The UK’s National Institute for Health and Clinical Excellence (NICE) published a Final Appraisal Determination (FAD) this month that should result in Merck Serono’s EGFR-targeting monocolonal antibody Erbitux (cetuximab) becoming the UK’s first biologic treatment to be reimbursed on the NHS for treatment of metastatic colorectal cancer (mCRC). The final guidance should be published in July and be implemented within three months after that. Caveats apply however. Patients must have had primary tumours resected and have secondary tumours confined to the liver. Tumours must be those exhibiting the wild type KRAS gene which is predictive of a high response to Erbitux. Patients must receive irinotecan alongside Erbitux and can be treated only for 16 weeks before their condition is re-assessed.
The news was greeted with enthusiasm by UK oncologists who have been unable to offer the treatment outside of clinical trials. UK, colorectal cancer expert Dr Harpreet Wasan, Consultant Medical Oncologist at Hammersmith Hospital, London, says the decision makes sound economic sense: “NICE should be congratulated for getting it right this time.” Where CRC tumours exhibit the non-mutated KRAS gene Erbitux achieves the highest response rate ever seen in a chemotherapy study, he explained. “There is a strong cost utility benefit to be gained from curing more patients, so NICE has reached a highly valid and pragmatic interpretation of the scientific data.” The implications for the UK will be to improve and assure quality in care pathways with advanced colon cancer patients likely to be referred in future to specialist liver centres for assessment and surgery, he suggested.
Commenting on the NICE decision at ASCO in Orlando, Dr Wolfgang Wein, Merck Serono’s Executive Vice President for Oncology Business said it was a powerful signal that personalising treatment - the theme of this year’s ASCO - was the right way forward.
Last year the big news at ASCO was the revelation that colorectal cancer patients whose tumours showed a wild type KRAS gene responded extremely well to Erbitux (response rate was over 70 per cent) while those with mutant KRAS derived no benefit. Patients with WT KRAS had a better progression-free survival and if their metastases were confined to the liver they had the chance of undergoing surgery following treatment and in 30 to 40 per cent of cases having all traces of cancer removed – effectively a cure.
“We are well positioned tying Erbitux in CRC to the predictive biomarker of KRAS. Where drugs lack a predictive biomarker there is always a question of how much treatment is wasted” he remarked. The company is actively researching predictive and prognostic biomarkers to guide treatment for lung cancer where a submisson for Erbitux as a first-line therapy was filed last year with European regulators and is awaiting approval to be decided later this year. It is already approved in Europe for first-line treatment in head and neck cancers where KRAS has also proved irrelevant to Erbitux therapy. NICE approved Erbitux treatment in the UK for patients with locally advanced squamous cell cancers of head and neck a year ago in June 2008.
Erbitux continuing to grow in Europe
Although the European licence for Erbitux in mCRC was updated to indicate its use only for patients with WT KRAS, the market had grown rather than contracted as clinicians became more confident about the drug’s efficacy, Dr Wein said. Where trials include only patients with WT KRAS tumours, the response rate is the highest ever seen and progression-free survival rates are very favourable. Despite a slow down in Q3 last year whilst clinicians gained access to KRAS-testing technology, the drug’s use over the year has been accelerating, he noted. Expansion is linked to its first-line indication in mCRC and its launch early in 2009 as a first-line therapy for squamous cell cancers of head and neck.
Erbitux launched in 2004 and has gone on to become one of the company’s leading performers. With total annual sales in pharmaceuticals of almost €5 billion, Erbitux sales contributed a substantial proportion of Merck Serono’s total revenues. Sales grew from €145 million in Q4 of 2008 to €162 million in Q1 2009. Considering these figures include no US sales they are impressive, he noted. “We are on track to reaching our declared goal of achieving €1 billion total sales for Erbitux by 2010.”
Merck Serono is growing its oncology business by expanding the role for Erbitux in other cancer areas. It has a phase II trial program in triple-negative breast cancer and is investigating Erbitux as a treatment for stomach cancer in a trial led by German investigators. A trial is also in progress testing Erbitux in the adjuvant setting in CRC – a potentially important role given the findings this year from the NSABP C-08 trial concerning the anti-angiogenesis biologic Avastin (bevacizumab). Avastin worked in the adjuvant setting apparently only so long as it was prescribed and had no significant impact on disease-free survival at three years.
High hopes for cilengitide and Stimuvax
The company also has high hopes for its late stage pipeline products, the integrin inhibitor cilengitide and the therapeutic lung cancer vaccine, Stimuvax, for which data were presented at ASCO. Results of the independently-run phase II NABTT-0306 study, sponsored by the National Cancer Institute and run by the New Approaches to Brain Tumor Therapy (NABTT) Adult Brain Consortium) were presented in oral session. They showed cilengitide given with chemoradiotherapy (concomitant and adjuvant temozolimide with radiotherapy) extended overall survival for patients with glioblastoma multiforme giving a median survival of 18.9 months. A year after starting treatment 79.5 per cent were still alive. This compares with a median survival of 14 months typically observed with chemoradiotherapy alone with about 60 per cent alive at one year. The drug is now going forward in phase III development in the CENTRIC stud, led by Dr Roger Stupp from University of Lausanne, Switzerland, which began recruiting 500 patients from 170 centres last year.
Phase II data for Stimuvax have shown a remarkable outcome for a subset of patients with stage IIIb local regional disease, some of whom are still alive and receiving Stimuvax more than eight years on, Dr Wein said. In fact survivors include two patients with stage IV lung cancer who would normally expect to survive less than one year. Data at ASCO shows patients who received the treatment for two years or more had no safety issues and there was no evidence of emerging auto-immune disease complications. Updated data on survivors will be presented later this year at the World Lung Cancer meeting in San Francisco. Meanwhile, START, a phase III trial is recruiting well and will give a more definitive appraisal of the vaccine’s potential when it reports, he said.