EU and Global Initiatives by the European Society …...EU and Global Initiatives by the European Society for Medical Oncology ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS)

EU and Global Initiatives by the European Society for Medical Oncology ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) and the value of cancer care

Track 2

Session Code: 28-T2

Disclosure of interest:None

Urania Dafni, University of Athens, Greece on behalf of the ESMO-MCBS working group

Development of an ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS)

ESMO • 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

The scale was developed by ESMO To highlight treatments which bring substantial improvements to

the duration of survival and/or the QoL of cancer patients To be used for accelerated reimbursement evaluation

ESMO-MCBS v1.0 for solid tumors was developed with the “Snowball” method

“Snowball” method

Sobrero A et al. J Clin Oncol 2009 Sobrero A et al. Clin Cancer Res 2015 Cherny N et al. Ann Oncol 2015

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 of the scale

Feedback

Integration work on role of HR, prognosis & absolute gain in data interpretation (Sobrero et al)

+

Factors taken into account for ESMO-MCBS v1.0

Magnitude of Clinical Benefit

Overall survival, Progression - free

survival, ORR

Toxicity

Costs

Prognosis of the

condition

Quality of Life

HR, Absolute Gain, Long term survival

Not analyzed in view of significant “Heterogeneity” across Europe

ESMO-MCBS substantial improvements

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

5

4

3

2

1

A B C

Curative Non-curative

3 Rules, #1 ESMO-MCBS v1.0 Data derived from comparative research:

ONLY IF STATISTICALLY SIGNIFICANT BENEFIT

• Priority: Strong level of evidence from large phase III studies lower level of evidence from comparative cohort or randomized phase II studies

• Examination of “control arm” adequacy and identification of endpoints • Subgroup analysis:

– ONLY IF preplanned and ≤ 3 subgroups defined «a priori»: benefit in a subgroup for the primary endpoint can be «used», provided it is adjusted for multiple comparisons

– unplanned NOT in ESMO-MCBS: considered hypothesis generating

3 Rules, #2 ESMO-MCBS v1.0

Example: for threshold set at HR ≤ 0.70 it is the lower limit of the 95%CI which has to be ≤ 0.70

Trial X

Trial Y

Trial Z HR

0.5 1.0 0.7

0.86 0.78 0.71

0.65 0.76 0.89

0.58 0.69 0.82

Trial X does not qualify Trials Y and Z do qualify

a. More than one outcome may be applicable b. Dual Cutoff: for relative benefit (HR) and for absolute benefit (in months) c. For a required HR, not the point estimate but the lower limit of the 95% CI is used

taking into account the variability of the estimate

3 Rules, #3 ESMO-MCBS v1.0 1. Ni v1.0 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 taking into account toxicity

and QoL, when applicable

toxicity

quality of life

Forms ESMO-MCBS v1.0

Curative Setting → Evaluation form 1 Non-curative setting → Evaluation form 2 a, b, c 2a: primary endpoint OS 2b: primary endpoint PFS or TTP 2c: other primary endpoint

On top of each form

Name of study: Study drug: Indication: First author: Year: Journal: Name of evaluator:

Substantial Improvement Curative setting

Highest Grade Primary Endpoint Criterion A DFS HR*≤0.65

Non-curative setting Highest Grade Primary Endpoint Criterion

OS HR* GAIN 4 ≤ 12 m ≤0.65 AND ≥3 m >12 m ≤0.70 AND ≥5 m PFS HR* GAIN 3 ≤ 6 m ≤0.65 AND ≥1.5 m >6 m ≤0.65 AND ≥3 m

* Thresholds refer to the lower limit of the 95% CI. HR; hazard ratio, DFS; disease free survival, OS; overall survival, m; months.

Combined thresholds for the HR and the minimum observed absolute benefit

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 0.65 - 0.8) 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


Mark with X if





Mark with X if





A B C Magnitude of clinical benefit grade (highest grade scored)

ESMO-MCBS v1.0 distinctions: for treatment with non-curative intent

PFS or TTP

Primary endpoint

OS

Median with standard therapy

≤ 1 year > 1 year

Median with standard therapy

≤ 6 months > 6 months

Other than OS or PFS

Evaluation form 2a: treatments with non-curative intent, primary endpoint OS

Mark with X if

relevant

IF median OS with the standard treatment is ≤ 1 year

HR ≤ 0.65 AND Gain ≥ 3 months Increase in 2 year survival alone ≥ 10% Grade 3

Grade 2

HR ≤ 0.65 AND Gain 2.5-2.9 months Increase in 2 year survival alone 5- <10%

HR > 0.65-0.70 AND Gain 1.5-2.4 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%

Grade 4


Mark with X if

relevant

IF median OS with the standard treatment is ≤ 1 year

HR ≤ 0.65 AND Gain ≥ 3 months Increase in 2 year survival alone ≥ 10% Grade 3

Grade 2

HR ≤ 0.65 AND Gain 2.5-2.9 months Increase in 2 year survival alone 5- <10%

HR > 0.65-0.70 AND Gain 1.5-2.4 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%

Grade 4


4 3 2 1

Preliminary magnitude of clinical benefit grade (highest grade scored)

Step 1


4 3 2 1


Does secondary endpoint QoL show improvement Are there statistically significantly < grade 3-4 toxicities impacting daily well-being*

Assessment QoL & grade 3-4 toxicities

*not including alopecia, myelosuppression, but rather chronic nausea, diarrhea, fatigue, etc.

Step 1

Step 2


4 3 2 1


Does secondary endpoint QoL show improvement Are there statistically significantly < grade 3-4 toxicities impacting daily well-being*

Assessment QoL & grade 3-4 toxicities

Final adjusted magnitude of clinical benefit grade 5 4 3 2 1

Adjustment: Upgrade 1 level if improved QoL or less toxicity is shown *not including alopecia, myelosuppression, but rather chronic nausea, diarrhea, fatigue, etc.

Step 1

Step 2

Step 3

Studies with median PFS with standard treatment ≤ 6 months

HR ≤ 0.65 BUT Gain < 1.5 months Grade 2

Grade 1

Grade 3 HR ≤ 0.65 AND Gain ≥ 1.5 months

HR > 0.65

Mark with X if

relevant

Evaluation form 2b: treatments with non-curative intent, primary endpoint PFS or TTP

Step 1


Studies with median PFS with standard treatment > 6 months

HR ≤ 0.65 AND Gain ≥ 3 months

HR ≤ 0.65 BUT Gain < 3 months Grade 2

Grade 1

Grade 3

HR > 0.65

Mark with X if relevant

Step 1


3 2 1

Preliminary magnitude of clinical benefit grade (highest grade scored) Step

1

Toxicity and QoL adjustment when only a PFS improvement


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 control arm)

Step 2 Mark with

X if relevant

Assessment QoL & grade 3-4 toxicities Was QoL measured as a secondary outcome Does secondary endpoint QoL show improvement Are there statistically significantly < grade 3-4 toxicities impacting daily well-being*

*not including alopecia, myelosuppression, but rather chronic nausea, diarrhea, fatigue, etc.

Step 2


Final, toxicity and QoL adjusted, magnitude of clinical benefit grade

4 3 2 1

Highest final grade that can be achieved grade 4

Final Adjustments a. Downgrade 1 level if ≥ 1 of above incremental toxicities b. Upgrade 1 level if > QoL or if <grade 3-4 toxicities that bother patients c. When OS as 2nd endpoint is improved, it prevails, score according to

form 2a d. Downgrade 1 level if the drug ONLY leads to improved PFS and QoL

assessment does not demonstrate improvement

Step 3

Evaluation form 2c: treatments with non-curative intent, primary endpoint other than OS or PFS or equivalence studies

Primary outcome is Toxicity or Quality of Life Grade 4 Reduced toxicity or improved QoL (using validated scale) with evidence for statistical non inferiority or superiority in PFS/OS

Grade 3

Primary outcome is Response Rate

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

Mark with X if relevant

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 (0.43-0.67)

A

T-DM1 vs capecitabine + lapatinib

EMILIA 2nd line metastatic after trastuzumab failure

PFS & OS 6.4 m 3.2 m 0.65 (0.55-0.77)

25 m 6.8 m 0.68 (0.55-0.85)

Later deteriora

tion

5

Trastuzumab + chemo +/- pertuzumab

CLEOPATRA 1st line metastatic PFS 12.4 m 6 m 0.62 (0.52-0.84)

40.8 m 15.7 m 0.68 (0.56-0.84)

~ 4

Lapatinib +/- trastuzumab

EGF 104900

3rd line metastatic PFS 2 m 1 m 0.73 (0.57-0.93)

9.5 m 4.5 m 0.74 (0.57-0.97)

4

Capecitabine +/- lapatinib

Geyer, 2006 2nd line metastatic after trastuzumab failure

PFS 4.4 m 4 m 0.49 (0.34-0.71)

NS 3

Eribulin vs other chemo

EMBRACE 3rd line metastatic after anthracycline & taxane

OS 10.6 m 2.5 m 0.81 (0.66-0.99)

2

Paclitaxel +/- bevacizumab

Miller, 2007 1st line metastatic PFS 5.9 m 5.8 m 0.6 (0.51-0.70)

NS ~ 2

Exemestane +/- everolimus

BOLERO-2 Metastatic after failure aromatase inhibitor+PFS

PFS 4.1 m 6.5 m 0.43 (0.36-0.54)

NS ~

2

ESMO-MCBS Website

ESMO-MCBS – inclusion of scores in Guidelines

Table for new therapies/indications in Renal Cell Carcinoma*

*EMA approvals in 2016 to end August 2016. **ESMO-MCBS version 1.0

Therapy Disease setting

Trial Control Absolute survival gain

Hazard Ratio (95% CI)

QoL/ Toxicity

MCBS Score**

Nivolumab Advanced Study of nivolumab vs. everolimus in pre-treated advanced or metastatic clear-cell renal cell carcinoma (CheckMate 025) [40] Phase III NCT01668784

Everolimus, in patients with renal-cell carcinoma who had received previous TKI treatment. Median OS 19.6 months

OS gain: 5.4 months

OS: HR for death 0.73 (0.57-0.93)

Improved toxicity profile and QoL

5 (Form 2a)

ESMO-MCBS – inclusion of scores in Guidelines Metastatic NSCLC

aEMA approvals in 2016 up to August 2016. bESMO-MCBS version 1.0 [181], cEMA approval, October 2015 dCo-primary end points (overall survival and progression-free survival both in the total population and in patients with PD-L1 expression on at least 50% of tumour cells)

Therapy Disease setting

Trial Control Absolute survival gain

HR (95% CI)

QoL/ toxicity

MCBS scoreb

Nivolumab Advanced Nivolumab versus docetaxel in advanced squamous-cell NSCLC [98] Phase III NCT01642004

Docetaxel in patients with advanced SCC who have disease progression during or after 1st-line chemotherapy. Control OS 6 months

OS gain: 3.2 months. 2-year survival gain 15%

OS: HR for death 0.59 (0.44-0.79)

Improved toxicity profile

5 (Form 2a)c

Nivolumab Advanced Nivolumab versus docetaxel in advanced non-squamous NSCLC [104] Phase III NCT01673867

Docetaxel in patients with NSCC who progressed during or after platinum-based doublet chemotherapy. Control OS 9.4 months

OS gain: 2.8 months. 2-year survival gain 16%

OS: HR for death 0.73 (0.59-0.89)


5 (Form 2a)

Ramucirumab Advanced Ramucirumab plus docetaxel vs placebo + docetaxel for 2nd-line treatment of stage IV NSCLC after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial [94] Phase III NCT01168973

Placebo + docetaxel in patients with SCC or NSCC who progressed during or after a 1st-line platinum-based chemotherapy regimen. Control OS 9.1 months

OS gain: 1.4 months OS: HR for death 0.86 (0.75-0.98)

Deteriorated toxicity profile

1 (Form 2a)

Pembrolizumab Advanced Pembrolizumab vs docetaxel for previously treated, PD-L1-positive, advanced NSCLC (KEYNOTE-010): a randomised controlled trial [96] Phase III NCT01905657

Docetaxel in patients with previously treated, PD-L1-positive, advanced NSCLC. Control OS 8.5 months

In PD-L1 >1%:d OS gain: 1.9 months In PD- L1 >50%:d OS gain: 6.7 months

In PD-L1 >1%:d OS: HR for death 0.71 (0.58–0.88) In PD-L1 >50%:d OS: HR for death 0.54 (0.38–0.77)


In PD-L1 >1%: 3 (Form 2a) In PD-L1 >50%: 5 (Form 2a)

Conclusions and next steps ESMO-MCBS An objective and reproducible approach to grade drugs and

• To determine which drugs are immediately required for European citizens

• To include findings in guidelines • To support clinical decision making and counselling of patients

A «living» instrument subject to regular updates ESMO-MCBS v1.0: Ann Oncol 2015;26:1547-73 Updates: www.esmo.org/Policy/Magnitude-of-Clinical-Benefit-Scale

http://www.esmo.org/Policy/Magnitude-of-Clinical-Benefit-Scale

Currently work in progress for ESMO-MCBS v1.1

Version ESMO-MCBS 1.1 Draft Form 3:

• NEW Form 3: For single arm studies in “orphan diseases” and for diseases with “high unmet need” when primary outcome is PFS or ORR

Acknowledgments

• ESMO MCBS Task Force members Elisabeth de Vries & Martine Piccart, Co-Chairs Richard Sullivan Nathan Cherny Urania Dafni Martijn Kerst Alberto Sobrero Christoph Zielinski

• ESMO Executive Board • ESMO Staff: Keith McGregor and Nicola Latino

• Numerous people who helped testing the scale

ESMO-MCBS Working Group • Jan Bogaerts, Belgium • Nathan I. Cherny, Israel • Urania Dafni, Greece • George Pentheroudakis, Greece • Martine J. Piccart, Belgium • Josep Tabernero, Spain • Christoph Zielinski, Austria • Elisabeth G. E. de Vries, Netherlands

• ESMO office: Nicola Latino, Keith McGregor, CEO, Jean-Yves

Douillard; CMO

Thank you for your attention

1. Field tested in 73 studies with extensive peer review 2. Used in clinical and HTA settings 3. Applied to over 30+ cases (2015-2016) 4. Successfully employed by the ESMO Guidelines

committee 5. Respected by industry 6. Widely cited

Experience

COMPARISON OF RULES/THRESHOLDS 80% power - median control PFS

COMPARISON OF RULES/THRESHOLDS 90% power - median control PFS

ESMO Guidelines eUpdates

• Appendix 1: Cutaneous melanoma (1) • eUpdate with MCBS scoring for nivolumab and updated treatment

recommendation

• Appendix 3: Neuroendocrine tumours • eUpdate with MCBS scoring for everolimus and updated treatment

recommendation

• Appendix 4: Metastatic colorectal cancer (1) • eUpdate with MCBS scoring for ramucirumab and updated treatment

recommendation

• Appendix 5: Metastatic colorectal cancer (2) • eUpdate with MCBS scoring for TAS-102 and updated treatment

recommendation

Appendices to the Clinical Practice Guideline supplement:

1ST PRESIDENTIAL SYMPOSIUM MONALEESA-2

Drug Trial Name Setting Primary outme

PFS/DFS control

PFS/DFS Gain PFS/DFS HR OS

control OS Gain OS HR QoL Toxicity ESM0-MCBS V1.0

letrozole +/- ribociclib MONALEESA-2

1st line MBC post-men. ER/PR +ve PFS 14.7 mth 6+mth 0.56 (0.43–0.72)

3 (form 2b)

1ST PRESIDENTIAL SYMPOSIUM EORTC 18071

Drug Trial

Name Setting Primary outme

PFS/DFS control

PFS/DFS Gain

PFS/DFS HR OS control OS Gain OS HR QoL Toxicity ESM0-

MCBS V1.0

Ipilumimab 10mg/kg vs Placebo

EORTC 18071

Adjuvant stage III Melanoma 5 yr RFS 54.4% 11% 0.76 (0.64-0.89 A (Form 1)

1ST PRESIDENTIAL SYMPOSIUM NOVA

Drug Trial

Name Setting Primary outme PFS/DFS control

PFS/DFS Gain PFS/DFS HR OS

control OS Gain OS HR QoL Toxicity ESM0-MCBS V1.0

PFSgBRCA 5.5mth 15.5mth 0.27 ( 0.17- 0.41) 3 (form 2b)

non-gBRCA HRD +ve 3.8 mth 9.1 mth 0.38 (0.24-0.59) 3 (form 2b)

non-gBRCA 3.9 mth 5.4 mth 0.54 (0.34-0.61) 3 (form 2b)

Niraparib vs placebo

NGOT-OV16/NOVA

Platinum sensitive relapsed ovarian cancer: Planned cohorts gBRCA, non-gBRCA homologous recomb .defic. (HRD) +ve,non-gBRCA

ASCO value framework

ESMO-MCBS v1.0 versus ASCO Framework v1.0 Factors taken into account ESMO-MCBS ASCO Framework

Separate scaling for curative and non curative disease X X Descending weighting for OS, PFS and RR X x Prognostically stratified scoring for OS and PFS X Absolute gain thresholds for OS and PFS X Applicable to single arm studies X Stratified approach for primary outcomes X Applicable to QoL studies X Applicable to non inferiority studies X Toxicity assessment X (selective) X (all inclusive) Stratified toxicity penalties X Differential toxicity weighting for curative and non curative disease X Stratified QoL scoring X Costs X

ASCO value framework update

ESMO & ASCO

• Join efforts with regard to clinical benefit

Documents

EU and Global Initiatives by the European Society …...EU and Global Initiatives by the European Society for Medical Oncology ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS)