Cetuximab and First-cycle Rash: Correlation with NSCLC Outcomes

Abstract & Commentary

By William B. Ershler, MD

Synopsis: The occurrence of skin rash in patients receiving cetuximab is common, and for patients with colon cancer, this has been associated with better clinical outcomes. In a multicenter, phase III trial (FLEX), cetuximab combined with chemotherapy, compared with chemotherapy alone was associated with better overall survival for patients with EGFR+ NSCLC, although the improvement was small. In the current report, a post-hoc analysis was undertaken to determine if the occurrence of rash conferred similar favorable prognostic information for patients with lung cancer. For those who developed rash during the first cycle, overall and progression-free survival was greater than for those receiving cetuximab/chemotherapy but who did not develop rash, or for those who received chemotherapy without cetuximab. Thus, as for cetuximab treatment for colon cancer, the appearance of rash may confer favorable prognosis for treated patients with lung cancer.

Source: Gatzemeier U, et al. 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. Lancet Oncology. 2011;12:30-37.

Cetuximab, a monoclonal antibody directed at epidermal growth factor receptor (EGFR) has been approved for treatment of colorectal cancer and, more recently, head and neck cancer. The clinical experience in those settings has suggested that patients who develop skin rash seem to have a greater chance of experiencing favorable outcomes.1,2 A randomized, phase III trial was undertaken to establish whether cetuximab (Erbitux®) would be effective as an adjunct to cisplatin/vinorelbine for patients with advanced non-small cell lung cancer whose tumors expressed EGFR. This multicenter trial (First-Line Erbitux in Lung Cancer [FLEX]) enrolled 1,125 patients and demonstrated a modest improvement in overall survival for the group receiving cetuximab with the two chemotherapy agents compared to the group receiving chemotherapy alone.3 Consistent with the clinical experience of drugs in this class administered for other conditions, the main cetuximab-related side effect was an acne-like rash. The current research was undertaken to determine whether those who developed the typical acne-like rash during the first cycle were more likely to benefit from treatment. For this, a post-hoc analysis was performed on the data from the FLEX study.

For this, the investigators assessed if the development of acne-like rash in the first 21 days of treatment (first-cycle rash) was associated with improved clinical outcome, on the basis of patients in the intention-to-treat population alive on day 21. At that point (day 21), there were 518 patients in the chemotherapy plus cetuximab group — 290 of whom had first-cycle rash — and 540 patients in the chemotherapy alone group. 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 also were 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 who 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 vs. without was seen in all histology subgroups.

The findings from the FLEX trial indicated improved survival for patients with NSCLC who received cetuximab in combination with a standard chemotherapy regimen, but improvement was modest and the treatment very expensive, leading at least some to wonder whether this drug will have a role in the standard approach to this disease.4 A disappointing feature of the FLEX study was the inability to predict from genetic or molecular markers which EGFR+ lung-cancer patients would benefit. Nonetheless, the appearance of rash during the first cycle, as detailed in this report, may be a significant lead in that direction, as 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.

Commentary

Yet, as pointed out in the accompanying editorial by Francesco Perrone, there remain some fundamental questions.5 He points out that although it would be nice to conclude that patients who develop rash in response to cetuximab treatment are those who are likely to benefit, the data are insufficient to support that conclusion. In the FLEX study, cetuximab treatment with chemotherapy was only slightly better than chemotherapy alone, but the difference was quite dramatic for the subset that developed rash and, correspondingly, those who did not develop rash fared worse. Thus, it could be that the development of rash in response to cetuximab identifies those with more favorable prognosis, and that the drug has little or no effect on the tumor, per se. It will take a well-designed clinical trial to sort this out; in the meantime, the use of cetuximab for patients with NSCLC must be considered investigational.

References

1. Bonner JA, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 2010;11:21-28.

2. Jonker DJ, O'Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357:2040-2048.

3. Pirker R, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): An open-label randomised phase III trial. Lancet. 2009;373:1525-1531.

4. Fojo T, Grady C. How much is life worth: Cetuximab, non-small cell lung cancer, and the $440 billion question. J Natl Cancer Inst. 2009;101:1044-1048.

5. Perrone F. Cetuximab in NSCLC: Another trial needed. Lancet Oncol. 2011;12:3-4.