Everolimus Plus Octreotide Long-Acting Repeatable in Patients With Advanced Lung Neuroendocrine Tumors

Transcription

1 CHEST Original Research Everolimus Plus Octreotide Long-Acting Repeatable in Patients With Advanced Lung Neuroendocrine Tumors Analysis of the Phase 3, Randomized, Placebo-Controlled RADIANT-2 Study LUNG CANCER Nicola Fazio, MD ; Dan Granberg, MD, PhD ; Ashley Grossman, MD ; Stephen Saletan, MD ; Judith Klimovsky, MD ; Ashok Panneerselvam, PhD ; and Edward M. Wolin, MD Background: 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. Methods: 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. Results: Patients were randomly assigned to everolimus plus octreotide LAR (n 5 33) or placebo plus octreotide LAR (n 5 11). Median PFS was 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, ; 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. Conclusions: 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. Trial registry: ClinicalTrials.gov; No.: NCT ; URL: CHEST 2013; 143(4): Abbreviations: 5-HIAA 5 5-hydroxyindoleacetic acid; AE 5 adverse event; CgA 5 chromogranin A; LAR 5 long-acting repeatable; mtor 5 mammalian target of rapamycin; NET 5 neuroendocrine tumor; PFS 5 progression-free survival; RADIANT 5 RAD001 in Advanced Neuroendocrine Tumors; RECIST 5 Response Evaluation Criteria In Solid Tumors Neuroendocrine tumors (NETs) are a family of neoplasms that can arise from neuroendocrine cells of most organs in the body. 1 Their incidence is increasing, with one analysis reporting a nearly fivefold rise in the annual age-adjusted incidence of NETs since The rise in incidence may be due, at least partially, to increased awareness of NETs and the ability to diagnose NET earlier. The primary tumor site for approximately 25% to 30% of all NETs is the lung. 2,3 Lung NETs represent approximately 25% of all lung cancers, 4 with an annual incidence of 1.35 patients per 100,000 in the United States 2 ; this appears to be a dramatic increase For editorial comment see page 884 since 1973, when it was approximately 0.3 per 100,000 in the United States. 2 Lung NETs were classified by Travis et al 5 into four types: two highly malignant journal.publications.chestnet.org CHEST / 143 / 4 / APRIL

2 (small cell and large cell neuroendocrine carcinoma) representing slightly. 20% and two with low- to intermediate-grade malignancy (typical and atypical carcinoids) representing, 5%. Although surgery is the treatment of choice for patients with resectable tumors, therapeutic options are limited for those with unresectable or metastatic disease because no standard treatment exists. 6,7 Patients with low- to intermediate-grade metastatic lung NETs have poor prognoses; median survival is 17 months, and the associated 5-year survival rate is approximately 27%. 2,7 Thus, patients with lung NETs urgently need new treatment approaches. In a small number of lung NETs included in some phase 2 studies, chemotherapy caused stable disease or partial radiologic response in approximately 60% of patients, but had little impact on time to progression. 8 Somatostatin analogs, such as octreotide and lanreotide, are widely used in patients with NETs for the control of carcinoid symptoms, 9 but their benefit in tumor control has been demonstrated prospectively only by octreotide long-acting repeatable (LAR) in midgut NETs in the PROMID (Placebo-Controlled, Double-Blind, Prospective Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients With Metastatic Neuroendocrine Midgut Tumors) trial. 