Cabozantinib Shows Promise for Progressive Carcinoid and Pancreatic NETs but Requires Phase III Confirmation

Cabozantinib Shows Promise for Progressive Carcinoid and Pancreatic NETs but Requires Phase III Confirmation

Findings from a prospective phase II trial suggest that treatment with cabozantinib confers marked clinical benefit in patients with progressive, well-differentiated neuroendocrine tumors (NETs)—lesions that historically are difficult to treat given their chemoresistant nature. Single-agent therapy shrank or held disease in check in at least 78% of patients and provided long-lasting disease control (Abstract 228), as reported by lead investigator Jennifer A. Chan, MD, MPH, of the Dana-Farber Cancer Institute.

Dr. Jennifer A. Chan
Cabozantinib, a small-molecule inhibitor that targets several tyrosine kinase receptors including VEGFR, MET, AXL, and RET, is already an established treatment option in renal cell carcinoma and medullary thyroid carcinoma. The investigators opted to explore whether cabozantinib might also be effective in managing NETs based on several lines of evidence implying that the agent may confer dual VEGF-MET inhibition to halt disease growth. First, VEGF pathway inhibitors are active in advanced NETs; second, aberrant MET activity may fuel NET growth and progression; and third, cabozantinib reduced cell viability and decreased metastases and invasion in NET preclinical models.

The current phase II trial included 61 patients with progressive, well-differentiated, grade 1 or 2 unresectable or metastatic NETs. Patients were divided into one of two cohorts: those with carcinoid NETs (41 patients) and those with pancreatic NETs (20 patients).

All patients received oral cabozantinib 60 mg daily at the study start, although dose reduction was common. Study participants completed a median of nine treatment cycles, with 87% finishing at least one cycle and 82% finishing at least two cycles. Notably, 81% of the 53 patients who completed more than one treatment cycle required a decrease in dose to either 20 or 40 mg cabozantinib once daily.

Despite the decreases in dosing, cabozantinib still proved active. Among the 20 patients with pancreatic NETs, the agent produced an objective response rate of 15% (all partial responses), despite the fact that patients received a median of three prior therapies, including sunitinib, everolimus, and temozolomide. When factoring in a stable disease rate of 75%, this brought the rate of clinical benefit with cabozantinib to 90% among those with pancreatic disease.

Similar findings emerged among the 41 patients with carcinoid tumors. Although these patients were less heavily pretreated, having received a median of only one prior therapy, the objective response rate was 15% (all partial responses), and the clinical benefit rate was 78% after factoring in individuals with stable disease.

Based on a median follow-up duration of 23.3 months, median progression-free survival (PFS) reached 21.8 months in patients with pancreatic NETs and 31.4 months in patients with carcinoid NETs. According to Dr. Chan, these values are encouraging in the context of historical PFS data for other tyrosine kinase inhibitors that have been studied in NETs, which have yielded PFS values on the order of 8 to 16 months.

Cabozantinib toxicities were largely consistent with observations from other disease settings and typically mild or moderate in severity. The most common treatment-related grade 3/4 adverse events included hypertension (13%), hypophosphatemia (11%), and diarrhea (10%).

In summing up the results, Dr. Chan said that “it will be important to confirm the activity of cabozantinib in a randomized phase III setting.”

“Cabozantinib is a very interesting drug that can offer benefits,” discussant Vincent J. Picozzi, MD, MMM, of the Virginia Mason Hospital and Seattle Medical Center, said. “It is very well tolerated. These results are quite intriguing. But I’m still a little uncertain as to how cabozantinib will broadly impact progression-free and overall survival in [patients with NETs]. As such, I would certainly agree with Dr. Chan that further exploration is needed and will be eagerly awaited.”

—Kara Nyberg, PhD