HOW CAN WE DEAL WITH THE EXPLOSION OF NEW TREATMENTS?

ESMO Magnitude of Clinical Benefit Scale (MCBS) as a tool for treatment decision and prioritization

Focus on Gastro-Intestinal Cancers

Jean-Yves DOUILLARD MD, PhDMedical OncologistESMO Chief Medical OfficerESMO World GI Congress Barcelona June 23rd 2018

THE EXPLOSION OF CANCER THERAPEUTIC OPTIONS

2013 192014 192015 332016 232017 59May 2018 26

https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm279174.htm

Approval, Extension of approval, modification of

approval

The 86 drugs approved by the US FDA from 2006 and 2017 had a median OS gain of 2.45 months

0

5

10

15

20

25

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 57 59 61 63 65 67 69 71 73 75 77 79 81 83

Median Gain2.45 months

BASED ON THE NUMBER OF NEW DRUGS/NEW INDICATIONS:HOW TO SELECT/PRIORITIZE THESE DRUGS?

MAGNITUDE OF CLINICAL BENEFIT EVALUATIONWhat do we have in the tool box?

1. NCCN evidence blocks2. NICE3. ESMO-MCBS v1.14. ASCO Framework

1 NCCN 2 NICE 3 ESMO 4 ASCOPrimary purpose Providers, patients & other

stakeholders in treatment decisionProduce guidance:Public healthClinical practiceHealth technologies

Inform public policy, clinical guidelines, clinical practice

Shared decision making, patients/MDs

Treatment modalities Systemic therapies in all major cancer types

Medicines, treatments and procedures

Drugs or strategies for solid tumours

Drugs for solid &hematologic malignancies

Data source informing framework

Clinical trials & expert consensus Clinical trials, experts, service users, carers & public

Clinical trials Clinical trials

Scoring/Grading

Evidence blocks Score: 5-1 Clinical benefit, health benefit, A-C: curative disease5-1: advanced disease

Net Health Benefit score

Cost Affordability scale (1-5) Costs, cost effectiveness (QALY) NOT ADDRESSED Cost/month (Adv disease), Cost/course (Adj disease)Drug costOut of pocket cost

Updating Yearly, changes as impact of therapies change

Dynamic Dynamic Dynamic

Adapted from Schnipper et al. Oncologist 2016

NCCN Evidence Blocks™ Development

NCCN Panel members score each measure using a standardized scale from “1” being the least and “5” the most favorable based on:

Efficacy and safety published data and their clinical experience with treatments in real-world patient population Quality and consistency data supporting the treatment Affordability overall cost of the regimen

Final scores rounded to the closest whole number are used to build the 5 x 5 table Each column corresponds to an outcome characteristic: efficacy, safety, quality & quantity of evidence, consistency of

evidence & affordability.

Evidence blocks NCCN

Responsible for providing national guidance on promotion of good health and prevention and treatment of ill health

Produces guidance in:1. Public health2. Clinical practice- guidance on appropriate treatment and care of people with specific diseases and

conditions within NHS3. Health technologies- guidance on use of new and existing medicines, treatments and procedures within

NHS

Outcomes of interest to NICE Each appraisal takes ~12–18 months and is undertaken by a

committee of ~15–20 experts: clinicians, academics, researchers, managers and patient representatives

Clinical benefit Health benefit (quality adjusted life year) Cost-health service specific Cost-effectiveness

Incremental cost-effectiveness ratio Additional cost per additional QALY gained

Service impact

ASCO value framework

ASCO value framework v1.0: net health benefit (NHB)

NHB = Clinical benefit + toxicity scores + bonus points (in advanced disease only) The maximum NHB score is 130 for the advanced disease framework and 100 for the curative framework.

