Drug-Related Pneumonitis in Patients With Advanced Renal Cell Carcinoma Treated With Temsirolimus

Maroto, José Pablo; Hudes, Gary R.; Dutcher, Janice P.; Logan, Theodore F.; White, Charles S.; Krygowski, Mizue; Cincotta, Maria; Shapiro, Mark; Durán, Ignacio; Berkenblit, Anna

doi:10.1200/jco.2010.29.2235

Cited by 103 publications

(76 citation statements)

References 24 publications

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“…A retrospective blinded review of chest computerized tomography (CT) images in the ARCC phase III trial indicated that 29% of patients treated with temsirolimus developed temsirolimus-related pneumonitis [Maroto et al 2011]. This incidence is similar to that reported in other retrospective radiographic analyses of patients treated with TOR inhibitors and confirms that pneumonitis is a class-effect toxicity of mTOR inhibitors.…”

Section: Clinical Presentation and Management Of Side Effects Relatedsupporting

confidence: 66%

Clinical experience with temsirolimus in the treatment of advanced renal cell carcinoma

Zanardi

Verzoni

Grassi

et al. 2015

Therapeutic Advances in Urology

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Abstract:Temsirolimus is an inhibitor of the mammalian target of rapamycin (mTOR) kinase, a protein that has been shown to be particularly active in metastatic renal cell carcinoma (mRCC) with poor prognosis. Therefore, temsirolimus should be considered as the first-line treatment indicated in mRCC patients classified as poor risk. The benefits of temsirolimus are not limited to an increased survival but are also related to a better quality of life, which is certainly one of the most important aspects in the clinical management of these frail patients. Temsirolimus is a well-tolerated treatment, and the most frequent adverse events are manageable with supportive care. To this end, the identification of predictive factors of response to temsirolimus could help us to better select patients and obtain a more tailored clinical management of mRCC.

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Section: Clinical Presentation and Management Of Side Effects Relatedsupporting

confidence: 66%

Clinical experience with temsirolimus in the treatment of advanced renal cell carcinoma

Zanardi

Verzoni

Grassi

et al. 2015

Therapeutic Advances in Urology

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“…In the global ARCC Phase III trial, treatment-related pneumonitis was reported in 2% of patients receiving temsirolimus (13). A retrospective analysis of the global ARCC trial showed that 29% (52 of 178 evaluable patients) developed radiographically identified drug-related pneumonitis (20). In our study, treatment-related ILD was reported in 17% (14 patients) and was the most frequent cause of treatment discontinuation or dose modification.…”

Section: Discussionmentioning

confidence: 78%

Phase II Study of the Safety and Efficacy of Temsirolimus in East Asian Patients with Advanced Renal Cell Carcinoma†

Sun

Rha

Lee

et al. 2012

Japanese Journal of Clinical Oncology

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Objective: Temsirolimus, an inhibitor of the mammalian target of rapamycin, is approved for treatment of patients with advanced renal cell carcinoma in the USA and Europe. Temsirolimus was not yet evaluated in East Asian patients. Methods: This non-randomized Phase II study enrolled 82 patients with advanced renal cell carcinoma [20 (24%) Japanese, 30 (37%) Korean and 32 (39%) Chinese patients; median age (range): 55 (26 -83) years]. Most (71%) received prior systemic therapy for metastatic disease; two-thirds were intermediate risk. Six Japanese patients received intravenous temsirolimus 20 mg/m 2 weekly for tolerability assessment (Group A); the remaining 76 received a 25 mg flat dose weekly (Group B). Temsirolimus was dosed once weekly. Primary efficacy end point was the Response Evaluation Criteria in Solid Tumors-defined clinical benefit rate in the intent-to-treat population. Results: In the entire population, regardless of treatment group, the clinical benefit rate was 48% (95% confidence interval: 36, 59). Objective response rate was 11% (95% confidence interval: 5, 20), median progression-free survival was 7.3 months (95% confidence interval: 4.0, 9.2) and median time to treatment failure was 5.4 months (95% confidence interval: 3.5, 7.4). No patient in Group A demonstrated dose-limiting toxicity. The most frequent Grade 3 or 4 drug-related adverse events were anemia, hyperglycemia, hypophosphatemia and stomatitis (5% each). Serious adverse events reported in 5% of patients were pneumonia (9%) and interstitial lung disease (7%). Temsirolimus and its major metabolite, sirolimus, were long-lived throughout the dosage interval, with no evidence of accumulation. Conclusion: Temsirolimus was well tolerated and showed promising activity in Japanese, Korean and Chinese patients with advanced renal cell carcinoma.

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“…Often called interstitial pulmonary fibrosis, ILD is characterized by chronic inflammation and progressive fibrosis of the pulmonary interstitium. A very high frequency of patients (up to 36%) treated with rapalogs were found to have radiographic evidence of ILD, but the pathology often regressed upon discontinuation of mTORtargeted treatment (29)(30)(31)(32)(33)(34)(35). Interestingly, there is mounting evidence that aberrant activation of EMT could contribute to pulmonary fibrosis through the transdifferentiation of alveolar epithelial cells into proliferating fibroblasts (36)(37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

Genetic and Pharmacologic Inhibition of mTORC1 Promotes EMT by a TGF-β–Independent Mechanism

et al. 2013

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Epithelial-to-mesenchymal transition (EMT) is a transdifferentiation process that converts epithelial cells into highly motile mesenchymal cells. This physiologic process occurs largely during embryonic development but is aberrantly reactivated in different pathologic situations, including fibrosis and cancer. We conducted a siRNA screening targeted to the human kinome with the aim of discovering new EMT effectors. With this approach, we have identified mTOR complex 1 (mTORC1), a nutrient sensor that controls protein and lipid synthesis, as a key regulator of epithelial integrity. Using a combination of RNAi and pharmacologic approaches, we report here that inhibition of either mTOR or RPTOR triggers EMT in mammary epithelial cells. This EMT was characterized by the induction of the mesenchymal markers such as fibronectin, vimentin, and PAI-1, together with the repression of epithelial markers such as E-cadherin and ZO-3. In addition, mTORC1 blockade enhanced in vivo migratory properties of mammary cells and induced EMT independent of the TGF-b pathway. Finally, among the transcription factors known to activate EMT, both ZEB1 and ZEB2 were upregulated following mTOR repression. Their increased expression correlated with a marked reduction in miR-200b and miR-200c mRNA levels, two microRNAs known to downregulate ZEB1 and ZEB2 expression. Taken together, our findings unravel a novel function for mTORC1 in maintaining the epithelial phenotype and further indicate that this effect is mediated through the opposite regulation of ZEB1/ZEB2 and miR-200b and miR-200c. Furthermore, these results suggest a plausible etiologic explanation for the progressive pulmonary fibrosis, a frequent adverse condition associated with the therapeutic use of mTOR inhibitors. Cancer Res; 73(22); 6621-31. Ó2013 AACR.

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Drug-Related Pneumonitis in Patients With Advanced Renal Cell Carcinoma Treated With Temsirolimus

Abstract: Patients with ARCC receiving temsirolimus should be monitored closely for development of pneumonitis, and their management should be altered if clinical symptoms appear.

Cited by 103 publications

References 24 publications

Clinical experience with temsirolimus in the treatment of advanced renal cell carcinoma

Clinical experience with temsirolimus in the treatment of advanced renal cell carcinoma

Phase II Study of the Safety and Efficacy of Temsirolimus in East Asian Patients with Advanced Renal Cell Carcinoma†

Genetic and Pharmacologic Inhibition of mTORC1 Promotes EMT by a TGF-β–Independent Mechanism

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