DECISION AND SUMMARY OF RATIONALE

DECISION AND SUMMARY OF RATIONALE Indication under consideration Clinical evidence Everolimus in combination with exemestane hormone therapy for oestrogen receptor positive locally advanced or metastatic breast cancer Score The application was for everolimus to remain in the CDF as part of a combination with exemestane hormonal therapy for patients with locally advanced or metastatic breast cancer whose tumours are positive for the oestrogen receptor and negative for the HER-2 receptor and who are also without symptomatic visceral disease. The CDF panel was aware that this indication for everolimus has been appraised but not approved by NICE. The CDF panel was aware that the manufacturer plans to re-submit to NICE the everolimus indication in breast cancer. PFS = 3 OS = 0 QoL= 1 Tox = -1 Unmet need = 0 There was one randomised trial (the BOLERO-2 study) submitted by the manufacturer as the main evidence base related to this indication. This randomised 724 patients with metastatic breast cancer previously untreated with exemestane but previously treated with another aromatase inhibitor (as adjuvant treatment or for advanced disease or for both) to receive everolimus plus exemestane vs placebo plus exemestane. The primary end point was investigator-assessed progression free survival (PFS). Updated PFS was based on 510 events and was significantly greater with everolimus (7.8 vs 3.2 mo, 4.6 mo, hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.38-0.54, p<0.0001) respectively and overall survival (OS) was not significantly different. Updated independently reviewed PFS was based on 320 events and was significantly greater with everolimus (11.0 vs 4.1 mo, 7.1 mo, HR 0.38, 95% CI 0.31-0.48, p<0.0001) respectively. Cross over was not allowed in this study. The manufacturer submitted subgroup analyses from the BOLERO-2 study, the paper on this primarily examining the effect of visceral metastases on outcomes. 56% of the trial participants had visceral spread of their breast cancer (ie disease in the liver, lungs, pleura and peritoneum). Stratification in the trial had been according to the presence of visceral metastases and previous sensitivity to endocrine therapy. Pre-planned analyses had specified the comparison of outcomes for patients with visceral secondaries versus those without (ie disease in the bones, lymph nodes and skin). The conclusion from these analyses was that the benefits of everolimus were achieved regardless of the presence of visceral metastases. A pre-specified analysis examined the effect of everolimus on 151 patients with just bone secondaries, the PFS being 12.9 vs 5.3 mo, 7.6 mo, HR 0.33, 95% CI 0.21-0.53, p<0.05, respectively. This latter bone only group was also submitted for scoring in the manufacturer s CDF application. The CDF panel was concerned that this subgroup represented a relatively small subgroup within the trial (21% of the enrolled populations) and that assessing PFS for bone disease was very difficult in metastatic breast

cancer. It was concerned that this bone only subgroup was not sufficiently robust for separate consideration. Toxicity was increased in the everolimus arm with increased grade 3 and 4 stomatitis, anaemia, pneumonitis and fatigue. 67% of patients receiving everolimus required dose interruptions or reductions of dose. The rate of discontinuation of trial medication was 26 vs 5%, respectively. The median duration of treatment in the everolimus arm was 23.9 weeks (5.5 mo). Quality of life data was collected in the study using the EORTC QLQ- C30 general questionnaire and its breast cancer module. The times to deterioration in quality of life were not statistically different between the two treatment groups. The panel noted the toxicity recorded in the everolimus arm and the high rates of dose interruptions and reductions, together with the much greater rate of discontinuation of trial medication in the everolimus arm. It discussed whether in this setting with the comparator being the use of exemestane with its relatively well tolerated profile of side-effects, the score should be minus 2 for toxicity. However, it noted the maintenance of QOL in the study and thus scored toxicity as being minus 1. The CDF panel considered whether everolimus fulfilled the CDF criteria for the scoring of unmet need. It recognised that there were other systemic therapies available in breast cancer. It also did not regard the benefits of everolimus in this indication to be a step change in the management of breast cancer as there was no proven overall survival advantage and the absence of any differential tail in the PFS curve over time. The CDF panel thus declined to award everolimus a positive score for unmet need. The CDF panel understood that its decision making could affect the opportunity for patients and clinicians in England to participate in international trials of the systemic therapy of breast cancer. The panel chose to use the intention to treat PFS data as used in the primary end point for analysis ie with investigator-assessed PFS. It did not regard the subgroup of patients with only bone metastases to be robust and was also not the requested indication for CDF use by the manufacturer. The panel s scores for everolimus in combination with exemestane in advanced breast cancer were as follows: - 3 for PFS (7.8 vs 3.2 mo, 4.6 mo) - 0 for OS (no significant difference) - 1 for QOL - minus 1 for toxicity - 0 for unmet need - and this resulted in a total of 3B. The CDF panel considered that its scoring of 0 for OS was appropriate as there had been no statistical significant difference observed in OS and crossover to everolimus from the control arm had not been allowed

