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Young Onset Colorectal
Cancer:
Treatment Implications
Andrea Cercek, MD
Assistant Attending
Section Head, Colorectal Oncol...
Young Onset Colorectal Cancer Background• Young Onset CRC
• Not associated with genetic
predisposition or family
history
•...
Tumor Biology
Yaeger R, et al Cancer Cell 2018
Cercek,ChatilaASCO 2018, ESMO 2018
Cohort Description
• Young Onset
• 377 C...
Patient Characteristics
All patients (n=377) MSS
(n=361)
MSI H
(n=13)
POLE
(n=3)
Age (years)
Mean (range) 42 (17-49) 42 (1...
Patient Characteristics
All patients (n=377) MSS
(n=361)
MSI H
(n=13)
POLE
(n=3)
Age (years)
Mean (range) 42 (17-49) 42 (1...
Patient Characteristics- MSS cohort
80% left sided
Cohort Characteristics
Age 17-39
(n=105)
Mean (SD) or %
Age 40-49
(n=23...
Patient Characteristics- MSS cohort
MSS
N= 361
Pathologic Grade
Well differentiated 8
Mod differentiated 294
Poorly differ...
Mutation burden Young Onset vs
Average Onset
Wilcoxon rank sum test
P-value: 0.17
P-value: 0.09
Cercek, Chatila unpublishe...
Mutation burden by primary tumor
location: YO vs AO
** **
Cercek, Chatila unpublished data
Genomic Differences in MSS mCRC: EO
vs AO
*
20q Amp
Alteration Frequencies:Young vs Average Onset
Cercek, Chatila unpublis...
Pathway alterationsEarly Onset Average Onset
Cercek, Chatila unpublished data
Response To Chemotherapy ?
• Majority of patients received first line FOLFOX
• Response rate ~50%
• Analogous to published...
Survival Analyses
• Young onset patients
have significantly
better survival.
65
Dos Santos Fernandes,Chatila, Cercek ASCO ...
Survival differences Young Onset vs Average
Onset
Yaeger R, et al Cancer Cell 2018
17-35
50+
35-45
Cercek, Chatila unpubli...
Young Onset CRC Landscape
• ~15% hereditary CRC
• Majority are Lynch
• Treatment of MSI or dMMR CRC
• immunotherapy in the...
Locally advanced rectal cancer
• Locally advanced rectal cancer
• Treated with total neoadjuvant therapy (FOLFOX, chemoRT ...
dMRR Rectal Cancer
Characteristic No. (%) of Patients (n = 50)
Sex
Male 34 (68)
Female 16 (32)
Race
White 39 (78)
Hispanic...
dMMR rectal cancer
Outcome
No. of Patients (%)
dMMR pMMR
FOLFOX as initial
treatment
n = 21 n = 63
Progression of
disease
...
dMMR locally advanced rectal cancer
Important to keep in mind given the increase in young patients with left sided,
rectal...
What are the effects of treatment on young patients?
• Longitudinal sexual health and fertility
• Psychological impact
• B...
Center for Young Onset Colorectal Cancer:
A Coordinated Clinical and Research Program
GI Oncology
Gastroenterology
Colorec...
Center for Young Onset Colorectal Cancer:
A Coordinated Clinical and Research Program
GI Oncology
Gastroenterology
Colorec...
Fertility• Among young women cancer related infertility is associated with
greater risk for emotional distress and worse Q...
Fertility –Effects of Radiation and
Chemotherapy
• MSK retrospective review
• Incidence of amenorrhea in premenopausal wom...
Center for Young Onset Colorectal Cancer:
A Coordinated Clinical and Research Program
GI Oncology
Gastroenterology
Colorec...
Chemotherapy
FOLFOX, 5FU/Cape induced vascular toxicity
•increased incidence of CVD and CHF in pts aged >65
Longitudinal e...
Physical Unmet Needs
• Symptom managements in young patients
• Symptoms diarrhea (37%), sleep disorder (32%) and sexual fu...
Center for Young Onset Colorectal Cancer:
A Coordinated Clinical and Research Program
GI Oncology
Gastroenterology
Colorec...
Social Work and Psychology/Psychiatry• Unique dilemmas
• Increased isolation not only from their healthy peers, but also f...
Center for Young Onset Colorectal Cancer:
A Coordinated Clinical and Research Program
GI Oncology
Gastroenterology
Colorec...
Sexual Health
• Body Image and Sexual function in women after treatment for anal
and rectal cancer
• Median age 55
• 86% r...
Research is Needed to Understand:
• Biology of young onset CRC
• Epidemiology
• Diagnosis
• Treatment strategies
• Survivo...
AcknowledgementsGI Oncology
• Luis Diaz
• Gustavo Dos Santos Fernandes
• Rona Yaeger
• Diane Reidy-Lagunes
• Len Saltz
• Z...
YOUNG-ONSET COLORECTAL CANCER
OPTIMIZING PRESERVATION OF FERTILITY
Nicole Noyes MD, Professor
System Chief, Reproductive M...
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 –...
HUMAN FEMALE OVARY – CONCEPTION TO AGE 40
20 weeks gestation: 6 - 7 x 106 oocytes
No further germ cell proliferation
Progr...
Temporal Trends in Male Parenthood
169MM US Births: 1975 - 2015
Ramjit Raghav
1st child with
his wife at
age 94; 2nd at
ag...
Causes of Treatment-Related Infertility
All treatments can impact fertility
• Surgery – Integral to cure
• Procedures prox...
ASSISTED REPRODUCTIVE FERTILITY PRESERVATION TECHNIQUES
Options
Mature Oocyte
Freeze Embryos
Sperm
Freeze
Mature Oocytes
F...
FERTILITY PRESERVATION - CANCER
Factors
Intrinsic factors
Health status of the patient
Age/Assessment of ovarian reserve
I...
Ovarian Transposition
Radiation Therapy Tolerance Doses: TD
Ovary: TD 5/5: 300 cGy; TD 50/5: 1200 cGy
Sterility = endpoint...
OVARIAN TISSUE CRYOPRESERVATION
Still considered experimental
• First HUMAN live birth reported in 2004 (Donnez, Lancet)
•...
EMBRYO CRYOPRESERVATION
• First HUMAN birth 1984 (34 y ago)
• Early successes rapidly followed by application
of reproduci...
OOCYTE CRYOPRESERVATION
• First HUMAN live birth reported in 1986
(32 y ago)
• Early results disappointing/non-reproducibl...
OOCYTE CRYOPRESERVATION
• Advantages over embryo cryopreservation
• Enhanced reproductive autonomy
• Decreased ethical, pe...
OOCYTE CRYOPRESERVATION
LIVE BIRTH OUTCOME
0
10
20
30
40
50
Frozen Eggs
Autologous
<35 35-37 38-40 41-42
%
0
10
20
30
40
5...
FERTILITY PRESERVATION - CANCER
Oocyte Thaw Cycles
Oocytes
No. thaw cycles 12
(10 patients)
No. embryo transfers (ET) 10
M...
SUMMARY
• Cancer cure is no longer defined simply by eradication of
disease but now includes addressing quality-of-life is...
Thank you
Dr. Nicole Noyes
nnoyes@northwell.edu
Department of GI Medical Oncology
Novel Approaches to Metastatic Mismatch Repair
(MMR) deficient and Microsatellite
Stable...
Disclosures
● Bayer
● BMS
● Merck
● Roche
● Taiho
Discussion Points
● What can we learn from prior IMT trials in mCRC?
● Impact factors?
○ TMB
○ Immunoscore
● Are all immun...
Treatment of MSI-H mCRC
CheckMate-142 Study Design: Nivo/Ipi in MSI-H mCRC Patients
10
7
Primary endpoint:
• ORR per investigator
assessment (RECI...
Checkmate 142: Best Reduction in Target Lesions
10
8
aEvaluable patients per investigator assessment.
• 78% of patients ha...
Checkmate 142: Progression-Free and Overall Survival
• With similar follow-up, combination therapy provided improved PFS a...
Lenz et al: LBA 18, ESMO 2018
Lenz et al: LBA 18, ESMO 2018
Checkmate 142: Nivo/Ipi Front-Line mCRC
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
...
COMMITT
Phase III NRG/SWOG CR-1556 for Metastatic CRC
MSI-high mCRC
without prior
systemic treatment
for metastatic
diseas...
