Safety Analysis in RADIANT-2

David Gross, MD, Hadassah-Hebrew University Medical Center, Jerusalem, Israel, reported that the majority of treatment-related adverse events (AEs) in RADIANT-2 were grade 1 or 2. When considering AEs of all grades, stomatitis was the most common event (61.9%), followed by rash (37.2%) and fatigue (31.6%; Table 1). Other AEs included diarrhea (27.4%) and infections (20%). Pneumonitis was relatively infrequent, occurring in 9.3% in the everolimus + octreotide LAR group; 3 of these patients (1.4%) had grade 3 pneumonitis—this was modest compared with that reported in association with traditional cytotoxic chemotherapy.

The rate of grade 3 and 4 AEs was 40% and 5%, respectively, in the everolimus + octreotide LAR group, compared with 15% and 1% in the placebo + octreotide LAR group. The most common grade 3 AEs that were associated with everolimus were fatigue and stomatitis, each occurring in 7% (compared with 3% and 0% in the placebo groups). Diarrhea, infections, hyperglycemia, and thrombocytopenia also occurred in more than 3% of the everolimus + octreotide LAR group (Table 2).

Overall, the AEs were modest compared with that reported in association with traditional cytotoxic chemotherapy. Most AEs were easily managed with dose modification or treatment interruptions, concomitant medication, or dietary interventions. Disease progression was the primary reason for treatment discontinuation in both groups. The rate of treatment-related AEs that led to discontinuation was 19.5% for the everolimus+octreotide LAR group compared with 3.8% for the placebo+octreotide LAR group.

Safety Analysis in RADIANT-3

Dieter Hörsch, MD, Klinik für Innere Medizin, ENETS Center of Excellence, Bad Berka, Germany, reported similar rates of treatment-related AEs in RADIANT-3. As in RADIANT-2, stomatitis, rash, fatigue, diarrhea, and infections were the most common events in RADIANT-3, although the rates of some events differed from those in RADIANT-2 (Table 1). Also similar was the infrequent occurrence of pneumonitis, which developed in 12.3% of patients who were treated with everolimus, 3 (1.4%) of whom had grade 3 pneumonitis.

Most AEs were manageable, resolving with dose modification or treatment interruptions or concomitant medication. The rate of treatment-related AEs that led to discontinuation was 13.7% for the everolimus group compared with 2.0% for the placebo group. Disease progression was the primary reason for treatment discontinuation in both groups.

The overall rate of grade 3 or 4 AEs in RADIANT-3 was also similar to that in RADIANT-2, affecting 41% and 5% of patients, respectively (Table 3). In addition, the rates of most AEs were similar to those in the other study, but the grade 3 events that occurred most frequently were different, with hyperglycemia being the most common (6%). Anemia was the second most common event (5%), followed by stomatitis (5%), thrombocytopenia (3%), and diarrhea (3%). The overall frequency of all treatment-related events (all grades) remained the same as in the initial safety analysis.

Both Prof. Gross and Prof. Hörsch noted that the findings provide further evidence of the favorable risk-benefit profile of everolimus in patients with advanced neuroendocrine tumors and support the use of the drug as standard therapy in this setting. The findings of RADIANT-3 led to the United States Food and Drug Administration approval for the use of everolimus as treatment for progressive unresectable, locally advanced, or metastatic pancreatic neuroendocrine tumors in May 2010.