Safety Profile Of Everolimus Research Articles

Real-Life Analysis of Efficacy and Safety of Everolimus Plus Exemestane in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor-2-Negative Metastatic Breast Cancer Patients: A Turkish Oncology Group (TOG) Study

Purpose This study evaluated the efficacy and safety of everolimus (EVE) plus exemestane (EXE) in hormone-receptor positive (HR+), human epidermal growth factor receptor-2-negative (HER2−) metastatic breast cancer (MBC) patients in real-life settings. Methods Overall, 204 HR+, HER2− MBC patients treated with EVE + EXE after progressing following prior endocrine treatment were included. Overall survival (OS) and progression-free survival (PFS) and safety data were analyzed. Results The objective response rate, median PFS, and median OS were 33.4%, 8.9 months, and 23.4 months, respectively. Multivariate analysis revealed that negative progesterone receptor status was a significant determinant of poor treatment response (p = 0.035) and PFS (p = 0.024). The presence of bone-only metastasis was associated with better treatment response (p = 0.002), PFS (p < 0.001), and OS (p = 0.001). Conclusion We confirmed the favorable efficacy and safety profile of EVE + EXE for HR+, HER − MBC patients.

A randomized double-blind controlled trial of everolimus in individuals with PTEN mutations: Study design and statistical considerations

This randomized, double-blind controlled trial of everolimus in individuals with germline phosphatase and tensin homolog mutations (PTEN) was designed to evaluate the safety of everolimus compared with placebo and to evaluate the efficacy of everolimus on neurocognition and behavior compared to placebo as measured by standardized neurocognitive and motor measures as well as behavioral questionnaires. The safety profile of everolimus is characterized by manageable adverse events that are generally reversible and non-cumulative. The primary safety endpoint of this study was drop-out rate due to side effects, comparing everolimus versus placebo. We also sought to determine the frequency of adverse events by type and severity. The main efficacy endpoint was a neurocognitive composite computed in two ways: 1) an average for working memory, processing speed, and fine motor subtests; and 2) the same average as above except weighted 2/3, and an additional average based on all other available neurocognitive testing measures assessing the additional domains of nonverbal ability, visuomotor skills, verbal learning, and receptive and expressive language, weighted 1/3. Secondary efficacy endpoints examined the effect of everolimus on overall global clinical improvement, autism symptoms, behavioral problems, and adaptive abilities as measured by validated, standardized instruments. We predicted that the rate of adverse events would be no more than 10% higher in the everolimus group compared to placebo, and overall severity of side effects would be minimal. We also expected that individuals receiving everolimus would show more improvement, relative to those taking placebo, on the composite neurocognitive index.

Everolimus in adult tuberous sclerosis complex patients with epilepsy: Too late for success? A retrospective study.

There is evidence that everolimus (EVE) significantly reduces seizure frequency in epilepsy patients with tuberous sclerosis complex (TSC). Given that TSC-related proliferative processes are more dynamic during brain development, seizure outcomes of patients treated with EVE may be age-related and may be less convincing in adult patients. The aim of this study was to assess the effectiveness and the safety profile of EVE in adults in clinical practice. We performed a multicenter retrospective chart review of TSC subjects with active epilepsy who started EVE in adulthood (≥18years of age) at seven German epilepsy centers. The primary endpoint was the retention rate after 6months. A total of 45 subjects with a mean age of 31.6±11.1years at EVE start fulfilled the inclusion criteria. Retention rate after 6months was 98% (43/44 evaluable subjects). Response rate (seizure reduction ≥ 50%) was 33% (14/43 evaluable subjects; four completely seizure-free). We did not find a significant relationship between epilepsy outcome parameters and patient age at EVE start. Adverse events were reported in 19 subjects and were judged to be serious in six patients. Three patients died during the observation period. Evidence suggests that EVE is an effective add-on treatment for epilepsy in adult TSC patients, surprisingly without any age limit to individual benefit. A strong age-dependent effect within the period of adulthood seems unlikely. Even if there was no proof of a causal relationship between deaths and EVE intake, patients with EVE should be carefully monitored, especially for infections and stomatitis.

Everolimus for the treatment of advanced gastrointestinal or lung nonfunctional neuroendocrine tumors in East Asian patients: a subgroup analysis of the RADIANT-4 study.

BackgroundIn RADIANT-4, everolimus showed an improvement of 7.1 months in median progression-free survival (PFS) vs placebo among patients with advanced, well-differentiated, nonfunctional neuroendocrine tumors (NETs) of gastrointestinal (GI) or lung origin. The present analysis focuses on the effect of everolimus on the East Asian-subgroup population of the RADIANT-4 study.MethodsPatients were randomized to receive everolimus 10 mg/day or matching placebo. The primary end point was PFS (central review). Secondary end points were overall response rate, safety, and tolerability.ResultsAmong 302 patients enrolled in RADIANT-4, 46 were included in the East Asian subgroup (everolimus, n=28; placebo, n=18) analysis. Everolimus was associated with an 82% reduction in the relative risk of disease progression or death (HR 0.18, 95% CI 0.09–0.38). The median PFS (central review) in this subgroup was 11.2 months with everolimus vs 3.1 months with placebo. Adverse events (AEs) occurred in all 28 patients treated with everolimus and ten patients receiving placebo. The majority of these AEs were grade 1 or 2. Most commonly reported ($30% of incidence) drug-related AEs of any grade included stomatitis (75%, n=21) and rash (43%, n=12) in the everolimus arm.ConclusionEverolimus demonstrated a clinically meaningful PFS benefit in the East Asian population. The safety findings were consistent with the known safety profile of everolimus. These results support the use of everolimus in the East Asian population with advanced, nonfunctional NETs of GI or lung origin.

