According to a subgroup analysis of the FLEX (First-Line Erbitux in Lung Cancer) study, the development of acne-like rash (main side-effect of cetuximab) during the first cycle of cetuximab in combination with cisplatin and vinorelbine was associated with a better outcome in patients with advanced non small cell lung cancer (NSCLC).  

The Phase III FLEX study compared chemotherapy (cisplatin and vinorelbine) plus cetuximab with chemotherapy alone in patients with advanced EGFR-positive NSCLC.  The results of this study have been previously published (see link below for related NeLM report) – briefly, 1,125 chemotherapy-naive patients ( ≥ 18 years) with stage IIIB or stage IV NSCLC were randomised to treatment with chemotherapy (n=568) or chemotherapy plus cetuximab (n=557). The group assigned to chemotherapy plus cetuximab had a small but statistically significant survival advantage (primary endpoint), with a median survival of 11.3 months vs. 10.1 months, respectively (hazard ratio for death 0.871; 95% CI 0.762 to 0.996, p=0.044).     

The authors note that rash and other cutaneous adverse events have been established as class side-effects associated with EGFR-targeting drugs; previous studies have suggested that rash may be associated with efficacy.  The current analysis looked at whether the development of an acne-like rash of any grade that arose on days 1–21 of the first cycle (defined as first-cycle rash) was associated with clinical outcome in the FLEX intention-to-treat population alive on day 21 (518 patients in the chemotherapy plus cetuximab group and 540 patients in the chemotherapy alone group). 

The main findings reported were as follows:

• A total of 290 patients in the cetuximab group had a first-cycle rash – this was associated with a prolonged overall survival (median 15.0 months versus 8.8 months in those without first-cycle rash; HR 0.631; 95% CI 0.515-0.774; p<0.0001).  This benefit was seen in patients with adenocarcinoma, squamous-cell carcinoma, and carcinomas of other histology.

• Overall survival for patients without first-cycle rash was similar to that of patients receiving chemotherapy alone (median 8.8 months vs. 10.3 months; HR 1.085 [0.910-1.293]; p=0.36).

• First-cycle rash was also associated with improved progression-free survival (median 5.4 months vs. 4.3 months; HR 0.741 [0.607—0.905]; p=0.0031) and improved rate of response (44.8% vs. 32.0%; odds ratio 1.703 [1.186-2.448]; p=0.0039).

Based on their findings, the authors suggest that first-cycle rash could be used as a surrogate clinical marker to identify patients who will derive a substantial overall survival benefit from the addition of cetuximab to standard platinum-based first-line chemotherapy.  Further prospective studies will be required to verify this finding and assess it fully in the context of possible clinical application.