Development ASCO Framework V2

Lowell E. Schnipper; et al JCO 2015, 33, 2563-2577. DOI: 10.1200/JCO.2015.61.6706

Version 1.0 published in Annals of Oncology online May 2015

Version 1.1 published in Annals of Oncology September 2017

ESMO-MCBS PRINCIPLESUnderlying Priorities for ESMO-MCBS

1. Cure takes precedence over deferral of death2. Direct endpoints such as survival and QoL take

precedence over surrogates such as PFS or RR3. DFS in curative disease is a more valid surrogate than PFS

or RR in non-curative disease4. Interpretation of the evidence for benefit

derived from surrogate outcomes (such as PFS) may be influenced by secondary outcome data

Magnitude of Clinically Benefit

Overall survival,

Progression free survival

Toxicity

Costs

Prognosis of the

condition

Quality of Life

HR,Long term survival,

RR

Not analyzed in view of significant “Heterogeneity”across Europe

Factors taken into account for ESMO-MCBS

Definition ESMO-MCBS substantial improvements

• Curative setting A & B or non-curative setting 5 & 4

Curative Non-curative5

4

3

2

1

A

B

C

FORMS ESMO-MCBS V1.1

Curative Setting → Evaluation form 1A, B, C

Non-curative setting → Evaluation form 2a5, 4, 3, 2, 1Evaluation form 2b4, 3, 2, 1Evaluation form 2c4, 3, 2, 1

Non-curative setting → Evaluation form 3Single arm studies 4, 3, 2, 1

Evaluation form 2a: for therapies that are not likely to be curative with primary endpoint OS

IF median OS with the standard treatment 2.0 - 1.5 - 0.65-0.70 AND Gain >1.5 months

HR > 0.70 OR Gain

Evaluation form 2a: for therapies that are not likely to be curative with primary endpoint OS

4 3 2 1

Preliminary magnitude of clinical benefit grade

Assessment QoL & grade 3-4 toxicities

Final adjusted magnitude of clinical benefit grade

5 4 3 2 1

Upgrade 1 level if improved QoL or toxicity is shown

Step 1

Step 2

Step 3

If there is a long term plateau in the survival curve, and OS advantage continues to be observed at 5/7 year, also score according to Form 1 (treatments with curative potential) and present both scores i.e. A/4

Does secondary endpoint quality of life show improvementAre there statistically significantly less grade 3-4 toxicities impacting on daily well-being*

Non Curative Disease: Discordant Cases

r = 0.6108

ASCO>>ESMO

ESMO>>ASCO

Vivot A et al Ann Oncol. 2017;28(5):1111-1116. doi:10.1093/annonc/mdx053

Clinical benefit, price and approval characteristics of FDA-approved new drugs for treating advanced solid cancer, 2000–2015

HOW CAN WE DEAL WITH THE EXPLOSION OF NEW TREATMENTS?

MCBS Scoring of “recent” drugs in GI tumours

COLORECTAL CANCER DRUGS SCORED WITH ESMO-MCBSMedicines Setting ESMO-MCBS

score

FOLFOX4 + panitumumab 1st line metastatic colorectal cancer (post hoc KRAS, NRAS BRAF WT). RAS mutations 4Panitumumab + mFOLFOX6 1st line metastatic CRC (KRAS-WT) 4FOLFIRI + cetuximab 1st line metastatic stratified for KRAS-WT (post hoc KRAS, MRAS WT). RAS WT 4Cetuximab Refractory metastatic KRAS-WT 42nd line Nivolumab + Ipilumumab (SAT) MSI-High Colorectal cancer 4FOLFOX4 + panitumumab 1st line metastatic KRAS-WT Exon 2 3FOLFIRI + cetuximab 1st line metastatic stratified for KRAS-WT Exon 2 3FOLFIRI + panitumumab 2nd line metastatic KRAS-WT 3ILF + bevacizumab 1st line metastatic 3

