MH Guide - Die Zukunft der automatisierten Variantenannotation (Broschüre für Pathologen)

Jetzt entdecken: die Zukunft der automatisierten Variantenannotation MH Guide interpretiert schnell und qualitätsgesichert komplexe genetische Daten für die wachsenden Herausforderungen von heute und morgen

MH Guide – Information für Pathologen

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Die Vorteile von MH Guide

Weltweites Wissen lokal nutzen – evidenzbasierte Therapieplanung

Big Data – Analysen für Labore

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Die klinische Varianteninterpretation

Die sieben Schritte für eine MH Guide Analyse

Der MH Guide Report

7 So erreichen Sie Molecular Health

Sie haben Fragen? Kontaktieren Sie uns unter +49 6221 43851-150 oder Kundendienst@molecularhealth.com

1 Die Vorteile von MH Guide CHE DATE INIS N KL

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Automatisierte Varianteninterpretation – schnell, präzise und effizient MH Guide ist eine in Europa als In-vitroDiagnostikum zugelassene Software, die Molekularpathologen bei der Interpretation umfangreicher molekularer Datensätze unterstützt. MH Guide kann unabhängig von der verwendeten Sequenziertechnologie komplexe Datensätze interpretieren und

automatisiert relevante genetische Varianten identifizieren, die für die Behandlung von Krebspatienten von Bedeutung sind. Diese Informationen werden in klinisches Wissen übersetzt, das Sie bei der individuellen Therapieentscheidung unterstützt.

So profitieren Labore von MH Guide • Automatisierte Interpretation von NGS-Daten für kleine und große Panels sowie Whole Exome Sequencing (WES) oder Daten aus anderen kompatiblen Analysemethoden • S icherstellung des Zugriffs auf umfassende aktuelle Daten zur Varianteninterpretation durch Nutzung von Daten aus einer der weltweit größten digitalen Datenbanken für biomedizinische Informationen (Dataome)

• Schnelle, qualitätsgesicherte klinische Variantenannotation und Berichterstellung • Hoher Individualisierungsgrad für den Ergebnisreport durch Möglichkeit der Filterung relevanter Informationen und des Einpflegens eigener Daten und Quellen • Digitale Plattform zur interdisziplinären Fallbesprechung in molekularen Tumorboards

2 Weltweites Wissen lokal nutzen – evidenzbasierte Therapieplanung Integration von MH Guide in die klinische Routine

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Beauftragung der Molekulardiagnostik

Molekularpathologie 3.

NGS-Analytik

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Upload der Daten im MH Order Portal

Onkologie/Tumorboard Indikationsstellung

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Ortsunabhängige Fallbesprechung im MTB und Therapieentscheidung

Why deep understanding of the cancer’s molecular profile is key for treatment success in oncology

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Making therapeutic options visible: the MH Guide Report

Klinische Varianteninterpretation

Each tumor is unique, with individual patterns of DNA mutations, gene recombination, and gene fusions, amplifications, deletions, and insertions. The changes can alter protein function and protein expression, which may constitute targets for personalized cancer therapies.

Which gene variants are clinically significant? How severe is the tumor mutational burden?

Which therapy is best suited for an individual cancer patient? And which patients are more likely to experience adverse events?

In order to answer these questions, it is crucial to analyze each cancer sample as intensively as possible, and use the best molecular and clinical data, and drug and disease information available worldwide.

MH Guide uses expertly reviewed and up-to-date biological, clinical, and drug related information. This wealth of data makes MH Guide the best choice to help you analyze the molecular profile of tumor samples and support you as you choose the best treatment for your patients.

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Sample report: Lung adenocarcinoma* *(2 of 11 pages)

Patient ID — — Case ID Date of birth —

Sex Ethnicity Country Trial ZIP code

NGS data

Clinical variant interpretation (CVI): Identification and interpretation of relevant gene variants

Identified biomarkers

Identified therapeutic options and clinical studies

Get most out of your patient’s genomic data Advances in sequencing technologies enable scientists and physicians to generate massive quantities of data using next-generation sequencing (NGS). However, identifying and interpreting the relevant gene variants and their meaning for treatment choice is still challenging.

The CE IVD certified MH Guide analyzes NGS data of your patient to gain deep insight into the molecular profile of the patient’s tumor. MH Guide can analyze NGS data from whole exome sequencing data with the complete set of over 20,000 functional genes, or customized gene panels.

