5th Annual Early Age Onset Colorectal Cancer Summit - Session IV

Young Onset Colorectal
Cancer:
Treatment Implications
Andrea Cercek, MD
Assistant Attending
Section Head, Colorectal Oncology
Co-Director, Center for Young Onset Colorectal Cancer
May 02 2019

Young Onset Colorectal Cancer Background• Young Onset CRC
• Not associated with genetic
predisposition or family
history
• Majority are sporadic
• Patients present with later
stage disease
• More aggressive histology
• Poorly differentiated tumors
• Associated with worse
survival
O’Connell JB, et alAm Surg 2003
BaileyCE, et al JAMA Surg 2015
Yantiss RK, et alAm J Surg Pathol 2009
Sporadic
62%
Familial
23%
Hereditary
15%
YouYN et al.ASCRS Annual Meeting 2013.

Tumor Biology
Yaeger R, et al Cancer Cell 2018
Cercek,ChatilaASCO 2018, ESMO 2018
Cohort Description
• Young Onset
• 377 CRC patients 50 and
younger
• Average Onset
• 543 CRC patients age 51
and older

Patient Characteristics
All patients (n=377) MSS
(n=361)
MSI H
(n=13)
POLE
(n=3)
Age (years)
Mean (range) 42 (17-49) 42 (17-49) 40 (28-47) 44 (39-47)
Median 43 43 41 45
Gender
Male 200 (53%) 189 (52%) 8 (54%) 3 (100%)
Female 176 (47%) 171 (48%) 5 (46%) 0 (0%)
Stage at diagnosis
I 7 (1.9%) 6 (1.7%) 1 (8%) 0
II 25 (7%) 18 (5%) 6 (46%) 1 (33%)
III 90 (24%) 86 (24%) 3 (23%) 1 (33%)
IV 255 (68%) 251 (70%) 3 (23%) 1 (33%)
Primary Tumor Site
Right Colon 79 (21%) 66 (18%) 11 (85%) 2 (67%)
Left Colon 197 (53%) 194 (54%) 2 (15%) 1 (33%)
Rectum 100 (27%) 100 (28%) 0 0
NOS 1 (0.26%) 1 (0.28%) 0 0
Dos Santos Fernandes,Chatila, Cercek ASCO 2018, ESMO 2018

Patient Characteristics- MSS cohort
80% left sided
Cohort Characteristics
Age 17-39
(n=105)
Mean (SD) or %
Age 40-49
(n=233)
Mean (SD) or %
P-Value
Ever Smoker 21.9% 29.6% 0.15
Male (%) 56.2% 50.2% 0.29
Right-sided primary 23.6% 16.3% 0.14
Stage III/IV at dx 95.2% 95.3% 1
Chemotherapy exposure 48.5% 57.8% 0.12
Metastatectomy 58.9% 59.9% 0.89
# of first sites of Metastasis 1.267 (0.62) 1.249 (0.59) 0.96
HAI Pump 36.4% 37.2% 1
BMI
-Male
-Female
26.18 (5.7)
27.04 (5.0)
25.1 (6.4)
27.46 (6.1)
28.20 (5.7)
25.77 (6.0)
0.05
0.01
0.33

Patient Characteristics- MSS cohort
MSS
N= 361
Pathologic Grade
Well differentiated 8
Mod differentiated 294
Poorly differentiated 71
NOS 17
First Site of Metastases
liver 254
lung 19
peritoneum 37
Lymph nodes 39
ovaries 12
bone/brain 4
multifocal 67

Mutation burden Young Onset vs
Average Onset
Wilcoxon rank sum test
P-value: 0.17
P-value: 0.09
Cercek, Chatila unpublished data

Mutation burden by primary tumor
location: YO vs AO
** **

Genomic Differences in MSS mCRC: EO
vs AO
*
20q Amp
Alteration Frequencies:Young vs Average Onset

Pathway alterationsEarly Onset Average Onset

Response To Chemotherapy ?
• Majority of patients received first line FOLFOX
• Response rate ~50%
• Analogous to published data on first line FOLFOX/FOLFIRI for average onset
CRC
Saltz L., et al JCO 2008
Cercek unpublished data

Survival Analyses
• Young onset patients
have significantly
better survival.
65

Survival differences Young Onset vs Average
Onset
Yaeger R, et al Cancer Cell 2018
17-35
50+
35-45

Young Onset CRC Landscape
• ~15% hereditary CRC
• Majority are Lynch
• Treatment of MSI or dMMR CRC
• immunotherapy in the metastatic
setting
• Treatment of dMMR
locally advanced rectal cancer?
- currently treated as pMMR
Le, NEJM 2015
Willauer, Cancer 2019

Locally advanced rectal cancer
• Locally advanced rectal cancer
• Treated with total neoadjuvant therapy (FOLFOX, chemoRT and surgery)
• Excellent response rates and outcomes
• What are the response rates and outcomes of dMMR/MSI locally
advanced rectal cancer?
Cercek, Stadler manuscript submitted

dMRR Rectal Cancer
Characteristic No. (%) of Patients (n = 50)
Sex
Male 34 (68)
Female 16 (32)
Race
White 39 (78)
Hispanic 3 (6)
Black 1 (2)
Asian 5 (10)
Ashkenazi Jewish 9 (18)
Not declared 2 (4)
Clinical stage at diagnosis
I 8 (16)
II 8 (16)
III 30 (60)
IV 3 (6)
Not available 1 (2)
First treatment for rectal cancer
Surgery 13 (26)
Chemoradiation 16 (32)
FOLFOX chemotherapy 21 (42)

dMMR rectal cancer
Outcome
No. of Patients (%)
dMMR pMMR
FOLFOX as initial
treatment
n = 21 n = 63
Progression of
disease
6 (29) 0
Response or stable
disease
15 (71) 63(100)
Chemoradiation as
initial treatment
n = 16 n = 48
Progression of
disease
0 0
Response or stable
disease
2 (13) 8 (17)
• 29% developed
progression of disease
on FOLFOX
chemotherapy

dMMR locally advanced rectal cancer
Important to keep in mind given the increase in young patients with left sided,
rectal tumors
• IHC should be checked on all patients with rectal cancer for dMMR
• Patients who are dMMR may consider chemoradiation as first line treatment
• Clinical trial of immunotherapy in dMMR locally advanced patients
• Neoadjuvant anti PD1 therapy (opening at MSK 6/2019)