in this study. In addition, it was aware that there were a number of treatment options available to patients in the study after disease progression (other hormonal therapies, a variety of chemotherapies). Cost Conclusion CDF criteria for use Total clinical score 3B The cost of everolimus per 4-week cycle at the list price (including VAT) for a patient for this indication is 3326. The median drug cost of everolimus resulted in this indication scoring a value within the confidential CDF cost scoring system which, when combined with the clinical score of 3, resulted in an overall score which represented insufficient value for retention within the CDF. However, the manufacturer expressed a clear intent to comply with the requirements as set out in 6.16 of the CDF Standard Operating Procedures and thus everolimus in this indication in breast cancer was retained in the CDF pending agreement of appropriate arrangements. As per current criteria Key for strength of evidence: Criteria Two or more good quality Phase III Randomised Controlled Trials, both published One good quality Phase III Randomised Controlled Trial, published Comparative Phase II trial, published Non-Comparative Phase II, published Unpublished data (in abstract form only) 1 Unpublished data (in abstract form only) 2 Grade A B C D U1 U2

NATIONAL CANCER DRUG FUND PRIORITISATION SCORES Drug Indication Regimen (where appropriate) Everolimus In combination with exemestane hormone therapy for oestrogen receptor positive locally advanced or metastatic breast cancer As above 1 Magnitude of Survival Benefit (progression free survival and overall survival) Additional incremental benefit over comparator treatment in pivotal Phase III trial. Abstracts will be accepted if they are updates of published and peer-reviewed papers Phase II data allowable only for: rare cancers or rare subgroups, e.g. of common cancers or patients with refractory/relapsed disease when Phase III trial is unlikely because of rarity of condition and small case numbers. Quality trial criteria would be when a valid historical control group is available or there are several preferably large studies with similar patient eligibility or inclusion criteria and pre-specified patient outcomes. Score half the points for Phase II evidence (PFS only) i.e. divide PFS score by 2. For phase II trials, do not score for OS. Phase I data is not appropriate. Record exact score to one decimal place if necessary (e.g. 2.5). Specify where Phase III data may be in progress, where Phase II data have been quoted. If the main evidence base is a randomized phase II study, then score as for phase III study if comparator(s) appropriate; indicate clearly in this situation that this is data from a randomized phase II study NB where the time falls halfway between two scores, use the higher score. 1.A Disease Free Survival, Progression Free Survival, Time to Treatment Progression (Specify) DFS Y/N PFS Y/N TTP Y/N Other (specify) Of trials which report measures of PFS,DFS and TTP, it is the primary specified outcome measure for the trial which is to be used for scoring purposes Criteria Score Absolute values for benefit e.g. 12.3 months versus 8. 4 months = 3.9 months (Please quote p value below) Less than 2 months 0 Recorded Score 2.0 to 3.0 months 2 4 to 5 months 3 6 to 7 months 4 8 to 9 months 5 7.8 vs 3.2 mo, 4.6 mo 3 10 to 11 months 6 12 to 13 months 7

