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.

Keywords: PRRT; chemotherapy; neuroendocrine tumors; progression-free survival; somatostatin analogs.

Conflict of interest statement

Disclosure The authors report the following types of declarations of interest: consultant/advisory relationship (C/A), employment (E), honoraria received (H), intellectual property rights/inventor/patent holder (IP), leadership position (L), ownership interest (OI), research funding (RF), speaker’s bureau (SB), and travel and accommodation expenses (TAE). Roberto Buzzoni: Italfarmaco, Novartis, Otsuka (RF); Ipsen, Italfarmaco, Novartis (TAE); Jonathan Strosberg: Novartis (H); Ipsen, Lexicon, Novartis (C/A); Novartis, Pfizer (RF); Bayer, Genentech (SB); Nicola Fazio: Ipsen, Novartis (H); Ipsen, Lexicon, Novartis, Italfarmaco (C/A); Novartis (RF); Ipsen, Novartis (TAE); Simron Singh: Novartis (H, C/A, TAE, RF); Fabian Herbst: Novartis (E, OI); Antonia Ridolfi: Novartis (E); Marianne E Pavel: Ipsen, Lexicon, Novartis, Pfizer (H); Ipsen, Lexicon, Novartis, Pfizer (C/A); Novartis (RF); Ipsen, Novartis (TAE); Edward M Wolin: Celgene, Ipsen, Novartis (C/A); Juan W Valle: Novartis (H, C/A, RF); James C Yao: Ipsen, Lexicon, Novartis (C/A); Novartis (RF); Rodney Pommier: Novartis, Pfizer, Ipsen, Lexicon (C/A); Novartis, Ipsen, Lexicon (TAE). The other authors report no conflicts of interest in this work.

Figures

Figure 1

Progression-free survival by central review (full analysis set). Notes: Kaplan–Meier curves are shown for progression-free survival as assessed by central radiology review for both treatment arms (everolimus and placebo) in the patients who received (A) prior SSA, (B) no prior SSA, (C) prior chemotherapy, (D) no prior chemotherapy, (E) prior radiotherapy, and (F) no prior radiotherapy. The HRs in subgroups are obtained from unstratified Cox proportional hazards model. Abbreviations: CI, confidence interval; HR, hazard ratio; SSA, somatostatin analogs.

Figure 2

Percentage change from baseline in size of target lesion, central review (full analysis set). Notes: The plot shows the best percentage change from baseline in the size of the target lesion (ie, the best response in each patient) in the everolimus arm (left) and placebo arm (right) in the patients who received (A) prior SSA, (B) no prior SSA, (C) prior chemotherapy, (D) no prior chemotherapy, (E) prior radiotherapy, and (F) no prior radiotherapy. Abbreviations: PD, progressive disease; SSA, somatostatin analogs.

Figure 2

Percentage change from baseline in size of target lesion, central review (full analysis set). Notes: The plot shows the best percentage change from baseline in the size of the target lesion (ie, the best response in each patient) in the everolimus arm (left) and placebo arm (right) in the patients who received (A) prior SSA, (B) no prior SSA, (C) prior chemotherapy, (D) no prior chemotherapy, (E) prior radiotherapy, and (F) no prior radiotherapy. Abbreviations: PD, progressive disease; SSA, somatostatin analogs.