Phase II Study of Everolimus (RAD001) in Previously Treated Small Cell Lung Cancer

Abstract

Purpose: Mammalian target of rapamycin (mTOR) is a promising target in small cell lung cancer (SCLC). We designed a phase II study of everolimus, an mTOR inhibitor, in previously treated, relapsed SCLC. Experimental Design: Patients were treated with everolimus 10 mg orally daily until disease progression. The primary endpoint was disease control rate (DCR) at 6 weeks. PI3K/Akt signaling pathway biomarkers were evaluated on baseline tumor tissue. Results: A total of 40 patients were treated: 23 had 1 prior regimen/sensitive relapse, 4 had 1 prior regimen/refractory, and 13 had 2 prior regimens. Twenty-eight patients received 2 or more cycles of everolimus, 7 received 1 cycle, and 5 did not complete the first cycle. Best response in 35 evaluable patients: 1 (3%) partial response (in sensitive relapse), 8 (23%) stable disease, and 26 (74%) progression; DCR at 6 weeks was 26% (95% CI = 11–40). Median survival was 6.7 months and median time to progression was 1.3 months. Grade 3 toxicities included thrombocytopenia (n = 2), neutropenia (n = 2), infection (n = 2), pneumonitis (n = 1), fatigue (n = 1), elevated transaminases (n = 1), diarrhea (n = 2), and acute renal failure (n = 1). High phosphorylated AKT expression was modestly associated with overall survival (HR = 2.07; 95% CI = 0.97–4.43). Baseline S6 kinase protein expression was significantly higher in patients with disease control versus patients with progression (P = 0.0093). Conclusions: Everolimus was well tolerated but had limited single-agent antitumor activity in unselected previously treated patients with relapsed SCLC. Further evaluation in combination regimens for patients with sensitive relapse may be considered. Clin Cancer Res; 16(23); 5900–7. ©2010 AACR.

Pulmonary complications with the use of mTOR inhibitors in targeted cancer therapy: A systematic review and meta-analysis.

“…Twenty trials reported pneumonitis events, eight trials reported cough, and twelve trials reported dyspnea. Sixteen trials (seven temsirolimus, eight everolimus, and one ridaforolimus) were single arm studies or randomized patients to different doses/schedules of an mTOR inhibitor (Table 2) [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]. Six trials (one temsirolimus, four everolimus, and one ridaforolimus) randomized patients to an mTOR inhibitor arm or a non-mTOR inhibitor control arm (Table 3) [22-27].…”

Origins, genetic landscape, and emerging therapies of small cell lung cancer

“…The inhibition of individual components of the pathway leads to a potent induction of apoptosis and reversion of chemoresistance in preclinical studies (Razzini et al 2000;Wu et al 2005). In clinical trials, however, single agent administration of mTOR inhibitors exerted only limited antitumor activity (Tarhini et al 2010). Combination therapies using more potent dual PI3K/mTOR inhibitors that circumvent the reactivation of the PI3K pathway through a negative feedback loop may possibly be more effective (Sun et al 2005).…”

Expression and Clinical Significance of mTOR in Surgically Resected Non-small Cell Lung Cancer Tissues: a Case Control Study

“…Thus, the Akt/mTOR signaling pathway became an especially promising target for cancer therapy (Yuan et al, 2009). The mTOR inhibitor rapamycin and its analogues, such as temsirolimus (CCI-779), everolimus (RAD001), and ridaforolimus (AP23573), have been tested extensively in clinical trials for the past few years and have shown preliminary promise of efficacy in several tumor types, including NSCLC (Price et al, 2010;Tarhini et al, 2010;Witzig et al, 2011). However, the single-agent use of mTOR inhibitors for cancer therapy did not meet expectations (Dowling et al, 2009), while combination of an mTOR inhibitor with other anticancer agents was shown a better therapeutic efficacy in several clinical trials.…”