ABSTRACT
BACKGROUND: Treatment options are scarce in pretreated advanced non-small-cell lung cancer (NSCLC) patients. RAD001, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown phase I efficacy in NSCLC. METHODS: Stage IIIb or IV NSCLC patients, with two or fewer prior chemotherapy regimens, one platinum based (stratum 1) or both chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors (stratum 2), received RAD001 10 mg/day until progression or unacceptable toxicity. Primary objective was overall response rate (ORR). Analyses of markers associated with the mTOR pathway were carried out on archival tumor from a subgroup using immunohistochemistry (IHC) and direct mutation sequencing. RESULTS: Eighty-five patients were enrolled, 42 in stratum 1 and 43 in stratum. ORR was 4.7% (7.1% stratum 1; 2.3% stratum 2). Overall disease control rate was 47.1%. Median progression-free survivals (PFSs) were 2.6 (stratum 1) and 2.7 months (stratum 2). Common > or =grade 3 events were fatigue, dyspnea, stomatitis, anemia, and thrombocytopenia. Pneumonitis, probably or possibly related, mainly grade 1/2, occurred in 25%. Cox regression analysis of IHC scores found that only phospho AKT (pAKT) was a significant independent predictor of worse PFS. CONCLUSIONS: RAD001 10 mg/day was well tolerated, showing modest clinical activity in pretreated NSCLC. Evaluation of RAD001 plus standard therapy for metastatic NSCLC continues.
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , ErbB Receptors/antagonists & inhibitors , Immunosuppressive Agents/therapeutic use , Lung Neoplasms/drug therapy , Sirolimus/analogs & derivatives , Adult , Aged , Anemia/chemically induced , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Disease-Free Survival , Dyspnea/chemically induced , Everolimus , Fatigue/chemically induced , Female , Follow-Up Studies , Humans , Immunohistochemistry , Immunosuppressive Agents/adverse effects , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Middle Aged , Neoplasm Staging , Pneumonia/chemically induced , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Regression Analysis , Sirolimus/adverse effects , Sirolimus/therapeutic use , Stomatitis/chemically induced , Thrombocytopenia/chemically induced , Time Factors , Treatment OutcomeABSTRACT
The thermal structure of the upper atmosphere of Mars has been theoretically investigated. The exospheric temperature, for a pure CO(2) model atmosphere, lies between 400 degrees and 700 degrees K. The origin of the Martian atmosphere is discussed in the light of these results.
