Final overall survival analysis for the phase II RECORD-3 study of first-line everolimus followed by sunitinib versus first-line sunitinib followed by everolimus in metastatic RCC

Knox, J. J.,Barrios, C. H.,Kim, T. M.,Cosgriff, T.,Srimuninnimit, V.,Pittman, K.,Sabbatini, R.,Rha, S. Y.,Flaig, T. W.,Page, R. D.,Beck, J. T.,Cheung, F.,Yadav, S.,Patel, P.,Geoffrois, L.,Niolat, J.,B Oxford University Press 2017 ANNALS OF ONCOLOGY Vol.28 No.6

<P><B>Background</B></P><P>RECORD-3 compared everolimus and sunitinib as first-line therapy, and the sequence of everolimus followed by sunitinib at progression compared with the opposite (standard) sequence in patients with metastatic renal cell carcinoma (mRCC). This final overall survival (OS) analysis evaluated mature data for secondary end points.</P><P><B>Patients and methods</B></P><P>Patients received either first-line everolimus followed by second-line sunitinib at progression (<I>n = </I>238) or first-line sunitinib followed by second-line everolimus (<I>n = </I>233). Secondary end points were combined first- and second-line progression-free survival (PFS), OS, and safety. The impacts of neutrophil lymphocyte ratio (NLR) and baseline levels of soluble biomarkers on OS were explored.</P><P><B>Results</B></P><P>At final analysis, median duration of exposure was 5.6 months for everolimus and 8.3 months for sunitinib. Median combined PFS was 21.7 months [95% confidence interval (CI) 15.1–26.7] with everolimus-sunitinib and 22.2 months (95% CI 16.0–29.8) with sunitinib-everolimus [hazard ratio (HR)<SUB>EVE-SUN/SUN-EVE</SUB>, 1.2; 95% CI 0.9–1.6]. Median OS was 22.4 months (95% CI 18.6–33.3) for everolimus-sunitinib and 29.5 months (95% CI 22.8–33.1) for sunitinib-everolimus (HR<SUB>EVE-SUN/SUN-EVE</SUB>, 1.1; 95% CI 0.9–1.4). The rates of grade 3 and 4 adverse events suspected to be related to second-line therapy were 47% with everolimus and 57% with sunitinib. Higher NLR and 12 soluble biomarker levels were identified as prognostic markers for poor OS with the association being largely independent of treatment sequences.</P><P><B>Conclusions</B></P><P>Results of this final OS analysis support the sequence of sunitinib followed by everolimus at progression in patients with mRCC. The safety profiles of everolimus and sunitinib were consistent with those previously reported, and there were no unexpected safety signals.</P><P><B>Clinical Trials number</B></P><P>ClinicalTrials.gov identifier, NCT00903175</P>

Experience of a Single Center in Treating Multiple Manifestations of Tuberous Sclerosis Complex with Everolimus

Hyunji Ahn,Mi-Sun Yum,Han Na Jang,Cheryn Song,Tae-Sung Ko 대한소아신경학회 2019 대한소아신경학회지 Vol.27 No.4

Purpose: The aim of this study was to evaluate the efficacy and tolerability of everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, for the treatment of tuberous sclerosis complex (TSC) manifestations. Methods: A retrospective analysis was conducted using an in-house research database with the keywords “tuberous sclerosis AND everolimus.” Twenty patients were treated with everolimus for TSC from 2013 to February 2019. Results: The mean age of the 20 patients was 25.6 years (range, 0 to 57), and the average duration of everolimus treatment was 87.6 weeks (range, 0 to 290). Everolimus was given with a usual daily dosage of 5 to 10 mg (mean, 7.1) or 0.0625 to 0.5 mg for neonates. Twelve patients were prescribed everolimus for more than 1 year for kidney angiomyolipoma (AML). Two of those patients (16.7%) experienced reductions of >50% in tumor size, and four patients (33.3%) experienced reductions of 25% to 50%. The four patients who were prescribed everolimus for subependymal giant cell astrocytoma (SEGA) had 25% to 50% reductions. Neonates with cardiac rhabdomyoma showed significant tumor reduction with everolimus, but their tumors exhibited rebound size increases after treatment was halted. Of the three patients with intractable seizures, one patient became seizure-free, and two patients had >50% reductions. Overall, everolimus therapy was well tolerated. Conclusion: Everolimus, an mTOR inhibitor, was effective for seizure control and size reduction of kidney AML, SEGA, and cardiac rhabdomyoma tumors in patients with TSC. However, clinicians should also be aware of the adverse event profile of everolimus.

