Dr Ulrich Gatzemeier MD a , Joachim von Pawel MD b, Ihor Vynnychenko MD c, Prof Petr Zatloukal MD d e, Filippo de Marinis MD f, Wilfried EE Eberhardt MD g, Luis Paz-Ares MD h i, Karl-Maria Schumacher MD j, Thomas Goddemeier Dipl Stat j, Prof Kenneth J O'Byrne MD k, Prof Robert Pirker MD l. The Lancet Oncology, Volume 12, Issue 1, Pages 30 - 37, January 2011. Published Online: 20 December 2010
Background
The randomised phase 3 First-Line Erbitux in Lung Cancer (FLEX) study showed that the addition of cetuximab to cisplatin and vinorelbine significantly improved overall survival compared with chemotherapy alone in the first-line treatment of advanced non-small-cell lung cancer (NSCLC). The main cetuximab-related side-effect was acne-like rash. Here, we assessed the association of this acne-like rash with clinical benefit.
Methods
We did a subgroup analysis of patients in the FLEX study, which enrolled patients with advanced NSCLC whose tumours expressed epidermal growth factor receptor. Our landmark analysis assessed if the development of acne-like rash in the first 21 days of treatment (first-cycle rash) was associated with clinical outcome, on the basis of patients in the intention-to-treat population alive on day 21. The FLEX study is registered with ClinicalTrials.gov, number NCT00148798.
Findings
518 patients in the chemotherapy plus cetuximab group—290 of whom had first-cycle rash—and 540 patients in the chemotherapy alone group were alive on day 21. Patients in the chemotherapy plus cetuximab group with first-cycle rash had significantly prolonged overall survival compared with patients in the same treatment group without first-cycle rash (median 15·0 months [95% CI 12·8—16·4] vs 8·8 months [7·6—11·1]; hazard ratio [HR] 0·631 [0·515—0·774]; p<0·0001). Corresponding significant associations were also noted for progression-free survival (median 5·4 months [5·2—5·7] vs 4·3 months [4·1—5·3]; HR 0·741 [0·607—0·905]; p=0·0031) and response (rate 44·8% [39·0—50·8] vs 32·0% [26·0—38·5]; odds ratio 1·703 [1·186—2·448]; p=0·0039). Overall survival for patients without first-cycle rash was similar to that of patients that received chemotherapy alone (median 8·8 months [7·6—11·1] vs 10·3 months [9·6—11·3]; HR 1·085 [0·910—1·293]; p=0·36). The significant overall survival benefit for patients with first-cycle rash versus without was seen in all histology subgroups: adenocarcinoma (median 16·9 months, [14·1—20·6] vs 9·3 months [7·7—13·2]; HR 0·614 [0·453—0·832]; p=0·0015), squamous-cell carcinoma (median 13·2 months [10·6—16·0] vs 8·1 months [6·7—12·6]; HR 0·659 [0·472—0·921]; p=0·014), and carcinomas of other histology (median 12·6 months [9·2—16·4] vs 6·9 months [5·2—11·0]; HR 0·616 [0·392—0·966]; p=0·033).
Interpretation
First-cycle rash was associated with a better outcome in patients with advanced NSCLC who received cisplatin and vinorelbine plus cetuximab as a first-line treatment. First-cycle rash might be a surrogate clinical marker that could be used to tailor cetuximab treatment for advanced NSCLC to those patients who would be most likely to derive a significant benefit.
Funding
Merck KGaA.
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