Cabozantinib studies in advanced neuroendocrine tumors show efficacy signal and mixed cost-effectiveness

Cabozantinib in advanced neuroendocrine tumors showed activity in a phase 2 study of cabozantinib plus metronomic temozolomide, while a separate economic analysis found cabozantinib was cost-effective for pancreatic NETs in both China and the U.S. but not in the extrapancreatic NET cohort. Treatment options for patients with advanced neuroendocrine tumors are limited, and cabozantinib has demonstrated a notable benefit in prolonging progression-free survival compared to placebo in patients with advanced neuroendocrine tumors.

An open-label, single-arm, phase 2 study (NCT04893785) assessed the safety and efficacy of cabozantinib and metronomic temozolomide in patients with advanced, progressive, well-differentiated NETs of gastroenteropancreatic, pulmonary or unknown origin. Patients received cabozantinib 40 mg daily and temozolomide 100 mg/m2/day one week on/one week off. Of the 37 patients enrolled, 14 harbored gastrointestinal NETs, 12 pancreatic NETs, 9 lung NETs and 2 NETs of unknown primary. Neoplasms were classified as G1, G2 or G3 in 9, 24 and 4 cases respectively.

While all enrolled patients were assessable for toxicity, 33 met the criteria for per protocol assessment of efficacy. The overall response rate was 15% (95% CI, 5-31%) and did not meet the primary endpoint. However, after a median follow-up of 19.2 months, the clinical benefit rate was 100% (95% CI, 89.5-100%) and the median progression-free survival was 28.5 months (95% CI, 16.8-28.5 months). The median overall survival was not reached, with a 3-year overall survival rate of 68.5% (±9.1%). The median duration of response was 19.5 months.

Lymphopenia (16%), thrombocytopenia (11%), diarrhea (8%) and colitis (8%) emerged as the most frequent grade ≥3 treatment-related adverse events. No treatment-related deaths were recorded. Deficiency of O⁶-methylguanine–DNA methyltransferase and c-MET expression were associated with response. The proportion of the patients benefitting of the treatment and its safety profile justify larger, controlled studies to further investigate the added role of combining cabozantinib with metronomic temozolomide.

A separate study provided a cost-effectiveness assessment of cabozantinib from the perspectives of both the U.S. healthcare payer and the Chinese healthcare system. A Markov state-transition model evaluated quality-adjusted life-years, incremental cost-effectiveness ratio, incremental net health benefit and incremental net monetary benefit, and the impact of crossover in the control group was carefully analyzed.

In the extrapancreatic NET cohort, where 33.00% of patients crossed over, cabozantinib resulted in an incremental cost-effectiveness ratio of $78,705.52 per QALY in China and $412,189.62 per QALY in the U.S., both exceeding the willingness-to-pay thresholds of $40,354.27 per QALY in China and $150,000.00 per QALY in the U.S. In the pancreatic NET cohort, with a 41.00% crossover, cabozantinib demonstrated greater cost-effectiveness. In China, it achieved an ICER of $11,095.91 per QALY, with an incremental net health benefit of 0.06 QALYs, an incremental net monetary benefit of $2,497.95 and a probabilistic sensitivity analysis probability of 52.39%. In the U.S., cabozantinib provided an incremental gain of 0.09 QALYs at an additional cost of $2,334.04, yielding an ICER of $24,571.17 per QALY, with an incremental net health benefit of 0.08 QALYs, an incremental net monetary benefit of $11,914.62 and a probabilistic sensitivity analysis probability of 52.48%.

The economic analysis concluded that cabozantinib is cost-effective for pancreatic NETs in both China and the U.S., but not in the extrapancreatic NET cohort. Due to the high crossover rate, discrepancies may arise when comparing ICER values with other economic evaluation metrics, such as incremental net health benefit, incremental net monetary benefit, one-way sensitivity analysis and probabilistic sensitivity analysis outcomes.