The MH Guide report delivers all information about identified, clinically relevant gene variants in a comprehensive format to choose the best treatment for your patients.

MH Guide allows you to have full control over your patient data, and your report while ensuring highest patient data security.

7.

Male — US —

Patient ID — — Case ID Date of birth —

Lung adenocarcinoma Diagnosis — ICD-10-CM code — MeSH ID/term Additional MeSH IDs —

Primary tumor site — Surgical pathology — — Tissue type — Metastatic

Collected Tumor cellularity Barcode Sample type

— — — —

General dataset ID — CVI dataset ID — Organizational unit —

Labtest

—

Software version

—

Ordering — physician — Facility Email — Phone — Fax — Product MH Guide — Report

Molekularpathologischer Befund mit MH Guide Report MH_Broschüre_Onkologie_ELCC.indd 4-6

Sie haben Fragen? Kontaktieren Sie uns unter +49 6221 43851-150 oder Kundendienst@molecularhealth.com

ABCB1 not identified

ALK 1 fusion, 1 SNV

BRAF not identified

ROS1 1 del

STK11 not identified

TP53 not identified

EGFR not identified

ERBB2 not identified

KRAS not identified

MET not identified

NF1 not identified

NRAS not identified

PIK3CA not identified

Potential impact Effective

Treatment

Disease

Disease details

Guideline

Evidence Level

Brigatinib

Non-Small Cell Lung Cancer

Squamous cell carcinoma, Adenocarcinoma (with mixed subtypes), Large cell carcinoma

NCCN

1 for first-line therapy as a single agent if ALK rearrangement discovered prior to first-line systemic therapy

RET not identified

Recommended use: Single-agent therapy for ALK rearrangement-positive recurrent, advanced or metastatic disease Overview of prognostic and diagnostic findings

Overview of potential treatment impacts 3 Effective

2 Ineffective

1 Safety

Treatment

Effective

Lorlatinib

Effective

Ceritinib

Effective

Brigatinib

0 Prognostic

Drug approval*

Biomarker

0 Diagnostic

VAF

Biomarker score

Clinical trials found 8

Trials

ALK/EML4 (fusion)

—

2

ALK/EML4 (fusion)

—

3

ALK/EML4 (fusion)

—

5

Approved

Dabrafenib

Approved

G6PD p.R285H (SNV)

99.56%

—

Ineffective

Crizotinib

Approved

ALK p.L1196M (SNV)

23.80%

—

Ineffective

Alectinib

Approved

ALK p.L1196M (SNV)

23.80%

—

Effective

Signed by 11 Dec 2019 12:20 (UTC+01:00)

Ceritinib

Non-Small Cell Lung Cancer

Squamous cell carcinoma, Adenocarcinoma (with mixed subtypes), Large cell carcinoma

NCCN

1 for first-line therapy as a single agent if ALK rearrangement discovered prior to first-line systemic therapy 2A for all others 2B for locoregional recurrence or symptomatic local disease (excluding mediastinal lymph node recurrence with prior radiation therapy) with no evidence of disseminated disease

Recommended use: Single-agent therapy for ALK rearrangement-positive recurrent, advanced or metastatic disease

* in the patient's disease; VAF = Variant allele frequency Biomarker score: AMP score and CVI score. Clinically approved: Approved biomarker (by the FDA, EMA, or NCCN) to predict a specific effect in the patient's disease. Clinical: Not yet approved biomarker for the patient's disease. Observed in clinical studies as a potential biomarker to predict a specific effect of the drug. Preclinical: This biomarker has not yet been observed/tested in patients to predict a specific effect of the drug. It is supported by preclinical evidence or translational data.

You can find more details on the biomarker score (AMP and CVI score) in the glossary.

Molecular Health GmbH, Kurfuersten-Anlage 21, 69115 Heidelberg | www.molecularhealth.com | +49 6221 43851-150

• as first-line therapy • for patients who are intolerant to crizotinib • as subsequent therapy following disease progression on first-line therapy with crizotinib, except in cases of symptomatic systemic disease with an isolated lesion • as continuation of therapy if used first line, except in cases of symptomatic systemic disease with multiple lesions

Trials

Approved

Approved

Safety

Order date 14 Nov 2019 Report Version 5

2A for all others 2B for locoregional recurrence or symptomatic local disease (excluding mediastinal lymph node recurrence with prior radiation therapy) with no evidence of disseminated disease

SUMMARY

Potential impact

Lung adenocarcinoma Diagnosis — ICD-10-CM code — MeSH ID/term Additional MeSH IDs —

MEDICAL GUIDELINES Relevant treatment information from medical guidelines and potential impact based on detected biomarkers

Mutational status of commonly mutated genes in the patient disease

MH Guide Report A

1.

