Lilly (ImClone)/ Bristol-Myers Squibb/Merck KGaA's EGFR-targeted anticancer Erbitux (cetuximab) improves median overall survival benefit by about three months in first-line metastatic colorectal cancer (mCRC) patients who are EGFR-positive and KRAS wild-type, shows a new retrospective analysis of the Phase III CRYSTAL study.

The drug failed to show the same benefit in the independently sponsored Phase III COIN trial, however, in the same setting and population in combination with different chemotherapy regimens. The COIN trial investigators continue to analyse the potential reasons for this. The new CRYSTAL data, and the first data from COIN, were both presented recently at the ECCO-ESMO conference in Berlin.

Erbitux is not yet approved in the US as first-line therapy in mCRC, although it is approved there for second-line use in the approximately 55-65% of mCRC patients who have a wild-type (non-mutated) KRAS gene. This approval is based on retrospective KRAS data from several studies of EGFR inhibitors, including CRYSTAL, which showed that they did not benefit, and even in some cases harmed, mCRC patients with mutated KRAS.

KRAS is a well-known proto-oncogene that is downstream of EGFR in a critical cell signalling pathway. In the EU, Erbitux is approved for both first-line and later use in mCRC, again in a KRAS wild-type population.

Bristol-Myers Squibb told Scrip that it and Lilly continue to analyze the recent results from CRYSTAL and COIN, and are evaluating the most appropriate path forward to share the information with US regulatory authorities. Unlike CRYSTAL, COIN, which was primarily conducted by the UK's Medical Research Council, was not designed for registrational purposes, BMS added.

CRYSTAL and COIN are the only Phase III trials of Erbitux in first-line mCRC to be completed so far. A large Phase II trial, OPUS, in first-line mCRC showed a four-month median survival benefit for Erbitux in KRAS wild-type patients.

New CRYSTAL survival result

At the ESMO 2008 conference, a survival analysis was also presented for the CRYSTAL study.

The analysis was conducted on 540 evaluable patients (45%) of the 1,198 patients of the trial.

It failed to show a significant survival benefit for Erbitux in combination with FOLFIRI chemotherapy compared with FOLFIRI alone for KRAS wild-type patients (65% of patients in the analysis), although there was a trend towards improved overall survival of approximately four months for these patients. This was 24.9 months for the cetuximab plus chemotherapy arm versus 21.0 months for the FOLFIRI arm, with a hazard ratio of 0.84. The result did not reach significance (p=0.2).

The trial's lead investigator, Professor Eric Van Cutsem of the University Hospital Gasthuisberg in Leuven, Belgium told Scrip at that time that the failure to demonstrate benefit was probably due to two reasons. First, the trial was not powered to detect a survival benefit in the overall population or in the smaller KRAS wild-type population. Second, overall survival would have been affected by later lines of treatment.

The new retrospective survival analysis presented at this year's ECCO-ESMO conference was conducted on 89% of the trial's population. It was conducted as a result of an effort to increase the tissue ascertainment rate to determine the KRAS status of patients’ tumours.

Oliver Kisker, at Merck KGaA, told Scrip that previously it was unclear whether already stained slides of tumour tissue could be used to evaluate KRAS. "We tried to find other solutions, as the FDA requested samples from at least 90% of patients", he said.

The much higher number of evaluable patients samples translated into a much larger number (666) of KRAS wild-type patients who could be ascertained for a survival benefit. This in turn has now translated into a significant median overall survival benefit in KRAS wild-type patients: 23.5 months versus 20 months (HR 0.796; 95% CI 0.67–0.95 ; p=0.0094). Progression-free survival (PFS) was also significantly improved, with the risk of disease progression reduced by 30% (HR 0.696; p=0.0012).

“Overall survival is a critically important outcome in metastatic colorectal cancer so it is extremely rewarding to achieve this result for the first time with an EGFR-targeted therapy added to a standard chemotherapy,” said Professor Van Cutsem.

Also at this year's conference, first-line Phase III results (the PRIME trial) of Amgen's rival EGFR drug Vectibix (panitumumab), which is so far approved only for third-line EGFR-positive, wild-type KRAS mCRC, were presented. Overall survival data is not yet available, however, and is expected towards the end of this year.

