A Phase I Trial of Temsirolimus and Pemetrexed in Patients with Advanced Non-Small Cell Lung Cancer

Abstract

Background: Pemetrexed is an antifolate chemotherapeutic agent approved for use in non-small cell lung cancer (NSCLC). The mammalian target of rapamycin (mTOR) pathway is implicated in lung cancer development and inhibited by temsirolimus. Methods: We performed a phase I study evaluating the combination of pemetrexed and temsirolimus in advanced non-squamous NSCLC. Results: Eight patients were enrolled in this study. The dose-limiting toxicities included grade 4 thrombocytopenia, grade 3 leukopenia and grade 3 neutropenia. The maximum tolerated dose was determined to be pemetrexed 375 mg/m² intravenously on day 1 and temsirolimus 25 mg intravenously on days 1, 8 and 15. No objective responses were noted and 3 patients had stable disease as the best response. Conclusion: The combination of pemetrexed and temsirolimus is feasible and well tolerated. This combination may be further evaluated in patients with mTOR pathway activation, particularly in those with TSC1 or STK11 mutations.

A phase I/II study of pemetrexed with sirolimus in advanced, previously treated non-small cell lung cancer

“…To determine if concurrent administration of sirolimus can influence pemetrexed-induced activation of TS at the MTD, western blotting with protein derived from PBMC was performed in a total of 18 patients who were treated at the MTD. In contrast to our in vitro and in vivo mouse study, where sirolimus blocked activation of TS in cells/tumor tissue (14), TS activation was only temporarily affected by concurrent treatment of sirolimus ( Figure 2).…”

“…Although these observations still need to be validated, inhibition of TS activation is a mechanism that may support the observation of activity with the combination in this phase I/II study. The combination of pemetrexed and sirolimus in this study was relatively well tolerated, and appeared to have no new safety concern when compared with other combinations of pemetrexed with an mTOR inhibitor except as described below (13,14). Although grade 3 and higher neutropenia frequently occurred in other studies using pemetrexed and mTOR inhibitors (37-60%) (13,14), it was observed in 14% of participants in this study.…”

“…The combination of pemetrexed and sirolimus in this study was relatively well tolerated, and appeared to have no new safety concern when compared with other combinations of pemetrexed with an mTOR inhibitor except as described below (13,14). Although grade 3 and higher neutropenia frequently occurred in other studies using pemetrexed and mTOR inhibitors (37-60%) (13,14), it was observed in 14% of participants in this study. Other hematological and nonhematological grade 3-4 events such as dyspnea (5%) were also less frequently or similarly seen in this study.…”

“…The best overall response for intent-to-treat patients at pemetrexed 500 mg/m 2 /sirolimus 10 mg load/3 mg/day was 22% which appears to be higher than historical data from single-agent pemetrexed studies in unselected patients in the literature (4). Other regimens using pemetrexed with mTOR inhibitors yielded relatively low response rates of 0-11% (13,14). The response rate was higher in patients with EGFR mutation.…”

“…The combination of mTOR inhibitors with pemetrexed has previously been evaluated in small phase I trials and found to be safe and tolerable (13,14). To our knowledge this is the largest trial for the phase II portion reported to date to determine the safety and clinical activity of pemetrexed in combination with an mTOR inhibitor in previously treated NSCLC (13,14).…”