DECISION AND SUMMARY OF RATIONALE

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1 DECISION AND SUMMARY OF RATIONALE Indication under consideration Clinical evidence Vandetanib as 1st line treatment for medullary thyroid cancer Score The application was for the 1st line use of vandetanib as systemic therapy in the treatment of advanced/metastatic medullary thyroid cancer to be retained in the CDF. The CDF was aware that the use of vandetanib in medullary thyroid cancer has not been appraised by NICE. PFS = 7 OS = 0 QoL= 1 Tox = -2 Unmet need = 3 The panel noted that vandetanib was the first tyrosine kinase inhibitor to be licensed for the treatment of medullary thyroid cancer, cabozantinib being the other agent and also available via the CDF as an alternative choice for 1st line therapy. The CDF panel examined the results of the vandetanib trial which was a double blind randomised controlled study against placebo and contained 331 patients with locally advanced or metastatic medullary thyroid cancer. The patients in the vandetanib trial did not have to demonstrate disease progression prior to study entry and could cross over from placebo to vandetanib on disease progression. The median duration of follow-up was 24 months. The primary end point of the study was progression free survival (PFS) and the trial design assumed that the placebo PFS would be 12 months (mo). Previous therapy with a tyrosine kinase inhibitor was allowed although only a very small number of patients were pre-treated in this way. The median PFS in the vandetanib arm was not reached and the estimated PFS (based on statistical modelling of data observed up to the 43rd percentile using the Weibull model) for vandetanib was 30.5 vs 19.3 mo for placebo, 11.2 mo, hazard ratio (HR) 0.46, 95% confidence interval , p< There was no difference in OS on relatively immature follow up, both medians not being reached, HR 0.89, 95% CI The median duration of treatment with vandetanib in the trial was 20.8 mo. Further OS analysis is awaited. The panel noted that patients could come off the trial on investigator-assessed disease progression and then receive open label vandetanib until independent review of the imaging. The panel noted that 93% of progressing patients on placebo subsequently received vandetanib. Of concern to the panel was the finding that 61% of patients progressing on vandetanib, subsequently received it as open label treatment until progression was confirmed by an independent review, this raising the likelihood that actual treatment duration might be considerably longer than just the duration determined by the trial. The panel noted that the European Medicines Agency had restricted the license for vandetanib to patients with aggressive and symptomatic medullary thyroid cancer ie to a smaller population to the one in the trial.

2 The manufacturer submitted the results of a post hoc analysis of 186 patients, the aim of this analysis being to identify the licensed group within the vandetanib trial. This retrospective analysis defined aggressive and symptomatic as those patients with progressive disease (documented progression within 12 months of entry into the trial) and symptomatic as those patients with one of the following: significant pain, opioid use, diarrhoea, flushing, fatigue, nausea, dysphagia, dysphonia, respiratory symptoms and weight loss. There were 186 patients in this group. PFS as measured by independent review (81 events) was 28.0 vs 16.4 mo, 11.6 mo, HR 0.47, 95% CI , p=0.0024, respectively. Investigator-assessed PFS figures (103 events) were 22.1 mo vs 8.3 mo, 13.8 mo, HR 0.33, 95% CI , p<0.0001, respectively. The median duration of treatment with vandetanib in this progressive and symptomatic subgroup was 20.5 mo. In conclusion, the CDF panel accepted that the restriction of the license resulted in the need to retrospectively analyse a corresponding subgroup but preferred to use the independentlyassessed PFS figures for this group ( 11.6 mo), noting that this was very similar to the intention to treat difference ( 11.2 mo). It did not consider that a positive score for OS should be made given the absence of any proven OS benefit in the vandetanib trial (with cross over) and the cabozantinib trial (without cross over) in a disease with a slowly progressive nature. As a consequence of the latter, the CDF panel noted the immaturity of the reported OS results in the vandetanib trial with only 15% of patients having died in the whole cohort and 17% in the symptomatic progressive cohort. Quality of life was measured in this study although this was not mentioned in the primary trial publication. The EPAR stated that there was no difference in the FACT-G scores between the two arms. One patient-reported outcome was reported in the whole cohort, that of time to worsening of pain (a secondary endpoint) and this was greater with vandetanib than placebo, median 8.0 vs 3.0 mo, HR 0.61, 95% CI , p< In the symptomatic progressive cohort, the time to worsening of pain was 11.1 vs 3.4 mo, HR 0.62, 95% CI , p= % of the intention to treat patients had dose reductions of vandetanib vs 3% for placebo. Grade 3 toxicities were as follows: diarrhoea 11 vs 2%, hypertension 9 vs 0%, fatigue 6 vs 1%, anorexia 4 vs 1%, rash 4 vs 1% and ECG Q-T prolongation 8 vs 1%, respectively. 12% of patients discontinued vandetanib on account of drug-related adverse events. In the progressive and symptomatic subgroup, 61% of patients receiving vandetanib suffered a grade 3 adverse event whereas the figure was 24% with placebo. 12% discontinued vandetanib due to adverse events wherease the figure was 2% for placebo. The panel noted that the toxicity of vandetainib is such that a paper had been published describing the management strategies required to manage the sideeffects of vandetanib. The panel observed that the posology of the Summary of Product Characteristics of vandetanib stated that treatment with vandetanib should be initiated and supervised by a physician experienced in the assessment of electrocardiograms and that in view of the associated risks, it is important to limit treatment with vandetanib to patients who are in real need for treatment, ie with a symptomatic-

