Everolimus in Combination with Pemetrexed in Patients with Advanced Non-small Cell Lung Cancer Previously Treated with Chemotherapy: A Phase I Study Using a Novel, Adaptive Bayesian Dose-Escalation Model

Vansteenkiste, Johan; Solomon, Benjamin; Boyer, Michael; Wolf, Juergen; Miller, Neil; Scala, Lilla Di; Pylvaenaeinen, Ilona; Petrović, Katarina; Dimitrijević, Saša; Anrys, Beatrijs; Laack, Eckart

doi:10.1097/jto.0b013e3182307ede

Cited by 31 publications

(21 citation statements)

References 25 publications

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“…Early clinical trials combining mTOR inhibitors with pemetrexed have been completed. A phase I study of RAD001 given simultaneously with pemetrexed in previously treated NSCLC patients has been reported, and the regimen was well tolerated with a 42% disease control rate (partial response (PR) and stable disease) [23]. These results are similar to what might be expected for pemetrexed alone, but biomarkers and TS levels were not analyzed in this study.…”

Section: Discussionmentioning

confidence: 58%

Rapamycin downregulates thymidylate synthase and potentiates the activity of pemetrexed in non-small cell lung cancer

et al. 2014

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Non-small cell lung cancer (NSCLC) accounts for 80–85% of lung cancer cases, and almost half of newly diagnosed patients have metastatic disease. Pemetrexed is a widely used drug for NSCLC and inhibits several folate-dependent enzymes including thymidylate synthase (TS). Increased expression of TS confers resistance to pemetrexed in vitro and predicts poor response to pemetrexed. Rapamycin is an mTOR inhibitor and suppresses cap-dependent synthesis of specific mRNA species. Here, we show that the combination of rapamycin and pemetrexed synergistically inhibits proliferation of NSCLC cells. Although pemetrexed as a single agent induced TS, pretreatment with rapamycin suppressed pemetrexed-induced TS expression. In vivo, the combination of rapamycin and pemetrexed inhibited growth of NSCLC xenografts, which correlated with decreased mTOR activity and suppression of pemetrexed-induced TS expression. The ability of rapamycin to enhance the efficacy of pemetrexed and prevent TS expression has implications for the design of Phase I and/or Phase II NSCLC clinical trials with mTOR inhibitors in combination with pemetrexed.

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Section: Discussionmentioning

confidence: 58%

Rapamycin downregulates thymidylate synthase and potentiates the activity of pemetrexed in non-small cell lung cancer

et al. 2014

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“…Clinically, everolimus, a mTOR inhibitor, has been widely prescribed for advanced renal carcinoma and breast carcinoma 20, 21. A moderate efficacy of everolimus was demonstrated for NSCLC in previous studies 22, 23. A combined use of EGFR‐TKIs and everolimus was found to be more effective than everolimus alone in one study 22.…”

Section: Discussionmentioning

confidence: 96%

Mutation and prognostic analyses of PIK3CA in patients with completely resected lung adenocarcinoma

Song

Zhang

2016

Cancer Medicine

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PIK3CA mutation represents a clinical subset of diverse carcinomas. We explored the status of PIK3CA mutation and evaluated its genetic variability, treatment, and prognosis in patients with lung adenocarcinoma. A total of 810 patients with completely resected lung adenocarcinoma were recruited between 2008 and 2013. The status of PIK3CA mutation and other three genes, that is, EGFR mutation, KRAS mutation and ALK fusion were examined by reverse transcription‐polymerase chain reaction (RT‐PCR). Survival curves were plotted with the Kaplan–Meier method and log‐rank for comparison. Cox proportional hazard model was performed for multivariate analysis. Among the 810 patients, 23 cases of PIK3CA mutation were identified with a frequency of 2.8%. There were 14 men and 9 women with a median age of 61 years. Seventeen tumors revealed concurrent gene abnormalities of EGFR mutation (n = 12), KRAS mutation (n = 3), and ALK fusion (n = 2). Seven patients with EGFR & PIK3CA mutations recurred and administrated of EGFR‐TKIs yielded a median progression free‐survival of 6.0 months. Among four eviromous‐treated patients, stable disease was observed in three patients with a median Progression‐free survival (PFS) of 3.5 months. Patients with and without PIK3CA mutation had different overall survivals (32.2 vs. 49.6 months, P = 0.003). Multivariate analysis revealed that PIK3CA mutation was an independent predictor of poor overall survival (HR = 2.37, P = 0.017). The frequency of PIK3CA mutation was around 2.8% in the Chinese patients of lung adenocarcinoma. PIK3CA mutation was associated with reduced PFS of EGFR‐TKIs treatment and shorter overall survival.

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“…A Phase II study combining everolimus with docetaxel as second- or third-line therapy for advanced NSCLC only showed par tial response in two patients (7%) [40]. Combination of everolimus with pemetrexed in patients with stage IIIB/IV NSCLC showed partial response in five out of 24 patients in a Phase I study [41]. …”

Section: Drugs Targeting the Pi3k/akt/mtor Pathway In Nsclcmentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR pathway: potential for lung cancer treatment

Cheng

Shcherba

Pendurti

et al. 2014

Lung Cancer Manage.

118

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SUMMARY The PI3K/AKT/mTOR pathway is commonly activated in non-small-cell lung cancer. It plays important roles in promoting oncogenesis in lung cancer and mediating resistance to EGF receptor tyrosine kinase inhibitors. Targeted agents against the components of this pathway are currently in development and their clinical benefits remain to be defined. This review provides an overview of the pathway dysregulation and novel agents targeting the pathway in lung cancer. In addition, potential predictive biomarkers guiding patient selection for targeted PI3K/AKT/mTOR inhibition is also discussed.

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Everolimus in Combination with Pemetrexed in Patients with Advanced Non-small Cell Lung Cancer Previously Treated with Chemotherapy: A Phase I Study Using a Novel, Adaptive Bayesian Dose-Escalation Model

Abstract: Everolimus 5 mg/d or 50 mg/wk with the standard regimen of pemetrexed are feasible dosages in patients with stage IIIb/IV NSCLC.

Cited by 31 publications

References 25 publications

Rapamycin downregulates thymidylate synthase and potentiates the activity of pemetrexed in non-small cell lung cancer

Rapamycin downregulates thymidylate synthase and potentiates the activity of pemetrexed in non-small cell lung cancer

Mutation and prognostic analyses of PIK3CA in patients with completely resected lung adenocarcinoma

Targeting the PI3K/AKT/mTOR pathway: potential for lung cancer treatment

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