RASH IS A PROGNOSTIC FACTOR FOR NSCLC PATIENTS RECEIVING CETUXIMAB IN FLEX STUDY

December 23, 2010 — Patients with non–small cell lung cancer (NSCLC) who develop a rash after treatment with cetuximab (Erbitux; ImClone) appear to have better outcomes. According to a new study, patients who developed first-cycle rash during first-line treatment with chemotherapy plus cetuximab had improved overall survival compared with those patients who did not develop a rash.

Patients with a rash had a median overall survival of 15.0 months (95% confidence interval [CI], 12.8 - 16.4 months) compared with 8.8 months (95% CI, 7.6 - 11.1 months) for those in the same group who did not have a rash (hazard ratio [HR], 0.631; P < .0001).

The study was published online December 20 in the Lancet Oncology.

Possible Explanations

There are 2 possible explanations for the results seen in this study, commented Francesco Perrone, MD, from the Istituto Nazionale Tumori in Naples, Italy. The most appealing explanation is that patients who develop a rash have a survival advantage that could be attributed to cetuximab use.

However, the only way of verifying this hypothesis is to conduct a randomized trial that compares interruption vs continuation of cetuximab in patients with skin rash after 3 weeks of treatment with cetuximab and chemotherapy, Dr. Perrone writes in a commentary that accompanied the paper.

"This study could be extremely important: if skin rash does predict a large cetuximab effect, we should advise in favor of its use in clinical practice," writes Dr. Perrone. "We should also try to explain the mechanism of the detrimental effect for patients who did not develop the rash."

The second explanation, which may be more probable, is that the rash is simply a prognostic marker, he notes, and serves to identify a subset of patients who survive longer independent of treatment with cetuximab.

"The large survival difference between these two subgroups might be consistent with the prognostic hypothesis, because it is well known that the effect of strong prognostic factors is much larger than that of treatment," Dr. Perrone points out.

In any event, he emphasizes that these data must be validated prospectively before cetuximab can be introduced into clinical practice for the treatment of patients with advanced NSCLC.

Improved Overall and Progression-Free Survival

Ulrich Gatzemeier, MD, from Hospital Grosshansdorf in Heidelberg, Germany, and colleagues, conducted a subanalysis of patients who participated in the First-Line Erbitux in Lung Cancer (FLEX) study, which showed that the addition of cetuximab to platinum-based chemotherapy offered a small survival advantage in patients with advanced NSCLC.

The multicenter FLEX study, which included 1125 patients with epidermal growth factor receptor–expressing advanced NSCLC, demonstrated that cetuximab added to cisplatin and vinorelbine improved overall survival compared with chemotherapy alone (HR, 0.871; 95% CI, 0.762 - 0.996; P = .044).

In this analysis, the authors assessed the association of an acne-like rash — the main adverse effect associated with cetuximab — with clinical benefit in the intention-to-treat population who were alive on day 21.

The analysis included 518 patients who received cisplatin/vinorelbine chemotherapy plus cetuximab and 540 patients in the chemotherapy-alone group. Among those who received cetuximab, 290 developed first-cycle rash (rash that occurred on days 1 - 21 of the first cycle of treatment).

In addition to prolonged survival, patients who developed first-cycle rash also had a significantly prolonged progression-free survival (median, 5.4 months vs 4.3 months; HR, 0.741; P = .0031). Similarly, the response rate was also higher among patients with a first-cycle rash, at 44.8% vs 32.0% (odds ratio, 1.703; P = .0039).

The authors further evaluated the association between first-cycle rash and clinical outcome, according to NSCLC histology. The significant overall survival benefit was observed across all histology subgroups:

* adenocarcinoma: median, 16.9 months vs 9.3 months (HR, 0.614; P = .0015);
* squamous cell carcinoma: median, 13.2 months vs 8.1 months (HR, 0.659; P = .014); and
* carcinomas of other histology: median, 12.6 months vs 6.9 months (HR, 0.616; P = .033).

"Our findings represent the first sign of an association between the early development of acne-like rash and outcome in NSCLC patients treated with a chemotherapy plus cetuximab regimen," write the authors. "Further prospective clinical studies are needed before the usefulness of our findings can be fully assessed outside the investigational setting."

The FLEX study was supported by Merck KGaA. Several of the coauthors disclosed relationships with a number of pharmaceutical companies, as indicated in the paper. Dr. Perrone reports receiving a grant from Merck Italy.

Lancet Oncol. Published online December 20, 2010.