Trial Data Suggest New Standard of Care for Neuroendocrine Tumors

FigureSAN FRANCISCO—Treatment with octreotide long-acting release doubled the median time to disease progression relative to placebo in patients with neuroendocrine tumors of the midgut in a randomized double-blind trial, researchers reported here at the Gastrointestinal Cancers Symposium. Octreotide LAR is thus effectively a new standard of care for such patients, experts interviewed for this article agree. Researchers also presented Phase II data at the Symposium suggesting that everolimus, an mTOR inhibitor, is well tolerated and has activity in pancreatic neuroendocrine tumors. “I think it is an exciting time for neuroendocrine tumors,” said the Discussant for the studies, Lillian Siu, MD, a staff physician at Princess Margaret Hospital and Associate Professor of Medicine at the University of Toronto. During an interview with OT following the formal session, Dr. Siu pointed to the large groups of attendees crowding around the study authors as evidence of the interest generated by the two positive abstracts. Previous trials suggested that somatostatin analogues, including octreotide LAR, might have anti-proliferative effects in neuroendocrine tumors. Randomized, placebo-controlled studies have been absent, however, and thus the drug's impact on the natural history of these slow growing tumors has been unclear. To address the question directly, Rudolf Arnold, MD, Professor of Internal Medicine at Philipps University in Marburg, Germany, and colleagues enrolled 85 patients from 18 German medical centers between 2001 and 2008 in the PROMID study, a double-blind, placebo-controlled randomized trial, designed to include 162 patients. Patients had to have newly diagnosed locally inoperable or metastatic histologically confirmed neuroendocrine tumors of the midgut or unknown primary if no primary tumor was found outside the midgut. Sixty-five patients (76%) had surgical resection of their primary tumor prior to study entry, but other treatment was not allowed. Ki-67 staining was below 2% in 95% of the patients, indicating that the patients had well-differentiated tumors. In a planned interim analysis, patients treated with 30 mg octreotide LAR every four weeks had a median time to disease progression of 14.3 months compared with 6.0 months for patients in the placebo arm. “This is a highly significant difference,” Dr. Arnold said. At six months on therapy, there was one patient in each arm of the study who had a partial response by World Health Organization criteria. Additionally, 28 patients (67%) in the octreotide arm and 16 (38%) in the placebo arm had stable disease. The researchers said they could not assess the impact of octreotide therapy on overall survival, which was a secondary endpoint, because median survival was not reached in the active-drug arm. The median overall survival in the placebo arm was 73.7 months; and at the time of the interim analysis, median overall survival had to be beyond 77.4 months in the treatment arm. The investigators looked at patient subgroups to identify characteristics that might predict response to therapy. There was no difference in response in patients with functionally active and inactive tumors or in patients with elevated or non-elevated chromogranin A (CgA). However, patients who had a hepatic tumor load below 10%, which was 75% of the study population, had a much better outcome than those with a hepatic tumor load above 10%. Specifically, in the active treatment arm, 32 patients with a low hepatic tumor load had a median time to progression of 27 months compared with 10 months for the 10 patients with a high tumor load. The patients in the placebo arm with a low hepatic tumor load also did somewhat better than patients on placebo with a high hepatic tumor load, but the difference was not as great as in the octreotide arm, with a median time to progression of seven months for low-tumor load patients versus five months for high-tumor load patients.Figure: RUDOLF ARNOLD, MD: “Octreotide LAR should be considered the standard of care in patients with newly diagnosed, functionally active or inactive, well-differentiated midgut neuroendocrine tumors with a low hepatic tumor load.”Dr. Arnold speculated that this difference in response between patients with low and high hepatic tumor load may reflect differences in the underlying disease. “If a newly diagnosed patient has a high hepatic tumor load they may belong to a group of more malignant variants of this disease, despite very differentiated histology,” he said. “Octreotide LAR should be considered the standard of care in patients with newly diagnosed, functionally active or inactive, well-differentiated midgut neuroendocrine tumors with a low hepatic tumor load,” Dr. Arnold concluded. Homogeneous Population a Strength During her discussion, Dr. Siu noted that one of the strengths of the PROMID study was the homogeneous patient population. However, the design leaves several questions unanswered, including the generalizability of the results to other neuroendocrine tumors. Also, because patients were not required to have progressive disease at study entry, “the role of therapy in patients with truly non-progressing tumors remains unclear,” she said. Moreover, octreotide LAR's impact on overall survival remains an open question, she continued. “Given the significant results of this interim analysis, I think it is unlikely that this study will ever be able to address the effect on survival in these patients. And I think it is fair to say there is unlikely to be a confirmatory study in the future.” In conclusion, Dr. Siu concurred with Dr. Arnold that this was a new standard of care: “This is a very important study. We now have randomized data confirming the anti-proliferative effects of somatostatin analogs in patients with midgut neuroendocrine tumors. It is acceptable now as a therapeutic option to delay disease progression in patients with midgut or unknown primary neuroendocrine tumors.” Inhibiting mTOR in Pancreatic Neuroendocrine Tumors Following Dr. Arnold's presentation of the PROMID trial results, James Yao, MD, Associate Professor and Deputy Department Chair of Gastrointestinal Medical Oncology at the University of Texas M. D. Anderson