Axitinib Shows Promise in Carcinoid Tumors

The rate of progression-free survival (PFS) with axitinib (Inlyta) in patients with advanced carcinoid tumors is promising. Phase II data in this setting show that axitinib was well tolerated overall but with a high rate of hypertension, said Mauro Cives, MD, at the 2014 NANETS Symposium.

Neuroendocrine tumors overexpress VEGF and VEGF receptor (VEGFR), and interfering with the VEGF pathway can impair tumor growth in vivo. Axitinib inhibits the proliferation and survival of endothelial cells and inhibits new vessel sprouting in vitro by rapidly blocking the eNOS/Akt pathway, which is strongly implicated in tumor neoangiogenesis, said Cives, a fellow in Medical Oncology at the H. Lee Moffitt Cancer Center and Research Institute. Antitumor effects in vivo, including central necrosis, reduced proliferative activity, and inducement of apoptosis, have been demonstrated with axitinib.

Several antiangiogenic tyrosine kinase inhibitors (TKIs) have been studied in advanced carcinoids. Phase II data with sunitinib (J Clin Oncol. 2008;26[20]:3403-3410) showed a low response rate in patients with carcinoid (2.4%) and pancreatic neuroendocrine tumors (16.7%), but time to tumor progression and 1-year overall survival (OS) were quite encouraging in both cohorts, Cives said. Similarly, more recent phase II data with pazopanib (Votrient) in metastatic gastroenteropancreatic neuroendocrine tumors demonstrated an objective response rate of only 19% but a disease-free control rate of 76% and a median PFS of 9 months (Br J Cancer. 2013;109:1414-1419).

Given the low likelihood of a radiographic response with antiangiogenic agents in neuroendocrine tumors but the possibility of improved PFS, Cives and colleagues focused on the PFS rate at 1 year as the primary endpoint in their phase II study of axitinib. Patients with unresectable or metastatic low-to-intermediate—grade carcinoid tumors were treated with 5 mg twice daily of axitinib. Thirty patients were entered into the trial and were assessable for toxicity; 22 were assessable for response.

After a median of ten 28-day treatment cycles, the 1-year PFS was 65%, corresponding to a median PFS of 28 months. The median PFS data are not reliable due to only six progression events recorded, Cives said. The 1-year OS rate was 93%.

Best radiographic response was a partial response in one patient and stable disease in 21. Of 25 patients with elevated levels of CgA at baseline, four experienced reductions of levels of this tumor marker, and there was a trend toward an overall reduction in CgA levels after treatment (P = .0611). “There was statistical significance regarding the 5-HIAA response [P = .0137], but an insufficient number of patients had baseline elevations of 5-HIAA to draw a reliable conclusion about it,” Cives said.

Axitinib was fairly well tolerated. Hypertension (93%) and fatigue (60%) were the most common treatment-related adverse events. This rate of hypertension was higher compared with other antiangiogenic TKIs, Cives noted. Eight patients discontinued treatment for adverse events, two because of hypertension. “After axitinib interruption, recovery from hypertension was rapid and without sequelae,” Cives said.

Pancreatic neuroendocrine tumors seem to respond better to TKIs than do the carcinoids, as evidenced by the low response rates observed previously in TKI trials of carcinoid, “but given the prolonged PFS recognized in single-arm studies, there could be a signal there that we don’t want to miss,” commented Diane Reidy-Lagunes, MD, a gastrointestinal oncologist at Memorial Sloan Kettering Cancer Center. “Because carcinoid therapies have been such a hard nut to crack, we’ve all tried very hard to use different types of VEGF therapies, and there’s no paucity of trials of VEGF therapies for carcinoid tumors, with the idea that there has been some evidence of activity but not enough to get us there.”

The response rate with axitinib in the study by Cives et al was not high, as is traditional for other TKIs. “However, the OS was high, which is very hard to interpret, but the PFS is exceptional,” she said. Accurate interpretation of median PFS can only occur after more progression events, she cautioned.

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