ESMO MAGNITUDE OF CLINICAL BENEFIT SCALE

Rolf Stahel

University Hospital Zürich

Mexico 21.4..2018

BACKGROUND

Differences between countries in:

– drug related health care expenditures

– drug prices

– access time to drugs after approval by EMA

Sometimes lack of drug supply in “countries with cheaper drugs” due to parallel import to “countries where the drug is more expensive”.

Unequal access within some countries:

– sometimes (co)-payment of the drug costs by patients required

Differences in access to relevant new anticancer drugs in

Europe

BACKGROUND

• Committed

to promote high-quality, rational, responsible & affordable cancer care

• Recognises

the need for clear and unbiased statements regarding the magnitude of clinical benefit from new therapeutic approaches

• Wants to

highlight treatments which bring substantial improvements to the duration of survival and/or the QoL of cancer patients

use the scale for accelerated reimbursement evaluation

ESMO position

ESMO MCBS

• Cure takes precedence over deferral of death

• Direct endpoints such as survival and QoL take precedence over surrogates* such as PFS or RR

• DFS in curative disease is a more valid surrogate than PFS or RR in non-curative disease

• Interpretation of the evidence for benefit derived from surrogate outcomes (such as PFS) may be influenced by secondary outcome data

Underlaying premises

* EMA recognizes PFS and valid endpoint

Factors taken into account for ESMO-MCBS

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

Definition ESMO-MCBS substantial improvements

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

Curative Non-curative

5

4

3

2

1

A

B

C

ESMO-MCBS v1.0developed by task force, field testing & simulation scenarios

v1.0

Patients

ESMO MCBS V1.1

Reasons to develop an updated version

• The ESMO-MCBS is a dynamic tool

• v1.0 only scored comparative studies need grade single arm studies

• Further reasons for revision

– Experience field testing and scoring recent studies

– Input/queries from clinicians and industry

– Active internal peer review

• Detailed discussions & field testing

• ESMO-MCBS v1.1: Annals of Oncol, Cherny et al. September 2017

FORMS ESMO-MCBS V1.1

Curative Setting → Evaluation form 1

A, B, C

Non-curative setting → Evaluation form 2a

5, 4, 3, 2, 1

Evaluation form 2b

4, 3, 2, 1

Evaluation form 2c

4, 3, 2, 1

Non-curative setting → Evaluation form 3

Single arm studies 4, 3, 2, 1

Evaluation form 1: for new approaches to adjuvant therapy or new potentially curative therapies

Grade AMark with X if

relevant

>5% improvement of survival at ≥3 years follow-up

Improvements in DFS alone (primary endpoint) (HR <0.65) in studies

without mature survival data

≥ 3% but ≤ 5% improvement at ≥3 years follow-up

Improvement in DFS alone (primary endpoint) (HR 0.65 - 0.8) without

mature survival data

Non-inferior OS or DFS with reduced treatment toxicity or improved

Quality of Life (with validated scales)

Non-inferior OS or DFS with reduced treatment cost as reported study

outcome (with equivalent outcomes and risks)

<3% improvement of survival at ≥ 3 years follow-up

Improvement in DFS alone (primary endpoint) (HR >0.8) in studies

without mature survival data

Improvements in pCR alone (primary endpoint) by >30% relative AND

>15% absolute gain in studies without mature survival data

Grade B

Grade C

Trastuzumab after Adjuvant Chemotherapyin HER2-Positive Breast Cancer

Picart, NEJM 2005

ESMO-MCBS distinctions v1.1: for treatment with non-curative intent

PFS or TTP

Primary endpoint

OS

Median with

standard therapy

≤ 1 year > 1-2 years

Median with

standard therapy

≤ 6 months > 6 months

Other than

OS or PFS

> 2 years

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

IF median OS with the standard treatment <12 months

Grade 4Mark with X

if relevant

HR ≤0.65 AND Gain ≥3 months

Increase in 2 year survival alone ≥10%

HR ≤0.65 AND Gain >2.0 - <3 months

HR ≤0.65 AND Gain >1.5 - <2 months

HR >0.65-0.70 AND Gain >1.5 months

HR > 0.70 OR Gain <1.5 months

Grade 3

Grade 2

Grade 1

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 improvement

Are there statistically significantly less grade 3-4 toxicities

impacting on daily well-being*

Nivolumab versus docetaxel in advanced squamous cell NSCLC

Brahmer, NEJM 2015

Less toxicity with immune checkpoint inhibitors in second line comparative studies

18 |

ToxicityGade

% of patients

Check-mate 17 Checkmate 57 KEYNOTE 10

N Doc N Doc P2 P10 Doc

All 59 87 69 88 63 66 35

3-5 8 60 10 54 13 16 79

Gemcitabine and cisplatin with or without necitumumab in squamous cell lungcancer

