Cabozantinib is a very interesting drug in pancreatic [neuroendocrine tumors]—very well tolerated, and these study results are quite intriguing. But I am still uncertain how cabozantinib will impact progression-free and overall survival in this tumor.

— Vincent J. Picozzi, MD

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Vincent J. Picozzi, MD, a pancreatic cancer specialist at Virginia Mason Hospital in Seattle, commented on the findings by Chan et al presented at the 2017 Gastrointestinal Cancers Symposium.

Dr. Picozzi first acknowledged that there is a strong biologic rationale for evaluating cabozantinib (Cometriq) in carcinoid and neuroendocrine tumors, since it offers dual inhibition of vascular endothelial growth factor and MET, “which are two very important pathways in the progression of these diseases.”

Questions and Concerns

Although he found the results of the study “intriguing,” Dr. Picozzi had some questions and concerns. “How representative is the patient selection? Is objective response rate by RECIST [Response Evaluation Criteria in Solid Tumors] the primary endpoint we want? How compelling are the results of the statistical analysis (with wide confidence limits for progression-free survival)? And what should the next steps be with this drug?” he asked during his discussion of the abstract.

Addressing these questions, Dr. ­Picozzi said, “Patients with neuroendocrine tumors vary greatly with respect to prognosis. In addition to the primary tumor site, a number of factors influence prognosis, including age, sex, race, histologic grade, and year of diagnosis. We are dealing with a heterogeneous patient population.”

He suggested other “potential biases” in the study: variable time from initial diagnosis to protocol entry (median = 49 months, range = 4–192 months) and a requirement that patients demonstrate progression by computed tomography (CT) but uncertainty whether patients had ­RECIST-based progression. The inclusion of patients with prior antiangiogenic therapy could have inserted a negative bias, as well, he said, “as some of the best responses were in patients without previous exposure” to these agents.

Response Rates

Dr. Picozzi also questioned objective response rate as the primary endpoint. “In general, progression-free survival is the preferred primary endpoint in phase II–III studies in [neuroendocrine tumors],” he noted. “Overall survival is not used, but I ask whether, as we get better at treating neuroendocrine tumors, we should hold ourselves to a higher standard?”

Responses are typically low (5%–15%) in the neuroendocrine tumor population. Also, consistent CT imaging is challenging due to slow tumor growth, variability in imaging relative to contrast timing, and suboptimal imaging in some sites, such as bone. “I also ask whether the addition of an antiangiogenic agent might change tumor perfusion and thus serial CT interpretation, or whether it could be favorable in that it provides a functional biomarker,” he continued.

“With respect to objective response rates, the study has a fairly substantial conclusion that rests on a relatively small amount of radiographic information and a small amount of change,” Dr. Picozzi observed.

“My take on all this is that cabozantinib is a very interesting drug in pancreatic [neuroendocrine tumors]—very well tolerated, and these study results are quite intriguing,” he concluded. “But I am still uncertain how cabozantinib will impact progression-free and overall survival in this tumor. I agree that further exploration is needed and is eagerly awaited.” ■

Disclosure: Dr. Picozzi disclosed relationships with AbbVie, Amgen, Gilead Sciences, Johnson & Johnson, Cornerstone Pharmaceuticals, and Halozyme.