전이성 신세포암에서 Everolimus 사용 후 유발된 당뇨병성 케톤산증 1예

김이경 ( Lee Kyung Kim ),안창호 ( Chang Ho Ahn ),이지은 ( Jie Eun Lee ),정찬현 ( Chan Hyeon Jung ),구보경 ( Bo Kyung Koo ),문민경 ( Min Kyong Moon ) 대한내과학회 2014 대한내과학회지 Vol.86 No.6

신세포암, 유방암, 췌장의 신경내분비종 등의 치료에 사용이 증가하고 있는 mTOR 억제제인 everolimus의 치료 시고혈당, 고지질혈증 등의 대사 이상이 발생할 수 있음이 알려져 있으나 당뇨병성 케톤산증의 발생은 보고된 바 없다. 저자들은 전이성 신세포암에서 everolimus 투여 후 발생한 당뇨병성 케톤산증 1예를 경험하였기에 문헌고찰과 함께 보고하는 바이다. Everolimus, an inhibitor of the mammalian target of the rapamycin (mTOR) pathway, is widely used as an immunosuppressant for the prevention of organ rejection following transplant and to treat metastatic clear-cell type renal cell carcinoma (RCC), breast cancer, and pancreatic neuroendocrine tumors. Everolimus commonly induces metabolic abnormalities such as hyperglycemia, hypercholesterolemia, and hypertriglyceridemia due to concomitant increases in blood glucose levels via the induction of insulin resistance and a decrease in β cell function, which both lead to insulin deficiency. Although abnormal blood glucose levels are observed in more than 50% of patients treated with Everolimus, hyperglycemia exceeding 500 mg/dL is not common and there have been no reports of Everolimus-induced acute hyperglycemic crisis conditions. Here, a novel case of Everolimus-associated diabetic ketoacidosis (DKA) in a patient with RCC is reported. (Korean J Med 2014;86:761-765)

