The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION. 14 May 2008

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1 Page 1 The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 14 May 2008 AVASTIN 25 mg/ml Pack of 1 vial containing 4 ml (CIP: ) Pack of 1 vial containing 16 ml (CIP: ) Applicant: ROCHE bevacizumab List I Medicinal product reserved for hospital use. To be prescribed only by specialists or oncologists or cancer specialists ATC Code: L01XC07 Dates of MA and variations: Centralised MA: 12 January 2005: metastatic colorectal cancer MA variations: 27 March 2007: extension of indication: metastatic breast cancer 21 August 2007: extension of indication: to be assessed Reason for request: Inclusion on the list of medicines approved for use by hospitals in the extension of indication Avastin, in addition to platinum-based chemotherapy, is indicated for first line treatment of patients with unresectable advanced, metastatic or recurrent non-small cell lung cancer other than predominantly squamous cell histology. Health Technology, Economic and Public Health Assessment Division 1

2 1 CHARACTERISTICS OF THE MEDICINAL PRODUCT 1.1. Active ingredient: Bevacizumab 1.2. Background Bevacizumab is a recombinant humanised monoclonal antibody produced by DNA technology in Chinese hamster ovary cells Indication - Avastin (bevacizumab) is indicated for treatment of patients with metastatic carcinoma of the colon or rectum in combination with fluorouracil/folinic acid-based intravenous chemotherapy with or without irinotecan. - Avastin in combination with paclitaxel is indicated for first-line treatment of patients with metastatic breast cancer. - Avastin in combination with platinum-based chemotherapy is indicated in the first-line treatment of patients with unresectable advanced, metastatic or relapsing non-small cell lung cancer other than with predominantly squamous cell histology Dosage Non-small cell lung cancer (NSCLC): Avastin is administered in addition to platinum-based chemotherapy for up to 6 cycles of treatment followed by Avastin as a single agent until disease progression. The recommended dose of Avastin is 7.5 mg/kg or 15 mg/kg of body weight given once every 3 weeks as an intravenous infusion. Clinical benefit in NSCLC patients has been demonstrated with both 7.5 mg/kg and 15 mg/kg doses. Specific populations: Children and adolescents: The safety and efficacy of Avastin in children and adolescents have not been established. Due to a lack of data, Avastin is not recommended for use in children and adolescents. Elderly subjects: No dose adjustment is required in the elderly. Renal impairment: The safety and efficacy have not been studied in patients with renal impairment. Hepatic impairment: The safety and efficacy have not been studied in patients with hepatic impairment. 2

3 2 SIMILAR MEDICINAL PRODUCTS 2.1. ATC Classification (2007) L L01 L01X L01XC L01XC07 Antineoplastic and immunomodulating agents Antineoplastic agents Other antineoplastic drugs Monoclonal antibodies Bevacizumab None 2.2. Medicines in the same therapeutic category 2.3. Medicines with a similar therapeutic aim In non-small cell lung cancer Cytotoxic agents used alone or in combination: - GEMZAR (gemcitabine) - NAVELBINE (vinorelbine) - TAXOTERE (docetaxel) - TAXOL (paclitaxel), and its generic drugs - ADRIBLASTINE (doxorubicin) - TARCEVA (erlotinib) - ALIMTA (pemetrexed) - HOLOXAN (ifosfamide) Cytotoxic agents used in combination: - CISPLATYL (cisplatin), and its generic drugs - CARBOPLATYL (carboplatin), and its generic drugs 3