14 to 15 months 8 16 to 17 months 9 18 to 19 months 10 20 to 21 months 11 22 to 23 months 12 24 months 13 Precision of PFS/DFS/TTP (Please quote p value) HR (quoted in trial) Absolute values (HR) e.g. 0.821 ; 95%CI 0.673 to 1.001 ; p= 0.051 Hazard Ratio Hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.38-0.54, p<0.0001 1.B Overall Survival If Phase II data, the score for OS benefit will automatically be set at zero, unless it is a randomized phase II study (with appropriate comparators and marked clearly as a randomized phase II study) or there is a very robust comparison possible with a contemporaneous study of equivalent patients who did not receive the treatment under evaluation. Criteria Score Absolute values for benefit e.g. 12.3 months versus 8. 4 months = 3.9 months (Please quote p value below) Less than 2 months 0 Recorded Score 2 to 3 months 2 4 to 5 months 3 6 to 7 months 4 8 to 9 months 5 10 to 11 months 6 12 to 13 months 7 14 to 15 months 8 16 to 17 months 9 18 to 19 months 10 20 to 21 months 11 22 to 23 months 12 24 months 13 31.0 months versus 26.6 months (not significant) 0 Precision of OS (Please quote p value) HR (quoted in trial) Absolute values (HR) e.g. 0.821 ; 95%CI 0.673 to 1.001 ; p= 0.051 Hazard Ratio No statistically significant difference in OS (HR = 0.89 (95% CI, 0.73-1.10; Log-rank P= 0.1426

2 Quality of life Criteria Score Recorded Score Published evidence of significant improvement in overall Quality of Life (QOL), using a validated tool. 2 Measurable evidence of significant improvement in relevant aspect(s) of QOL using a validated tool or evidence of lack of deterioration in overall QOL using a validated tool or clear evidence of major improvement in QOL without validated tool (e.g. clinically significant reduction in blood transfusion) No QOL data collected in the trial or QOL data not analysed 0 1 1 Measurable evidence of significant deterioration in relevant aspect(s) of QOL using a validated tool or clear evidence of major deterioration in QOL without a validated tool (e.g. clinically significant increase in incidence of febrile neutropenia) Published evidence of significant deterioration in overall QOL using a validated tool. Minus 1 Minus 2 3 Toxicity compared to the existing active standard therapy (best supportive care is considered an active standard therapy for the purposes of scoring toxicity). Criteria Score Recorded Score Significant improvement 2 Improved 1 Equal 0 Worsened Minus 1-1 Significantly worsened Minus 2 4 Degree of clinical unmet need, i.e. either the first demonstration of efficacy of a systemic therapy for the disease concerned or a step change for the clinical setting concerned. N.B. If there has been no score in section 1 of this tool, then no score can be assigned for this section unless case made for exception Criteria Score Recorded Score or N/A This drug is the first demonstration of efficacy of a systemic therapy for the disease concerned or a step change for the clinical setting concerned 3 0 Neither of the above applies 0

5 Cost per QALY if available. The Costs per QALY calculated by NICE in the course of an appraisal are the most accurate costs per QALY for use in England and Wales. NB Cost per QALY scores will only be used as a tie-breaker for prioritisation in the event of the overall scores incorporating evaluation of clinical efficacy and median drug cost being equal and cost per QALY data is available for compared options at the same drug prices offered to the CDF. The NICE TA number must also be identified below. Cost per QALY, NICE TA identification number and confirmation that this cost/qaly has incorporated the same price as offered to the CDF must be set out here. Manufacturer stated: The current cost per QALY gained is 68k. This cost per QALY was generated from an old NICE appraisal and is no longer accurate in the the current clinical environment as the data set from BOLERO-2 has matured. Novartis have indicated that they would like to resubmit everolimus in it s breast cancer indication and are in dialogue with NICE 6 Cost A further score will be given depending on the median cost of the drug under evaluation. This score will depend on the cost bands used by the NCDF Panel. This scoring system and the score for a drug in this scoring system remains commercially confidential as it would provide an indication of the cost at which the drug was offered to the CDF. 7 Treatment pathway and other key clinical issues Describe the place in the treatment pathway that this application refers to. Set out what the standard comparators are to this application in terms of everyday practice in England State the treatments that this drug will replace and thus be potentially eligible for de-commissioning State whether introduction of this drug/indication into the treatment pathway will increase, decrease or not change the other treatment options in the pathway Set out the eligibility criteria for treatment with this drug/indication State what the rules should be for continuation and discontinuation of the drug/indication Set out the evidence of national support for this application