10 More recently, novel targeted therapies have been under investigation for use in patients with advanced NETs, and phase 2 data have been reported for sunitinib, bevacizumab, and everolimus Unfortunately, few patients with lung as the primary tumor site were included in these studies. In addition, no specific studies with molecularly targeted agents in lung NETs have been published. In vitro studies have shown that everolimus, an oral mammalian target of rapamycin (mtor) inhibitor, had inhibitory effects on lung NET cells. In an in vitro study of bronchial NETs, everolimus significantly reduced cell viability, inhibited the downstream signaling pathway of mtor, and blocked the proliferative effects of insulin-like growth factor Because Manuscript received May 14, 2012; revision accepted August 13, Affiliations : From the European Institute of Oncology (Dr Fazio), Milan, Italy; Departments of Medical Sciences and Endocrine Oncology (Dr Granberg), Uppsala University, Uppsala, Sweden; Oxford Centre for Diabetes, Endocrinology and Metabolism (Dr Grossman), Churchill Hospital University of Oxford, Oxford, England; Novartis Pharmaceuticals Corp (Drs Saletan, Klimovsky, and Panneerselvam), Florham Park, NJ; and Cedars-Sinai Medical Center (Dr Wolin), Los Angeles, CA. Funding /Support: This study was funded by Novartis Pharmaceuticals Corp. Correspondence to: Nicola Fazio, MD, Upper Gastrointestinal and Neuroendocrine Tumors Unit, Department of Medicine, Via Ripamonti, Milan, Italy; nicola.fazio@ieo.it American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: /chest octreotide has also been shown to downregulate insulin-like growth factor-1, 15 it has been postulated that the combination of everolimus plus octreotide may be able to act synergistically to increase antitumor activity by targeting both upstream and downstream components of the mtor pathway. RAD001 in Advanced Neuroendocrine Tumors, Second Trial (RADIANT-2), was an international, double-blind, phase 3, randomized, placebo-controlled study of 429 patients with low- or intermediate-grade NETs and a history of secretory symptoms (diarrhea, flushing, or both). 16 Patients eligible for enrollment were treated with the combination of everolimus plus octreotide LAR or placebo plus octreotide LAR. 16 Results of this trial demonstrated that everolimus plus octreotide LAR provided clinically meaningful 5.1-month improvement in progression-free survival (PFS) in this patient population compared with patients receiving placebo plus octreotide LAR. Median PFS was 16.4 months for everolimus plus octreotide LAR compared with 11.3 months for placebo plus octreotide LAR (HR, 0.77; 95% CI, ; P 5.026). 16 We present an exploratory subgroup analysis of the RADIANT-2 study in patients whose primary tumor site was the lung. Patients Materials and Methods Patients were eligible for enrollment in the study if they were at least 18 years of age and had low- or intermediate-grade advanced (unresectable or metastatic) tumors and radiologic documentation of disease progression within the past 12 months. Patients also had to have a history of secretory symptoms (diarrhea, flushing, or both) attributed to carcinoid syndrome; the presence of measurable disease as assessed according to Response Evaluation Criteria In Solid Tumors (RECIST) version ; World Health Organization performance status 2 18 ; adequate bone marrow, renal, and hepatic function; and adequately controlled lipid concentrations. Patients previously treated with octreotide LAR were eligible if they had a washout period of at least 2 weeks prior to randomization. For this subanalysis, documentation of the lung as the primary tumor site was required. Exclusion criteria included poorly differentiated or high-grade NET; cytotoxic chemotherapy, immunotherapy, or radiotherapy within 4 weeks and octreotide LAR or other long-acting somatostatin analog within 2 weeks before randomization; and previous treatment with an mtor inhibitor. The protocol was approved by the institutional review board or ethics committee at each participating center (e-appendix 1). The study was conducted in accordance with Good Clinical Practice and the Declaration of Helsinki. All patients provided written informed consent. The study was monitored by an independent data monitoring committee and was overseen by the protocol steering committee. Study Design The RADIANT-2 design has been described in detail. 16 In brief, this was an international, multicenter, double-blind, phase Original Research

