What a difference a day makes. On Tuesday, Merck KGaA was basking in glory at Europe’s premier annual oncology meeting, the joint European Cancer Organisation/ European Society of Medical Oncology held in Berlin. On Wednesday it was reeling in shock.

Earlier in the week the German company's Merck Serono unit showed their star oncology product Erbitux (cetuximab) significantly increases overall survival in both metastatic lung cancer (regardless of background platinum-based chemotherapy) and in metastatic colorectal cancer (mCRC) when used first-line with either FOLFIRI or FOLFOX chemotherapy. By Wednesday, the UK Medical Research Council had dropped a devastating bombshell, with preliminary results from COIN suggesting Erbitux and a different type of chemotherapy has no impact on mCRC outcomes at all. The findings have undoubtedly rocked the company’s confidence.

The MRC trial of first-line Erbitux added to continuous chemotherapy (Arm B) vs chemotherapy alone (Arm A) in 729 patients with wild-type KRAS mCRC showed Erbitux made no impact at all on overall survival (the primary endpoint) or even on the softer secondary endpoint of progression-free survival. The results have left Merck Serono reeling but it looks as though the data will have considerable fallout for Roche also.

The devil of the finding is in the detail and it is now being mooted by MRC trial leader Professor Tim Maughan of Cardiff University that the chief chemotherapy used by two-thirds of patients – Roche’s Xeloda (capecitabine) - negated Erbitux’s benefits by a yet-to-be explored adverse interaction. However he stresses: “It is not a done deal yet.” Much further detailed analysis of the results needs to be done to prove the point. The work is in progress and if completed in time may be presented at the ASCO-GI meeting in January, he said.

Speaking in Berlin during his COIN presentation, Dr Maughan said combining Erbitux with the chemotherapy most commonly used in Arm B of the COIN trial (capecitabine) generated a significant increase in unacceptable grade 3 non-haematological toxicity affecting 80% of patients. Toxicity was so great that the dose of capecitabine had to be considerably reduced in half the patients and the trial protocol had to be amended accordingly.

The trial investigators examined survival by chemotherapy regimen and found that whilst there appeared to be a progression-free survival benefit for patients who chose a chemotherapy that excluded capecitabine, the opposite was the case for those receiving capecitabine. The finding was in line with other trials of first-line Erbitux and chemotherapy including CRYSTAL, OPUS and CAIRO 2, which also included Roche's Avastin (bevacizumab), he said. A further full meta-analysis of these and other trials is planned that will also include data from trials of Amgen’s EGFR-inhibitor Vectibix (panitumumab), he added

Dr Oliver Kisker, Merck Serono’s Senior Vice President of Global Clinical Development (Oncology), told Pharma Times his faith in Erbitux was unshaken. However, “when I heard the MRC/COIN trial results I felt shock. I was so completely surprised I could not believe what I was hearing. Again and again, I have seen only consistent robust data of benefit for Erbitux - most recently in the CRYSTAL and OPUS trials. It was these data that formed the basis of our regulatory submissions leading to approval of Erbitux for treatment of mCRC around the world.”

Overall survival data, excluding patients without wild-type KRAS tumours, from the large Phase III CRYSTAL trial of first-line Erbitux and FOLFIRI (infusional 5FU and irinotecan) in mCRC were also presented at ECCO-ESMO. A meta-analysis of 845 patients’ results from CRYSTAL and the Phase II OPUS study which tested first-line Erbitux with FOLFOX (infusional 5FU and oxaliplatin) chemotherapy was also presented. Both showed a very highly significant improvement in overall survival in patients with mCRC tumours of the wild type KRAS genetic make-up with around a four-month survival difference favouring Erbitux and chemotherapy versus chemotherapy alone.

The independent MRC/COIN study, also looking at wild-type KRAS mCRC, shows adding Erbitux makes no difference to survival despite Erbitux increasing response rate, particularly shrinking liver-only metastases in the study. But ironically, the overall COIN findings may turn out to be worse news for competitor Roche which makes Xeloda as well as Avastin. If the COIN investigators prove their hunch that Xeloda interferes with Erbitux activity, Xeloda may turn out to be the drug that oncologists eschew rather than Erbitux. Prof Maughan told the audience of oncologists: “The clinical message from COIN is that we need to be cautious in selecting which partner chemotherapy we use with cetuximab. There will be much more of the story to tell with further analysis ongoing.”

The oncology community was unfazed by the discovery that Erbitux works only in the 60% of mCRC patients with wild-type KRAS tumours and it did Merck Serono no harm. Presumably oncologists will equally easily take on board a finding that Erbitux improves survival so long as it is not combined with Xeloda. Tailored therapy, personalising medicines to patients, is the buzz phrase of the moment so oncologists are getting accustomed to fine-tuning treatments according to patient selection. It may turn out that it is sales of Xeloda that takes the greater pounding in mCRC.

Xeloda is a popular treatment choice in view of its oral administration and toxicity appears not to be so great an issue when it is combined with other agents. With Erbitux, Prof Maughan says the GI toxicity of capecitabine is compounded as both drugs damage the lining of the gut.

Results of the three-arm Phase III AGITG-MAX trial of Xeloda, Avastin and mitomycin C in first-line treatment of 471 patients with mCRC were also presented at ECCO-ESMO. All trial arms included capecitabine and while adding bevacizumab and mitomycin C significantly improved progression-free survival there was no difference in overall survival among the three treatment arms. For Xeloda alone and Xeloda plus Avastin it was 18.9 months and for Xeloda/Avastin/mitomycin C it was two months fewer (16.4 months). The investigators who used a similar dose of capecitabine to that in COIN in a relatively elderly population concluded: “All treatment regimens were well tolerated”. They also claim the three-drug combination in AGITG-MAX “is an active low-toxicity regimen”. By Olwen Glynn Owen in Berlin