Phone —

• as first-line therapy • for patients who are intolerant to crizotinib • as subsequent therapy following disease progression on first-line therapy with crizotinib except in cases of symptomatic systemic disease with an isolated lesion • as continuation of therapy if used first line, except in cases of symptomatic systemic disease with multiple lesions

Effective

Order date 14 Nov 2019 Report Version 5 Page 1 of 11

Lorlatinib

Non-Small Cell Lung Cancer

Squamous cell carcinoma, Adenocarcinoma (with mixed subtypes), Large cell carcinoma

Signed by 11 Dec 2019 12:20 (UTC+01:00)

NCCN

2A for all others 2B for locoregional recurrence or symptomatic local disease (excluding mediastinal lymph node recurrence with prior radiation therapy) with no evidence of

Phone —

Molecular Health GmbH, Kurfuersten-Anlage 21, 69115 Heidelberg | www.molecularhealth.com | +49 6221 43851-150

Page 2 of 11

The report lists identified, clinically relevant gene variants of the patient’s tumor, targetable biomarkers and their clinical validity.

One of the key benefits of the report is the list of therapeutic options with country-specific drug approval status, along with the potential impact of each drug for individual patients.

The MH Guide report can be adapted to your individual needs.

Our scientific field support teams are available whenever you need them.

13.02.20 16:38

Der MH Guide Prozess Diagnostische und molekularpathologische Labore setzen unsere softwarebasierte Invitro-Diagnostik-Anwendung MH Guide ein, um relevante Biomarker in Tumorproben zu identifizieren und behandelnden Ärzten Informationen über individuelle Therapie- und Studienoptionen zur Verfügung zu stellen.

Bedeutung in den jeweiligen Krebsentitäten. Diese Informationen werden in einem übersichtlichen Patientenreport zusammengefasst. Diesen Report können Sie individuell anpassen und für die Diskussion im Tumorboard in Ihren Pathologiereport integrieren.

Die Software vergleicht dazu die Daten der Patientenprobe mit aktuellem publiziertem biomedizinischem Wissen und Arzneimittelinformationen. Dabei liefert MH Guide relevante Informationen zu identifizierten, relevanten Biomarkern und deren klinischer

Die klinisch tätigen Kollegen erhalten dadurch schnell einen aussagefähigen Befund, der alle wichtigen Informationen über wirksame und sichere medikamentöse Therapieoptionen und verfügbare klinische Studien enthält – ganz im Sinne der Präzisionsmedizin.

3 Big Data – Analysen für Labore Automatisierte Varianteninterpretation mit Daten aus Dataome – der „lernenden Datenbank“ Die Wissensdatenbank Dataome bildet die Grundlage für die Analyseplattform MH Guide. Dataome ist eine über ein Jahrzehnt entwickelte proprietäre globale Datenplattform für biomedizinisches Wissen, die sich durch drei Innovationen auszeichnet: Dataome Capture: Die Plattform nutzt künstliche Intelligenz und maschinelles Lernen, um molekulare und klinische Datenquellen in Echtzeit zu durchsuchen. Für die klinische Varianteninterpretation erfolgt eine Kuratierung der Daten durch Experten (Molekularbiologen, Molekularpathologen, Onkologen).

Dataome Knowledge: Dataome screent und bündelt weltweite medizinische Fachliteratur. Dadurch können Analysedaten in einen medizinischen Kontext eingeordnet werden.

Dataome Analytics: Komplexe genetische Tumordaten, wie NGS-Daten, werden von Analyseplattformen wie MH Guide effizient und automatisiert mit aus Dataome gewonnenen Informationen abgeglichen und für die klinische Varianteninterpretation genutzt.

