Tissue Agnostic Oncology

Prof. Dr. Hans Prenen

Oncology Department

University Hospital Antwerp, Belgium

Annual meeting 2019

Mutations and cancer

Hundreds of genes, whenmutated, can cause cancer

Small number of thosemutations is required toconvert a normal cell into a cancer cell

Genes differ according tocancer type

Many driver genes have not been identified yet.

• Study in 7664 tumors accross 29 different cancers

• Nearly all codingmutations are toleratedand escape negativeselection !

• Somatic cells evolve bypositive selection

How many mutations are needed for a normal cell to turn into a cancer cell ???

GOAL: Identify the specific mutations responsible for a patient’scancer, among the thousands of mutations that are found

A unique approach: Moving beyond chemotherapy, Dr Jacques De Grève …

“The ideas are simple, but getting them

figured out is

very complicated”

• Suggested there is a high need todo PRECISION trials• PRECISION 1: platform for

sharing NGS and clinical data• PRECISION 2: exploratory

studies in genotypes

Extremely difficult to explore rare signatures

Misale et al, Cancer discovery 2014

Umbrella trial

HER2 NRAS MET NTRK PIK3CA

Actionable alterations can be detected across cancers in the clinic

Presented By Alexander Drilon at 2018 ASCO Annual Meeting

There is a ‘long tail’ of hotspot mutations across different cancers

Tumor agnostic therapy = targeting oncogenic drivers regardless of tissue histology

Drillon A ASCO 2018

Agnostic oncology

CONTEXT INDEPENDENT ACTIVITY

CONTEXT SPECIFIC ACTIVITY

Agnostic oncology

CONTEXT INDEPENDENT ACTIVITY

CONTEXT SPECIFIC ACTIVITY

Trials were all single arm !

Pembrolizumab: agnostic activity in MSI-high cancers

Le et al

MSI: frequency

Entrectinib / Larotrectinib: agnostic activity in TRK fusion+ cancers

1. Rolfo, et al. Expert Opin Investig Drugs 2015; 2. Ahn, et al. WCLC 2017; 3. Doebele, et al. WCLC 2018; 4. Amatu, et al. ESMO Open 2016 Figure modified from Khotskaya, et al. Pharmacol Therap 2017

Pro-survival genes

TRKA

NGF

Ras

Raf

MEK 1/2

ERK 1/2

PLCγ

Ca2+ PKCγ

PI3K

AKT

P

P

P

P

TRKB

BDNF or NT-4/5

P

P

P

P

TRKC

NT-3

P

P

P

P

GSK3β S6K1

IκB

Pro-differentiation genes

Synaptic

plasticity

Transcription factors

Regulation of actin

cytoskeleton

Ubiquitin-

mediated

proteolysis

- NTRK1/2/3 genes encode TRK A/B/C proteins, respectively

- NTRK1/2/3 gene fusions are oncogenic drivers 4

esmo.org

Efficacy and safety of entrectinib in patients with

NTRK fusion-positive tumours: pooled analysis of

STARTRK-2, STARTRK-1 and ALKA-372-001Demetri GD1, Paz-Ares L2, Farago AF3, Liu SV4, Chawla SP5, Tosi D3, Kim ES6,

Blakely C7, Krauss JC8, Sigal D9, Bazhenova L10, John T11, Besse B12, Wolf J13,

Seto T14, Chow-Maneval E15, Multani PS15, Johnson A15, Simmons B16, Doebele RC17

1Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; 2Hospital Universitario Virgen del Rocío, Sevilla, Spain; 3Massachusetts General Hospital, Boston, MA, USA; 4Georgetown University, Washington, DC, USA; 5University of California Los Angeles,

Los Angeles, CA, USA; 6Carolinas Healthcare System, Charlotte, NC, USA; 7University of California San Francisco, San Francisco, CA, USA; 8University of Michigan, Ann Arbor, MI, USA; 9Scripps Clinic, La Jolla, CA, USA; 10University of California San Diego, San Diego, CA, USA; 11Olivia Newton-John Cancer Research Institute, Austin Health, Heidelberg, Victoria, Australia; 12Gustave Roussy Cancer Campus,

Villejuif Cedex, France; 13University Hospital of Cologne, Cologne, Germany; 14National Kyushu Cancer Center, Fukuoka, Japan; 15Ignyta, Inc., San Diego, CA, USA; 16Genentech, South San Francisco, CA, USA; 17University of Colorado, Aurora, CO, USA

NTRK genes, TRK proteins And entrectinib

1. Rolfo, et al. Expert Opin Investig Drugs 2015; 2. Ahn, et al. WCLC 2017; 3. Doebele, et al. WCLC 2018; 4. Amatu, et al. ESMO Open 2016 Figure modified from Khotskaya, et al. Pharmacol Therap 2017

AKT: v-akt murine thymoma viral oncogene homologue; BDNF: brain-derived neutrophic factor; CNS: central nervous system; DoR: duration of response; ERK: extracellular signal-regulated kinase; GSK3β: glycogen synthase kinase β; IκB: inhibitor of nuclear factor κ B;

MEK: mitogen-activated protein kinase; NGF: nerve growth factor; NT: neurotrophin; NTRK: neutrophic TRK; ORR: overall response rate; PI3K: phosphatidylinositol-4,5-bisphosphate 3-kinase; PKC: protein kinase C; PLC: phospholipase C; Raf: rapidly accelerated fibrosarcoma kinase;