Negative COIN data

The only other first-line Phase III trial of Erbitux, the 1,630-patient COIN trial, disappointed many observers with its negative result.

COIN used two different chemotherapy regimens than CRYSTAL; both were oxaliplatin-based, whereas FOLFIRI is irinotecan-based. The oxaliplatin-based chemotherapy regimens, FOLFOX (using intravenous 5-FU and folinic acid) and XELOX (using Roche's oral chemotherapy capecitabine, or Xeloda), are more commonly used as first-line treatment in mCRC, especially in the US.

Tumour samples from 80% of patients were available for KRAS genotype analysis, and 56% were found to be KRAS wild-type.

The patients were of poorer prognosis than those in CRYSTAL and OPUS, said the trial's lead investigator, Professor Tim Maughan of Cardiff University. 8% of patients had ECOG performance status 2, 9% were over 75, and 41% had unresected or unresectable primary tumours .

Median overall survival was not significantly different between the two arms in the KRAS wild-type population - 17.0 months in the Erbitux treatment arm compared with 17.9 months for the chemotherapy-alone group (HR 1.038; p=0.68). Median PFS was also similar and not significantly different.

Erbitux-treated patients experienced significantly greater Grade 3/4 toxicities, including diarrhoea, skin rash, lethargy, hand-foot syndrome and hypomagnesaemia. There was no evidence of differences in treatment-related or 60-day all cause mortality between the two arms, however.

Professor Maughan said that the main hypothesis for the lack of survival benefit observed for Erbitux was its interaction with capecitabine, which resulted in more Grade 3 toxicity and led to dose reductions of the chemotherapy in the Erbitux arm. "We will undertake a full analysis of toxicity by treatment regimen, dose delivered, what toxicities drove the dose reductions, and how outcome correlates with that", he told Scrip.

However, the potential negative interaction with capecitabine was unlikely to be a complete answer, he said, and there were other issues to explore, such as how patient characteristics affected the outcome and whether the patients with poorer prognosis in the trial were unable to tolerate triple therapy with Erbitux plus combination chemotherapy.

mCRC landscape

Despite the negative COIN study, Professor Maughan said that based on the positive CRYSTAL data, Erbitux would be an option in first-line mCRC for KRAS wild-type patients. He said he didn’t think there was much difference between Erbitux and Vectibix, although Erbitux had more mature first-line survival data.

Jeffrey Holford, an analyst at Jeffries International, agreed that the failure of the COIN trial was most likely due to the use of capecitabine and/or a more frail population. He wrote that the main lesson from the trial was not that Erbitux would not be used in first-line mCRC, but rather that the COIN result may pigeon hole Erbitux for use in combination with FOLFIRI or other irinotecan-based regimens. He also did not see Vectibix as replacing Erbitux in first-line use with FOLFIRI or in second-line use, unless clear superiority data on survival emerged for Vectibix.

The Vectibix PRIME survival data are expected later this year. That trial's lead investigator, Jean-Yves Douillard, of Centre Rene Gauducheau, Nantes, France, said that the median PFS benefit in PRIME and CRYSTAL was similar. On the basis of available data, he guessed that the median overall survivals would be similar as well. PRIME used FOLFOX chemotherapy rather than FOLFIRI.

The only "targeted" therapy currently approved for first-line use in combination with chemotherapy in mCRC, and commonly used, is Roche (Genentech's) VEGF-targeted Avastin. It has a broader indication, unrestricted to EGFR-positive or KRAS wild-type patients. Despite a lot of investigation, no definitive biomarker has been shown to predict a benefit for a specific population of patients.

Avastin's approval in the first-line setting in mCRC is based on the pivotal AVF2107 g trial, which showed close to a five month median overall survival benefit when Avastin was added to an older chemotherapy regimen, IFL.

However, a second Phase III first-line trial testing Avastin in combination with FOLFOX and XELOX, the NO16966 trial, did not find a significant survival benefit.

A head-to-head study of Erbitux and Avastin sponsored by the US National Cancer Institute, is currently ongoing, but results are not expected for a couple years.