4 Die klinische Varianteninterpretation

Präzise Varianteninterpretation in Therapieoptionen übersetzen Die klinische Varianteninterpretation als Ergebnis der MH Guide Analyse kombiniert die nach ACMG-Standards präklassifizierten Varianten mit therapierelevanten Erkenntnissen und listet die relevanten Informationen auf: • Identifizierte Variante (Keimbahn oder somatisch, Zygosität)

• E influss und Zulassungsstatus möglicher Behandlungsoptionen

• Krankheitsassoziation der Variante

• Gegebenenfalls geeignete klinische Studien

• V alidität von identifizierten prädiktiven, prognostischen und diagnostischen Biomarkern

• Zusammenfassung (sog. Narrative)

Flexibilität und Transparenz der Variantenevaluation • Eine Individualisierung der MH Guide Analyse durch das Setzen von Filtern oder die Implementierung von Regeln ist möglich.

• M H Guide gibt dem Anwender vollen Zugriff auf die Evidenzgrundlage der klinischen Varianteninterpretation.

Sie haben Fragen? Kontaktieren Sie uns unter +49 6221 43851-150 oder Kundendienst@molecularhealth.com

Die Komponenten der klinischen Varianteninterpretation mit MH Guide – Clinical Variant Interpretation (CVI)

e f

a

g

b ga

gb

h c

d

a

Varianten

b

• Gensymbol • Variantenname (HGVS) • Somatisch oder Keimbahn • Zygosität

d

Quellenangaben

Biomarker-Score

ga

CVI Score (Evidenzlevel: präklinisch [1–3], klinisch [4–6], klinisch genehmigt [7]) AMP/ASCO/CAP-Kategorie (Tier I–IV)

gb

c

• Liste der Krankheiten, für die der Biomarker beschrieben wurde

e

• L iste von Publikationen und ihre entsprechenden PubMed-IDs

g

Krankheiten

Biomarkertyp • Prädiktiv (wirksam, unwirksam, Sicherheit) • Diagnose • Prognostisch

h

Narrativ • Zusammenfassung der CVI

Behandlungsoptionen • Liste der Therapien • CVI Score •A ssociation for Molecular Pathology (AMP) Kategorie

f

Match quality Wie gut passt die Interpretation zu Variante und Patientenerkrankung?

5 Die sieben Schritte für eine MH Guide Analyse 1

Indikationsstellung Der Onkologe stellt die Indikation für die molekularpathologische Diagnostik.

Molekulardiagnostik beauftragen

2 3 4 5

Der Onkologe sendet Probenmaterial (Tumorbiopsie oder Tumorprobe) mit Überweisung (Muster 10) und Arztbrief an seinen Pathologen vor Ort. Er beauftragt dabei den Nachweis tumorrelevanter Mutationen.

NGS-Analyse durchführen Der Pathologe führt neben weiteren Untersuchungen des Tumors (a) die NGS-Analyse selbst durch oder (b) beauftragt dazu ein molekularpathologisches Labor.

NGS-Daten in MH Guide hochladen Der ausführende Pathologe führt die NGS-Analyse durch und lädt die Daten im Web-Portal zur MH Guide Auswertung hoch.

NGS-Daten analysieren MH Guide analysiert die NGS-Daten, vergleicht sie mit bereitgestellten Informationen der Dataome-Wissensdatenbank und ermöglicht die Erstellung eines individuellen Berichts.

Befunderstellung

6 7

Der ausführende Pathologe bearbeitet den MH Guide Bericht und zeichnet ihn frei. Das ausführende Labor oder der Pathologe vor Ort fasst die gesamten pathologischen Ergebnisse und Informationen aus dem MH Guide Bericht zusammen.

Auswahl von Therapieoptionen Der Onkologe erhält den Befund von seinem zuständigen Pathologen einschließlich individueller Therapieinformationen und möglicher Studien.

Sie haben Fragen? Kontaktieren Sie uns unter +49 6221 43851-150 oder Kundendienst@molecularhealth.com

6 Der MH Guide Report

Evidenzbasierte Entscheidungshilfe für die Behandlungsplanung Der interaktive MH Guide Report gibt einen Überblick über alle wichtigen Informationen zu den in einer Tumorprobe detektierten Biomarkern. Er beinhaltet die Variantenbezeichnung sowie die Bewertung und klinische Validität der Biomarker nach internationalen Richtlinien (AMP, ASCO, CAP).