3 aggressive course of the disease. The CDF panel observed a French retrospective audit of vandetanib in medullary thyroid cancer aimed at describing the toxicity profile and efficacy of the drug when given to 60 symptomatic or diseaseprogressive patients outside a clinical trial. The median duration of follow-up was 20.0 mo. The median duration of treatment was 9.7 mo and 15 patients were continuing on vandetanib for longer than 18 mo. The median PFS was 16.1 mo. 27% of patients discontinued treatment on account of toxicity and one patient died from vandetanib-induced cardiac toxicity. The CDF panel accepted the limitations imposed by the retrospective nature of the audit but was concerned that the median PFS was substantially less than the symptomatic and progressive subgroup identified in the phase 3 trial and that twice as many discontinued vandetanib on account of toxicity. The CDF panel noted the international treatment guidelines for medullary thyroid cancer submitted by the manufacturer and various clinical background papers concerning medullary thyroid cancer. The CDF panel also noted the contents of the European Public Assessment Report for vandetanib in medullary thyroid cancer. 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 medullary thyroid cancer. The CDF panel also examined the results of the cabozantinib study which are summarised here and the more detailed considerations are in the cabozantinib CDF decision summary. The CDF panel observed the trial design of cabozantinib versus placebo and that all patients were required to have evidence of radiological progression of disease in the 14 months prior to entry into the study. Median follow-up was 14 months in the first published report. The panel also observed that cross over was not allowed in this study. The median progression-free survival (PFS) was significantly increased by cabozantinib (11.2 vs 4 mo, hazard ratio [HR] 0.28, 95% confidence interval [CI] , p<0.001). The final overall survival (OS) analysis has been reported in abstract form, there being no difference in median OS, 26.6 vs 21.1 mo, HR 0.85, 95% CI , p=0.24, respectively. Side-effects of cabozantinib over placebo were significantly increased with grade 3 toxicities as follows: diarrhoea 13 vs 0%, palm/sole effects 5 vs 0%, anorexia 5 vs 1%, fatigue 9 vs 3% and hypertension 8 vs 1%. There was no clinically relevant prolongation of the Q-T interval on ECG. Dose delays were observed in 65% and dose modifications in 79%. 6% of patients discontinued cabozantinib on account of drug toxicity. There was no QOL measurement incorporated into the design of this trial. The median duration of treatment with cabozantinib was 10.8 mo. The CDF panel had previously scored the impact of cabozantinib to be as follows: 4 for PFS, 0 for OS, 0 for QOL and minus 1 for toxicity. The CDF had again noted the intention to treat PFS differences in the vandetanib and cabozantinib trials and in particular the very different results for PFS in the placebo arms. It had previously concluded that the