Impact of prior therapies on everolimus activity: an exploratory analysis of RADIANT-4.

BackgroundRecently, everolimus was shown to improve median progression-free survival (PFS) by 7.1 months in patients with advanced, progressive, well-differentiated, nonfunctional neuroendocrine tumors (NET) of lung or gastrointestinal (GI) tract compared with placebo (HR, 0.48; 95% CI, 0.35–0.67; P<0.00001) in the Phase III, RADIANT-4 study. This post hoc analysis evaluates the impact of prior therapies (somatostatin analogs [SSA], chemotherapy, and radiotherapy) on everolimus activity.Trial registrationClinicalTrials.gov identifier: NCT01524783.Patients and methodsPatients were randomized (2:1) to everolimus 10 mg/day or placebo, both with best supportive care. Subgroups of patients who received prior SSA, chemotherapy, or radiotherapy (including peptide receptor radionuclide therapy) were analyzed and reported.ResultsA total of 302 patients were enrolled, of whom, 163 (54%) had any prior SSA use (mostly for tumor control), 77 (25%) received chemotherapy, and 63 (21%) were previously exposed to radiotherapy. Patients who received everolimus had longer median PFS compared with placebo, regardless of previous SSA (with SSA: 11.1 vs 4.5 months [HR, 0.56 {95% CI, 0.37–0.85}]; without SSA: 9.5 vs 3.7 months [0.57 {0.36–0.89}]), chemotherapy (with chemotherapy: 9.2 vs 2.1 months [0.35 {0.19–0.64}]; without chemotherapy: 11.2 vs 5.4 months [0.60 {0.42–0.86}]), or radiotherapy (with radiotherapy: 9.2 vs 3.0 months [0.47 {0.24–0.94}]; without radiotherapy: 11 vs 5.1 months [0.59 {0.42–0.83}]) exposure. The most frequent drug-related adverse events included stomatitis (59%–65%), fatigue (27%–35%), and diarrhea (24%–34%) among the subgroups.ConclusionThese results suggest that everolimus improves PFS in patients with advanced, progressive lung or GI NET, regardless of prior therapies. Safety findings were consistent with the known safety profile of everolimus in NET.

Emerging use of everolimus in the treatment of neuroendocrine tumors.

Neuroendocrine tumors (NETs) consist of a diverse family of malignancies, which are derived from neuroendocrine cells, most commonly originating from the gastroenteropancreatic (GEP) tract or the bronchopulmonary system. In general, NETs are more indolent than epithelial tumors, with median survival rates of longer than 30 months. The upregulation of mTOR pathway has been shown to play a pivotal role in NET pathogenesis. Inhibition of mTOR protein with everolimus represents a progress in the treatment of advanced NETs. Everolimus has shown a significant improvement in progression-free survival (PFS) among patients with pancreatic NETs (pNETs) and nonfunctional GEP and lung NETs in the Phase III RAD001 in Advanced Neuroendocrine Tumors (RADIANT)-3 and RADIANT-4 studies, respectively. In addition, the combination of everolimus with octreotide showed a clinically significant improvement versus octreotide alone in functional NETs in the RADIANT-2 trial. These studies led to the US Food and Drug Administration (FDA) and European Medical Agency (EMA) approval of everolimus. Safety profile of everolimus is generally acceptable. The most common adverse events are stomatitis, diarrhea, rash and fatigue. There is a growing range of novel treatment options in the setting of NETs, but there are no data comparing the activity of different treatment strategies. Thus, treatment decisions are based on different aspects, such as clinical course, patient symptomatology, primary tumor site, tumor functionality, rate of progression and burden of disease. Further research is required to clarify the treatment sequencing to achieve the maximum prolongation in survival and maintenance of quality of life. Future research should concentrate on identification of predictive biomarkers for benefit from different therapies, and studies should also include quality of life as an important measurement in this disease.

Phase II trial of second-line everolimus in patients with metastatic renal cell carcinoma (RECORD-4)

