Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors
Researchers found only phospho AKT as a significant independent predictor of worse PFS
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. Of 14 NSCLC patients treated with either 30 or 70 mg weekly RAD001 in two phase I studies, disease stabilization and partial response (PR) were observed in four patients and one patient, respectively. The most commonly observed adverse events associated with RAD001 are stomatitis, rash, anemia, fatigue, and anorexia. In addition, pneumonitis is also a known side-effect of mTOR inhibitors. Based on these considerations, the phase II study of RAD001 was conducted by multi-institutional group of researchers led by Dr Vassiliki A Papadimitrakopoulou of the Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, USA. They assessed the efficacy of RAD001 monotherapy in advanced NSCLC patients heavily pretreated with systemic therapy.
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.
Eighty-five patients were enrolled, 42 in stratum 1 and 43 in stratum 2. 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 ≥ 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.
The authors published results in the October issue of Annals of Oncology and concluded that RAD001 administered orally at a continuous daily dose of 10 mg was well tolerated and showed modest clinical activity in heavily pretreated patients with advanced-stage NSCLC. Preclinical evidence suggests additive or synergistic interactions of combinations of EFGR and mTOR inhibitors in NSCLC and sensitization of cells to DNA-damaging agents via mTOR inhibition. Based on the activity seen with monotherapy and preclinical results, further clinical evaluations of RAD001 in combination with erlotinib and chemotherapeutic agents for advanced NSCLC have been initiated.
Δεν υπάρχουν σχόλια:
Δημοσίευση σχολίου