4 only satisfactory explanation for these contrasting PFS figures in the 2 placebo arms related to the types of patients recruited into the studies the cabozantinib trial patients had to have evidence of disease progression whereas the vandetanib patients did not. The CDF panel had again concluded that both drugs were active in medullary thyroid cancer but it was not known whether one was superior to the other in terms of efficacy. Some side effects appeared broadly similar in these contrasting populations entered into these 2 trials but the rate of discontinuation of therapy appeared higher for vandetanib. It was clear, however, that cabozantinib causes less cardiac toxicity and this is an important issue. The panel understood that some comorbidities might result in one drug being preferred to the other drug. The CDF panel scored the vandetanib application as follows: - 7 for PFS (28.0 vs 16.4 mo, 11.6 mo) - 0 for OS (no significant difference) - 1 for QOL - -2 for toxicity - and 3 for unmet need. The overall total score was 9 B. The CDF panel had previously concluded that both drugs could be available via the CDF and clinicians could choose one or the other depending on patient circumstances. The CDF panel again decided that given these unusual circumstances of very different evidence bases and the fact that patient tolerance was an important issue, both drugs could be considered as offering the only systemic therapy for medullary thyroid cancer. The panel considered that in this situation, it was reasonable to insist that both drugs cost the CDF the same. The panel considered that in this situation, it was reasonable to expect that the CDF would pay the same for each drug but if one drug was priced lower than the other, then this drug would be preferred within the CDF for those patients that did not have a comorbidity or tolerance issue which directed treatment to the other drug. The CDF panel wished to see cabozantinib and vandetanib appraised by NICE within a multiple technology appraisal and urged NHS England to use its influence for this to be done. Total clinical score 9B Cost The cost of vandetanib per 4-week cycle at the list price (including VAT) for a patient does not depend on body surface area or weight and for this indication is 5600 (4-week cycle). Conclusion The CDF panel had already concluded that vandetanib could be regarded as being the only systemic therapy available for medullary thyroid cancer for the reasons set out above. Although its cost score was calculated using the CDF rare cancer drug banding system and thus brought the sum of the clinical and cost scores to below the current threshold for retention in the CDF, the use of vandetanib in medullary thyroid cancer was additionally retained in the CDF on account of it being regarded as the sole systemic therapy for medullary thyoid cancer for some of the indicated population. CDF criteria for As per current criteria use

5 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

6 NATIONAL CANCER DRUG FUND PRIORITISATION SCORES Drug Indication Regimen (where appropriate) Vandetanib 1st line treatment for medullary thyroid 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 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 10 to 11 months vs 16.4 mo, 11.6 mo 7 12 to 13 months 7 14 to 15 months 8 16 to 17 months 9

7 18 to 19 months to 21 months to 23 months months 13 Precision of PFS/DFS/TTP (Please quote p value) HR (quoted in trial) Absolute values (HR) e.g ; 95%CI to ; p= Hazard Ratio HR 0.47, 95% CI , p= 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 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 to 21 months to 23 months months 13 Medians were not reached at time of data cut-off 0 Precision of OS (Please quote p value) HR (quoted in trial) Absolute values (HR) e.g ; 95%CI to ; p= Hazard Ratio NA 2 Quality of life

8 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 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 1-2 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 3 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. N/A

9 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: Vandetanib is indicated as single-agent first line treatment of progressive metastatic medullary thyroid cancer (MTC) no longer controlled with symptomatic treatments as anti-diarhial and pain medication. This position is supported by European and American guidelines1,2. Until license of Cabozantinib in March 2014, no other treatments have been approved for patients in this indication in Europe. Cabozantinib is funded by the Cancer Drugs Fund since March 2015 and is the only other treatment option. No other treatments will be replaced. Vandetanib was the first licensed drug by European Medicines Agency in this indication and till license of Cabozantinib in 2014 the only indicated therapy. Therefore no other drugs in the treatment pathway were decreased or increased. Eligibility criteria for treatment with Vandetanib: Eligible patients are adults who have got measurable, unresectable locally advanced or metastatic, hereditary or sporadic MTC without contraindications: Contraindications (SmPC Section 4.3): Contraindicated in patients with congenital long QTc syndrome, patients with an increased QTc interval over 480 msec, in breast-feeding women, and in combination with drugs known to also prolong the QT interval and/or induce torsades de pointes (arsenic, cisapride, erythromycine IV, toremifene, mizolastine, moxifloxacine, Class IA and III antiarrhythmics). In General, Vandetanib may be administered until patients with MTC are no longer benefiting from treatment. Prior to initiation of treatment, QTc interval should be carefully assessed. In the event of common terminology criteria for adverse events (CTCAE) grade 3 or higher toxicity or prolongation of the ECG QTc interval, dosing with vandetanib should be at least temporarily stopped and resumed at a reduced dose when toxicity has resolved or improved to CTCAE grade 1 (see SmPC7 section 4.4). The 300 mg daily dose can be reduced to 200 mg (two 100 mg tablets), and then to 100 mg if necessary. The patient must be monitored appropriately. Due to the 19-day half-life, adverse reactions including a prolonged QTc interval may not resolve quickly (see SmPC7 section 4.4).Cabozantinib should be discontinued in patients who develop nephrotic syndrome.

10 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. N/A References: Please provide Word, pdf or hard copy references with the application

11 1. Wells Samuel A. Jr., Asa Sylvia L., Dralle Henning, Elisei Rossella, Evans Douglas B., Gagel Robert F., Lee Nancy, Machens Andreas, Moley Jeffrey F., Pacini Furio, Raue Friedhelm, Frank-Raue Karin, Robinson Bruce, Rosenthal M. Sara, Santoro Massimo, Schlumberger Martin, Shah Manisha, and Waguespack Steven G.. Thyroid. June 2015, 25(6): doi: /thy Schlumberger M, Bastholt L, Dralle H, et al European Thyroid Association Guidelines for Metastatic Medullary Thyroid Cancer. European Thyroid Journal. 2012;1(1):5-14. doi: / Chougnet Cecile N., Borget Isabelle, Leboulleux Sophie, de la Fouchardiere Christelle, Bonichon Françoise, Criniere Lise, Niccoli Patricia, Bardet Stéphane, Schneegans Olivier, Zanetta Sylvie, Schvartz Claire, Drui Delphine, Chauffert Bruno, Rohmer Vincent, and Schlumberger Martin. Thyroid. April 2015, 25(4): doi: /thy Gilliland, F. D., Hunt, W. C., Morris, D. M. and Key, C. R. (1997), Prognostic factors for thyroid carcinoma. Cancer, 79: doi: /(SICI) ( )79:3<564::AID-CNCR20>3.0.CO; Cancer Research UK - Thyroid cancer incidence statistics 6. Roman S, Lin R, Sosa JA. Prognosis of medullary thyroid carcinoma: demographic, clinical, and pathologic predictors of survival in 1252 cases. Cancer 2006;107: Summary of Product Characteristics Vandetanib _Product_Information/human/002315/WC pdf 8. European Medicines Agency Assessment Report Caprelsa Procedure No.: EMEA/H/C/002315// _Public_assessment_report/human/002315/WC pdf 9. AstraZeneca Submission to GBA - Dossier zur Nutzenbewertung Modul 4 A 10. Wells ZETA paper 11. AstraZeneca Submission to GBA Supporting Data 12. Quayle FJ, Moley JF. Medullary thyroid carcinoma: including MEN 2A and MEN 2B syndromes. J Surg Oncol 2005;89: Orlandi F, Caraci P, Mussa A et al. Treatment of medullary thyroid carcinoma: an update. Endocr Relat Cancer 2001;8: Sherman SI. Advances in chemotherapy of differentiated epithelial and medullary thyroid cancers. J Clin Endocrinol Metab 2009;94: SEER Surveillance, Epidemiology, and End Results (SEER) Program ( SEER*Stat Database: Incidence - SEER 9 Regs Research Data, Nov 2011 Sub ( ) <Katrina/Rita Population Adjustment> - Linked To County Attributes - Total U.S., Counties, National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, released April 2012, based on the November 2012 submission. Available at: Grande E, Kreissl MC, Filetti S, et al. Vandetanib in Advanced Medullary Thyroid Cancer: Review of Adverse Event Management Strategies. Advances in Therapy. 2013;30(11): doi: /s Brierley J, Tsang R, Simpson WJ et al. Medullary thyroid cancer: analyses of survival and prognostic factors and the role of radiation therapy in local control. Thyroid 1996;6: Publication 4 th MC Kreissl, O Hauch, A Webster, M Schlumberger. Efficacy and safety of vandetanib September 2015 in aggressive and symptomatic medullary thyroid cancer (MTC) post-hoc analysis from the ZETA trial (NCT ). Presentation at ETA Annual Meeting 2015.

12 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 9B and a confidential cost score