LUNG CANCER EARLY MOLECULAR ASSESSMENT

KIM MONKHORST WEEK VAN DE PATHOLOGIE 29 MAART

(potentiële) belangenverstrengeling Zie hieronder

Voor bijeenkomst mogelijk relevante

relaties met bedrijvenBedrijfsnamen

Sponsoring of onderzoeksgeld

Honorarium of andere (financiële)

vergoeding

Aandeelhouder

Andere relatie, namelijk …

LEMA: Pfizer, Roche, MSD, Novartis, AstraZenica Pfizer, BMS, Roche, MSD

NVT

NVT

Disclosure belangen spreker

VRAAG 1

• EGFR gemuteerd NSCLC lijkt minder baat te hebben van immunotherapie

• A: juist

• B: onjuist

SPONSORS AND PARTICIPATING CENTERS

SPONSORS

The LEMA project is supported by

PARTICIPATING CENTERS

4

PI: Michel van den Heuvel,

thoraxoncoloog NKI-AVL

DIAGNOSTIC DELAY AND PERFORMANCE STATUS

• If the patients performance score is too poor:

• Some patients are not fit enough for chemotherapy or TKI therapy

• There is not enough time to wait for immunotherapy response (2-3 weeks) >> standard chemotherapy

• The patient cannot be included in clinical trials

• In the NKI-AVL there was a 20-30% dropout / month diagnostic delay

6

DAILY PRACTICE PREDICTIVE PROFILING FOR NSCLC

• When a patient presents with stage IV NSCLC

• Predictive analysis >> EGFR, ALK, ROS1 and PD-L1

• Driver >> TKI

• PD-L1 positive (>50%) >> immunotherapy

• Chemotherapy

• Progression:

• Referral to center for clinical trials, ‘compassionate use’ and ‘off label’ drugs

• Biopsy material for additional predictive analysis

• Problems:

• Average time for block to arrive is 7-9 days

• The block is empty or does not contain enough material

• A new biopsy takes 1-2 weeks average time

Rangachari et al. JTO 2017

TPS < 50% TPS > 50%

DAILY PRACTICE PREDICTIVE PROFILING FOR NSCLC

Outpatient

clinic

Waiting

for

block

Molecular

analysis

Not sufficient

tissue >> new

biopsy

Molecular

analysis

Start therapy

5,5 weeks

Start therapy

8 weeks

PREDICTIVE PROFILING FOR NSCLC

• So predictive profiling for NSCLC must be done within an acceptable timeframe

• Also: tissue loss must be minimized

INCIDENCE OF NSCLC

• Most recent IKNL data estimated 9289 new cases of NSCLC in NL in 2016

• Stage at diagnosis:

• Stage I-II: 25%

• Stage III: 25%

• Stage IV: 50%

• Many will eventually develop disseminated disease

• Stage I-II: 44%

• Stage III: 75%

• Stage IV: 100%

• Adding up to a total of well over 7000 patients eligible for systemic treatment each year in the context of stage IV disease

10

HYPOTHESIS

MOLECULAR PROFILING

• 15% - 20% have a targetable oncogenic driver mutation

• For example in: EGFR, ALK, ROS1, BRAF, HER2, MET, RET, NTRK-1…

• 1100 – 1500 patients per year could be treated with targeted agents

• Current efficacy of molecular profiling is suboptimal

• EGFR: 70% coverage in stage IV, lower % in lower stages

• ALK: 50% coverage in stage IV, lower % in lower stages

HYPOTHESIS

• Early molecular profiling will improve diagnostic yield and increase the number of patients

receiving proper targeted treatment. Goal: 85% overall coverage of molecular profiling.

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STUDY DESIGN

STUDY POPULATION

• All treatment naïve patients with suspected thoracic malignancy, main interest in NSCLC

• FIRST PART: run-in period of half a year in which molecular profiling is performed as is

currently standard of care

• SECOND PART: comprehensive upfront profiling according to local standards

• 1300 patients total, expected duration 1,5-2 years

TISSUE BASED MOLECULAR ANALYSIS

• Tumor biopsy at baseline and at progression

BLOOD BASED MOLECULAR ANALYSIS

• Blood sampling and ctDNA analysis dependent therapy

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Tumour biopsy

Blood sample (‘Liquid

biopsy’)

Diagnostics1st Line Treatment

not targeted/immunoFollow

Up

Start of treatment Progression

2nd Line Treatment

not targeted/immunoFollow

Up

Informed Consent

STUDY DESIGN

Diagnostics1st Line Treatment

targeted or immunoFollow

Up

Start of treatment Progression

2nd Line Treatment

targeted or immunoFollow

Up

3 month interval

Diagnostics1st Line Treatment

not targeted/immunoFollow

Up

Start of treatment Progression

2nd Line Treatment

targeted/immunoFollow

Up

3 month interval

TISSUE LOSS MUST BE MINIMIZED

• All biopsies in a separate cassette

• They are superficially cut for first H&E

• If possible cut all slides at once

• Only necessary immunohistochemistry (TTF1 / P63)

