TRANSPARENCY COMMITTE OPINION. 19 December 2007

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1 The legally binding text is the original French version TRANSPARENCY COMMITTE OPINION 19 December 2007 ATRIANCE 5 mg/ml, Solution for Infusion Pack of 6 vials ( ) Applicant: GlaxoSmithKline nelarabine List I Medicinal product for hospital use only. Only for prescription by oncologists, haematologists and experienced physicians in oncology. Orphan medicinal product status Date of centralised MA granted under exceptional circumstances : 22 August 2007 A marketing authorisation under exceptional circumstances was granted for this medicinal product. This means that due to the rarity of this disease it was impossible to obtain complete information about this proprietary drug. The European Drug Agency (EMEA) will review any new published information on a yearly basis and where necessary the SPC will be updated. Reason for request: Inclusion on the list of medicines approved for hospital use. Health Technology Assessment Division 1

2 1 CHARACTERISTICS OF THE MEDICINAL PRODUCT 1.1. Active ingredient Nelarabine 1.2. Indication Nelarabine is indicated for the treatment of patients with T-cell acute lymphoblastic leukaemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) whose disease has not responded to or has relapsed following treatment with at least two chemotherapy regimens. Due to the small patient populations in these diseases, the information to support these indications is based on limited data Dosage Nelarabine is for intravenous use only and must only be administered under the supervision of a physician experienced in the use of cytotoxic agents. Nelarabine is not diluted prior to administration. Complete blood count including platelet count must be regularly controlled. Patients receiving nelarabine are recommended to receive intravenous hydration according to standard medical practice for the management of hyperuricemia in patients at risk for tumour lysis syndrome. For patients at risk of hyperuricemia, the use of allopurinol should be considered. Adults and adolescents (aged 16 years and above): In adults, the recommended dose of nelarabine is 1,500 mg/m 2 administered intravenously over two hours on days 1, 3 and 5 and repeated every 21 days. Children and adolescents (aged 21 years and younger): In children, the recommended dose of nelarabine is 650 mg/m 2 administered intravenously over one hour daily for 5 consecutive days, repeated every 21 days. In clinical studies, the 650 mg/m 2 and 1,500 mg/m 2 doses have both been used in patients in the age range 16 to 21 years. Efficacy and safety were similar for both regimens. The prescribing physician should consider which regimen is appropriate when treating patients in this age range. Limited clinical pharmacology data are available for patients below the age of 4 years. 2

3 2 SIMILAR MEDICINAL PRODUCTS 2.1. ATC 2007 classification L: Antineoplastic and immunomodulatory agents L01: Antineoplastic agents L01B: Antimetabolites L01BB: Purine analogues L01BB07: Nelarabine 2.2. Medicines in the same therapeutic category Comparator medicines In paediatrics: In the treatment of T-cell acute lymphoblastic leukaemia: EVOLTRA (Clofarabine) In the treatment of T-cell acute lymphoblastic lymphoma: None In adults: None 2.3. Medicines with a similar therapeutic aim There are medicinal products indicated at various stages of T-cell acute lymphoblastic leukaemia or lymphoblastic lymphoma treatment, mainly proprietary medicines containing daunorubicin, cytarabine and etoposide. 3

4 3 ANALYSIS OF AVAILABLE DATA The dossier consists of two studies: - Study PGAA2002 (CALGB19801) conducted in adults (De Angelo et al., 2007; Cohen et al., 2006). - Study PGAA2001 (COG P9673) conducted in paediatric patients (Berg et al., 2005; Cohen et al., 2006) Efficacy A/ In adults Study PGAA2002 Non-comparative phase II study including 39 adult patients with T-cell acute lymphoblastic leukaemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LBL) failing to respond or with relapsing disease after at least one induction treatment Nelarabine was administered intravenously at a dosage of 1,500 mg/m²/day on days 1, 3 and 5 of each 21-day cycle. Primary efficacy endpoints were the following response rates: complete, complete without haematological recovery and partial, defined as follows: - The complete response corresponds to a disappearance of the disease (percentage of blast cells in bone marrow 5%, no clinical signs of the disease) and a complete haematological recovery (no circulating blasts, platelets > 100,000/µL, neutrophils > 1,500/µL); - A complete response without haematological recovery was the disappearance of the disease with a percentage of blast cells in bone marrow 5%, and partial haematological recovery; - A partial response was defined by a percentage of blasts 25% for ALL; and for T- LBL by a reduction > 50% in the sum of the diameters of the lesions. Secondary endpoints were the response duration and median overall survival. Results The mean age of patients was 34 years (range: years). Nearly three quarters of included patients (28/39) had refractory or relapsing disease after at least two previous induction treatments (MA population). Twenty six patients had T-ALL at baseline and 13 had T-LBL. A complete response was observed in 5 of the 28 patients who received at least two prior treatments. The duration of this response was variable and was between 15 and more than 195 weeks. A complete response without total haematological recovery was observed in one patient. In these two response categories the time required to obtain a complete response was from 2.9 to 11.7 weeks. The response durations (n = 6) were between 15 and 195 weeks. The median overall survival was 20.6 weeks [95% CI: ] and the one-year survival rate was 29% [95% CI: 12% - 45%]. 4

