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In advanced, progressive, well-differentiated nonfunctional GI and lung NET

AFINITOR prolonged median PFS by >7 months vs placebo (P<0.00001)1,2

Median PFS with AFINITOR was >2.5 times longer vs placebo1,2

Kaplan-Meier curve for progression-free survival in the RADIANT-4 study of AFINITOR

AFINITOR arm, 95% CI: 9.23-13.31. Placebo arm, 95% CI: 3.58-7.43. HR=0.48. 95% CI: 0.35-0.67. P<0.00001 by stratified one-sided log-rank test.

 

Treatment with AFINITOR resulted in a 52% reduction in risk of progression or death (HR=0.48; 95% CI: 0.35-0.67; P<0.00001)1,2

OS analysis is not yet mature1

  • The pre-planned OS interim analysis after 101 deaths (out of 191 required for final analysis) and 33 months follow-up favored the everolimus arm; however, no statistically significant difference in OS was noted (HR= 0.73 [95% CI: 0.48 to 1.11; P=0.071]).
Abbreviations:
CI, confidence interval; GI, gastrointestinal; HR, hazard ratio; NET, neuroendocrine tumor(s); OS, overall survival; PFS, progression-free survival.

The overall PFS benefit favored AFINITOR across predefined demographic and prognostic stratification subgroups3*

Progression-free survival in predefined patient subgroups based on stratification factors2

Kaplan-Meier curve for progression-free survival in the RADIANT-4 study of AFINITORProgression-free survival in predefined patient subgroups based on stratification factors

Tumor origin
  • Stratum A [better prognosis]: appendix, cecum, jejunum, ileum, duodenum, NET of unknown primary origin
  • Stratum B [worse prognosis]: lung, stomach, rectum, colon (except cecum)

 

  • The analysis of PFS treatment effect by stratification factors, shown above, was a prespecified analysis2
  • Patients in the RADIANT-4 trial were individually randomized to AFINITOR vs placebo and stratified based on factors known to have prognostic value: prior SSA treatment, tumor origin, and WHO PS2
  • The results of this analysis are consistent with the primary efficacy analysis and demonstrate the consistency of the treatment effect of AFINITOR across these subgroups2

Major demographic and prognostic subgroups2

Progression-free survival in major demographic and prognostic subgroups

In the supportive analyses shown above, a positive treatment effect has been observed in all subgroups with the exception of the subgroup of patients with ileum as primary site of tumor origin (Ileum: HR=1.22 [95% CI: 0.56 to 2.65]; Non-ileum: HR=0.34 [95% CI: 0.22 to 0.54]; Lung: HR=0.43 [95% CI: 0.24 to 0.79])1

  • The RADIANT-4 subgroups analyzed above were not individually randomized to AFINITOR vs placebo (stratified)2
  • Subgroup analyses were not adjusted to reflect differences in known prognostic factors between study arms2
  • Analysis of treatment effect by primary tumor of origin (Lung, Ileum, Non-ileum) was not a prespecified analysis2
*With the exception of the subgroup of patients with ileum as the primary site of origin (Ileum: HR=1.22 [95% CI: 0.56 to 2.65]; Non-ileum: HR=0.34 [95% CI: 0.22 to 0.54]; Lung: HR=0.43 [95% CI: 0.24 to 0.79]).
Non-ileum: stomach, colon, rectum, appendix, cecum, duodenum, jejunum, NET of unknown primary origin, and other gastrointestinal origin.
Abbreviations:
BSC, best supportive care; CgA, chromogranin A; CI, confidence interval; GI, gastrointestinal; HR, hazard ratio; NET, neuroendocrine tumor(s); NSE, neuron specific enolase; PFS, progression-free survival; SSA, somatostatin analogue; ULN, upper limit of normal; WHO PS, World Health Organization performance status.

A post-hoc subgroup analysis of PFS for sites of tumor origin by gastrointestinal, lung, and carcinoma of unknown primary/other origin, showed a positive PFS benefit3

Retrospective subgroup analysis of PFS2

Kaplan-Meier curve for progression-free survival in the RADIANT-4 study of AFINITORRetrospective subgroup analysis of progression-free survival

One patient with thymus as primary tumor origin was not included. Stomach, colon, rectum, appendix, cecum, ileum, duodenum, and jejunum are grouped under GI. Hazard ratio obtained from unstratified Cox model.

 

Abbreviations:
BSC, best supportive care; CI, confidence interval; CUP, cancer of unknown primary; GI, gastrointestinal; HR, hazard ratio; NET, neuroendocrine tumor(s); PFS, progression-free survival.
References:
  1. AFINITOR [summary of product characteristics]. Basel, Switzerland: Novartis Pharma AG; May 2016.
  2. Yao JC, Fazio N, Singh S, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet. 2016;387(10022):968-977.
  3. Data on file. Novartis Pharma AG.
  4. Singh S, Carnaghi C, Buzzoni R, et al. Efficacy and safety of everolimus in advanced, progressive, nonfunctional neuroendocrine tumors of the gastrointestinal tract and unknown primary: a subgroup analysis of the phase 3 RADIANT-4 trial. Presented at: ASCO Gastrointestinal Cancers Symposium. San Francisco, CA. January, 2016: Abstract 315.