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Tissue Agnostic Oncology Prof. Dr. Hans Prenen Oncology Department University Hospital Antwerp, Belgium Annual meeting 2019

Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell

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Page 2: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell

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.

Page 3: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell

• Study in 7664 tumors accross 29 different cancers

• Nearly all codingmutations are toleratedand escape negativeselection !

• Somatic cells evolve bypositive selection

Page 4: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell

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

Page 5: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell

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

Page 6: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell

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

Page 7: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell

Extremely difficult to explore rare signatures

Misale et al, Cancer discovery 2014

Umbrella trial

HER2 NRAS MET NTRK PIK3CA

Page 8: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell

Actionable alterations can be detected across cancers in the clinic

Presented By Alexander Drilon at 2018 ASCO Annual Meeting

Page 9: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell

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

Page 10: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell

Tumor agnostic therapy = targeting oncogenic drivers regardless of tissue histology

Drillon A ASCO 2018

Page 11: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell

Agnostic oncology

CONTEXT INDEPENDENT ACTIVITY

CONTEXT SPECIFIC ACTIVITY

Page 12: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell

Agnostic oncology

CONTEXT INDEPENDENT ACTIVITY

CONTEXT SPECIFIC ACTIVITY

Page 13: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell

Trials were all single arm !

Page 14: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell

Pembrolizumab: agnostic activity in MSI-high cancers

Le et al

Page 15: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell

MSI: frequency

Page 16: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell
Page 17: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell

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

Page 18: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell
Page 19: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell
Page 20: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell
Page 21: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell
Page 22: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell
Page 23: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell

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

Page 24: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell

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

Page 25: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell

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

Page 26: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell

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

Page 27: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell

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

Page 28: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell

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)

Page 29: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell

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 ??

Page 30: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell
Page 31: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell
Page 32: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell
Page 33: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell
Page 34: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell
Page 35: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell

LOXO-292: agnostic activity in RET fusion+ cancers

Page 36: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell

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

Page 37: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell

Agnostic oncology

CONTEXT INDEPENDENT ACTIVITY

CONTEXT SPECIFIC ACTIVITY

Page 38: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell

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%

Page 39: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell

Slide 9

Page 40: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell

Slide 10

Page 41: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell

Neratinib HER Mutation Basket Study (SUMMIT)

Page 42: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell
Page 43: Tissue Agnostic Oncology · 2019-04-15 · Mutations and cancer Hundreds of genes, when mutated, can cause cancer Small number of those mutations is required to convert a normal cell

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