What are the effects of treatment on young patients?
• Longitudinal sexual health and fertility
• Psychological impact
• Bone health
• Cardiac toxicities
• Potential overtreatment
• Surveillance intervals

Center for Young Onset Colorectal Cancer:
A Coordinated Clinical and Research Program
GI Oncology
Gastroenterology
Colorectal Surgery
Radiation Oncology
Genetics
Sexual Health
Fertility
Psychology/Psychiatry
SocialWork
Nutrition
Epidemiology
Pathology
Integrative Medicine
Translational Research
Coordinated
Patient Centered Care
Hepatobiliary Surgery
Survivorship
https://www.mskcc.org/cancer-care/types/colorectal/colorectal-cancer-young-adults

Fertility• Among young women cancer related infertility is associated with
greater risk for emotional distress and worse QoL
• Some women are willing to trade off survival to maintain fertility
• Fertility issues are discussed less with male patients c/w female
most appreciate support
• Lack of evidence for GI cancer patients
Ganz et al 1998, 2003
Tesauro 2002
Crawshaow et al 2009

Fertility –Effects of Radiation and
Chemotherapy
• MSK retrospective review
• Incidence of amenorrhea in premenopausal women
• Chemo induced ovarian toxicity
• Preclinical model moderate gonadal tox decrease in AMH level
• RT induced uterine toxicity
• Limited data available very limited for rectal CA or more modern RT
techniques
Cercek et al 2013
Levi et al 2015

Chemotherapy
FOLFOX, 5FU/Cape induced vascular toxicity
•increased incidence of CVD and CHF in pts aged >65
Longitudinal effects on younger patients are unknown
Kenzik et al JCO 2017
• Potential for overtreatment
• Neuropathy
• Chemo brain
• Cardiovascular toxicity
• Potential cardiovascular toxicity in older patients with
CRC who receive -adjuvant chemotherapy

Physical Unmet Needs
• Symptom managements in young patients
• Symptoms diarrhea (37%), sleep disorder (32%) and sexual function (40%)
• Deterioration in occupation activities and coping with children
• Patients need for nutritional counseling and psychosocial support
• Multimodality treatment (rectal CA)- higher unmet needs
• OvarianTransposition
• Improved QoL
• Bone Health
• UterineTransposition
• Research of potential to carry a fetus post RT
Perl et al BMC 2016
Benedict et al Psychooncology 2016

Social Work and Psychology/Psychiatry• Unique dilemmas
• Increased isolation not only from their healthy peers, but also from the general
population of CRC patients, most of whom are over the age of 50
• In the US and globally, most of the research, support, and programming targets
individuals ages ~18 – 39, which excludes YOCRC patients ages 39 – 49.
• CRC carries a unique and damaging stigma
• bowel movements and
• digestive/GI symptoms
• ostomy bags
• Premature confrontation with mortality and end of life concerns
• Of the YOCRC patients who established care through MSK’s CYOC,
• ~75% of them identified as married or partnered, and
• ~50% of them identified as having children under the age of 18
Courtesy of Hadley Maya, LMSW

Sexual Health
• Body Image and Sexual function in women after treatment for anal
and rectal cancer
• Median age 55
• 86% reported at least one body image problem
• Younger age, lower global health status and greater severity of symptoms related to
poorer body image (p<0.05)
• Poor body image inversely related to all aspects of sexual function
• In women in particular data support early intervention and strategies
to improve QoL and sexual health
• Vaginal dilators
• Pelvic floor exercises
• Vaginal lubricants
Benedict et al Psycho-oncology 2016
Cantley and Carter et al, Sexual Medicine Reviews 2018

Research is Needed to Understand:
• Biology of young onset CRC
• Epidemiology
• Diagnosis
• Treatment strategies
• Survivorship/psychosocial outcomes
• Surveillance
• Prevention/screening

AcknowledgementsGI Oncology
• Luis Diaz
• Gustavo Dos Santos Fernandes
• Rona Yaeger
• Diane Reidy-Lagunes
• Len Saltz
• Zsofia Stadler
• Karuna Ganesh
• Neil Segal
• Anna Varghese
Colorectal Surgery
• Julio Garcia Aguilar
• Martin Weiser
• Jose Guillem
• Garrett Nash
• Josh Smith
• Phillip Paty
• Iris Wei
• Emmanouil Pappou
Gastroenterology
• Leslie Park
• Mark Schattner
Bioinformatics
•Nicholas Schultz
•Walid Chatila
•Michael Berger
•David Solit
Pathology
•Jinru Shia
•EfseviaVakiani
•Jaclyn Hechtman
Genetics
•Zsofia Stadler
•Kenneth Offit
•Mark Robson
•Yelena Kemel
Infectious Disease
•Elizabeth Robilloti
•Eric Pamer
Epidemiology and Biostatistics
•KelliO’Connell
•Mengmeng Du
•Elizabeth Kantor
•Ann Zauber
Nursing
•Abigail Baldwin-Medsker
•Joseph Bacani
•GI and Colorectal Surgery
OPN, NPs and APPs
•Chemotherapy RNs
•Peter Kingham
Radiation Oncology
•Carla Hajj
•John Cuaron
•AbrahamWu
•Chris Cane
SocialWork
•Hadley Maya
•Anne Martin
•Andrew Edelstein
•Katherine Duhamel
•Gary Deng
Nutrition
Survivorship
• ZanaCorrea
Administration
• Lerie Palmaira
• Mindy Sovel
• Michelle Karlin
• KellyTurner

YOUNG-ONSET COLORECTAL CANCER
OPTIMIZING PRESERVATION OF FERTILITY
Nicole Noyes MD, Professor
System Chief, Reproductive Medicine
Northwell Health
New York, New York USA
May, 2019
NYC

Datamonitor 2018 (US)
Young Onset CRC
Newly Diagnosed Cases by Age
2170

Births: 3.8MM
US Birth and Fertility Rates
Lowest in 30+ years
NCHS, National Vital Statistics System 2018
2018 US STATS – 61MM ♀ Reproductive Age
⏚ 70%
70 to 17/1,000
General Fertility
Rate: 60/1000
Total Births:
1,765/1000
Births >50 y: 840
Birthrate Decline: 15-34; Rise: 35-44
2005
Birth by Age of US Women: 1990 – 2017.

