TRANSPARENCY COMMITTEE OPINION. 18 October 2006

Transcription

1 The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 18 October 2006 ERBITUX 2 mg/ml, Solution for infusion 1 bottle of 50 ml (CIP: ) Applicant : MERCK LIPHA SANTE Cetuximab List I Medicinal product reserved for hospital use. Prescription restricted to doctors specialised or trained in oncology or haematology. MA Date (centralised): 29 June 2004 Correction of 29 March 2006 Reason for request : inclusion on the list of medicines approved for use by hospitals in the extension of indication In combination with radiotherapy, Erbitux is indicated in the treatment of patients with locally advanced epidermoid carcinoma of head and neck. Health Technology Assessment Division 1

2 1 CHARACTERISTICS OF THE MEDICINAL PRODUCT 1.1. Active Ingredient Cetuximab 1.2. Background Erbitux is a chimeric monoclonal antibody which inhibits the proliferation of tumoral cells expressing the EGFR (epidermic growth factor receptor) and induces apoptosis Indication - In combination with irinotecan, Erbitux is indicated in the treatment of patients with a metastatic colorectal cancer expressing the epidermic growth factor receptor (EGFR) after irinotecan-based chemotherapy has failed. - In combination with radiotherapy, Erbitux is indicated in the treatment of patients with locally advanced epidermoid carcinoma of the head and neck Dosage It is recommended to perform the detection of the EGFR expression by an experienced laboratory using a validated analytical method (see SPC). Erbitux must be administered under the supervision of a physician experienced in the administration of cytotoxic chemotherapies. Close supervision is essential during the infusion and for at least one hour after its completion. It is essential to have intensive care equipment available. Prior to the first infusion, the patient must be premedicated with antihistamine. This premedication is recommended prior to all subsequent infusions. For all indications, Erbitux is administered once a week. The initial dose is of 400 mg per m 2 of body surface area. All subsequent weekly doses are of 250 mg/m 2. For patients with locally advanced epidermoid carcinoma of the head and neck, cetuximab is used in combination with radiotherapy. It is recommended to start the treatment with cetuximab one week prior to radiotherapy and to continue the cetuximab treatment until the end of the radiotherapy period. 2

3 2 SIMILAR MEDICINAL PRODUCTS 2.1. ATC Classification (2005) L L01 L01X L01XC L01XC06 Antineoplastic and immunomodulating agents Antineoplastic agents Other antineoplastic agents Monoclonal antibodies Cetuximab 2.2. Medicines in the same therapeutic category None 2.3. Medicines with a similar therapeutic aim Cytotoxic drugs indicated in the treatment of cancers of the upper aerodigestive tract: - FLUOROURACIL ICN (fluorouracil) and proprietary drugs containing fluorouracil - BELLON BLEOMYCIN (bleomycin) - CISPLATYL (cisplatin) and proprietary drugs containing cisplatin - PARAPLATIN (carboplatin) and proprietary drugs containing carboplatin - BELLON METHOTREXATE (methotrexate) and proprietary drugs containing methotrexate 3

4 3 ANALYSIS OF AVAILABLE DATA 3.1. Efficacy The file included three studies: - A Phase I-II study (IMCL Study CP ) - A non-comparative Phase II study 1 (IMCL CP ) conducted on 21 patients with non-metastatic locally advanced cancer of the upper aerodigestive tract (UADC) after assessing the treatment by radiotherapy combined with cetuximab (ERBITUX) plus cisplatin. This study was stopped prematurely due to the occurrence of five serious adverse drug reactions, including two deaths. - A Phase III study (EMR Study ) EMR Study It is a randomised Phase III study 2 comparing radiotherapy alone with radiotherapy combined with cetuximab in 424 patients with non-metastatic locally advanced (stages III and IV) carcinoma of the upper aerodigestive tract (UADC). Treatment with cetuximab was started one week prior to radiotherapy at a dosage of 400 mg/ m 2 of body surface area followed by the weekly administration of 250 mg/ m 2 of body surface area throughout the radiotherapy period. The radiotherapy was administered in the two groups according to three schemas: Standard radiotherapy (1 daily-session, total dose 70 Gy), fractionated radiotherapy (2 daily-sessions, total dose Gy in 60 to 64 sessions) and accelerated radiotherapy (72 Gy in 42 sessions). The primary endpoint was the duration of the locoregional control of the disease defined by a clinical and radiological absence of locoregional progression. The secondary endpoints were as follows: Overall survival, progression-free survival, the overall response rate (complete and partial 3 ) at week 8 from the end of the radiotherapy, and tolerance. Results Cancer of the oropharynx was predominant, accounting for 63% of the cases in the radiotherapy alone group and 56% of the cases in the combination group. Cancer of the larynx accounted for approximately one quarter of each group. Cancer of the hypopharynx accounted for 13% of the cases in the radiotherapy alone group and 17% of the cases in the combination group. Three quarters of the patients were in stage IV of the disease. The median age was 58 in the radiotherapy alone group and 56 in the combination group. 1 Pfister DG, Su YB, Kraus DH et al. Concurrent cetuximab, cisplatin and concomitant boost radiotherapy for locoregionally advanced squamous cell head and neck cancer: a pilot phase II study of a new combined-modality paradigm. J Clin Oncol 2006 ; 24/7 : Bonner J A. Radiotherapy plus Cetuximab for Squamous-Cell Carcinoma of the head and Neck. N Engl J Med 2006; 354: Tumour size reduction of at least 50% 4

