Hear about the latest breaking colorectal cancer research! Fight CRC will be joined by Dr. Axel Grothey who will spend the hour detailing the research presented at the 2020 Gastrointestinal (GI) Cancers Symposium hosted by the American Society of Clinical Oncology.

1. OUR WEBINAR WILL BEGIN SHORTLY

2. GI ASCO 2020 RECAP WEBINAR

3. TODAY’S
WEBINAR
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QUESTIONS
02 Watch a recording of this webinar on the Fight
CRC website. Visit FightCRC.org
WEBINAR ARCHIVE
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4. Resources
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variety of resources for
those touched by colorectal
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to view, download, and
order the latest resources.

5. The information and services provided by Fight Colorectal Cancer are for general informational
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6. TODAY’S
PRESENTER
Dr. Axel Grothey
Axel Grothey, MD, is a consultant at the West Cancer Center, University of Tennessee, in Memphis, TN.
Dr. Grothey received his medical degree at Ruhr-Universität Bochum, Germany, and completed
residencies at West German Tumor Center and the Institute of Pathology at the University of Essen and a
residency and fellowship at the University of Bochum. He also completed a research fellowship at MD
Anderson Cancer Center at the University of Texas. He joined Mayo Clinic as a consultant in 2005 and was
appointed as Professor of Oncology in 2007. He left Mayo Clinic in 2018 to join West Cancer Center.
Dr. Grothey’s clinical interests focus on gastrointestinal cancers, in particular, colorectal cancer,
antiangiogenesis, signal transduction inhibitors, and clinical trial design and statistics. As a consultant and
investigator, his research has been funded by the National Cancer Institute (NCI) and the National
Institutes of Health, among other organizations.
He currently co-chairs the NCI Gastrointestinal Cancer Steering Committee after having served as chair of
the Colon Cancer Task Force for 6 years. He currently holds professional positions in multiple associations
and societies. He is a member of the NCCN Guidelines Committee for Colon, Rectal, and Anal Cancer and
also a member of the European Society of Medical Oncology (ESMO) guidelines committee for colorectal
cancer. Dr. Grothey performs journal review and editorial activities for numerous medical journals and is
the editor for Clinical Colorectal Cancer, Emerging Cancer Therapeutics, Practice Updates, and
Therapeutic Advances in Medical Oncology. He is a member of the editorial board of the Journal of
Clinical Oncology and Journal of the National Cancer Institute.
In educational activities, he is a five-time recipient of Teacher of the Year recognition at Mayo Clinic. Dr.
Grothey has given numerous international, national, and regional presentations, as well as invited and
visiting professor presentations. He has co-authored more than 500 articles, books, book chapters,
editorials, abstracts, and letters.

7. Updates on Colorectal Cancer
Axel Grothey, MD
Director, GI Oncology Research
West Cancer Center and Research Institute

8. Goal of medical therapy in GI Cancers
Finding the right treatment
for the right patient
at the right time
Individualized therapy
did not start with
molecular profiling

9. New IDEAs in the Adjuvant Setting
• Immunotherapy
• In MSI-H / MMR-D cancers: US ATOMIC trial (FOLFOX +/- Atezolizumab)
ongoing
• ctDNA
• As marker of minimal residual disease to select patients for therapy in stage II
(various trials ongoing or planned around the world)
– superiority question
• Select patients who do not need adjuvant therapy in stage III
– non-inferiority question
• Stem cell inhibitors?
• BRAF targeted agents and combinations (Adjuvant BEACON?)

