1. On behalf of the RADIANT-4 Study Investigators
Everolimus in Advanced, Nonfunctional Neuroendocrine Tumors of Lung or Gastrointestinal Origin: Efficacy and Safety Results from the Placebo-Controlled, Double-blind, Multicenter, Phase 3 RADIANT-4 Study
James C. Yao, Nicola Fazio, Simron Singh, Roberto Buzzoni, Carlo Carnaghi,
Edward Wolin, Jiri Tomasek, Markus Raderer, Harald Lahner, Maurizio Voi,
Lida Bubuteishvili Pacaud, Jeremie Lincy, Carolin Sachs, Juan W. Valle,
Gianfranco Delle Fave, Eric Van Cutsem, Margot Tesselaar, Yasuhiro Shimada,
Do-Youn Oh, Jonathan Strosberg, Matthew H. Kulke, Marianne E. Pavel
On behalf of the RADIANT-4 Study Investigators
James C. Yao,1 Nicola Fazio,2 Simron Singh,3 Roberto Buzzoni,4 Carlo Carnaghi,5 Edward Wolin,6 Jiri Tomasek,7 Markus Raderer,8 Harald Lahner,9 Maurizio Voi,10 Lida Bubuteishvili Pacaud,11 Jeremie Lincy,11 Carolin Sachs,11 Juan W. Valle,12 Gianfranco Delle Fave,13 Eric Van Cutsem,14 M.E.T. Tesselaar,15 Yasuhiro Shimada,16 Do-Youn Oh,17 Jonathan Strosberg,18 Matthew H. Kulke,19 Marianne E. Pavel20
1University of Texas/MD Anderson Cancer Center, Houston, Texas, USA; 2Istituto Europeo di Oncologia - IRCCS, Milano, Italy; 3Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; 4Fondazione IRCCS - Istituto Nazionale dei Tumori, Milano, Italy; 5IRCCS Istituto Clinico Humanitas, Rozzano, Italy; 6Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA; 7Masaryk Memorial Cancer Institute, Faculty of Medicine, Masaryk University, Brno, Czech Republic; 8Univ. Klinik f. Innere Medizin I, AKH, Wien, Austria; 9Universitaetsklinikum Essen, Zentrum f. Innere Medizin, Essen, Germany; 10Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA; 11Novartis Pharma AG, Basel, Switzerland; 12Institute of Cancer Studies, University of Manchester, The Christie Hospital, Manchester, United Kingdom; 13Azienda Ospedaliera Sant'Andrea - Università La Sapienza, Roma, Italy; 14Digestive Oncology, University Hospitals Gasthuisberg/Leuven and KULeuven, Leuven, Belgium; 15Nederlands Kanker Instituut - Antoni van Leeuwenhoek, Amsterdam, Netherlands; 16National Cancer Center Hospital, Tokyo, Japan; 17Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; 18Department of Medicine, Moffitt Cancer Center, Tampa, Florida, USA; 19Dana Farber Cancer Institute, Boston, USA; 20Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.

2. Background
NET: Heterogeneous group of tumors with different anatomic locations
Everolimus, an mTOR inhibitor, has shown antitumor efficacy in advanced NET of diverse origin in phase 2 and 3 studies1-5
Everolimus is one of the standard of care for advanced pancreatic NET6
RADIANT-2: Everolimus + octreotide LAR prolonged median PFS by 5.1 months in patients with advanced NET and a history of carcinoid symptoms vs placebo + octreotide LAR (although statistically not significant)3
Effective therapeutic options for patients with advanced, progressive, nonfunctional NET of lung or GI are very limited
RADIANT-4: First, large, placebo-controlled, phase 3 study to evaluate the efficacy and safety of everolimus in advanced, nonfunctional, progressive lung or GI NET
1. Yao JC et al. J Clin Oncol 2010;28: Yao JC et al. J Clin Oncol 2008; 26: Pavel ME et al. Lancet 2011;378: Yao JC et al. N Engl J Med 2011;364: Pavel ME et al. J Clin Oncol 2012;30. Abstract 4122.
6. Öberg et al. Ann Oncol 2012;23 (Supp 7): vii124–vii130.
GI, gastrointestinal; LAR, long-acting repeatable; mTOR, mammalian target of rapamycin; NET, neuroendocrine tumors; PFS, progression-free survival.

3. Treated until PD, intolerable AE, or consent withdrawal
RADIANT-4 Study Design
Everolimus 10 mg/day
N=205
Treated until PD, intolerable AE, or consent withdrawal
Patients with well-differentiated (G1/G2), advanced, progressive, nonfunctional NET of lung or GI origin (N=302)
Absence of active or any history of carcinoid syndrome
Pathologically confirmed advanced disease
Radiologic disease progression in ≤ 6 months
2:1
RANDOMI ZE
Placebo
N=97
Endpoints:
Primary: PFS (central)
Key Secondary: OS
Secondary: ORR, DCR, safety, HRQoL (FACT-G), WHO PS, NSE/CgA, PK
Stratified by:
Prior SSA treatment (yes vs. no)
Tumor origin (stratum A vs. B)*
WHO PS (0 vs. 1)
Abbreviations: AE, adverse event; CgA, chromogranin A; DCR, disease control rate; FACT-G, functional assessment of cancer therapy-general; GI, gastrointestinal; HR, hazard ration; HRQOL, Health Related Quality of Life; NET, Neuroendocrine tumors; NSE, neuron-specific enolase; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PK, Pharmacokinetics; SSA, somatostain analogues; WHO PS, World Health Organization performance status.
*Based on prognostic level, grouped as: Stratum A (better prognosis)  appendix, caecum, jejunum, ileum, duodenum, and NET of unknown primary. Stratum B (worst prognosis)  lung, stomach, rectum, and colon except caecum.
Crossover to open-label everolimus after progression in the placebo arm was not allowed prior to the primary analysis.