RECORD-1 demonstrated clinical benefit of everolimus in patients with metastatic renal cell carcinoma (mRCC) previously treated with sunitinib, sorafenib, or both; prior treatment with cytokines, bevacizumab, and chemotherapy was also permitted. RECORD-4 prospectively assessed everolimus in a purely second-line setting. Patients with clear-cell mRCC were enrolled into one of three cohorts based on first-line therapy with sunitinib, other anti-VEGF agents, or cytokines. Patients were treated with everolimus 10 mg/day until progression (RECIST, v1.0) or intolerance. The primary end point was progression-free survival (PFS) per investigator review. Data cutoff was 1 September 2014, for the primary analysis and 26 June 2015, for the final overall survival (OS) analysis. Enrolled patients (N = 134) previously received sunitinib (n = 58), other anti-VEGF therapy (n = 62; sorafenib, 23; bevacizumab, 16; pazopanib, 13; tivozanib, 5; and axitinib, 3), or cytokines (n = 14). Overall median age was 59 years, and most patients were men (68%) and of favorable/intermediate MSKCC risk (52/37%). Overall median PFS was 7.8 months [95% confidence interval (CI) 5.7-11.0]; in the cohorts, it was 5.7 months (95% CI 3.7-11.3) with previous sunitinib, 7.8 months (95% CI 5.7-11.0) with other previous anti-VEGF therapy, and 12.9 months [95% CI 2.6-not estimable (NE)] with previous cytokines. Overall, 67% of patients achieved stable disease as their best objective response. At final OS analysis, total median OS was 23.8 months (95% CI 17.0-NE) and, in the cohorts, it was 23.8 months (95% CI 13.7-NE) with previous sunitinib, 17.2 months (95% CI 11.9-NE) with other previous anti-VEGF therapy, and NE (95% CI 15.9-NE) with previous cytokine-based therapy. Overall, 56% of patients experienced grade 3 or 4 adverse events (regardless of relationship to study drug). These results confirm the PFS benefit of second-line everolimus after first-line sunitinib or other anti-VEGF therapies. The safety profile of everolimus was consistent with previous experience. Everolimus as Second-line Therapy in Metastatic Renal Cell Carcinoma (RECORD-4), ClinicalTrials.gov identifier, NCT01491672.

Abstract P4-13-12: Everolimus plus trastuzumab and vinorelbine for trastuzumab-resistant, taxane-pretreated, HER2+ advanced breast cancer: Overall survival results from BOLERO-3

Abstract Background PI3K/AKT/mTOR pathway activation due to PTEN loss may lead to trastuzumab (TRAS) resistance. mTOR inhibition has been shown to restore TRAS sensitivity in PTEN-deficient tumors. This provided the rationale for the BOLERO-3 trial which evaluated the combination of everolimus (EVE), an mTOR inhibitor, plus TRAS and a taxane in HER2+ advanced breast cancer (ABC). The addition of EVE to TRAS plus vinorelbine (VNB) led to a statistically significant prolongation of 1.2 months in median progression free survival (PFS) vs TRAS plus VNB in patients with TRAS-resistant and taxane-pretreated, HER2+ ABC (7.0 months vs 5.78 months; hazard ratio, 0.78; p=0.0067). The final overall survival (OS) analysis from this study is presented here. Materials and methods BOLERO-3 is a randomized, double-blind, placebo-controlled, phase 3 trial. Women with HER2+ ABC progressing on prior TRAS and taxane therapy were randomized (1:1) to receive either daily EVE (5 mg) or PBO plus weekly TRAS (2 mg/kg) and VNB (25 mg/m2), in 3-week cycles, stratified by previous lapatinib use. The primary endpoint was PFS by local investigator assessment. Overall survival was a key secondary endpoint. Results Overall, 569 patients were enrolled; 284 patients received EVE and 285 patients received PBO. As of April 1, 2015, after a median follow-up of 44.7 months, 388 deaths had occurred, 191 (67.3%) in the EVE arm and 197 (69.1%) in the PBO arm. The median OS in the EVE arm vs PBO arm was 23.5 months vs 24.1 months (HR = 0.96; 95% CI, 0.79-1.17; p = 0.3392). In the HR+ subgroup, the median OS with EVE was 23.5 months (vs 25.5 months with PBO; HR = 1.03; 95% CI, 0.79-1.35); in the HR subgroup, the median OS with EVE was 22.9 months (vs 23.1 months with PBO; HR = 0.86; 95% CI, 0.64-1.17). AEs leading to treatment discontinuation were reported in 81 (28.9%) vs 46 (16.3%) patients in the EVE vs PBO arms. Serious adverse events (SAEs) were reported in 122 (43.6%) vs 58 (20.6%) patients in the EVE vs PBO arms. Overall, 14 on-treatment deaths were observed, 7 (2.5%) in the EVE arm and 7 (2.5%) in the PBO arm; on-treatment deaths due to AEs were balanced between treatment arms (0.7% in each treatment arm). Types of post-progression therapies were balanced across both treatment arms. Conclusions In BOLERO-3, EVE showed a statistically significant prolongation of PFS. OS was similar in both treatment arms. The safety profile of EVE was comparable to that observed previously with EVE in breast cancer. (Funded by Novartis; BOLERO-3 ClinicalTrials.gov number, NCT01007942.) Citation Format: Isaacs C, O'Regan R, Xu B, Masuda N, Arena F, Yap Y-S, Papai Z, Lang I, Armstrong A, Lerzo G, White M, Shen K, Zhang Y, Jappe A, Pacaud LB, Taran T, Ozguroglu M. Everolimus plus trastuzumab and vinorelbine for trastuzumab-resistant, taxane-pretreated, HER2+ advanced breast cancer: Overall survival results from BOLERO-3. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-12.

Efficacy and safety of sequential use of everolimus in patients with metastatic renal cell carcinoma previously treated by bevacizumab with or without interferon therapy: Results from pooled analysis of AVATOR, CHANGE, and TRAIN studies.

