1. ESMO Magnitude of Clinical Benefit Scale for new anticancer drugs
Roundtable on Immuno-Oncology
Federal Parliament – Brussels, July 02nd 2015
ESMO Magnitude of Clinical Benefit Scale for new anticancer drugs
Martine Piccart on behalf of ESMO Magnitude
of Clinical Benefit Scale task force
Institut Jules Bordet, Université Libre de
Bruxelles
Cette présentation est la propriété de l’ESMO

2. New anticancer drugs hit the market at very high costs !
The average cost of recently approved anticancer drugs is ≈ €/month
The cost to gain one year of life
In ≈ €
Today ≈ €
L. Salz – ASCO 2015

3. Value ≠ Benefit

4. Possible scenarios in outcome of pivotal, randomized phase III clinical trials Survival results
No difference
Small, statistically significant
difference
possible EMA registration
of new treatment
Large, statistically significant
difference
very likely EMA registration
of new treatment
Standard treatment
New treatment

5. Different impacts of new drugs on patient outcome
Standard treat A B C
The new treatment
controls the disease
better initially, but
the life of the pt is
not extended.
What about QoL ?
New treat A B C
The new treatment
controls the disease
better and the pt
lives longer
New treat A B C
Is this extension
measured in days,
weeks or months ?

6. Why an ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) ?
Committed
to promote high-quality, rational, responsible & affordable cancer care
Recognizes
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
Hopes
The scale will facilitate access to important anticancer drugs all over Europe

7. Factors taken into account for ESMO-MCBS
Overall survival, Progression free survival
Quality of Life
Magnitude of Clinically Benefit
Toxicity
Prognosis of the condition
Costs
Not analyzed in view of
significant “Heterogeneity”
across Europe

8. ESMO-MCBS substantial improvements
Curative setting A & B or non-curative setting 5 & 4
These drugs
should ideally
be accessible
to all
European
citizens
Curative
Non-curative 5 4 3 2 1 A B C

9. Evaluation form 1: for adjuvant and other treatments with curative intent
Mark with X if relevant
Grade A
>5% improved survival at ≥ 3 years follow-up
Improvement in DFS alone (primary endpoint) (HR < 0.65) in studies without mature survival data
Grade B
≥ 3% but ≤ 5% improvement at ≥ 3 years follow-up
Improvement in DFS alone (primary endpoint) (HR )
without mature survival data
Non inferior OS or DFS with reduced treatment toxicity or improved QoL (with validated scales)
Non inferior OS or DFS with reduced treatment cost as reported
study outcome (with equivalent outcomes and risks)
Grade C
< 3% improvement at ≥ 3 years follow-up
Improvements in DFS alone (primary endpoint) (HR > 0.8) in studies without mature survival data

10. Evaluation form 1: for adjuvant and other treatments with curative intent
Mark with X if relevant
Grade A
>5% improved survival at ≥ 3 years follow-up
Improvement in DFS alone (primary endpoint) (HR < 0.65) in studies without mature survival data
Grade B
≥ 3% but ≤ 5% improvement at ≥ 3 years follow-up
Improvement in DFS alone (primary endpoint) (HR )
without mature survival data
Non inferior OS or DFS with reduced treatment toxicity or improved QoL (with validated scales)
Non inferior OS or DFS with reduced treatment cost as reported
study outcome (with equivalent outcomes and risks)
Grade C
< 3% improvement at ≥ 3 years follow-up
Improvements in DFS alone (primary endpoint) (HR > 0.8) in studies without mature survival data

11. ESMO-MCBS distinctions:
for treatment with non-curative intent
Primary endpoint OS
PFS or TTP
Other than
OS or PFS
Median with
standard therapy
≤ 1 year
> 1 year
Median with
standard therapy
≤ 6 months
> 6 months

12. A. Application of the scale to new drugs for poor prognosis diseases
Non curative setting

13. Evaluation form 2a: treatments with non-curative intent, primary endpoint OS
IF median OS with the standard treatment is ≤ 1 year
Mark with X if relevant
Grade 4
HR ≤ 0.65 AND Gain ≥ 3 months
Increase in 2 year survival alone ≥ 10%
Grade 3
HR ≤ 0.65 AND Gain months
Increase in 2 year survival alone 5- <10%
Grade 2
HR > OR Gain months
Increase in 2 year survival alone 3- <5%
Grade 1
HR > 0.70 OR Gain < 1.5 month
Increase in 2 year survival alone < 3%

14. Application of the scale for diseases with a medium prognosis
Non curative setting

15. Evaluation form 2a: treatments with non-curative intent, primary endpoint OS
IF median OS with the standard treatment is > 1 year
Mark with X if relevant
Grade 4
HR ≤ 0.70 AND Gain ≥ 5 months
Increase in 3 year survival alone ≥ 10%
Grade 3
HR ≤ 0.70 AND Gain months
Increase in 3 year survival alone 5- <10%
Grade 2
HR > OR Gain months
Increase in 3 year survival alone 3- <5%
Grade 1
HR > 0.75 OR Gain < 1.5 month
Increase in 3 year survival alone <3%