HUMAN FEMALE OVARY – CONCEPTION TO AGE 40
20 weeks gestation: 6 - 7 x 106 oocytes
No further germ cell proliferation
Progressive atresia begins
Birth: 1 - 2 x 106 oocytes
Oocytes arrested at prophase 1
as primordial or primary oocytes
Puberty: 300,000 (15%) oocytes
Monthly cohort of follicles initiate
growth and development
One “ovulates”
Others become atretic
Age 30, 240,000 (~12%) oocytes
Age 40, 60,000 (~3%) oocytes
Accelerated atresia
Coincident is a ↓ in quality of oocytes
FERTILEINFERTILE

Temporal Trends in Male Parenthood
169MM US Births: 1975 - 2015
Ramjit Raghav
1st child with
his wife at
age 94; 2nd at
age 96
Given the choice, both men AND women are delaying childbearing in favor of
REPRODUCTIVE AUTONOMY making for more people diagnosed with cancer
who have not yet had or completed their family
National Vital Statistics. Hum Reprod. 2017;32:2110

Causes of Treatment-Related Infertility
All treatments can impact fertility
• Surgery – Integral to cure
• Procedures proximate to reproductive organs
• Adhesions
• Chemo –Adjunct before and after surgery
• Systemic effect on ovarian function
• Radiation – Rectal cancer
• Proximity to reproductive organs
• Ovaries: Compromised function – extreme: menopause –
Mitigate with transposition moving ovaries further from field
• Uterus: Compromised endometrial function - not conducive to
implantation/pregnancy. Need for gestational carrier
• Interdisciplinary discussion with REI

ASSISTED REPRODUCTIVE FERTILITY PRESERVATION TECHNIQUES
Options
Mature Oocyte
Freeze Embryos
Sperm
Freeze
Mature Oocytes
Freeze Tissue
Donor
oocytes
Ovarian Transposition
Ovary with Oocytes

FERTILITY PRESERVATION - CANCER
Factors
Intrinsic factors
Health status of the patient
Age/Assessment of ovarian reserve
If no functional uterus - 3rd party reproduction
Extrinsic factors
Time available
Partnership Status
Finances
Important to avoid unnecessary intervention or procedures of uncertain
benefit in unwell patients at a time of extreme stress
More than one option may be possible for a given patient

Ovarian Transposition
Radiation Therapy Tolerance Doses: TD
Ovary: TD 5/5: 300 cGy; TD 50/5: 1200 cGy
Sterility = endpoint of severe complication
TD lower for preserving fertility – egg quantity & quality
compromise
Uterus: Cannot be moved.
“Curative” doses can result in endometrial damage which
essentially precludes successful pregnancy
May result in need for 3rd Party Reproduction – Gestational
Carrier
The primary benefit of ovarian transposition is prevention or delay of
premature menopause, not preservation of fertility

OVARIAN TISSUE CRYOPRESERVATION
Still considered experimental
• First HUMAN live birth reported in 2004 (Donnez, Lancet)
• Advantages
• Requires no ovarian stimulation or partner
• Minimal delay in treatment
• Can be performed at time of CR surgery
• Represents only option in prepubertal girls
• Disadvantages
• If chemo 1st, requires addition surgical intervention
• Emerging data demonstrates efficacy
• ~100 live births at this point
• Youngest ~14 yo; Oldest: 36 yo

EMBRYO CRYOPRESERVATION
• First HUMAN birth 1984 (34 y ago)
• Early successes rapidly followed by application
of reproducible techniques at various early
embryo stages
• Today >1 million births – “safe” technology
Common freezing stages
D1
D5D3
D2
0
10
20
30
40
50
Autologous Eggs
<35 35-40 41-42 >43
%
n = 40,015
0
10
20
30
40
50
Donor-Egg Embryos Donated Embryos
Donor Eggs and
Donated Embryos
%
n = 8,172 n = 1,201

OOCYTE CRYOPRESERVATION
• First HUMAN live birth reported in 1986
(32 y ago)
• Early results disappointing/non-reproducible
Zenzes 2001 Fertil Steril 75;769
• Why oocytes difficult to freeze
• Large cell size (100 micrometers)
• Ice crystal formation
• Aqueous: High water content (80%)
• Chromosomal arrangement (spindle)
• Precise dehydration protocols

• Advantages over embryo cryopreservation
• Enhanced reproductive autonomy
• Decreased ethical, personal, and religious dilemmas
• Reported live-birth outcomes now comparable to those of fresh IVF at some
centers; embryos remain more efficient
• >7,000 live births to date
• No reported increase in birth anomalies
• Cancer Patients: Quality of assessed oocytes retrieved normal and equivalent to
those retrieved from non-cancer patients (Werner, Rey, Labella, Noyes. JARG,
2010)
Noyes, Borini, Porcu. Reprod Biomed Online 2009;18:769

LIVE BIRTH OUTCOME
0
10
20
30
40
50
Frozen Eggs
Autologous
<35 35-37 38-40 41-42
%
0
10
20
30
40
50
US Frozen Embryos
Autologous
<35 35-40 41-42 >43

FERTILITY PRESERVATION - CANCER
Oocyte Thaw Cycles
Oocytes
No. thaw cycles 12
(10 patients)
No. embryo transfers (ET) 10
Mean age at cryopreservation (y) 34±5
Partnered at cryopreservation 55%
Mean time until first thaw (y) 3.5±2.0
Mean no. cryopreserved/cryo cycle 11±10
Mean no. thawed/thaw cycle 8±4
Mean no. embryos transferred 2±1
Delivered pregnancies per ET 50%
(5 deliveries, 1 twin)
Druckenmiller…Noyes. Obstet Gynecol. 2016 Mar;127:474

SUMMARY
• Cancer cure is no longer defined simply by eradication of
disease but now includes addressing quality-of-life issues such
as parenthood.
• If treatment of a disease process impacts gynecologic organ
function, fertility-sparing procedures and fertility preservation
should be considered, when possible.
• 3rd-party (and even posthumous) reproduction may become
part of the equation and should be addressed early – “deal
breaker”.
• Of all fertility preservation options available to women, those
with widest application and greatest chance for success:
embryo and oocyte cryopreservation