4 3 ANALYSIS OF AVAILABLE DATA Roche presented the E4599 study [1] and the AVAIL study (BO17704) for the extension of indication first-line treatment of patients with unresectable advanced, metastatic or relapsing non-small cell lung cancer other than with predominantly squamous cell histology, in combination with platinum-based chemotherapy. The interim analysis of the AVAIL study was presented Study E4599 Objective: To assess the efficacy and safety of the carboplatin/paclitaxel (PAC/CAR) + bevacizumab (BEV) combination versus PAC/CAR alone as first-line treatment for advanced or relapsing non-small cell lung cancer (NSCLC) at stage IIIb with malignant pleural effusion or stage IV, in systematic chemotherapy-naive patients. Design: This was a randomized, controlled, open-label phase II/III study [2]. The BEV group was treated with the dose of 15 mg/kg body weight intravenously every 3 weeks, for 90 minutes (434 patients), immediately after CAR. The dosages of the combined chemotherapies were as follows: 200 mg/m 2 of PAC by IV infusion over 3 hours; CAR at a dose calculated to produce an area under the curve of 6 mg/ml/min administered by the IV route, over minutes immediately after PAC. Chemotherapy was repeated every 21 days for a total of 6 cycles, except in the case of disease progression or the occurrence of intolerable adverse events. This is a common chemotherapy regimen. In the CAR/PAC group, the tumour was evaluated at weeks 7 and 13 and after the end of treatment every 3 months until progression. In the BEV group, the tumour was evaluated at week 7 and 13, and every 3 cycles (9 weeks) until progression. For the 2 groups, after discontinuation of treatment, the adverse events were collected every 3 months for the first 2 years then every 6 months during the following 3 years if the patients had a previously unreported severe long-term adverse event reaction (grade 3). Endpoints: The primary efficacy endpoint was overall survival, defined as the time from randomisation to death whatever cause. 1 Sandler A, Gray R, Perry M et al., Paclitaxel-Carboplatin Alone or with Bevacizumab for Non-Small-Cell Lung Cancer, N Engl J Med 2006;355: The E4599 study protocol was amended 9 times. 4

5 Secondary efficacy endpoints were: objective response rate [3], objective response duration, progression-free survival, adverse events. The objective response (partial 4 + complete 5 ) to treatment was evaluated according to the Response Evaluation Criteria in Solid Tumours (RECIST [6, 7] ). Inclusion criteria: - Adult patients aged at least 18 years; - with a histologically and cytologically confirmed non-small cell tumour; - who have received no prior chemotherapy for local relapse or metastatic bronchial cancer (first-line treatment). Exclusion criteria: - Patients with squamous NSCLC (predominant squamous histology in the case of mixed tumours); - Prior or concomitant chemotherapy; - History of significant haemoptysis (> ½ tablespoon); - Organic dysfunction; - ECOG performance status [8] >1; - Brain metastasis; - Coagulation disorder, therapeutic use of an anticoagulant or nonsteroidal anti-inflammatory drugs, routine use of aspirin, platelet aggregation inhibitor; - Cardiovascular disease, hypertension; - Pregnancy or lactation; - Treatment by radiotherapy, hormone therapy or immunotherapy during the 3 weeks before randomisation. Results: o Efficacy A total of 878 patients were enrolled: patients in the paclitaxel/carboplatin group (PAC/CAR group) patients in the PAC/CAR+BEV group. The baseline characteristics of patients in both groups were similar. In the studied population, 40% of patients had an ECOG performance index of 0; 12.3% were at stage IIIB; 69% had adenocarcinomas. Median overall survival (primary endpoint) was 12.3 months for the PAC/CAR+BEV group and 10.3 months in the PAC/CAR group (hazard ratio: 0.80 [ ]; p=0.003), i.e. an absolute gain of two months. 3 Ratio between the number of responder patients and the total number of evaluable patients for this endpoint 4 Defined as a reduction of at least 30% in the sum of the largest diameters of each target lesion, by taking as reference the initial sum of the largest diameters 5 Defined as the disappearance of all target lesions 6 James K, Eisenhauer E, Christian M et al. Measuring response in solid tumors: unidimensional versus bidimensional measurement. J Natl Cancer Inst 1999;91: Therasse P, Arbuck S, Eisenhauer E et al. New Guidelines to Evaluate the Response to Treatment in Solid Tumors. J Natl Cancer Inst 2000;92: ECOG scale (Eastern Cooperative Oncology Group): 4 grades are defined: Grade 0 = Fully active, able to carry on all pre-disease performance without restriction; Grade 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; Grade 2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours; Grade 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. Grade 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5