5 Two of the 6 responders (complete response, complete response without complete haematological recovery) received a stem cell transplant. One patient was alive at last followup and the second patient died after graft rejection 10 months later. B/ In children Study PGAA2001 The efficacy and safety of nelarabine were evaluated in a non-comparative Phase II study including 151 patients aged 21 years old or less with T-cell acute lymphoblastic leukaemia or T-cell non-hodgkin's lymphoma (mainly T-ALL) including 39 who failed to respond to treatment or had refractory disease after at least two previous induction treatments (MA population). In the subgroup of patients in treatment failure or refractory to at least two previous treatments, nelarabine was administered at the dosage of 650 mg/m 2 /day intravenously for one hour per day, for 5 consecutive days, every 21 days. Primary efficacy endpoints were the following response rates: complete, complete without haematological recovery and partial. The definitions of these criteria were the same as for the study in adults. Results: Only the results for the MA population (39 children) are presented here. The median age of patients was 10.9 years (range: years). Thirty patients had T-ALL at baseline and 9 had lymphoblastic lymphoma. 17 patients presented extramedullary involvement. Eight patients had previously received a transplant: an allograft in 6 patients and a haematopoietic stem cell autograft in 2 patients. Five of these 39 patients had a complete response and 4 a complete response without complete haematological recovery. In these 9 patients, the median response duration was 12.3 weeks, median overall survival was 13.1 weeks [95% CI: ] and one-year survival was 14 % [95% CI: 3% - 26%]. Four children subsequently had a stem cell transplant. 5

6 3.2. Safety The most frequent adverse events in adults and paediatric patients were haematological (anaemia, neutropenia and thrombocytopenia which occurred in 1/3 of paediatric cases and 2/3 of adult cases) and neurological reactions (1/3 of paediatric cases and approximately ½ of adult cases, mainly involving peripheral sensory neuropathy) Conclusion The efficacy and safety data for nelarabine in adults were obtained during a non-comparative Phase II study which included 28 patients with T-cell acute lymphoblastic leukaemia (T-ALL) or T-cell lymphoblastic lymphoma who failed to respond or had relapsing disease after at least two previous induction treatments. A complete haematological response was observed in 5 of the 28 patients who received at least two prior treatments. The duration of this response was variable and ranged from 15 weeks to more than 195 weeks. A complete response without total haematological recovery was observed in one patient. The median overall survival was 20.6 weeks [95% CI: ] and survival at one year was 29% [95 % CI: 12% - 45%]. Nelarabine treatment made it possible to give a haematopoietic stem cell transplant to 2 of the 6 responder patients. In the child, the efficacy and safety data for nelarabine were obtained during a noncomparative Phase II study that included 39 children with T-cell acute lymphoblastic leukaemia or T-cell lymphoblastic lymphoma and who had failed treatment or were refractory to at least two previous treatments. Five patients had a complete haematological response and four a complete response without complete haematological recovery. In these 9 patients, the median response duration was 12.3 weeks, median overall survival was 13.1 weeks [95% CI: ] and one-year survival was 14 % [95% CI: 3% - 26%]. Nelarabine treatment made possible to give a haematopoietic stem cell transplant to 4 of the 9 responder patients. There are currently few safety data. The main identified risk is neurological toxicity and in particular, peripheral sensory neuropathy. 6