Thank you
Dr. Nicole Noyes
nnoyes@northwell.edu

Department of GI Medical Oncology
Novel Approaches to Metastatic Mismatch Repair
(MMR) deficient and Microsatellite
Stable (MSS) metastatic Colorectal Cancer
May 2, 2019
Cathy Eng, MD, FACP, FASCO
The University of Texas MD Anderson Cancer Center
Sophie Caroline Steves Distinguished Professorship in Cancer Research
Professor
Vice-Chair, SWOG GI Committee
Contact info: ceng@mdanderson.org Twitter: @cathyengmd

Disclosures
● Bayer
● BMS
● Merck
● Roche
● Taiho

Discussion Points
● What can we learn from prior IMT trials in mCRC?
● Impact factors?
○ TMB
○ Immunoscore
● Are all immunotherapeutic oncologic agents equivalent?
● Ongoing trials

CheckMate-142 Study Design: Nivo/Ipi in MSI-H mCRC Patients
10
7
Primary endpoint:
• ORR per investigator
assessment (RECIST v1.1)
Other key endpoints:
• ORR per BICR, DCR,b
DOR, PFS, OS, and safety
aEnrollment was staggered with additional patients being enrolled if ≥ 7 of the first 19 centrally confirmed MSI-H patients had a confirmed response (CR or PR). CheckMate-
142 monotherapy and combination therapy cohorts were not randomized or designed for a formal comparison. bPatients with a CR, PR, or SD for ≥12 weeks. cDefined here
as the time from first dose to data cutoff.
1. Overman MJ, et al. Lancet Oncol 2017;18:1182–1191.
• Histologically
confirmed metastatic
or recurrent CRC
• dMMR/MSI-H per
local laboratory
• ≥ 1 prior line of
therapy
Nivolumab 3 mg/kg +
ipilimumab 1 mg/kg Q3W
(4 doses and then
nivolumab 3 mg/kg Q2W)
Combination
cohorta
• Median follow-up in the combination therapy cohort (N = 119) was 13.4 months (range, 9–25)c
Nivolumab 3 mg/kg Q2W
Monotherapy
cohorta
Phase 2 Nonrandomized Study
• Results of the monotherapy cohort (N = 74) with a similar median follow-up of 13.4 months (range, 10–32)
are also presented1,c
Overman et al: JCO, 2018

Checkmate 142: Best Reduction in Target Lesions
10
8
aEvaluable patients per investigator assessment.
• 78% of patients had a reduction in tumor burden from baseline with combination therapy
Nivolumab + ipilimumab
Bestreductionfrombaseline
intargetlesionsize(%)a
100
50
75
0
-50
-75
-25
25
-30
20
-100
********** ************ ********** ************
*
*** ************
*
**
**
⃰Confirmed response per investigator assessment

Checkmate 142: Progression-Free and Overall Survival
• With similar follow-up, combination therapy provided improved PFS and OS relative to monotherapya,e,f
Nivolumab 74 48 41 32 1217 11 612 3 0
Nivolumab
Months
No. at Risk
119Nivolumab + ipilimumab 95 86 78 1239 10 311 0 0
100
90
80
70
60
50
40
30
20
10
0
0 3 6 9 1512 21 2418
Progression-freesurvival(%)c
27 30
100
90
80
70
60
50
40
30
20
10
0
0 3 6 9 1512 21 2418
OverallSurvival(%)
27 30 33
Months
119 113 107 104 3378 17 1119 0 0 0
74 64 59 55 2137 17 1119 6 1 0
Nivolumab
Nivolumab +
ipilimumaba,d Nivolumab1,e,f
9-month rate (95% CI), % 87 (80.0, 92.2) 78 (66.2, 85.7)
12-month rate (95% CI), % 85 (77.0, 90.2) 73 (61.5, 82.1)
aMedian follow-up was 13.4 months (range, 9–25). bMedian PFS was not reached (95% CI, not estimable). cPFS per investigator assessment. dMedian OS was not reached (95% CI, 18.0, not estimable).
eMedian follow-up was 13.4 months (range, 10–32). fCheckMate-142 monotherapy and combination therapy cohorts were not randomized or designed for a formal comparison.
1. Overman MJ, et al. Lancet Oncol 2017;18:1182–1191.
Nivolumab +
ipilimumaba,b Nivolumab1,e,f
9-month rate (95% CI), % 76 (67.0, 82.7) 54 (41.5, 64.5)
12-month rate (95% CI), % 71 (61.4, 78.7) 50 (38.1, 61.4)
10
9

Lenz et al: LBA 18, ESMO 2018
Checkmate 142: Nivo/Ipi Front-Line mCRC

ATOMIC: FOLFOX ± Atezolizumab as Adjuvant Therapy of Pts With Stage III
dMMR CRC
• Randomized, open-label phase III trial
• Primary endpoint: DFS
• 90% power to detect HR of 0.60 (inc. of 3-yr DFS from 75% to 84%); 175 events
required
• Secondary endpoints: OS, safety
Open since 9/12/2017
Accrual: 175/700
Atezolizumab Q2W x 1 yr +
mFOLFOX6 x 24 wks
mFOLFOX6 x 24 wks
Pts with stage III MSI-H CRC
s/p R0 resection
(planned N = 700)
Stratified by: No. of LN+ (1-4 vs > 4);
T stage (T1-3 vs T4), pt age (< or > 50 yrs)
MSI-H/MMRD status assessed locally
 MSI determined using a PCR-based assay
 MMRD status determined by IHC for MMR protein expression
(MLH1, MSH2, MSH6, PMS2) where loss of 1 or more
proteins indicates MMRD
ClinicalTrials.gov. NCT02912559.
PI: F. Sinicrope

COMMITT
Phase III NRG/SWOG CR-1556 for Metastatic CRC
MSI-high mCRC
without prior
systemic treatment
for metastatic
disease
(N = 29/347)
R
mFOLFOX6/Bevacizumab
(Arm 1: Control)
mFOLFOX6/Bevacizumab
+
Atezolizumab
(Arm 3: Combination)
Endpoints
• Primary: PFS
• Secondary: OS, ORR, duration of response, safety and tolerability
Randomization
• 1:1:1 randomization.
• Stratified according to BRAF mutation (WT, MT), metastatic disease: (liver-only, extra-hepatic), and
prior adjuvant therapy for CRC (yes, no).
Specified crossover at the time of disease progression
• Arm 1: Atezolizumab +/- mFOLFOX6/Bevacizumab components at physician discretion
• Arm 2: mFOLFOX6/Bevacizumab plus Atezolizumab
• Arm 3: SOC chemotherapy at physician discretion 114
Atezolizumab
(Arm 2: Single Agent)
PI’s: Lee and Overman

