Oral mTOR inhibitor everolimus in patients with gemcitabine-refractory metastatic pancreatic cancer

Abstract

Purpose: The PI3K/Akt/mTOR pathway is activated in the majority of pancreatic cancers, and inhibition of this pathway has antitumor effects in preclinical studies. We performed a multi-institutional, single-arm, phase II study of RAD001(everolimus), an oral inhibitor of mTOR, in patients who experienced treatment failure on first-line therapy with gemcitabine.

Patients and methods: Thirty-three patients with gemcitabine-refractory, metastatic pancreatic cancer were treated continuously with RAD001 at 10 mg daily. Prior treatment with fluorouracil in the perioperative setting was allowed. Patients were observed for toxicity, treatment response, and survival.

Results: Treatment with single-agent RAD001 was well-tolerated; the most common adverse events were mild hyperglycemia and thrombocytopenia. No patients were removed from the study because of drug-related adverse events. No complete or partial treatment responses were noted, and only seven patients (21%) had stable disease at the first restaging scans performed at 2 months. Median progression-free survival and overall survival were 1.8 months and 4.5 months, respectively. One patient (3%) had a biochemical response, defined as > or = 50% reduction in serum CA19-9.

Conclusion: Although well-tolerated, RAD001 administered as a single-agent had minimal clinical activity in patients with gemcitabine-refractory, metastatic pancreatic cancer. Future studies in metastatic pancreatic cancer should assess the combination of mTOR inhibitors with other agents and/or examine inhibitors of other components of the PI3K/Akt/mTOR pathway.

Figures

Fig 1.

Best overall percentage change from baseline in target lesion measurement by Response Evaluation Criteria in Solid Tumors guidelines. Note: Eleven patients had progressive disease as a result of the development of new lesions, rather than growth of the target lesions by ≥ 20%.

Fig 2.

Schematic representation of the PI3K/Akt/mTOR pathway. Binding of insulin or IGF to transmembrane receptors leads to activation mTOR via PI3K and Akt. Activation of mTOR promotes protein synthesis, cell growth, and cytoskeletal modeling, important factors stimulating malignant progression and spread. A possible mechanism of tumor cell resistance to mTOR inhibition in some tumor types may be the abrogation of negative feedback on the PI3K/Akt/mTOR pathway by S6K1, a target protein of mTOR. IGF, insulin-like growth factor; IRS, insulin receptor substrate; PI3K, phosphatidylinositol 3-kinase; Akt, also known as protein kinase B; mTOR, mammalian target of rapamycin; S6K1, ribosomal S6 kinase 1; 4EBP1, eukaryotic translation initiation factor 4E binding protein.