3 study in which patients with advanced NET and with radiologic documentation of disease progression within the previous 12 months and history of carcinoid symptoms were randomly assigned 1:1 to treatment with oral everolimus (10 mg once daily) or matching placebo, both in conjunction with intramuscular octreotide LAR (30 mg every 28 days). Patients randomly assigned to the placebo plus octreotide LAR arm could cross over to open-label everolimus plus octreotide LAR at the time of investigator determination of disease progression. In addition, dose adjustments were permitted for patients unable to tolerate the protocol-specified dosing schedule. The primary end point was PFS defined as time from randomization to first documentation of disease progression or death from any cause, as determined by adjudicated central review. Secondary end points included objective response rate, overall survival, change from baseline in 5-hydroxyindoleacetic acid (5-HIAA) and chromogranin A (CgA) levels, and safety. Tumor measurements were assessed by multiphasic CT scans or MRI at baseline and every 12 weeks thereafter. Serum CgA and 24-h urine samples for 5-HIAA were collected at baseline. Safety assessments included monitoring of adverse events (AEs), vital signs, physical examinations every 4 weeks, and regular monitoring of hematologic and clinical biochemistry levels (laboratory evaluations). Statistical Analysis Efficacy assessments were conducted on the full analysis population, which was composed of all randomly assigned patients. All patients who received at least one dose of study drug and who had at least one postbaseline safety assessment were included in the safety population. This is an exploratory subgroup analysis of patients with lung NET enrolled in the RADIANT-2 study. Sample size calculations were not performed for the cohort of patients described in this report. PFS was analyzed using Kaplan-Meier methods; study groups were compared using log-rank tests. Hazard ratios and corresponding CIs were calculated using a Cox proportional hazards model. Results Demographics and Disposition The RADIANT-2 study enrolled 429 patients; 44 had lung as the primary tumor site and were included in the present analysis; 33 received everolimus plus octreotide LAR, and 11 received placebo plus octreotide LAR. Baseline demographics and characteristics were well balanced for sex, region, histologic grade, previous somatostatin analog use, number of organs involved, and carcinoid symptoms ( Table 1 ). The uneven distribution in treatment arms probably occurred because the overall RADIANT-2 trial design did not stratify patients according to site of tumor origin. More patients in the everolimus plus octreotide LAR arm were aged 65 years (42% vs 18%) and received the diagnosis at least 2 years earlier (76% vs 55%). At enrollment, median CgA was 1,324.4 ng/ml in patients with lung NET and ng/ml in the overall RADIANT-2 patient population. Median CgA in patients with lung NETs was 1,278.8 ng/ml and 1,687.7 ng/ml, respectively, in the everolimus plus octreotide LAR arm and the placebo plus octreotide arm. Median 5-HIAA at enrollment was mmol/d in patients with lung NETs and m mol/d in the overall RADIANT-2 population. Median 5-HIAA in patients with lung NET was m mol/d and m mol/d, respectively, in the everolimus plus octreotide LAR arm and the placebo plus octreotide arm. Unfortunately, the patient numbers were too small for further analyses to derive clinically meaningful conclusions regarding biomarker values in patients with lung NETs. Treatment Median treatment duration with everolimus plus octreotide LAR was 36 weeks compared with 13 weeks with placebo plus octreotide LAR for patients in the lung NET subgroup. Mean relative dose intensities were 0.77 and 1.13 for everolimus and octreotide LAR, respectively, in the everolimus plus octreotide LAR group and 1.0 for both in the placebo plus octreotide LAR group. In the everolimus plus octreotide LAR group, 21 patients (63.6%) had at