OPINION 3 April 2013

Transcription

1 The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 3 April 2013 AFINITOR 5 mg, tablet B/30 (CIP: ) AFINITOR 10 mg, tablet B/30 (CIP: ) Applicant: NOVARTIS PHARMA S.A.S INN ATC Code (2012) everolimus L01XE10 (protein kinase inhibitor) Reason for the review Extension of the indication Lists concerned Indication concerned National Health Insurance (French Social Security Code L ) Hospital use (French Public Health Code L ) "AFINITOR is indicated for the treatment of hormone receptor-positive, HER2/neu negative advanced breast cancer, in combination with exemestane, in post-menopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor " HAS - Medical, Economic and Public Health Assessment Division 1/18

2 Actual Benefit The actual benefit of AFINITOR, in combination with exemestane, is low in this extension of the indication in the Marketing Authorisation. Improvement Actual Benefit in In the current state of the dossier, given the uncertainties regarding the benefit of exemestane and the low level of effect of the combination everolimus/exemestane the Committee considers that the addition of AFINITOR to exemestane, does not provide an improvement in actual benefit (IAB V, non existent) compared with standard hormone receptor-positive, HER2/neu negative advanced breast cancer treatments, in post-menopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor. Therapeutic use AFINITOR in combination with exemestane is a second-line treatment and beyond for the treatment of hormone receptor-positive, HER2/neu negative advanced breast cancer, in post-menopausal women without symptomatic visceral disease after recurrence or progression following previous treatments (at adjuvant or metastatic stage) with a non-steroidal aromatase inhibitor (letrozole or anastrozole). The therapeutic use of this combination is yet to be determined given the uncertainties regarding the additional effect of exemestane for patients who have had previous treatments with non-steroidal aromatase inhibitors and while waiting for the results from the BOLERO-6 study. Recommendations The Committee would like to be informed about the results of the BOLERO-6 study requested within the scope of awarding the Marketing Authorisation. HAS - Medical, Economic and Public Health Assessment Division 2/18

3 01 ADMINISTRATIVE AND REGULATORY INFORMATION Marketing Authorisation (centralised procedure) Prescribing and dispensing conditions / special status Initial date: 03/08/2009 Amendment of 23/07/2012 (advanced breast cancer) Additional study requested by EMA: see Summary and discussion section List I For hospital prescription Medicine requiring special monitoring during treatment Prescription restricted to cancer treatment, haematology and clinical oncology specialists and departments. ATC Classification 2012 L L01 L01X L01XE: L01XE10: Antineoplastic and immunomodulating agents Antineoplastic agents Other antineoplastic agents protein tyrosine kinase inhibitors everolimus 02 BACKGROUND This opinion concerns a request to change the conditions of inclusion for AFINITOR on the list of medicines reimbursed through National Health Insurance and approved for hospital use following an extension of the indication in combination with exemestane in the treatment of hormone receptor-positive, HER2/neu negative advanced breast cancer, in post-menopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor (amendment to Marketing Authorisation of 23/07/2012). Within the scope of the Marketing Authorisation procedure, the Marketing Authorisation holder for AFINITOR has claimed a wider indication wording than that finally validated by the Marketing Authorisation, which is in combination with an aromatase inhibitor in post-menopausal women previously treated with hormone therapy. 1 1 EPAR AFINITOR of 21/06/2012, pages 3/79 and 5/79 HAS - Medical, Economic and Public Health Assessment Division 3/18

4 03 THERAPEUTIC INDICATION "Hormone receptor-positive advanced breast cancer AFINITOR is indicated for the treatment of hormone receptor-positive, HER2/neu negative advanced breast cancer, in combination with exemestane, in post-menopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor. Neuroendocrine tumours of pancreatic origin AFINITOR is indicated for the treatment of unresectable or metastatic, well- or moderately-differentiated neuroendocrine tumours of pancreatic origin in adults with progressive disease. Renal cell carcinoma AFINITOR is indicated for the treatment of patients with advanced renal cell carcinoma, whose disease has progressed on or after treatment with VEGF-targeted therapy." 04 DOSAGE "Treatment with AFINITOR should be initiated and supervised by a physician experienced in the use of anticancer therapies. Dosage The recommended dose is 10 mg everolimus once daily. Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs. If a dose is missed, the patient should not take an additional dose, but take the next prescribed dose as usual. Dose adjustment due to adverse reactions Management of severe and/or intolerable suspected adverse reactions may require a dose adjustment. This may be a dose reduction and/or temporary interruption (e.g. for one week) followed by re-starting treatment at a dose of 5 mg. If dose reduction is required, the recommended dose is 5 mg daily (see section 4.4). Special populations Paediatric population The safety and efficacy of AFINITOR in children aged 0 to 18 years have not been established. No data are available. Elderly patients ( 65 years) No dose adjustment is required (see section 5.2). Renal impairment No dose adjustment is required (see section 5.2). Hepatic impairment For patients with moderate hepatic impairment (Child-Pugh B), the recommended dose should be reduced to 5 mg daily. Everolimus has not been evaluated in patients with severe hepatic impairment (Child-Pugh C) and its use is therefore not recommended in this population (see sections 4.4 and 5.2). Method of administration AFINITOR should be administered orally once daily at the same time every day, consistently either with or without food (see section 5.2). AFINITOR tablets should be swallowed whole with a glass of water. The tablets should not be chewed or crushed." HAS - Medical, Economic and Public Health Assessment Division 4/18

