Biomarker analyses from the phase III placebo-controlled SATURN study of maintenance erlotinib following first-line chemotherapy for advanced NSCLC

Abstract

8020 Background: The SATURN (BO18192) study investigated whether erlotinib maintenance therapy improved PFS in patients (pts) with advanced NSCLC who had obtained clinical benefit from 1st-line chemotherapy. This study included a prospective analysis of the prognostic/predictive value of several molecular markers. Methods: 889 pts with advanced NSCLC whose disease had not progressed following 4 cycles of 1st-line platinum-doublet chemotherapy were randomized to erlotinib 150 mg/day or placebo. Mandatory tumor specimens were collected at baseline and tested for EGFR protein expression using immunohistochemistry (IHC), EGFR gene copy number using fluorescent in-situ hybridization (FISH), and EGFR and KRAS somatic mutations using DNA sequencing. Pts were stratified according to EGFR IHC status (any membranous staining in ≥10% tumor cells used as cut-off); the co-primary endpoint was PFS in EGFR IHC+ pts. Baseline whole blood samples were obtained for genotyping of EGFR (intron 1 CA-repeat polymorphisms). Results: In the overall population, erlotinib significantly prolonged PFS vs placebo (HR 0.71, p<.0001; primary endpoint). The co-primary endpoint was also met, with erlotinib significantly improving PFS in the EGFR IHC+ group (HR 0.69, p<.0001). Many tumor samples were assessable for molecular marker status (see table). Biomarker data suggest that patients derived a PFS benefit with erlotinib irrespective of EGFR FISH or EGFR intron 1 CA-repeat status. The magnitude of benefit with erlotinib was similar in both KRAS-mutant and KRAS wild-type pts. Conclusions: This is the largest biomarker analysis performed for erlotinib in a randomized, placebo-controlled setting, and answers key scientific questions regarding the prognostic and predictive value of potential biomarkers of efficacy. Full data will be presented. [Table: see text] [Table: see text]

Erlotinib in Advanced Non-small Cell Lung Cancer: Efficacy and Safety Findings of the Global Phase IV Tarceva Lung Cancer Survival Treatment Study

“…In the recent phase III SATURN study of erlotinib maintenance therapy in patients obtaining clinical benefit from standard first-line chemotherapy, erlotinib significantly prolonged both PFS and OS in patients whose tumors did not harbor EGFR mutations. 19,20 As there was still some uncertainty about the relevance of biomarkers to EGFR TKIs when the TRUST study was designed, biomarker investigations were only conducted as exploratory analyses. Collection of tumor samples in this study was optional, and, as a result, only a small number of TRUST patients provided samples suitable for EGFR mutation analyses (4.4%; Roche, data on file).…”

A multicentre phase II gene expression profiling study of putative relationships between tumour biomarkers and clinical response with erlotinib in non-small-cell lung cancer

“…Post hoc molecular analyses of samples from the BR.21 study found increased EGFR gene copy number to be the only significant molecular predictor of a differential survival benefit from treatment with erlotinib [ 8 ]. Recently, a prospective biomarker analysis carried out for erlotinib as part of the phase III, randomised, placebo-controlled Sequential Tarceva in Unresectable NSCLC (SATURN) study showed that maintenance erlotinib produced a progression-free survival (PFS) benefit in all patients, irrespective of the status of candidate biomarkers investigated; however, those with EGFR mutations had a particularly notable extension of PFS [ 9 ].…”

Biomarkers of clinical benefit for anti-epidermal growth factor receptor agents in patients with non-small-cell lung cancer

“…Patients with EGFR-expressing tumours had significantly higher response rate (RR) in the BR.21 ( P =0.03) and ISEL trials (8.2 vs 1.5% P not reported; Tsao et al , 2005 ; Hirsch et al , 2006 ). In three trials (SATURN, BR.21 and ISEL), patients with tumours showing positive EGFR immunostaining had a significantly reduced risk of death or progression with TKI treatment vs placebo ( Tsao et al , 2005 ; Hirsch et al , 2006 ; Brugger et al , 2009 ) with hazard ratios (HRs) of 0.68–0.77 in favour of EGFR TKI therapy ( Table 1 ). However, it should be noted that in the ISEL trial, the benefit was of borderline significance (treatment by biomarker interaction test P =0.049; Hirsch et al , 2006 ).…”

“…In patients treated with placebo, high EGFR copy was associated with a numerically shorter survival, indicating that copy number might also be prognostic. In the biomarker analysis of the SATURN trial, patients derived a PFS benefit with erlotinib irrespective of EGFR FISH status in their tumours ( Brugger et al , 2009 ). Similarly, in the biomarker analysis of the ATLAS trial, EGFR FISH status had no statistically significant predictive value for PFS, although HRs for PFS were numerically different within patient subsets ( Table 2; Johnson et al , 2009 ).…”