Everolimus plus exemestane for second-line endocrine treatment of oestrogen receptor positive metastatic breast cancer

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1 LONDON CANCER NEWS DRUGS GROUP RAPID REVIEW Everolimus plus exemestane for second-line endocrine treatment of oestrogen receptor positive metastatic breast cancer Everolimus plus exemestane for second-line endocrine treatment of oestrogen receptor positive metastatic breast cancer Contents Background 1 Epidemiology 2 Safety / Cost 4 Issues for consideration 4 Reference 5 Produced for the London New Drugs Group Contact: Angela Bennett Medicines Information Pharmacist London & South East Medicines Information Service Guy s Hospital London SE1 9RT Tel: Fax: Angela.Bennett@gstt.nhs.uk Further copies of this document are available from URL NeLM-Area/Evidence/Drug- Specific-Reviews/ Produced for use within the NHS. Not to be reproduced for com- Background There were over 48,000 women and around 300 men newly diagnosed with breast cancer in England and during 2009, and over 11,000 deaths (1). Approximately 5% of women presenting with breast cancer have advanced disease with distant metastases (where cancer cells have spread to other parts of the body), and it is estimated that approximately 40 50% of women presenting with early or localised breast cancer will eventually develop metastatic breast cancer (2). The role of current treatments for metastatic breast cancer is to palliate symptoms, prolong survival and maintain a good quality of life with minimal adverse events. Treatment depends on previous therapy, oestrogen receptor status, HER2 status, and the extent of the disease (3). NICE clinical guideline 81 (CG81) for advanced breast cancer, which covers both first and subsequent lines of therapy, recommends endocrine therapy as first-line treatment for the majority of patients with oestrogen receptor positive advanced breast cancer. CG 81 does not include any specific recommendations on the treatment of HER 2 negative, oestrogen receptor positive breast cancer in post-menopausal women whose disease has recurred or progressed following treatment with nonsteroidal aromatase inhibitors. It does recommend however that on disease progression, systemic sequential therapy should be offered to the majority of patients who choose to be treated with chemotherapy. For patients with oestrogen receptorpositive advanced breast cancer who have been treated with chemotherapy as their first-line treatment, endocrine therapy should be offered following the completion of chemotherapy (4). In clinical practice, post-menopausal women often receive anastrozole or letrozole first-line followed by either tamoxifen or exemestane, then exemestane or tamoxifen depending on the previous treatment received. Fulvestrant is licensed for the treatment of oestrogen receptor positive advanced breast cancer with disease relapse or progression after anti-oestrogen therapy (9). It is sometimes used after exemestane and tamoxifen, although this is not recommended by NICE in their technology appraisal guidance (8). Subsequent treatment options are dependent on whether the patient initially presented with early HER2 positive or HER2 negative disease and subsequently developed metastatic HER2 negative breast cancer or if they initially presented with metastatic HER2 negative breast cancer. These include anthracycline-based chemotherapy, taxane monotherapy (docetaxel, paclitaxel or nab-paclitaxel), single agent capecitabine, vinorelbine oral or intravenous preparations, gemcitabine monotherapy or gemcitabine with paclitaxel or carboplatin (3). NICE recommends gemcitabine in combination with paclitaxel as an option for the treatment of metastatic breast cancer only when docetaxel monotherapy or docetaxel plus capecitabine are also considered appropriate (4). Everolimus (Afinitor, Novartis Pharmaceuticals UK) is an oral active inhibitor of the mammalian target of rapamycin (mtor) protein, a central regulator of tumour cell division and blood vessel growth in cancer cells (3). Everolimus is licensed in the U.K for the treatment of hormone receptor-positive, HER2/neu negative advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor (5). There was no comparative data of everolimus plus exemestane with chemotherapy, which is the treatment of choice for patients with more aggressive course of disease characterised by symptomatic visceral disease. Thus, the EMEA proposed that the licensed indication for everolimus in this setting should be restricted to patients without symptomatic visceral disease in order to avoid the possibility of under treatment (10).

2 Epidemiology NICE produced a costing statement for fulvestrant for the treatment of locally advanced or metastatic breast cancer (6). This costing statement will also apply to everolimus in this setting. The calculation of the population eligible for everolimus is as follows: Proportion Number of women Breast cancer diagnosed in 2009 in postmenopausal women invasive breast cancer early and locally advanced invasive breast cancer early and locally advanced invasive breast cancer who will not die before disease progression 36,158 90% 32,542 95% 30,915 70% 21,641 early breast cancer who will develop advanced cancer 35% % 1627 advanced invasive breast cancer at diagnosis Total number of women with locally advanced or 9201 metastatic breast cancer oestrogen-receptor-positive breast cancer oestrogen-receptor-positive cancer for whom endocrine therapy is appropriate Number of postmenopausal women in whom disease progresses or relapses while on or after adjuvant anti-oestrogen therapy 85% % % 1752 Women eligible for everolimus 1752 With a total population of ~55 million, the number of patients eligible per 100,000 population would be 3.18/100,000. This costing statement does not take in to account HER2 status. NICE advanced breast cancer costing template, 2009, states that HER2 negative status accounts for 75% of these patients. Therefore, the number of patients eligible for everolimus who have HER2 negative disease would be 2.4/100,000.