Thatcher, Lancet Oncol 2015

Docetaxel taxel plus ramucirumab (REVEL) versus docetaxel plus placebo for 2nd line treatment of stage IV NSCLC

20 |

OS 10.5 vs 9.1 months

Garon, Lancet Oncol 2014

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

IF median OS with the standard treatment > 12 months <24 months

Grade 4Mark with X

if relevant

HR ≤0.70 AND Gain ≥5 months

Increase in 3 year survival alone ≥10%

HR ≤0.70 AND Gain >3-<5 months

HR ≤0.70 AND Gain >1.5-<3 months

HR >0.70-0.75 AND Gain >1.5 months

HR > 0.75 OR Gain <1.5 months

Grade 3

Grade 2

Grade 1

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

IF median OS with the standard treatment >24 months

Grade 4Mark with X

if relevant

HR ≤0.70 AND Gain ≥9 months

Increase in 5 year survival alone ≥10%

HR ≤0.70 AND Gain >6 - <9 months

HR ≤0.70 AND Gain >4 - <6 months

HR >0.70-0.75 AND Gain >4 months

HR >0.75 OR Gain <4 months

Grade 3

Grade 2

Grade 1

Studies with median PFS with standard treatment <6 months

Grade 3Mark with X

if relevant

HR ≤0.65 AND Gain >1.5 months

HR <0.65 BUT Gain <1.5 months

HR >0.65

Grade 2

Grade 1

Evaluation form 2b: for therapies that are

not likely to be curative with primary endpoint PFS

Studies with median PFS with standard treatment >6 months

Grade 3Mark with X

if relevant

HR ≤0.65 AND Gain > 3 months

HR <0.65 BUT Gain < 3 months

HR >0.65

Grade 2

Grade 1

Evaluation form 2b: for therapies that are not likely to be curative with primary

endpoint PFS

Evaluation form 2b: for therapies with PFS improval without an OS benefit that are

not likely to be curative

3 2 1

Preliminary magnitude of clinical benefit grade (highest grade scored)

Step 1

Step 2

Early stopping or crossover

Did the study have an early stopping rule based on interim analysis of

survival?

Was there early crossover because or early stopping or crossover based

on detection of survival advantage at interim analysis

(If the answer to both is “yes”, then see adjustment “a” below)

Evaluation form 2b: for therapies with PFS improval without an OS benefit that are

not likely to be curative

Step 3Toxicity and QoL adjustment when only a PFS improvement

Is the new treatment associated with a statistically significant incremental

rate of:

Mark with X

if relevant

«toxic» death >2%

Cardiovascular ischemia >2%

Hospitalization for «toxicity» >10%

Excess rate of severe CHF >4%

Grade 3 neurotoxicity >10%

Severe other irreversible or long lasting toxicity >2% please specify:

Toxicity assessment

(Incremental rate refers to the comparison versus standard therapy in the control arm)

Evaluation form 2b: for therapies with PFS improval without an OS benefit that are not

likely to be curative Assessment QoL & grade 3-4 toxicities

Highest grade that can be achieved grade 4

Step 3

a) When OS as 2nd endpoint is improved, it prevails, score according to form 2a

b) Downgrade 1 level if ≥ 1 of above incremental toxicities

c) Downgrade 1 level if the drug ONLY leads to improved PFS (mature data shows no OS advantage) and

QoL assessment does not demonstrate improved QoL

d) Upgrade 1 level if > QoL or if less grade 3-4 toxicities that bother patients

e) Upgrade 1 level if study had early crossover because of early stopping or crossover based on detection

of survival advantage at interim analysis

f) Upgrade 1 level if there is a long term plateau in the PFS curve, and there is >10% improvement in PFS

at 1/2 year

Final, toxicity and QoL adjusted, magnitude clinical benefit grade

Step 4

Was quality of life (QoL) evaluated as secondary outcome?

Does secondary endpoint quality of life show improvement

Are there statistically significantly less grade 3-4 toxicities impacting on

daily well-being*

4 3 2 1

EGFR-mutated advanced NSCLC: Erlotinib with bevacizumab in frist-line

JO25567: Ph2, randomized, Japanese multicenter, open-label trial

Seto, Lancet Oncol 2014

Erlotinib alone or with bevacizumab as first-line therapy in advancedNSCLC harbouring EGFR mutations (JO25567)

29 |Seto. Lancet Oncol 2014

Evaluation form 2c: for therapies that arenot likely to be curative with primary endpoint other than