PREDICTIVE PROFILING FOR NSCLC

Target Technique

KRAS, EGFR, HER2, BRAF, MET

amplification, MET exon 14 skipping

NGS, other validated techniques

ALK, ROS1 (NTRK) Immunohistochemistry / FISH

RET (MET amplification) FISH

MET exon 14 skipping One Step RT PCR @ NKI-AVL

PD-L1 22C3 (Agilent) and SP142 (Roche)

TISSUE BASED ANALYSIS

TUMOR BIOPSIES

17

18

TISSUE BASED ANALYSIS

TUMOR BIOPSIES

BLOOD BASED ANALYSIS

LIQUID BIOPSIES

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Costs old – Costs new

Effects old – Effects new

Incremental Cost-Effectiveness Ratio = (ICER)

Acceptance of «upfront molecular profiling» if:ICER < Maximum willingness to pay (€80,000/QALY)

Effects: Costs include e.g.:

-survival(life years) -chemotherapy/targeted therapy/immunotherapy,

-QoL (QALY) -diagnostic work-up (including molecular profiling)

-Treatment of adverse events, follow-up visits

-palliative care

(calculated over the total trajectory from diagnosis until death, including all switches)

COST-EFFECTIVENESS

PRIMARY AND SECONDARY ENDPOINTS

• PRIMARY ENDPOINT:

• percentage of patients with EGFR mutation or ALK translocation

• SECUNDARY ENDPOINTS:

• Percentage of patients with a predefined actionable genetic alteration

• How does liquid biopsy perform in different stages of disease

• Influence of the liquid biopsies on the diagnostic yield

• Cost effect evaluation

• To explore the reasons for insufficient tumor material available for molecular profiling

• To explore the epidemiology of the PD-L1 biomarker expression in all stages of NSCLC

• To explore the epidemiology of MET exon 14 skipping in all stages of NSCLC

TIMELINE ENROLMENT

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DETECTION OF ROS1 GENE REARRANGEMENT IN LUNG

ADENOCARCINOMA

• ROS1 (D4D6) rabbit monoclonal (Cell Signaling Technology, Danvers, MA, USA)

• Conclusion: IHC is a reliable and rapid screening tool in routine pathologic laboratories for the identification of suitable

candidates for ROS1-targeted therapy.

• ROS1 IHC is highly sensitive, but less specific compared with ALK IHC for detection of the corresponding rearrangement.

ROS1 IHC-reactive tumors, especially when the tumor is stained with moderate to strong intensity or a diffuse pattern, are

recommended to undergo FISH to confirm the gene rearrangement.

KNOWN PD-L1 DIAGNOSTIC ASSAYS DIFFER IN MANY KEY ASPECTS

CLIA, Clinical Laboratory Improvement Amendments; EQA, external quality assessment; IC, immune cell; NSCLC, non-small cell lung cancer; PD-1, programmed cell death-1; PD-L1, programmed cell death ligand-1; SCCHN, squamous cell carcinoma of the head and neck; TC, tumour cell; TM, tumour membrane; UC, urothelial carcinoma

1. http://www.accessdata.fda.gov/cdrh_docs/pdf15/P150013c.pdf (accessed 18Aug2016);

2. http://www.accessdata.fda.gov/cdrh_docs/pdf15/P150025c.pdf (accessed 18Aug 2016);

3 http://productlibrary.ventanamed.com/ventana_portal/OpenOverlayServlet?launchIndex=1&objectI

=790-49051014247US (accessed 18Aug2016);

4. Rebellato, MC, et al. J ClinOncol 2015;33(15_Suppl.):8033 (abstr);

5. http://www.accessdata.fda.gov/cdrh_docs/pdf16/P160002c.pdf (accessesd18Aug2016)

Many labs will

develop their own

PD-L1 assay with a

commercially

available clone

CLIA/EQA

schemes offer the

sole oversight of the

quality of these

tests. These assays

are laboratory-

developed tests

Lead asset Pembrolizumab

KEYTRUDA

(anti-PD-1)1

Nivolumab

OPDIVO

(anti-PD-1)2

Durvalumab

(anti-PD-L1)3

Atezolizumab

TECENTRIQ

(anti-PD-L1)5

Diagnostic partner Dako Dako Ventana Ventana

PD-L1 antibody clone 22C3 28–8 SP263 SP142

Machines utilised Link 48 Link 48 BenchMark ULTRA BenchMark ULTRA

Compartment TM TM TM TC/IC

Variables % of cells % of cells % of cells % of cells

Cut-off used for patient

subgroups

Strong(+): ≥50% >1% TC PD-L1(high): ≥25%4 ≥5% IC

Diagnostic type Companion diagnostic in

NSCLC

Complementary

diagnostic in NSCLC

Companion diagnostic in

NSCLC, SCCHN and

UC

Complementary

diagnostic in UC1

Regulatory status Launched Launched Not yet launched Launched

RESULTS FROM BLUEPRINT DEMONSTRATE

CONCORDANCE BETWEEN THREE ASSAYS WITH

RESPECT TO TC STAINING

Three assays (22C3, 28–8, SP263)

demonstrate similar analytical

performance with respect to percentage

of TC positive, and dynamic range

• SP142 consistently labels fewer TC

AZ, AstraZeneca; BMS, Bristol-Myers Squibb; TC, tumour cell Hirsch FR, et al. Oral presentation at AACR 2016b.