10. Clinical Applications for ctDNA
Diagnosis
Minimal Residual Disease
Treatment Response
Acquired Resistance

11. Circulating Tumor DNA (ctDNA)
• Tumors release small cell-free DNA fragments
• ctDNA ≠ CTC (circulating tumor cells)
• Identify point mutations (or other genetic changes) in
tumor  examine blood for matching mutation
Biology of ctDNA
ctDNA in Solid Tumors
• Frequently detected in metastatic solid malignancies1
• ? Useful marker of minimal residual disease after early-
stage cancer surgery (lung2, breast3, pancreas4) 1. Bettegowda et al. Sci Transl Med. 2014;6(224):224ra24.
2. Newman et al. Nat Med. 2014 May; 20(5): 548–554
3. Garcia-Murillas et al. Sci Transl Med. 2015;7(302):302ra133
4. Sausen et al. Nat Commun. 2015 Jul 7;6:7686

12. ctDNA as Marker for MRD (molecular residual disease)
• Two main types of tests:
• Tumor-agnostic
• NGS or PCR panel of common mutations in CRC
• E.g. LUNAR-1 (Guardant)
• Methylation markers
• E.g. Colvera (Quest)
Pro: easy logistics; Con: lower sensitivity
• Tumor-informed
• NGS or PCR panel of mutations detected in patient’s primary tumor
• E.g. Signatera (Natera)
Pro: high sensitivity; Con: logistics more complicated

13. 0 12 24 36 48 60
0
20
40
60
80
100
Time from Surgery (months)
PercentageRecurrence-Free
Stage II Recurrence-Free Survival
(Patients not treated with chemotherapy)
n Events 3-yr RFS
ctDNA Negative 164 16 90%
ctDNA Positive 14 11 0%
HR: 18 (95% CI: 7.9–40), p < 0.001
Tie et al. Sci Transl Med 2016

14. Clinical Low-Risk
(dMMR or pMMR + no poor prognostic features)
Clinical High-Risk
(pMMR + at least one poor prognostic features)
HR: 28 (95% CI: 8.3–93)
p < 0.001
HR: 7.5 (95% CI: 2.6–22)
p < 0.001
Recurrence-Free Survival
Tie et al. Sci Transl Med 2016

15. PPV = 100%
Post-op ctDNA
Positive
8%
Yes
0%
ctDNA and 3-year Recurrence Prediction Accuracy
= Recurrence = No Recurrence
92%
No
NPV = 91%
9%
Tie et al. Sci Transl Med 2016

16. ctDNA and Outcome in Stage III Colon Cancer
Tie et al., JAMA Oncol 2019N=96, all received adjuvant Tx
HR 3.8 HR 6.8

17. ctDNA and Outcome in Stage III Colon Cancer
Tie et al., JAMA Oncol 2019
HR 3.7 HR 6.5

18. NRG GI005 (COBRA): ctDNA as a predictive marker for response
to adjuvant chemotherapy in stage II colon cancer
PI V. Morris
Endpoints:
Phase II: Clearing rate of ctDNA
Phase III: DFS
N=1408
Activated Dec 2019

19. Potential Applications
Opportunity
Monitor
adjuvant
therapy effect
Opportunity
Recurrence
surveillance
SurveillanceDiagnosis Assessment Surgery Assessment
Lower Risk Observation
Higher Risk Chemotherapy
Opportunity
High-risk
screening or
equivocal finding
adjudication
Opportunit
ctDNA detecti
/ clearance as
surrogate
endpoint
Opportunity
Molecular staging
using ctDNA to
determine whether to
give neoadjuvant
therapy
Opportunity
Molecular staging
using ctDNA to
determine whether
to give adjuvant
therapy
Planned “IDEA-2”: Non-inferiority study for ctDNA-neg low-risk
stage III CC --- one of several potential designs
 ctDNA test
(week 4-5)
 BRAF testing*
 MSI testing*
Stratified by:
 Age (<70/≥70)
 Particip. Group
Primary endpoint: DFS
Study design: Non-inferiority
Non-inferiority margin: TBD
International collaboration
Low-risk Stage III
colon cancer
after curative surgery
RctDNA negative
3 months CAPOX
Observation only
ctDNA analysis every 3 months
until 2 years after surgery
*Results of BRAF and MSI testing will be used
in pre-specified subgroup analysis

20. BRAF Mutations in CRC
•BRAF is primary effector of KRAS
signaling
•BRAF mutations:
•Occur most frequently in exon 15
(V600E)
•Found in 4%-14% of patients with CRC
•Mutually exclusive with KRAS
mutations
•Associated with poor prognosis
Raf
MEK
Erk
P
P P
P
Tumor cell
proliferation
and survival
EGF
Tumor Cell
Ras
Yarden. Nat Rev Mol Cell Biol. 2001; Di Nicolantonio. J Clin Oncol. 2008;
Artale. J Clin Oncol. 2008.

