Overall survival: 1 st line therapy

2-year OS phase III studies mm Prices per month of oncology medicin Bloomberg Business weekly 26 Feb 2015

Presented By Veena Shankaran at 2016 ASCO Annual Meeting Presented By Veena Shankaran at 2016 ASCO Annual Meeting

30 countries, leading national melanoma centers 30 countries filled the survey 35 oncology Sweden center included 500 Russian Federation 4000 Belgium 350 Poland 1000 Belarus 250 Slovenia 150 Spain 400 Albania 30

Western Europe Eastern Europe and South Eastern Europe VEMURAFENIB DABRAFENIB VEMURAFENIB COBIMETINIB DABRAFENIB TRAMETINIB IPILIMUMAB PEMBROLIZUMAB NIVOLUMAB Austria Belgium ** ** Denmark France Germany Greece ** ** Italy Netherlands Portugal ** ** ** ** ** ** ** Spain *** *** Sweden Switzerland ** UK Albania Belarus Bosnia and Herzegovina Bulgaria Croatia Czech republic * * ** ** Estonia Hungary ** ** ** ** ** Lithuania Macedonia Montenegro ** Poland * * ** ** Romania Russia *** **** **** ** Serbia Slovenia Ukraine Registered Reimbursed Not registered Not reimbursed Switzerland: T-Vec registration and reimbursement *Reimbursed, but only for first-line treatment **Reimbursed, but with large and time-consuming administrative work needed to obtain the medicine for the patient ***Reimbursed, but not fully available due to the hospital-restricted budget ****Reimbursed, but not available due to the drug shortage

Country Estimated total number of metastatic melanoma patients Estimated % of patients treated with innovative medicines Estimated % of patients without access to innovative medicines Western Europe Austria 200 >90% 10%* / Belgium 350 70-90% 10%* / Denmark 350 >90% 10%* / France 2000 >90% 10%* / Germany 3000 >90% 10%* / Greece NA 70-90% 10%* / Italy 2000 70-90% 10%* / Netherlands 800 70-90% 10%* / Portugal 200 30-50% 50% 100 Spain 400 70-90% 10%* / Sweden 100 50-70% 30%* / Switzerland 350 70-90% 10%* / UK 2000 10-30% 10%* / Total WE 11750 100 Eastern and South-Eastern Europe Albania 30 10-30% 70% 21 Belarus 250 <10% 90% 225 Bosnia and 60 <10% 90% 54 Herzegovina Bulgaria 150 30-50% 50% 75 Croatia 100 10-30% 70% 70 Czech republic 400 30-50% 50% 200 Estonia 50 50-70% 30% 15 Hungary 400 50-70% 30% 120 Lithuania 50 30-50% 50% 25 Macedonia 80 <10% 90% 72 Montenegro 30 10-30% 70% 21 Poland 1000 70-90% 10%* / Romania NA 10-30% 70% NA Russia 4000 <10% 90% 3600 Serbia 200 <10% 90% 180 Slovenia 150 >90% 10%* / Ukraine 500 <10% 90% 450 Total SEE 7450 5128 Total WE+EE+SEE 19250 5228 Estimated number of patients without access to innovative medicines 19250 patients with metastatic melanoma in Europe 7450 (39.7%) treated in Eastern and South-Eastern Europe 5128/7450 (69%) do not have the access to first-line therapy recommended by the European guidelines (ESMO, EDF/EORTC/EADO). 5228/19250 (27%), i.e. almost third of all metastatic melanoma patients do not have access to innovative medicines. *never in the first-line treatment

Serbia: vemurafenib reimbursed (without MEK inhibitor) pembrolizumab reimbursed for BRAF negative patients Croatia: dabrafenib trametinib reimbursed pembrolizumab reimbursed Romania: vemurafenib, dabrafenib trametinib nivolumab reimbursed Estonia: nivolumab, pembrolizumab reimbursed BRAF+MEK inhibitor reimbursed DELAY IN ACCESS THROUGH REIMBURSEMENT: 4-5 YEARS