OS or PFS and or equivalence studies

Primary outcome is Toxicity or Quality of life AND Non-inferiority Studies

Grade 4

Mark with X

if relevant

Reduced toxicity or improved QoL (using validated scale) with evidence

for statistical non-inferiority or superiority in PFS/OS

Improvement in some symptoms (using a validated scale) BUT without

evidence of improved overall QoL

RR is increased >20% but no improvement in toxicity/QoL/PFS/OS

RR is increased <20% but no improvement in toxicity/QoL/PFS/OS

Grade 2

Grade 1

Grade 3

Evaluation form 3: for single-arm studies in “orphan diseases” and for diseases with “high unmet need” when primary

outcome is PFS or ORR

Grade 3Mark with X

if relevant

PFS >6 months

ORR (PR+CR) >60%

ORR (PR+CR) >20, <60% AND Duration of response >9 months

PFS >3-<6 months

ORR (PR+CR) >40, <60%

ORR (PR+CR) >20, <40% AND Duration of response >6 months <9 months

PFS 2-<3 months

ORR (PR+CR) >20, <40% AND Duration of response <6 months

ORR (PR+CR) >10, <20% AND Duration of response >6 months

Grade 2

Grade 1

Preliminary magnitude of clinical benefit grade

Final adjusted magnitude of clinical benefit grade

Step 1

Step 2

Step 3

Adjustments 1. Downgrade 1 level if there are > 30% grade 3-4 toxicities impacting

on daily well being2. Upgrade 1 level if improved QoL 3. Upgrade 1 level for confirmatory, adequately sized, phase 4

experience

Evaluation form 3: for single-arm studies in “orphan diseases” and for diseases with “high unmet need” when primary outcome is PFS or ORR

3 2 1

4 3 2 1

EMA APPROVED SINCE 2016 SCORED WITH ESMO-MCBS

Tumor type Medicine ESMO-MCBS score

NSCLC 2L Nivolumab 5

NSCLC 2L Pembrolizumab 5 in PD-1 > 50%

NSCLC 2L Pembrolizumab 3 in PD-L1 > 1%

NSCLC (EGFR mutated together with erlotinib) Bevacizumab 2

NSCLC 2L Ramucirumab 2

NSCLC 2L Squamous Afatinib 1

NSCLC 1L Squamous Necitumumab 1

NSCLC change to existing indication (2L non-mutated)

Erlotinib 1

New EMA approval after Jan

1st, 2016

a. ESMO Guideline staff

b. Guideline SE + Author

E-Update MCBS WG

Final E-Update approved by ESMO

GL-SC and Presidents

Exec Board

Arbitration only

ESMO-MCBS included in ESMO Guidelines

ESMO guidelines

• In 2016 and 2017 there were over 1 million unique page views* of ESMO Guidelines pages on the ESMO.org website

• These totals represent ~22% of all unique page views on the ESMO.org website

2011 2012 2013 2014 2015 2016 2017

Total 89 530 100 738 394 889 734 150 892 540 1 052 185 1 377 993

*Unique Page views: the number of visits during which a page was viewed one or more times

1 NCCN 2 NICE 3 ESMO 4 ASCO

Primary purpose Providers, patients & other stakeholders in treatment decision

Produce 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 for solid tumors 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: adv disease

Net Health Benefit score

Cost Affordability scale (1-5) Costs, cost effectiveness (QALY)

Not addressed Cost/month (Advdisease), Cost/course (Adjdisease)

Updating Yearly, changes as impact of therapies change

Dynamic Dynamic Dynamic

Modified from Schnipper et al. Oncologist 2016

Clinical benefit of 37 anticancer drugs approved by the FDA from 2000 to 2015

Vivot, Ann Oncol 2017

No relation between price and clinical benefit of 37 FDA approved anticancer drugs 2000-2015

Vivot, Ann Oncol 2017

MAGNITUDE OF CLINICAL BENEFIT OF CANCER DRUG APPROVED BY FDA 2006-2015

• 63 individual drugs for 118 indications

• 135 studies, among which were 105 RCTs for which ESMO-MCBS could beapplied

• Over time, there has been an increase in the number of trials meeting the ESMO-MCBS threshold (Ptrend = .04)

• However, fewer than half of RCTs supporting FDA approval meet thethreshold for clinically meaningfulbenefit

Tibau, JNCI 2018

Tumor type Drug ESMO-MCBS score

NSCLC Nivolumab 5

NSCLC Pembrolizumab 5 in PD-1 > 50%

Renal cell carcinoma Nivolumab 5

Melanoma Nivolumab 4 nivolumab alone

Renal cell carcinoma Lenvatinib 4

Soft tissue sarcoma Olaratumab 4 olaratumab + doxorubicin

Breast cancer Palbociclib 4 palbociclib + fulvestrant

3 palbociclib + letrozole

NSCLC Pembrolizumab 3 in PD-L1 > 1%

Colorectal cancer Ramucirumab 3

Neuroendocrine tumor Everolimus 3

Renal cell carcinoma Cabozantinib 3

NSCLC Bevacizumab 2

NSCLC Ramucirumab 2

Colorectal cancer Trifluridine/tipiracil 2

Melanoma Nivolumab 2 nivolumab + ipilimumab

NSCLC Afatinib 1

NSCLC Necitumumab 1

NSCLC change to existing indication Erlotinib 1

EMA approved since 2016 scored with ESMO-MCBS