1. Incorporating Genomics into Clinical Care
Araba A. Adjei, PhD
AACR (SSP)
April 4, 2017
Washington, DC.
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2. Cancer occurs when something goes wrong with our genes
ASCO Curriculum: Cancer Genetics & Cancer Predisposition Testing
Cancer occurs when something goes wrong with our genes
DNA is the building block of a gene. Genes are stored in the chromosome A C T T G A G C
Basic Genetics 3

3. Gene Mutation

4. Chromosomal Aberrations

5. Somatic mutations: Passengers and Drivers
acquired alterations in DNA that occur in body cells other than germ cells (sperm and egg) and therefore not passed on to offsprings
alterations in DNA can (but do not always) cause cancer or other diseases
Driver mutations
somatic mutations within a gene with functional consequences
confer selective growth advantage to the cell thus promoting cancer development
mutations occur frequently at the same genes, loci, or pathways in different patients

6. Somatic mutations: Passengers and Drivers
Passenger mutations
majority of somatic alterations with no functional consequence
no positive or negative selective advantage to the tumor; considered to just go along “for the ride”
studies suggest “mob mentality”: individually exert small effect; collectively may have enough significant effect to alter the course of cancer progression
Oncogene
An oncogene is a gene that when mutated or expressed at abnormally-high levels contributes to converting a normal cell into a cancer cell.

7. Passenger mutations in whole genome sequencing
Cancer(s)
Protein-coding mutations
Driver mutations*
11 breast
115.4
5.1
10 colon 75 4
4 astrocytomas
206
5.5
Acute myeloid leukemia 10 2
26 melanomas
366
Small-cell lung
100
*Classified as drivers in COSMIC database
McFarland et al,  PNAS, 2013

8. Proportion of cancer genes with mutations
<10%
>10%
> 80%
Futreal et al, Nat Rev Cancer, 2004

9. “Driver” Genes as Cancer Targets in TKI therapy
EGFR
Erlotinib, Gefitinib, Afatinib, Osimertinib
EML4-ALK
Crizotinib, Alectinib, Ceritinib
Bcr-abl
Imatinib, Dasatinib, Ponatinib
HER2-neu
Trastuzumab, Perzutumab
B-raf
Vemurafenib, Dabrafenib
Ret
Vandetanib, Cabozantinib
Hedgehog
Vismodegib
Ros-1
Crizotinib
MET
Crizotinib, Cabozantinib, Tivatinib 9

10. Paradigm change:
from treating clinical characteristics to Genomic – based therapy
Drugs that target the molecular
mechanisms involved in cancer
progression can improve outcome
DNA mutations
Aberrant proteins
Normal Cell
Cancer cell

11. Kinase inhibition in oncogene-addicted NSCLC
Erlotinib in NSCLC EGFR mut+
Crizotinib in NSCLC ALK+
ORR: 54–83%; PFS: 12 months
Rosell Lancet Oncol 2012
This EGFR mutation predicts response to erlotinib in NSCLC
The ALK fusion also predicts response to crizotinib
ORR: 50–65%; PFS: 9months
Kwak NEJM 2010

12. Not all “oncogenic” mutations are predictive biomarkers

13. BRAF Gene Mutations in NSCLC
21 (56.7%) V600E hotspot mutations
16 (43.3%) non-V600E mutations distributed in narrow areas between codons 594 and 606 (exon 15) and 446 and 449 (exon 11)
Marchetti A, et al. J Clin Oncol. 2011;9:

14. Prognostic Significance of BRAF Mutations
Litvak AM, et al. J Thorac Oncol. 2014;9:

15. BRAF V600E Mutant NSCLC: Confirmed Response to Dabrafenib in ≥2nd Line
ORR = 33%; N=78
Planchard D, et al. Lancet Oncol 20146

16. Poor Survival of BRAF mutant CRC
Hazard Ratio of 10.6 for OS
Less than 1 year OS
Tran, Kopetz, et al, Cancer ‘11

17. Poor Response of BRAFmut CRC to Standard Therapies
BRAF wild type
Progression at
First Restaging
Morris et al Clin Colorect Can ‘14