Country Austria Belgium Bulgaria Croatia Cyprus Czech Republic Denmark Estonia Finland France Germany Greece Hungary Iceland Ireland Italy Latvia Lithuania Luxembourg Malta Netherlands Norway Poland Portugal Romania Slovakia Slovenia Spain Sweden Switzerland United Kingdom nivo+ipi X X X X X X X X X X X X EMA registration: May 2016 Reimbursed in 32.4% countries

Difficulties in implementing CU and EAP programmes: unharmonised legislative in some countries programmes are active only until the EMA registration, while reimbursement is in significant delay Insufficient number of clinical studies At least one clinical study for stage IV melanoma was available in 12/13 (92%) Western centers, and 6/17 (35%) from Eastern Europe centers in the survey period.

Clinically meaningful benefit of the treatment Acceptable toxicity profile Improvement of quality of life 17

MCBS v1.1 19

Grading derived from the ESMO-MCBS provides a backbone for value evaluations for cancer medicines. ESMO-MCBS A+B for curative therapies and 4+5 for noncurative therapies should be highlighted for accelerated assessment of value and cost-effectiveness. While a high ESMO-MCBS score does not automatically imply high value (that depends on the price), the scale can be used to frame such considerations and can help public policymakers advance accountability for reasonableness in resource allocation deliberations 21

Presented By Elisabeth De Vries at 2017 ASCO Annual Meeting 22

1. ESMO in current and future guidelines 2. Doctors in everyday practice (patient care and teaching) 3. Academic groups 4. Industry 5. Organisations and countries using the scale as policy tool Presented By Elisabeth De Vries at 2017 ASCO Annual Meeting 23

ESMO-MCBS could be used as a policy tool in HTA and reimbursement decisions at the national level?

Presented By Elisabeth De Vries at 2017 ASCO Annual Meeting 30

WHO Essential antineoplastic medicines 2015 31

Added: nilotinib and dasatinib for imatinib resistant CML Establishment of EML cancer medicines working group to coordinate comprehensive evaluation of cancer medicines for the EML Cooperation between ESMO and WHO: possible implementation of ESMO-MCBS in evaluation of medicines for the WHO essential list? 32

Non-curative setting: 1 st line Medication Trial name First author Early crossover Primary outcome PFS control (months) PFS gain (months) PFS HR OS control (months) OS gain (months) OS HR Increase in 2-year OS 10% QoL Toxicity ESMO MCBS v1.1 non-curative DABRAFENIB TRAMETINIB COMBI-D Long G 2015, 2017 no PFS 8.8 2.2 0.67 18.7 6.4 0.63 YES + 4 VEMURAFENIB Ascierto P COBRIM 2016 COBIMETINIB no PFS 7.2 1 0.58 17.4 4.9 0.65 YES + 4 IPILIMUMAB Maio 2015 Maio 2015 yes OS 2.6 0.2 0.76 6.4 2.1 0.72 YES 4 NIVOLUMAB PEMBROLIZUMAB NIVOLUMAB + IPILIMUMAB CHECKMATE 066 KEYNOTE-006 CHECKMATE 067 Robert 2015 Atkinson SMR 2015 no OS 2.2 2.9 0.43 11.2 NR 0.43 YES + 4 Robert 2015 Schachter ASCO 2016 yes OS 3.3 5 0.58 15.9 16.4 0.7 YES 4 Larkin 2015 Larkin AACR 2017 Scadendorf 2017 no OS 4 4.6 0.42 NR NR ND ND same + 3 NIVOLUMAB + IPILIMUMAB PDL1 CHECKMATE 067 Larkin 2015 Larkin AACR 2017 no OS 3.9 6.2 0.57 NR NR ND ND 4 33

