Noninfectious Pneumonitis after Everolimus Therapy for Advanced Renal Cell Carcinoma Dorothy A. White1, Philippe Camus2, Masahiro Endo3, Bernard Escudier4, Emiliano Calvo5, Hideyuki Akaza6, Hirotsugu Uemura7, Euloge Kpamegan8, Andrea Kay8, Matthew Robson8, Alain Ravaud9, and Robert J. Motzer1 1 Pulmonary Section, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York; 2Department of Pulmonary ˆ pital Le Bocage and PneumotoxÒ, Dijon, France; 3Division of Diagnostic Radiology, Shizuoka Cancer Center, Shizuoka, Japan; 4Institut Medicine, Ho Gustave Roussy, Villejuif, France; 5Centro Integral Oncologico Clara Campal, Madrid, Spain; 6University of Tsukuba, Tsukuba, and 7Kinki University, ˆ pital Saint Andre´, Centre Hospitalier Universitaire, Bordeaux, France Osaka, Japan; 8Novartis Oncology, Florham Park, New Jersey; and 9Ho
Rationale: Noninfectious pneumonitis is a known class effect of mammalian target of rapamycin (mTOR) inhibitors. Objectives: To assess the incidence, radiographic patterns, management, and outcome of pneumonitis in patients with advanced renal cell carcinoma receiving everolimus. Methods: Clinical study data from 416 patients, randomized to receive everolimus versus placebo, were analyzed for adverse events of pneumonitis. Radiographic studies performed every 8 weeks were subject to a prospective, independent, blinded central review for the presence of findings indicative of pneumonitis. Measurements and Main Results: Of 274 patients receiving everolimus, clinical pneumonitis was suspected for 37 patients (13.5%) (none with placebo). Nine cases (3.3%) were grade 1 (asymptomatic), 18 (6.6%) were grade 2 (not interfering with daily living), and 10 (3.6%) were grade 3 (interfering with daily living or oxygen indicated). No grade 4 (life-threatening) pneumonitis was observed. Of the 10 patients with grade 3 pneumonitis, 5 had baseline radiological evidence of pneumonitis before everolimus therapy. Twenty of the 37 cases (54.0%) were reversible within the follow-up period; resolution followed dose reduction for 20 patients and treatment discontinuation in 10 patients. Corticosteroid therapy was initiated in 16 cases. Dedicated radiological review of available serial radiographic studies (245 patients receiving everolimus and 132 receiving placebo) found a higher percentage of new radiographic findings even in patients without a diagnosis of clinical pneumonitis who were receiving everolimus versus placebo (38.9 vs. 15.2%). Conclusions: Early recognition, prompt intervention, and a conservative approach are important in managing the risk associated with noninfectious pneumonitis in association with everolimus. Clinical trial registered with www.clinicaltrials.gov (NCT 00410124). Keywords: mTOR (mammalian target of rapamycin) inhibitors; lung toxicity; RAD001
Everolimus (formerly RAD001; Novartis Pharmaceuticals, East Hanover, NJ) is a selective inhibitor of the mammalian target of rapamycin (mTOR), a central regulator of intracellular signaling pathways involved in cell growth and proliferation, cellular metabolism, and angiogenesis. This drug is currently in use to prevent allograft rejection after solid organ transplantation (Certican) (1) and in the treatment of advanced renal cell (Received in original form November 16, 2009; accepted in final form February 24, 2010) Supported by Novartis Oncology (Florham Park, NJ). The sponsor was responsible for the collection and analysis of the data. The authors and sponsor were involved in the study design, data interpretation, manuscript preparation, and the decision to publish. Correspondence and requests for reprints should be addressed to Dorothy A. White, M.D., Memorial Sloan-Kettering Cancer Center, Pulmonary Medicine, 1275 York Avenue, New York, NY 10021. E-mail:
[email protected] This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org Am J Respir Crit Care Med Vol 182. pp 396–403, 2010 Originally Published in Press as DOI: 10.1164/rccm.200911-1720OC on March 1, 2010 Internet address: www.atsjournals.org
AT A GLANCE COMMENTARY Scientific Knowledge on the Subject
Inhibitors of the mammalian target of rapamycin (mTOR), including everolimus, are used for the prevention of solid organ transplant rejection and the treatment of cancer. This class of drugs has been associated with the development of pneumonitis. Little information is currently available on the incidence and outcome of pneumonitis in patients with advanced cancer receiving mTOR inhibitors. What This Study Adds to the Field
Everolimus is associated with a 13.5% incidence of clinically identified pneumonitis in patients with renal carcinoma. Dedicated radiological review of serial computed tomography scans during treatment showed new radiographic findings in a higher percentage of patients without clinical evidence of pneumonitis. Radiographic findings, outcomes, and a management strategy are described. Adoption of a conservative approach (in the absence of infection) of dose reduction or discontinuation with corticosteroid administration as needed in those with clinical pneumonitis is associated with manageable risk.