5 Over 90% of the patients had a Karnofsky index > 70%. The median duration of locoregional control of the disease (primary endpoint) improved by 9 months in the radiotherapy plus cetuximab group (24.4 months) compared with the radiotherapy alone group (14.9 months), p = In the subgroup analysis conducted according to the site concerned, the benefit in terms of locoregional control of the disease was only observed in the group with oropharyngeal cancer (23 months in the radiotherapy alone group versus 49 months in the combination group; RR=0.61 [ ]). Progression-free survival was 17.1 months in the combination group versus 12.4 months in the radiotherapy alone group (p = 0,006). The median overall survival improved by 20 months in the radiotherapy plus cetuximab group (49 months in the combination group versus 29.3 months in the radiotherapy alone group, p = 0.03). This survival benefit was not observed in the subgroups of patients with cancer of the larynx (RR=0.85 [ ]) or of the hypopharynx (RR=0.88 [ ]). The estimated overall survival at 3 years was 55% in the combination group versus 45% in the radiotherapy alone group (p = 0.032). At week 8 after the end of the radiotherapy, the overall response rate was almost the same for both groups: 77.3% in the combination group versus 75.1% in the radiotherapy alone group; p = No clinical benefit was demonstrated in patients over 65 or having a Karnofsky index < Adverse effects The grade 3/4 adverse reactions most frequently observed in the Phase III study included: - acne: 10.6% under radiotherapy plus cetuximab, none under radiotherapy alone. - acneiform rash: 5.3% under radiotherapy plus cetuximab, 1.4% under radiotherapy alone. - mucous membrane disorders: 51.9% under radiotherapy plus cetuximab, 50% under radiotherapy alone. - radiodermatitis: 22.6% under radiotherapy plus cetuximab, 17.9% under radiotherapy alone. - dysphagia: 26% under radiotherapy plus cetuximab, 29,7% under radiotherapy alone. Cetuximab was stopped in 6.7% of the patients because of grade 3/4 adverse reactions (acne, allergy, anaphylactoid reaction and exfoliative dermatitis). 5

6 3.3. Conclusion In a randomised study conducted on 424 patients with locally advanced (stages III and IV) epidermoid carcinoma of the upper aerodigestive tract, the median duration of locoregional control of the disease (primary endpoint) was improved by 9 months in the radiotherapy plus cetuximab group compared with radiotherapy alone (24.4 months in the radiotherapy plus cetuximab group versus 14,9 months in the radiotherapy alone group; p = 0.005). The median overall survival improved by 20 months in the radiotherapy plus cetuximab group (49 months in the combination group versus 29.3 months in the radiotherapy alone group; p = 0.03). In the subgroup analysis conducted according to the site concerned, the benefit in terms of locoregional control of the disease or of survival was only observed in the subgroup with oropharyngeal cancer (representing over half of the patients in the study). Tolerance to cetuximab was found acceptable. The addition of cetuximab to the radiotherapy did not exacerbate the normal side effects of irradiation, in particular radiomucitis, xerostoma, dysphagia, local pains and loss of weight. On the other hand, it did cause a significant increase in cutaneous toxicity. The addition of cetuximab to radiotherapy significantly improved locoregional control and overall survival compared with radiotherapy alone. However, no comparative data are available versus the recognised reference treatment, namely a concomitant radiotherapychemotherapy combination containing platinum salt. 6