Für die Therapieplanung liefert der MH Guide Report einen Überblick über: • Potenzielle Behandlungsmöglichkeiten • Unwirksame Arzneimittel sowie solche mit Sicherheitsbedenken • Informationen zu relevanten rekrutierenden klinischen Studien

Der Report kann durch Integration von Analyseergebnissen aus Nicht-NGSMethoden wie FISH, IHC oder qPCR ergänzt und durch Verwendung von digitalen Standardformaten individualisiert und in die lokale Infrastruktur integriert werden

Ausgabe in den Formaten PDF, JSON, XML

the theMH MH Guide Guide ReaR Sample Sample report: report: Lung Lung ade

Sample Sample report: report: Lung Lung ade a Sample Sample report: report: Lung Lung adea *(2 of*(2 11 of pages) 11 pages) *(2 of*(2 11 of pages) 11 pages)

*(2 of*(2 11 of pages) 11 pages) Alles im Blick:

Informationen zum vorliegenden Tumor

Identified Identified therapeutic therapeutic options options and and clinical clinical Identified Identified therapeutic therapeutic Identified Identified therapeutic therapeutic studies studies options options and and clinical clinical options options and and clinical clinical studies studies studies studies

— ID — Patient IDPatient —ID — Case ID Case Date of birth Date—of birth —

— ID — Patient IDPatient —ID — Case ID Case — — Patient IDDate Patient ID — Date of birth —of birth Primary tumor sitetumor — site — — Primary Sex Male Sex Collect — Case ID Case ID Collected Darstellung derMale detektierten — Surgical pathology — Ethnicity Ethnicity — — Surgical pathology Tumor Tumor Date of birth Date —of birth — cellularity Biomarker deren klinischer — Country US undUS Country Tissue type Barcode Barcod Tissue type— — ZIP — MetastaticMetastatic — — Trial ZIP Trial Sample type Sample Validität Primary tumor Primary sitetumor — site — Sex Sex Male Male Collected Collect code code pathology Surgical pathology — Ethnicity Ethnicity — — Surgical Tumor Tumor General dataset — ID — Labtestcellularity GeneralIDdataset — Labtes Primary tumor Primary site tumor — — Sex Sex Male Male Collected Collect Country Country US US Tissue type Tissue type Barcode Barcod CVI dataset IDdataset —ID site — CVI — pathology Surgical — — ——ZIP ——Surgical — Ethnicity Ethnicity Tumor Tumor Software version Softwa Trial ZIP Trial Metastatic Metastatic Samplecellularity type Sample Organizational unitpathology — unit — Organizational — — code code Country Country US US Tissue type Tissue type— Barcode Barcod General dataset GeneralIDdataset — ID — Labtest Labtes — ZIP — Metastatic — Trial ZIP Trial Metastatic— Sample type Sampl CVI dataset CVIIDdataset—ID — code code Zulassungsstatus der Medikamente Software Softwa dataset General IDdataset ID in —the Labtest Labtes MutationalMutational status of commonly mutated genes in patient disease statusGeneral of commonly mutated genes patient diseaseversion Organizational Organizational unit —the unit — in Bezug auf die Indikation CVI dataset CVIIDdataset—ID — ABCB1 ABCB1 ALK EGFR ERBB2 ERBB2 KRAS MET ALKBRAF BRAF EGFR KRAS Software version Softwa unit — not unit des not Patienten not 1 Organizational not— not 1 fusion, 11 Organizational fusion, not not not not not not identified SNVof commonly identified identified identified identified iden identified SNVof identified identified identified Mutational Mutational status status commonly mutated genes mutated in the genes patient in the disease patient diseaseidentifi

ABCB1 ABCB1 ALK BRAF BRAF EGFR EGFR ERBB2 ERBB2 KRAS KRAS MET STK11 ALK TP53 STK11 TP53 Mutational status of commonly status of mutated mutated in the genes patient disease patient ROS1 Mutational ROS1 Zusammenfassung: Dieses Feld not not 1not fusion, 11not fusion, notcommonly 1 notgenes not not notin the not notdiseasenot not 1 del 1 del identified identified SNV SNV identified identified identified identified identifi iden ABCB1 vom ABCB1 ALK ALKidentified BRAFfrei identified BRAF EGFR EGFR ERBB2 identified ERBB2 KRAS KRAS MET identified identified kann Anwender not not1 fusion, 11 fusion, not 1 notnot notnot notnot notnot genutzt werden STK11 STK11 TP53 TP53 identified identified SNV SNVidentified identified identified identified identified identified identified identifi iden ROS1 ROS1 not not not not 1 del SUMMARY 1 del SUMMARY identified identified identified identified STK11 STK11 TP53 TP53 ROS1 ROS1 not notnot not 1 del 1 del identified identified identified identified Overview O o Overview Overview of potential of treatment potential treatment impacts impacts

SUMMARY SUMMARY 3 Effective 3 Effective 2 Ineffective 2 Ineffective 1 Safety1

Safety

0 Progn

SUMMARY SUMMARY Overview Overview of potential of treatment potential treatment impacts impacts

Overview O o Potential impact Potential impact Treatment Treatment Drug Drug approval*Biomarker Bio 3 Effective 3 Effective 2 Ineffective 2 Ineffective 1 Safety 1 approval* Safety 0 Progn Overview oO Overview of Overview potential oftreatment potential treatment impacts impacts ALK/EML4 ALK 3 Effective Effective 3Effective Effective 2 Ineffective 2 Ineffective 1 Safety 1 Safety 0 Progn Lorlatinib Lorlatinib Approved Approved (fusion) (fus Potential impact Potential impact TreatmentTreatment Drug approval* Drug approval*BiomarkerBio

ALK/EML4ALK Effectiveimpact Effectiveimpact Treatment Ceritinib Ceritinib Approved Approved Potential Potential Treatment Drug approval* Drug approval*ALK/EML4 BiomarkerALK Bio (fusion) (fus (fusion) (fus ALK/EML4AL ALK/EML4ALK (fusion) (fu ALK/EML4ALK (fusion) (fus (fusion) (fus ALK/EML4AL Effective Effective Ceritinib CeritinibApproved Approved G6PD p.R285 G6 (fusion) (fu ALK/EML4ALK Safety Safety Dabrafenib Dabrafenib ApprovedApproved Effective Effective Brigatinib Brigatinib Approved Approved (SNV) (SN Effektiv (fusion) (fus ALK/EML4AL Effective Effective Brigatinib Brigatinib Approved Approved ALK p.L1196M ALK (fusion) (fu G6PD p.R285 G6 IneffectiveIneffective Crizotinib Crizotinib ApprovedApproved Ineffektiv Safety Safety Dabrafenib Dabrafenib ApprovedApproved (SNV) (SN (SNV) (SN G6PD p.R285 G6 Safety Safety DabrafenibDabrafenib Approved Approved Mögliches Sicherheitsrisiko ALK p.L1196M ALK (SNV) (SN ALK p.L1196M ALK IneffectiveIneffective Alectinib AlectinibApprovedApproved IneffectiveIneffective Crizotinib Crizotinib ApprovedApproved (SNV) (SN (SNV) (SN ALK p.L1196M AL * in the patient's * in thedisease; patient'sVAF disease; = Variant VAFallele = Variant frequency allele frequency IneffectiveIneffective Crizotinib Crizotinib Approved Approved (SNV) (SN Biomarker Biomarker score: AMP score: scoreAMP andscore CVI score. and CVI Clinically score. Clinically approved: approved: Approved Approve biomar ALK p.L1196M ALK Ineffective Ineffective Alectinib Alectinib Approved Approved disease.

Clinical: disease.

Not Clinical: yet approved Not yet approved biomarker biomarker for the patient's for thedisease. patient'sObserved disease. Ob in c (SNV) (SN drug. Preclinical: drug. Preclinical: This biomarker This biomarker has not yethas been notobserved/tested yet been observed/tested in patients intopatie pre ALK p.L1196M AL Ineffective Approved Approved *translational in Ineffective the patient's *translational in data. the disease; patient's VAF disease; =Alectinib Variant VAFallele =Alectinib Variant frequency allele frequency data.

(SNV) (SN Biomarker Biomarker score: AMP score: score AMP and score CVI score. and CVI Clinically score.

Clinically approved: approved: Approved Approve biomar You can find Youmore can find details more ondetails the biomarker on the biomarker score (AMP score and (AMP CVI score) and CVI in the score) glossary. in the disease.

Clinical: disease.

Not Clinical: yet approved Not yet approved biomarker biomarker for the patient's for the disease. patient's Observed disease.

Ob in c * in the patient's * in thedisease; patient'sVAF disease; = Variant VAFallele = Variant frequency allele frequency drug. Preclinical: drug.

