Patterns of Interstitial Lung Disease During Everolimus Treatment in Patients with Metastatic Renal Cell Carcinoma

427 Background: Interstitial lung disease (ILD) is known as one of the adverse events during treatment with everolimus for metastatic renal cell carcinoma (mRCC). Methods: We retrospectively assessed the incidence and outcome of ILD in mRCC patients treated with everolimus. From April 2010 to August 2012, 25 cases were treated with everolimus after failure of one or two TKIs in our institute. All adverse events were graded in accordance with NCI CTCAE, version 3.0. Results: A total of 25 patients received treatment with everolimus. They included 18 male and 7 female patients ranging in age from 21 to 84 years (median 62). According to MSKCC risk criteria, 6 cases were at favorable risk, 16 cases were at intermediate risk, and 3 cases were at poor risk. Median treatment term was 4 months (range 2-17 months). SD was in 19 cases and PD was in 6 cases. Progression free survival was 3.5 months and overall survival was 12 months. ILD was found in 7 cases (28%). 1 was G1, 5 were G2 and 1 was G3. Corticosteroid therapy was initiated in 3 cases. In 5 of 7 ILD cases, everolimus was re-challenged. In our series, patients with ILD showed significantly better progression free survival than those without ILD (PFS was 8 months vs. 3 months. Log-rank, p < 0.001). There were no significant different between the 2 groups in over all survival (12 months in patients with ILD vs. 10 months in patients without ILD. Log-rank, NS). Conclusions: Everolimus appears to be effective and well-tolerated in our institute. Re-challenge of everolimus was feasible after improving of everolimus-induced ILD in cases of grade 1-2.

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Temsirolimus-induced interstitial lung disease as an on-target effect in patients with metastatic renal cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e16086 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e16086-e16086 ◽

Cited By ~ 1

Author(s):

Masatoshi Eto ◽

Takanobu Motoshima ◽

Yutaka Sugiyama ◽

Kiyohide Fujimoto ◽

Chikara Ohyama ◽

...

Keyword(s):

Clinical Trial ◽

Renal Cell Carcinoma ◽

Interstitial Lung Disease ◽

Lung Disease ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Immune Modulation ◽

Clinical Practices ◽

Immune Parameters

e16086 Background: An inhibitor for mammalian target of rapamycin (mTORi), temsirolimus, has been used for metastatic renal cell carcinoma (mRCC) pts with poor risk. mTOR is known to regulate proliferation of lymphocytes, which has been rationale of applying mTORi for preventing graft rejection in transplantation. However, nobody knows the immune status of mRCC pts treated with temsirolimus. In addition, accumulation of clinical practices of temsirolimus has revealed a variety of AEs including interstitial lung disease (ILD). The underlying mechanisms of ILD by mTORi remain uncertain. Moreover, the clinical impact of ILD on the clinical response to mTORi remains unknown. So, we have conducted a prospective clinical trial investigating immune parameters in mRCC pts treated with temsirolimus. This project was denominated in Japanese m-TOR Immune Modulation trial (J-TORIM) (UMIN000009662). Methods: J-TORIM was a prospective observational study recruited pts at 25 hospitals in Japan with a targeted sample size of 30. The primary objective was to evaluate whether administration of temsilorimus has consistent effects on immune parameters collected from the peripheral blood before and 3-to-5 weeks after the beginning of temsirolimus therapy. The secondary objectives were to evaluate the associations of immune parameters or ILD with ORR, PFS, and OS, and the associations of immune parameters with ILD. Immune parameters include PBMC culture with con A or lipopolysaccharide (LPS), PBMC flow cytometry with anti- CD4, CD8, CD3, PD-1, PD-L1, CD25, Foxp3 mAbs. Results: Twenty-eight patients were enrolled in the study. ORR of temsirolimus was 10.7% (1 CR and 2 PR). The most commonly reported treatment-related AEs were ILD (28.5%) and stomatitis (28.5%). There were no significant changes after temsirolimus therapy for any immunological parameters. Interestingly, a significant correlation between ILD development and ORR was observed (p < 0.01). In addition, a significant increase of regulatory T cells was also observed after the recovery of ILD (p < 0.05). Conclusions: This is the first prospective study demonstrating that ILD development can be predictive for response to temsirolimus in mRCC pts. Clinical trial information: 000009662.

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Interstitial lung disease during targeted therapy in metastatic renal cell carcinoma: a case series from three centres

Medical Oncology ◽

10.1007/s12032-014-0147-9 ◽

2014 ◽

Vol 31 (9) ◽

Cited By ~ 6

Author(s):

Philipp Ivanyi ◽

Thomas Fuehner ◽

Meike Adam ◽

Christian Eichelberg ◽

Edwin Herrmann ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Targeted Therapy ◽

Interstitial Lung Disease ◽

Lung Disease ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Case Series

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Pazopanib-associated interstitial lung disease in a patient with renal cell carcinoma

BMJ Case Reports ◽

10.1136/bcr-2020-235177 ◽

2020 ◽

Vol 13 (7) ◽

pp. e235177 ◽

Cited By ~ 1

Author(s):

Yukinori Harada ◽

Shintaro Kakimoto ◽

Taro Shimizu

Keyword(s):