least one adjustment in everolimus dosage. Of these, 20 adjustments (60.6%) were due to AEs; no patient required adjustments in octreotide LAR dosage. In the placebo plus octreotide LAR group, no patients required adjustment in placebo dosage, and one patient (9.1%) had at least one adjustment in octreotide LAR dosage because of an AE. Efficacy For patients with lung NETs, median PFS was increased 2.4-fold by the addition of everolimus to octreotide LAR treatment. By central review, median PFS was months (95% CI, ) for patients receiving everolimus plus octreotide LAR compared with 5.59 months (95% CI, ) for those receiving placebo plus octreotide LAR ( Fig 1A ). Everolimus plus octreotide LAR was associated with a 28% reduction in the estimated risk for progression (HR, 0.72; 95% CI, ; P 5.228). By local investigator review, median PFS was 8.8 months (95% CI, ) for patients receiving everolimus plus octreotide LAR compared with 2.83 months (95% CI, ) for those receiving placebo plus octreotide LAR ( Fig 1B ). The HR for the estimated risk for progression was 0.62 (95% CI, ; P 5.106). In addition, more patients treated with the combination of everolimus plus octreotide LAR (67%) experienced tumor shrinkage than did those treated with placebo plus octreotide LAR (27%) ( Fig 2, Table 2 ). The decrease in tumor size did not meet RECIST criteria for partial response. journal.publications.chestnet.org CHEST / 143 / 4 / APRIL

4 Table 1 Baseline Demographics and Disease Characteristics Characteristics Everolimus 1 Octreotide LAR (n 5 33) Placebo 1 Octreotide LAR a (n 5 11) Age, y, (57.6) 9 (81.8) (42.4) 2 (18.2) Sex Male 20 (60.6) 7 (63.6) Female 13 (39.4) 4 (36.4) White 33 (100) 11 (100) Region Europe 19 (57.6) 6 (54.5) United States 12 (36.4) 5 (45.5) Other 2 (6.1) 0 (0) Time since initial diagnosis, mo 6 4 (12.1) 4 (36.4) (12.1) 1 (9.1) (30.3) 1 (9.1) (45.5) 5 (45.5) Histologic grade Well differentiated 25 (75.8) 8 (72.7) Moderately differentiated 6 (18.2) 3 (27.3) Unknown 2 (6.1) 0 (0) WHO performance status 0 15 (45.5) 7 (63.6) 1 17 (51.5) 3 (27.3) 2 1 (3.0) 1 (9.1) Previous somatostatin analog therapy 22 (66.7) 7 (63.6) Other previous, systemic, antitumor therapy 16 (48.5) 4 (36.4) Chemotherapy 13 (39.4) 4 (36.4) Immunotherapy 4 (12.1) 1 (9.1) Targeted therapy 5 (15.2) 1 (9.1) Other 3 (9.1) 2 (18.2) Organs involved 1 6 (18.2) 2 (18.2) 2 9 (27.3) 2 (18.2) 3 18 (54.5) 7 (63.6) History of diarrhea, flushing, or both 31 (93.9) 11 (100) History of diarrhea 27 (81.8) 8 (72.7) History of flushing 25 (75.8) 8 (72.7) Data given as No. (%) unless otherwise indicated. LAR 5 long-acting repeatable; WHO 5 World Health Organization. a Data missing for two patients in the placebo plus octreotide LAR group. Safety The most frequently reported AEs potentially related to drug administration in the lung NET subgroup (everolimus plus octreotide LAR vs placebo plus octreotide LAR) included stomatitis (69.7% vs 0%), rash (33.3% vs 0%), diarrhea (27.3% vs 0%), and asthenia (24.2% vs 9.1%) ( Table 3 ). This was in line with AEs reported in the overall RADIANT-2 population 16 and consistent with the known safety profiles of everolimus and octreotide LAR. Of specific concern to patients with lung NETs, one incidence each was reported of pneumonitis, interstitial lung disease, and lung infection (3.0% each), all in patients receiving everolimus plus octreotide LAR. Drug-related pulmonary fibrosis was not reported. Grade 3/4 AEs potentially related to drug treatment occurred in 16 patients (48.5%) treated with everolimus plus octreotide LAR and in one patient (9.1%) treated with placebo plus octreotide LAR ( Table 4 ). AEs were reversible with dose reduction or discontinuation. Three (9.1%) on-treatment deaths occurred in the everolimus plus octreotide LAR arm, and no on-treatment deaths occurred in the placebo plus octreotide LAR arm. Cause of death included tumor progression in two patients (at 13 and 9 days after discontinuation of study medication because of abnormal hepatic function [grade 4] and stomatitis [grade 3], respectively) and lung sepsis (grade 3) in a third. In the opinion of the investigator, the abnormal hepatic function was not related to study drug. Regarding stomatitis, however, the investigator did suspect a relation to everolimus. In the third death, lung sepsis was diagnosed 4 days after the last dose of everolimus and led to respiratory failure (grade 3); 958 Original Research