5 05 THERAPEUTIC NEED Breast cancer is the most common form of cancer and is the number one cause of death from cancer amongst women in France. The aim of treatment for advanced breast cancer is to maintain or improve quality of life and overall survival. The presence of oestrogen and/or progesterone receptors is one of the most significant markers indicating the response to treatment. Within the scope of treating post-menopausal women with hormone-dependent breast cancer: At an early stage The reference adjuvant hormone therapy is no longer just tamoxifen. For post-menopausal women, aromatase inhibitors: ARIMIDEX (anastrozole), FEMARA (letrozole) and AROMASIN (exemestane) are currently recommended even before tamoxifen, as first-line or subsequent treatments. 2,3 At an advanced stage 4,5,6 - with poor prognosis factors, especially with visceral disease, the 1 st line treatment for metastatic breast cancer is chemotherapy; - in the absence of poor prognosis factors and in the presence of hormone receptors, the 1 st line treatment for metastatic breast cancer is hormone therapy involving non-steroidal aromatase inhibitors: ARIMIDEX (anastrozole) and FEMARA (letrozole) in patients who have not received adjuvant treatment with an aromatase inhibitor or who have discontinued this treatment more than 12 months ago. Although the superiority of aromatase inhibitors has been demonstrated compared with tamoxifen as a first-line treatment in terms of response rate and progression-free survival, tamoxifen continues to be a first-line treatment option. Second-line treatment options are: tamoxifen, aromatase inhibitors (non-steroidal: anastrozole, letrozole or steroidal: exemestane) if they have not been administered previously, fulvestrant, megestrol and androgens. The optimal hormone therapy sequence is yet to be established, especially after progression on a first-line aromatase inhibitor treatment. Chemotherapy is usually reserved for patients with aggressive progression of breast cancer or in cases of systematic visceral disease. It should be noted, however, that AROMASIN (exemestane) and FASLODEX (fulvestrant) only have Marketing Authorisation in the treatment of hormone-dependent advanced breast cancer in post-menopausal women after failure of treatment with anti-oestrogens, which corresponds to a very limited number of patients due to the increased use of aromatase inhibitors as 1 st line treatments (see section 6 on comparators). 2 Burstein H, Prestrud A et al. American Society of Clinical Oncology Practice Guideline: Update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer, Journal of Clinical Oncology NICE. Early and locally advanced breast cancer: Diagnosis and treatment guideline; February Cardoso F. Locally recurrent or metastatic breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol: 23 Suppl 7:11-19; Recommandations pour la Pratique Clinique [Clinical practice recommendations]: Saint Paul de Vence 2007 "cancers du sein" [breast cancer]: National Comprehensive Cancer Network Breast cancer (NCCN 2012) HAS - Medical, Economic and Public Health Assessment Division 5/18