585 Background: Everolimus is a mammalian target of rapamycin (mTOR) inhibitor. It gained approval based on the results of the RECORD-1 trial, which included patients with metastatic renal cell carcinoma (mRCC) whose disease progressed after receiving vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs). Bevacizumab is a monoclonal antibody targeting angiogenesis that is approved in patients (pts) with mRCC. AVATOR was the 1st study to explore the sequential use of bevacizumab followed by everolimus but with limited number of pts. Methods: In order to further explore this sequence pooled data from the AVATOR, CHANGE and TRAIN studies were analysed retrospectively. All pts had mRCC and were previously or currently treated with everolimus after failure of bevacizumab ± IFN. The primary end point was everolimus time to progression (TTP). Secondary end points were related to the overall survival (OS) of patients receiving the drug sequence, everolimus treatment and safety. Results: 89 pts were included in the analysis. Median age was 68 years [18-90]. At everolimus initiation ECOG was 0-1 for 72% pts and 16% were classified as poor prognosis from Heng classification. Exploring the duration of second-line everolimus treatment, 32% of patients received less than 3 months of everolimus and 35% received at least 6 months of treatment. At the time of data analysis, 20 pts (24%) were still receiving everolimus. Pts receiving everolimus after bevacizumab experienced a median TTP of 6 months [95%CI 4 - 14]. Median OS was not reached for everolimus second-line therapy. At 36 months after the start of first-line therapy, 60.4% of pts were still alive. All grades of common adverse events were consistent with the known safety profile of everolimus. Conclusions: The larger size of this cohort confirms the signal previously seen with AVATOR that the sequence of bevacizumab followed by everolimus displays interesting efficacy with not unexpected toxicity from everolimus and compares favourably with RECORD-1.

Efficacy and Safety of Sequential Use of Everolimus in Patients With Metastatic Renal Cell Carcinoma Previously Treated With Bevacizumab With or Without Interferon Therapy: Results From the European AVATOR Study

BackgroundEverolimus is a mammalian target of rapamycin (mTOR) inhibitor. It gained approval based on the results of the RECORD-1 (Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism 1) trial, which included patients with metastatic renal cell carcinoma (mRCC) whose disease progressed after receiving vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs). Bevacizumab is a monoclonal antibody targeting angiogenesis that is approved in patients with mRCC. The sequence of everolimus second-line therapy after failure of bevacizumab ± interferon (IFN) first-line therapy has not yet been studied. MethodsAVAstin® followed by afiniTOR® (AVATOR) was a noninterventional retrospective multicenter European observational study of 42 unselected patients with mRCC who were previously or currently treated with everolimus after failure of bevacizumab ± IFN. The primary end point was everolimus progression-free survival (PFS). Secondary end points were related to the overall survival (OS) of patients receiving the drug sequence and everolimus treatment and safety. ResultsExploring the duration of second-line everolimus treatment, 63.8% of patients received at least 3 months of everolimus and 28.8% received at least 8 months of treatment. At the time of data analysis, 15 patients (36%) were still receiving everolimus, 40% had stopped because of progressive disease, and 24% had discontinued treatment for other reasons. Patients receiving everolimus after bevacizumab experienced a median PFS of 17 months (95% confidence interval [CI], 5 [not reached]). Median OS was not reached with everolimus second-line therapy. At 32 months after the start of first-line therapy, 53.3% of patients were still alive. All grades of common adverse events (AEs) were consistent with the known safety profile of everolimus. ConclusionThe AVATOR-studied sequence displayed a longer than expected median PFS. Further prospective exploratory studies need to be performed to confirm these encouraging results in a larger cohort of patients.

Safety profile and treatment response of everolimus in different solid tumors: an observational study.

Only few efforts have been taken to investigate the potential existence of disease-specific differences in the safety profile of everolimus. We analyze here the correlation between different patient and tumor characteristics on the safety profile of this molecule. Information on treatment response is also provided. Consecutive patients with metastatic renal cell carcinoma (mRCC), pancreatic neuroendocrine tumors (pNET) or biliary tract cancer were included in this retrospective study. All patients received everolimus 10 mg/day or 5 mg/day. Clinical assessments were performed every 3 weeks. In total, 98 patients were enrolled: 51 with mRCC, 25 with pNET and 22 with biliary tract cancer. The incidence of toxicities (any grade) was 76% with mRCC, 64% with pNET and 95% with biliary tract cancer. Patients with biliary tract cancer also presented a higher frequency of severe toxicities: 64 versus 18% with mRCC and 32% with pNET. Multivariate analysis disclosed that biliary tract cancer (odds ratio [OR]: 23.8; 95% CI: 6.0-117.8; p < 0.0001) is a predictive factor for the development of toxicities during everolimus treatment. No correlations between liver metastasis and toxicities were identified. Disease control rate (DCR) was 45% in mRCC patients, 96% in pNET and 50% for biliary tract cancer patients. pNET tumors were associated with a higher DCR than the mRCC and biliary tract cancer (OR vs mRCC: 66.7; 95% CI: 6.2-276.5; p = 0.004; OR vs biliary tract cancer: 2.6; 95% CI: 0.5-14.2; p = 0.025). This study suggests that the safety profile of everolimus is acceptable in patients with either mRCC or pNET. In addition, the onset of toxicities is associated with an improved DCR. In patients with biliary tract cancer, everolimus is safe but associated with a higher incidence of adverse events.

Targeting the mammalian target of rapamycin pathway with everolimus: implications for the management of metastatic breast cancer.