6 The estimated 1-year survival rate was 51% in the PAC/CAR+BEV group versus 44% in the PAC/CAR group. The estimated 2-year survival rate was 23% in the PAC/CAR+BEV group versus 15% in the PAC/CAR group. Median progression-free survival was 6.4 months in the PAC/CAR+BEV group versus 4.8 months in the PAC/CAR group. The objective response rate was 29% in the PAC/CAR+BEV group versus % in the PAC/CAR group. No quality-of-life evaluation was planned during this study. o Safety Safety was followed-up for 12.1 months in the BEV+PAC/CAR group versus 9.6 months in the PAC/CAR group. Table 1: Main adverse events in study E4599 PAC/CAR+BEV PAC/CAR N Grade 3 Grade 5 Grade 3 Grade 5 Adverse events n (%) Haemorrhage 19 (4.4 %) 8 (1.9 %) 5 (1.1 %) 3 (0.7 %) Haemoptysis 7 (1.6 %) 5 (1.2 %) 2 (0.5 %) 1 (0.2 %) Venous thromboembolic event 20 (4.7 %) 1 (0.2 %) 14 (3.2 %) 0 Arterial thromboembolic event 10 (2.3 %) 5 (1.2 %) 6 (1.4 %) 1 (0.2 %) Hypertension 32 (7.5 %) 0 3 (0.7 %) 0 Proteinuria 13 (3 %) Congestive heart failure 1 (0.2 %) 0 2 (0.5 %) 0 Grade 5 adverse events were more frequently observed in the BEV+CAR/PAC group. The most frequent were haemorrhage including 1.9% which led to death in the BEV+CAR/PAC group. Four patients out of 427 (0.9%) in the BEV+CAR/PAC group had a gastrointestinal perforation including 3 that were confirmed as perforations; one case was associated with fatal sepsis. No gastrointestinal perforation occurred in the control group. The incidence of grade 3 hyponatraemia was 3.5% in the BEV+PAC/CAR group versus 1.1% in the CAR/PAC group; the incidence of febrile neutropenia was 4.4% in the BEV+PAC/CAR group versus 1.8%. The other adverse events are summarized in table AVAIL study (BO17704) Objective and design: This was a randomised, double-blind, phase III study evaluating BEV in combination with cisplatin (CIS) and gemcitabine (GEM) versus placebo in combination with CIS and GEM, as first-line treatment of locally advanced, metastatic or relapsing NSCLC other than predominant squamous cell histology (stage IllB with supraclavicular lymph node metastases or malignant pleural effusion or pericarditis). The primary efficacy endpoint was progression-free survival. The planned interim analyses in the protocol are presented. 6

7 Study plan: A total of 1043 patients were randomised in 150 centres in 20 countries, mainly in Europe: 347 patients received the cisplatin/gemcitabine combination + placebo 345 patients received the cisplatin/gemcitabine combination + bevacizumab 7.5 mg/kg every 3 weeks and, 351 patients received the cisplatin/gemcitabine combination + bevacizumab 15 mg/kg every 3 weeks, Patients were treated by BEV+CIS/GEM every 3 weeks for a maximum of 6 cycles and then by BEV monotherapy until disease progression. BEV was administered at the dose of 7.5 mg/kg or 15 mg/kg. Placebo + CIS/GEM were administered every 3 weeks for a maximum of 6 cycles. CIS was administered at a dose of 80 mg/m 2 IV, D1 GEM was administered at a dose of 1250 mg/m 2 IV, D1 and D8 Inclusion criteria: - Adults aged over 18 years; - with a histologically and cytologically confirmed, unresectable tumour; - with a locally advanced stage IIIB tumour (with supraclavicular lymph node metastases or malignant pleural effusion or pericarditis) or stage IV disease; - normal hepatic, renal and haematological function; - ECOG performance status = 0 or 1. Endpoints: Primary efficacy endpoint: progression-free survival (primary outcome variable); Secondary endpoints: overall survival, time to relapse during treatment, objective response rate to treatment according to RECIST criteria, treatment response duration, quality of life (secondary endpoints), occurrence of adverse events. Results: Baseline characteristics were homogeneous between the 3 treatment groups. Nearly 40% of patients had an ECOG performance index = 0; 77% of patients had stage IV NSCLC; 85% had an adenocarcinoma. Approximately 30% of patients were aged over 65 years. o Efficacy: The main results are presented in table 2. Study BO17704 showed that BEV administered at dosages of 7.5 mg/kg and 15 mg/kg every 3 weeks increased progression-free survival and the response rate. The analysis of interim overall survival data did not result in any conclusion in terms of benefit on overall survival as follow-up was insufficient (results promised for November 2008). At the time of the analysis, 356 patients out of 1043 had died. This was only half the required number of deaths according to the assumptions made for the final analysis of overall survival (709 deaths). No conclusion about benefit on overall survival may be made because of the short duration of follow-up of study BO