6 06 CLINICALLY RELEVANT COMPARATORS 06.1 Medicinal products There is no hormone therapy with Marketing Authorisation in the treatment of hormone dependent advanced breast cancer after failure with a non-steroidal aromatase inhibitor: - AROMASIN (exemestane), an irreversible steroidal aromatase inhibitor, with Marketing Authorisation: - "is indicated for the adjuvant treatment of post-menopausal women with oestrogen receptor-positive invasive early breast cancer, following 2 3 years of initial adjuvant tamoxifen therapy; - "is indicated for the treatment of advanced breast cancer in women with natural or induced post-menopausal status whose disease has progressed following anti-oestrogen therapy. Efficacy has not been demonstrated in patients with oestrogen receptor negative status." - FASLODEX (fulvestrant), an oestrogen receptor competitive antagonist, has Marketing Authorisation for hormone dependent oestrogen receptor-positive advanced breast cancer but only in cases of relapse during or after adjuvant treatment with an anti-oestrogen or disease progression on anti-oestrogen treatment (substantial AB, TC opinion for renewal of inclusion of 08/09/2010). The request to widen the indication to patients with failed treatment with aromatase inhibitors was denied by CHMP (decision of 25/10/2010) due to insufficient efficacy data, in particular from the CONFIRM study, which compared the efficacy and safety of fulvestrant 500 mg with fulvestrant 250 mg. One of the major criticisms of the CONFIRM study was the absence of a placebo group, which made the evaluation of the efficacy of fulvestrant difficult for patients who received an aromatase inhibitor as their last hormone therapy treatment. 7 Nevertheless, the results from the sub-group of patients previously treated with an aromatase inhibitor in the CONFIRM study are included for information in section 5.1 of the SPC "Pharmacodynamic properties " of FASLODEX, stating that FASLODEX is indicated for patients with relapsed or progressed disease under anti-oestrogen treatment and that no conclusions can be made from the results of this sub-group. - NOLVADEX (tamoxifen) and its generics, anti-oestrogens, indicated either in the "adjuvant treatment of breast carcinoma (preventive treatment for relapses), or locally advanced and/or metastatic forms. The efficacy of this treatment is higher for women whose tumour contains oestradiol and/or progesterone receptors." Chemotherapy is usually reserved for patients with aggressively progressing breast cancer or with symptomatic visceral disease. In view of the wording of the indication validated by the Marketing Authorisation excluding patients with symptomatic visceral disease, 8 chemotherapy is not considered as a comparator. Conclusion There is no clinically relevant comparator available with a Marketing Authorisation. 7 EPAR FASLODEX du 25/10/2010, _Assessment_Report_-_Variation/human/000540/WC pdf 8 According to EPAR for AFINITOR of 21 June 2012, in the absence of a direct comparison with chemotherapy, which is the treatment of choice for patients with an aggressive progression of the disease characterised by symptomatic visceral disease, the Marketing Authorisation indication of the combination of AFINITOR with exemestane has been restricted to exclude these patients. HAS - Medical, Economic and Public Health Assessment Division 6/18

7 07 INTERNATIONAL INFORMATION ON THE MEDICINAL PRODUCT Reimbursed in the extension of the indication for metastatic breast cancer in Europe and the United States: Country Germany Austria Denmark United States Finland Norway YES/NO YES REIMBURSED Population Marketing Authorisation population United Kingdom* Sweden Belgium -- Spain -- Greece Still being evaluated -- Italy -- The Netherlands -- Switzerland -- * Reimbursed via the Cancer Drug Fund - NICE assessment not available on 23 January 2013 HAS - Medical, Economic and Public Health Assessment Division 7/18

8 08 ANALYSIS OF AVAILABLE DATA In support of its application for inclusion, the applicant supplied a clinical dossier including: - two phase II studies: - study C2222, a randomised, double-blind study evaluating the efficacy and safety of everolimus (10 mg/day) combined with letrozole (2.5 mg/day) versus letrozole alone (2.5 mg/day) as neo-adjuvant treatment (pre-surgery) in 270 post-menopausal women with localised breast cancer; - TAMRAD study, a randomised, open-label study evaluating the efficacy and safety of everolimus (10 mg/day) combined with tamoxifen (20 mg/day) versus tamoxifen alone (20 mg/day) in 111 post-menopausal women with metastatic, oestrogen receptor-positive, HER2 negative breast cancer, who have had a previous failed treatment with aromatase inhibitors. Although comparative, these studies were not used for the analysis of the therapeutic use of everolimus as they were carried out outside of the conditions of the Marketing Authorisation (in combination with a treatment other than exemestane and/or a localised stage of the disease). - a randomised, double-blind phase III study (CRAD001Y2301 or BOLERO-2) comparing the combination of everolimus/exemestane with exemestane alone, which is described below Efficacy The aim of the randomised, double-blind phase III BOLERO-2 study was to evaluate the efficacy and safety of everolimus (AFINITOR) at a dosage of 10 mg/day in combination with exemestane (25 mg/day) versus exemestane alone (25 mg/day) in post-menopausal women with locally advanced or metastatic hormone receptor-positive breast cancer not over-expressing HER2, with relapse or progression on or after letrozole or anastrozole (non-steroidal aromatase inhibitors) within the context of adjuvant and/or advanced stage treatment. Inclusion criteria included: - Post-menopausal women aged 18 years with metastatic or locally advanced breast cancer, not curable with surgery or radiotherapy - ECOG score 2 - adequate hepatic (ASAT and ALAT < 2.5 x LSN; bilirubin < 1.5 x LSN) and renal (creatinine < 1.5 x ULN) function - oestrogen receptor positive (RE+) - with a disease refractory 9 to non-steroidal aromatase inhibitors defined as: - relapse under adjuvant treatment with letrozole or anastrozole or in the 12 months following stopping treatment or, - progression under treatment with letrozole or anastrozole or in the month following stopping this treatment for locally advanced or metastatic breast cancer. Note: letrozole or anastrozole did not necessarily have to be the last treatment administered before randomisation. Patients who had previously received a line of chemotherapy, tamoxifen or fulvestrant for advanced breast cancer, could also be included. 9 Reoccurrence or progression were highlighted in X-rays in accordance with RECIST criteria. Patients should have: - at least one lesion 20 mm that can be measured in at least one dimension with standard imaging techniques or 10 mm with CT or MRI or - lytic or mixed bone lesions, in the absence of a measurable disease, as defined above. HAS - Medical, Economic and Public Health Assessment Division 8/18

