First-cycle rash and survival in patients with advanced non-small-cell lung cancer receiving cetuximab in combination with first-line chemotherapy: a subgroup analysis of data from the FLEX phase 3 study.

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.