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Everolimus in advanced, progressive, well‐differentiated, non‐functional neuroendocrine tumors: RADIANT‐4 lung subgroup analysis

In the phase III RADIANT‐4 study, everolimus improved median progression‐free survival (PFS) by 7.1 months in patients with advanced, progressive, well‐differentiated (grade 1 or grade 2), non‐functional lung or gastrointestinal neuroendocrine tumors (NETs) vs placebo (hazard ratio, 0.48; 95% confidence interval [CI], 0.35‐0.67; P < .00001). This exploratory analysis reports the outcomes of the subgroup of patients with lung NETs. In RADIANT‐4, patients were randomized (2:1) to everolimus 10 mg/d or placebo, both with best supportive care. This is a post hoc analysis of the lung subgroup with PFS, by central radiology review, as the primary endpoint; secondary endpoints included objective response rate and safety measures. Ninety of the 302 patients enrolled in the study had primary lung NET (everolimus, n = 63; placebo, n = 27). Median PFS (95% CI) by central review was 9.2 (6.8‐10.9) months in the everolimus arm vs 3.6 (1.9‐5.1) months in the placebo arm (hazard ratio, 0.50; 95% CI, 0.28‐0.88). More patients who received everolimus (58%) experienced tumor shrinkage compared with placebo (13%). Most frequently reported (≥5% incidence) grade 3‐4 drug‐related adverse events (everolimus vs. placebo) included stomatitis (11% vs. 0%), hyperglycemia (10% vs. 0%), and any infections (8% vs. 0%). In patients with advanced, progressive, well‐differentiated, non‐functional lung NET, treatment with everolimus was associated with a median PFS improvement of 5.6 months, with a safety profile similar to that of the overall RADIANT‐4 cohort. These results support the use of everolimus in patients with advanced, non‐functional lung NET. The trial is registered with ClinicalTrials.gov (no. NCT01524783).

supportive care. This is a post hoc analysis of the lung subgroup with PFS, by central radiology review, as the primary endpoint; secondary endpoints included objective response rate and safety measures. Ninety of the 302 patients enrolled in the study had primary lung NET (everolimus, n = 63; placebo, n = 27). Median PFS (95% CI) by central review was 9.2 (6.8-10.9) months in the everolimus arm vs 3.6 (1.9-5.1) months in the placebo arm (hazard ratio, 0.50; 95% CI, 0.28-0.88). More patients who received everolimus (58%) experienced tumor shrinkage compared with placebo (13%). Most frequently reported (≥5% incidence) grade 3-4 drug-related adverse events (everolimus vs. placebo) included stomatitis (11% vs. 0%), hyperglycemia (10% vs. 0%), and any infections (8% vs. 0%). In patients with advanced, progressive, well-differentiated, non-functional lung NET, treatment with everolimus was associated with a median PFS improvement of 5.6 months, with a safety profile similar to that of the overall RADIANT-4 cohort. These results support the use of everolimus in patients with advanced, non-functional lung NET. The trial is registered with ClinicalTrials.gov (no. NCT01524783).

K E Y W O R D S
everolimus, lung carcinoid, neuroendocrine tumors, progression-free survival, RADIANT-4

| INTRODUCTION
Neuroendocrine tumors are a diverse group of malignancies arising from neuroendocrine cells throughout the body. 1 The majority (>90%) of NETs originating from the lungs are non-hormone secreting (i.e., non-functional). 2 Lung carcinoids (otherwise called lung NETs) represent 22%-27% of all NETs 3,4 and approximately 1%-2% of all primary lung cancers. 5 The annual age-adjusted incidence of lung NETs increased approximately 5-fold from 1973 to 2004. 1 Neuroendocrine neoplasms originating in the lungs are categorized into well-differentiated (low grade to intermediate grade), otherwise termed as NETs, and poorly differentiated (high grade), named neuroendocrine carcinomas. The well-differentiated subgroup includes TC and AC, comprising 2% and 0.2% of all lung cancers, respectively. 6 Approximately 4% of TC and 26% of AC develop distant metastases. 7 According to an analysis of the Surveillance, Epidemiology and End Results registry, the 5-year survival rate in patients with well-differentiated lung NETs with distant metastases is 27%. 1 Platinum and etoposide represent a relatively standard treatment in poorly differentiated lung neuroendocrine carcinoma, such as large-cell neuroendocrine carcinoma and small-cell lung cancer. 8,9 By contrast, therapeutic approaches are more varied for well-differentiated lung NETs, with several different potentially active therapies being explored in this patient group, including SSAs, 10 PRRT, 11,12 molecular targeted agents, [13][14][15] and some chemotherapeutics such as alkylating agents, oxaliplatin, and fluoropyrimidines. [16][17][18] However, substantial evidence regarding the efficacy of these agents as antiproliferative therapies is lacking. Therefore, no antitumor therapy has yet been approved for patients with lung NETs.
Everolimus, an oral selective inhibitor of mTOR, a key component that mediates cell growth, proliferation, and survival, has shown antitumor activity in patients with advanced NETs. [19][20][21] In the phase III RADIANT-4 study, comprising of patients with advanced, progressive, well-differentiated, non-functional lung or GI NET (n = 302), everolimus showed an improvement in median PFS of 7.1 months and a 52% reduction in the risk of disease progression or death (HR, 0.48; 95% CI, 0.35-0.67; P < .00001) compared with placebo. 22 The present analysis aimed to further explore the efficacy and safety of everolimus in the lung subgroup of the RADIANT-4 study cohort.