9 Non-inclusion criteria included: - patients over-expressing HER2 - only with immeasurable lesions, other than bone lesions (i.e. pleural effusion, ascites, etc.) - with symptomatic brain metastases - bilateral diffuse lymphangitis carcinomatosa - received more than one line of chemotherapy for advanced breast cancer - previously treated with exemestane or an mtor inhibitor - treated with radiotherapy in the 4 weeks prior to randomisation, with the exception of radiotherapy for pain relief for bone lesions or lytic lesions at risk of fracturing carried out in the 2 weeks prior to randomisation. - significant symptomatic deterioration in lung function Treatments: Patients were randomised (2:1) into the two following groups: - group 1 (N=485): everolimus (10 mg per day) + exemestane (25 mg per day) taken orally; - group 2 (N=239): placebo + exemestane (25 mg per day) taken orally. Randomisation was stratified according to whether there were visceral metastases or not and whether there was sensitivity to previous hormone therapies or not, defined by a documented clinical benefit (complete response, partial response or stable disease 24 weeks) after at least one previous hormone therapy treatment administered at an advanced stage of the disease or at least 24 months of adjuvant hormone treatment before relapse. In cases of disease progression, cross over was not permitted. No cross over was permitted in cases where the interim analysis showed an SSP superiority in the everolimus plus exemestane group. Primary efficacy endpoint: progression-free survival, defined as the time between randomisation and the date on which objective progression of the tumour occurred, in accordance with RECIST criteria or death from any cause and evaluated by the clinical investigator after amendment to the protocol on 17 February 2010 (after the randomisation of 157 patients) with the aim of reducing the amount of censored data. The initial study protocol included an independent review of the tumour scan evaluations. The primary analysis was scheduled after the occurrence of 528 events for progression-free survival. An interim analysis was scheduled after the occurrence of 317 (60%) events for progression-free survival. As the initial study protocol included an independent review, the protocol was also amended on 11 May 2010 to state that the study could only be declared positive in favour of everolimus + exemestane in the interim analysis if, and only if, analysis for progression-free survival evaluated by the clinical investigators and by an independent committee were both statistically significant, with p values of < (investigator's review) and < (independent review) respectively. Secondary endpoints included: - overall survival, defined as the time between randomisation and death from any cause. - objective response rate (complete or partial confirmed according to RECIST criteria) 10 - clinical benefit rate (complete and partial response and stabilisation of the disease for more than 6 months) - quality of life. 10 Full response: disappearance of all tumour lesions Partial response: reduction of 30% of the greatest lesion diameter Disease progression: increase of 20% of the greatest lesion diameter Stable disease: changes in tumour size not meeting the conditions indicated previously. HAS - Medical, Economic and Public Health Assessment Division 9/18

10 Results: A total of 724 patients were randomised: 485 in the everolimus + exemestane group and 239 in the exemestane alone group. The median age of patients was 61 years. Patients were in good general health (ECOG score 0: 60% and ECOG 1: 36%). Almost all patients had metastatic cancer at inclusion (99.6% or 721/724). Nearly 77% of patients had at least one bone metastasis, 59% visceral disease and 32% hepatic involvement. More than 84% of patients were sensitive to previous hormone therapy. Treatments received previously were comparable (see Table 1). More than half of the patients included had received at least 3 previous treatments (53.7%), which included: letrozole and/or anastrozole (100%), tamoxifen (48%), fulvestrant (16%) and chemotherapy (68%). Patients had previously received a non-steroidal aromatase inhibitor (letrozole and/or anastrozole) as adjuvant or neo-adjuvant (27%) treatment or at the metastatic stage (68%). The non-steroidal aromatase inhibitor was the last treatment received for 74% of patients. Patients included were given 1 st line treatment at the metastatic stage in 19% of cases, as 2 nd line treatment in 42% of cases and as 3 rd line treatment in 27% of cases. HAS - Medical, Economic and Public Health Assessment Division 10/18