결절경화증의 표적치료제(Everolimus) 투여 후 호전된 망막성상세포과오종

김현아(Hyuna Kim),박성희(Song-hee Park) 대한안과학회 2021 대한안과학회지 Vol.62 No.6

목적: 결절경화증 환아에서 mammalian target of rapamycin (mTOR) 억제제(everolimus) 치료 후 망막성상세포과오종 병변의 두께가 감소하는 호전을 보여 이를 보고하고자 한다. 증례요약: 결절경화증으로 진단받은 12세 여아가 정기적 안저검사를 위해 방문하였다. 환아는 생후 3개월경 양안 안저에서 다발성성상세포과오종이 발견된 후 1년마다 경과 관찰하였고 만 10세경 안저검사까지 병변의 변화가 없었다. 마지막 검사 2개월 후 경련이 있어 치료를 위해 소아신경과에서 everolimus (5 mg, AFINITOR??, Novartis, Bazel, Switzerland)을 17개월간 처방하였고, 이후 시행한 안저검사와 빛간섭단층촬영에서 뚜렷한 3군데 과오종의 평균두께가 676 μm에서 500 μm로 25% 감소하였다. 결론: 결절경화증 환자에서 mTOR 억제제는 심각한 부작용 없이 전신의 과오종과 경련을 치료할 수 있는 표적치료제이며, 일반적으로 자연적인 호전이 극히 드물다고 알려진 망막성상세포과오종의 크기를 감소시키는 효과가 있었다. 후극부나 시신경유두 주변에 발생하여 시력과 시야에 영향을 주는 과오종의 경우 everolimus를 치료적 수단으로 고려할 수 있겠다. Purpose: We report a case of regressed retinal astrocytic hamartomas (RAHs) in tuberous sclerosis complex (TSC) patients by mammalian target of rapamycin inhibitor (everolimus) treatment. Case summary: A 12-year-old girl diagnosed with TSC visited for regular checkups. The patient had undergone regular fundus examinations every year after the finding of multiple RAHs in both eyes in the initial screening at 3 months of age. There was no change in the size or thickness of the lesions until she reached 10 years of age. Two months later, the patient started systemic everolimus (5 mg, AFINITOR??, Novartis, Basel, Switzerland) treatment for 17 months under the care of a pediatric neurologist for seizure control. Subsequent fundus examination and measurements by optical coherence tomography showed improvement in the maximal thickness of all lesions, specifically, a reduction of 25%. Conclusions: mTOR inhibitors are targeted agents that regress systemic hamartomas and control convulsions without serious side effects in TSC patients. The particular one used in this study, Afinitor everolimus, reduced the RAH size in our patient. Thus, in cases where an RAH affects vision due to its location, everolimus can considered as a therapeutic option.

간 이식 환자에서의 Everolimus 사용 현황 분석

이슬이,김수진,민명숙,김정미,이영미 한국병원약사회 2018 병원약사회지 Vol.35 No.2

Purpose : The Korean health insurance has covered the use of everolimus in adult patients receiving liver transplants with the concomitant use of both tacrolimus and corticosteroids since June 1st 2015. This study was conducted to analyze the use of everolimus in patients who have received a liver transplantation at the Samsung Medical Center. Methods : The secured electronic medical records of 105 patients, who took everolimus from June 1st 2015 to June 30th 2016, were retrospectively reviewed. We analyzed adherence to the recommended prescription as requried and noted and mesured the incidence of side effects. Results : Among the 105 patients, there were 103 patients (98.1%) who started everolimus treatment 4 weeks after having received their transplantation, and 62 (59.0%) started 0.5 mg/dose and 32 (30.5%) took 1 mg/dose of everolimus twice a day. The rate of maintaining the trough concentration of 3 to 8 ng/mL of everolimus was 53.0% within 1 month after the administration, 46.8% from 1 to 3 months, and 48.2% from 3 to 6 months. There were a number of patients whose serum levels were below the recommended range, but the recoded serum trough concentrations were continuously monitored and the incidence of a post-transplant rejection was low (1.9%). The blood analysis data showed more than 240 mg/dL of total cholesterol in 40 patients (38.1%) during the administration period. Conclusion : Further studies on the proper initial dose and maintenance of an adequate drug concentration ranges in the Korean population are needed. In addition, due to the increased risk of dyslipidemia after everolimus administration, the periodic monitoring of the blood lipid profiles is important and appropriate measures should be taken when necessary. Therefore, in order to contribute to effective drug use and minimize side effects, it requires a more proactive role of pharmacists in prescription monitoring and interventions with use of this therapy.

Biomarkers of Everolimus Sensitivity in Hormone Receptor-Positive Breast Cancer

Zongbi Yi,Fei Ma 한국유방암학회 2017 Journal of breast cancer Vol.20 No.4

Activation of the mammalian target of rapamycin (mTOR) signaling pathway is an important mechanism of resistance to endocrine therapy in breast cancer. Everolimus, an mTOR inhibitor, has been shown to increase the efficacy of endocrine therapy and overcome resistance to endocrine therapies. Clinical studies have suggested that everolimus combined with endocrine ther- apy prolongs progression-free survival in hormone receptor-positive breast cancer patients. However, because breast cancer includes a group of highly heterogeneous tumors, patients may have different responses to everolimus. Therefore, finding biomarkers that can predict a patient’s positive response or resistance to everolimus is critical. Numerous preclinical studies have shown that PIK3CA/PTEN mutations are predictive of sensitivity to everolimus; however, clinical trials have not confirmed the correlation between mutation status and clinical response. KRAS or BRAF mutations can bypass the phosphatidylinositol 3-kinase pathway; therefore, mutations in KRAS or BRAF may lead to resistance to mTOR inhibitors, and preclinical studies have shown that PIK3CA mutant cells which also contain KRAS mutations are resistant to everolimus. However, there are no clinical data in breast cancer patients to support this conclusion. Therefore, large-scale clinical studies are needed to identify biomarkers of efficacy and resistance to everolimus.