The inhibitors of mammalian target of rapamycin (mTOR) have documented antitumor activity via disruption of various signaling pathways leading to impaired cellular growth, proliferation, and survival. In preclinical studies, mTOR inhibitors use in combination with hormonal therapy has shown promising results in overcoming endocrine resistance in breast cancer cells. The role of everolimus in breast cancer was established in the Breast Cancer Trial of Oral Everolimus-2 (BOLERO-2) trial in combination with exemestane for patients with advanced metastatic hormone receptor-positive (HR+) breast cancer, who relapsed after initial hormonal manipulation. The study met its primary endpoint of significant improvement in progression free survival (PFS) with a median time to progression of 6.9 months in the combination group versus 2.8 months in exemestane group. Favorable improvements in PFS were reported across all patient subgroups regardless of age, Eastern Cooperative Oncology Group performance status, number of prior therapies, and presence of visceral metastases. Adverse events were mostly mild to moderate in severity and consistent with the known safety profile of everolimus. Major toxicities reported include stomatitis, non-infectious pneumonitis, and hyperglycemia. The purpose of this review is to discuss the role of everolimus as a valuable component in advanced metastatic breast cancer and delineate current strategies to prevent and manage the most common toxicities associated with this combination regimen.

Efficacy and safety of sequential use of everolimus (EVE) in patients (pts) with metastatic renal cell carcinoma (mRCC) previously treated with bevacizumab (BEV) with or without interferon (INF) therapy: Overall survival (OS) result from the European AVATOR retrospective study.

e15607 Background: EVE (Afinitor) has demonstrated activity in the treatment of mRCC after failure of VEGF-targeted tyrosine kinase inhibitors. However, to this date, there is no published data evaluating its activity/safety after failure of first line BEV-based therapy. Methods: Our non-interventional multicenter international study reports retrospective data on EVE in routine use. Eligible patients had mRCC; were given EVE after 1 prior first-line systemic therapy with BEV +/- INF. The data were provided by each center and centralized. Results: Here are the final results: 20 sites included 43 pts between 2011 and 2012, with 42 evaluable patients. Baseline patient characteristics included median age of 69 [38-90] years old; 64.3% male; 97.5% with prior nephrectomy. First-line therapy was BEV + INF in 69% of patients, BEV only for 31%. Prognostic groups at the time of EVE initiation according to Heng (1) and to MSKCC (2) were respectively: (1): good 25%, intermediate 59.4% and poor prognosis 15.6% and (2) good 28.1%, intermediate 56.3% and poor 15.6%. Median duration of treatment with first line therapy was 7.5 months, and it was discontinuated for disease progression in 61.9 % of pts. From initiation of first line therapy 53.3 % of patients were alive at 32 months. Median OS was not reached for the second line; with 52.3% patients who had not progressed 8 months after the start of everolimus. Overall response rate was 9.5 % and disease stabilization rate was 50%. At least one adverse event (AE) occurred in 73.8 % of pts with 13 serious AEs. All grade common AEs were consistent with the toxicity profile of EVE with 31 % of stomatitis, 16.7 % of pneumonitis, 31 % of fatigue. Conclusions: This study provided encouraging results for the activity and safety profile of EVE in this second line mRCC setting after 1 prior first-line therapy with bevacizumab-based regimen. Further studies with larger numbers of pts are planned based on these novel findings.

Everolimus Plus Octreotide Long-Acting Repeatable in Patients With Advanced Lung Neuroendocrine Tumors: Analysis of the Phase 3, Randomized, Placebo-Controlled RADIANT-2 Study

The incidence of neuroendocrine tumors (NETs) has increased approximately fivefold since the 1980s. A similar increase in the incidence of lung NETs has been reported, but therapy has not been optimized. This exploratory subanalysis evaluated the efficacy and safety of everolimus plus octreotide long-acting repeatable (LAR) in a cohort of patients with low- to intermediate-grade advanced lung NET from the phase 3, randomized, placebo-controlled RADIANT-2 (RAD001 in Advanced Neuroendocrine Tumors) study. The primary end point was progression-free survival (PFS). Secondary end points included objective response rate, overall survival, change from baseline in biomarker levels, and safety outcomes. Patients were randomly assigned to everolimus plus octreotide LAR (n 5 33) or placebo plus octreotide LAR (n 5 11). Median PFS was 13.63 months in the everolimus plus octreotide LAR arm compared with 5.59 months in the placebo plus octreotide LAR arm (relative risk for progression: HR, 0.72; 95% CI, 0.31–1.68; P 5 .228). More patients receiving everolimus plus octreotide LAR (67%) experienced minor tumor shrinkage (not partial response as per RECIST [Response Evaluation Criteria in Solid Tumors]) than those receiving placebo plus octreotide LAR (27%). Most frequently reported adverse events (AEs) included stomatitis, rash, diarrhea, and asthenia. This was consistent with the overall RADIANT-2 trial and the safety profile of everolimus. This exploratory subgroup analysis of the RADIANT-2 trial indicates that in patients with advanced lung NET, the addition of everolimus to octreotide LAR improves median PFS by 2.4-fold compared with placebo plus octreotide LAR. These clinically significant observations support the continued evaluation of everolimus treatment regimens in this patient population. ClinicalTrials.gov; No.: NCT00412061

Abstract P6-04-02: Final progression-free survival analysis of BOLERO-2: a phase III trial of everolimus for postmenopausal women with advanced breast cancer