Preclinical: This biomarker This has yethas been not observed/tested yet Clinically been observed/tested in patients intopatie pre Biomarker Biomarker score: AMP score: score AMP andbiomarker score CVI not score. and CVI Clinically score. approved: approved: Approved Approve biomar translational translational data.Not data. disease.

Clinical: disease.

Clinical: yet approved Not yet vom approved biomarkerbiomarker for the patient's for thedisease. patient'sObserved disease. Ob in c Elektronische Signatur You find You more can find details ondetails the biomarker onnot the yet biomarker score (AMP score and (AMP CVI score) andinCVI inpatients the score) glossary. inpatie the drug.can Preclinical: drug.

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You can find Youmore can find details more on details the biomarker on the biomarker score (AMPscore and CVI (AMP score) and CVI in the score) glossary. in the Lorlatinib Lorlatinib ApprovedApproved Effective Effective Zusammenfassung und Klassifikation Lorlatinib Lorlatinib Approved Approved Effective Effectiveder identifizierten Effective Effective BrigatinibBrigatinib ApprovedApproved Effective Effective Ceritinib CeritinibApprovedApproved Therapieoptionen

ans to to generate generate .owever, However, identifying identifying ans to to generate generate ans to generate to generate tment choice choice is still is still .eatment owever, However, identifying identifying .owever, However, identifying identifying tment eatment choice choice is still is still tment eatment choice choice is still is still gain n deep deep insight insight egain yze NGS data data from from nNGS deep deep insight insight gain n deep deep insight insight nctional functional genes, genes, eyze NGS NGS data data from from

Order date 14 Nov Order 2019 date 14 Nov 2019 Report VersionReport 5 Version 5

Signed by Signed by 11 Dec 2019 12:20 11 Dec (UTC+01:00) 2019 12:20 (UTC+01:00)

Molecular Health Molecular GmbH, Health Kurfuersten-Anlage GmbH, Kurfuersten-Anlage 21, 69115 Heidelberg 21, 69115| Heidelberg www.molecularhealth.com | www.molecularhealth.com | +49 6221 4 Order date 14 Nov Order 2019 date 14 Nov 2019 Report VersionReport 5 Version 5

Signed by Signed by 11 Dec 2019 12:20 11 Dec (UTC+01:00) 2019 12:20 (UTC+01:00)

Molecular Health Molecular GmbH, Health Kurfuersten-Anlage GmbH, Kurfuersten-Anlage 21, 69115 Heidelberg 21, 69115Signed | Heidelberg www.molecularhealth.com | www.molecularhealth.com | +49 6221 4 Order date 14 Nov Order 2019 date 14 Nov 2019 by Signed by Report Version 5Report Version 5

11 Dec 2019 12:20 11(UTC+01:00) Dec 2019 12:20 (UTC+01:00)

Molecular Health Molecular GmbH, Health Kurfuersten-Anlage GmbH, Kurfuersten-Anlage 21, 69115 Heidelberg 21, 69115| www.molecularhealth.com Heidelberg | www.molecularhealth.com | +49 6221 4

Sie haben Fragen? Kontaktieren Sie uns unter +49 6221 43851-150 oder Kundendienst@molecularhealth.com

Sample report: Lung adenocarcinoma* *(2 of 11 pages) *(2 of 11 pages)

Patient ID — — Case ID Date of birth —

Lung adenocarcinoma Diagnosis — ICD-10-CM code — MeSH ID/term Additional MeSH IDs Lung — adenocarcinoma Diagnosis Patient ID — — — ICD-10-CM code Case ID — MeSH Date of birth — — ID/term Primary tumor site — Ordering — Sex Male Collected Additional MeSH IDs — — physician Surgical pathology — Ethnicity — Tumor cellularity — — — Facility Country US Tissue type Barcode — — Email — Trial ZIP — Metastatic Sample type — Primary tumor site — Ordering — Sex Male Collected Phone — code physician Surgical pathology General dataset ID — — Labtestcellularity — Ethnicity — Tumor Fax — — — — Facility CVI dataset — Country US Tissue type ID Barcode Product MH Guide — — — Softwaretype version Email — Organizational unit — Trial ZIP Metastatic Sample — Report Phone — code — General dataset ID — Labtest Fax — CVI dataset ID — Product MH Guide — Software version Mutational status of commonly mutated genes in the patient disease Organizational unit — — Report ABCB1 ALK BRAF EGFR ERBB2 KRAS MET NF1 NRAS PIK3CA RET not 1 fusion, 1 not not not not not not not not not identified status SNVof commonly identified identified identified Mutational mutated genes in the patient diseaseidentified identified identified identified identified identified ABCB1 ROS1 not 1 del identified