Crizotinib in Combination with Everolimus Synergistically Inhibits Proliferation of Anaplastic Lymphoma KinasePositive Anaplastic Large Cell Lymphoma

Wendan Xu,김지원,정우준,고영일,윤성수 대한암학회 2018 Cancer Research and Treatment Vol.50 No.2

Purpose Anaplastic large cell lymphoma (ALCL) is a rare aggresive non-Hodgkin lymphoma, of which over 50% of cases have an aberrant nucleophosmin (NPM)anaplastic lymphoma kinase (ALK) fusion protein. Both mechanistic target of rapamycin (mTOR) inhibitor everolimus and ALK inhibitor crizotinib have shown promising antitumor activity in ALK-positive cancer cell lines. However, their combined effect has not yet been investigated. Materials and Methods We evaluated the anti-proliferative effects of everolimus and/or crizotinib in ALK-positive ALCL cell lines, Karpas 299 and SU-DHL-1, and lung adenocarcinoma cell line, NCI-H2228. Results We found that individually, both everolimus and crizotinib potently inhibited cell growth in a dose-dependent manner in both Karpas 299 and SU-DHL-1 cells. A combination of these agents synergistically inhibited proliferation in the two cell lines. Crizotinib down-regulated aberrant AKT and ERK phosphorylation induced by everolimus. Combination treatment also significantly increased G0/G1 cell-cycle arrest, DNA damage, and apoptosis compared with everolimus or crizotinib alone in ALK-positive ALCL cells. In the Karpas 299 xenograft model, the combination treatment exerted a stronger antitumor effect than monotherapies, without significant change in body weight. The synergistic effect of everolimus and crizotinib was also reproduced in the ALK-positive lung adenocarcinoma cell line NCI-H2228. The combination treatment abrogated phosphoinositide 3-kinase/AKT and mTOR signaling pathways with little effect on the Ras/ERK pathway in NCI-H2228 cells. Conclusion Crizotinib combined with everolimus synergistically inhibits proliferation of ALK-positive ALCL cells. Our results suggest that this novel combination is worthy of further clinical development in patients with ALK-positive ALCL.

증례 : 혈액종양 ; 전이성 신세포암에서 Everolimus 사용 후 유발된 간질성 폐렴 1예

이소라 ( So Ra Lee ),김영민 ( Young Min Kim ),정지연 ( Ji Yun Jung ),김형준 ( Hyung Joon Kim ),김도형 ( Doh Hyung Kim ),박건우 ( Keon Woo Park ),이순일 ( Soon Il Lee ) 대한내과학회 2012 대한내과학회지 Vol.83 No.4

Everolimus, an inhibitor of the mammalian target of rapamycin, is an active agent against metastatic renal cell carcinoma. Treatment with everolimus prolongs progression-free survival in patients with clear cell-type renal cell carcinoma that has progressed on vascular endothelial growth factor receptor tyrosine kinase inhibitors, such as sunitinib and/or sorafenib. Everolimus-induced interstitial pneumonitis is not rare and is sometimes fatal. Due to the potential for pulmonary toxicity due to everolimus, it is recommended that pulmonary complications be periodically evaluated. We report a case of everolimus-associated interstitial pneumonitis in a patient with metastatic renal cell carcinoma. (Korean J Med 2012;83:520-524)

Cross-sectional analysis of immunosuppressive regimens focused on everolimus after liver transplantation in a Korean high-volume transplantation center