11 Table 1: description of treatments received prior to inclusion Everolimus + exemestane Placebo + exemestane Results for the primary efficacy endpoint: progression-free survival During the interim analysis scheduled in the protocol with a median follow-up of 7.6 months (cut-off on 11/02/2011): - the median progression-free survival, evaluated by the clinical investigators, was 6.9 months in the everolimus + exemestane group and 2.8 months in the exemestane alone group, which is an absolute increase of 4.1 months in favour of the combination of everolimus + exemestane (HR=0.43 [0.35; 0.54]; p < ); - the median progression-free survival, evaluated by an independent committee, was 10.6 months in the everolimus + exemestane group and 4.1 months in the exemestane alone group, which is an absolute increase of 6.4 months in favour of the combination of everolimus + exemestane (HR=0.36 [0.27; 0.47]; p < ), see Table 2. During the final analysis scheduled in the protocol, with a median survival of 17.6 months (cut-off on 15 December 2011): Total N=485 N=239 N=724 n (%) n (%) n (%) Previous therapy 485 (100.0) 239 (100.0) 724 (100.0) Previous surgery 451 (93.0) 220 (92.1) 671 (92.7) Previous radiotherapy 340 (70.1) 164 (68.6) 504 (69.6) Number of previous treatments at metastatic stage None 100 (20.6) 37 (15.5) 137 (18.9) (39.6) 112 (46.9) 304 (42.0) (26.4) 66 (27.6) 194 (26.8) 3 52 (10.7) 16 (6.7) 68 (9.4) 4 13 (2.6) 8 (3.3) 21 (3) Number of previous hormone therapies at advanced stage None 107 (22.1) 42 (17.6) 149 (20.6) (52.0) 141 (59.0) 393 (54.3) ( 21.4) 46 (19.2) 150 (20.7) 3 22 (4.5) 10 (4.2) 32 (4.4) Non-steroidal aromatase inhibitor (NSAI) 485 (100.0) 239 (100.0) 724 (100.0) Letrozole alone 237 (48.9) 106 (44.4) 343 (47.4) Anastrozole alone 210 (43.3) 114 (47.7) 324 (44.8) Letrozole and anastrozole 38 (7.8) 19 (7.9) 57 (7.9) Prescription background for last NSAI treatment 361 (74.4) 178 (74.5) 539 (74.4) Metastatic 262 (54.0) 140 (58.6) 402 (55.5) Adjuvant / neo-adjuvant 97 (20.0) 37 (15.5) 134 (18.5) Prevention a 2 (0.4) 1 (0.4) 3 (0.4) Anti-oestrogen 276 (56.9) 140 (58.6) 416 (57.5) Tamoxifen 230 (47.4) 118 (49.4) 348 (48.1) Fulvestrant 80 (16.5) 39 (16.3) 119 (16.4) Tamoxifen and fulvestrant 39 (8.0) 20 (8.4) 59 (8.1) Toremifene 8 (1.6) 4 (1.7) 12 (1.7) Raloxifene 0 2 (0.8) 2 (0.3) Chemotherapy background 336 (69.3) 156 (65.3) 492 (68.0) Adjuvant / neo-adjuvant alone 211 (43.5) 95 (39.7) 306 (42.3) Metastatic alone 67 (13.8) 23 (9.6) 90 (12.4) Adjuvant / neo-adjuvant and metastatic 58 (12.0) 38 (15.9) 96 (13.3) HAS - Medical, Economic and Public Health Assessment Division 11/18

12 - the median progression-free survival, evaluated by the clinical investigators, was 7.82 months in the everolimus + exemestane group and 3.19 months in the exemestane alone group, which is an absolute increase of 4.63 months in favour of the combination of everolimus + exemestane (HR=0.45 [0.38; 0.54]; p < ); - the median progression-free survival, evaluated by an independent committee, was months in the everolimus + exemestane group and 4.14 months in the exemestane alone group, which is an absolute increase of 6.87 months in favour of the combination of everolimus + exemestane (HR=0.38 [0.31; 0.48]; p < ), see Table 2. Table 2: Efficacy results for the primary efficacy endpoint of the BOLERO-2 study: progression-free survival Review by investigators everolimus + exemestane (n = 485) Progression-free survival (primary efficacy endpoint) exemestane (n = 239) Interim analysis (11 February 2011) everolimus + exemestane (n = 485) Independent review exemestane (n = 239) Median (months) Difference in medians (months) Relative risk [95% CI]; p 0.43 [0.35; 0.54]; p < [0.27; 0.47]; p < Final analysis (15 December 2011) Median (months) Difference in medians (months) 4.63 Relative risk [95% CI]; p 0.45 [0.38; 0.54]; p < HR=0.38 [0.31; 0.48]; p < Results for the secondary endpoints based on the review by the clinical investigators - The median overall survival was not achieved in either of the two groups on the date of the interim analysis or in subsequent analyses (four analyses of overall survival, including two scheduled in the protocol are provided in the dossier). A total of 200 deaths were observed during the last analysis (cut-off of 15 December 2011): 25.4% in the everolimus + exemestane group and 32.2% in the exemestane alone group. Within the scope of being awarded Marketing Authorisation, the applicant is expected to provide the results for overall survival with a longer follow-up period. During the final analysis, the objective response rate (complete or partial response) was 12.6% in the everolimus + exemestane (including 0.6% for complete response) group and 1.7% in the exemestane alone group (with no complete responses), p < the clinical benefit rate (complete and partial response and stabilisation of the disease for more than 6 months) was 51.3% in the everolimus + exemestane group and 26.4% in the exemestane alone group (p < ). Evaluations of the responses made by the clinical investigators and the independent committee were in agreement. - The median time until deterioration in general health/quality of life measured with the EORTC QLQ-C30 questionnaire ( 5 points) was comparable in the two groups (HR= % CI [ ]; NS). The time until deterioration in ECOG score ( 1 point) was also similar in the two groups (HR =0.88; 95% CI [ ]; NS). HAS - Medical, Economic and Public Health Assessment Division 12/18