ALK STK11 1not fusion, 1 SNV identified

BRAF TP53 not identified

STK11 ROS1 not 1 del SUMMARY identified

TP53 not identified

EGFR not identified

ERBB2 not identified

KRAS not identified

2 Ineffective

NF1 not identified

NRAS not identified

PIK3CA not identified

Relevant

MEDIC

Potenti

Relevant Effect

Potenti

Effect

RET not identified

Recomm Single-a Overview of prognostic and diagnostic findings

Overview of potential treatment impacts

SUMMARY 3 Effective

MET not identified

MEDIC

1 Safety

0 Prognostic

Overview of potential treatment impacts Potential impact 2 Ineffective Treatment 1 Safety Drug approval* 3 Effective

0 Diagnostic

Overview of prognostic and diagnostic findings Biomarker Biomarker score 0 PrognosticVAF 0 Diagnostic

Clinical trials found 8

Trials

Recomm Single-a

Clinical trials found Trials 8 Trials

Lorlatinib Treatment

Approved Drug approval*

ALK/EML4 (fusion) Biomarker

— VAF

Effective Effective

Ceritinib Lorlatinib

Approved Approved

ALK/EML4 ALK/EML4 (fusion) (fusion)

— —

3 2

Effective Effective

Brigatinib Ceritinib

Approved Approved

ALK/EML4 ALK/EML4 (fusion) (fusion)

— —

5 3

Safety Effective

Dabrafenib Brigatinib

Approved Approved

G6PD p.R285H ALK/EML4 (SNV) (fusion)

99.56% —

— 5

Ineffective Safety

Crizotinib Dabrafenib

Approved Approved

ALK p.L1196M G6PD p.R285H (SNV) (SNV)

23.80% 99.56%

— —

Recomm Single-a

Ineffective Ineffective

Alectinib Crizotinib

Approved Approved

ALK p.L1196M ALK p.L1196M (SNV) (SNV)

23.80% 23.80%

— —

Recomm Single-a

Effective Potential impact

Biomarker score

2 Trials

Effect

* in the patient's disease; VAF = Variant allele frequency Biomarker score: AMP score and CVI score. Clinically approved: Approved biomarker (by the FDA, EMA, or NCCN) to predict a specific effect in the patient's ALK p.L1196M Ineffective Alectinib Approved 23.80% — of the disease.

Clinical: Not yet approved biomarker for the patient's disease. Observed in clinical studies as a potential biomarker to predict a specific effect (SNV) drug. Preclinical: This biomarker has not yet been observed/tested in patients to predict a specific effect of the drug. It is supported by preclinical evidence or * in the patient's disease; VAF = Variant allele frequency translational data.

Biomarker AMP score and CVI score.score Clinically approved: Approved biomarker (by the FDA, EMA, or NCCN) to predict a specific effect in the patient's You can findscore: more details on the biomarker (AMP and CVI score) in the glossary. disease. Clinical: Not yet approved biomarker for the patient's disease. Observed in clinical studies as a potential biomarker to predict a specific effect of the drug. Preclinical: This biomarker has not yet been observed/tested in patients to predict a specific effect of the drug. It is supported by preclinical evidence or translational data.

You can find more details on the biomarker score (AMP and CVI score) in the glossary.

Order date 14 Nov 2019 Report Version 5

Signed by 11 Dec 2019 12:20 (UTC+01:00)

Phone —

Molecular Health GmbH, Kurfuersten-Anlage 21, 69115 Heidelberg | www.molecularhealth.com | +49 6221 43851-150 Order date 14 Nov 2019 Report Version 5

Signed by 11 Dec 2019 12:20 (UTC+01:00)

Molecular Health GmbH, Kurfuersten-Anlage 21, 69115 Heidelberg | www.molecularhealth.com | +49 6221 43851-150

Effect

Effect

Effect

Order date 14 Report Versio Page 1 of 11

Phone —

Molecular

Order date 14 Report Versio Page 1 of 11

Molecular

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