Abstract Introduction: Treatment options for postmenopausal women with hormone receptor-positive (HR+) breast cancer (BC) who relapse or progress on a nonsteroidal aromatase inhibitor (NSAI) are limited. Interim analyses of the BOLERO-2 trial demonstrated that combining the oral mammalian target of rapamycin (mTOR) inhibitor, everolimus (EVE), with the steroidal aromatase inhibitor, exemestane (EXE), significantly prolonged progression-free survival (PFS) in this patient population. Protocol-specified final PFS analyses are presented. Methods: The phase III, double-blind, BOLERO-2 trial randomized postmenopausal women with HR+ BC progressing or recurring after NSAIs to EVE (10 mg once daily; n = 485) plus EXE (25 mg once daily) or placebo (PBO; n = 239) plus EXE. The primary endpoint was PFS. Secondary endpoints included overall survival, safety, bone turnover, and overall response rate. Results: At a median follow-up of 18 months, 510 PFS events were reported. The addition of EVE to EXE significantly prolonged median PFS versus EXE monotherapy as per local assessment (7.8 vs 3.2 mo, respectively; HR = 0.45 [95% CI, 0.38–0.54]; log-rank P &amp;lt; .0001). Furthermore, these data were consistent with results based on central assessment (11.0 mo for EVE + EXE vs 4.1 mo for EXE alone; HR = 0.38 [95% CI, 0.31–0.48]; log-rank P &amp;lt; .0001). Fewer deaths were reported with EVE + EXE (25.4%) vs PBO + EXE (32.2%). In addition to significantly improving PFS and delaying disease progression in bone, PFS benefits with EVE + EXE versus PBO + EXE were consistent in all prospectively defined subgroups, including subsets of patients with visceral metastases (n = 406), 3 or more sites of metastasis (n = 271), and Eastern Cooperative Oncology Group (ECOG) performance status 1 or 2 (n = 274). The safety profile of EVE + EXE was consistent with that reported at the interim analysis and with data for EVE from other oncology settings. Updated overall survival data will be presented. Conclusions: Adding EVE to EXE markedly prolonged PFS in the overall population and in all patient subsets, validating the rationale of targeting the mTOR pathway to improve clinical outcome in patients with HR+ advanced BC progressing during or after NSAI therapy. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-02.

Safety of everolimus for women over age 65 with advanced breast cancer (BC): 12.5-month follow-up of BOLERO-2.

104 Background: Postmenopausal women with estrogen-receptor–positive (ER+) BC who relapse/progress on a nonsteroidal aromatase inhibitor (NSAI) are usually treated with the steroidal AI exemestane (EXE), but there is no currently approved treatment for this indication. The BOLERO-2 trial showed that adding everolimus (EVE), an oral inhibitor of mammalian target of rapamycin (mTOR), to EXE significantly improved clinical benefit beyond that of EXE alone (Hortobagyi et al, SABCS 2011, Abstract S3-7). As many women with advanced BC are elderly, the tolerability profile of EVE + EXE in this population is of interest. Methods: BOLERO-2 is a phase III, randomized trial comparing EVE (10 mg once daily) vs placebo (PBO), both plus EXE (25 mg once daily), in postmenopausal women with advanced ER+ BC progressing or recurring after NSAIs. Safety data with a focus on elderly patients are reported at 12.5 months’ median follow-up. Results: Baseline disease characteristics, age, and prior cancer therapy were well balanced between treatment arms (N = 724). At 12.5 months’ median follow-up, the addition of EVE to EXE significantly improved progression-free survival in patients &lt;65 (HR, 0.37; p &lt; .05) or ≥65 years of age (HR, 0.56; p &lt; .05). Adverse events (AEs) of special interest (all grades) occurring more frequently with EVE vs PBO (overall study population) included stomatitis (66.6% vs 11.3%), infection (50.4% vs 25.2%), rash (44.0% vs 8.4%), pneumonitis (18.7% vs 0.4%), and hyperglycemia (15.4% vs 2.5%). Elderly EVE-treated patients (≥65 years) had similar or marginally lower incidence of stomatitis (52.1%), rash (32.3%), pneumonitis (14.6%), and hyperglycemia (12.5%) compared with the overall population. Grade 3-4 AEs in patients ≥70 years of age (n = 161) reported only among patients receiving EVE (n = 118) included fatigue (10.2%), anemia (10.2%), hyperglycemia (8.5%), stomatitis (7.6%), dyspnea (6.8%), pneumonitis (5.1%), neutropenia (3.4%), and hypertension (3.4%). Conclusions: Adding EVE to EXE was well tolerated in the overall population and in elderly patients with advanced BC; grade 3-4 AEs were uncommon and manageable. Overall, AEs were consistent with the known safety profile of EVE.

