PI3K‐AKT pathway

Radiation-Induced Lung Injury With Lung Cancer Treated With the Combination Therapy of Nintedanib and Dexamethasone

Noninvasive Quantification of Radiation-Induced Lung Injury using a Targeted Molecular Imaging Probe

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