Merck KGaA’s epidermal growth factor receptor inhibitor Erbitux added a positive Phase III study of first-line use to its metastatic colorectal cancer (mCRC) evidence base this week with data from the large multicentre CRYSTAL study presented at the American Society of Clinical Oncology meeting in Chicago.

Erbitux (cetuximab) is already approved for second and third-line use in mCRC in the US and for third-line use in Europe and the latest study compared first-line use of the drug in combination with the standard irinotecan-based chemotherapy FOLFIRI against FOLFIRI alone in 1,198 patients with mCRC. The company announced in January that the study met its primary endpoint but no details were released until now.

The data, presented by lead investigator Eric Van Cutsem of University Hospital Gasthuisberg, Leuven, Belgium, showed that adding Erbitux to FOLFIRI gave patients a 15% reduction in the risk of disease progression. The study’s primary endpoint of progression-free survival was met by a narrow but statistically significant margin with a p value of 0.0479. Median PFS was 8.9 months for patients randomised to the combined therapy versus eight months for those randomised to FOLFIRI alone. The respective one-year PFS rates were 34% and 23%.

However, Prof Van Cutsem said the hazard ratio of 0.85 translating to a 15% risk reduction was of greater importance and conveyed a clear benefit for patients adding Erbitux to FOLFIRI; this was reflected in the study’s secondary endpoints. The tumour response rate was significantly higher for the combination at 46.9% versus 38.7% (p 0.0038). There was a significant (p 0.0034) three-fold increase in patients able to undergo complete resection, leaving no residual tumour, in the Erbitux arm (4.3% versus 1.5%) and the proportion with liver metastases able to undergo resection as a result of treatment, with a chance of cure, was almost doubled from 4.5% to 9.8%.

Commenting on the findings, Prof Van Cutsem said: “Some patients such as those with liver metastases derived a greater benefit from adding Erbitux to FOLFIRI than others. Our next challenge is to look at subgroups of patients who did well to try and identify biological markers that predict response to treatment. If we can induce high response rates, more initially-unresectable patients will become resectable and this can lead to cure.” The most reliable marker of response to Erbitux to date is the marked skin rash seen with all drugs that target the EGFR. In CRYSTAL, 18% of patients experienced a grade 3 skin reaction.

CRYSTAL was the second Phase III trial of first-line Erbitux to be presented this week at ASCO. The EXTREME trial showed a significant survival benefit for first-line Erbitux in recurrent or metastatic head and neck cancer. OPUS, a randomised Phase II study of 337 patients comparing first-line Erbitux and the oxaliplatin-based chemotherapy FOLFOX-4 to FOLFOX-4 alone in mCRC patients showed response rates of 45.6% compared to 35.7% for FOLFOX-4 alone. These are similar to response rates seen in CRYSTAL.

Commenting on CRYSTAL, Merck Serono spokesman Wolfgang Wein said: “Once all the supporting data are available, the results from the CRYSTAL study put Merck Serono in a solid position to be able to apply for a future license extension from the EMEA”.