5 Figure 1. Progression-free survival in patients with primary lung neuroendocrine tumors (NETs). P value is obtained from the one-sided log-rank test. HR is obtained from unadjusted Cox model. A, Central radiology review. B, Local investigator review. E 1 O 5 everolimus plus octreotide; HR 5 hazard ratio; LAR 5 long-acting repeatable; P 1 O 5 placebo plus octreotide. death occurred 7 days after the last dose of everolimus. It was not attributed to the study drug; however, an immunosuppressive effect of everolimus could not be ruled out. None of the investigators suspected a relation between the deaths and the study medication. Discussion To date, clinical data on treatment outcomes in patients with advanced low- to intermediate-grade lung NETs have been sparse, possibly because the proportion of patients with metastatic NETs has been small, and few of these patients have been available for enrollment into trials and treatment analyses. Given the increasing incidence of lung NETs in recent years, the clinical evaluation of potential new treatments in this field is of vital importance. Results of this exploratory analysis from the RADIANT-2 study suggest that the addition of everolimus to octreotide LAR is beneficial to patients with advanced low- to intermediate-grade (unresectable or metastatic) lung NETs. Median PFS was increased by 8 months, from 5.59 months in patients receiving placebo plus octreotide LAR to months in patients receiving everolimus plus octreotide LAR. Though not statistically significant ( P 5.228), this was a clinically meaningful improvement in PFS, and it represents a benefit similar to that seen in the overall RADIANT-2 population (a PFS increase of 5.1 months), 16 despite the generally poorer prognosis of lung NETs compared with other types of NETs. 7 Moreover, this increase in PFS was associated with a 28% reduction in the estimated relative risk for progression in patients with lung NETs, in line with the 23% reduction observed in the main trial cohort. 16 In both the total NET and the lung NET populations, tumor shrinkage, though not meeting RECIST criteria for partial response, occurred more frequently in the everolimus plus octreotide LAR arm than in the placebo plus octreotide LAR arm (75% and 67% vs 45% and 27%, respectively). In a recent multivariate analysis journal.publications.chestnet.org CHEST / 143 / 4 / APRIL

6 Figure 2. Best percentage change from baseline in tumor response. * denotes change in size of target lesion contradicted by lesion response of progressive disease (see Table 2). See Figure 1 legend for expansion of abbreviation. performed on the total RADIANT-2 population, primary tumor site (lung vs other) was found to be a significant prognostic factor for PFS end point. Adjustment for imbalance between treatment arms in the primary site and other factors showed the significant benefit of everolimus plus octre otide LAR. 19 There are no specific data about everolimus in patients with nonfunctioning lung carcinoids. However, this year, a phase 2 clinical trial entitled Multicenter 3-arm trial to evaluate the efficacy and safety of pasireotide LAR or everolimus alone or in combination in patients with well-differentiated neuroendocrine carcinoma of the lung and thymus (LUNA trial) is planned to start enrolling patients. 