In updated results from the RADIANT trials of treatment for advanced neuroendocrine tumors, everolimus provided a 2.4-fold increase in median progression-free survival (PFS) for patients with pancreatic neuroendocrine tumors. In combination with the long-acting formulation of the somatostatin analog octreotide (Sandostatin LAR) in patients with carcinoid syndrome, however, the benefit was more questionable. The updates were reported at the 2011 Gastrointestinal Cancers Symposium.

The phase III RADIANT-3 trial randomly assigned 410 patients with advanced pancreatic neuroendocrine tumors to everolimus (10 mg/d) or best supportive care, with crossover allowed upon progression. Median duration of exposure was 38 weeks for the active arm and 16 weeks for the placebo arm.

Median PFS was 11.0 months with everolimus and 4.6 months with placebo, for a highly significant 65% reduction in risk (P < .0001). The 18-month PFS rates were 34% and 9%, respectively, reported Manisha H. Shah, MD, of Ohio State University Comprehensive Cancer Center in Columbus, Ohio.¹

To control symptoms, 50% of patients on each arm had prior somatostatin analog use, and 40% used these drugs concomitantly with study treatment. Prior or concomitant use of somatostatin analogs was not associated with any detriment in efficacy. “Everolimus showed a consistent benefit in all subgroups regardless of the presence or absence of somatostatin analog treatment,” she said.

Everolimus Plus Octreotide LAR

In RADIANT-2, which was conducted in 429 patients with advanced neuroendocrine tumors and a history of secretory symptoms, everolimus added to long-acting octreotide at 30 mg monthly “demonstrated a clinically meaningful prolongation of median PFS,” according to James Yao, MD, of The University of Texas MD Anderson Cancer Center, Houston.²

However, the 5.1-month prolongation of median PFS (HR = 0.77; P = .026) did not reach statistical significance by central review, according to the prespecified P value (P = .0246). “The combination narrowly missed the prespecified boundary,” he noted. By local assessment, the same risk reduction was seen (HR = 0.78) but the P value was significant at P = .018.

According to Dr. Yao, the lack of statistical significance can be attributed to the “informative censoring,” in which patients with progressive disease per investigator but who are later judged to have nonprogressive disease on central review are “informatively censored” in the central PFS analysis due to a change in therapy—and this can create bias. To correct for this, the RADIANT-2 investigators used an inverse probability of censoring weights (IPCW) analysis. This produces a “corrected treatment effect estimate” that, in this case, became statistically significant, he said (Table 1).

 “In all three analyses the hazard ratios favor everolimus, and the prespecified statistical analysis [inverse probability of censoring weights] adjusting for informative censoring, loss of power, and imbalances in baseline prognostics factors demonstrate a consistent benefit,” Dr. Yao reported.

Exploratory Analysis

In an exploratory analysis, patients without prior somatostatin analog use had greater absolute and relative benefits, he added. In this group, median PFS with the combination was 25.2 months compared with 13.6 months for long-acting octreotide alone; in patients with prior use of these agents, PFS was 14.3 vs 11.1 months, respectively.

The treatment was well tolerated, but more treatment-related adverse events were seen in the everolimus arm, especially stomatitis, which occurred (all grades) in 62% of everolimus patients vs 14% of placebo patients with the single agent; grade 3 or 4 stomatitis was seen in 7% and 0%, respectively. Rash, fatigue, and diarrhea were also greater with everolimus plus long-acting octreotide. ■

Editor’s note: The Oncologic Drugs Advisory Committee (ODAC) of the FDA recently recommended that everolimus (Afinitor) be approved for the treatment of advanced pancreatic neuroendocrine tumors. In a decision made that same day (April 12, 2011), the ODAC committee voted to recommend that the multikinase inhibitor sunitinib (Sutent) be approved for the treatment of unresectable pancreatic neuroendocrine tumors.

ODAC’s unanimous decision to recommend approval of everolimus was based on data from the clinical trials described in this report showing a significant increase in median progression-free survival for patients with pancreatic neuroendocrine tumors who received everolimus compared to those who received placebo and best supportive care. ■

Financial Disclosure: Dr. Shah and Dr. Yao reported no potential conflicts of interest.

References

1. Shah MH, Ito T, Lombard-Bohas C, et al: Everolimus in patients with advanced pancreatic neuroendocrine tumors: Updated results of a randomized, double-blind, placebo-controlled multicenter phase III trial (RADIANT-3). 2011 Gastrointestinal Cancers Symposium. Abstract 158. Presented January 21, 2011.

2. Yao JC, Hainsworth JD, Baudin E, et al: Everolimus plus octreotide LAR versus placebo plus octreotide LAR in patients with advanced neuroendocrine tumors: Updated results of a randomized, double-blind, placebo-controlled, multicenter phase III trial (RADIANT-2). 2011 Gastrointestinal Cancers Symposium. Abstract 159. Presented January 21, 2011.