Manufacturer stated: Metastatic breast cancer treatment pathway There is good evidence to support the use of endocrine therapy in postmenopausal women with ER-positive advanced breast cancer and as such NICE make the following recommendations: o Offer endocrine therapy as first-line treatment for the majority of patients with ER-positive advanced breast cancer. [Advanced breast cancer (update) NICE clinical guideline 81, 2014 ] o Offer chemotherapy as first-line treatment for patients with ER positive advanced breast cancer whose disease is imminently life-threatening or requires early relief of symptoms because of significant visceral organ involvement, providing they understand and are prepared to accept the toxicity. [Advanced breast cancer (update) NICE clinical guideline 81, 2014] o For patients with ER-positive advanced breast cancer who have been treated with chemotherapy as their first-line treatment, offer endocrine therapy following the completion of chemotherapy. [Advanced breast cancer (update) NICE clinical guideline 81, 2014] Endocrine therapy options for postmenopausal women with hormone receptor positive (HR+) advanced breast cancer include selective non-steroidal aromatase inhibitors (NSAI); anastrozole and letrozole, the steroidal aromatase inhibitor (AI) exemestane, the oestrogen receptor (ER) antagonist fulvestrant, and the selective ER modulator (SERM) tamoxifen. Aromatase inhibitors are generally prescribed as the first line of therapy for the treatment of postmenopausal women with ER+ breast cancer [Beslija 2009, Cardoso 2011, NCCN 2011.2]. Despite the broad spectrum of available options of endocrine therapy for patients with HR+ ABC, all patients will eventually develop resistance to initial treatment and their disease will progress. As highlighted by NICE [NICE clinical guideline 81, 2014] there is little evidence to determine optimal sequencing of hormone therapy once a patient progresses on their first line treatment. The BOLERO-2 study provides data to demonstrate the efficacy of everolimus plus exemestane in this setting. Other available options, based on common clinical practice and several treatment guidelines (e.g. National Comprehensive Cancer Network [NCCN] treatment guidelines 2009), include fulvestrant and exemestane. Following registration, the combination of everolimus plus exemestane is recommended by the NCCN [NCCN 2014.3], The German Arbeitsgemeinschaft Gynäkologische Onkologie e.v. (AGO) [Arbeitsgemeinschaft Gynäkologische Onkologie 2013] and Canadian consensus guidelines which specifically recommend everolimus plus exemestane as a first line option following relapse within 12 months on an adjuvant AI and second line after pretreatment with at least a non-steroidal AI in the metastatic and/or adjuvant setting. The Canadian Consensus clinical practice guidelines have also recommended everolimus plus exemestane therapy for HR+, HER2 advanced breast cancer in most clinical cohorts as a result of the rigour of the evidence and the magnitude of the clinical benefit [Pritchard 2013] Included in this application are two data sets. The first data set relates to the entire BOLERO-2 patient population and generates a score of 3B according to this scoring tool. The PFS benefit of everolimus in combination with exemestane was prospectively evaluated in several patient subgroups, including a subgroup defining patients according to the presence of bone-only metastases. This is a robust cohort of patients, whose disease characteristics are measured in routine clinical practice to inform treatment decisions. In this cohort, the absolute difference in PFS in favour of the everolimus plus exemestane arm versus control was 7.6 months. The overall score attributed to this subgroup as per the scoring tool is 5B. We would respectfully ask that this sub-group is considered as part of this review.