Cancer Center, reported the results of a multinational single-arm Phase II trial testing everolimus, an inhibitor of the mTOR-signaling pathway, in patients with advanced pancreatic neuroendocrine tumors, who to be enrolled, had to have progressive disease based on Response Evaluation Criteria in Solid Tumors (RECIST) following cytotoxic chemotherapy. The mTOR pathway is often dysregulated in cancer and has been associated with the development of neuroendocrine tumors. A single-institution Phase II study had suggested that a dose of 5 or 10 mg daily of everolimus in combination with octreotide had activity in neuroendocrine tumors. The researchers hypothesized that mTOR inhibition may inhibit tumor growth and angiogenesis in these tumors. In the current trial, patients were stratified into two groups based on whether they were taking octreotide LAR at study entry or not. The primary aim of the trial was the objective response rate by central radiological review in 115 patients taking 10 mg of everolimus. Secondary endpoints included objective response rate in 45 patients taking 10 mg of everolimus and octreotide LAR, as well as progression-free survival, response duration, overall survival, and safety in both patient groups. The cutoff date for the current analysis was January 15, 2008, six months after the last patient in the everolimus-only group started treatment.Figure: LILLIAN SIU, MD: “This is a very important study. We now have randomized data confirming the anti-proliferative effects of somatostatin analogs in patients with midgut neuroendocrine tumors. It is acceptable now as a therapeutic option to delay disease progression in patients with midgut or unknown primary neuroendocrine tumors.”Nine patients (7%) in the single-agent group achieved a partial response by RECIST, and 79 (69%) had stable disease, with a median response duration of 10 months. In the combination arm, two (4%) patients had partial responses and 35 (78%) had stable disease. (Response duration was not provided for the patients in the combination-therapy group.) “The majority of the patients had disease stabilization or some degree of tumor shrinkage following initiation of therapy,” Dr. Yao said while showing a waterfall plot of the best responses to therapy in the two patient groups. Median progression-free survival was 9.3 months in the everolimus-only group and 12.9 months in the patients taking both everolimus and octreotide. The six-month progression-free survival rates were 65% and 70.6% in the single-agent and combination-therapy groups, respectively; and the 12-month progression-free survival rates were 41% and 59% in the two groups. Overall survival had not been reached in either patient group. Adverse Events Everolimus was relatively well tolerated. The most common adverse events were stomatitis, rash, and diarrhea, with any grade affecting 44%, 40%, and 37% of the patients treated with single-agent everolimus, respectively. It was not clear, however, if the rash and diarrhea were due to underlying disease or were treatment induced, Dr. Yao said. In terms of Grade 3 adverse events, asthenia and fatigue were the most common, each affecting about 5% of patients, followed by stomatitis and rash in 4% and 3.5% of patients, respectively. One patient developed Grade 4 anemia. As in Dr. Arnold's study, Dr. Yao and colleagues looked for correlates of response that might be used as biomarkers in the future, including CgA. Eighty patients (69.5%) on single-agent everolimus had elevated CgA at baseline and 39 (49%) had a 50% or greater reduction or normalization in CgA during the course of the study. A Kaplan-Meier plot of the patients who had elevated CgA at baseline and who had a 30% or greater drop or normalization of CgA within four weeks of starting therapy showed a significant difference in progression-free survival compared with those who did not have a rapid decline in CgA. No Evidence of Interaction Importantly, Dr. Yao said, there was no evidence of interaction between everolimus and octreotide. There was no difference in plasma levels of everolimus in patients taking the combination of octreotide and everolimus versus those on everolimus only. “In conclusion, durable objective responses were observed in patients with refractory neuroendocrine pancreatic tumors,” Dr. Yao said. “Progression-free and overall survival were higher in the everolimus-plus-octreotide group than in the everolimus-alone group.” Dr. Siu agreed that the Phase II data suggest that everolimus is active in pancreatic neuroendocrine tumors and that the pharmacokinetic data showing a lack of interaction between the two agents is very important. However, final evaluation of everolimus will require data from an ongoing randomized Phase III trial comparing everolimus and best supportive care with placebo and best supportive care. Such a Large Phase II Trial Needed? With that caveat in mind, Dr. Siu asked whether the community needed such a large Phase II trial. “With this many patients, could we have performed a randomized placebo-controlled study and perhaps have learned more in terms of the activity of this drug before moving on to a Phase III study?” She later told OT that it is always easier to see other approaches in retrospect: “Hindsight is 20-20. If I knew that with a rare tumor you could recruit so many patients, a randomized Phase II study would have been interesting.” And that point may be one of the most important ones—that trials can be completed in rare tumors. “Obviously this is feasible,” Dr. Siu said, who co-chairs the Neuroendocrine Task Force of the National Cancer Institute's Gastrointestinal Steering Committee with Dr. Yao. The Phase III everolimus trial is recruiting ahead of schedule, and there are several other interesting trials ongoing as well, Dr. Siu noted. “We have a very strong group of investigators who are interested in and dedicated to a disease, and I think everyone wants to address these important questions.” www.oncology-times.com Meeting Cosponsors The Gastrointestinal Cancers Symposium is cosponsored by the American Society of Clinical Oncology, the American Gastroenterological Association Institute, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

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