Erlotinib in combination with pemetrexed for patients with advanced non-small-cell lung cancer (NSCLC): a phase I dose-finding study.
BACKGROUND
Erlotinib and pemetrexed are approved single agents for second-line treatment of non-small-cell lung cancer (NSCLC) and, in combination, have shown synergistic antitumor activity in NSCLC cell lines. We investigated the safety, pharmacokinetics and preliminary efficacy of combined erlotinib-pemetrexed in patients with refractory advanced NSCLC.


METHODS
A nonrandomized, open-label, phase IB study was performed in patients with advanced NSCLC whose disease had progressed on or following first-line chemotherapy with a platinum-containing regimen or for whom the erlotinib-pemetrexed combination was considered appropriate. Patients received i.v. pemetrexed 500-700 mg/m² every 3 weeks and oral erlotinib 100-150 mg/day.


RESULTS
Twenty patients were recruited. The most common adverse events (AEs) were rash, diarrhea and fatigue. Serious AEs occurred in eight patients (three treatment related) and there were eight deaths (none treatment related). Dose-limiting toxic effects were not experienced up to erlotinib 150 mg/day plus pemetrexed 600 mg/m². Concurrent administration did not affect pharmacokinetic parameters. Two patients achieved partial responses and nine had stable disease.


CONCLUSIONS
Erlotinib-pemetrexed combination is well tolerated at doses equal to the licensed single-agent doses (150 mg/day and 500 mg/m², respectively). The good tolerability profile and promising efficacy indicate that this combination warrants further investigation for patients with advanced NSCLC.
Ranson
M
M
Department of Medical Oncology, University of Manchester, Christie Hospital, Manchester, UK. Electronic address: malcolm.ranson@manchester.ac.uk.
Reck
M
M
Department of Thoracic Oncology, Krankenhaus Grosshansdorf, Grosshansdorf, Germany.
Anthoney
A
A
Department of Medical Oncology, Leeds Institute of Molecular Medicine and St James' University Hospital, Leeds, UK.
Hanauske
A-R
AR
Medical Department, St Georg Hospital, Hamburg, Germany.
Dean
E
E
Department of Medical Oncology, University of Manchester, Christie Hospital, Manchester, UK.
Melezinek
I
I
Department of Science, Roche Products Ltd, Welwyn Garden City, UK.
Klingelschmitt
G
G
Department of Statistics.
Kletzl
H
H
Department of Clinical Pharmacology, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Blatter
J
J
Department of Medical Department, Eli Lilly & Co., Indianapolis, IN, USA.
Twelves
C
C
Department of Medical Oncology, Leeds Institute of Molecular Medicine and St James' University Hospital, Leeds, UK.
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018287:Carcinoma, Large Cell / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D018450:Disease Progression; D066246:ErbB Receptors / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005260:Female; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D000068437:Pemetrexed; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000008:administration & dosage; D015996:Survival Rate; D013997:Time Factors; D014018:Tissue Distribution; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics
D005971:Glutamates; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D000068437:Pemetrexed; D006147:Guanine; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins