ESMO-MCBS

Rolf StahelESMO Past President

27 March 2017

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Differences in access to relevant new anticancer drugs in Europe

• 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

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Therefore development of an ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS)

ESMO• 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 evaluation3r

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ESMO-MCBS

Underlying Premises

• 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

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ESMO-MCBS

Factors taken into account

Magnitude of Clinically Benefit

Overall survival,

Progression free survival

Toxicity

Costs

Prognosis of the

condition

HR,Long term survival,

RR

HR,Long term survival,

RR

Quality of Life

Not analysed in view of significant “Heterogeneity”across Europe

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ESMO-MCBS

Scoring

When a new anticancer medicine is EMA approved, its benefit will be «scaled» by the Guidelines Committee and reviewed by the ESMO-MCBS Working Group

1. All new anticancer EMA approved medicines will be highlighted in the ESMO Guidelines where relevant or as an eUpdate

2. Medicines which obtain the highest scores (A&B or 5&4), represent the highest priority for rapid endorsement by national bodies across Europe

54321

A

B

C

Curative Non-curative

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ESMO-MCBS

Forms v1.0

Curative Setting → Evaluation form 1

A, B, C

Non-curative setting → Evaluation form 2a (primary end point OS)

Evaluation form 2b(primary end point PFS or TTP)

Evaluation form 2c(primary end point other than OS or PFS or equivalence studies)

5, 4, 3, 2, 1

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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

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Nivolumab versus docetaxel in advanced NSCLC

Borghaei, NEJM 2015 3r

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Afatinib versus erlotinib as second-line treatment of patientswith advanced squamous cell carcinoma of the lung (LUX-Lung

8): an open-label randomised controlled phase 3 trial

Soria, Lancet Oncol 20153r

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Gemcitabine and cisplatin with or without necitumumab in squamous cell lung cancer

Thatcher, Lancet Oncol 20153r

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Evaluation form 2a: for therapies that are

not likely to be curative with primary endpoint OS

IF median OS with the standard treatment is <12 months

Grade 4Mark with X

if relevant

HR ≤0.65 AND Gain ≥3 months

Increase in 2 year survival ≥10%

HR ≤0.65 AND Gain >2.0-<3 months

HR ≤0.65 AND Gain >1.5-<2.0 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

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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*

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Magnitunde of Clinical Benefit Scale: Second line squamous cellcarcinoma

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Inclusion of scores in Clinical Practice GuidelinesMetastatic NSCLC

Therapy Disease setting Trial Control Absolute survival gain

HR(95% CI)

QoL/toxicity MCBS scoreb

Nivolumab, a fully human IgG4 PD-1 immune-checkpoint–inhibitorantibody

Advanced

Nivolumab versus docetaxel in advanced squamous cellNSCLC [98]Phase IIINCT01642004

Docetaxel in patients withadvanced SCC who havediseaseprogressionduring or after first-linechemotherapy. Control OS 6 months

OS gain: 3.2 months. 2-year survivalgain15%

OS: HR for death 0.59 (0.44–0.79)

Improvedtoxicityprofile

5

(Form2a)c

ESMO-MCBS

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Inclusion of scores in Clinical Practice GuidelinesMetastatic NSCLC

Therapy Disease setting Trial Control Absolute survival gain

HR(95% CI)

QoL/toxicity MCBS scoreb

Afatinib, an irreversible ErbBfamily blocker

Advanced Afatinib versus erlotinib as second-line treatment ofpatients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial [101]Phase IIINCT01523587

Erlotinib, as second-line treatment of patients with advanced SCC of the lung. Median OS 6.6 months

OS gain: 1.1 months

OS: HR for death 0.81 (0.69-0.95)

Similar toxicity profile

Improved overall health-related QoL

1 (Form 2a)

Necitumumab, a second-generation, recombinant, human IgG1 EGFR antibody in combination with gemcitabine and cisplatin

Advanced Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous NSCLC (SQUIRE): an open-label, randomised, controlled phase 3 trial. [52]Phase IIINCT00981058

Gemcitabine and cisplatin as first-line therapy in patients with stage IV SCC. Control OS 9.6 months

OS gain: 1.6 months

OS: HR for death0.84 (0.74-0.96)

Deteriorated toxicity profile

1 (Form 2a)

ESMO-MCBS

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

18 | Seto, Lancet Oncol, 20153rd

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IF 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

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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 below)

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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%

Hospitalisation 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)

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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

Adjustment:

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

Downgrade 1 level if ≥ 1 of above incremental toxicities

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

Upgrade 1 level if > QoL or if <grade 3-4 toxicities that bother patients

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

of survival advantage at interim analysis

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

*This does not include alopecia, myelosuppression, but rather chronic nausea, diarrhoea, fatigue, etc.

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Inclusion of scores in Clinical Practice GuidelinesMetastatic NSCLC

Therapy Disease setting Trial Control Absolute survival gain

HR(95% CI)

QoL/toxicity MCBS scoreb

Bevacizumab, a humanised anti-VEGF monoclonal antibody, in combination with erlotinib

Advanced Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer (NSCLC) harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study [116]Phase IIJapan PharmaceuticalInformation Center, number JapicCTI-111390

Erlotinib alone as a first-line therapy until disease progression or unacceptable toxicity. Median PFS 9.7 months

PFS gain: 6.3 months

PFS HR: 0.54 (0.36-0.79)

Deteriorated toxicity profile. No improvement in QoL

2 (Form 2b)

ESMO-MCBS

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Evaluation form 2c: for therapies that are

not 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

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NEW Form 3:

For single arm studies in “orphan diseases” and for diseases with

“high unmet need” when primary outcome is PFS or ORR

– Addresses a major shortcoming in v1.0

– Will credit PFS, ORR, CR, duration of response

– Upgradable for improved QoL

– Down gradable for excessive toxicity

– Maximal score of 4

STRUCTURAL AMENDMENT (n=1)

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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

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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

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• Form 2a

1. If there is a long-term plateau in the survival curve, and OS

advantage continues to be observed at 5 years (or 7 years for

diseases with median survival >24 months), also score according

to Form 1 (treatments with curative potential)

• present both scores i.e. A/4

• Form 2b

1. Additional upgrade when there is a long-term plateau in the PFS

curve, and there is >10% improvement in PFS at 2/3 years

2. Upgrade 1 level if study had early crossover because of early

stopping and crossover based on detection of survival advantage

at interim analysis

IMMUNOTHERAPY TRIGGERED

REVISIONS V1.1 (n=3)

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Thank you!

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