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

Takefumi Komiya1, Regan M Memmott1, Gideon M Blumenthal1

  • 1Medical Oncology Service, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.

Translational Lung Cancer Research
|August 2, 2019
PubMed
Abstract

Insights

Adding sirolimus to pemetrexed shows activity in patients with non-small cell lung cancer (NSCLC). This combination therapy demonstrated a partial response rate of 22.2% in a phase I/II clinical trial.

Area of Science:

  • Oncology
  • Pharmacology
  • Clinical Trials

Background:

  • Single-agent pemetrexed offers limited benefit for recurrent non-squamous non-small cell lung cancer (NSCLC).
  • Preclinical data suggested synergistic effects between pemetrexed and the mTOR inhibitor sirolimus.

Purpose of the Study:

  • To determine the maximum tolerated dose (MTD) and safety of the pemetrexed-sirolimus combination in NSCLC patients.
  • To evaluate the overall response rate (ORR) of the combination therapy at the MTD.

Main Methods:

  • A single-institution phase I/II clinical study was conducted.
  • Patients received oral sirolimus daily and intravenous pemetrexed every 21 days.
  • Eligibility criteria included recurrent, metastatic NSCLC and adequate organ function.

Main Results:

  • The MTD was established as pemetrexed 500 mg/m² every 3 weeks with sirolimus 10 mg loading dose followed by 3 mg daily.
  • Grade 3-4 adverse events included lymphopenia (31%) and hypophosphatemia (19%).
  • Among 27 patients at MTD, 22.2% had partial response, 44.4% stable disease, and median progression-free survival was 18.4 weeks.

Conclusions:

  • The combination of pemetrexed and sirolimus demonstrates activity in heavily pretreated NSCLC.
  • This regimen warrants further investigation in non-squamous NSCLC treatment.
Keywords:
Lung cancerpemetrexedphase I/II, sirolimusthymidylate synthase (TS)

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