Cabozantinib and temozolomide in patients with advanced progressive neuroendocrine tumors: a phase 2 study

Treatment options for patients with advanced neuroendocrine tumors (NETs) are limited. Preclinical and early clinical evidence suggest that cabozantinib and temozolomide may exert synergistic antitumor activity. We performed an open-label, single-arm, phase 2 study (NCT04893785) to assess 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. The primary endpoint was overall response rate (ORR) by blinded local review. Secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR), duration of response (DOR) and safety. 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 ORR was 15% (95% CI, 5-31%) and did not meet the primary endpoint. However, after a median follow-up of 19.2 months, the CBR was 100% (95% CI, 89.5-100%) and the median PFS was 28.5 months (95% CI, 16.8-28.5 months). The median OS was not reached, with a 3-year OS rate of 68.5% ( ± 9.1%). The median DOR 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 (MGMT) 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. ClinicalTrials.gov identifier: NCT04893785.