Join Fight CRC in a webinar about biomarkers. In this session, Dr. Chris Lieu will focus the discussion on the NTRK biomarker, in addition to ctDNA, and Next-Generation Sequencing.

1. OUR WEBINAR WILL BEGIN SHORTLY

2. Impact of Biomarker Testing for
Colorectal Cancer
(and a quick COVID-19 update)

3. TODAY’S
WEBINAR
01 Ask a question in the panel on the right side of
your screen
QUESTIONS
02 Watch a recording of this webinar on the Fight
CRC website. Visit FightCRC.org
WEBINAR ARCHIVE
03 Follow along on Twitter. Use the hashtag
#CRCWebinar
TWEET ALONG!

4. Resources
Fight CRC offers a wide
variety of resources for
those touched by colorectal
cancer. Visit FightCRC.org
to view, download, and
order the latest resources.

5. The information and services provided by Fight Colorectal Cancer are for general informational
purposes only. The information and services are not intended to be substitutes for professional
medical advice, diagnoses or treatment.
If you are ill, or suspect that you are ill, see a doctor immediately. In an emergency, call 911 or go to the
nearest emergency room.
Fight Colorectal Cancer never recommends or endorses any specific physicians, products or
treatments for any condition.

6. TODAY’S
PRESENTER
Christopher Lieu, MD
Dr. Lieu joined the University of Colorado School of Medicine faculty in July 2011. He trained
in internal medicine at the University of Colorado, where he also served as a Chief Medical
Resident. He completed his fellowship training in medical oncology at the University of Texas
MD Anderson Cancer Center and served as the Chief Medical Oncology Fellow in 2010. He
currently serves as the Director of GI Medical Oncology at the University of Colorado Cancer
Center, the Vice-Chair of the National Cancer Institute Colon Cancer Task Force, and he
serves on the National Comprehensive Cancer Network (NCCN) Panel for Neuroendocrine
Cancers.
Research: Dr. Lieu is a member of the Developmental Therapeutics (phase I clinical trials) and
Gastrointestinal (GI) Medical Oncology Program. These comprehensive programs include
multidisciplinary cancer clinics, tumor boards, and research endeavors. Dr. Lieu is interested
in resistance mechanisms to targeted therapy in GI cancers, and he was awarded the
Conquer Cancer Foundation Career Development Award and a NIH K23 grant to study
targeted therapies in colorectal cancer. Dr. Lieu is also investigating novel therapeutic
strategies to more effectively treat and prevent colorectal cancer in young adults.

7. Impact of Biomarker Testing for Colorectal Cancer
(and a quick COVID-19 update)
Christopher Lieu, MD
Director, GI Medical Oncology
Associate Director for Clinical Research
University of Colorado Cancer Center

8. Disclosures
• Consulting
– Merck
• Data Safety Monitoring Board
– Immune Concepts
– Incyte
– Ipsen

9. Objectives
• What is a biomarker?
• How can biomarkers affect the treatment of your cancer?
• What are some examples of meaningful biomarkers for
colorectal cancer (CRC)?
• Quick COVID-19 update

10. Personalized Medicine is Advancing
• Personalized medicine aims to individualize medical
treatment plans
• Steps can be taken to identify patients that may be
more likely to benefit, or may be at great risk of side-
effects

11. Medical Treatment Plans
• Medical treatment plans for metastatic colorectal cancer may include:
– Surgery
– Radiotherapy
– Chemotherapy
– Targeted Therapy
• Chemotherapy is a type of cancer treatment that works by killing rapidly
dividing cells as found in cancer
• Targeted therapy and immunotherapy are a type of cancer treatment
that works by targeting specific genes or proteins that are altered in
cancer cells
– May be used alone or in combination with chemotherapy

12. “Cytotoxics” Mechanism
1. 5-Fluorouracil (5-FU) -> pyrimidine analog
2. capecitabine -> oral 5-FU pro-drug
3. TAS-102 -> 5-FU drug with metabolism inhibitor
4. irinotecan -> topoisomerase I inhibitor
5. oxaliplatin -> 3rd generation platinum
“Biologics/Targeted” Mechanism
1. cetuximab -> antibody against EGFR
2. panitumumab -> antibody against EGFR
3. bevacizumab -> antibody against VEGF
4. ziv-aflibercept -> VEGF trap
5. ramucirumab -> antibody against VEGFR2
6. regorafenib -> tyrosine kinase inhibitor
7. ramucirumab -> antibody against VEGFR2
8/9. pembrolizumab/nivolumab -> antibody against PD-1 (MSI-high only)
10. ipilimumab -> antibody against CTLA-4 (MSI-high only)
VEGF= Vascular Endothelial Growth Factor
EGFR= Epidermal Growth Factor Receptor
15 FDA-Approved Drugs for Metastatic Colorectal Cancer

13. Colorectal Cancer is Expensive
• 5-FU (2800 mg/m2) $45
• Leucovorin (400 mg/m2) $178
• Capecitabine (2000 mg/m2/day) $5,460
• Irinotecan (180 mg/m2) / generic $179
• Oxaliplatin (85 mg/m2) / generic $721
• Bevacizumab (5 mg/kg) $6,694
• Ramucirumab (8 mg/kg) $14,914
• Cetuximab (250 mg/m2) $3,640
• Panitumumab (6 mg/kg) $5,985
• Aflibercept (4 mg/kg) $5,760
• Regorafenib (160 mg, 3/1) $20,232
• Trifluridine/tipiracil (70mg/m2/day) $15,027
• Pembrolizumab (200 mg) $11,159
• Ipilimumab/nivolumab (1 mg/kg, 3 mg/kg) $18,660/total

14. Current Cancer Treatment Strategy:
One-size-fits-all

15. Biomarker testing
• Biomarkers, short for biological markers, are biological
molecules found in blood, other body fluids or tissues,
that may be measured to provide information about your
tumor
• Once biomarker testing is done, results of the test may:
– Indicate normal or abnormal cell function
– Provide insight on the likely outcome from the cancer if it is
left untreated (ie. prognosis)
– Predict the likelihood of the cancer’s response to a specific
treatment plan or lack of response to a treatment plan
– Help you and your doctor make decisions about care (CEA)

16. Biomarker Testing vs. Genetic Testing
• Biomarkers (or genomic/mutation testing): particular
abnormalities, rearrangements, and/or mutations that
are found in the cancer cells that are different than
normal cells
– Some of these mutations may be driving the cancer to
grow
• Genetic testing: genetic sequence of the DNA we are
born with (and can be inherited)

17. Amgen. Know Your Biomarker. 2015

18. Fakih & Wong, 2010; Williams & Lockhart, 2009.
Monoclonal Antibodies Target Cell-Bound EGFR
Cetuximab (FDA Approval 2004)
Panitumumab (FDA Approval 2006)

19. RAS Mutations Predict (Lack of) Benefit to Targeted Therapy
Karapetis et al. NEJM 2008, 359 (17): 1757
Refractory CRC R
Cetuximab alone
Best supportive care

20. Take Home Point:
RAS Mutations Predict a Lack of Benefit to
Targeted Therapy (EGFR inhibitors)
50-55% of our patient population

21. Biomarkers Beyond RAS: BRAF V600E

22. Fakih & Wong, 2010; Williams & Lockhart, 2009.
Monoclonal Antibodies Target Cell-Bound EGFR
Cetuximab (FDA Approval 2004)
Panitumumab (FDA Approval 2006)

23. Van Cutsem et al, J Clin Oncol 2011
BRAF V600E mutations suggest
more aggressive tumor biology
“CRYSTAL” Trial: 1st Line FOLFIRI/Cetuximab

24. BRAF inhibition in Melanoma

25. BRAF Inhibition in Melanoma
Wagle et al. J Clin Oncol. 2011.

26. BRAF Inhibition in Melanoma
Wagle et al. J Clin Oncol. 2011.

27. Single-Agent Activity of Vemurafenib in
BRAF-Mutant Metastatic Colorectal Cancer
Kopetz S et al. J Clin Oncol. 2010;28( 15 suppl): abstract
3534. 1. Corcoran RB et al. Cancer Discov. 2018;8(4):428-443.
Modest activity in BRAF-mutant mCRC compared with BRAF-mutant
melanoma
(Response rate of ~5% vs ~60%–80%)1
mCRC (N = 19)
(RECIST cutoff for PR, 30%)
100
75
50
25
0
–25
–50
–75
–100
ChangefrombaselineIsumof
lesionsize(%)

28. A key finding: Feedback EGFR
signaling after BRAF inhibition
BRAFm
ut
PI3K
AKT
RAS
ERK
EGFR
and others
CDC25
pERK1/2
Vinculin
HT29 Colo205
EGFR
Mao et al CCR ‘12, Prahallad et al Nature ‘12

29. Triplet Combination: BRAF+MEK+EGFR
BRAFm
ut
PI3K
AKT
RAS
MEK
EGFR
Slide courtesy of Scott Kopetz, MD, PhD
Encorafenib + Cetuximab + Binimetinib

30. Addressing BRAF/EGFR Resistance
Van Cutsem et al. J Clin Oncol 2019
Response rate and PFS of BRAFi/EGFRi may be augmented by MEKi
41% response rate
PFS > 6+ months ?
Encorafenib + Cetuximab + Binimetinib
ORR = 48%
mPFS = 8.0 months
mOS = 15.3 months

31. 5-10% of our patient population
NCCN Guidelines Version 1.2019
Colon Cancer

32. Targeting NTRK Fusions

33. What is a gene fusion?
• NTRK genetic
rearrangements
lead to activation
of the TRK protein
receptor
https://www.biooncology.com/pathways/cancer-tumor-
targets/ntrk/ntrk-oncogenesis.html

34. - Four patients with colorectal
cancer in pivotal NEJM paper
- Relatively rare in mCRC, ~1%
- All patients: 80% response rate
- 16% complete response rate
Drilon, et al. N Engl J Med 2018;378:731-9.
Copyright © 2018 Massachusetts Medical Society.
NTRK Fusions and CRC

35. Drilon, et al. N Engl J Med 2018;378:731-9.
Copyright © 2018 Massachusetts Medical Society.
NTRK: Largest change in tumor volume

36. Drilon, et al. N Engl J Med 2018;378:731-9.
Many responses
are prolonged
Responses are durable!

37. >2nd line setting
- footnote a:
“Larotrectinib is a
treatment option for
patients with
metastatic
colorectal cancer
that is NTRK gene
fusion positive.”
COL-D
© 2019 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form
without the express written permission of NCCN®. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org.
NCCN Guidelines Version 1.2019
Colon Cancer

38. Hallmarks of Cancer
http://www.researchcancerimmunotherapy.com/images/overview/
evading-immune-destruction/hallmark-cancer.png

39. Microsatellite Instability-High CRC
MSI-high

40. The Importance of Mismatch Repair
Wakamatsu et al. J Bio Chem 2010;285: 9762-9769

41. MSI-high tumors have more mutations

42. MSI-high Cancers Have Tumor Infiltrating
T-cells (which can help kill cancer)
Redston M. Mod Pathol 2001;14(3).

43. Pembrolizumab is a PD-1 inhibitor tested in patients with
metastatic colorectal cancer
Tested in patients with microsatellite stable and MSI-H CRC
http://directorsblog.nih.gov/2015/06/09/a-surprising-
match-cancer-immunotherapy-and-mismatch-repair/
Pembrolizumab

44. Responses in MSI-high CRC
Le et al. NEJM 2015; 372:2509-20.
3 6 5 7 3 0
-1 2 5
-1 0 0
-7 5
-5 0
-2 5
0
2 5
5 0
7 5
1 0 0
1 2 5
%ChangefromBaselineSLD
M M R -d e fic ie n t C R C
M M R -p ro fic ie n t C R C
Le et al. 2016 ASCO Annual Meeting

45. aEvaluable patients per investigator assessment.
• 78% of patients had a reduction in tumor burden from baseline with combination therapy
Bestreductionfrombaseline
intargetlesionsize(%)a
100
50
75
0
-50
-75
-25
25
-30
20
-100
********** ************ ********** ************
*
*** ************
*
**
**
⃰Confirmed response per investigator assessment
3 5
12
26
31
38
51.3
31
3.4
CR
PR
SD
PD
Unknown
Patients(%)
ORR (95% CI):
31% (20.8, 42.9)
Nivolumab
N = 741,c
Nivolumab + ipilimumab
N = 119a
ORR (95% CI):
55% (45.2, 63.8)
20
40
60
80
100
0
• BRAF V600E RR 55%
Overman et al: JCO 2018
Nivolumab and Ipilimumab

47. Take Home Point:
MSI-high colorectal cancer predicts for benefit
from immune therapy
~4% of our patient population

48. KRAS Remainder
Snapshot of Molecularly-Directed Therapy for CRC (2008)
KRAS
Undefined/Unknown

49. KRAS NRAS BRAF Her2 MSI NTRK Remainder
Snapshot of Molecularly-Directed Therapy for CRC
KRAS
NRASBRAF
HER2
MSI
Undefined
NTRK

50. Biomarkers may direct cancer treatment
• Each patient’s mutational makeup of his/her tumor is
unique
• Knowing a tumor's biomarker status may help the
selection of the most effective and appropriate treatment
plan
• Talk with your doctor about biomarker testing
– “Has my tumor been tested for biomarkers?”
– “How will the biomarker status affect my treatment plan?”

51. What about ctDNA?
Liquid Biopsies

52. Liquid Biopsies
Corcoran and Chabner. NEJM 2019.

53. Characteristics and terminology for
circulating tumor DNA (ctDNA)
The linker DNA between nucleosomes is cleaved leaving 167 bp
cell-free DNA fragments (145 bp plus a ~20 bp segment
wrapping histone H1). Originally described by Wyllie in 1980.
Chandrananda et al. 2015 BMC Medical Genomics.
Wyllie 1980 Nature.; Slide from Rick Lanman
Circulating cell-free
DNA
cfDNA, ccfDNA
ctDNA
167 bp fragments of DNA, a nucleosome
Tumor
Normal
cells/tissue
Initially described by Madel and Metais in 1948
Half-life: ~ 0.5 hours

54. Clinical applications of liquid biopsy
Corcoran and Chabner. NEJM 2019.

55. Adjuvant Therapy in Stage III Colon Cancer:
Room for Improvement
Adjuvant Therapy for Stage III:
- Treat 10 patients with stage III
CRC; save 2-3
- Unfortunately, 5 treated, who
don’t need chemotherapy
- Unfortunately, 2-3 treated,
who relapse anyways
- No ability to monitor efficacy in
real time
Slide courtesy of Wells Messersmith, MD
43%
20%
6%
31%
Long Term Survival for Stage III Colon Cancer
Recurrence Surgery
FP
(ACCENT)
Oxaliplatin

56. 0 200 400 600 800 1000 1200 1400
0
20
40
60
80
100
Days
Percentsurvival
ctDNA+ (n=4)
ctDNA- (n=81)
0 200 400 600 800 1000 1200 1400
0
20
40
60
80
100
Days
Percentsurvival
ctDNA+ (n=8)
ctDNA- (n=51)
Stage II (5% prevalence of ctDNA+)
NGS Assay (Roche Molecular)
Assay with 197 genes; at least one mutation detected 99.3% of tumor tissue
57% sensitivity for recurrence; 100% specificity
Stage III (16% prevalence of ctDNA+)
HR 54.4
95% CI: 9.5-311.7
p<0.0001
HR 20.0
95% CI: 5.9-67.8
p<0.0001
Diehn et al ASCO ‘17

57. ctDNA in Colorectal Cancer: Ready for primetime?
• Identifying actionable alterations
• Predicting treatment response
• Monitoring therapeutic resistance
• Detection of minimal-residual
disease
• Ready for primetime
• No: Possibly in the future
• Potentially: clinical trials ongoing
• Potentially: clinical trials ongoing

58. Update on COVID-19

59. https://coronavirus.jhu.edu/map.html

60. https://coronavirus.jhu.edu/map.html

61. Special considerations for patients with cancer
• If you are currently receiving therapy:
– Continue to receive treatment as planned unless notified otherwise
by your care team
– Have a conversation with your doctor about the benefits/risks of
continuing treatment, delaying treatment, or reducing treatment
• If you are currently in surveillance (not treating cancer)
– Consider postponing visits until the summer (if possible)
– Consider virtual health visits – Medicare and insurance companies
are covering this service
1.CDC
2.Coronavirus Disease 2019 (COVID-

62. Special considerations for patients with cancer
• CDC general guidelines recommends using a mask in public
• Not all patients with cancer are severely immunocompromised
• Many healthcare institutions are postponing elective or non-critical
procedures:
– Elective surgeries and procedures
– Non-urgent CT and MRI scans
1.CDC
2.Coronavirus Disease 2019 (COVID-

63. Special considerations for patients with cancer
• What about clinical trials?
• Patients currently enrolled on clinical trials will most likely continue
as planned
• Patients seeking to enroll onto clinical trials may experience delays
in clinical trial enrollment depending on the clinical situation
1.CDC
2.Coronavirus Disease 2019 (COVID-

64. Good News
• We live in the internet age:
– Zoom/Skype/Telehealth and Virtual Visits
– Widely available grocery/medication delivery
• We appear to be flattening the curve!

65. Questions and Discussion
COVID-19 Support:
https://medschool.cuanschutz.edu/psychiatry/covid-19-support
COVID-19 Information:
https://www.cancer.org/latest-news/common-questions-about-
the-new-coronavirus-outbreak.html

66. Questions

67. QUESTION AND
ANSWER
Type in your questions on the panel on
the right side of your screen

68. Fight Colorectal Cancer Mission
We FIGHT to cure colorectal cancer and serve as relentless champions of
hope for all affected by this disease through informed patient support,
impactful policy change, and breakthrough research endeavors.

69. THANK YOU