Curative setting Medication Trial name First author Early crossover Primary outcome PFS control (months) PFS gain (months) PFS HR OS control (months) OS gain (months) OS HR Increase in 2-year OS 10% >5% imp. of survival at 3 year FU QoL Toxicity ESMO MCBS v1.1 curative ESMO MCBS v1.1 non-curative DABRAFENIB TRAMETINIB COMBI-D Long G 2015, 2017 no PFS 8.8 2.2 0.67 18.7 6.4 0.63 YES YES + A 4 VEMURAFENIB COBIMETINIB COBRIM Ascierto P 2016 IPILIMUMAB Maio 2015 Maio 2015 NIVOLUMAB CHECKMATE 066 Robert 2015 Atkinson no PFS 7.2 1 0.58 17.4 4.9 0.65 YES NA + ND 4 yes OS 2.6 0.2 0.76 6.4 2.1 0.72 YES YES A 4 SMR 2015 no OS 2.2 2.9 0.43 11.2 NR 0.43 YES YES + A 4 PEMBROLIZUMAB NIVOLUMAB + IPILIMUMAB KEYNOTE-006 CHECKMATE 067 Robert 2015 Schachter ASCO 2016 Larkin 2015 Larkin AACR 2017 yes OS 3.3 5 0.58 15.9 16.4 0.7 YES YES A 4 no OS 4 4.6 0.42 NR NR ND ND NA same + ND 3 NIVOLUMAB + IPILIMUMAB PDL1+ CHECKMATE 067 Larkin 2015 Larkin AACR 2017 no OS 3.9 6.2 0.57 NR NR ND ND NA ND 4 34

Adjuvant interferon-alpha meta analysis Ives NJ et al. Eur J Cancer 2017; 82: 171-83. OS improvement 3% at 5 years (HR 0.9, CI 0.85-0.97), grade B Subgroup analysis: Ulcerated tumors OS improvement 10.5% at 10 years (HR 0.77, CI 0.64-0.92), grade A Adjuvant ipilimumab, EORTC 18081 OS improvement 11% at 5 years (HR 0.72), grade A Substantial toxicity, QoL not deteriorated, downgrade to B? ESMO 2017: Dabrafenib+trametinib? Vemurafenib? Pembrolizumab? 35

Percentage of countries (%) 100 90 80 70 60 50 40 30 20 10 0 Vemurafenib Dabrafenib Vemurafenib cobimetinib registration Dabrafenib trametinib Ipilimumab Pembrolizumab Nivolumab Nivolumab ipilimumab ESMO MCBS 4 4 4 (5) 4 (5) 4 4 (5) 4 (5) 3 (4) reimbursement 36

o o o EU Directive recommendation that registered medicine should be available on the market in 120 days, but delays are common EU Network for Health Technology Assessment: o Harmonization of cost-effectiveness analysis until 2020 o Parallel submissions to EMA and EU HTA proposed o Common EU price? o ESMO-MCBS as a tool for centralized prioritization? Harmonization of reimbursement process? o Added value reimbursement prioritization based on the central assessment of added value for each medicine OR assessment of added value at the national level

Pricing?

National reimbursement listing determinants of new cancer drugs: a retrospective analysis of 58 cancer treatment appraisals in 2007 2016 in South Korea. Kim ES, et al. Expert Rev Pharmacoecon Outcomes Res. 2017 Jan 3:1-9. Three variables increased the likelihood of reimbursement listing: clinical improvement, below alternative s price, risk-sharing arrangement. Cancer drug s listing increased from 17% to 47% after risk-sharing agreement implementation.

Take an active role through involvement in professional oncological organizations to start and maintain a dialogue with: European and national policy makers Patients organizations Pharmaceutical industry to improve the access to innovative medicines for their patients. Education of practicing oncologists is necessary to ensure basic understanding of the process of drug approval and reimbursement in order to be able to actively participate in the process.

A dynamic tool with planned revisions and updates based on careful and transparent revision process Commitment to accountability for reasonableness Could serve as useful tool for establishing a fair process for priority setting in public policy Further adjustments: patient reported outcomes 44

EU Policy Committee, Global Policy Committee Working Group for the access to medicines Task Force for innovation in skin cancer care Thank you for your attention!