13 08.2 Adverse effects Safety data is taken from the comparative BOLERO-2 study. Treatment discontinuations due to adverse events affected 19.1% (92/482) of patients in the everolimus + exemestane group and 4.6% (11/238) of patients in the exemestane alone group. The percentage of patients who had serious adverse events was 23% (110/482) in the everolimus + exemestane group and 12% (29/238) in the exemestane alone group. The most common events were of a respiratory nature: pulmonary disease (2.5%) and pneumonia (1.5%). Death following a serious adverse event was observed in 7 patients (1.5%) in the everolimus + exemestane group and in 1 patient (0.4%) in the exemestane alone group. Grade 3 or 4 events affected 44% of patients in the everolimus + exemestane (211/482) group and 26% of patients (61/238) in the exemestane alone group. The most common events in the everolimus + exemestane (n=482) group compared with the exemestane alone group were (n=238): - stomatitis (56% including 8% grades 3 vs. 11% including 1% grades 3), - rash (36% including 1% grades 3 vs. 6% with no grade 3), - fatigue (33% including 4% grades 3 vs. 26% including 1% grades 3), - diarrhoea (30% including 2% grades 3 vs. 16% including 1% grades 3). According to the SPC, the most common grade 3-4 adverse effects (frequency 2% in at least one phase III trial) were: anaemia, fatigue, diarrhoea, infections, stomatitis, hyperglycaemia, thrombocytopenia, lymphopenia, neutropenia, hypophosphataemia, hypercholesterolaemia, diabetes mellitus and pulmonary disease. The risk management plan specifically states the identified significant risks, such as: non-infectious pulmonary disease, severe infection, hypersensitivity reactions, stomatitis, wound healing complications, increased serum creatinine and proteinuria, renal failure, hyperglycaemia, dyslipidaemia and hypophosphataemia etc Summary & discussion In 724 post-menopausal women with locally advanced or metastatic hormone receptor-positive breast cancer and no HER2 over-expression, with relapse or progression on or after letrozole or anastrozole (non-steroidal aromatase inhibitors), the combination of everolimus 10 mg/day + exemestane 25 mg/day was compared with exemestane alone (25 mg/day) in a randomised, double-blind phase III study. Patients had a median age of 61 years, were in good general health (ECOG score 0: 60% and ECOG 1: 36%), at a metastatic stage (99.6%), with at least one visceral lesion (59%) and were sensitive to one previous hormone therapy treatment (84%). Treatments received previously were varied (see Table 1) and 53.7% of patients had received at least three: letrozole and/or anastrozole (100%), tamoxifen (48%), fulvestrant (16%) and chemotherapy (68%). Patients had previously received a non-steroidal aromatase inhibitor (letrozole and/or anastrozole) as an adjuvant or neo-adjuvant treatment (27%) or at the metastatic stage (68%). A non-steroidal aromatase inhibitor was the last treatment received for 74% of patients. The patients included were given 1st line treatment at the metastatic stage in 19% of cases, as a 2nd line treatment in 42% of cases and as a 3rd line treatment in 27% of cases. The final analysis showed with the addition of everolimus compared with exemestane alone: - an increase in the median progression-free survival evaluated by the clinical investigators (primary efficacy endpoint): 7.82 months versus 3.19 months, which is a gain of 4.63 months (HR=0.45; 95% CI [0.38; 0.54]). - a similar overall survival; the median overall survival was not achieved in any of the groups; HAS - Medical, Economic and Public Health Assessment Division 13/18