8 Strength of Evidence Criteria Grade Recorded Grade Two or more good quality Phase III Randomised Controlled Trials, both published A One good quality Phase III Randomised Controlled Trial, published Comparative Phase II trial, published B C B Non-Comparative Phase II, published Unpublished data (in abstract form only) 1 Unpublished data (in abstract form only) 2 D U1 U2 1 Appropriate methodology for the treatment setting, presented at an international meeting 2 Methodology inappropriate for treatment setting and/or not presented at international meeting 9 Overall score The overall score will take into account the score of clinical benefit in conjunction with the assessment of median drug cost. This score is subject to interpretation and modification by the NCDF Panel if the scoring tool does not adequately reflect the assessed clinical benefit. This overall score is commercial in confidence as it includes the price at which the drug is made available to the CDF. 10 References and Search Strategy: PubMed Search Strategy: Indicate below e.g.: Search terms (MeSH Terms) used in PubMed searches and dates of access for websites viewed. Everolimus, exemestane, advanced breast cancer, guidelines, NICE References: Please provide Word, pdf or hard copy references with the application

Advanced breast cancer (update) Diagnosis and treatment. NICE clinical guideline 81 Issued July 2014. Available at: http://www.nice.org.uk/guidance/cg81/resources/guidance-advancedbreast-cancer-update-pdf. Accessed 3 Nov 2014 Afinitor summary of product characteristics. Updated 27 Nov 2014. Available at: http://www.medicines.org.uk/emc/medicine/27051. Accessed 02 Nov 2014 Arbeitsgemeinschaft Gynäkologische Onkologie (2013) Diagnosis and treatment of patients with primary and metastatic breast cancer: guidelines of the AGO Breast Committee. www.ago-online.de. Accessed 3 Nov 2014 Aromasin summary of product characteristics. Update Jan 2013. Available at: https://www.medicines.org.uk/emc/medicine/2484 Baselga J, Campone M, Piccart M, et al (2012) Everolimus in Postmenopausal Hormone Receptor-Positive Advanced Breast Cancer (BOLERO-2) N Engl J Med 2012; 366: 520 529. Beslija S, Bonneterre J, Burstein HJ, et al (2009) Third consensus on medical treatment of metastatic breast cancer. Ann Oncol; 20(11): 1771-1785. Burris et al (2013) Health-Related Quality of Life of Patients With Advanced Breast Cancer Treated With Everolimus Plus Exemestane Versus Placebo Plus Exemestane in the Phase 3, Randomized, Controlled, BOLERO-2 Trial. Cancer; 15; 119(10): 1908-15. Campone M et al (2013) Effect of visceral metastases on the efficacy and safety of everolimus in postmenopausal women with advanced breast cancer: Subgroup analysis from the BOLERO-2 study. European Journal of Cancer; 49; 2621-2632. Cardoso F, Fallowfield L, Costa A, et al (2011) Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol; 22 (Suppl 6): vi25-30. Everolimus, 5mg and 10mg tablets (Afinitor ) SMC No. (872/13) http://www.scottishmedicines.org.uk/smc_advice/advice/872_13_everolimus_afinitor/everol mus_afinitor NCCN clinical practice guidelines in oncology. Available at: http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed 3 Nov 2014 NICE technology appraisals TA295 Everolimus in combination with exemestane for treating advanced HER-2 negative hormone receptor positive breast cancer after endocrine therapy. Available at: http://www.nice.org.uk/guidance/ta295 : Accessed 02 Nov 2014 Polanyi Z et al (2014) A Cost Effectiveness analysis of Everolimus plus Exemestane compared to chemotherapy agents for the treatment of ER+ HER2- Metastatic Breast Cancer in the United Kingdom. Presented at the ISPOR, 17th Annual European Congress, Amsterdam, 8-12 NOV 2014 Pritchard KI, Gelmon KA, Rayson D, Provencher L, Webster M, McLeod D, Verma S. Endocrine therapy for postmenopausal women with hormone receptor-positive HER2-negative advanced breast cancer after progression or recurrence on nonsteroidal aromatase inhibitor therapy: a Canadian consensus statement. Curr Oncol. 2013; 20(1):48 61. Yardley DA, Noguchi S, Pritchard KI et al (2013) Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression free survival analysis. Adv Ther; 30(10): 870-884. 11 Additional Information: For example: Definitive benefits of new treatment not captured above Trial data planned to prove non-inferiority with existing standard treatment. No unpublished/ In-House/Data on File Pharma contributions to be submitted

N/A For NCDF Panel use only Total Score Additional Notes 3B and a confidential cost score