| Study design
RADIANT-4 was a prospective, double-blind, randomized, parallelgroup, placebo-controlled, multicenter phase III study in which everolimus 10 mg/d was compared with placebo, both with best supportive care, in patients with advanced, progressive, welldifferentiated (grade 1 or grade 2), non-functional lung or GI NET with no history of or active symptoms of carcinoid syndrome (NCT01524783). Details of the study design were published previously. 22  | 175 stomach, rectum, and colon except cecum), and WHO performance status (0 vs. 1). Crossover was not allowed prior to primary analyses.
If the primary analyses results indicated a statistically significant improvement in PFS, the remaining patients in the placebo arm could be provided with the option to crossover to open-label treatment with everolimus, based on the feedback from the data monitoring committee.

| Patients
Adult patients (≥18 years) with pathologically confirmed, advanced (unresectable or metastatic), well-differentiated (grade 1 or grade 2 per 2010 WHO gastroenteropancreatic NET classification), 23,24 nonfunctional NET of the lung or GI origin were eligible for enrollment if radiologically progressing and enrolled within 6 months from diagnosis of progression before randomization. In addition to the treatment-na€ ıve patients, patients who discontinued previous treatments like SSA (for tumor control), interferon, or one line of chemotherapy for ≥4 weeks and PRRT for ≥6 months prior to randomization were allowed, if they had disease progression after their last treatment.
Patients with poorly differentiated or high-grade neuroendocrine carcinoma were excluded from the study. Also, patients with pancreatic NET, or carcinoid syndrome, history of one or more lines of chemotherapy, targeted therapy, therapy with mTOR inhibitors, hepatic intra-arterial embolization within 6 months, or cryoablation or radiofrequency ablation of hepatic metastases within 2 months of randomization, or chronic treatment with corticosteroids or other immunosuppressive agents were excluded from the study. The study was carried out in accordance with Good Clinical Practice, the ethical principles outlined in the Declaration of Helsinki, and local regulations. An independent ethics committee or institutional review board at each participating center reviewed and approved the study and all protocol amendments. All patients provided written informed consent. An independent data monitoring committee provided ongoing oversight of safety and study conduct.

| Statistical analysis
This is an exploratory subgroup analysis of patients with lung NET as a primary site enrolled in the RADIANT-4 study. The full analysis set (all randomized patients) was used for all efficacy analyses. Sample size calculations were not undertaken for the cohort of patients described in this report and so this analysis was not powered to compare the treatment groups. Progression-free survival, by central radiology review, was analyzed using Kaplan-Meier methods. Hazard ratios and corresponding CIs were estimated using an unstratified Cox proportional hazards model. All patients who received on or more doses of study drug and who had one or more post-baseline safety assessments were included in the safety cohort.

| Patient characteristics
Of the 302 patients in the RADIANT-4 study, 90 patients had advanced, progressive, well-differentiated, non-functional NET of lung origin and were included in this analysis; of them, 63 received everolimus and 27 received placebo. In the everolimus arm, one patient was not treated due to withdrawal of consent. Therefore, the safety cohort in the everolimus arm was comprised of 62 patients.  Table 1.
Either tumor morphology or grade of malignancy was collected for the lung NET patient group (n = 90). Tumors were defined as "well" or "moderately" differentiated based on local pathology assessment. Among the patients in whom tumor morphology was reported (n = 38), the majority were reported to have well-differentiated NET (n = 32; 84.2%). Moderately differentiated NET was reported in 6 patients (15.8%). Considering the lack of consensus among pathologists on the precise definition, patients with moderately differentiated NETs were eligible for inclusion in this study provided that a poorly differentiated high-grade neuroendocrine carcinoma was ruled out, consistent with the exclusion criteria of the study protocol. Among the patients in whom tumor grade was reported (n = 51), majority (86.2%) had an intermediate grade NET.
In the patients in whom Ki-67 percentage was reported (n = 63), it varied from 0% to 60% (median, 8%). Three patients in the everolimus arm had a Ki-67 index >20% (30%, 50%, and 60%). The investigators confirmed the eligibility of these three patients based on well-differentiated tumor morphology as reviewed by the local pathologist. These dose adjustments were primarily attributable to AEs (69.4%).

| Treatment
In the placebo arm (n = 27), 8 patients (29.6%) had one or more adjustments (reduction or interruption) of dosage and 18.5% of dose adjustments were due to AEs.

| Safety
The most common AEs in the lung NET subgroup, irrespective of the study drug relationship (≥20% incidence in either arm), were stomatitis (53.2% with everolimus vs. 18 with pneumonitis had stable disease as their best response per central radiology review. The most frequent grade 3-4 drug-related AEs (≥5% incidence in either arm) were stomatitis, hyperglycemia, and infections (Table 3).
There were two on-treatment deaths in each arm. In the everolimus arm, one of the two deaths was considered to be related to the primary disease and/or to disease progression, and the other was

Probability of progression-free survival (%)
Everolimus Placebo  These results strongly support the results of the central review.
Based on the results obtained in the RADIANT-4 study, everolimus has been approved worldwide for the treatment of patients with advanced, progressive, well-differentiated, non-functional (GI and lung) NET. 22 22 The data from our analysis supports the preliminary evidence of efficacy that was observed when everolimus was added to octreotide in patients with functional lung NET. 19 The results from the three-arm, randomized phase II LUNA trial (n = 112), comparing pasireotide in combination with everolimus vs everolimus alone and pasireotide alone in patients with typical and atypical lung or thymic carcinoids further support the efficacy of everolimus in this setting. 27 The LUNA study achieved the preplanned statistical objective of a