14 - a higher objective response rate (complete or partial response): 12.6% (including 0.6% complete response) versus 1.7% (with no complete responses) (p < ). The low objective response rate in the exemestane alone group is highlighted. - a similar quality of life. Evaluations made by the clinical investigators and the independent committee were in agreement. The addition of everolimus to exemestane compared with exemestane alone increased the frequency: - of treatment discontinuations due to adverse events (19.1% vs. 4.6%); - of serious adverse events (23% vs. 12%) and grade 3 or 4 events (44% vs. 26%), - of stomatitis (56% including 8% grades 3 vs. 11% including 1% grades 3), - of rash (36% including 1% grades 3 vs. 6% with no grade 3), - of fatigue (33% including 4% grades 3 vs. 26% including 1% grades 3), - of diarrhoea (30% including 2% grades 3 vs. 16% including 1% grades 3). The Committee emphasises the following points: - the questionable selection of exemestane as a comparator in this study makes interpreting the results difficult. Exemestane was used in relapse situations or progression on or after letrozole or anastrozole, i.e. for a wider indication than that in its Marketing Authorisation, which is limited to failure of anti-oestrogens. In addition, although current guidelines include exemestane as one of the options as a second-line treatment or beyond, its use after failure of a non-steroidal aromatase inhibitor is highly questionable as the sequence "non-steroidal aromatase inhibitor then steroidal aromatase inhibitor (exemestane)" may not be ideal as highlighted by the low objective response rate (0.4%) in the exemestane alone group. - it would have been desirable to be able to assess the effect of adding everolimus to exemestane compared with everolimus alone and therefore have a third group evaluating everolimus as a monotherapy. To this end, within the scope of being granted Marketing Authorisation, 11 the applicant will be required to implement a study (BOLERO-6 or Y2201) clarifying the benefit of adding exemestane to everolimus compared with everolimus alone. This randomised study will enable a comparison to be made between three treatments (everolimus/exemestane, everolimus alone and capecitabine) in 300 patients with metastatic, oestrogen receptor-positive breast cancer, in relapse or progression after letrozole or anastrozole. The final report for this study is expected in the third quarter of the proportion of patients with symptomatic visceral disease (among the 59% of patients included with visceral disease) therefore likely to have chemotherapy is not known. In the absence of data comparing everolimus to chemotherapy, the Marketing Authorisation indication for everolimus, for locally advanced or metastatic stages, was limited to patients not requiring such intensive treatment, i.e. patients with no symptomatic visceral disease. In summary, given all the points raised above, the level of effect of the combination of everolimus with exemestane is low with the dossier in its current state. Finally, despite preliminary information available, data from the BOLERO-2 pivotal study corresponding to the use of everolimus exclusively in combination with exemestane, the benefit of everolimus combined with non-steroidal aromatase inhibitors is yet to be established Study programmes One study (BOLERO-6) has been requested within the scope of the awarding of the Marketing Authorisation (see Summary and discussion section). Two other phase III studies are in progress, investigating breast cancer: 11 EPAR AFINITOR of 21/06/2012, page 41/79 and Appendix II of the Marketing Authorisation for AFINITOR (everolimus): requirement to implement post-authorisation measures HAS - Medical, Economic and Public Health Assessment Division 14/18

15 - a randomised, double-blind study, CRAD001J2301, evaluating everolimus (versus placebo) in combination with trastuzumab and paclitaxel as first-line treatments for locally advanced or metastatic, HER2 positive breast cancer - a randomised, double-blind study, CRAD001W2301, evaluating everolimus (versus placebo) in combination with trastuzumab and vinorelbine in previously treated patients with locally advanced or metastatic, HER2 positive breast cancer 09 THERAPEUTIC USE AFINITOR combined with exemestane is a second-line treatment and beyond for hormone receptor-positive, HER2/neu negative advanced breast cancer in post-menopausal women without symptomatic visceral disease after recurrence or progression following previous treatments (at adjuvant or metastatic stage) with a non-steroidal aromatase inhibitor (letrozole or anastrozole). In view of the current data, the therapeutic use of this combination is yet to be determined given the uncertainties regarding the additional effect of exemestane for patients who have had previous treatments with non-steroidal aromatase inhibitor and while waiting for the results from the BOLERO-6 study. HAS - Medical, Economic and Public Health Assessment Division 15/18