7 4 TRANSPARENCY COMMITTEE CONCLUSIONS 4.1. Actual Benefit Cancer of the upper aerodigestive tract is life-threatening. This proprietary drug is intended to provide curative treatment. The efficacy/adverse effects balance is high. This proprietary drug is intended for first-line therapy. There are few alternative treatments. Public health benefit Cancers of the upper aerodigestive tract represent a major burden in terms of public health. The burden represented by patients with locally advanced epidermoid carcinoma unable to be treated by a radiotherapy + chemotherapy combination is moderate because of the small number of patients. Improving the treatment of cancers of the upper aerodigestive tract is an established public health requirement (GTNDO 4 priority). This proprietary drug is expected to have little impact in terms of morbi-mortality and quality of life, despite the absence of available data on the population likely to benefit from this treatment (patients unable to be treated by a radiotherapy + chemotherapy combination). Thus this proprietary drug should provide a supplementary response to the identified public health requirement. Consequently, ERBITUX is expected to have an impact on public health, although this impact will be slight. The actual medical benefit of this proprietary medicinal product is high Improvement in Actual Benefit For patients unable to be treated by radiochemotherapy, in terms of efficacy a combination of ERBITUX + radiotherapy provides a moderate improvement in actual benefit (level III) compared with radiotherapy alone Therapeutic use In France, the standard treatment of inoperable tumours in the otorhinolaryngology sphere currently consists of a concomitant combination of radiotherapy and chemotherapy based on platinum salts with or without 5-fluorouracil. The superiority of this protocol over conventional exclusive radiotherapy, proven in several randomised studies, is reflected in terms of locoregional control rate and overall survival Groupe Technique National de Définition des Objectifs (DGS-2003) 5 Brizel and Esclamado. Concurrent Chemoradiotherapy for Locally Advanced, Non metastatic, Squamous Carcinoma. J Clin Oncol.2006; 24: Denis F, Garaud P, Bardet E, et al: Final results of the GORTEC randomized trial comparing radiotherapy alone to concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. J Clin Oncol 22:69-76,

8 The use of this combination has increased the overall survival rate up to 3 years from 15-20% to 30-50% 8. However, this benefit is achieved at the cost of an increase in both immediate and delayed toxicity, radiomucitis in particular. In the absence of comparative data versus the recognised reference treatment, namely a radiotherapy + chemotherapy combination based on platinum salt, it is difficult to define the role of cetuximab in unselected patients with an inoperable cancer in the ENT sphere. Good tolerance to the radiotherapy + cetuximab combination means that it may well be an alternative to the radiotherapy alone reference treatment when the general condition or medical history of the patient contraindicate concomitant chemotherapy Target Population In 2000, the number of new cases of cancers of the upper aerodigestive tract (UADC) was estimated at approximately 20, In over 95% of the cases 10, these cancers are epidermoid carcinomas. The locally advanced stage accounts for approximately 60% of the cases 11, 12, or around 12,000 cases a year. According to the experts, 50% of these patients could benefit from a surgical treatment. The other 50%, some 6,000 patients, are candidates for a radiotherapy + chemotherapy combination treatment. However, (according to the experts), around half of them cannot receive chemotherapy because of co-morbidity or intolerance, and some 3,000 patients can only be treated by radiotherapy. These 3,000 patients would therefore justify the combination of radiotherapy and ERBITUX Recommendations of the Transparency Committee The Transparency Committee recommends inclusion on the list of medicines approved for use by hospitals and various public services in the new indication and at the posology in the marketing authorisation. 7 Wendt T, Grabenbauer G, Rodel C, et al. Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: A randomized multicentre study. J Clin Oncol 16: , Posner MR, and Wirth L. Cetuximab and Radiotherapy for Head and Neck Cancer. N Engl J Med 2006; 354: Orientation Committee report on cancer, INVS (2003) 11 State of the art management of locally advanced head and neck cancer. Br J Cancer 2005; 92: Edwards S.Kim, Current opinion oncology, 2002, 14 :