Merck Serono’s Erbitux (cetuximab) featured prominently at the European Society for Medical Oncology conference in metastatic colorectal cancer (mCRC), head and neck cancer and non-small cell lung cancer (NSCLC).

The European cancer meeting included updated results from the CRYSTAL study and a re-run of the FLEX study presented in the US in June at ASCO. New data from CRYSTAL – the first-line Erbitux and FOLFIRI chemotherapy vs FOLFIRI alone in mCRC study – showed a benefit in overall survival for patients with tumours expressing the wild-type KRAS gene (KRAS-WT). About two-thirds of mCRC tumours contain this.

The overall survival benefit of 4 months among patients with KRAS-WT treated with Erbitux (24.9 vs 21 months) over Erbitux-treated patients with a mutant or undetectable KRAS gene status is impressive but did not reach statistical significance, explained lead investigator Professor Eric Van Cutsem of Leuven, Belgium. This was because the trial had not been powered originally to look at the impact of KRAS and numbers were small (less than half the study population had tumour samples that could be evaluated for KRAS status).

In addition, by the time of the overall survival analysis, many patients failing FOLFIRI alone had crossed over to the Erbitux arm, he added.

The multi-centre double blind study involved 1198 patients who were originally randomised to either Erbitux plus FOLFIRI (5 FU plus irinotecan) or FOLFIRI alone before the KRAS status of their tumours was determined. Those in the Erbitux arm saw a small but significant 15 per cent reduction in relative risk of disease progression HR 0.85 (p<0.04). However, when patients were later stratified by the KRAS status of their tumours, those with wild type KRAS more than doubled their chances of progression-free survival, reducing risk of disease progression by 32 per cent HR 0.68 (p<0.017).

The trial’s more impressive finding was a very high response rate (77 per cent) for Erbitux and FOLFIRI among patients with KRAS-WT whose metastases were confined to the liver only (50 per cent for FOLFIRI alone), said Prof Van Cutsem. Those with wild-type KRAS also experienced much higher response rates generally when treated with additional Erbitux (59 versus 43 per cent for FOLFIRI alone) p<0.0025.

“This is a potentially very important finding because it suggests 3 out of 4 patients will shrink their tumours if they have wild-type KRAS proteins and they are treated with cetuximab and chemotherapy” commented Prof Van Cutsem. “ If tumours are confined to the liver they may become resectable giving the chance of cure.”

Van Cutsem’s findings were supported by the smaller phase II CELIM study from Germany which saw a 79 per cent response rate for mCRC patients with KRAS-WT non-resectable liver tumours treated with only 8 cycles (about two months treatment) of first-line Erbitux and either FOLFOX6 or FOLFIRI compared with a 50 per cent response in patients without detectable KRAS-WT in their tumours.

Lead investigator Dr Gunnar Folprecht of Dresden University Hospital said there was a high rate of KRAS-WT tumours (over 70 per cent) in the study and overall 42 per cent of patients (all of whom had responded to Erbitux and chemotherapy) were able to shrink their previously inoperable tumours and undergo surgery. Overall 35 per cent of patients in the study had no residual metastases after surgery and had the potential to be cured.

Dr Folprecht commented: “We saw a very high response rate with both Erbitux and chemo regimens (85 per cent overall) in patients with liver-only metastases, particularly those with KRAS-WT. I believe these data together with those seen in CRYSTAL set a new standard for such patients.”

Salvage Erbitux doubles survival in KRAS-WT mCRC

Erbitux also did well in a separate study at ESMO showed adding Erbitux monotherapy to best supportive care in patients with end-stage mCRC almost doubled their survival provided their tumours coded for the wild-type KRAS gene.

A phase III study presented by Dr Christos Kapetis of Flinders University, Australia, randomised patients who had failed three lines of prior chemotherapy to Erbitux plus best supportive care or the latter alone until their disease progressed. When KRAS status was determined, patients whose tumours exhibited wild-type KRAS (69 per cent of the study population 198 Erbitux and 196 BSC) and who received Erbitux were found to have almost double the survival time of patients of the same KRAS status receiving only best supportive care. The difference 9.5 vs 4..8 months was highly statistically significant (p<0.0001). These patients had a progression-free survival of 3.8 months with Erbitux versus 1.9 months with best supportive care alone, reported Dr Kapetis in Stockholm.

Patients whose tumours showed a mutant KRAS protein however experienced the same survival regardless of treatment received (4.6 months with Erbitux and 4.5 months with best supportive care). Their progression-free survival was 1.8 months in both groups.

“There was no harm in giving these patients Erbitux but they saw no advantage from it” he commented.

He and colleagues also looked at the impact of having wild-type KRAS on patients who received only best supportive care without Erbitux. These patients experienced a similar median survival to patients with mutant KRAS (4.8 vs 4.6 months).

KRAS may not apply in other cancers

The KRAS-WT factor showing enhanced results for Erbitux is likely to boost the agent in mCRC despite narrowing the potential market by one third. However, investigators here said KRAS was not a significant factor in head and neck cancer outcomes and there were no biomarkers or even skin rash to predict which of these patients would benefit from Erbitux. Results of the EXTREME study showing increased survival for first-line Erbitux in head and neck cancer were published this week in the New England Journal of Medicine.

In NSCLC the situation for predicting patients likely to benefit from Erbitux is also unclear. First-line Erbitux and platinum-based chemotherapy showed an increased survival benefit in the FLEX study of patients with advanced Stage IV NSCLC, presented at ESMO by Professor W. Eberhardt of Essen, Germany.

“In NSCLC the importance of KRAS type in determining benefit is unclear at present “ he said.

The KRAS analysis from FLEX is expected in a few weeks and doctors at ESMO intimated they would be disclosed within the next three months.

Merck Serono submitted a licence application for Erbitux and platinum-based chemotherapy use in 1st-line NSCLC in Europe earlier this month.

Erbitux is already approved for locally advanced SCCHN in combination with radiotherapy. In mCRC Erbitux’s European license was updated in July for patients with WT-KRAS. Reimbursement is now restricted to use in KRAS-WT patients in some countries.

Olwen Glynn Owen in Stockholm