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CRYSTAL trial reveals benefits of first-line cetuximab in mCRC

CRYSTAL trial reveals benefits of first-line cetuximab in mCRC


Results of the CRYSTAL trial investigating first-line cetuximab therapy in addition to irinotecan-based therapy in metastatic colorectal cancer (mCRC) were presented by the study’s lead investigator, Professor Eric Van Cutsem of University Hospital, Gasthuisberg, Leuven, Belgium.
Last Updated: 27-Aug-2010

The anti-EGFR targeting cancer therapy Erbitux (cetuximab), has been approved in Europe for the treatment of locally advanced head and neck cancer in conjunction with radiotherapy and as a third-line treatment in combination with irinotecan-based chemotherapy for patients with metastatic colorectal cancer. New data from the phase III EXTREME and CRYSTAL trials, presented at the American Society of Clinical Oncology’s annual meeting, show cetuximab added to chemotherapy is also an effective first-line therapy for both these cancers.

Two large multicentre phase III trials presented in June 2007 at ASCO have revealed that significant benefits can be achieved by using cetuximab as a first-line therapy for metastatic disease in two common cancers – head and neck and colorectal.

Late-breaking data from EXTREME, which investigated first-line cetuximab plus chemotherapy in recurrent or metastatic squamous cell cancers of the head and neck (RMSCCHN), show the strategy has extended survival for patients to an unprecedented level. The EGFR is highly expressed in metastatic head and neck cancers and is associated with a poor outcome.

The EXTREME study, led by Professor Jan Baptist Vermorken of University of Antwerp, Belgium, randomised 442 patients with RMSCCHN from 80 centres in 17 European countries to receive six, three-weekly cycles of standard cisplatin or carboplatin plus 5-FU chemotherapy (carboplatin AUC 5d1 or cisplatin 100mg/m2 IV d1 + 5-FU 1000mg/m2 IV d1-4) with or without the addition of weekly cetuximab (loading dose 400mg/m2 week 1 then 250mg/m2 at succeeding weekly intervals). Patients continued on cetuximab until their disease progressed or until they experienced unacceptable toxicity.

Results showed patients allocated to chemotherapy plus cetuximab significantly reduced their risk of dying by over 20 per cent (HR 0.79) p=0.0362. Median overall survival, the primary endpoint, was 7.4 months for chemotherapy alone and 10.1 months for chemotherapy plus cetuximab.

“Median survival beyond 7 months has not been exceeded in 25 years with any other systemic therapy,” Professor Vermorken observed. The study was planned and powered to demonstrate an improvement in overall survival; but the aim of extending survival by as much as two months was originally considered highly optimistic, he disclosed. “These are patients with extremely severe disease whose prognosis is very poor, so extending their survival from the standard 6 or 7 months by 2.7 months is a tremendous increase and represents a breakthrough. The finding should change clinical practice,” he predicted.

The EXTREME study was conducted over 34 months and showed one-year survival rates of 39 per cent for the cetuximab plus chemotherapy arm vs 31 per cent for the chemotherapy-alone arm. Very little difference in side effects was observed between the two study arms other than a greater incidence of skin reactions in the cetuximab arm as would be expected, he noted.

Commenting on the study immediately after its presentation, head and neck cancer expert Professor Marshall Posner of the Dana-Farber Cancer Institute in the US, told the meeting: “EXTREME is a study of major importance with an impressive 35 per cent increase in median survival.” The study could never be replicated, he remarked, because in future patients progressing on standard chemotherapy only would have to be permitted to cross over to cetuximab. Patients whose disease progressed whilst on cetuximab might have seen a further survival improvement had they continued on treatment, he suggested. Further research will now want to probe cetuximab with other promising chemotherapy combinations, he added. “For now, in a palliative-treatment setting, it is reasonable that every patient should expect to get an anti-EGFR therapy for recurrent disease at some time point in their therapy.”

SCCHN is the sixth most commonly occurring cancer with an estimated 500,000 new cases occurring worldwide each year. About 40 per cent of head and neck cancers occur in the oral cavity, followed by a third occurring in in the pharynx and a quarter in the larynx. There are over 65,000 deaths from the disease each year in Europe.

CRYSTAL trial reveals benefits of first-line cetuximab in mCRC

Results of the CRYSTAL trial investigating first-line cetuximab therapy in addition to irinotecan-based therapy in metastatic colorectal cancer (mCRC) were presented by the study’s lead investigator, Professor Eric Van Cutsem of University Hospital, Gasthuisberg, Leuven, Belgium.