3 Published data There is one phase III, international, double-blind, randomised control trial (BOLERO-2) evaluating the efficacy and safety of the combination of everolimus with exemestane compared to exemestane with placebo in patients with hormone-receptor-positive breast cancer refractory to non-steroidal aromatase inhibitors (e.g. letrozole or anastrozole) (7). The study was sponsored by Novartis. The data were analysed by the sponsor s statistical team. Eligibility criteria included: Postmenopausal women with oestrogenreceptor-positive, HER2 negative metastatic or locally advanced breast cancer. Disease refractory to previous letrozole or anastrozole (defined as recurrence during or within 12 months after the end of adjuvant treatment or progression during or within 1 month after the end of treatment for advanced disease). Other previous anticancer endocrine treatments and a single prior chemotherapy regimen for advanced disease were allowed. At least one measurable lesion, or mainly lytic bone lesions in the absence of measurable disease. ECOG performance status of 2 or less. Adequate organ and haematological functions. Exclusion criteria included a history of brain metastases and previous treatment with exemestane or mtor inhibitors. 724 women in 24 countries were randomised in a 2:1 ratio to receive oral everolimus 10mg daily in combination with exemestane 25mg daily (485 patients) or placebo with exemestane 25mg daily (239 patients). Randomisation was stratified according to the presence of visceral metastases, and previous sensitivity to endocrine therapy (defined as at least 24 months of endocrine therapy before recurrence in the adjuvant setting, or a response or stabilisation for at least 24 weeks of endocrine therapy for advanced disease). The primary endpoint for the trial was progressionfree survival (PFS), based on radiographic studies assessed by the local investigators, with central assessment by an independent radiology committee used in a supportive analysis. Secondary endpoints included overall survival, overall response rate, clinical benefit rate, time to deterioration of ECOG performance status, safety, and quality of life (using the European Organisation for Research and Treatment of Cancer quality-of-life core questionnaire (QLQ- C30) and the breast cancer module (QLQ-BR23)). The trial arms were well balanced at baseline in terms of patient and tumour characteristics. The median age was 62 years (range 28 93). It is noted that over 80% had received at least two previous therapies and over 50% had received 3 or more previous therapies. Only 16% and 18% of patients recruited to the arms that received everolimus plus exemestane and exemestane alone had received only one line of treatment (either letrozole or anastrozole). 56% of patients had visceral involvement and 76% had bone metastases. Thirty-six percent of patients had metastases in at least three organs. At the cut-off date, 296 patients were still receiving study treatment (227 (47%) in the everolimus/ exemestane arm and 69 (29%) in the exemestanealone arm). The most frequent primary reason for discontinuation was disease progression (37% in the everolimus/exemestane arm and 66% in the exemestane-alone arm). The main results were as follows: The median PFS based on radiographic studies assessed by the local investigators (primary endpoint) was 6.9 months for everolimus plus exemestane versus 2.8 months for placebo plus exemestane, resulting in an absolute gain of 4.1 months (hazard ratio for progression or death 0.43; 95% CI ; P<0.001). The median PFS based on central assessment (supportive analysis) were 10.6 months for everolimus plus exemestane versus 4.1 months, resulting in an absolute gain of 6.5 months (hazard ratio 0.36; 95% CI ; P<0.001). A subgroup analysis shows that the relative benefit achieved with PFS was not significantly affected by the number of previous therapies received (1, 2, or 3 or more). Response rates, based on local assessment, were 9.5% and 0.4% in the everolimus/ exemestane combination arm and exemestane-alone arms, respectively (P<0.001). Central assessment showed consistent results. At the time of analysis survival data were immature with death rates of 10.7% and 13% observed in the combination and control arms respectively. Piccart et al presented updated results at ASCO, 2012 (12). They reported that median PFS was 7.8 months in the everolimus/exemestane arm compared to 3.2 months in the placebo/exemestane arm and, at the cut-off date, 200 deaths had occurred: 25.4% in the everolimus/exemestane arm and 32.2% in the placebo plus exemestane arm.