16 010 TRANSPARENCY COMMITTEE CONCLUSIONS In view of all the above information, and following the debate and vote, the Committee s opinion is as follows: Actual benefit Breast cancer at an advanced stage is a disease that has a life-threatening prognosis. This medicinal product, in combination with exemestane, is intended as a curative therapy, specifically for breast cancer. The efficacy/adverse effects ratio for this combination is low (see Summary and discussion section). Public health benefit: The public health burden of breast cancer is high. The burden of the sub-population of women likely to benefit from AFINITOR, in this extension of the indication, is small. Improving the management of cancer patients and their quality of life is a public health need which is an established priority (specifically the Plan for improving the quality of life of patients with chronic diseases and the Cancer Plan ). In light of the available data (relevance of the combination and questionable comparator medicine, the gain in progression-free survival with no impact on overall survival and the increased toxicity compared with exemestane alone) and while waiting for additional data, the impact of this combination on the morbidity and mortality of patients treated is difficult to determine. Furthermore, no impact was observed on quality of life with the combination compared with everolimus alone in the pivotal study. The transferability of data into current clinical practice is questionable, given the study design. The impact of the combination everolimus-exemestane on care organisation is not quantifiable. Also, AFINITOR, in combination with exemestane, is unlikely to meet an identified public health need. Consequently, taking all of these points into account, AFINITOR combined with exemestane is not expected to benefit public health in this extension of the indication. This medicinal product is a second-line therapy and beyond, i.e. after reccurrence or progression of the disease on or following previous treatment with a non-steroidal aromatase inhibitor (letrozole or anastrozole). Alternative medicinal products exist. Taking account of these points, the Committee considers that the actual benefit of AFINITOR, in combination with exemestane, is low in this extension of the Marketing Authorisation indication Improvement in actual benefit (IAB) In the current state of the dossier, given the uncertainties regarding the benefit of exemestane and the low level of effect of the combination everolimus/exemestane, the Committee considers that the addition of AFINITOR to exemestane, does not provide an improvement in actual benefit (IAB V, non existent) compared with standard hormone receptor-positive HER2/neu negative advanced breast cancer treatments, in post-menopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor. HAS - Medical, Economic and Public Health Assessment Division 16/18

17 010.3 Target population The target population of AFINITOR in combination with exemestane is represented by post-menopausal women with hormone receptor-positive, HER2/neu negative advanced breast cancer, without symptomatic visceral disease after recurrence or progression following previous treatments with a non-steroidal aromatase inhibitor. In the absence of reliable prevalence data for breast cancer, 12 the estimation of the target population is based on its incidence. The annual number of incident cases of breast cancer in France evaluated recently by INCa is 53, The number of cases in post-menopausal women can be estimated by the number of cases affecting women over 50 years, 14 which is 41,711 (78.7%). Between 60% and 70% of breast cancers are hormone receptor-positive (HR+) and do not over-express HER2 (HER2 negative), 15 which is between 25,027 and 29,198. The population of post-menopausal women with metastatic, hormone receptor-positive, HER2 negative breast cancer combines two sub-populations: - immediately metastatic. This sub-group representing 5% 16 to 15% 17 of cases diagnosed is not eligible for the combination everolimus/exemestane; patients should have a reccurrence or progression of the disease and have been previously treated with a non-steroidal aromatase inhibitor; - localised which develops into metastatic. At the localised stage, the reference adjuvant hormone therapy is with aromatase inhibitors. Among the localised stage of the disease, which represents 85% to 95% of cases (which is 21,273-27,738), the proportion of relapse is estimated from data from the ATAC study. 18 According to this data, localised cases treated with an aromatase inhibitor lasting 5 years complying with current guidelines and which progress towards a metastatic stage are estimated as 8%, which is between 1,702 and 2,219 patients who may be eligible for a 1 st line treatment at the metastatic stage. Among these patients, it is possible to deduct those who have previously been treated with exemestane, as well as those who had chemotherapy, and in particular those with symptomatic visceral disease. This latter sub-group is estimated as 40%. 19 Based on these estimations, the target incident population of AFINITOR in combination with exemestane is between 1,100 and 1,330 patients. 12 Cardoso F. Harbeck N. et al. Locally recurrent or metastatic breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up Annals of oncology 23(7) :11-19, INCa. La situation du cancer en France en Collection Rapports & synthèses, ouvrage collectif édité par l INCa, Boulogne-Billancourt, October "Evolution de l incidence et de la mortalité par cancer en France de 1978 à 2002", INVS, October Sotiriou C., Phil D. and Pusztai L.Gene-Expression Signatures in Breast Cancer N Engl J Med 2009; 360: FRANCIM 17 FLNCC investigation 18 Cuzick J., Sestak I. et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial Lancet Oncol 2012;11: Largillier R, Ferrero JM et al. Prognostic factors in women with metastatic breast cancer. Annals of oncology 19(12): , 2008 HAS - Medical, Economic and Public Health Assessment Division 17/18

18 011 TRANSPARENCY COMMITTEE RECOMMENDATIONS The Committee recommends inclusion on the list of medicines refundable by National Health Insurance and on the list of medicines approved for hospital use in the extension of the Marketing Authorisation indication and at the dosage in the Marketing Authorisation. Request for data The Committee would like to be informed about the results of the BOLERO-6 study requested within the scope of awarding the Marketing Authorisation. Packaging Appropriate for the prescription conditions according to the indication, the dosage and the treatment duration. Proposed reimbursement rate: 100% HAS - Medical, Economic and Public Health Assessment Division 18/18