Erbitux: emerging data at ASCO reveal potential to further exploit benefits of the targeted EGFR therapy in mCRC

Administering treatment in community oncology units achieves results that match those of specialist centres, according to the MABEL study; and phase III trials in the US and Europe are now focusing on investigating Erbitux as a first-line therapy option for mCRC.

 Fortnightly regimen could make life easier for patients

Patients with mCRC could be spared the need for weekly visits to the oncology unit for treatment with Erbitux according to a new European study. Fortnightly infusions with a higher dose are apparently equally safe and effective and could be administered at the same time as chemotherapy, most of which is given at two-weekly intervals. 
   Erbitux, an IgG1 monoclonal antibody specifically targeting the EGFR, is currently approved in Europe for treatment of mCRC in combination with irinotecan after the latter has failed. Blocking the EGFR inhibits tumour growth, tissue invasion and metastasis to distant sites.  It also stops tumours repairing damage induced by chemotherapy and inhibits tumour angiogenesis.  After an initial 2-hour iv loading dose of 400mg/m2, weekly maintenance therapy as 250mg/m2 infused over one hour at a maximum infusion rate of 5ml/minute for 6 to 7 weeks is the recommended schedule.
      Dr Andres Cervantes of Hospital Clinico Universitario, Valencia, Spain and others believe a fortnightly, higher-dose, Erbitux regimen would improve patients’ quality of life without compromising therapeutic response. “Travelling to the hospital is tiring and being weekly it focuses patients’ minds on their cancer all the time,” he pointed out during a poster presentation at ASCO. Oncologists from Spain and Italy are therefore comparing the safety and efficacy of the standard weekly administration of Erbitux 250mg/m2 against a double dose (400-700mg/m2) given fortnightly for six weeks in a phase I open-label study.  Data on the initial part of the study, reflecting safety, including results concerning the first 29 patients tested after receiving Erbitux alone for six-weeks, were presented.  The remaining part of the study, investigating Erbitux in conjunction with a FOLFORI regimen, also administered fortnightly, will be presented at a later date.
     Skin and tumour biopsies taken at baseline and after 28 days ,and compared against biopsies from patients receiving the standard weekly dose in a control arm of the study, were used to assess safety. Blood samples were also taken for pharmacokinetic (PK) analysis, pre and post infusion, at several time intervals.
   Results show no major differences between the two regimens in EGFR-signalling inhibition.   PK parameters and trough concentrations are comparable for the weekly and fortnightly dosing regimens.  AUC values at two weeks after a 400mg/m2 or 500mg/m2 dose were approximately 80 per cent of the values achieved by two weeks of standard weekly dosing and no difference was noted between the regimens with regard to the number or severity of adverse events. No dose-limiting toxicities were observed and the maximum tolerated dose has not yet been established.
  Principal investigator Dr Josep Tabernero of Vall d’Hebron University Hospital, Barcelona said: “ From the point of view of patient convenience, this study means a great deal.  It suggests patients can be spared the time and distress of having to attend weekly.”   Fortnightly dosing would also be more convenient because it fits in with the dosing schedule of chemotherapy, he added.
 
Scaling up Erbitux dose to achieve skin reaction is safe in combination with irinotecan according to EVEREST

While there are as yet no clear-cut markers to indicate which patients will benefit most from Erbitux therapy, the appearance of a marked acne-like rash has been associated with a better response and survival outcome.  Oncologists have therefore investigated whether patients initially showing little or no skin reaction after the standard regimen could elicit a better response from a higher dose.
    EVEREST is a phase 1/II dose-escalating study, for which preliminary data were also presented during ASCO.  The study includes 166 patients who had received the standard Erbitux regimen for three weeks but demonstrated no rash or only a grade 1 reaction.  They had also experienced no severe adverse or toxic effects.  The 3-arm study randomised patients to three groups : Groups A and B received either standard regimen or up to a doubling of the standard dose, while Group C patients simply continued on their normal regimen.   
    EVEREST results so far on the 44 patients in Group B show Erbitux dosing can be safely scaled up to 500mg/m2 in more than half of patients who exhibit only a minor rash after the standard initial 400mg/m2 loading dose and the first two 250mg/m2 weekly doses.  In some cases the skin reaction was boosted up to the grade 3/4 level associated with longer survival. 
    Professor Eric Van Cutsem, whose department at University Hospital Gasthuisberg in Leuven, Belgium, led the study, said:  “In several studies of Erbitux treatment in different tumour types, but especially in CRC, patients who showed a more intense rash following treatment survived the longest.  The EVEREST study shows you can increase the skin reaction by scaling the dose up as far as 500mg/m2.” The higher dose was well tolerated by patients, he added, and no other relevant side effects were reported after increasing the dose.                 
    Data regarding treatment efficacy as a result of increasing the dose are to be presented at a future date and the hope is  this will prove dose-increasing in initial poor responders provides the same survival benefits seen in patients with intense skin reactions to lower doses from therapy onset.

