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
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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):
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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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