Combining everolimus with chemotherapy in the treatment of SCLC

This study examined the optimal dose of everolimus (Afinitor) when combined with etoposide and cisplatin, chemotherapy agents used in the treatment of small-cell lung cancer.

Chemotherapy is the main course of therapy used for the treatment of small-cell lung cancer. The most common chemotherapy agents used are etoposide and cisplatin, however the combination of which leads to an average 2-year survival rate of under 10%. Regrettably, no other chemotherapy agents have been found that can increase survival without causing a significant amount of toxicity, or adverse effects.

Roughly half of small-cell tumors express a protein known as mammalian target of rapamycin, or mTOR. Everolimus (Afinitor) is a drug that inhibits mTOR, and has been shown to suppress tumor growth. The combination of chemotherapy Everolimus may hold the key to extending survival among small-cell cancer patients. However, the safety of this combination has not yet been examined. The current study investigated different dosages of everolimus when combined with etoposide and cisplatin to determine the safest and most effective therapeutic combination.

In this study, 40 patients were treated with up to 6 cycles of etoposide and cisplatin, and either daily or weekly doses of everolimus. Dose-limiting toxicities, or the incidence of significant adverse effects which prevented further treatment at the same dosage, were measured. Ten patients received either 2.5 mg or 5 mg of everolimus daily, 18 patients received 20 or 30 mg weekly, and the remaining 12 patients received 2.5 mg or 5 mg daily, as well as granulocyte colony-stimulating factor, or G-CSF, a drug which increases white blood cells, which help the body fight infections.

50% of patients receiving 2.5 or 5 mg of everolimus daily without G-CSF experienced a dose-limiting toxicity on the first chemotherapy cycle, and 70% experienced one within the study period. Of the patients receiving 20 or 30 mg weekly, 22.2% experienced a dose-limiting toxicity on the first cycle, and 39% during the entire study. Of the patients receiving 2.5 or 5 mg daily along with G-CSF, a cycle 1 dose-limiting toxicity occurred in 16.7%, and in 25% of patients overall. A partial response, indicating tumor shrinkage, was seen in each treatment group, ranging from 40% to 61% of patients not receiving G-CSF, and 58.3% of patients for those also receiving G-CSF.

Toxicities for each treatment group included febrile neutropenia, when a patient has both a fever and a reduction in their white blood cell count (neutropenia), leaving them open to infection. Neutropenia was noted in 96% of patients that did not receive G-CSF, versus 58% of patients that did receive G-CSF.

This study concluded that when combined with chemotherapy, the safest dose of everolimus is 2.5 mg per day, with the addition of G-CSF. This combination of treatments was effective and led to the least amount of toxicities.

This study was funded by Novartis, the manufacturer of everolimus.