Dataset Information

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

ABSTRACT:

Background

Recently, 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 registration

ClinicalTrials.gov identifier: NCT01524783.

Patients and methods

Patients 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.

Results

A 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.

Conclusion

These 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.

SUBMITTER: Buzzoni R

PROVIDER: S-EPMC5652899 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

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

Buzzoni Roberto R Carnaghi Carlo C Strosberg Jonathan J Fazio Nicola N Singh Simron S Herbst Fabian F Ridolfi Antonia A Pavel Marianne E ME Wolin Edward M EM Valle Juan W JW Oh Do-Youn DY Yao James C JC Pommier Rodney R

OncoTargets and therapy 20171016

<h4>Background</h4>Recently, 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; <i>P</i><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 a ...[more]

PMID: 29081664

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Project description:Purpose Everolimus improved median progression-free survival by 6.4 months in patients with advanced pancreatic neuroendocrine tumors (NET) compared with placebo in the RADIANT-3 study. Here, we present the final overall survival (OS) data and data on the impact of biomarkers on OS from the RADIANT-3 study. Methods Patients with advanced, progressive, low- or intermediate-grade pancreatic NET were randomly assigned to everolimus 10 mg/day (n = 207) or placebo (n = 203). Crossover from placebo to open-label everolimus was allowed on disease progression. Ongoing patients were unblinded after final progression-free survival analysis and could transition to open-label everolimus at the investigator's discretion (extension phase). OS analysis was performed using a stratified log-rank test in the intent-to-treat population. The baseline levels of chromogranin A, neuron-specific enolase, and multiple soluble angiogenic biomarkers were determined and their impact on OS was explored. Results Of 410 patients who were enrolled between July 2007 and March 2014, 225 received open-label everolimus, including 172 patients (85%) randomly assigned initially to the placebo arm. Median OS was 44.0 months (95% CI, 35.6 to 51.8 months) for those randomly assigned to everolimus and 37.7 months (95% CI, 29.1 to 45.8 months) for those randomly assigned to placebo (hazard ratio, 0.94; 95% CI, 0.73 to 1.20; P = .30). Elevated baseline chromogranin A, neuron-specific enolase, placental growth factor, and soluble vascular endothelial growth factor receptor 1 levels were poor prognostic factors for OS. The most common adverse events included stomatitis, rash, and diarrhea. Conclusion Everolimus was associated with a median OS of 44 months in patients with advanced, progressive pancreatic NET, the longest OS reported in a phase III study for this population. Everolimus was associated with a survival benefit of 6.3 months, although this finding was not statistically significant. Crossover of patients likely confounded the OS results.

Project description:Renal cell carcinoma (RCC) is the most common type of cancer arising from the kidney, with a male to female ratio of 2:1. The incidence of RCC is rising. In males, it was the seventh most common cancer in the People's Republic of China in 2012. RCC is resistant to radiotherapy and chemotherapy, but approximately 20% of patients with advanced RCC respond to immunotherapy. Novel therapies targeting angiogenesis and signaling pathways have been proven to be effective for advanced or metastatic RCC in Western countries. Due to the heterogeneity of RCC between races, it is necessary to have an overview of targeted therapies, especially everolimus, for patients with advanced RCC in the People's Republic of China. Three targeted therapeutic agents have been approved in Mainland China for the treatment of patients with advanced RCC, ie, two tyrosine kinase inhibitors (sorafenib and sunitinib) and one mammalian target of rapamycin (mTOR) inhibitor (everolimus). Compared with Western patients with advanced or metastatic RCC, Chinese patients with the same disease respond better to sorafenib and sunitinib as first-line targeted therapy, but sunitinib has a relatively higher risk of toxicity. Everolimus, an mTOR inhibitor that can be administered orally, is well tolerated and acceptable to Chinese patients. Everolimus has competitive advantages as second-line targeted treatment for Chinese patients with advanced RCC who are resistant to first-line tyrosine kinase inhibitors. Despite a lack of noninferiority when compared with sunitinib as first-line therapy, the sunitinib-everolimus paradigm is still recommended as standard therapy for patients with advanced RCC. Although most studies of targeted therapies for advanced RCC have obvious limitations, such as small sample size and retrospective design, up-to-date evidence indicates that everolimus would be an ideal agent as second-line targeted treatment for advanced or metastatic RCC in the People's Republic of China.

Project description:BackgroundEffective systemic therapies for patients with advanced, progressive neuroendocrine tumours of the lung or gastrointestinal tract are scarce. We aimed to assess the efficacy and safety of everolimus compared with placebo in this patient population.MethodsIn the randomised, double-blind, placebo-controlled, phase 3 RADIANT-4 trial, adult patients (aged ≥18 years) with advanced, progressive, well-differentiated, non-functional neuroendocrine tumours of lung or gastrointestinal origin were enrolled from 97 centres in 25 countries worldwide. Eligible patients were randomly assigned in a 2:1 ratio by an interactive voice response system to receive everolimus 10 mg per day orally or identical placebo, both with supportive care. Patients were stratified by tumour origin, performance status, and previous somatostatin analogue treatment. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoint was progression-free survival assessed by central radiology review, analysed by intention to treat. Overall survival was a key secondary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01524783.FindingsBetween April 3, 2012, and Aug 23, 2013, a total of 302 patients were enrolled, of whom 205 were allocated to everolimus 10 mg per day and 97 to placebo. Median progression-free survival was 11·0 months (95% CI 9·2-13·3) in the everolimus group and 3·9 months (3·6-7·4) in the placebo group. Everolimus was associated with a 52% reduction in the estimated risk of progression or death (hazard ratio [HR] 0·48 [95% CI 0·35-0·67], p<0·00001). Although not statistically significant, the results of the first pre-planned interim overall survival analysis indicated that everolimus might be associated with a reduction in the risk of death (HR 0·64 [95% CI 0·40-1·05], one-sided p=0·037, whereas the boundary for statistical significance was 0·0002). Grade 3 or 4 drug-related adverse events were infrequent and included stomatitis (in 18 [9%] of 202 patients in the everolimus group vs 0 of 98 in the placebo group), diarrhoea (15 [7%] vs 2 [2%]), infections (14 [7%] vs 0), anaemia (8 [4%] vs 1 [1%]), fatigue (7 [3%] vs 1 [1%]), and hyperglycaemia (7 [3%] vs 0).InterpretationTreatment with everolimus was associated with significant improvement in progression-free survival in patients with progressive lung or gastrointestinal neuroendocrine tumours. The safety findings were consistent with the known side-effect profile of everolimus. Everolimus is the first targeted agent to show robust anti-tumour activity with acceptable tolerability across a broad range of neuroendocrine tumours, including those arising from the pancreas, lung, and gastrointestinal tract.FundingNovartis Pharmaceuticals Corporation.

Dataset Information

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

Background

Trial registration

Patients and methods

Results

Conclusion

Publications

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

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