Elsevier

The Lancet Oncology

Volume 14, Issue 8, July 2013, Pages 777-786
The Lancet Oncology

Articles
Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial

https://doi.org/10.1016/S1470-2045(13)70254-7Get rights and content

Summary

Background

The results of FASTACT, a randomised, placebo-controlled, phase 2 study, showed that intercalated chemotherapy and erlotinib significantly prolonged progression-free survival (PFS) in patients with advanced non-small-cell lung cancer. We undertook FASTACT-2, a phase 3 study in a similar patient population.

Methods

In this phase 3 trial, patients with untreated stage IIIB/IV non-small-cell lung cancer were randomly assigned in a 1:1 ratio by use of an interactive internet response system with minimisation algorithm (stratified by disease stage, tumour histology, smoking status, and chemotherapy regimen) to receive six cycles of gemcitabine (1250 mg/m2 on days 1 and 8, intravenously) plus platinum (carboplatin 5 × area under the curve or cisplatin 75 mg/m2 on day 1, intravenously) with intercalated erlotinib (150 mg/day on days 15–28, orally; chemotherapy plus erlotinib) or placebo orally (chemotherapy plus placebo) every 4 weeks. With the exception of an independent group responsible for monitoring data and safety monitoring board, everyone outside the interactive internet response system company was masked to treatment allocation. Patients continued to receive erlotinib or placebo until progression or unacceptable toxicity or death, and all patients in the placebo group were offered second-line erlotinib at the time of progression. The primary endpoint was PFS in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00883779.

Findings

From April 29, 2009, to Sept 9, 2010, 451 patients were randomly assigned to chemotherapy plus erlotinib (n=226) or chemotherapy plus placebo (n=225). PFS was significantly prolonged with chemotherapy plus erlotinib versus chemotherapy plus placebo (median PFS 7·6 months [95% CI 7·2–8·3], vs 6·0 months [5·6–7·1], hazard ratio [HR] 0·57 [0·47–0·69]; p<0·0001). Median overall survival for patients in the chemotherapy plus erlotinib and chemotherapy plus placebo groups was 18·3 months (16·3–20·8) and 15·2 months (12·7–17·5), respectively (HR 0·79 [0·64–0·99]; p=0·0420). Treatment benefit was noted only in patients with an activating EGFR gene mutation (median PFS 16·8 months [12·9–20·4] vs 6·9 months [5·3–7·6], HR 0·25 [0·16–0·39]; p<0·0001; median overall survival 31·4 months [22·2–undefined], vs 20·6 months [14·2–26·9], HR 0·48 [0·27–0·84]; p=0·0092). Serious adverse events were reported by 76 (34%) of 222 patients in the chemotherapy plus placebo group and 69 (31%) of 226 in the chemotherapy plus erlotinib group. The most common grade 3 or greater adverse events were neutropenia (65 [29%] patients and 55 [25%], respectively), thrombocytopenia (32 [14%] and 31 [14%], respectively), and anaemia (26 [12%] and 21 [9%], respectively).

Interpretation

Intercalated chemotherapy and erlotinib is a viable first-line option for patients with non-small-cell lung cancer with EGFR mutation-positive disease or selected patients with unknown EGFR mutation status.

Funding

F Hoffmann-La Roche.

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.

Section snippets

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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