Predictive value of epidermal growth factor receptor expression for first-line chemotherapy plus cetuximab in patients with head and neck and colorectal cancer: Analysis of data from the EXTREME and CRYSTAL studies
Introduction
In randomised phase III studies, the addition of the epidermal growth factor receptor (EGFR) antibody cetuximab to standard first-line chemotherapy regimens has been shown to significantly improve clinical outcome in the treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (recurrent/metastatic SCCHN),1 metastatic colorectal cancer (mCRC),2, 3 and advanced non-small-cell lung cancer (NSCLC).4 While the clinical efficacy of chemotherapy plus cetuximab was initially demonstrated in these trials in patient populations which were unselected according to the molecular characteristics of their tumours, the clinical relevance of predictive biomarkers was highlighted by the finding that the benefit associated with the addition of cetuximab to chemotherapy in mCRC was only apparent in patients with KRAS wild-type tumours.3, 5 Subsequently, the analysis of outcome according to a series of tumour biomarkers in patients receiving chemotherapy with or without cetuximab in the first-line Erbitux in lung cancer (FLEX) study did not identify KRAS mutation status as a predictive biomarker in this setting.6 In addition, KRAS mutations occur infrequently in SCCHN.7, 8 These observations show that particular biomarkers may be informative in one disease but not another, dependent on the characteristic biological features and pathogenesis of each tumour type.
Analysis of prospectively collected immunohistochemistry data from FLEX study patients indicated that the level of membranous expression of EGFR in tumour cells was of predictive value in relation to the survival benefit associated with the addition of cetuximab to chemotherapy.9 A discriminatory immunohistochemistry score of 200 on a scale of 0–300 was identified which allowed the separation of a patient subgroup benefiting from the addition of cetuximab to chemotherapy (high EGFR expression; immunohistochemistry score ⩾200) from one deriving little or no benefit (low EGFR expression; immunohistochemistry score <200). For patients in the high EGFR expression group, overall survival was longer in the chemotherapy plus cetuximab arm compared with the chemotherapy alone arm, with no meaningful increase in side effects. This survival benefit was apparent for patients in both major histological subtypes of NSCLC, squamous cell carcinoma and adenocarcinoma. No corresponding survival benefit was apparent for patients in the low EGFR expression group.
These data raised the question of whether the EGFR expression level might also be of predictive value in the selection of those patients with recurrent/metastatic SCCHN or KRAS wild-type mCRC who would be likely to benefit from the addition of cetuximab to first-line chemotherapy. The availability of tumour tissue for the assessment of EGFR expression was an inclusion criterion in the phase III Cetuximab (Erbitux) in Combination With Cisplatin or Carboplatin and 5-Fluorouracil in the First Line Treatment of Subjects With Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck (EXTREME) study and EGFR expression was evaluated during the course of the trial.1 In the randomised phase III Cetuximab Combined With Irinotecan in First-line Therapy for Metastatic Colorectal Cancer (CRYSTAL) study, EGFR expression was an inclusion criterion and data allowing the calculation of an immunohistochemistry score were prospectively collected as part of the screening process to determine eligibility. The aim of the current analysis was to use calculated immunohistochemistry scores from EXTREME and CRYSTAL study patients to investigate whether tumour EGFR expression level could be used to separate a subpopulation of patients in each setting who derived a clear clinical benefit from the addition of cetuximab to chemotherapy from one deriving essentially no benefit.
Section snippets
Participants
The EXTREME and CRYSTAL study designs, treatments and eligibility criteria have previously been reported in detail.1, 2 Briefly, in the EXTREME study, patients with previously untreated recurrent/metastatic SCCHN were randomised to receive a maximum of six cycles of platinum (cisplatin or carboplatin) and 5-fluorouracil (5-FU) with or without cetuximab. Subsequently, patients in the cetuximab group with at least stable disease received cetuximab monotherapy until disease progression or the
Results
Tumour EGFR immunohistochemistry data were available for 411 of 442 (93%) patients from the EXTREME study intention-to-treat (ITT) population and 664 of 666 (100%) patients from the CRYSTAL study ITT population with KRAS wild-type disease. In both studies, where sample derivation was known, the majority of tissue specimens evaluable for EGFR immunohistochemistry score were from primary tumours (EXTREME: 313 of 370 [85%]; KRAS wild-type population in CRYSTAL: 544 of 629 [86%] patients) rather
Discussion
The current study confirmed that a clinically meaningful survival benefit associated with the addition of cetuximab to standard first-line chemotherapy for the treatment of both recurrent/metastatic SCCHN and KRAS wild-type mCRC was apparent across the full range of tumour EGFR expression levels. These findings differ qualitatively from those in advanced NSCLC, where the analysis of the FLEX study indicated that the survival benefit associated with the addition of cetuximab to platinum-based
Contributions of authors
L.L.: data analysis, data interpretation; S.S.: expression analysis, data interpretation; K.M.K.: data analysis, data interpretation; E.V.C.: design of CRYSTAL study, data analysis, data interpretation, figures, literature search, study design, writing of the report; R.P.: data interpretation, writing of the report; F.R.H.: data interpretation, literature search, writing of the report; J.B.V.: design of EXTREME study, data analysis, data interpretation, study design; A.v.H.: study conception,
Conflict of interest statement
Regarding the work under consideration: L.L., S.S., K.M.K. and R.P. 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 KGaA; E.V.C. has been a consultant for Merck Serono and has received research funding; F.R.H. has a compensated consultancy role with Merck Serono and is the co-inventor on a University of Colorado owned patent: “EGFR gene copy number
Acknowledgements
The sponsor of the CRYSTAL and EXTREME studies was Merck KGaA, Darmstadt, Germany. The authors would like to thank Barbara de Blas and Christopher Stroh of Merck KGaA for data interpretation, and critical review and revision of the report. Jim Heighway of Cancer Communications & Consultancy Ltd. (Knutsford, UK) provided medical writing services, which were funded by the study sponsor. These included drafting and amending an initial outline under the guidance of the authors and subsequently
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