20 This trial will enroll 112 patients with well-differentiated, advanced NET and primary tumor site in the lung or thymus. It will exclude patients with severe functional dis ease requiring symptomatic treatment with somatostatin analogs and patients with prior exposure to mtor inhibitors. There is a well-established molecular rationale for the use of everolimus plus octreotide LAR in the management of lung NETs. The somatostatin receptors sstr 2a and sstr 3 are highly expressed in typical and atypical carcinoid tumors and progressively less so in high-grade large cell and small cell neuroendocrine carcinomas. 21 Furthermore, bronchial NETs demonstrate overactivation of the mtor signal ing pathway in vitro. 22 Low- to intermediate-grade tumors show high expression levels of phosphorylated mtor, and the activation of mtor correlates with the phosphorylation of downstream kinase signaling (p70 S6 kinase). In preclinical data obtained from experiments in cell lines derived from human lung NETs, low- to intermediate-grade lung NETs show preferential sensitivity to everolimus compared with high-grade lung NETs. 14 Moreover, everolimus has demonstrated antiproliferative effects, with mtor expression significantly higher in responsive human bronchial carcinoma cultures than in nonresponder tissues. 14 Several limitations of the present analysis should be noted, including the small sample size (n 5 44), the imbalanced patient numbers between groups, and the retrospective nature of the evaluation. The RADIANT-2 study did not stratify based on the primary tumor site, resulting in more patients with lung NETs in the everolimus plus octreotide LAR therapeutic arm than in the placebo plus octreotide arm. Traditionally, patients with lung NETs are perceived as less likely to have secretory symptoms; 2% to 5% of lung NETs are associated with carcinoid syndrome Table 2 Change From Baseline in Tumor Response Variable Everolimus 1 Octreotide LAR (n 533) Placebo 1 Octreotide LAR (n 511) Increase in size of target lesion from baseline 10 (33.3) 7 (63.6) Decrease in size of target lesion from baseline 20 (66.7) 3 (27.3) Change in size of target lesion contradicted by lesion response 0 (0) 1 (9.1) of progressive disease Not available 3 (10.0) 0 (0) Data are given as No. (%). See Table 1 for expansion of abbreviation. 960 Original Research

7 AE Table 3 Drug-Related AEs Occurring in 10% of Patients Everolimus 1 Octreotide LAR (n 5 33) Placebo 1 Octreotide LAR (n 5 11) Any grade AE 30 (90.9) 3 (27.3) Stomatitisa 23 (69.7) 0 (0.0) Rash 11 (33.3) 0 (0.0) Diarrhea 9 (27.3) 0 (0.0) Asthenia 8 (24.2) 1 (9.1) Thrombocytopenia 6 (18.2) 0 (0.0) Anemia 5 (15.2) 0 (0.0) Dyspnea 5 (15.2) 0 (0.0) Erythema 5 (15.2) 0 (0.0) Hyperglycemia 5 (15.2) 0 (0.0) Decreased appetite 4 (12.1) 0 (0.0) Dysgeusia 4 (12.1) 1 (9.1) Fatigue 4 (12.1) 0 (0.0) Leukopenia 4 (12.1) 0 (0.0) Nausea 4 (12.1) 0 (0.0) Pruritus 4 (12.1) 0 (0.0) Weight decreased 4 (12.1) 0 (0.0) Data given as No. (%) unless otherwise indicated. AE 5 adverse event. See Table 1 legend for expansion of other abbreviation. a Stomatitis included the following terms: stomatitis, aphthous stomatitis, mouth ulceration, tongue ulceration. Because the eligibility criteria applied in RADIANT-2 specified a history of secretory symptoms, it was anticipated that few patients with lung NETs would be enrolled; therefore, no stratification for these patients was implemented when the study was initiated. It is now clear that lung was the primary tumor site in approximately 10% of patients in RADIANT-2, possibly indicating that secretory symptoms in patients with advanced lung NET may not be as rare as previously thought. This was previously reported in a retrospective analysis in which 76% (16 of 21) of patients had carcinoid syndrome. 