EVEROLIMUS AN DSUNITINIB FOR PANCREATIC NETs

February 10, 2011 — Pancreatic neuroendocrine tumors are relatively rare but challenging to manage because few treatment options exist. However, 2 groups of investigators are reporting promising study results with oral drugs, potentially leading to new therapeutic strategies.
One group evaluated the mTOR inhibitor everolimus (Afinitor, Novartis); the other group studied the tyrosine kinase inhibitor sunitinib (Sutent, Pfizer). Both agents prolonged progression-free survival in patients with advanced pancreatic neuroendocrine tumors, compared with placebo.
The results of both studies were initially presented at the 2010 Gastrointestinal Cancers Symposium, and were reported by Medscape Medical News at that time. Both studies appear in the February 10 issue of the New England Journal of Medicine.
The authors of the everolimus trial report a median progression-free survival of 11.0 months, compared with 4.6 months in the placebo group (hazard ratio [HR] for disease progression or death from any cause with everolimus, 0.35; P < .001). This represents a 65% reduction in the estimated risk for progression or death.
In the sunitinib study, median progression-free survival was 11.4 months, compared with 5.5 months in the placebo group (HR for progression or death, 0.42; P < .001). The objective response rate was 9.3% in the sunitinib group and 0.0% in the placebo group.
Guarded Optimism
The fact that both of these drugs improved disease-free survival, even in patients in whom other treatments have failed, provides optimism about the treatment of this malignancy, note the authors of an accompanying editorial.
The drugs offer effective therapies where there were none before, write Robert T. Jensen, MD, from the National Institutes of Health in Bethesda, Maryland, and Gianfranco Delle Fave, MD, from University La Sapienza in Rome, Italy. "However, the studies also raise some unanswered questions that make the optimism guarded."
The editorialists wonder whether patients taking these drugs will have to continue doing so for years, because both agents primarily stabilize, rather than cure, the disease. The also wonder whether patients who no longer respond to one drug can be effectively treated with the other drug or with a combination of both agents.
Another issue Drs. Jensen and Delle Fave raise is whether these agents can be used in the neoadjuvant setting, as adjuvant therapy with surgery, or in combination with peptide-receptor radionuclide therapy or somatostatin analogue therapy. It also remains unclear how the adverse-effect profiles will affect long-term adherence to treatment.
"The answers to these latter questions will be particularly important in helping to determine the widespread usefulness of these new drugs in the treatment of malignant pancreatic neuroendocrine tumors," they write.
Everolimus Results
The RAD001 in Advanced Neuroendocrine Tumors, third trial (RADIANT-3), was conducted to determine whether everolimus would prolong progression-free survival in patients with advanced pancreatic neuroendocrine tumors.
"These are phase 3 data and confirm our earlier results that the drug is effective in this disease," said lead author James Yao, MD, associate professor in the Department of Gastrointestinal Medical Oncology at the University of Texas M.D. Anderson Cancer Center in Houston.
"The study is designed for progression-free survival; the data are not mature for overall survival," he told Medscape Medical News. "We picked progression-free survival as a primary end point because survival duration following progression in this disease can be lengthy. The number of patients that would have been needed to detect survival would have been quite large, and would have been very challenging because of the rarity of the disease."
Dr. Yao noted that it might be difficult to see a survival benefit because of the planned crossover. "Over 90% of patients who experienced progression in the placebo arm crossed over; that can confound the detection of overall survival," he said. "But since our end point was progression-free survival, from an ethical, investigator, and patient standpoint, crossover was desirable."
In this multicenter phase 3 study, Dr. Yao and colleagues randomized 410 patients with advanced low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive either everolimus 10 mg (n = 207) or placebo (n = 203).
The estimated proportion of patients still alive and progression-free at 18 months was 34% (95% confidence interval [CI], 26 to 43) in the everolimus group and 9% (95% CI, 4 to 16) in the placebo group. This indicates that a sizable proportion of the cohort derived a prolonged benefit from everolimus, note the authors.