IMblaze370: Randomised, Phase III,
multicentre, open-label study in mCRC
Atezo, atezolizumab; cobi, cobimetinib; INV, investigator; rego, regorafenib.
a Two-sided type I error rate of 0.05 was controlled by hierarchical testing (testing atezo vs rego only if atezo + cobi vs rego was positive). NCT02788279.
116
• Unresectable locally
advanced or metastatic
CRC
• Received ≥ 2 prior
regimens of cytotoxic
chemotherapy for
metastatic disease
• ECOG PS 0-1
• MSI-H capped at 5%
Regorafenib 160 mg oral 21/7 days
Atezolizumab 840 mg IV q2w
+ cobimetinib 60 mg oral 21/7 days
Atezolizumab 1200 mg IV q3w
R
2:1:1
Lossof
clinicalbenefit
Primary endpoint
• OSa
– Atezo + cobi vs rego
– Atezo vs rego
INV-assessed key secondary endpoints
• PFS
• ORR
• DOR
Stratification
• Extended RAS mutation status (≥ 50% patients in each arm)
• Time since diagnosis of first metastasis (< 18 months vs ≥ 18 months)
• Data cutoff date: March 9, 2018

Overall survival
N/A, not applicable. HRs are from stratified log-rank tests.
Data cutoff: March 9, 2018. a For descriptive purposes
only.
117
Atezo + cobi
(n = 183)
Atezo
(n = 90)
Rego
(n = 90)
Median OS, mo
(95% CI)
8.9
(7.00, 10.61)
7.1
(6.05, 10.05)
8.5
(6.41, 10.71)
HR vs rego
(95% CI)
1.00
(0.73, 1.38)
1.19
(0.83, 1.71)
N/A
P value 0.9871 0.3360a N/A
12-mo OS, % 38.5% 27.2% 36.6%

CCTG CO.26 Study Schema:
Presented By Eric Chen at 2019 Gastrointestinal Cancer Symposium
Primary endpoint: OS

Results: efficacy

Results: overall survival

Case: 70yoF, unresected colon to lung, MSS, KRAS mutant

Nov 2018 January 2019
Anecdotal Case: IMT in MSI-S patient

Other IMT non-anti-PD-1/PD-L1 approaches

CO40939 study: Phase Ib, Multicenter, Open-Label Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of
Cibisatamab in Combination With Atezolizumab After Pretreatment With Obinutuzumab in Patients With Previously
Treated MSI-S mCRC With High CEACAM5 Expression
Brief description: single-arm study to evaluate the safety, efficacy, pharmacokinetics, and
immunogenicity of cibisatamab in combination with atezolizumab administered after pretreatment with
obinutuzumab in patients with Stage IV microsatellite stable (MSS) metastatic colorectal cancer
(mCRC) whose tumors have high carcinoembryonic antigen-related cell adhesion molecule 5
(CEACAM5) expression and who have progressed on two or more chemotherapy regimens.
The study is composed of: Safety run-
in
Exploratory
part
• NCT03866239
• Study Sponsor: Hoffmann-La Roche
Primary outcome measures:
- Percentage of Participants with Adverse Events (AEs)
- Confirmed Objective Response Rate (ORR)

- Patient population: colorectal carcinoma patient: patients with Stage IV microsatellite stable (MSS)
metastatic colorectal cancer
- Estimated enrollment: 46 patients
- Study treatments:
- Obinutuzumab (Gazyva) will be administered by intravenous (IV) infusion as either a split or single dose
approximately 2 weeks before Cycle 1, Day 1 (cycle = 21 days)
- Atezolizumab (Tecentriq) will be administered at a fixed of 1200 mg dose by IV infusion on Day 1 of each 21-day
cycle until radiographic progression, unacceptable toxicity, or loss of clinical benefit
- Cibisatamab will be administered at a fixed dose of 100 mg by IV infusion on Day 1 of each 21-day cycle until
radiographic progression, unacceptable toxicity, or loss of clinical benefit.
- Tocilizumab will be administered by IV infusion as necessary to manage adverse events (AEs)
CO40939 study: Phase Ib, Multicenter, Open-Label Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of
Cibisatamab in Combination With Atezolizumab After Pretreatment With Obinutuzumab in Patients With Previously Treated
MSI-S mCRC With High CEACAM5 Expression

What other diagnostic tools are there for identifying a possible role
for IMT in
MSI-S patients?

Innocenti et al: JCO, March 2019
TMB Prognostic Indicator: CALGB/SWOG 80405
• 843 formalin-fixed, paraffin embedded
tumor blocks
• 475 tumors were analyzed for TMB
• Greater OS with high TMB vs. low TMB
([HR], 0.73 [95% CI, 0.57 to 0.95]; p
=0.02).
• The median TMB for MSI-S was 6 (0-
361)
• 366 patients with < 8 MT’s/Mb in
their tumors classified as TMB low
(77%),
• 107 patients > 8 MT’s were
classified as TMB high (23%).
Med OS: 33.8M vs. 28.1M

TMB and Possible Benefit of IMT in MSI-S mCRC
● Multi-institutional study by Foundation of
Medicine; 315 gene panel.
● N= 6004 cases
○ 95% were MSI-S (N=5702)
■ 97% were considered TMB – low
■ 2.9% (N=164) were considered TMB
– high
● 100x’s more likely to have
variants of PMS2 and POLE
Fabrizio et al: J Gastrointestinal Onc, 2018

ESMO: Development of TMB as a Standard Diagnostic Tool
Chan et al: Ann of Onc, 2019

Conclusions:
● The role of immunotherapy is well established in MSI-H patients.
● The role of immunotherapy continues to be explored in MSI-S
patients
● Tumor mutation burden may have a bearing in the role of IMT in
MSI-S patients.
● Other novel approaches continues to be explored

Wasif M. Saif, MD, MD
• Deputy Physician-in-Chief & Medical Director,
Northwell Health Cancer Institute
• Professor, Medical Oncology, Donald and
Barbara Zucker School of Medicine
• Professor at the Feinstein Institute of Research
From “Bench to Bedside” CRC Experimental Therapeutics
and Phase I & II Trials.
What’s New & What’s Next?

Discussion Points
● What are the emerging targeted therapies available for mCRC?
● Addition of biologics to chemotherapy has improved outcomes. How can we expand
the role of immunotherapy in combination therapy for mCRC?
● What are the additional therapeutic agents with a broad range of diverse molecular
targets currently being evaluated in combination with ICIs in mCRC, esp. MSS CRC?
● Ongoing trials
● Future prospects

Introduction
MSI vs MSS RAS WT vs
mutant
Right vs left vs
rectal
Young vs old
Stool flora typesBRAF WT vs
mutant
HER2
Molecular Anatomic
 Addition of biologics to chemotherapy has improved outcomes, but to a more limited extent than hoped
 Identification of molecular predictive factors is improving potential for individualized therapy
“Colon Cancer: More Than 1 Disease “
 Attempts underway to expand role of immunotherapy beyond treating patients with MSI high CRC

BRAFV600E mutation in mCRC
• Occurs in 10%–15% of patients and confers a poor prognosis
• Standard therapies have limited benefits after ≥1 line of
treatment:
• Median OS 4–6 mo, median PFS ~2 mo and ORR <10%
• SWOG S1406 results with vemurafenib, irinotecan, cetuximab
(VIC): Median OS of 9.6 mo, median PFS of 4.3 mo, and ORR in
16%
• BRAF inhibitors cause feedback activation of EGFR in BRAF-
mutant CRC, leading to continued cell proliferation
• Feedback may be overcome by targeting multiple nodes in the
pathway
• Updated mature phase 2 results with doublet of ENCO +
CETUX*:
• Median OS of 9.3 mo, median PFS of 4.2 mo and ORR in 24%
MAPK Signaling in CRC

Triple MAPK Pathway Inhibition in BRAF-mutant CRC
MAPK Signaling in CRC HT-29 BRAFV600E CRC xenografts
Strickler JH. Cancer Treatment Reviews. 2017; 60:109-119

NCCN Guidelines: BRAF mutant CRC

BEACON CRC Phase 3 Study Design

RAS: Difficult to target due to redundancies and cross-talk in MAPK pathway

HER2• Her2 amplification in 3-5% of CRC
• HERACLES study – trastuzumab + lapatinib
• RR 30%; DCR 74%
• Ongoing studies:
• SWOG 1613: Trastuzumab + Pertuzumab vs.
Irinotecan-Cetuximab
• MOUNTAINEER: Tucatinib + Trastuzumab in
HER2-Amplified mCRC (Phase II)
Lancet Oncol 2016; 17: 738–46

 Flexible-design trial with treatment arm selected based on genomic profiling by FFPE
tumor testing or blood screening; arms open and close with best available science
 Primary endpoint: ORR by RECIST 1.1
 Secondary endpoints: PFS, OS, DoR, QoL, safety and tolerability
COLOMATE: COlorectal and Liquid BiOpsy Molecularly Assigned ThErapy
mCRC patients
previously treated with
fluoropyrimidine,
oxaliplatin, irinotecan,
and anti-VEGF
(planned N = 500)
Anti-HER (n=25)
cfDNA/tissue
screening
HER2-amplified
MET-amplified
EGFR mutation
FGFR
Other (myc, RET,
TRK, etc)
No actionable
change
Anti-MET (n = 75)
Anti-EGFR (n = 50)
Anti-FGFR (n = 27)
TBD
Standard of Care (n = 32)

Unfulfilled promises: Wnt Pathway
• Wnt pathway inhibitors
• Multiple agents
• Significant toxicities
• Wnt pathway involved in polyp formation
• Early step in CRC development
•Essential for stem cell homeostasis
Willert K et al. Genes & Development. 2006

Wnt Pathway: Phase I/II Studies in mCRC
Compound Mechanism of Action Phase of Trial Manufacturer Diseases Concomitant Therapy Response/Adverse effects Trial Identifier
LGK974 Porcupine inhibitor 1/2 Novartis mCRC with Wnt pathway
mutations, H/N with Notch
mutations
PDR001 No clinical data NCTO2278133
NCTO2649530
ETC 159 Porcupine
Inhibitors
1 D3-Institute
experimental
therapeutics
Refractory solid tumors, 10
patients (9 CRC,1 Renal)
Oral single agent 2 stable disease NCTO2521844
OMP131R10 Anti-R- spondin 3 antibody 1 Oncomed/Cel gene RSPO3 positive mCRC FOLFIRI No clinical data yet NCTO2482441
PRI-724 TCF-CBP
interaction
1/2 Prism Biolab AML, CML, CRC, Gemcitabine in APC 8 pts (40%), 2 minor
responses
NCT01764477
Foxy 5 Wnt 5 a derived peptide 1 Wnt Research Breast cancer, CRC, Prostate
cancer
Single agent No dose limiting toxicity
in phase I trial.
NCTO2655952
RO4929097 Gamma
Secretase
Inhibitors
Phase 2 Roche APC, CRC Single agent 12 patients with APC, 3
SD.
NCT01116687

Wnt pathway is involved in 5-FU drug
resistance of colorectal cancer cells
He L, Zhu H, Zhou S, et al. Wnt pathway is involved in 5-FU drug resistance of colorectal cancer cells. Exp Mol Med. 2018;50(8):101.
• Background: 5-Fluorouracil (5-FU) is widely used in the treatment of
cancers, but its antineoplastic activity is limited in drug-resistant cancer cells.
• Methods: Using a model of 5-FU-resistant cells from HCT-8 cells, drug-
resistant cells demonstrated high expression of TCF4 and β-catenin,
indicating an upregulated Wnt pathway.
• Results: A microarray analysis revealed that the suppression of the
checkpoint kinase 1 (CHK1) pathway explained the resistance to 5-FU,
especially in p53 wild-type cancer cells such as HCT-8.
• Conclusion: Our data also demonstrated that the CHK1 pathway is
suppressed by the Wnt pathway in 5-FU-resistant cells.  novel mechanism
for 5-FU resistance mediated by histone deacetylation, which also revealed
the crosstalk between the Wnt pathway and CHK1 pathway.