26 As an exploratory subgroup analysis, this study is not powered to support conclusions regarding treatment outcomes in the cohort with lung NET; consequently, the results should be considered with caution. Table 4 Grade 3/4 Drug-Related AEs Occurring in 5% of Patients With Lung Neuroendocrine Tumors Grade 3/4 AE Everolimus 1 Octreotide LAR (n 5 33) Placebo 1 Octreotide LAR (n 5 11) Any grade 3/4 AE 16 (48.5) 1 (9.1) Diarrhea 3 (9.1) 0 (0.0) Stomatitisa 3 (9.1) 0 (0.0) Thrombocytopenia 3 (9.1) 0 (0.0) Hyperglycemia 2 (6.1) 0 (0.0) Constipation 0 (0.0) 1 (9.1) Data given as No. (%) unless otherwise indicated. See Table 1 and Table 3 legends for expansion of abbreviations. a Stomatitis included the following terms: stomatitis, aphthous stomatitis, mouth ulceration, tongue ulceration. However, to our knowledge, this analysis represents one of the largest trial populations of patients with lung NET and thus provides important data regarding their treatment. In conclusion, the combination of everolimus plus octreotide LAR in the phase 3 RADIANT-2 study improved PFS in a cohort of patients with progressing and advanced low- to intermediate-grade lung NET. Clinical data and effective therapeutic options in these patients have been lacking, despite a rising disease incidence and poor prognosis. Results of this exploratory analysis suggest that the addition of everolimus to octreotide LAR provides additional treatment benefit for patients with lung NET and history of carcinoid symptoms and should be considered an option. These observations support the continued evaluation of everolimus treatment regimens in patients with lung NET. Acknowledgments Author contributions: Dr Fazio is the guarantor of the manuscript. Dr Fazio: contributed to the data analysis and data interpretation and wrote the first and final drafts of this manuscript. Dr Granberg: contributed to data interpretation, writing of the manuscript, and approval of the final version of the manuscript. Dr Grossman: contributed to data interpretation, writing of the manuscript, and approval of the final version of the manuscript. Dr Saletan: contributed to the study design, review and interpretation of data, review and revision of the manuscript, and approval of the final version of the manuscript. Dr Klimovsky: contributed to data interpretation, clinical review, and approval of the final version of the manuscript. Dr Panneerselvam: contributed to the data analysis and interpretation, writing of the manuscript, and approval of the final version of the manuscript. Dr Wolin: contributed to the study design; data collection, analysis, and interpretation; writing of the manuscript; and approval of the final version of the manuscript. Financial/nonfinancial disclosures: Dr Fazio has received honoraria and advisory board fees from Novartis AG, Ipsen Group, and Pfizer, Inc. Dr Granberg has received honoraria from Novartis AG. Dr Grossman has received honoraria, lecture fees, and advisory board fees from Novartis AG. Drs Saletan, Klimovsky, and Panneerselvam are employees of Novartis AG. Dr Wolin has received advisory board fees from Novartis AG. Role of sponsors : The RADIANT-2 trial was designed by the clinical investigators in conjunction with representatives of the sponsor, Novartis Pharmaceuticals Corp. Novartis Pharmaceuticals provided financial support for data collection and statistical analysis. The first manuscript draft was prepared by the first author and a medical writer funded by Novartis Pharmaceuticals. The authors who are employees of Novartis Pharmaceuticals Corp participated in the development and review of each draft of the manuscript. The protocol, including the statistical analysis plan, was published with the primary results. 16 Other contributions: We thank the participating patients and their families and the global network of research nurses, trial coordinators, and operations staffs for their contributions, and we thank the investigators who enrolled patients in this trial. A complete list of trial investigators and institutions at which the work was conducted is available in e-appendix 2. Additionally, we thank Jennifer M. Kulak, PhD, of ApotheCom, for assistance with the preparation of the manuscript; this writing assistance was funded by Novartis Pharmaceuticals Corp. Additional information: The e-appendixes can be found in the Supplemental Materials area of the online article. journal.publications.chestnet.org CHEST / 143 / 4 / APRIL