8 Table 2: Interim analysis of the efficacy data from the AVAIL study Endpoint Placebo + CIS/GEM N=347 BEV CIS/GEM N=345 BEV 15 + CIS/GEM N=351 Progression-free survival Median time 6.1 months 6.7 months (p=0.0026) 6.5 months (p=0.0301) Hazard Ratio 0.75 [ ] 0.82 [ ] Best overall response 20.1 % 34.1 % (p<0.0001) 30.4 % (p=0.0023) rate* Overall survival (HR 95 %)** 0.88 [ ] 1.02 [ ] * patients with measurable disease on entry in the study **exploratory analysis based on approximately 50% of the 709 deaths required for the final analysis in the protocol. o Safety: The most frequent adverse events in patients who received BEV were haemorrhage and hypertension. The grade 3 pulmonary haemorrhage rate was 2% (5/330), 1% (3/329) and 0.7 % (1/327) in groups BEV CIS/GEM, BEV 15 + CIS/GEM and placebo + CIS/GEM respectively. The grade 5 (fatal) pulmonary haemorrhage rate was 1% (4/330) and <1% (2/329) in groups BEV CIS/GEM and BEV 15 + CIS/GEM respectively. A similar proportion of patients dropped out of the study because of adverse events: 32 %, 31 % and 39 % in the Placebo + CIS/GEM, BEV 7.5+ CIS/GEM and BEV 15+ CIS/GEM groups respectively. Other grade 3 adverse events were neutropenia, thrombocytopenia, anaemia, hypertension, vomiting, asthenia, nausea, deep vein thrombosis, epistaxis (cf. Table 3). Table 3: AVAIL study - grade 3 adverse events CIS/GEM + Placebo n = 327 CIS/GEM + BEV 7.5 mg/kg n = 330 CIS/GEM + BEV 15 mg/kg n = 329 All grade 3 adverse events (%) Neutropenia (%) Thrombocytopenia (%) Anaemia (%) Hypertension (%) Vomiting (%) Asthenia (%) Nausea (%) Deep vein thrombosis (%) Epistaxis (%) <1 2 3 Other grade 3 non-haemorrhagic events with a high incidence in the bevacizumab group were arterial and venous thromboembolic events, hypertension and proteinuria. 8

9 Conclusion: Study E4599 showed that patients with NSCLC, receiving first-line treatment with the paclitaxel/carboplatin combination and bevacizumab had an absolute gain of 2 months in median overall survival compared to patients treated by paclitaxel/carboplatin alone: 12.3 months versus 10.3 months (hazard ratio: 0.80 [ ]; p=0.0003). Median progressionfree survival was 6.4 months in the paclitaxel /carboplatin + bevacizumab group compared to 4.8 months in the group receiving chemotherapy alone. There were no quality-of-life data. The main adverse event with a high incidence in the group receiving bevacizumab was grade 3 haemorrhages (19/427), which lead to death in 8 cases (1.9%). Other grade 3 events with a high incidence in the bevacizumab group were arterial and venous thromboembolic events, hypertension and proteinuria. 4 TRANSPARENCY COMMITTEE CONCLUSIONS 4.1. Actual benefit Non-small cell lung cancer (NSCLC) is a life-threatening disorder; This proprietary drug is intended to provide curative treatment; Taking into account the limited effect (2 months absolute gain in overall survival), the modest safety profile because of the bleeding risk and the absence of quality-of-life data, the efficacy/safety ratio is moderate. This proprietary drug is intended for first-line therapy. Alternative drugs are available. Public health benefit In terms of public health, the burden of locally advanced or metastatic non-small cell lung cancer (NSCLC), in particular in the patients concerned by the MA indication (in particular first line chemotherapy for cancer other than with predominantly squamous cell histology), is high. This cancer, has a relatively high incidence and a high morbidity and mortality. The improved management of bronchial cancer is a public health need coming within the scope of identified priorities (GTNDO 9 for the management of cancer). Despite the existence of numerous possible treatments, there is a large therapeutic public health need in this disease as patients rapidly fail treatment. However, data are currently lacking and it is impossible to conclude that AVASTIN has an additional impact on the morbidity and mortality related to NSCLC compared to existing therapies. Moreover, no data were submitted to assess the impact of this proprietary medicine on quality of life. In the current state of knowledge, it is difficult to predict whether AVASTIN provides a response to an identified public health need. Consequently, AVASTIN is not expected to benefit public health in this extension of indication. The actual benefit of AVASTIN is substantial. 9 National Technical Group for Defining Public Health Objectives (DGS-2003) 9