16. (highest grade scored)
Evaluation form 2a: treatments with non-curative intent, primary endpoint OS
Preliminary magnitude of clinical benefit grade
(highest grade scored)
Step 1 4 3 2 1
Step 2
Assessment QoL & grade 3-4 toxicities
Does secondary endpoint QoL show improvement
Are there statistically significantly fewer grade 3-4 toxicities
impacting daily well-being*
*not including alopecia, myelosuppression, but rather chronic nausea, diarrhea, fatigue, etc.
Adjustment: Upgrade 1 level if improved QoL or less toxicity or is shown
Step 3
Final adjusted magnitude of clinical benefit grade 5 4 3 2 1

17. ESMO-MCBS distinctions:
for treatment with non-curative intent
Primary endpoint OS
PFS or TTP
Other than
OS or PFS
Median with
standard therapy
≤ 1 year
> 1 year
Median with
standard therapy
≤ 6 months
> 6 months

18. Evaluation form 2b: treatments with non-curative
intent, primary endpoint PFS or TTP
Studies with median PFS with standard treatment > 6 months
Mark with X if relevant
Grade 3
HR ≤ 0.65 AND Gain ≥ 3 months
Grade 2
HR ≤ 0.65 BUT Gain < 3 months
Grade 1
HR > 0.65

19. (highest grade scored)
Evaluation form 2b: treatments with non-curative intent, primary endpoint PFS or TTP
Preliminary magnitude of clinical benefit grade
(highest grade scored)
Step 1 3 2 1
Step 2 Look at OS : if improved, go to the OS scale;
if not improved, go to steps 2 and 3
Toxicity and QoL adjustment when only a PFS improvement

20. Evaluation form 2b: treatments with non-curative intent, primary endpoint PFS or TTP
Toxicity assessment (adverse effect criterion)
Is the new treatment associated with a statistically significant
incremental rate of:
«toxic» death > 2%
cardiovascular ischemia > 2%
hospitalization for «toxicity» > 10%
excess rate of severe CHF > 4%
grade 3 neurotoxicity > 10%
severe other irreversible or longlasting toxicity > 2%
please specify:
(Incremental rate refers to the comparison versus standard therapy in the control arm)
Step 2
Mark with X if relevant
Assessment QoL & grade 3-4 toxicities
Step 3
Was QoL measured as a secondary outcome
Does secondary endpoint QoL show improvement
Are there statistically significantly fewer grade 3-4 toxicities
impacting daily well-being*
*not including alopecia, myelosuppression, but rather chronic nausea, diarrhea, fatigue, etc.

21. Evaluation form 2b: treatments with
non-curative intent, primary endpoint PFS or TTP
Step 4
Final Adjustments
Downgrade 1 level if ≥ 1 of above incremental toxicities
Upgrade 1 level if > QoL or if <grade 3-4 toxicities that bother patients
When OS as 2nd endpoint is improved, it prevails, score according to form 2a
Downgrade 1 level if the drug ONLY leads to improved PFS and QoL assessment does not demonstrate improved QoL
Final, toxicity and QoL adjusted, magnitude of clinical benefit grade 4 3 2 1
Highest grade that can be achieved is grade 4

22. Field testing Breast Cancer
Medication
Trial
Setting
Primary outcome
PFS control
PFS gain
PFS HR
OS control
OS gain
OS HR
QoL
ESM0-MCBS
Chemo +/- trastuzumab
HERA
(Neo)Adjuvant HER-2 positive tumors
DFS
2 y DFS 77.4%
8.4%
0.54
( ) A
T-DM1 vs capecitabine + lapatinib
EMILIA
2nd line metastatic after trastuzumab failure
PFS & OS
6.4 m
3.2 m
0.65
( )
25 m
6.8 m
0.68
( )
Later deterioration 5
Trastuzumab + chemo +/- pertuzumab
CLEOPATRA
1st line metastatic
PFS
12.4 m
6 m
0.62
( )
40.8 m
15.7 m
( ) ~ 4
Lapatinib +/-
trastuzumab
EGF
104900
3rd line metastatic
2 m
1 m
0.73
( )
9.5 m
4.5 m
0.74
( )
Capecitabine +/- lapatinib
Geyer, 2006
4.4 m
4 m
0.49
( ) NS 3
Eribulin vs other chemo
EMBRACE
3rd line metastatic after anthracycline & taxane OS
10.6 m
2.5 m
0.81
( ) 2
Paclitaxel +/- bevacizumab
Miller, 2007
5.9 m
5.8 m
0.6
( )
Exemestane +/- everolimus
BOLERO-2
Metastatic after failure aromatase inhibitor+PFS >6 m
4.1 m
6.5 m
0.43
( )

23. Field testing Lung Cancer (1)
Medication
Trial
Setting
Primary outcome
PFS control
PFS gain
PFS HR
OS control
OS HR
QoL
Toxicity
ESM0-MCBS
Erlotinib vs carboplatin gemcitabine
OPTIMEL, CTONG-0802
1st line stage 3b/4 non-squamous + EGFR mutation
4.6 m
8.5 m
0.16
( )
12% < serious adverse events 4
Erlotinib vs Pt-based chemo doublet
EURTAC
PFS,
crossover allowed
5.2 m
4.5 m
0.37
( )
19.5 m NS
15% < severe adverse reactions
Gefitinib vs carboplatin + paclitaxel
IPASS
6.3 m
3.3 m
0.48
( )
< toxicity
Afatinib vs cisplatin + pemetrexed
LUX
Lung 3
6.9 m
4.2 m
0.58
( )
Del19/L858R
6.7 m
0.47
( )
Crizotinib vs chemo
Shaw
2013
1st line stage 3b/4 non-squamous + ALK mutation
3.0 m
4.7 m
0.49
( )
1% > toxic death
Crizotinib vs cisplatin + pemetrexed
Solomon
2014
7.0 m
3.9 m
0.45
( )

24. Conclusions and next steps
ESMO-MCBS offers an objective and reproducible approach to grade drugs and
To determine which drugs are immediately required for European citizens
Relevance clear based on ESMO Anti-neoplastic medicines survey
To include findings in guidelines
To support
clinical decision making
counseling patients
editorial decisions and commentaries
ESMO-MCBS v1 will be published in Annals of Oncology, early release
Version 1
A «lively» instrument needing regular updates by ESMO committee
As more mature data of clinical trials become available, allowing fine tuning for efficacy and toxicity
New drugs and new indications will become available
Adaptations of the grading of the scale may be required

25. Acknowledgments Task Force members Martine Piccart, Co-chair
Richard Sullivan Nathan Cherny
Urania Dafni Martijn Kerst
Alberto Sobrero Christoph Zielinski
ESMO ex Board
ESMO Staff: Keith McGregor and Nicola Latino
Numerous people who helped testing the scale

26. BACK-UPS

27. 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

28. ESMO-MCBS for solid tumors was developed with “Snowball” method

29. “Snowball” method + Simulation scenarios
Previous work of Task Force Members
1st draft scale
Biostatisticians
1st ESMO faculty field testing
2nd draft scale
Applied in wide range of settings by
Task Force & invited experts
2nd ESMO faculty field testing
Final Scale 13
drafts
scale
Feedback
Integration work Sobrero on role HR, prognosis & absolute differences in data interpretation +
Sobrero A et al. J Clin Oncol 2009
Sobrero A et al Clin Cancer Res 2015

30. Underlying Premises 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

31. 3 Rules, #1 ESMO-MCBS Data derived from comparative research:
Priority: Strong level of evidence from large phase III studies, > lesser level of evidence from comparative cohort studies or randomized phase II studies
Careful analyses “control arm” and identification of endpoints.
Subgroup analysis.   
preplanned in ESMO-MCBS when ≤ 3 subgroups defined «a priori»: benefit in a subgroup for the primary endpoint can be «scaled», provided adjusted for multiple comparisons
unplanned not in ESMO-MCBS considered hyposthesis generating

32. Example: for threshold set at HR ≤ 0.70
3 Rules, #2 ESMO-MCBS
More than one outcome may be applicable
For a required HR, not the point estimate but the lower limit of the 95% CI is used to take into account the variability of the estimate
Example: for threshold set at HR ≤ 0.70
it is the lower limit of the 95%CI which has to be ≤ 0.70
0.71
0.78
0.86
Trial X
0.65
0.76
0.89
Trial X does not qualify
Trials Y and Z do qualify
Trial Y
0.58
0.69
0.82
Trial Z HR
0.5
0.7
1.0

33. 3 Rules, #3 ESMO-MCBS Check for:Ni
Check for:
indicators of severe toxicity or reduced grade 3-4 toxicity that bothers patients
global QoL advantage using validated scale
Report final adjusted grade taken into account toxicity and QoL when applicable
toxicity
quality of life

34. Forms ESMO-MCBS Curative Setting → Evaluation form 1
Non-curative setting → Evaluation form 2 a, b, c
2a: primary endpount OS
2b: primary endpoint PFS or TTP
2c: other primary endpoint
On top of each form

35. Field testing Melanoma (2) version light
Medication
Trial
Setting
ESM0-MCBS
Dabrafenib + trametinib vs vemurafenib
Robert 2015
1st line unresectable or metastatic
+ BRAF V600E mutation 4*
Vemurafenib +/- cobimetinib
Larkin 2014
Dacarbazine +/- nevolumab 4
Dacarbazine +/- ipilimimab
Robert 2011
Maio 2015
1st line metastatic 3
* immature survival data