4 Safety The combination regimen in the BOLERO-2 trial was associated with a significantly higher rate of Grade 3/4 adverse events - 23% (of which 11% were attributed to the allocated treatment) versus 12% (of which 1% was attributed to the allocated treatment). This difference was also reflected in the drug discontinuation rates reported: 19% of patients discontinued everolimus compared with 4% that discontinued placebo and 7% discontinued exemestane in the combination arm compared with 3% in the control arm. The most common grade 3 or 4 toxicities reported were stomatitis (8% vs 1%), anaemia (6% vs <1%), dyspnea (4% vs 1%), hyperglycaemia (4% vs <1%), fatigue (4% vs 1%) and pneumonitis (3% vs 0). The authors however report that no significant differences in impact on quality of life were detected but they do not present the relevant data to support this within the trial report. Cost The price of 30 tablets of everolimus 10mg is approximately 3500 (including VAT at 20%). Patients in the BOLERO-2 trial had a median duration of exposure of 23.9 weeks according to updated results presented in December 2012 (11). This gives an additional cost per patient of approximately 19,600. Assuming epidemiology of 2.4/100,000, this would mean an additional cost of 47,000 per 100,000 population. Summary / Points for consideration BOLERO-2 is a high quality trial which showed that the combination regimen was associated with a month increase in median progression free survival compared with exemestane alone. The trial was not powered to assess impact on overall survival and at present that data are immature. The benefit described was seen in a population of women with fairly advanced disease - over 50% had received 3 or more previous lines of therapy, over 80% had received two or more lines of treatment and only 20% had just received one line of treatment. Similarly 56% of patients had visceral involvement and 76% had bone metastases at the time of recruitment. The combination regimen was associated with an increased incidence of serious adverse events and about 10% more patients that receive this regimen will develop a grade 3/4 adverse event than if they received singleagent exemestane. There are NICE approved treatments available for this group of patients. Fulvestrant is available within London via the CDF for third or fourth line use. There was no comparative data of everolimus plus exemestane with chemotherapy, which is the treatment of choice for patients with more aggressive course of disease characterised by symptomatic visceral disease. Thus, the EMEA proposed that the licensed indication for everolimus in this setting should be restricted to patients without symptomatic visceral disease in order to avoid the possibility of under treatment. There are potentially 3 patients per 100,000 population per year that might be considered for this regimen as licensed.

5 Drug Indication Incidence (number of patients per 100,000 eligible for this treatment) Average duration of treatment (taken from trial data) Cost per month/ cycle Cost per 100,000 population per month/ cycle Cost per 100,000 for average treatment duration Everolimus (with exemestane) 2 nd line ER+ HER2- advanced breast cancer, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a nonsteroidal aromatase inhibitor 2.4/100, months (median PFS by central assessment as treatment was until progression) 3500 (inc VAT) 8,400 (inc VAT) 89,000 (inc VAT) References 1. Cancer Research UK breast cancer incidence statistics. Accessed Available at types/breast/incidence/ 2. NICE Advanced Breast Cancer guideline needs assessment. Accessed Available at live/11778/44045/44045.pdf 3. NICE draft scope for Technology Appraisal: Everolimus in combination with exemestane for the treatment of advanced or metastatic HER2 negative, oestrogen receptor positive breast cancer after prior endocrine therapy. Accessed Available at live/13866/60583/60583.pdf 4. NICE clinical guideline 81. Advanced Breast Cancer. February Available at live/11778/43414/43414.pdf 5. Summary of Product Characteristics. Afinitor (everolimus) tablets. Novartis. Revised Available at 6. Patient information website for breast cancer (patient.co.uk). Accessed Available at 7. Baselga J. et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. New England Journal of Medicine. 2012; 366(6): NICE Technology Appraisal 239. Fulvestrant for the treatment of locally advanced or metastatic breast cancer. December Available at live/13631/57558/57558.pdf 9. Summary of Product Characteristics. Faslodex (fulvestrant) 250mg injection. Revised Available at EMEA Assessment Report for everolimus in breast cancer Accessed Available at en_gb/document_library/epar_- _Assessment_Report_-_Variation/ human/001038/wc pdf 11. Piccart M et al. Final progression-free survival analysis of BOLERO-2: A phase III trial of everolimus for postmenopausal women with advanced breast cancer. San Antonio breast cancer symposium, December Piccart M et al. Everolimus for postmenopausal women with advanced breast cancer: Updated results of the BOLERO-2 phase III trial. ASCO June 2012

6 Details of search strategy: NeLM Micromedex Cochrane Library 1. EMBASE; EVEROLIMUS/; 8234 results. 2. EMBASE; EXEMESTANE/; 3152 results. 3. EMBASE; BREAST CANCER/; results. 4. EMBASE; METASTASIS/; results. 5. EMBASE; 1 AND 2 AND 3 AND 4; 19 results. 6. EMBASE; 1 AND 2 AND 3; 124 results. 7. MEDLINE; everolimus.ti,ab; 1619 results. 8. MEDLINE; BREAST NEOPLASMS/; results. 9. MEDLINE; exemestane.ti,ab; 680 results. 10. MEDLINE; 7 AND 8 AND 9; 3 results. 11. EMBASE,MEDLINE; Duplicate filtered: [1 AND 2 AND 3], [7 AND 8 AND 9]; 127 results. The document reflects the views of LCNDG and may not reflect those of the reviewers Please direct any comments to Angela Bennett, London & South East Medicines Information Service, Guy s Hospital, Great Maze Pond, London SE1 9RT Tel: , Fax: ,