Renal Cell Carcinoma ◽

Interstitial Lung Disease ◽

Lung Disease ◽

Cell Carcinoma ◽

Renal Cell ◽

Kinase Inhibitor ◽

Lung Metastases ◽

Soft Tissue Sarcomas ◽

Positive Pressure ◽

Non Invasive

Pazopanib is a multi-targeted tyrosine kinase inhibitor, which is indicated for use in patients with advanced renal cell carcinoma or advanced soft-tissue sarcomas. Although rare, interstitial lung disease has been reported as among the adverse sequelae of pazopanib therapy. We report the case of a 75-year-old man who developed interstitial lung disease during treatment with pazopanib for renal cell carcinoma with multiple lung metastases. The patient presented with dry cough and new-onset fatigue 3 months after initiation of pazopanib. He had mild hypoxia with bilateral ground-glass opacities on chest CT. He was treated with antibiotics for presumptive pneumonia, but his respiratory status rapidly deteriorated, and he required non-invasive positive pressure ventilation. He recovered on discontinuation of pazopanib and systemic steroids. Clinicians should recognise that interstitial lung disease can occur in patients who are undergoing treatment with pazopanib.

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Real-world use of temsirolimus in Japanese patients with unresectable or metastatic renal cell carcinoma: recent consideration based on the results of a post-marketing, all-case surveillance study

Japanese Journal of Clinical Oncology ◽

10.1093/jjco/hyaa062 ◽

2020 ◽

Vol 50 (8) ◽

pp. 940-947

Author(s):

Shigeru Sugiyama ◽

Kazuo Sato ◽

Yoshiyuki Shibasaki ◽

Yutaka Endo ◽

Taku Uryu ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Interstitial Lung Disease ◽

Confidence Interval ◽

Lung Disease ◽

Cell Carcinoma ◽

Renal Cell ◽

Group Performance ◽

Performance Status ◽

Eastern Cooperative Oncology Group ◽

Data Set

Abstract Objective A prospective, observational, post-marketing surveillance was conducted to assess the safety and effectiveness of temsirolimus in patients with renal cell carcinoma in Japan. Methods Patients prescribed temsirolimus for advanced renal cell carcinoma were registered and received temsirolimus (25 mg weekly, intravenous infusion for 30–60 minutes) in routine clinical settings (observation period: 96 weeks). Results Among 1001 patients included in the safety analysis data set (median age, 65.0 years; men, 74.8%; Eastern Cooperative Oncology Group performance status 0 or 1, 69.6%), 778 (77.7%) reported adverse drug reactions. The most common (≥10%) all-grade adverse drug reactions were stomatitis (26.7%), interstitial lung disease (17.3%) and platelet count decreased (11.1%). The incidence rate of grade ≥3 interstitial lung disease was 4.5%. The onset of interstitial lung disease was more frequent after 4–8 weeks of treatment or in patients with lower Eastern Cooperative Oncology Group performance status (21.6% for score 0 vs 8.3% for score 4, P < 0.001). Among 654 patients in the effectiveness analysis data set, the response and clinical benefit rates were 6.7% (95% confidence interval 4.9–8.9) and 53.2% (95% confidence interval 49.3–57.1), respectively. The median progression-free survival was 18.3 weeks (95% confidence interval 16.9–21.1). Conclusions The safety and effectiveness profile of temsirolimus observed in this study was similar to that observed in the multinational phase 3 study. The results are generalizable to the real-world scenario at the time of this research, and safety and effectiveness of temsirolimus as a subsequent anticancer therapy for renal cell carcinoma warrants further investigation. (ClinicalTrials.gov identifier NCT01210482, NCT01420601).

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STAT3 polymorphism associates with mTOR inhibitor-induced interstitial lung disease in patients with renal cell carcinoma

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics ◽

10.3727/096504022x16418911579334 ◽

2022 ◽

Author(s):

Kazuhiro Yamamoto ◽

Takeshi Ioroi ◽

Kazuaki Shinomiya ◽

Ayaka Yoshida ◽

Kenichi Harada ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Interstitial Lung Disease ◽

Lung Disease ◽

Cell Carcinoma ◽

Cell Lines ◽

Renal Cell ◽

Mtor Inhibitor ◽

In Vitro Study ◽

Primary Analysis

We evaluated the association of signal transducer and activator of transcription 3(STAT3) polymorphisms with the incidence of mammalian target of rapamycin (mTOR) inhibitor-induced interstitial lung disease (ILD) in patients with renal cell carcinoma (RCC). We also used lung-derived cell lines to investigate the mechanisms of this association. Japanese patients with metastatic RCC who were treated with mTORinhibitors were genotyped for the STAT3 polymorphism, rs4796793. We evaluated the association of the STAT3 genotype with the incidence of ILD and therapeutic outcome.In the 57 patients included in the primary analysis, the ILD rate within 140 days was significantly higher in patients with the CC genotype compared with those with other genotypes (77.8% versus 23.1%, odds ratio = 11.67, 95% confidential interval = 3.06–44.46). Meanwhile, there were no significant differences in progression-free survival ortime-to-treatment failure between the patients with the CC genotype and those with other genotypes. An in vitro study demonstrated that some lung-derived cell lines carrying the CC genotype exhibited an increase in the expression of mesenchymal markers, such as fibronectin, N-cadherin, and vimentin and decreases in E-cadherin, which is an epithelial marker associated with exposure to everolimus, although STAT3 expression and activity were not related to the genotype. In conclusion, the CCgenotype of the STAT3 rs4796793 polymorphism increases the risk of mTOR inhibitorinduced ILD, supporting its use as a predictive marker for RCC.

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