tissue agnostic oncology · 2019-04-15 · mutations and cancer hundreds of genes, when mutated,...
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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