The study met its primary endpoint of increasing progression-free survival (PFS) by the addition of cetuximab to chemotherapy, he said. Median PFS was 8 months in the control group and 8.9 months in the group receiving additional cetuximab (p = 0.0479). PFS rates were 23 per cent and 34 per cent respectively. A 15 per cent risk reduction for disease progression was demonstrated for the experimental arm (HR 0.85).

CRYSTAL randomised almost 1200 patients with tumours testing positive for EGFR expression by immunohistochemistry to either FOLFIRI (irinotecan, folinic acid and 5-FU infused over 48 hours every two weeks) alone, or to the same regimen plus weekly infusions of cetuximab (loading dose 400mg/m2 followed at successive weekly intervals by 250mg/m2). Tumour response and disease progression were assessed from CT scans evaluated by a blinded independent review committee, said Professor Van Cutsem.

Cetuximab significantly boosted response by almost 9 per cent. Response rates were 38.7 per cent for FOLFIRI alone and 46.9 per cent for the cetuximab/FOLFIRI combination (p=0.0038). Disease control rates were approximately 85 per cent in each arm. Adding cetuximab increased toxicity, mainly because of skin rash, experienced to different degrees by 84 per cent of patients in the cetuximab arm, and by a greater frequency of grade 3/4 diarrhoea (15 per cent versus 10.5 per cent). Cetuximab also produced some infusion-related reactions (2.3 per cent vs 0 per cent). Patients received twice as many cetuximab infusions (administered weekly) as chemotherapy infusions (fortnightly). Median treatment duration, 26 weeks, was the same for both groups.

Three-fold difference in tumours becoming resectable

There was a significant three-fold difference in numbers of initially unresectable patients undergoing an RO resection with a chance of cure, favouring the cetuximab/chemotherapy combination (4.3 per cent versus 1.5 per cent, p = 0.0034). “These were patients with no residual tumour after resection of metastases,” he explained. For patients whose only metastases were confined to the liver (approximately 20 per cent of the study population) adding cetuximab almost doubled the rate at which resection became possible (9.8 versus 4.5 per cent). Patients with metastases in liver only had better outcomes than the rest of the trial population, experiencing a median PFS of 9.2 months if they received FOLFIRI alone and 11.4 months if they received additional cetuximab (HR 0.637 p=0.023).

A correlation between rash and PFS was confirmed by CRYSTAL. The 18 per cent of patients with grade 3 rash had a median PFS of 11.3 months compared with 9.54 months for grade 2 and 5.4 months for grade 0 or 1.

No cetuximab-related deaths occurred and no differences were observed between the treatment arms in all-cause 60-day mortality after treatment started and 30-day mortality after treatment stopped. Data on overall survival, quality of life and subgroup analyses correlating endpoints with biomarkers, will be presented at a future date, said Professor Van Cutsem.

The ASCO discussant for CRYSTAL was Dr Hans-Joachim Schmoll of Martin Luther University, Halle, Germany. “Phase III data on first-line cetuximab therapy has been eagerly awaited,” he said. “CRYSTAL shows the benefit of targeting EGFR with cetuximab seen in the salvage setting of mCRC is now definitely proven for first-line use also.” It confirms the findings of a smaller phase II trial CALGB 80203 which randomised 224 patients to first line oxaliplatin-based therapy (FOLFOX) with or without cetuximab. This trial found a significant difference in response rates of 52 per cent vs 38 per cent favouring the combination (p=0.029). “The curves for the cetuximab arms of both studies showed an identical slope” he noted. They show no separation from the control curves for PFS in the early weeks of treatment but later a wide separation emerges in each case.

The ideal chemotherapy to be used in conjunction with cetuximab is still a focus of much research. The definitive answer should be provided by the CALGB/SWOG 80405 study currently in progress, he said. This has so far randomised 641 patients to either FOLFIRI or FOLFOX and to cetuximab or the vascular endothelial growth factor inhibitor bevacizumab or to both. However, a further 1400 or so patients need to be recruited to complete the study and results are some years away.

There are around 370,000 new cases of CRC in Europe each year and approximately 25 per cent already have metastases on presentation

Cetuximab is an IgG1 monoclonal antibody with a high affinity for the EGFR expressed by about 90 per cent of CRC tumours, explained Professor Van Cutsem. “The drug inhibits endogenous ligand-binding, thereby blocking dimerisation, TK phosporylation and receptor-dependent downstream signalling. It also induces antibody-dependent cell-mediated cytotoxicity.” It is developed and marketed by Merck Serono in Europe and B-MS/Imclone in the US.

Olwen Glynn Owen
Pharmiweb Field Reporter