Data points represent the mean score from three

pathologists for each assay on each case.

Superimposed lines/points indicate identical TC scores.

No clinical diagnostic cut-off appliedT

um

our

stai

nin

g (

%)

0

10

20

30

40

50

60

70

80

90

100

% T

um

or

Sta

inin

g

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39

Cases

SP263SP14228-822C3

Mean tumour cell score per case, based on three readers

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39

0

10

20

30

40

50

60

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100

Cases

22C3 (Merck)

28–8 (BMS)

SP142 (Roche)

SP263 (AZ)

THE NSCLC CONCORDANCE STUDY SHOWED CORRELATION BETWEEN

THE THREE ASSAYS EXAMINED

The Ventana SP142 assay was not commercially available at the time of the study and was therefore not included.

AZ, AstraZeneca; BMS, Bristol-Myers Squibb; NSCLC, non-small cell lung cancer

Figure created using source data in Figure 2 of

Ratcliffe MJ, et al. Poster presentation at AACR 2016 (Abstract LB-094)

Marianne Ratcliffe personal communication.

22C3 (Merck)

28–8 (BMS)

SP263 (AZ)

0 100 200 300 400 500

0

10

20

30

40

50

60

70

80

90

100

Tum

our

stai

nin

g (

%)

Case rank

PD-L1 IMMUNOHISTOCHEMISTRY

• All sites are trained for the PD-L1 22C3 and the PD-L1 SP142 antibody

• UMCG developed a LDT IHC protocol for the 22C3 antibody on the Ventana BenchMark Ultra

• The 22C3 antibody concentrate will be validated using a TMA

• Trained pathologists score a digital image of 22C3 stained NSCLC TMA at the start of the study and 9 months and 18

months for quality control

• 18 participating sites

• Currently open for inclusion:

1. NKI

2. Erasmus

3. UMCU

4. Meander MC

5. VUMC

6. Radboud

7. LUMC

8. ETZ

9. Franciscus

10. NWZ

CPCT: SINCE STUDY LAUNCH IN SEPTEMBER 2016

The DRUP trial

Conclusion Acknowledgements

The DRUP trial

13 STUDY DRUGS AVAILABLE, 6 MORE EXPECTED SOON

DRUP@NKI.NL

Available Amgen Panitumumab KRAS-BRAF-NRASWT

AstraZeneca Olaparib BRCA 1/2, ATM

Bayer Regorafenib RET, VEGFR1, 2, 3, KIT, PDGFRB, RAF-1, BRAF

BMS Nivolumab MSI or high mutational load

Roche Erlotinib EGFR

Trastuzumab + Pertuzumab HER2

Vemurafenib + Cobimetinib BRAF V600

Vismodegib PTCH1

Novartis Dabrafenib BRAF V600

Nilotinib KIT, ABL1, PDGFRA, PDGFRB

Trametinib BRAF V600, NRAS

Expected BI Afatinib ERBB4, NRG1

Eisai Lenvatinib FGFR1, FGFR2, FGFR3, FGFR4

MSD Pembrolizumab High mutational load

Pfizer Axitinib VEGFR1, 2, 3

Crizotinib ALK, MET exon 14 en MET amplificatie, MST1R, ROS1

Sunitinib CSF1R, FGFR1,2,3, VEGFR1, 2, 3, KIT, PDGFRA, PDGFRB,

RET, VHL

VRAAG 2

• Betreffende de verschillende verkrijgbare PD-L1 antilichamen (22C3, 28.8, SP263 en SP142)

• A: alle zijn uitwisselbaar als predictieve test voor immunotherapy

• B: het PD-L1 antilichaam 22C3 is een complementary diagnostic voor NSCLC

• C: SP263 scoort naast de tumorcellen ook het immuuninfiltraat

• D: alle bovenstaande antwoorden zijn onjuist

ACKNOWLEDGEMENTS

• LEMA

• Michel van den Heuvel

• Robert Schouten (PhD student)

• Irene Schouten (project manager)

• Alle LEMA sites

• AKL AVL

• Daan van den Broek

• Daan Vessies

• MD / CFMPB NKI-AVL

• Maartje Vogel

• Annegien Broeks

• Rianne van der Wiel

36

• PA-klinische studies NKI AVL

• Jan-Nico Ridderbos

• Steven Vanhoutvin (contract

manager klinische trials)

• UMCG LEMA QA PD-L1

• Wim Timens

• Nils ’t Hart

• PD-L1 cursussen

• Milan van Rheenen (MSD)

• Leonie de Visser (Roche diagnostics)

• Valesca Retèl

• Kosten effectiviteits analyse

• Iedereen die ik vergeten ben!