ArticlesIntercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial
Introduction
Non-small-cell lung cancer, a leading cause of cancer death, is often diagnosed at advanced stages when treatment options are few.1 Advances in genetic testing allowed the discovery and clinical application of driver oncogenes, such as activating EGFR mutations, as a therapeutic target.2, 3 The results of several randomised studies have established EGFR-tyrosine-kinase inhibitors, specifically erlotinib and gefitinib, as standard first-line treatment for patients with activating EGFR mutations.4, 5, 6, 7, 8, 9 However, the practice of personalised medicine requires high-quality tumour samples for analysis and efficient testing facilities, which mean patients might still have unknown EGFR mutation status at the time when decisions are made about their first-line treatments.10, 11
One option is to treat patients with unknown EGFR mutations with a combination of chemotherapy and an EGFR-tyrosine-kinase inhibitor. Early concurrent combination studies were designed before the discovery of EGFR mutations, and the results of these studies in unselected populations showed that combination treatment compared with chemotherapy alone did not improve survival.12, 13, 14 An explanation for this lack of efficacy is that G1 cell-cycle arrest caused by EGFR-tyrosine-kinase inhibitors might reduce the cell-cycle phase-dependent activity of chemotherapy.15 By contrast, preclinical data showed that sequential administration of tyrosine-kinase inhibitors after chemotherapy might be effective.16, 17 To investigate this view, our group completed a randomised phase 2 study (FASTACT, First-line Asian Sequential Tarceva And Chemotherapy Trial) and noted significant improvement in progression-free survival (PFS; hazard ratio [HR] 0·47, 95% CI 0·33–0·68; p=0·0002).18 Few tumour samples were available for biomarker analysis, thus to what extent activating EGFR mutations affected the benefit from this regimen could not be determined.
FASTACT-2 was a phase 3 trial to confirm the phase 2 findings. The primary objective was to compare PFS of the intercalated combination regimen with standard chemotherapy. Biomarker analysis was also undertaken, but these data will be published separately.
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Study design and population
FASTACT-2 was a multicentre, randomised, placebo-controlled, double-blind, phase study of intercalated erlotinib or placebo with gemcitabine and carboplatin or cisplatin followed by maintained erlotinib or placebo in patients with stage IIIB/IV non-small-cell lung cancer. The study was undertaken in 28 centres in China (nine), Hong Kong (four), Indonesia (three), South Korea (one), the Philippines (three), Taiwan (four), and Thailand (four).
Patients aged 18 years and older, with stage IIIB/IV
Results
Between April 29, 2009, and Sept 9, 2010, 451 patients were randomly assigned to receive chemotherapy plus erlotinib (n=226) or chemotherapy plus placebo (n=225). 222 patients in the chemotherapy plus erlotinib group and 221 in the chemotherapy plus placebo group received at least one cycle of intercalated combination treatment. At completion of the combined treatment, 82 and 101 patients had withdrawn from the chemotherapy plus erlotinib and chemotherapy plus placebo groups, respectively, due
Discussion
To the best of our knowledge, this is the first randomised phase 3 trial to show an improvement in efficacy outcomes with an intercalated regimen of chemotherapy and an EGFR inhibitor for patients with advanced non-small-cell lung cancer. The magnitude of PFS improvement was similar to that in the phase 2 FASTACT study.18
Several other studies have assessed the use of intercalated regimens in patients with non-small-cell lung cancer. In a randomised phase 2 study, comparison of intercalated
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