18. Minimal Efficacy with BRAF or Dual BRAF + MEK Inhibition
BRAF inhibition
BRAF + MEK inhibition
-100
-75
-50
-25 25 50 75
100
%Change From Baseline
(Sum of Lesion Size)
5% Response Rate
12% Response Rate
Vemurafenib
GSK212 + GSK436
Corcoran et al ASCO ‘12, Kopetz et al ASCO ‘10

19. Genomics-based Therapy is Part of the future
Future Directions
Repeating molecular analysis can help
Drilon CCR 2015
In patients with lung cancer who have tested negative for EGFR, KRAS, ALK and ROS1, adding MET to the panel of mutations to be tested should be very strongly considered and this might be best accomplished as part of multi-gene panels. In fact, the NCCN guidelines have already adopted such recommendations given the powerful observations listed without a formal study in this area.
MET∆14 occurred mutually exclusively with known driver mutations but tended to coexist with MET amplification or copy number gain
As the technology, feasibility and costs of NGS improve and become more accessible, NGS as the standard for the evaluation of genomic alterations may prove to be the recommended testing modality and recent technological advances now allow testing for alterations such as MET exon 14 skipping as part of ctDNA-based NGS platforms.

20. Genomic-based Therapy
Current Study Design opened to community oncology programs
NCI-Molecular Analysis for Therapy Choice (NCI-MATCH / EAY131)
A phase II precision medicine cancer trial
Co-developed by the ECOG-ACRIN Cancer Research Group and the National Cancer Institute
ECOG: eastern cooperative oncology
ACRIN: American college of radiology imaging network;
ECOG-ACRIN program merger of the NCI/NCTN (National cancer trials network)program

21. What is NCI-MATCH?
ECOG-ACRIN-NIH-NCI
03/13/2017

22. NCI-MATCH Objective
To determine whether matching certain drugs or drug combinations in adults whose tumors have specific gene abnormalities will effectively treat their cancer, regardless of the cancer type
This is a signal-finding trial—treatments that show promise can advance to larger, more definitive trials
ECOG-ACRIN-NIH-NCI

23. NCI-MATCH Distribution of 1089 Sites
Participation Rates by Site Type:
NCORPS ~ 90%
NCI Cancer Centers ~ 80%
ECOG-ACRIN-NIH-NCI
03/13/2017

24. What do we know about NCI MATCH
The clinical trial opened August 12, 2015 with 10 treatment arms
Goal was to accrue 3000 patients
As new assays were designed treatment arms and patient accrual goals were expanded.
Today, patient accrual goal is 6000; treatment arms are 30
Patient Advocates helped design the trial and are overseeing its conduct

26. Molecular aberrations (gene abnormalities) and 30 treatment arms
Drug(s)
Abnormality
Accrual Goal (Actual) A
afatinib
EGFR mut
35 (0) B
HER2 mut
35 (29) C1
crizotinib
MET amp
35 (10) C2
MET exon 14 sk
35 (13) E
AZD9291
EGFR T790M
35 (3) F
ALK transloc
35 (1) G
ROS1 transloc H
dabrafenib and trametinib
BRAF V600E or V600K
35 (16) I
taselisib 
PIK3CA mut
70 (68) J
trastuzumab and pertuzumab
HER2 amp

27. Gene abnormalities and 30 Treatment Arms
Drug(s)
Abnormality
Accrual Goal (Actual) L
TAK-228
mTOR mut
35 (0) M
TSC1 or TSC2 mut N
GSK
PTEN mut
35 (24) *SUSPENDED* P
PTEN loss
35 (35) *FULL* Q
ado-trastuzumab emtansine
HER2 amp
70 (37)
*SUSPENDED* R
trametinib
BRAF nonV600
35 (24) S1
NF1 mut S2
GNAQ or GNA11
35 (3) T
vismodegib
SMO or PTCH1
35 (11) U
defactinib
NF2 loss
35 (18)