8 References 1. Klimstra DS, Modlin IR, Coppola D, Lloyd RV, Suster S. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas ; 39 (6): Yao JC, Hassan M, Phan A, et al. One hundred years after carcinoid : epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol ;26(18): Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer ;97(4): Rekhtman N. Neuroendrine tumors of the lung: an update. Arch Pathol Lab Med ;123(11): Travis WD, Brambilla E, Müller-Hermelink HK, Harris CC, eds. The concept of pulmonary neuroendocrine tumours. In: Pathology & Genetics: Tumours of the Lung, Pleura, Thymus and Heart. World Health Organization Classification of Tumours. Lyon, France : IARC Press ; 2004 : Oberg K, Akerström G, Rindi G, Jelic S ; ESMO Guidelines Working Group. Neuroendocrine gastroenteropancreatic tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol ; 21 ( suppl 5 ): v223 - v Phan AT, Oberg K, Choi J, et al ; North American Neuroendocrine Tumor Society (NANETS). NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-differentiated neuroendocrine tumors of the thorax (includes lung and thymus). Pancreas ; 39 ( 6 ): Ekeblad S, Sundin A, Janson ET, et al. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res ;13(10): Modlin IM, Pavel M, Kidd M, Gustafsson BI. Review article: somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours. Aliment Pharmacol Ther ;31(2): Rinke A, Müller HH, Schade-Brittinger C, et al ; PROMID Study Group. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol ;27(28): Yao JC, Phan A, Hoff PM, et al. Targeting vascular endothelial growth factor in advanced carcinoid tumor: a random assignment phase II study of depot octreotide with bevacizumab and pegylated interferon alpha-2b. J Clin Oncol ; 26 (8): Kulke MH, Lenz HJ, Meropol NJ, et al. Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol ;26(20): Yao JC, Phan AT, Chang DZ, et al. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to inter- mediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol ;26 (26 ): Zatelli MC, Minoia M, Martini C, et al. Everolimus as a new potential antiproliferative agent in aggressive human bronchial carcinoids. Endocr Relat Cancer ;17 (3 ): Susini C, Buscail L. Rationale for the use of somatostatin analogs as antitumor agents. Ann Oncol ;17 (12 ): Pavel ME, Hainsworth JD, Baudin E, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet ;378 (9808 ): Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Can cer, National Cancer Institute of the United States, National Can cer Institute of Canada. J Natl Cancer Inst ;92 (3 ): Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol ;5 (6 ): Yao JC, Hainsworth JD, Wolin EM, et al. Multivariate analysis including biomarkers in the phase III RADIANT-2 study of octreotide LAR plus everolimus (E+O) or pla cebo (P+O) among patients with advanced neuroendocrine tumors (NET) [abstract]. J Clin Oncol ;30 (suppl 4 ): National Institutes of Health Clinical Center. 3-Arm trial to evaluate pasireotide LAR/everolimus alone/in combination in patients with lung/thymus NET (MACS1328). NCT Clinicaltrials.gov. Bethesda, MD: National Institutes of Health; NCT Updated March 26, Righi L, Volante M, Tavaglione V, et al. Somatostatin receptor tissue distribution in lung neuroendocrine tumours: a clinicopathologic and immunohistochemical study of 218 clinically aggressive cases. Ann Oncol ;21 (3 ): Righi L, Volante M, Rapa I, et al. Mammalian target of rapamycin signaling activation patterns in neuroendocrine tumors of the lung. Endocr Relat Cancer ; 17 ( 4 ): McCaughan BC, Martini N, Bains MS. Bronchial carcinoids. Review of 124 cases. J Thorac Cardiovasc Surg ; 89 ( 1 ): Soga J, Yakuwa Y. Bronchopulmonary carcinoids: an analysis of 1,875 reported cases with special reference to a comparison between typical carcinoids and atypical varieties. Ann Thorac Cardiovasc Surg ;5 (4 ): Rekhtman N. Neuroendocrine tumors of the lung: an update. Arch Pathol Lab Med ;134 (11 ): Granberg D, Eriksson B, Wilander E, et al. Experience in treatment of metastatic pulmonary carcinoid tumors. Ann Oncol ;12 (10 ): Original Research