873 - Could the Safety Profile of Everolimus be Different in Different Cancers? Fondazione IRCCS Istituto Nazionale Tumori (INT) Experience in Renal Cell Carcinoma, Neuroendocrine Tumors (NETS) and Biliary-Tract Cancers

ABSTRACT Background Everolimus is an inhibitor of the mammalian target of rapamycin (mTOR), a kinase which plays a key role in cellular processes. The toxicity profile of antiangiogenic therapies lacks disease specificity; while few data on everolimus are available. Methods We retrospectively analyzed data about safety profile of everolimus in patients (pts) with different cancer treated in our Institution: 21 pts with metastatic renal cell cancer (mRCC), 20 pts with biliary tract cancer, 12 pts with pancreatic neuroendocrine tumors (NETs). All were pre-treated with 1 standard treatment (Tirosine Kinase Inhibitors/chemotherapy/somatostatine analogs +/- chemotherapy, respectively) at least and received everolimus at 10 mg od continuously. Results mRCC pts: median age 64 years (53-78), median treatment exposure 6.8 months (3-20); previous treatments (1/2/3:28%/47%/23% respectively) AEs: mucositis (68%, 1 pt G3), hypertriglyceridemia (56%; 20% G3), hypercholesterolemia (43%, 1 pt G3), rash (31% 1 pt G3), pneumonitis (10% all G1), no haematological AEs Biliary tract cancer pts: median age 61 years (48-74), median treatment exposure 4.6 months (2-10), previous treatments (1/2: 85%/15% respectively) AEs: thrombocytopenia (60%, 3 pts G3), fatigue (30%, 2 pts G3), mucositis (25% no G3), 20% rash (no G3) NETs pts: median age 57(38-76), median treatment exposure 8.1 months (3-12); previous treatments (1/2:45%/55% respectively) AEs: 60% fatigue (2 pts G3), neutropenia 35% (1 pt G3), mucositis 25% (no G3), 12% rash (no G3), thrombocytopenia 15% (no G3), hypercholesterolemia 12% (no G3), hypertriglyceridemia 8% (no G3) Dose reductions from 10 mg to 5 mg: 26% in mRCC, 27% in biliary cancers, 25% in NETs Drug interruptions( Conclusions Everolimus is safe and well tolerated. AEs seem to be maintained across the different baseline disease. However the differences in the frequencies of the same AEs observed suggest a potential impact of previous treatment on Everolimus tolerability. May be interesting to study the inter-individual and the oncotype variability of everolimus in terms of different activities of the drug efflux pump P-glycoprotein. Moreover the metabolism of cytochrome P450 and the polymorphism in his gene could be further investigated. Disclosure All authors have declared no conflicts of interest.

351P - Safety of Everolimus For Women Over 65 Years of Age With Advanced Breast Cancer: 18-Mo Follow-Up of BOLERO-2

ABSTRACT Background Hormone-receptor–positive (HR+) breast cancer (BC) refractory/resistant to nonsteroidal aromatase inhibitor (NSAI) may be treated with the steroidal AI exemestane (EXE), although there is no approved treatment standard. The BOLERO-2 trial showed that adding everolimus (EVE) to EXE significantly improved clinical benefit beyond that of EXE alone (Hortobagyi et al, SABCS 2011, Abstract S3-7). As many women with advanced BC are elderly (≥ 65 years), the efficacy and tolerability of EVE + EXE in this population are of interest. Methods BOLERO-2 is a phase 3, randomized trial comparing EVE (10 mg once daily) vs placebo (PBO), both plus EXE (25 mg once daily) in postmenopausal women with advanced HR+ BC progressing or recurring after NSAIs. Results Baseline disease and prior treatment characteristics were balanced between study arms (N = 724). At 18 months' median follow-up, adding EVE to EXE significantly improved progression-free survival in patients Conclusions Adding EVE to EXE was effective and well tolerated overall and, in elderly patients with advanced BC, grade 3/4 AEs were uncommon and manageable. Overall, AEs were consistent with the known safety profile of EVE. Disclosure M. Gnant: Research support from GSK, Sanofi-Aventis, Novartis, and Roche, consultant to Merrion and Novartis, and received honoraria & travel support from Amgen, Pfizer, Novartis, GSK, Bayer, Sandoz, AstraZeneca, and GenomicHealth. S. Noguchi: S. Noguchi received grant support from AstraZeneca, BMS, Chugai, GSK, Novartis, Pfizer, Sanofi-Aventis, and Takeda, and honoraria (speaking, advisory boards, etc.) from AstraZeneca, Chugai, GSK, Novartis, Pfizer, Sanofi-Aventis, and Takeda. M. Piccart: Board for PharmaMar, consultant Sanofi-Aventis, Amgen, BMS, GSK, Boehringer, Roche, & Bayer, grant support Pfizer, Amgen, Bayer, Boehringer, BMS, GSK, Roche, & Sanofi-Aventis, honoraria Bayer, BMS, GSK, Boehringer, Roche, Amgen, & AstraZeneca. J. Baselga: J. Baselga is a consultant to Novartis, Roche, Merck, Sanofi-Aventis, Verastem, Bayer, Chugai, Exelixis, Onyx, and Constellation. A. Panneerselvam: Employee of Novartis with stock/stock options. T. Taran: Employee of Novartis with stock/stock options. T. Sahmoud: Employee of Novartis with stock/stock options. G.N. Hortobagyi: Member of the Scientific Advisory Board of Allergan, is a consultant to Allergan, Novartis, Genentech, and Sanofi-Aventis, has received grant support from Novartis, and has received travel expense reimbursement from Novartis, Genentech, and Sanofi-Aventis. K. Pritchard: Consult sanaven AZE Roche PFE NVR ABR AMG GSK res funding NCICCT Grp contracted AZE BMS SanAven AMG PFE NVR GSK & OrthoBio honoraria & Spkr B SanAven AZE PFE Roche NVR & AMG paid expert test SanAven AZE & GSK AdCom SanAven AZE Roche PFE NVR GSK & AMG. All other authors have declared no conflicts of interest.