Ras: rat sarcoma kinase; S6K1, ribosomal protein S6 kinase beta-1; TRK: tropomyosin receptor kinase

• Entrectinib is an oral, potent and

selective inhibitor of all TRK

proteins and ROS1 tyrosine kinases

designed to be active in the CNS1,2

– Clinically meaningful benefit for

ROS1+ NSCLC patients with and

without CNS metastases

(ORR 77%, mDoR 24.6 months) 3

Pro-survival genes

TRKA

NGF

Ras

Raf

MEK 1/2

ERK 1/2

PLCγ

Ca2+ PKCγ

PI3K

AKT

P

P

P

P

TRKB

BDNF or NT-4/5

P

P

P

P

TRKC

NT-3

P

P

P

P

GSK3β S6K1

IκB

Pro-differentiation genes

Synaptic

plasticity

Transcription factors

Regulation of actin

cytoskeleton

Ubiquitin-

mediated

proteolysis

Integrated analysis of global population from 3 studies

Integrated analysis

STARTRK-2: 150+ sites in 15 countries

STARTRK-1: 10 sites in USA, Spain, South Korea

ALKA-372-001: 2 sites in Italy

North America

USA

Europe

Belgium

France

Germany

Italy

The Netherlands

Poland

Spain

UK

Study sites*

Asia Pacific

Australia

Hong Kong

Japan

South Korea

Singapore

Taiwan

*Diagnostic testing was completed centrally

Integrated efficacy and safety analysis of entrectinib:

NTRK fusion-positive solid tumours

1. https://clinicaltrials.gov/ct2/show/NCT02568267

2. Drilon, et al. Cancer Discov 2017

Data cut-off 31 May 2018§Patients with at least 6 months of follow up

*Per blinded independent central review measured by RECIST v1.1†Patients with measurable and non-measurable CNS lesions at baseline OS: overall survival; PFS: progression-free survival

Integrated analysis

Efficacy population§

54 adult patients with NTRK

fusion-positive, TRK inhibitor-

naïve solid tumours

Safety population

355 patients overall have

received entrectinib

(all tumour types and gene

rearrangements)

Primary endpoints*

ORR and DoR

Secondary endpoints*

PFS and OS

Intracranial ORR

and DoR†

Safety and tolerability

STARTRK-12

Phase I dose escalation

n=2 NTRK+ patients

ALKA-372-0012

Phase I dose escalation

n=1 NTRK+ patient

STARTRK-21

Phase II, multicentre, global basket study 600mg QD, 28-day cycle

n=51 NTRK+ patients

CRC: colorectal cancer; ECOG PS: Eastern Cooperative Oncology Group performance status;MASC: mammary analogue secretory carcinoma; NSCLC: non-small cell lung cancer

Cut-off date: 31 May 2018Note: Patients (n=6) without matched pre/post therapy scans were excluded from the plot

CI: confidence interval; CRC: colorectal cancer; MASC: mammary analogue secretory carcinoma; NSCLC: non-small cell lung cancer

Entrectinib activity in NTRK fusion-positive solid tumours: individual patient responses by tumour type

0

-30

-50

-90

Bes

t %

ch

ang

e fr

om

bas

elin

e

15

-80

-70

-60

-40

-20

-10

20

30

40

-100

50

CRCNSCLCSarcoma

Neuroendocrine tumours

PancreaticThyroidMASC Breast

CholangiocarcinomaGynaecological

NTRK+ patients (n=54)

ORR (95% CI) 57.4% (43.2–70.8)

SD 9 (16.7)

PD 4 (7.4)

Non-CR/PD, missing or unevaluable

10 (18.5)

Results per Blinded Independent Central Review (BICR)

Entrectinib / larotrectinib: next steps

• Neo-adjuvant setting (ex. Sarcoma limb sparing)

• Resistance:

• NTRK mutations

• Respond to next generation TKI’s !

• Downstream mutations

• Combination with other targeted therapy ??

LOXO-292: agnostic activity in RET fusion+ cancers

Cancer discovery 2018

• NRG1 fusions are mainly found in mucinous lungadenoca but alsopancreas and breast

• Targeting HER3 in NRG1 fusions is a novel paradigm

• Recent data also found NRG1 fusions in head and neck, renal, ovarian, prostate and uterine cancers

Agnostic oncology

CONTEXT INDEPENDENT ACTIVITY

CONTEXT SPECIFIC ACTIVITY

Paradigm Shift in Cancer therapy: improved outcome withprecision medicine

Trial Design Endpoints Population Results

MOSCATO 01 Open label PFS2/PFS1 ratio

N=199 1.3 in 33% of evaluablepatients

InterMountainHealthcare group

Retrospectiveanalysis vshistoricalcontrols

PFS N=36 Average PFS 22,9 weeks vs12.0 weeks

Meta-analysis of phase 1 trials

Meta-analysis comparingprecisionmedicine vsSOC chemo

ORR N=13,203 refractorymalignancies

ORR: 30,6% vs4.9%

Slide 9

Slide 10

Neratinib HER Mutation Basket Study (SUMMIT)

Conclusion

• Need to assess MSI and dMMR in a broad population

• Value of conducting multipanel NGS

• Cost and reimbursement barriers

• Multiple FDA approved NGS panels:

• MSK-IMPACT

• FoundationOne

• Oncomine

• Pembrolizumab, larotrectinib and entrectinib have demonstrated valueof tumor-agnostic approch BUT

• Model is not going to universally work

Thanks For your attention !