Annals of Oncology Advance Access originally published online on June 23, 2009
Annals of Oncology 2009 20(10):1674-1681; doi:10.1093/annonc/mdp060
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lung cancer |
Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors
1 Lung Cancer Unit, Gustave Roussy Institute, Villejuif, France
2 Department of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto, Canada
3 Medical Oncology Branch, Rene Gauducheau Cancer Center, St Herblain, France
4 Department I of Internal Medicine, Center for Integrated Oncology, University Hospital Cologne, Cologne, Germany
5 Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
6 Department of Oncology, Silvestrini Hospital, Perugia
7 Department of Medical Oncology, Humanitas Clinical Institute, Milan, Italy
8 Sections of Phase I and Gastrointestinal Oncology, Nevada Cancer Institute, Las Vegas, USA
9 Oncology Clinical Development, Novartis Oncology, Basel, Switzerland
10 Oncology Biomarkers and Imaging, Novartis Institutes for BioMedical Research, Cambridge
11 Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, USA
* Correspondence to: Dr V. Papadimitrakopoulou, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 432, Houston, TX 77030, USA. Tel: +1-713-7926363; Fax: +1-713-7921220; E-mail: vpapadim{at}mdanderson.org
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 
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.
Key words: everolimus, mTOR, non-small-cell lung cancer, NSCLC, RAD001
Received for publication October 21, 2008. Revision received February 11, 2009. Accepted for publication February 16, 2009.