28. Gene abnormalities and 30 Treatment Arms
Drug(s)
Abnormality
Accrual Goal (Actual) V
sunitinib malate
cKIT mut
35 (2) W
AZD4547
FGFR pathway aberrations
70 (42) X
dasatinib
DDR2 mut
35 (0) Y
AZD5363
AKT1 mut
35 (23)
Z1A
binimetinib
NRAS mut
Z1B
palbociclib
CCND1, 2, or 3 amp
35 (21)
Z1C
CDK4 or CDK6 amp
Z1D
nivolumab
dMMR status
70 (37)
Z1E
larotrectinib (LOXO-101)
NTRK fusions
Z1I
AZD1775
BRCA1 or BRCA2 mut
TOTAL: 1190 (495)

29. Study participation criteria
Adults (18 years and over)
solid tumors including rare tumors, lymphoma and myeloma
good ECOG performance status
able to tolerate being off treatment for 6 weeks
ECOG-ACRIN-NIH-NCI
03/13/2017

30. NCI-MATCH Tumor Gene Testing
ECOG-ACRIN-NIH-NCI

32. Basket Trial – NCI MATCH

33. NCI-MATCH : SUMMARY …As of March 13, 2017
4702 patients with tumor samples (N=6000)
4125 patients had received their test results
722 patients had a gene abnormality matching an available treatment arm and were further evaluated for specific eligibility
495 patients had enrolled for treatment
NOTE: These are strictly numbers reflecting a point in time and cannot be used to calculate overall rates
ECOG-ACRIN-NIH-NCI

34. NCI – MATCH: SUMMARY
About 72% of patients who get assigned to a treatment arm actually enroll for treatment
The laboratory network completes tumor testing for about 94% of patient cases
About 20% of the patients have a gene abnormality which matched the one being studied

35. Cautionary Note: sequenced tumor
Many genetic variants or mutations found when tumor is sequenced.
Only a small proportion of the mutations are “actionable mutations”
- mutations that are targets for drug therapy (MATCH panel)
Most of the mutations received from sequencing are gene variants with UNKNOWN SIGNIFICANCE
- not known if they are “actionable”; no known drugs that inhibit their action

36. Variants of Unknown Significance
Gene
Substitution
Nucleotide
Domain
ALK
G722C
2164G>T
Extracellular
N709I
2126A>T
DDR2
c.554delG (C185fs)
F5/8 type C
EGFR
R377W
1129A>T
R962C
2884C>T
Kinase
E97*
289G>T
G203A
608G>C
G779V
2336G>T
G779C
2335G>T
D1014N
3040G>A
Cytoplasmic
ERBB2
S310Y
929C>A
R784H
2351G>A
L62V
184C>G
S335C
1003A>T
D483V
1448A>T
KIT
K834R
2501A>G

37. Gene
Substitution
Nucleotide
Domain
KRAS
Y64N
190T>A
Uncharacterized
A11T
31G>A
GTP binding
V14L
40G>T
MAP2K1
E255Q
763G>C
Kinase
PDGFRA
Q24L
71A>T
Ig-like C2-type 1
S89G
265A>G
Y98*
294C>A
R293L
878G>T
Ig-like C2-type 3
R481M
1442G>T
Ig-like C2-type 5
A503S
1507G>T
L521M
1561C>A
R914L
2741G>T
PIK3CA
C695F
2084G>T
PIK helical
Q546H
1638G>C
PTEN
L186P
557T>C
Phosphatase tensin-type
RET
V53I
157G>A
Extracellular
R525L
1574G>T

38. NCI MATCH study conduct at Mayo Clinic
Study opened August 2, in Rochester
113 patients have consented
99 patients have been screened
57 biopsy’s have been done (archived samples were sent for the other patients)
7 matches so far (3 have gone onto treatment)
2 recently MATCHed to the additional arms
Proportion MATCHed = 7%

39. THANKS !