↑Adhesion molecules (ICAM-
1) and death receptors (FAS)
↑Peptide pools
Hodge. Semin Oncol. 2012;39:323
Dendritic cell
↓Treg cells
↓MDSC
↓M2 Macrophages
↑TAA cross-
presentation
CD8 T-cells
↑Effector immune
infiltrate
Release of tumor
antigens (cascade)
Translocation
of calreticulin
↑TAA
↑Upregulation of
MHC-I
↑Adhesion molecules
/death receptors
↑APM
CD8 T-cells
(Homeostatic peripheral
expansion)
Chemotherapy Small molecule inhibitors
Radiation
↓Treg cells
↓MDSC
↑CD8 T-cells
↑T-cell function
Chemokine release
↑Vascular normalization
↑T-cell infiltration
↑Activation of apoptosis
↑Blockage of cell cycle
↑Uploading of antigen
processing machinery
Upregulation of MHC-I
CD8 T-cell
Combination therapies of Immune Checkpoint
Inhibitors for development of durable CRC responses

Immune Checkpoint Inhibitors +
Chemotherapy
• Chemotherapy has been shown in vitro and in vivo to have favorable synergistic immunomodulatory
effects that can potentiate ICI efficacy.
• As known predictive biomarkers critical to ICI effectiveness, TILs, tumor neoantigens, and tumor PD-L1
expression have been shown to increase after 5-flourouracil plus oxaliplatin (FOLFOX) treatment in
murine models of CRC and human tumor sample correlates.
• Likewise, a host of concurrent immunomodulatory effects—including upregulation of cellular major
histocompatibility complex (MHC) class I, dendritic cell (DC) recruitment and activation, increased antigen
presentation and suppression of regulatory T-cells (Tregs) and myeloid-derived suppressor cells
(MDSCs)—have been reported post-chemotherapy and function synergistically in creating a more
immune-promoting tumor microenvironment.
• As a proof-of-principle, administration of oxaliplatin led to an increase in the overall immune response to
a PD-L1 trap fusion protein in an in vivo murine pMMR CRC model.
Liu WM et al. Br. J. Cancer. 2010;102:115–123.
Song W et al. Nat. Commun. 2018

Selected clinical trials of immune checkpoint inhibitors (ICIs) with
chemotherapy in patients with CRC
Selected clinical trials of immune checkpoint inhibitors (ICIs)
with chemotherapy in patients with CRC

Immune Checkpoint Inhibitors + VEGF/EGFR
Inhibitors +/− Chemotherapy
• Validated as robust therapeutic targets in CRC, both VEGF and EGFR are well-established mediators of
tumor growth and proliferation.
• Targeted agents directed against EGFR (cetuximab, panitumumab) and those directed against VEGF
(bevacizumab) have shown to facilitate a more immunogenic tumor profile in preclinical models and, as
such, are reasonable potential adjuncts to ICIs in MSS CRC.
• In vitro and in vivo preclinical studies describe increased tumor necrosis receptor CD137 expression on NK and T-
cells, decreased immunosuppressive cell populations (Tregs, MDSCs) and improved T-cell cytotoxicity and growth
after EGFR inhibition.
• Similarly, inhibition of VEGF has been shown in multiple studies to enhance immunity by decreasing
immunosuppressive cell populations, increasing TILs and improving T-cell effector function.
• Thus, the potential use of EGFR or VEGF inhibitors in conjunction with ICIs presents a promising strategy for
treating MSS CRC.
MacDonald F et al. Front. Pharmacol. 2017
Yang J. Front. Immunol. 2018.

Selected clinical trials of ICIs in combination with molecularly
targeted agents in patients with CRC.

Immune Checkpoint Inhibitors + Radiotherapy
• Similar to chemotherapy and anti-angiogenic therapy, preclinical
data support the use of radiotherapy as an effective means to
augment ICI efficacy by directly contributing to the process of
immunogenic cell death.
• Mechanistically validated in vivo and in vitro, radiotherapy can
elicit a pro-inflammatory tumor state through direct tumor
destruction, release of tumor antigens, up-regulation of
inflammatory cytokines and cell surface molecules (i.e., MHC-1),
and recruitment of immune cells into the tumor
microenvironment.
• The reported “abscopal effect”, in which tumors outside of the
radiation treatment field can regress following radiation therapy, can
be explained by a heightened systemic immune response induced by
radiotherapy and supports the immune-promoting effects of this
modality.
Saif MW et al. JCO 2005.
Walle T et al. Therap. Adv. Med. Onc. 2018

Clinical trials of combination ICIs and
radiotherapy in CRC patients.

Chemokines and chemokine receptors
Pathway Therapeutic Target Agent ICI Study
Chemokines, or small pro-
inflammatory cytokines, and
their receptors
Receptor CXCR2
Chemokine CXCL12
Receptor CCR5
Navarixin
Olaptesed pegol
Vicriviroc
Pembrolizumab
Pembrolizumab
Pembrolizumab
NCT03473925
NCT03168139
NCT03631407
NCT03274804

Indoleamine 2,3 dioxygenase - Kynurenine Pathway
Cytosolic enzyme
indoleamine 2,3-
dioxygenase-1
IDO1-inhibitor Epacadostat Pembrolizumab NCT02880371
Munn DH, Mellor AL (March 2013). Trends in Immunology. 34 (3): 137–43

Colony Stimulating factor 1 receptor (CSF1R) Pathway
Colony-stimulating factor 1 receptor CSF1R inhibitor Cabiralizumab Nivolumab NCT02777710
NCT02452424
NCT02829723
NCT02880371

Lymphocyte Activation Gene-3 (LAG3; CD223)
Novel checkpoint
inhibitor of
lymphocyte
activation gene-3
LAG-3 inhibitor Relatlimab Nivolumab NCT03642067
Long et al. Genes Cancer 2018;9(5-6): 176-89.

Future Prospective
• Survival of patients with mCRC has significantly improved in the last decade  but survival
gains are not driven by advances in first-line therapy, but by incremental additional effects of
subsequent treatment lines
• Elucidating beneficial, and tolerable, combination therapy targeting other targets including
but not limited to RAS/RAF/MEK/ERK pathway, Her2, IDH1, FGFR
• Development and validation of biomarkers, including liquid biopsy
• Promising immunotherapeutic strategies had added to the survival in mCRC
• Now we need to refine how to utilize immunotherapy:
1. Develop improved methods to deliver key antigens to make the tumor environment more receptive to immune
infiltration of effector T-cells
2. Combination approaches
3. Solid tumor CAR-T? (chimeric antigen receptor)

158
Supportive and Palliative
Care
What are the GAPS faced by
the Early Onset CRC Patient?
James T D’Olimpio MD, FACP, FAAHPM
Director, Supportive /Palliative Oncology
Services,Monter cancer center of the
Northwell Cancer Institute
Assistant Professor of Medicine
Zucker/Hofstra/Northwell SOM

What do we mean by GAPS?
• 1.GAPS in understanding what Supportive and Palliative care
is and what it isn’t (Definitions)
• 2.GAPS in effective models that extrapolate cost
effectiveness from Inpatient to Outpatient
• 3.GAPS in bridging “Best Practice” where the expertise
doesn’t exist
• 4.GAPS in the “math” of availability of BC PC practitioners ,
trained in Oncology
159

Composite Evolutionary Definition of
Supportive and Palliative care
1. The goal of palliative care is to prevent and relieve suffering and to
support the best possible quality of life for patients and their families,
regardless of the stage of the disease or the need for other therapies.
Palliative care is both a philosophy of care and an organized, highly
structured system for delivering care. Palliative care expands traditional
disease-model medical treatments to include the goals of enhancing
quality of life for patient and family, optimizing function, helping with
decision-making and providing opportunities for personal growth. As such,
it can be delivered concurrently with life-prolonging care or as the main
focus of care, and can be defined in the setting of SUPPORTIVE CARE.
2. The Multinational Association for Supportive Care in Cancer (MASCC)
defines supportive care as ‘the prevention and treatment of the adverse
effects of cancer and its treatment. Rehabilitation, secondary cancer
prevention, survivorship, and end-of-life care are all integral to supportive
care’ . Thus, supportive care has a wider scope than traditional palliative
care
160

161
• The Bottom Line
• – Compared to usual care, palliative care
consultation
• results in significant cost savings
• • $174/day or $1696/admission for patients
discharged alive
• • $374/day or $4,908/admission for patients
who die in
• hospital
• – Comparing costs/day for 48 hours before and
after
• consultation, palliative care consultation
resulted in
• significant cost reductions
• • $238/day for patients discharged alive
• • $574/day for patients who die in hospital

Potential GAP Filling or Bridging
1. Development of metrics that measure specific outcomes in a specific
population , ie EAOCRC
2. How best to incorporate SC/PC “EARLIER IS BETTER” in the era of the
EMR
3. Is “Rebranding of the term Palliative care to Supportive Care necessary?
4. How best to resource SC/PC “Interdisciplinary Team Approach”
(Idiosynchratic)
162

Overall, the evidence describing outpatient palliative care’s
benefit is stronger for QoL, resource utilization outcomes, patient
satisfaction, and mood outcomes, with weaker evidence
suggesting benefits on survival, symptom burden, psychosocial,
and caregiver outcomes. These observations are consistent with
the fact that outpatient palliative care programs are designed to
increase patient social support, patient self-advocacy, and
coordinated medical care; while palliative care is not focused on
improved survival as an indicator of effectiveness, the survival
benefit may be mediated by the other more directly influenced
outcomes of interest
source:Palliative Care in the Outpatient setting: Institute for Clinical and Economic Review, March 2016
164

Future Directions :Theme:If Earlier is Better,
How is it better? Re EAOCRC
1. Improved Symptom management both short and
long term unique to this group?
2. Less necessary hospitalizations/Interventions/ER
visits?
3. Improved survival in metastatic cases
4. Improved survivorship in those cured ( ie improved
QoL of Cognitive Impairment, Peripheral neuropathy
, PTSD like s/s, nutrition,sexuality, family dynamics,
financial integrity,etc
165

Center for Young Onset
Colorectal Cancer
Andrea Cercek, MD
Assistant Attending
Section Head, Colorectal Oncology
Co-Director, Center for Young Onset Colorectal
Cancer
Zana Correa NP
Nurse Practitioner
Colorectal Survivorship Clinic

Center for Young Onset Colorectal Cancer:
A Coordinated Clinical and Research Program
GI Oncology
Gastroenterology
Colorectal Surgery
Radiation Oncology
Genetics
Sexual Health
Fertility
SocialWork
Nutrition
Epidemiology
Pathology
Translational Research
Coordinated
Patient Centered Care
Survivorship

Survivorship Care : Living Beyond Cancer
Essential components of Survivorship Care:
Long-term follow-up / Surveillance
Late Effects management
Coordination of care with PCP/specialists
Health Promotion
MSK’s Center forYoung Onset Colorectal Cancer
1-800-525-2225
https://www.mskcc.org/cancer-care/types/colorectal/colorectal-
cancer-young-adults
Living Beyond Cancer
https://www.mskcc.org/experience/living-beyond-cancer

Young-Onset Colorectal Cancer Care at
Dana-Farber Cancer Institute
Kimmie Ng, MD, MPH
Karen Fasciano, PsyD
Early Age Onset Colorectal Cancer Summit
May 2, 2019
YoungCRC@dfci.harvard.edu
www.dana-farber.org/youngCRC

Mission
• Clinical Care
−Provide expert, compassionate, and multidisciplinary care to patients
with young-onset colorectal cancer
• Research
−Promote scientific discovery and innovation to elucidate underlying
biological mechanisms, identify risk factors, and facilitate development
of novel therapies
• Education and Awareness
−Increase public awareness and education around the rising burden of
colorectal cancer in young adults to improve prevention and early
detection

Integration of Psychosocial Care:
Young Adult Program /Young-Onset
Colorectal Cancer Program
• Enhance coping skills and promote
emotional resilience
• Provide innovations that use
technology
• Educate and train medical
professionals in unique social,
emotional and communication needs
• Develop clinical processes that
integrate and normalize psychosocial
care

5th Annual Early Age Onset Colorectal Cancer Summit - Session IV

5th Annual Early Age Onset Colorectal Cancer Summit - Session IV

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