10 4.2. Improvement in actual benefit In first-line treatment of patients with unresectable advanced, metastatic or relapsing nonsmall cell lung cancer other than with predominantly squamous cell histology, the therapeutic value of AVASTIN in combination with platinum-based chemotherapy in a nevertheless highly selected patient population (good general health, no history of haemoptysis, no coagulation disorders, cardiovascular disease or secondary cerebral site) is limited by the bleeding risk and absence of quality-of-life data. According to the current data and pending the final results of the AVAIL study, the committee considers that AVASTIN does not improve actual benefit (level V) in the current therapeutic strategy Therapeutic use NSCLC currently has a poor prognosis. Curative surgery may only be attempted in operable patients (stages I, II or IIIA) and is only possible when respiratory and cardiovascular function allows. In most cases, diagnosis is made at a locally advanced late stage (stage IIIB) or metastatic stage (stage IV). In this situation, both the ASCO and SOR-FNCLCC guidelines are that standard treatment proposed for first-line treatment of patients with unresectable (stage IIIB) or metastatic NSCLC (stage IV) consists in two-agent chemotherapy generally including a platinum derivative, in patients with a performance status 2. A meta-analysis [10] failed to demonstrate the advantage of a tritherapy over a bitherapy. The most frequently used combinations are cisplatin (or carboplatin if cisplatin is contraindicated) with vinorelbine, gemcitabine, paclitaxel or docetaxel [11 Pemetrexed is also used for second line therapy in patients who progressed after a first line platinum-based chemotherapy. The efficacy of targeted products such as erlotinib remains very low and its use is reserved for after second line therapy. Overall survival at these stages remains around 15% at 5 years [12]. Bevacizumab is an anti-angiogenic treatment which represents a new alternative treatment when administered with platinum-based chemotherapy for first line treatment; its toxicity must be considered and Avastin must not be prescribed to patients with a tumour located near the large vessels of the chest, or with predominantly squamous cell histology, brain metastases or concomitant cardiovascular disease Target Population The target population of AVASTIN is represented by patients with locally advanced or metastatic NSCLC other than with squamous histology in whom first-line chemotherapy is indicated. In 2000, the number of patients with lung cancer was 27,743 in France (2003 report of French Cancer Guidance Committee). 10 Cochrane Database Syst Rev Oct 17;(4):CD Second or third additional chemotherapy drug for non-small cell lung cancer in patients with advanced disease. Delbaldo C, Michiels S, Rolland E, Syz N, Soria JC, Le Chevalier T, Pignon JP 11 Schiller et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med, Vol. 346 N 2. January 10, Quinn M, Babb P, Brock A, Kirby L, Jones J. Cancer trends in England and Wales Studies on medical and population subjects n 66, London: The St ationery Office 10

11 NSCLC represents nearly 80% to 85% of cases, i.e. 22,194 to 23,582 patients. NSCLC with predominantly squamous histology are excluded from the target population, and they account for 30 to 35% of NSCLC; non-squamous NSCLC therefore accounts for 15,500 to 16,500 patients [13], [14]. The locally advanced or metastatic stages correspond to stages IIIA, IIIB and IV. Advanced stages IIIA, are excluded as they require surgical treatment. Stages IIIB and IV represent nearly 63% 15 of NSCLC cases; 34% of NSCLC patients have brain metastases which are a contraindication to AVASTIN [16, 17]. According to these assumptions, the target population of AVASTIN in this extension of indication is from 6,500 to 6,900 cases per year Transparency Committee recommendations 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 dosage of the marketing authorisation. 13 Molinié F, Velten M, Remontet L et al. Evolution de l incidence du cancer bronchopulmonaire en France ( ). Rev Mal Respir, 2006, 23, Blanchon F, Grivaux M, Collon T, et al. Épidémiologie du cancer bronchique primitif pris en charge dans les centres hospitaliers généraux français. Study KBP-2000-CPHG of the Collège des Pneumologues des Hôpitaux Généraux. Rev Mal Respir/ 2002; 19: Etude KBP Rev Mal Respir, 2002, 19, Cox JD, Yesner RA. Adenocarcinoma of the lung: recent results from the Veterans Administration Lung Group. Am Rev Respir Dis 1979; 120: Sperduto PW. A review of stereotactic radiosurgery in the management of brain metastasis. Technol Cancer Res Treat 2003; 2: