esmo magnitude of clinical benefit scale: integration into ... · integration into clinical...

ESMO magnitude of clinical benefit scale:

Integration into clinical guidelines and clinical practice

with the example of advanced NSCLC

Rolf Stahel

Comprehensive Cancer Center Zürich

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Lima, April 6, 201895t

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ESMO clinical practice guidelines: Levels of evidence3 |

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ESMO clinical practice guidelines: Grade of recommendation4 |

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ESMO magnitude of clinical benefit scale: Background

• In 2013 the ESMO board recognizes the differences between European

countries in regard to cancer outcome and access to anticancer drugs and

decides on a task force to define a way to highlight new medicines which

have a great impact on patient outcome with the aim to facilitate their rapid

introduction in patient care

• Specific aims:

1. To develop a validated and reproducible tool to assess the magnitude

clinical benefit of anti-cancer interventions

2. To present clear and unbiased statements regarding the magnitude of

clinical benefit for new treatments based on credible research

3. To highlight those treatments which bring substantial improvements to the

duration of survival and/or the QoL of cancer patients

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ESMO-MCBS v1.0 developed by task force, field testing and

simulation scenarios

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Patients

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ESMO MCBS: Underlaying premises

1. Cure takes precedence over deferral of death

2. Direct endpoints such as survival and QoL take precedence over

surrogates such as PFS or RR

3. DFS in curative disease is a more valid surrogate than PFS in non-

curative disease

4. Interpretation of the evidence for benefit may be influenced by secondary

outcome data such as QoL and toxicity

5. Tail of curve data may sometimes indicate important gain for a minority of

responders

6. Data from randomized controlled trials are more credible than from single

arm studies

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ESMO MCBS v1.1: Reasons to develop an update

• The ESMO-MCBS is a dynamic tool

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

• Further reasons for revision

• Experience of field testing and scoring recent studies

• Input/queries from clinicians and industry

• Active internal peer review

• Detailed discussions & field testing

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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

Quality of Life

HR,Long term survival,

RR

Not analyzed in view of significant “Heterogeneity”across Europe

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ESMO MCBS: Definition of substantial improvements12 |

Curative Non-curative

5

4

3

2

1

A

B

C

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ESMO MCBS Forms

• Curative Setting → Evaluation form 1

A, B, C

• Non-curative setting → Evaluation form 2a

Comparative studies 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

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ESMO MCBS v1.1: Non-curative intent14 |

PFS or TTP

Primary endpoint

OS

Median withstandard therapy

≤ 6 months > 6 months

Other thanOS or PFS

Comparative studies Single armstudies


≤ 1 year > 1-2 years > 2 years

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KEYNOTE-024: Pembrolizumab vs platinum-based

chemotherapy as first-Line therapy for advanced NSCLC with

a PD-L1 TPS ≥50%

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OS median between 1-2 years:

HR < 0.70 and gain > 5 months, Reck, JCO 2019

HR 0.63

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ESMO MCBS v1.1: Form 2a for OS as endpoint16 |

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KEYNOTE-024: Treatment related side effects with incidence >10%17 |

0

5

10

15

20

25

30

35

40

45

50

Incid

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%

1-2

Grade

3-4

Data cut-off: May 9, 2016.

Pembrolizumab

Chemotherapy

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ESMO MCBS: Form 2a18 |

X

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KN-189: Randomized double blind phase 3 study of pembrolizumab

or placebo plus pemetrexed and platinum as 1L for metastatic

non-squamous NSCLC

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Ghandi, AACR 2018

OS < 1 year,

HR < 0.65 and gain < 3 months

HR 0.47

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ESMO MCBS: Form 2a for OS as endpoint21 |

IF median OS with the standard treatment <12 months

Grade 4

Mark with

X if

relevant

HR ≤0.65 AND Gain ≥3 months X

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

X

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ESMO MCBS: Form 2a22 |

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Systemic therapy of advanced NSCLC without oncogenic driver

mutation: Immunotherapy is the new standard second line therapy

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Nivolumab Pembrolizumab Atezolizumab

Bramer, NEJM 2015; Borghai, NEJM 2015;

Horn, JCO 2017

Herbst, Lancet 2016 Rittmeyer, Lancet 2017

MCBS 5MCBS 5MCBS 5 MCBS 5

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Overall survival with durvalumab after chemoradiotherapy

in stage III NSCLC

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Antonia, NEJM 2018

HR 0.68 (95%CI 0.54 to 0.86)

Curative setting:

Improvement of DFS (HR <0.65)5t

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ESMO MCBS v1.1: Form 1 for new approaches to adjuvant therapy

or new potentially curative therapies

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ESMO MCBS v1.1: Form 1 for new approaches to adjuvant therapy

or new potentially curative therapies

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ESMO MCBS v1.1: Non-curative intent27 |

PFS or TTP

Primary endpoint

OS


≤ 6 months > 6 months

Other thanOS or PFS

Comparative studies Single armstudies


≤ 1 year > 1-2 years > 2 years

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Alectinib vs crizotinib in treatment-naïve advanced ALK+

NSCLC: primary results of the global phase III ALEX study

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Shaw, ASCO 2017; Peters, NEJM 20175t

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First line alectinib versus crizotinib in advanced ALK-positive

NSCLC: Progression-free survival

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Alectinib (n = 152)

Crizotinib (n = 151)

HR=0.43

(95% CI: 0.32–

0.58)

34.8 (17.7–NE)

10.9 (9.1–12.9)

0

20

40

60

80

100

Day 1 6 12 18 24 30 36

Time (months)

PF

S e

sti

ma

te (

%)

Peters, NEJM 2017, Camidge, ASCO 2018

PFS > 6 months and gain > 3 months

HR 0.43

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ESMO MCBS: Form 2b for not likely to be curative with PFS as

endpoint

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Studies with median PFS with standard treatment >6 months

Grade 3

Mark with

X if

relevant

HR ≤0.65 AND Gain > 3 months

HR <0.65 BUT Gain < 3 months

Grade 2

Grade 1

HR >0.65

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endpoint

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endpoint

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endpoint

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FLAURA: First or third generation TKI inhibitors as first

line therapy for patients with EGFR mutated NSCLC

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Ramalingam, ESMO 2017, Soria NEJM 2018

PFS > 6 months and gain

HR 0.46

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endpoint

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endpoint

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endpoint

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ROS1 rearrangement in NSCLC: Activity of crizotinib

• ROS1 fusion with the transmembrane solute carrier protein SLC34A2

resulting in a constitutive kinase activity in a NSCLC cell lineRikova, Cell 2007

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Shaw, NEJM 2014

Response rate 72% Median PFS 19.2 months

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ESMO MCBS v1.1: Form 3 for single-arm studies in “orphan

diseases” and for diseases with “high unmet need” when primary

outcome is PFS or ORR

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Dabrafenib plus trametinib in patients with previously untreated

BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-

label, phase 2 trial

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Median PFS 10.9

monthsRR 64%

Planchard, Lancet Oncol 20175t

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No relation between price and clinical benefit

of 37 FDA approved anticancer drugs 2000-2015

Vivot, Ann Oncol 2017

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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 be

applied

• 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 the

threshold for clinically meaningful

benefit

Tibau, JNCI 20185t

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ETOP | Name Project | Title Presentation | Zurich, July 27, 2009

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