21. Rationale for combined BRAF and EGFR blockade
BRAFmut
RAS
MEK
EGFR
ERK
EGFR
1Hong et al Cancer Disc ‘16

22. Encorafenib plus Cetuximab With or Without
Binimetinib for BRAF V600E–Mutant Metastatic
Colorectal Cancer:
Quality of Life Results from a Randomized, 3-Arm,
Phase 3 Study vs. the Choice of Either Irinotecan or
FOLFIRI plus Cetuximab (BEACON CRC)
Scott Kopetz, Axel Grothey, Eric Van Cutsem, Rona Yaeger, Harpreet Wasan,
Takayuki Yoshino, Jayesh Desai, Fortunato Ciardiello, Fotios Loupakis, Yong Sang Hong,
Neeltje Steeghs, Tormod Kyrre Guren, Hendrik-Tobias Arkenau, Pilar Garcia-Alfonso,
Ashwin Gollerkeri, Kati Maharry, Janna Christy-Bittel, Christopher Keir, Michael Pickard,
and Josep Tabernero
Scott Kopetz, MD
BEACON CRC: Binimetinib, Encorafenib, And Cetuximab COmbiNed to Treat BRAF-mutant ColoRectal Cancer

23. Triplet therapy
ENCORAFENIB + BINIMETINIB + CETUXIMAB
n = 205
Doublet therapy
ENCORAFENIB + CETUXIMAB
n = 205
Control arm
FOLFIRI + CETUXIMAB, or
irinotecan + CETUXIMAB
n = 205
R
1:1:1
Phase 3
Study Design
Primary
Endpoints:
OS
(All randomized Pts)
Randomization was stratified by ECOG PS (0 vs. 1), prior use of irinotecan (yes vs. no), and cetuximab source (US-licensed vs. EU-approved)
Triplet vs Control
Secondary Endpoints: Doublet vs Control and Triplet vs Doublet - OS & ORR, PFS, Safety
ORR –
Blinded Central
Review
(1st 331 randomized Pts)
Safety Lead-in
QOL Assessments: EORTC QOL Questionnaire (QLQ C30), Functional Assessment of Cancer Therapy Colon Cancer, EuroQol 5D5L, and
Patient Global Impression of Change).
ENCORAFENIB +
BINIMETINIB +
CETUXIMAB
N = 30
Encorafenib 300 mg PO daily
Binimetinib 45 mg PO bid
Cetuximab standard weekly
dosing
Patients with BRAFV600E mCRC with disease progression after 1 or 2 prior regimens; ECOG PS of 0 or 1;
and no prior treatment with any RAF inhibitor, MEK inhibitor, or EGFR inhibitor

24. Randomized
(N=665)
Control
(N=221)
Doublet
(N=220)
Triplet
(N=224)
Received allocated
treatment
99%
Did not receive
treatment
1%
Median follow-up time for OS for all patients was 7.8 months
Subject Disposition
*As of the data cutoff date of February 11, 2019. NOTE: Discontinued/Ongoing percentages may not add to 100 because denominator includes patients who did not receive treatment.
Discontinued treatment 64%
Treatment ongoing* 35%
Received allocated
treatment
87%
Did not receive
treatment
13%
Discontinued treatment 71%
Treatment ongoing* 17%
Received allocated
treatment
98%
Did not receive
treatment
2%
Discontinued treatment 63%
Treatment ongoing* 35%
Kopetz et al. N Engl J Med 2019; 381:1632-1643

25. Baseline Patient Characteristics
25
CHARACTERISTICPGICPGIC
Triplet
N=224
Doublet
N=220
Control
N=221
Female 53% 48% 57%
Age, median (range), years 62 (26, 85) 61 (30, 91) 60 (27, 91)
ECOG PS 0 52% 51% 49%
Location of primary tumor*
Left colon (includes rectum) 35% 38% 31%
Right colon 56% 50% 54%
≥3 organs involved 49% 47% 44%
Presence of liver metastases 64% 61% 58%
Prior lines of therapy
1 65% 66% 66%
>1 35% 34% 34%
MSI-H† 10% 9% 5%
CEA Baseline Value > 5 ug/L 80% 70% 81%
CRP Baseline Value > 10mg/L 42% 36% 41%
CA 19.9 Baseline Value > 35 U/mL 71% 68% 71%
FACT-C Total Score, median (range) 97 (36, 134) 96 (27, 135) 98 (29, 134)
EORTC QLQ-C30 Global Health Status, median (range) 67 (0, 100) 67 (0, 100) 67 (0, 100)
PGIC, median (range) 4 (1, 7) 4 (1, 7) 4 (1, 7)
Abbreviations: CEA, carcinoembryonic antigen; CRP, c-reactive protein; ECOG PS, Eastern Cooperative Oncology Group Performance Status; MSI-H, microsatellite instability high (abnormal high); FACT-C, Functional Assessment of Cancer
Therapy – Colorectal (version 4); EORTC QLQ-C30, European Organization for Research and Treatment of Cancer core quality-of-life Questionnaire (version 3.0); PGIC, Patient Global Impression of Change.
Baseline characteristics are summarized for all 665 randomized patients. †Based on assessment by polymerase chain reaction. MSI status is missing in 23% of patients. *Remaining patients had primary tumor in both left and right sides of
colon and those with unknown location of primary tumor.
Kopetz et al. N Engl J Med 2019; 381:1632-1643

26. Overall Survival and Objective Response Rate
Objective Response Rate (First 331 Randomized Patients)
Confirmed Response
by blinded central review
Triplet
N=111
Doublet
N=113
Control
N=107
Objective Response Rate 26% 20% 2%
95% (CI) (18%, 35%) (13%, 29%) (<1%, 7%)
p-value vs. Control <0.0001 <0.0001
Triplet vs Control* Doublet vs Control*
Kopetz et al. N Engl J Med 2019; 381:1632-1643*Overall survival analysis conducted in all randomized patients.

27. Maintenance of Quality of Life: EORTC QLQ-C30
27
Time to Definitive Deterioration in EORTC QLQ-C30 Global Health Status*
* The time to definitive deterioration is defined as the time from the date of randomization to the date of event, which is defined as at least 10% worsening relative to Baseline of the corresponding scale
score with no later improvement above this threshold observed during the course of the study or death due to any cause.

28. Maintenance of Quality of Life: FACT-C
28
Time to Definitive Deterioration in FACT-C Colorectal Cancer Subscale*
Results for EuroQol 5D5L
were similar as other QOL assessments.
* The time to definitive deterioration is defined as the time from the date of randomization to the date of event, which is defined as at least 10% worsening relative
to Baseline of the corresponding scale score with no later improvement above this threshold observed during the course of the study or death due to any cause.

29. BEACON CRC: Updated Analysis
• In this updated analysis of BEACON CRC
(which includes ORR for all randomized patients
(additional 364 patients) and 6 months additional
follow-up):
• The triplet and doublet demonstrated
improved OS and ORR in patients with BRAF
V600E-mutant mCRC when compared with
current standard of care chemotherapy
• The safety profile was consistent with the known
safety profile of each agent and consistent with the
primary analysis.
The full updated BEACON results with
subgroup analysis will be presented at a
future congress
Triplet vs Doublet
Objective Response Rate
Confirmed Response
by blinded central review
Triplet
N=224
Doublet
N=220
Control
N=221
Objective Response Rate 27% 20% 2%
95% (CI) (21%, 33%) (15%, 25%) (<1%, 5%)
p-value vs. Control <0.0001 <0.0001
Median OS Follow up:
12.8 months*

30. Efficacy Subgroup Analyses
Exploratory subgroup analyses suggest pts in some poorer prognostic categories may benefit
more from triplet than doublet therapy

31. Updated Grade ≥3 Adverse Events and Laboratory Abnormalities*
31
*Occurring in at least 2% of patients in either triplet or doublet arms.
Triplet
N=222
Doublet
N=216
Control
N=193
Adverse Event (Preferred term) Grade ≥3 Grade ≥3 Grade ≥3
Diarrhea 11% 3% 10%
Abdominal pain 6% 3% 5%
Nausea 5% <1% 2%
Vomiting 5% 1% 3%
Intestinal obstruction 5% 5% 3%
Pulmonary embolism 4% 1% 5%
Asthenia 4% 4% 5%
Acute kidney injury 3% 2% <1%
Dermatitis acneiform 3% <1% 3%
Fatigue 2% 4% 5%
Ileus 2% 2% 2%
Urinary tract infection 1% 2% 1%
Cancer pain <1% 2% <1%
Laboratory Abnormality**
Hemoglobin (g/L), hypo 23% 6% 5%
Creatinine (umol/L), hyper 5% 3% 1%
Creatine Kinase (IU/L), hyper 4% 0 <1%
Bilirubin (umol/L), hyper 3% 3% 3%
Consistent with previously reported safety profile
**Selected laboratory abnormalities associated with adverse events.

32. CheckMate-142 Study Design
• CheckMate-142 is an ongoing, multi-cohort, nonrandomized phase 2 study evaluating the efficacy and
safety of nivolumab-based therapies in patients with mCRC (NCT02060188)
• Median follow-up for the 1L nivolumab plus low-dose ipilimumab cohort was 13.8 months (range, 9–19)c
aUntil disease progression or discontinuation in patients receiving study therapy beyond progression, discontinuation due to toxicity, withdrawal of consent, or the study end; bPatients with a CR, PR, or SD for ≥12
weeks divided by the number of treated patients; cTime from first dose to data cutoff
BICR = blinded independent central review
• Histologically
confirmed
metastatic or
recurrent CRC
• MSI-H/dMMR per
local laboratory 1L
Nivolumab 3 mg/kg Q2Wa
Previously treated
Previously treated
Nivolumab 3 mg/kg +
ipilimumab 1 mg/kg Q3W
(4 doses and then
nivolumab 3 mg/kg Q2W)a
Nivolumab 3 mg/kg Q2W +
ipilimumab 1 mg/kg Q6Wa
Primary endpoint:
• ORR per investigator
assessment (RECIST v1.1)
Other key endpoints:
• ORR per BICR, DCRb,
DOR, PFS, OS, and safety
N=45
Lenz et al., ESMO 2018, ASCO GI 2020

33. Best Reduction in Target Lesions
*Confirmed response per investigator assessment
aEvaluable patients per investigator assessment
• 84% of patients had a reduction in tumor burden from baseline
Lenz et al., ASCO GI 2020
Who are these patients? Hyperprogression?

34. Progression-Free and Overall Survival
Lenz et al., ASCO GI 2020
Median follow-up: 20 months
PFS
OS
We do not see this with chemotherapy!

35. Progression-Free Survival
Lenz et al., ASCO GI 2020 Heinemann et al., Lancet Oncol 2014
FIRE-3

36. Evaluation of First-Line IO in MSI-H mCRC is Ongoing
MMR-D mCRC
Strat: BRAF mut,
site of met, prior
adj Tx
mFOLFOX6 + BEV
Atezolizumab
mFOLFOX6 + BEV +
Atezolizumab
R
COMMIT Trial
NRG-GI004/
SWOG 1610
N=51/347
(since 11/17)
Primary EP: PFS
PIs: James Lee, Mike Overman
KEYNOTE-177 has finished accrual
Results TBD
To be redesigned,
Atezo alone arm dropped

37. Clinicaltrials.gov: https://www.clinicaltrials.gov/ct2/show/NCT03406871 (Accessed April 15, 2019); Fukuoka S, et al. ASCO 2018:Poster TPS3124; Fukuoka S, et al. ASCO 2019:Poster 2522.
REGONIVO: A phase 1/2 study of regorafenib plus nivolumab in
advanced gastric cancer and CRC (EPOC1603/NCT03406871)
Dose escalation cohort: “3+3” design Expansion cohort
Regorafenib
Level 3: 160 mg/day
3 weeks on/1 week off
+
Nivolumab 3 mg/kg
q2w
N=3
Colorectal cancer
Gastric cancer
N=36
Regorafenib
Level 1: 80 mg/day
3 weeks on/1 week off
+
Nivolumab 3 mg/kg
q2w
N=4
Regorafenib
Level 2: 120 mg/day
3 weeks on/1 week off
+
Nivolumab 3 mg/kg
q2w
N=7
• Patients with
histologically or
cytologically confirmed
advanced or metastatic
solid tumors (selected
solid tumors in the
expansion cohort)
N=50
Translational research:
• T-cell phenotype assays including Treg analysis using
both flow cytometry and CyTOF
• In vitro functional assays
• HLA typing
• Immunohistochemistry (e.g., PD-L1, FoxP3, CD68,
CD163)
• Mutational analyses (whole exome sequencing)
• RNA sequencing
• 16S sequencing
Primary endpoints:
• Dose escalation: MTD/RD and
safety of combination treatment
• Dose expansion: Safety and efficacy of the combination
treatment at the regorafenib MTD/RD
Secondary endpoints:
• ORR (RECIST v1.1 and irRECIST)
• PFS
• OS
• DCR
• Incidence of TEAEs
Key inclusion criteria:
• Patients with unresectable, recurrent solid tumors
who are refractory or intolerant to standard
chemotherapy
• ECOG PS 0 or 1
Key exclusion criteria:
• Prior regorafenib treatment; prior immune
checkpoint blockade was permitted

38. Fukuoka S, et al. ASCO 2019:Poster 2522. Update: Shitara et al, ASCO GI 2020
REGONIVO: The ORR was 36% in CRC and 44% in gastric cancerChangefrombaseline(%)
PD SD PR CR
New lesion
Anti-PD-1/PDL-1 refractory
MSI-H (all other patients were MSS)
Colorectal cancer Gastric cancer
ORR 36%
(MSS 33%)
ORR 44%
(all responders were MSS)

39. Fukuoka S, et al. ASCO 2019:Poster 2522. Update: Shitara et al, ASCO GI 2020
REGONIVO: The ORR was 36% in CRC and 44% in gastric cancerChangefrombaseline(%)
PD SD PR CR
New lesion
Anti-PD-1/PDL-1 refractory
MSI-H (all other patients were MSS)
Colorectal cancer Gastric cancer
ORR 36%
(MSS 33%)
ORR 44%
(all responders were MSS)

40. Abstract 7: A randomized phase III trial
comparing primary tumor resection plus
chemotherapy with chemotherapy alone in
incurable stage IV colorectal cancer: JCOG1007
study (iPACS)
Yukihide Kanemitsu, MD et al

46. Conclusions
• Advances in molecular profiling have identified multiple colorectal
cancer subtypes which warrant specific interventions
• Tissue/ organ independent drug approvals based on molecular
signature are emerging
• Who to test, when and how….?
• Even common organ cancers are turned into a collection of rare
diseases
• Challenges for clinical trial design to provide proof of efficacy of
novel therapy
• Augmented immunotherapy can be real !
• ctDNA will change the way we diagnose and treat cancer patients

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

48. 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.

49. THANK YOU