Correspondence

Du Cane Medical Imaging Ltd/Science Photo Library

A STEPP too far for FLEX?

In their post-hoc biomarker analysis of the FLEX phase 3 trial, Pirker and colleagues1 reported a putative predictive value for EGFR immunostaining expression, using a semi-quantitative H-score. Previous ndings of the FLEX study2 have raised some unanswered questions, with an absolute gain in overall survival for patients receiving cetuximab of 12 months of uncertain clinical importance. In their new study,1 Pirker and colleagues used a cutpoint that was not prespecied to dichotomise the study population into subsets of patients with high (31%) or low (69%) EGFR tumour expression. This cutpoint was derived from the subpopulation treatment eect pattern plot (STEPP) graphical method3 to assess interactions between treatment and covariates, with a modied sliding windows version, the stability of which has been questioned.4 In Pirkers STEPP analysis, response to treatment was used as the outcome, and, subsequently, the new cutpoint was used to predict overall survival. We wonder why Pirker and colleagues did not use overall survival directly in their STEPP quest for a valid cutpoint? Moreover, an interaction test could be derived directly from the STEPP exploratory method; so why was such a test not reported? Pirker and colleagues now note a substantial benet in overall survival of 24 months for patients with a high EGFR tumour content (according to this new cutpoint) who received the combination of chemotherapy plus cetuximab. However, the interaction tests reported only came from univariate analysis (p=0044) and should have been adjusted at least for histology, since squamous-cell carcinomas were more frequent in the high than in the low expression group. Adjusted hazard ratios have been calculated in every EGFR group (high vs low) but an interaction test comparing those adjusted hazard ratios has not been provided.
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According to Bonetti and coworkers,3 STEPP is not meant to determine specic cutpoints in the range of values of the covariate of interest and investigation using other data sets [should] be performed to further study the behaviour of treatment eects. Since no stability study for the selected cutpoint is provided, such as bootstrapping with a c-index value determination, and because no external validation was done,5 we believe Pirkers study1 can only be regarded as hypothesis generating. A prospective study should be undertaken to assess whether this new cutpoint for EGFR staining would be useful to select patients for anti-EGFR monoclonal antibody treatment.
GZ has received reimbursement from Merck for travel, accommodation, and meeting expenses. EB and CC have no conicts of interest to declare.

Emmanuel Bergot, Christian Creveuil, *Grard Zalcman

zalcman-g@chu-caen.fr
Caen University Hospital, Pneumology Department, and UMR INSERM 1086, Caen 14033, France 1 Pirker R, Pereira JR, von Pawel J, et al. EGFR expression as a predictor of survival for rst-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol 2012; 13: 3342. Pirker R, Pereira JR, Szczesna A, et al, on behalf of the FLEX Study Team. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet 2009; 373: 152531. Bonetti M, Gerber GD. A graphical method to assess treatment-covariate interactions using the Cox model on subsets of the data. Stat Med 2000; 19: 2595609. Sauerbrei W, Royston P, Zapien K. Detecting an interaction between treatment and a continuous covariate: a comparison of two approaches Comp. Statist Data Anal 2007; 51: 405463. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM. Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst 2005; 97: 118084.

most closely represents the immediate eect of treatment. The choice of cutpoint was then further examined in an analysis of survival, which supported the selected score.1 STEPP analysis was therefore not used in isolation to dene a specic cutpoint associated with cetuximab benet; rather, as suggested by Bonetti and colleagues,2 to provide some indication on ranges of values where the treatment eect might have a particular behavior. Furthermore, although high expression was more common in squamous-cell carcinomas, the dierence in treatment eect between the high and low EGFR expression subgroups occurs in both major histological subtypes, which suggests that it cannot be explained by a dierential response according to histology.1 Our results, which are based on a large randomised study, are consistent with the mode of action of cetuximab and are a clinically relevant step towards improving outcome in patients with advanced non-small-cell lung cancer.
RP received consulting fees or honoraria, support for travel in relation to attending advisory boards and reviews of study results, and fees for participating in reviews of study results from Merck Serono. SSs institution received consulting fees or honoraria from Merck KGaA. AvH and IC are salaried employees of Merck KGaA, and AvH holds shares in the company. KJO received payment from Merck Serono in relation to a protocol writing committee and advisory boards and received travel costs for attendance at such meetings and received honoraria from Merck Serono associated with the presentation of data at satellite and company symposia.

*Robert Pirker, Stephan Strkel, Anja von Heydebreck, Ilhan Celik, Kenneth J OByrne
robert.pirker@meduniwien.ac.at
Department of Medicine I, Medical University Vienna, Vienna, Austria (RP); HELIOS Hospital Wuppertal, University Witten/Herdecke, Wuppertal, Germany (SS); Merck KGaA, Darmstadt, Germany (AvH, IC); St Jamess Hospital, Dublin, Ireland (KJO) 1 Pirker R, Pereira JR, von Pawel J, et al. EGFR expression as a predictor of survival for rst-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol 2012; 13: 3342. Bonetti M, Zahrieh D, Cole BF, Gelber RD. A small sample study of the STEPP approach to assessing treatment-covariate interactions in survival data. Stat Med 2009; 28: 125568.

Authors reply
We appreciate the comments by Emmanuel Bergot and colleagues. The association between EGFR expression and ecacy was rst assessed in terms of response, because this endpoint
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www.thelancet.com/oncology Vol 13 February 2012