The response rate with everolimus was also superior. Confirmed objective tumor responses (all partial responses) were observed in 10 patients (5%) who received everolimus, compared with 4 (2%) who received placebo.
Stable disease was observed in 73% of the patients in the everolimus group and 51% in the placebo group. Progressive disease as the best outcome occurred in 14% of the everolimus group and 42% of the placebo group. In addition, some degree of tumor shrinkage was observed in 64% of the everolimus group and in 21% of the placebo group.
"We believe that we are targeting a specific abnormality in these tumors. That's why we are seeing very good results," said Dr. Yao. "The treatment is showing delays in tumor progression by more than 6 months. The benefit also appears to be durable, so this is an exciting new option for these patients."
In regard to adverse events, the safety profile was consistent with that seen previously with everolimus. The majority of adverse events were grade 1 or 2, and the most common were stomatitis (in 64% of the everolimus group vs 17% of the placebo group), rash (49% vs 10%), diarrhea (34% vs 10%), fatigue (31% vs 14%), and infections (23% vs 6%).
Dr. Yao believes that everolimus is very much a viable treatment option for this patient population. "[Streptozotocin] is the only approved therapy for pancreatic neuroendocrine tumors, and it's not widely used because of toxicity," he said. "This is the largest phase 3 randomized trial for pancreatic neuroendocrine tumors, and the treatment really shows fairly robust benefit across all subtypes."
Sunitinib Results
In the sunitinib phase 3 study, Eric Raymond, MD, PhD, professor of medical oncology at Beaujon University Hospital in Clichy, France, and colleagues randomized 171 patients in a 1:1 ratio to receive best supportive care with either sunitinib 37.5 mg/day or placebo.
As in the everolimus trial, the primary end point was progression-free survival. Secondary end points included objective response rate, overall survival, and safety. All study participants had pathologically confirmed, well-differentiated pancreatic endocrine tumors that were advanced, metastatic, or both, and that could not be surgically resected.
Patients in the placebo group who experienced disease progression had the option of entering an open-label sunitinib extension protocol.
The probability of progression-free survival at 6 months was 71.3% in the sunitinib group and 43.2% in the placebo group.
In the sunitinib group, 8 patients experienced a confirmed tumor response (2 complete and 6 partial); there were no objective responses in the placebo group. The median time to tumor response was 3.1 months (range, 0.8 to 11.1), and response duration ranged from 0.9 to more than 15.0 months.
The authors were unable to estimate median overall survival for either of the study groups because of the relatively high number of censored events. In the sunitinib group, 9 patients (10%) died; in the placebo group, 21 patients (25%) died. However, the majority of patients were still in follow-up at the data cutoff point, and the HR for death was 0.41 (95% CI, 0.19 to 0.89; P = .02) in favor of sunitinib.
As previously reported by Medscape Medical News, the trial was terminated early because of the risk for serious adverse events, disease progression, and death among patients in the placebo group. Although the majority of adverse events were grade 1 or 2 in severity, grade 3 or 4 events were more commonly observed in patients in the sunitinib group.
The most common events associated with sunitinib were diarrhea, nausea, asthenia, vomiting, and fatigue; each was observed in 30% or more of the patients. The most common grade 3 or 4 adverse events in patients who received sunitinib were neutropenia (12%) and hypertension (10%).
"Although early termination of clinical trials may result in overestimation of the true treatment effect and in lower-than-anticipated numbers of enrolled patients, the magnitude of the observed treatment effect, the consistency of the hazard ratio for disease progression or death in the sensitivity analyses, and the favorable survival data in this trial all provide strong evidence of the clinically meaningful benefit of sunitinib," write the authors.
The everolimus study was funded by Novartis; the sunitinib study was supported by Pfizer. Dr. Yao reports receiving consulting fees/honoraria from Novartis; coauthors from both studies disclose financial relationships with various pharmaceutical companies, as noted in the papers.
N Engl J Med. 2011; 364:501-513, 514-523.