carcinoma (RCC) (Afinitor) (2). Everolimus and other rapamycin derivatives generally are well tolerated. Noninfectious pneumonitis, stomatitis/oral mucositis, and an increased risk of infection, including opportunistic infections, represent the most important toxicities seen with everolimus (2, 3). Noninfectious pneumonitis, apparently a class effect of mTOR inhibitors, is characterized by noninfectious, nonmalignant infiltrates and will be referred to as ‘‘pneumonitis’’ throughout this report. It has been described with sirolimus (rapamycin), temsirolimus, and everolimus in isolated case reports or retrospective series with a small number of patients (4–11). An incidence of 5–15% of clinical pneumonitis has been reported in transplant recipients receiving sirolimus (8, 12–14). Published reports suggest that it is relatively unaggressive and reversible on discontinuation of therapy in many cases, but there can be significant toxicity (9, 10). A similar experience with clinical pneumonitis has been noted with temsirolimus (15, 16). However, a radiological review of routine serial chest computed tomography (CT) scans during treatment showed a higher incidence (36%) of new radiographic abnormalities (5). Many patients were asymptomatic and continued treatment without progressing to more severe stages. Pneumonitis was initially reported in association with everolimus therapy in two investigator-initiated phase II trials in small numbers of patients with breast cancer and renal cancer
White, Camus, Endo, et al.: Pneumonitis and Everolimus Therapy
(17, 18). An incidence of 18.7–49% was noted. Many of the cases were grade 1/2 in severity (79 and 63% of affected patients, respectively, in these studies), and pneumonitis resolved after treatment suspension, dose reduction, or corticosteroid treatment. A retrospective independent radiological review of everolimus use in a phase II study of patients with advanced lung cancer found a 25% incidence of new radiographic findings consistent with pneumonitis with a probable or possible relationship to the study drug (19). Herein, we describe those patients who experienced pneumonitis during the course of the RECORD-1 (Renal Cell Cancer Treatment with Oral RAD001 Given Daily) study of the efficacy of everolimus in RCC and report their management and outcomes. In addition, to address the issue of a higher incidence of radiographic findings while on treatment with everolimus without clinically recognized pneumonitis (as was noted with temsirolimus), we report the results of a dedicated radiographic review of all available serial CT scans.
