A phase 2 study of an oral mTORC1/mTORC2 kinase inhibitor (CC-223) for non-pancreatic neuroendocrine tumors with or without carcinoid symptoms

Abstract

Second-generation mammalian target of rapamycin (mTOR) inhibitors such as CC-223 may have theoretical advantages over first-generation drugs by inhibiting TOR kinase in mTOR complex 1 (mTORC1) and 2 (mTORC2), potentially improving clinical efficacy for well-differentiated neuroendocrine tumors (NET).Enrolled patients had metastatic, well-differentiated NET of non-pancreatic gastrointestinal or unknown origin, with/without carcinoid symptoms, had failed ≥1 systemic chemotherapy, and were taking a somatostatin analog (SSA). Oral once-daily CC-223 was administered in 28-day cycles starting at 45 mg (n = 24), with a subsequent cohort starting at 30 mg (n = 23). Objectives were to evaluate tolerability, preliminary efficacy, and pharmacokinetic and biomarker profiles of CC-223. Forty-seven patients completed the study, with mean treatment duration of 378 days and mean dose of 26 mg; 26% of patients remained on the starting dose. Most frequent grade ≥3 toxicities were diarrhea (38%), fatigue (21%), and stomatitis (11%). By investigator, 3 of 41 evaluable patients (7%) showed partial response (PR) and 34 (83%) had stable disease (SD) for a disease control rate (DCR) of 90% (95% confidence interval [CI] 76.9–97.3%). Duration of PR was 125–401 days; median SD duration was 297 days (min–max, 50–1519 days). Median progression-free survival was 19.5 months (95% CI 10.4–28.5 months). Carcinoid symptoms of flushing, diarrhea, or both improved in 50%, 41%, and 39% of affected patients, respectively. For the first time, this study describes that a second-generation mTOR pathway inhibitor can result in highly durable tumor regression and control of NET carcinoid symptoms. The manageable safety profile, high DCR, and durable response, coupled with reduction in carcinoid symptoms refractory to SSA, make CC-223 a promising agent for further development.

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

“…Tolerability, preliminary efficacy and pharmacokinetic of CC-223 was evaluated in a daily dose. The results were consistent with those presented in cell lines; anti-tumor activity was assessed, and the data obtained indicated that the drug was safe for patients (221). Additionally, other mTORC1/mTORC2 known as vistusertib was evaluated in a phase II study for patients with relapsed or refractory diffuse large B cell lymphoma, in this specific case, the dual inhibitor vistusertib did not show any advantage over mTORC1 inhibitors in the group of patients evaluated (222).…”

Molecular Pathology of Well-Differentiated Gastro-entero-pancreatic Neuroendocrine Tumors

“…Tumor resistance to everolimus is common and can limit its clinical efficacy. Drugs that target the PI3K/Akt/mTOR pathway studied in clinical phase 2 trials include the AKT inhibitor MK-2206 [183] and the dual PI3K and mTORC1/mTORC2 inhibitor dactolisib (BEZ235) [184,185], although both showed poor activity and tolerability, while the mTORC1/ mTORC2 inhibitor onatasertib (CC-223) demonstrated evidence of disease stability but poor tolerability [186].…”

mTOR Pathway in Gastroenteropancreatic Neuroendocrine Tumor (GEP-NETs)

“…The mTORC1/2 kinase inhibitor named CC-223 was tested in a phase 1/2 study involving metastatic non-pancreatic GI-NETs patients treated with SSA who had failed treatment. The drug showed efficacy in induce tumor regression and carcinoid syndrome symptoms controls and led to an Improvement of median PFS (19.5 months) superior to Everolimus alone (PFS 11.0 months) ( 44 , 67 ). The CC-223 safety profile was found to be comparable to currently approved mTOR inhibitors, and toxicity was well-managed by dose adjustments or treatments ( 67 ).…”