4. Primary Endpoint: PFS by Central Review
52% reduction in the relative risk of progression or death with everolimus vs placebo
HR = 0.48 (95% CI, ); P <
205
168
145
124
101 81 65 52 26 1 3 97 39 30 24 21 17 15 11 6 5
Placebo
Everolimus
No.of patients still at risk 2 4 8 10 12 18 27
Months 20 40 50 60 70 80 90
100
Probability of Progression-free Survival (%)
Kaplan–Meier medians
Everolimus: 11.0 months (95% CI, )
Placebo: 3.9 months (95% CI, )
Censoring Times
Everolimus (n/N = 113/205)
Placebo (n/N = 65/97)
P-value is obtained from the stratified one-sided log-rank test; Hazard ratio is obtained from stratified Cox model.
CI, confidence interval; HR, hazard ratio.

5. Consistent Investigator-Assessed PFS
Everolimus vs Placebo
HR = 0.39 (95% CI, ); P <
205
171
148
132
108 93 75 59 33 15 5 97 70 47 35 27 25 21 19 10 6 4
Placebo
Everolimus
Time (Months) 20 30 40 50 60 80 90
100
Probability of Progression-free Survival (%)
No.of patients still at risk
Kaplan–Meier medians
Everolimus: 14.0 months (95% CI, )
Placebo: 5.5 months (95% CI, )
Censoring Times
Everolimus (n/N = 98/205)
Placebo (n/N = 70/97) 2 8 12 18 24
P-value is obtained from the stratified one-sided log-rank test; Hazard ratio is obtained from stratified Cox model.
CI, confidence interval; HR, hazard ratio.

6. Interim Overall Survival Analysis
First interim OS analysis performed with 37% of information fraction favored the everolimus arm
205
195
184
179
172
170
158
143
100 59 31 5 97 94 86 80 75 70 67 61 42 21 13
Placebo
Everolimus
No. of patients still at risk 2 4 6 8 10 12 15 18 24 27 30
Months 20 40 50 60 90
Probability of Overall Survival (%)
Censoring Times
Everolimus (n/N = 42/205)
Placebo (n/N = 28/97)
Everolimus vs Placebo
HR = 0.64 (95 % CI, ); P = (NS)*
Next interim analysis is expected in 2016
*P-value boundary for significance =
P-value is obtained from the stratified one-sided log-rank test; Hazard ratio is obtained from stratified Cox model.
CI, confidence interval; HR, hazard ratio; NS, not significant; OS, overall survival.

7. Summary and Conclusions
RADIANT-4 demonstrated a statistically significant and clinically meaningful prolongation of PFS in patients with well-differentiated, advanced, progressive, nonfunctional NET of lung or GI origin
52% reduction in risk for progression or death; HR = 0.48, P <
Central median PFS: 3.9 vs 11.0 months (∆ 7.1 months)
Local radiology review confirms the significant PFS benefit (∆ 8.5 months)
PFS improvement consistent across majority of the predefined subgroups
First interim OS analysis favored everolimus
HR = 0.64, statistically not significant
Next analysis expected in 2016
Safety profile is consistent with known safety profile for everolimus
Everolimus is the first targeted agent to show robust antitumor activity with acceptable tolerability across a broad spectrum of NET including those arising from the pancreas, lung, and GI tract

8. RADIANT-4 Study Investigators:
Acknowledgments
The patients participating in this trial
The investigators and their teams
The independent data monitoring committee: Prof. K. Öberg, Dr. D. Haller, and Dr. D. Sargent
Medical editorial assistance: Rohit Kachhadiya and Bhavik Shah (Novartis Healthcare Pvt. Ltd.)
RADIANT-4 Study Investigators:
J. Valle
D. Sarker
N. Reed
J. Cave
A. Frilling
P. Corrie
M. Raderer
G. Pall
J. Wang
L. Shen
J. Xu
J. Qian
L. Jia
G. Kaltsas
T. Ito
N. Okita
I. Komoto
B. Jarzab
M. Ruchala
J. Capdevila
R. Salazar
J.J.R. Zoilo
Z. Papai
M. Toth
E. Van Cutsem
I. Borbath
K. Geboes
M. Peeters
J. Kattan
A. Shamseddine
L. Vladimirova
J.S. Chen
C.C. Wu
Y.Y. Chen
Y. Chao
K. H. Yeh
B. Melichar
E. Sedlackova
J. Tomasek
P. Fanta
J. Yao
J. Strosberg
U. Verma
S. Libutti
R. Natale
R. Pommier
S. Lubner
A. Starodub
M. Kulke
D. Sigal
B. Polite
C. Lieu
K. Hande
D. Reidy-Lagunes
McCollum
L. Forero
C. Carnaghi
G. Luppi
N. Fazio
P. Tomassetti G. Delle Fave G. Cartenì
R. Buzzoni
C. Barone
A. Berruti
D. Giuffrida
G. Tortora
F. Di Costanzo S. Tafuto
M.E.T. Tesselaar
H. Raef
T. Asmis
W. Kocha
D. Rayson
J. Ruether
S. Singh
L. Sideris
H. Kennecke
V. Sriuranpong
S. Thongprasert
M. Pavel
J. Bojunga
P. Malfertheiner
H. Lahner
A. Vogel
M. Weber
D. Horsch
T.W. Kim
Y.S. Park
D.Y. Oh
M.A. Lee
H.J. Choi
T. Salek
H. Turna
A. Sevinc
P. Ruff
L.F. Maya