Sang-Hyun Kang,Shin Hwang,Tae Yong Ha,Gi Won Song,Dong-Hwan Jung,Chul-Soo Ahn,Deok-Bog Moon,Ki-Hun Kim,Gil-Chun Park,Young-In Yoon,Yo Han Park,Hui-Dong Cho,권재현,Yong-Kyu Chung,Jin-Uk Choi,Sung Gyu Lee 대한이식학회 2019 Korean Journal of Transplantation Vol.33 No.4

Background: The mammalian target of the rapamycin inhibitor has dual inhibitory effects on cell growth and angiogenesis. This study aimed to analyze the usage of everolimus on actual immunosuppression (IS) regimens through a cross-sectional study in a high-volume liver transplantation (LT) center. Methods: Our institutional LT database was searched for adult patients who underwent primary LT surgery between January 2010 and December 2016. We identified 2,093 LT recipients with observation periods of 1 to 8 years. Results: We divided the 2,093 recipients into three groups according to the posttransplant follow-up period as follows: group A (12–36 months; n=680), group B (37–60 months; n=560), and group C (>60 months; n=853). The individual IS agents were tacrolimus in 1,807 patients (86.3%), cyclosporine in 169 patients (8.1%), mycophenolate mofetil (MMF) in 1,310 patients (62.6%), and everolimus in 115 patients (5.5%). The most common IS regimens were tacrolimus-MMF combination and tacrolimus monotherapy, regardless of the posttransplant period. Patients with pretransplant malignancies were administered everolimus more frequently than those without pretransplant malignancies (P<0.001). In 102 patients with hepatocellular carcinoma recurrence or de novo malignancies, IS regimens included everolimus-tacrolimus in 41 patients (40.2%), tacrolimus-MMF in 27 patients (26.4%), tacrolimus in 20 patients (19.6%), MMF in 10 patients (9.8%), cyclosporine in three patients (2.9%), and cyclosporine-MMF in one patient (1.0%). Conclusions: Administration of everolimus after LT has been gradually increasing with the expansion of indications in our institutional practice. Currently, the role of everolimus is minimal and not comparable to that of tacrolimus, but it has a unique position in the field of IS after LT.

[P114] Fibrous plaque of the eyelid in a patient with tuberous sclerosis complex responding to everolimus

( Hyun-joo Lee ),( Dong-young Roh ),( Sung-min Park ),( Hyunju Jin ),( Hyang-suk You ),( Woo-haing Shim ),( Gun-wook Kim ),( Hoon-soo Kim ),( Byung-soo Kim ),( Moon-bum Kim ),( Hyun-chang Ko ) 대한피부과학회 2017 대한피부과학회 학술발표대회집 Vol.69 No.1

Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome with variable expression In recent years, various studies have reported that topical rapamycin can induce regression of angiofibroma. Everolimus, another derivative of sirolimus, works as an inhibitor of mammalian target of rapamycin, inhibiting tumorigenesis and angiogenesis. Herein, we report a compelling case of TSC with an eyelid showing mild improvement after treatment with systemic everolimus. A 5-year-old girl presented with a erythematous indurated plaque of the left lower eyelid. The patient was diagnosed with TSC at 28 months of age; when she presented with seizure, developmental delay, multiple subcortical tubers in the bilateral cerebral hemisphere, subependymal nodule with internal calcification suspicious of subependymal giant cell astrocytoma at the left lateral ventricle, and angiomyolipomas in both kidneys. On genetic testing, she was found to have the TSC2 mutation. Histological examination of an eyelid was consistent with fibrous plaque. She was treated with oral everolimus for subependymal giant cell astrocytoma, and then fibrous plaque showed reduced thickness and erythema gradually during 14 month follow-up. To the best of our knowledge, reports of unusual eyelid lesions in TSC have been rare. In addition, this case suggests that everolimus may be an effective treatment for fibrous facial plaques as well as angiofibromas and shagreen patches.