Safety of everolimus (EVE) in Asian patients (pts) with advanced gastric cancer (AGC) enrolled in the phase III GRANITE-1 study.

4081 Background: Previous subanalyses of the RECORD-1 (Jpn J Clin Oncol 2011;41:17-24) and RADIANT-3 (GICS 2011; abs. 289) studies of the oral mammalian target of rapamycin inhibitor EVE showed that incidences of stomatitis, rash, infections, and pneumonitis were greater in Asian pts; however, the number of Asian pts enrolled was small. GRANITE-1 provides an opportunity to evaluate EVE safety in a broader Asian population. Methods: In the randomized, double-blind, phase 3 GRANITE-1 study, pts aged ≥18 y with confirmed AGC and disease progression after 1 or 2 lines of systemic chemotherapy were randomized 2:1 to EVE 10 mg/d + best supportive care (BSC) or placebo + BSC. Randomization was stratified by region (Asia [China, Japan, Korea, Taiwan, Thailand, Hong Kong] vs rest of world [ROW]) and previous lines of chemotherapy (1 vs 2). Study drug was continued until disease progression or unacceptable toxicity. Adverse events (AEs) were collected throughout the study and for 28 d after final dose of study drug and assessed according to the Common Terminology Criteria for Adverse Events, v 3.0. Primary endpoint was overall survival. Safety was a secondary endpoint. Results: Of the 656 pts in the study, 363 (55%) were enrolled in Asia and received EVE (n=243) or placebo (n=120). EVE did not significantly reduce the risk of death in the overall (HR 0.90; 95% CI 0.75-1.08), Asian (HR 0.96; 95% CI 0.75-1.23), or ROW (HR 0.85; 95% CI 0.65-1.10) populations. The most common any-grade AEs among EVE-treated pts (Asia vs ROW) were decreased appetite (45% vs 51%), stomatitis (44% vs 35%), and fatigue (34% vs 35%). Among EVE-treated pts, rates of any-grade rash, infections, and pneumonitis (Asia vs ROW) were 22% vs 18%, 24% vs 28%, and 4% vs 2%, respectively; rates of grade 3/4 stomatitis, rash, infections, and pneumonitis (Asia vs ROW) were 4% vs 6%, 0% vs 0.5%, 6% vs 9%, and 0.4% vs 1%, respectively. No grade 4 pneumonitis was observed. Only 1 pt (from Asia) discontinued due to pneumonitis (grade 3). Conclusions: The safety profile of EVE in Asian pts with AGC was similar to that observed in ROW pts with AGC and with EVE in other cancers. No new safety signals were identified. Pneumonitis was relatively uncommon in Asian and ROW pts.

Safety of everolimus for women over 65 years of age with advanced breast cancer (BC): 12.5-mo follow-up of BOLERO-2.

551 Background: Postmenopausal women with estrogen-receptor–positive (ER+) BC who relapse/progress on a nonsteroidal aromatase inhibitor (NSAI) are usually treated with the steroidal AI exemestane (EXE); but there is no currently approved treatment for this indication. The BOLERO-2 trial showed that adding everolimus (EVE), an oral inhibitor of mammalian target of rapamycin (mTOR), to EXE significantly improved clinical benefit beyond that of EXE alone (Hortobagyi et al, SABCS 2011, Abstract S3-7). As many women with advanced BC are elderly, the tolerability profile of EVE + EXE in this population is of interest. Methods: BOLERO-2 is a phase III, randomized, trial comparing EVE (10 mg once daily) vs placebo (PBO), both plus EXE (25 mg once daily) in postmenopausal women with advanced ER+ BC progressing or recurring after NSAIs. Safety data with a focus on elderly patients are reported at 12.5 mo median follow-up. Results: Baseline disease characteristics, age, and prior cancer therapy were well balanced between treatment arms (N = 724). At 12.5 months’ median follow-up, the addition of EVE to EXE significantly improved progression-free survival in patients &lt;65 (HR = 0.37; P &lt; .05) or ≥65 years of age (HR = 0.56; P &lt; .05). Adverse events (AEs) of special interest (all grades) occurring more frequently with EVE vs PBO (overall study population) included stomatitis (66.6% vs 11.3%), infections (50.4% vs 25.2%), rash (44.0% vs 8.4%), pneumonitis (18.7% vs 0.4%), and hyperglycemia (15.4% vs 2.5%). Elderly EVE-treated patients (≥65 years) had similar or marginally lower incidence of stomatitis (52.1%), rash (32.3%), pneumonitis (14.6%), and hyperglycemia (12.5%) compared with the overall population. Grade 3/4 AEs in patients ≥70 years of age (n = 161) reported only among patients receiving EVE (n = 118) included fatigue (10.2%), anemia (10.2%), hyperglycemia (8.5%), stomatitis (7.6%), dyspnea (6.8%), pneumonitis (5.1%), neutropenia (3.4%), and hypertension (3.4%). Conclusions: Adding EVE to EXE was well tolerated in the overall population and in elderly patients with advanced BC; grade 3/4 AEs were uncommon and manageable. Overall, AEs were consistent with the known safety profile of EVE.