MABEL shows median survival of 9.2 months in CRC after Erbitux therapy  in community setting

New therapies are traditionally available first only in tertiary referral centres, so there is always a question as to whether the greater expertise of the centre plays a significant role in achieving good results observed.  MABEL - a major European trial involving 1147 patients with mCRC who failed initial irinotecan-based  therapy - has now shown that patients who went on to receive Erbitux in community-based cancer units for 12 weeks had a median survival of 9.2 months, similar to the experience of more specialised units. 
   Patients from 197 centres in eight European countries participated in MABEL of whom almost half were heavily pre-treated and had received more than three prior chemotherapy lines. 
     Presenting the data at ASCO, Professor Hansjochen Wilke of Kliniken Essen Mitte, Essen, Germany, said:   “Progression-free survival (PFS) at 12 weeks was 61 per cent overall for combinations of cetuximab and irinotecan.  This exceeded the expected rate of around 50 per cent.”
     The median survival time of 9.2 months is in line with the 8.6 months reported for the combination of cetuximab and irinotecan in the BOND study, he noted.  BOND  was the pivotal study of cetuximab plus irinotecan-based therapy in treatment of mCRC which secured regulatory approval for Erbitux in Europe and the US.
  “The results of this large trial indicate the benefits of combining cetuximab and irinotecan are achievable in routine clinical practice in a wider community setting,” Professor Wilke added.

First-line treatment with Erbitux under investigation

Data on 238 previously-untreated mCRC patients in the Cancer and Leukaemia Group B (CALGB) 80203 phase III trial of Erbitux and chemotherapy versus chemotherapy alone, show patients who received Erbitux experienced a significantly higher response rate (52 per cent versus 38 per cent).
     The CALGB trial, originally planned to include 2200 patients, was terminated when standard therapy for mCRC in the US changed to include the vascular endothelial growth factor (VEGF) inhibitor  bevacuzimab.  The trial would have shown the effects of first-line Erbitux in mCRC on survival.  However, Dr Richard Schilsky, CALGB’s Group Chairman said in a statement issued during ASCO the data that were obtained show promise and a further trial will continue to investigate the potential of Erbitux in first-line therapy in the US.   “The early findings of CALGB 80203 have already demonstrated that the addition of cetuximab to chemotherapy significantly improves tumour response in the first-line treatment of advanced CRC and it is important we move rapidly to fully understand etuximab’s potential benefit in this disease setting.”
   A National Cancer Institute-sponsored trial (CALGB/SWOG 80405), to be led by the same principal investigator, Dr Alan Venook,  will enrol 2289 patients with previously untreated, advanced or mCRC, and will determine whether or not adding cetuximab to chemotherapy or chemotherapy plus bevacuzimab prolongs survival beyond chemotherapy plus bevacuzimab alone.
   Meanwhile in Europe, the phase III CRYSTAL study is investigating progression-free survival survival, response rates and quality of life outcomes in 1221 patients with EGFR-positive mCRC treated with either cetuximab plus the irinotecan-based FOLFIRI chemotherapy regimen or the latter alone.  Initial safety data presented at ASCO show no cause for concern and the trial continues.
  Many oncologists, such as Professor Heinz-Josef Lenz of Norris Comprehensive Cancer Center, Los Angeles, US, believe offering Erbitux to patients with advanced or mCRC as soon as it is diagnosed would offer them a better chance of shrinking tumours to the point where they become resectable, thus enhancing their prospects of survival and cure. “The US is already using Erbitux as a second-line rather than third or fourth-line option. In future we will learn how to identify very fast who will respond to Erbitux and when we know the results of studies currently in progress I’m  confident we will want to offer it early.  This will change the landscape of mCRC management. “

Olwen Glynn Owen
PharmiWeb.com Field Reporter

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