7 4 TRANSPARENCY CONCLUSIONS 4.1. Actual benefit Acute lymphoblastic leukaemia (ALL) is the malignant clonal proliferation of immature haematopoietic cells which invade the bone marrow and then the peripheral blood and, finally, numerous organs. Lymphoblastic lymphoma is considered to be a lymphomatous variant of ALL with a predominantly extramedullary involvement, contrasting with a percentage of blast cells in the bone marrow of less than 25%. It is a serious and lifethreatening disorder. This proprietary drug is intended to provide curative treatment. The efficacy/safety ratio of this product is high. There is an alternative pharmacological treatment for patients aged less than 21 years in the treatment of T-ALL; Public health benefit: In terms of public health, the burden represented by T-cell acute lymphoblastic leukaemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) is low taking into account the small number of affected patients. The improved management of T-ALL and T-LBL is a therapeutic need lying within the scope of an identified public health priority which is the improved management of cancer (GTNDO priority 1, National rare diseases plan). Insofar as it facilitates the use of allografts, this proprietary medicine is expected to have an impact on morbidity and mortality which, according to available data (no formal comparison with historical morbidity and mortality data) can only be low. Moreover, because of the uncertainty about the tolerability of this drug, extrapolation of the trial results to real life is uncertain. ATRIANCE should not therefore provide a response to an identified public health need. Consequently, ATRIANCE is not expected to benefit public health in these indications. The actual benefit of ATRIANCE is substantial Improvement in actual benefit In adults, the Committee considers that ATRIANCE provides a significant improvement in actual benefit (IAB II) in the treatment of T-cell acute lymphoblastic leukaemia (T-ALL) or T- cell lymphoblastic lymphoma, in patients not responding or relapsing after at least two lines of chemotherapy. As there is no alternative treatment capable of inducing a lasting response in this population, ATRIANCE may facilitate access to an allograft for some patients. In paediatrics, ATRIANCE shares the same IAB II level (significant) assigned by the Committee to EVOLTRA on 13 December As there is no alternative treatment capable of inducing a lasting response in this population, ATRIANCE may facilitate access to an allograft for some patients. National Technical Group for Definition of Public Health Goals (DGS-2003) 7

8 4.3. Therapeutic use Lymphoblastic lymphoma is considered to be a lymphomatous variant of ALL with a predominantly extramedullary involvement, contrasting with a percentage of blast cells in the bone marrow of less than 25%. Its medical management is identical to that of T-ALL. After a first relapse of T-ALL, most patients receive a combination of cytotoxic agents within the scope of re-induction treatment. The complete remission rate observed in studies is more than 80% in the child and 30-76% in adults. Despite obtaining a remission, patients treated by chemotherapy alone are considered to be at high risk of relapse in absence of allograft if there is a donor or otherwise an autograft. Long-term, disease-free survival is much higher in the child after a haematopoietic stem cell transplant (70%) than in adults. Haematopoietic stem cell transplantation is considered to be an essential prerequisite for obtaining complete remission or a substantial eradication of blast cells in relapsing patients. A bone transplant is, at this stage, the only possible potentially curative therapy 2. In adults, Atriance provides a new alternative treatment for patients with T-cell acute lymphoblastic leukaemia or T-cell lymphoblastic lymphoma who have failed treatment after at least two lines of treatment mainly because it facilitates access to an allograft in certain patients. In the child, Atriance represents an alternative to clofarabine (Evoltra) in the treatment of T- cell acute lymphoblastic leukaemia and a new option in the treatment of lymphoblastic lymphoma relapsing in patients with refractory disease or who have failed treatment with at least two lines of treatment as it facilitates access to an allograft in certain patients. Close monitoring of the patients treated by ATRIANCE is recommended in order to detect any sign or symptom of neurological toxicity: drowsiness, mental confusion, convulsions, ataxia, paraesthesias or hypoesthesia. Nelarabine treatment must be stopped from the onset of the first signs of a grade 2 neurological adverse reaction according to the NCI CTCAE classification Target Population Children and adults with T-cell acute lymphoblastic leukaemia (T-ALL) or lymphoblastic lymphoma (T-LBL) who fail to respond or have relapsing disease after at least two lines of chemotherapy are the target population of Atriance. In 2000, the incidence of acute leukaemia was estimated to be 2591 cases per year including 465 cases in children and adolescents aged less than 20 years. According to expert opinion, T-ALL accounts for approximately 15% of acute leukaemias in the child and 5% in adults, i.e. 70 and 85 cases per year respectively. Approximately 15% of children and 25% of adults are treated by a third line of chemotherapy per year (expert opinion), i.e. 10 children and 22 adults. In 2000, the incidence of non-hodgkin's lymphoma was estimated to be 9,908 cases per year including 281 cases in children and adolescents aged less than 20 years. The proportion of T-LBL in patients with non-hodgkin s lymphoma is approximately 3% in adults and 30% in the children. 2. Approximately 10% of children and adults are treated by a third line of chemotherapy per year (expert opinion), i.e. 30 adults and 1 child. Hence the estimated target population of Atriance is approximately 60 patients per year. 2 EPAR 2007 / ATRIANCE 8

9 4.5. Transparency Committee recommendations The Transparency Committee recommends inclusion on the list of medicines reimbursed by National Insurance and on the list of medicines approved for hospital use and various public services in the MA indication and dosage. The Committee will re-examine ATRIANCE in the light of the results of the annual evaluation specified by the European Medicines Evaluation Agency (EMEA). 9