Everolimus-induced Pneumonitis Research Articles

Everolimus-Induced Pneumonitis in Patients with Neuroendocrine Neoplasms: Real-World Study on Risk Factors and Outcomes

BackgroundEverolimus-induced pneumonitis (EiP) has been poorly studied in patients with neuroendocrine neoplasms (NEN) outside clinical trials. The aim of this study was to evaluate the incidence, risk factors, and outcomes of EiP in patients with NENs using real-world data.MethodsRetrospective study of everolimus-treated patients with advanced NENs. Imaging reports were systematically reviewed for the presence of pneumonitis. Clinical features and treatment profiles for EiP were summarized. Overall survival (OS) was calculated from the initiation of everolimus to the date of death or last follow-up using the Kaplan-Meier method.ResultsA total of 122 patients were included. Median age at start of everolimus was 62 (19-86) years, 62% (76/122) were male, and half were from pancreatic origin (62, 51%). Twenty-eight patients (23%) developed EiP: 82% grade (G)1 or G2, 14% G3 and 4% G4. The median time to EiP was 3.6 (0.8-51) months. Primary tumor site, concurrent lung disease, smoking history, and prior therapies were not associated with the onset of EiP. Patients who developed EiP had longer time on everolimus treatment (median 18 months vs 6 months; P = .0018) and OS (77 months vs 52 months; P = .093). Everolimus-induced pneumonitis was a predictor of improved OS by multivariable analysis (HR 0.39, 95% CI 0.19-0.82; P = .013).ConclusionEverolimus-induced pneumonitis in the real-world clinical setting is present in one quarter of patients with NENs receiving everolimus and often occurs early. While risk factors for EiP were not identified, patients with EiP had improved survival.

Everolimus in the treatment of metastatic thymic epithelial tumors

IntroductionThere is emerging evidence to support the use of mTOR inhibitor everolimus in patients with advanced, relapsed-refractory thymic epithelial tumors (TETs). However, patient selection and identifying predictive biomarkers of response remains a challenge. Here, we describe a single-center experience with everolimus in patients with TETs and provide detailed molecular analysis of their thymic tumors. Materials and MethodsData on all patients with advanced TETs who were prescribed everolimus at Stanford University were retrospectively assessed. Time to treatment failure (TTF) and overall survival (OS) were calculated. STAMP, a 130-gene targeted next generation sequencing (NGS) panel, was performed on each tumor sample. ResultsTwelve patients with thymoma (T) and three with thymic carcinoma (TC) treated with everolimus were included. Patients had been heavily pre-treated with an average of three prior lines of therapy. Three patients discontinued treatment due to adverse events. The average TTF was 14.7 months in T and 2.6 months in TC with median OS of 27.6 months in the entire cohort (NR T and 5.3 months TC). Two patients with paraneoplastic autoimmune diseases had improvement in autoimmunity on everolimus. Pathogenic mutations were observed in 4/15 (27 %) of patients and includedTP53, KEAP1 and CDKN2A. Several variants of unknown significance in key genes responsible for modulating tumor response to mTOR inhibition were also found. ConclusionAs previously reported in a prospective trial, patients with previously treated advanced TETs appear to benefit from everolimus in this single institution cohort. Moreover, there was a manageable toxicity profile and no cases of everolimus-induced pneumonitis. A targeted NGS panel revealed several pathogenic mutations but there was no association between detectable tumor mutations and time to treatment failure in this cohort.

Everolimus-induced pneumonitis in neuroendocrine neoplasms: correlation of CT findings and clinical signs.

Everolimus, a mammalian target of rapamycin (mTOR)-inhibitor, is approved for the treatment of advanced neuroendocrine neoplasms (NEN). A rare major adverse event is the occurrence of drug-induced pneumonitis. To evaluate the correlation between clinical signs and computed tomography (CT) findings in everolimus-induced pneumonitis in patients with NEN. Ninety patients with NEN treated with everolimus were retrospectively enrolled (approved by our Institutional Review Board). All patients received chest CTs before the initiation of everolimus and during the treatment along with physical examinations. Clinical signs of pneumonitis were scored (symptomatic score) according to CTCAE v5.0. Pulmonary function tests (PFT) were evaluated if available. CT images were analyzed based on the severity of interstitial lung disease (ILD), the overall pneumonitis extent (PnE), and regarding presence of typical lung opacification patterns. Follow-up examinations of patients with pneumonitis were analyzed. Pneumonitis was diagnosed in 18 (20%) patients. There was no significant correlation between symptomatic score or PFT and ILD score or PnE. In case of a cryptogenic organizing pneumonia pattern (n = 14), symptomatic scores were significantly lower (P = 0.035) than in case of other opacification patterns (n = 4). In the follow-up analysis, we could identify four different clinical courses. CT detects everolimus-induced pneumonitis at a subclinical stage. In this setting, CT findings, clinical severity, and PFT do not clearly correlate. Opacification pattern analysis seems to be of importance when assessing the severity of CT findings. Asymptomatic patients with positive CT findings should be closely monitored to timely initiate specific treatment.

Everolimus-induced pneumonitis associates with favourable outcome in patients with metastatic renal cell carcinoma

BackgroundMammalian target of rapamycin inhibitors may induce pneumonitis. We analysed the association of pneumonitis with outcomes in everolimus treated metastatic renal cell carcinoma (mRCC) patients. Patients and methodsEighty-five mRCC patients received everolimus at Helsinki University Hospital (cohort A). Computed tomography (CT) verified pneumonitis was correlated with outcome using Kaplan–Meier, Cox regression and logistic regression. An independent cohort of 148 everolimus treated mRCC patients (cohort B) at Aarhus University Hospital was assessed for validation. ResultsIn cohort A, CT-verified pneumonitis (N = 29, 34.1%) was associated with improved overall survival (OS) (24.7 versus 8.5 months; P < 0.001), progression-free survival (PFS) (5.5 versus 3.2 months; P = 0.002) and clinical benefit rate (CBR) 57.1% versus 24.1% (P = 0.003). In multivariate analyses pneumonitis was associated with improved OS (hazard ratio [HR], 0.22; 95% confidence interval [CI] 0.12–0.44; P < 0.001), PFS (HR 0.37; 95% CI 0.21–0.66; P = 0.001) and CBR (odds ratio [OR] 4.11; 95% CI 1.42–11.95; P = 0.01).In cohort B, CT-verified pneumonitis (N = 29, 19.6%) was associated with improved OS (12.9 versus 6.0 months; P = 0.02), PFS (6.0 versus 2.8 months; P = 0.02) and CBR (79.3% versus 39.5%; P < 0.001). In multivariate analyses pneumonitis was associated with improved OS (HR 0.58; 95% CI 0.36–0.94; P = 0.03), PFS (HR 0.61; 95% CI 0.39–0.95; P = 0.03) and CBR (OR 5.65; 95% CI 2.10–15.18; P = 0.001).In a combined multivariate analysis (N = 233), with pneumonitis as a time-dependent covariate, CT-verified pneumonitis was associated with longer OS (HR, 0.67; 95% CI 0.46–0.97; P = 0.03). Furthermore, in a landmark analysis, pneumonitis was associated with longer OS (17.4 versus 7.8 months; P = 0.01). ConclusionsEverolimus-induced pneumonitis is associated with improved outcome in patients with mRCC and may serve as a biomarker of everolimus efficacy.

830P - Everolimus-induced pneumonitis as predictor of outcome in patients with metastatic renal cell carcinoma

830P - Everolimus-induced pneumonitis as predictor of outcome in patients with metastatic renal cell carcinoma

Interstitial pneumonitis caused by everolimus: a case-cohort study in renal transplant recipients

The use of inhibitors of the mammalian target of rapamycin (mTORi) in renal transplantation is associated with many side effects, the potentially most severe being interstitial pneumonitis. Several papers have reported on sirolimus-induced pneumonitis, but less is published on everolimus-induced pneumonitis (EIP). Data on risk factors for contracting EIP are even more scarce. In the present case-cohort study in renal transplant recipients (RTR), we aimed to assess the incidence and risk factors of EIP after renal transplantation. This study is a retrospective substudy of a multicenter randomized controlled trial. All patients included in the original trial and treated with prednisolone/everolimus were included in this substudy. RTR who developed EIP were identified as cases. RTR without pulmonary symptoms served as controls. Thirteen of 102 patients (12.7%) developed EIP. We did not find any predisposing factors, especially no correlation with everolimus concentration. On pulmonary CT scan, EIP presented with an organizing pneumonia-like pattern, a nonspecific interstitial pneumonitis-like pattern, or both. Median time (range) to the development of EIP after start of everolimus was 162 (38-407) days. In conclusion, EIP is common in RTR, presenting with an organizing pneumonia, a nonspecific interstitial pneumonitis-like pattern, or both. No predisposing factors could be identified (Trial registration number: NTR567 (www.trialregister.nl), ISRCTN69188731).

Early everolimus-induced pneumonitis in a renal transplant recipient: A case report

Everolimus is a derivative of sirolimus, and is considered to be free of the latter's pulmonary toxicity. Recently, a few cases of everolimus-induced lung injury have been reported. Early recognition of drug-induced lung disease is important because it can be reversed if appropriate therapy is instituted soon after the onset of symptoms. We present the case of an everolimus-induced pneumonitis in a renal transplant recipient, which occurred as early as on the 5th day after everolimus introduction. Shortly after the transplant procedure, the patient presented with typical symptoms of pulmonary infection. Chest radiography and computed tomography showed bilateral patchy lung infiltrates with peribronchial distribution that were suggestive of bacterial pneumonia. However, there was no improvement with empiric antibiotic treatment. Repeated cultures from the blood, sputum, and broncho-alveolar lavage (BAL) also were negative. Tuberculosis, Pneumocystis jiroveci, and Cytomegalovirus infections were excluded. A transbronchial lung biopsy performed 9 days after the onset of symptoms revealed mild nonspecific inflammation with a fibrotic component in the bronchial walls. Withdrawal of everolimus on the third day of hospitalization and after 8 days of its usage resulted in quick clinical recovery and resolution of radiological abnormalities within 1 month. Diagnosis of drug-induced pulmonary toxicity is difficult because it is essentially a diagnosis of exclusion. Lack of response to empiric antibiotic treatment and an imaging pattern of organizing pneumonia should raise suspicion of everolimus-induced pneumonitis in patients undergoing therapy with this drug.

Sirolimus and Everolimus Induced Pneumonitis in Adult Renal Allograft Recipients: Experience in a Center

Mammalian target of rapamycin (mTOR) inhibitors induce pneumonitis, an unusual but potentially fatal side effect of this drug group. We retrospectively collected the cases of pneumonitis induced by sirolimus or everolimus among 1471 adult cadaveric renal transplant recipients who were grafted at our institution from 1980-2008. Due to chronic transplant dysfunction or tumor, 205 patients were switched from calcineurin inhibitors to sirolimus (n = 88) or to everolimus (n = 117). Six patients (2.9%) developed pneumonitis: 1 was associated with sirolimus and 5 with everolimus (5 males and 1 female; median age, 60 years [range, 47-73 years]). Median times from conversion to pneumonitis onset were 34 days in 4 patients (range, 24-46 days) and 491 days in 2 subjects (range, 454-528 days). The mean drug trough level at presentation was 8.2 microg/L (range, 5.5-13.8 microg/L). The most common symptoms were dry cough (n = 6), fever (n = 5), and dyspnea (n = 4). Imaging tests revealed lower lobe involvement in all patients. Bronchoalveolar lavage performed in 4 patients showed lymphocytic alveolitis. All patients completely recovered after drug withdrawal. Five patients received steroids, 5 were switched to a calcineurin inhibitor, and 1 was switched to the other mTOR inhibitor. In conclusion, mTOR inhibitor-associated pneumonitis is a rare disease. Sirolimus did not cause more cases of pneumonitis than everolimus. Pneumonitis development was not dependent upon the drug blood level. Lower lobe involvement and lymphocytic alveolitis were usually present. Discontinuation of the mTOR inhibitor with steroid prescription resulted in adequate outcomes. A change to the other mTOR inhibitor should be contemplated if patient circumstances require this type of immunosuppression.

Everolimus-induced pneumonitis: report of the first case in a liver transplant recipient and review of treatment options

Everolimus-induced pneumonitis: report of the first case in a liver transplant recipient and review of treatment options