FOLFOX+ bevacizumab 2nd line metastatic after FOLFIRI 2Panitumumab 3rd line metastatic, stratified for WT KRAS 2FOLFOXIRI + bevacizumab 1st line metastatic 2Trifluridine/tipiracil Metastatic CRC 3rd line therapy 2FOLFIRI + ramucirumab 2nd line metastatic after bevacizumab, oxaliplatin, fluoropyrimidine 1 Regorafenib 3rd line metastatic 1FOLFIRI + aflibercept 2nd line after oxaliplatin based treatment 12nd line chemotherapy + bevacizumab 2nd line beyond progression on bevacizumab 1

GASTRO-OESOPHAGEAL CANCER TREATMENT SCORED WITH ESMO-MCBS

Medicines Setting ESMO-MCBS score

Surgery + perioperative epirubicin, cisplatin, 5-FU Gastric or distal oesophagus stage II-III A

Surgery + perioperative cisplatin/5-FU chemotherapy Gastric or distal oesophagus stage II-III A

Trastuzumab + Cisplatin-Fluoropyrimidine in HER-2 positive

Advanced gastric or EJ junction HER-2 + 5

Paclitaxel + ramucirumab 2nd line advanced or metastatic gastric or EGJ adenocarcinoma after platinum plus fluoropyrimidine +/-anthracycline

2

Ramucirumab 2nd line gastro-oesophageal or gastric cancer after cisplatin/5-FU

1

PANCREATIC CANCER TREATMENT SCORED WITH ESMO-MCBS

Medicines Setting ESMO-MCBS score

FOLFIRINOX 1st line advanced or metastatic. Good performance status 5

Gemcitabine + nab-paclitaxel 1st line advanced or metastatic. Good performance status (KPS>70%) 2

Gemcitabine + erlotinib 1st line advanced or metastatic 1

MCBS now added to Guidelines

T. Yoshino et al Ann Oncol 2018 29, 1: 44

HOW CAN WE DEAL WITH THE EXPLOSION OF NEW TREATMENTS?

• With additional treatments approved by Regulatory Agencies:• Several options are available for a similar clinical setting

• Accessibility and affordability may still be a concern• Patient preference has to be considered after information and consent obtained

• Guidelines can help for decision making when updated data are available

• Scales, scoring drug efficacy allow prioritization and facilitate treatment choice and patient agreement• Scores obtained by such scales should be:

• Easy to calculate from published data from clinical trials• Unbiased, Reliable and Objective

HOW CAN WE DEAL WITH THE EXPLOSION OF NEW TREATMENTS?

• The ESMO MCBS:• Fulfils these criteria• May be adapted in a dynamic fashion when additional data are published (OS, QoL, Late toxicities…)• Is a tool to be used

• In clinical practice for treatment choice• In Education for trainees and young oncologists• In Onco-Policy to facilitate prioritization and accessibility• By HTAs to correlate drug pricing with magnitude of benefit

NCCN and NICE scoring:you cannot do it yourself

ESMO MCBS and ASCO Framework Scoring: you can do it yourself

THANK YOU

How can we deal with the explosion of new treatments?The explosion of cancer therapeutic optionsSlide Number 3Slide Number 4���Based on the number of new drugs/new indications:�How to select/prioritize these drugs? ��Magnitude of Clinical Benefit evaluationSlide Number 6Slide Number 7Slide Number 8Slide Number 9Slide Number 10Slide Number 11Slide Number 12Slide Number 13Slide Number 14ESMO-MCBS principlesSlide Number 16Definition ESMO-MCBS substantial improvementsForms ESMO-MCBS v1.1Evaluation form 2a: for therapies that are �not likely to be curative with primary endpoint OSEvaluation form 2a: for therapies that are �not likely to be curative with primary endpoint OS Non Curative Disease: Discordant CasesSlide Number 22How can we deal with the explosion of new treatments?Slide Number 24Slide Number 25Slide Number 26Slide Number 27How can we deal with the explosion of new treatments?How can we deal with the explosion of new treatments?Slide Number 30