METHODS Between November 2006 and October 2007, 416 patients with metastatic RCC after failure of treatment with sunitinib, sorafenib, or both sunitinib and sorafenib were randomly assigned at a 2:1 ratio to receive treatment with everolimus 10 mg once daily or placebo as part of the RECORD-1 study (ClinicalTrials.gov identifier, NCT00410124) (2, 3). To help formulate a definitive approach to address pneumonitis occurring in this study, an advisory board consisting of several leading pulmonologists was convened by Novartis Pharmaceuticals Corporation. Routine screening of all patients via chest X-ray (CXR) and CT scan was proposed. Advice on the management of pneumonitis was provided in the form of a treatment algorithm (Table 1). CT scans and CXRs were performed on all patients on a routine basis (at 8-wk intervals). Pulmonary function tests (PFTs) were performed at baseline. Pneumonitis was considered to have occurred if the investigator coded for the adverse event of pneumonitis during the trial. These cases were assessed by review of the trial clinical database for the presence of this adverse event, associated symptoms, severity, treatment, and outcome. Decisions on the need for additional procedures, such as bronchoscopy to exclude infectious etiologies or other causes, were made by investigators during the study. In addition, a Medical Dictionary for Regulatory Activities (MedDRA) search strategy of the clinical database was followed to check for coding for other pulmonary events that could indicate pneumonitis or pneumonitis-like cases. These included terms such as alveolitis, interstitial lung disease, pneumopathy, and pulmonary toxicity. Pulmonary adverse events forming the basis for this search strategy are listed in the online supplement. All events were graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 3.0 (20). For pneumonitis, this corresponds to the following: grade 1 (mild)—asymptomatic, radiographic findings only; grade 2 (moderate)—symptomatic, not interfering with activities of
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daily living; grade 3 (severe)—symptomatic, interfering with activities of daily living or oxygen indicated; grade 4 (life-threatening or disabling)—life-threatening or ventilatory support indicated. Advice on management was provided to investigators in the form of a treatment algorithm developed by a pulmonary advisory panel and incorporated into the study protocol as detailed in Table 1. Serial routine CXRs and CT scans were subsequently subjected to an independent, blinded (with treatment and safety results unknown) central review for the presence or absence of new radiographic findings that could be pneumonitis; categorization of the findings if present; and details of its distribution, severity, incidence of associated pleural effusions, and evidence of progression. An incidence rate was calculated for newly occurring or worsening radiological evidence of pneumonitis that was confirmed on a CT scan. Imaging findings on chest CT scan were classified into four distinct patterns, consistent with the approach proposed by Endo and colleagues (21): pattern A—nonspecific areas of ground-glass attenuation, corresponding to diffuse and faint opacity without loss of lung volume on chest radiography; pattern B—multifocal areas of airspace consolidation (as in, but not diagnostic of, cryptogenic organizing pneumonia or bronchiolitis obliterans organizing pneumonia), corresponding primarily to peripheral consolidation on chest radiography; pattern C—patchy distribution of ground-glass attenuation accompanied by interlobular septal thickening (as in, but not diagnostic of, acute eosinophilic pneumonia), corresponding to patchy or diffuse faint, linear opacities on chest radiography; and pattern D—extensive bilateral ground-glass attenuation or airspace consolidation with traction bronchiectasis (as in, but not diagnostic of, acute interstitial pneumonia), corresponding to diffuse faint opacities or consolidation with lung volume loss on chest radiography. Progression-free survival curves based on the absence/presence of clinical pneumonitis were estimated by Kaplan-Meier methodology; cohorts of patients with radiographic findings consistent with pneumonitis versus those with no new findings were compared by log-rank test. The percentage of predicted absolute values for PFTs was calculated using the equations of Crapo (22, 23).
RESULTS A total of 274 patients received treatment with everolimus and 137 received placebo. Demographic characteristics are summarized in Table 2. Close to 80% of patients were male, and approximately one-third had a history of one or more respiratory disorders and/or symptoms at the start of treatment. This included patients with a wide range of pulmonary diseases including chronic obstructive pulmonary disease, asthma, restrictive pulmonary disease, and/or symptoms of dyspnea and cough, among others. Lung metastases were present in approximately three-fourths of the patients. Previous treatment with interferon had been received by 51 and 52% of patients in the everolimus and placebo groups, respectively. Treatment with interleukin-2 had been received by 22 and 24% of these
TABLE 1. MANAGEMENT OF PNEUMONITIS: TREATMENT ALGORITHM Grade
Intervention
1
No specific therapy required
2
Symptomatic only. Prescribe corticosteroids if cough is troublesome Prescribe corticosteroids if infectious etiology is ruled out. Taper as clinically indicated Prescribe corticosteroids if infectious etiology is ruled out. Taper as clinically indicated
3
4
Investigations CT scan and PFTs.* Repeat chest X-ray/CT scan every two cycles until return to baseline CT scan and PFTs.* Repeat each cycle until return to baseline. Consider bronchoscopy CT scan and PFTs.* Repeat each cycle until return to baseline. Bronchoscopy required CT scan and PFTs.* Repeat each cycle until return to baseline. Bronchoscopy required
Everolimus Dose Adjustment No change Reduce dose until improvement to grade