Treatment of MSI-S mCRC
IMblaze370: Randomised, Phase III,
multicentre, open-label study in mCRC
Atezo, atezolizumab; cobi, cobimetinib; INV, inve...
Overall survival
N/A, not applicable. HRs are from stratified log-rank tests.
Data cutoff: March 9, 2018. a For descriptiv...
CCTG CO.26 Study Schema:
Presented By Eric Chen at 2019 Gastrointestinal Cancer Symposium
Primary endpoint: OS
Results: efficacy
Presented By Eric Chen at 2019 Gastrointestinal Cancer Symposium
Results: overall survival
Presented By Eric Chen at 2019 Gastrointestinal Cancer Symposium
Case: 70yoF, unresected colon to lung, MSS, KRAS mutant
Presented By Eric Chen at 2019 Gastrointestinal Cancer Symposium
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
Cibisatam...
- Patient population: colorectal carcinoma patient: patients with Stage IV microsatellite stable (MSS)
metastatic colorect...
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 ...
TMB and Possible Benefit of IMT in MSI-S mCRC
● Multi-institutional study by Foundation of
Medicine; 315 gene panel.
● N= ...
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 b...
Wasif M. Saif, MD, MD
• Deputy Physician-in-Chief & Medical Director,
Northwell Health Cancer Institute
• Professor, Medic...
Discussion Points
● What are the emerging targeted therapies available for mCRC?
● Addition of biologics to chemotherapy h...
Introduction
MSI vs MSS RAS WT vs
mutant
Right vs left vs
rectal
Young vs old
Stool flora typesBRAF WT vs
mutant
HER2
Mole...
Emerging Targeted Therapies
BRAFV600E mutation in mCRC
• Occurs in 10%–15% of patients and confers a poor prognosis
• Standard therapies have limited ...
Triple MAPK Pathway Inhibition in BRAF-mutant CRC
MAPK Signaling in CRC HT-29 BRAFV600E CRC xenografts
Strickler JH. Cance...
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:
• ...
 Flexible-design trial with treatment arm selected based on genomic profiling by FFPE
tumor testing or blood screening; a...
Unfulfilled promises: Wnt Pathway
• Wnt pathway inhibitors
• Multiple agents
• Significant toxicities
• Wnt pathway involv...
Wnt Pathway: Phase I/II Studies in mCRC
Compound Mechanism of Action Phase of Trial Manufacturer Diseases Concomitant Ther...
Wnt pathway is involved in 5-FU drug
resistance of colorectal cancer cells
He L, Zhu H, Zhou S, et al. Wnt pathway is invo...
↑Adhesion molecules (ICAM-
1) and death receptors (FAS)
↑Peptide pools
Hodge. Semin Oncol. 2012;39:323
Dendritic cell
↓Tre...
Immune Checkpoint Inhibitors +
Chemotherapy
• Chemotherapy has been shown in vitro and in vivo to have favorable synergist...
Selected clinical trials of immune checkpoint inhibitors (ICIs) with
chemotherapy in patients with CRC
Selected clinical t...
Immune Checkpoint Inhibitors + VEGF/EGFR
Inhibitors +/− Chemotherapy
• Validated as robust therapeutic targets in CRC, bot...
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 suppor...
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 cytok...
Indoleamine 2,3 dioxygenase - Kynurenine Pathway
Pathway Therapeutic Target Agent ICI Study
Cytosolic enzyme
indoleamine 2...
Colony Stimulating factor 1 receptor (CSF1R) Pathway
Pathway Therapeutic Target Agent ICI Study
Colony-stimulating factor ...
Lymphocyte Activation Gene-3 (LAG3; CD223)
Pathway Therapeutic Target Agent ICI Study
Novel checkpoint
inhibitor of
lympho...
Future Prospective
• Survival of patients with mCRC has significantly improved in the last decade  but survival
gains are...
158
Supportive and Palliative
Care
What are the GAPS faced by
the Early Onset CRC Patient?
James T D’Olimpio MD, FACP, FAA...
What do we mean by GAPS?
• 1.GAPS in understanding what Supportive and Palliative care
is and what it isn’t (Definitions)
...
Composite Evolutionary Definition of
Supportive and Palliative care
1. The goal of palliative care is to prevent and relie...
161
• The Bottom Line
• – Compared to usual care, palliative care
consultation
• results in significant cost savings
• • $...
Potential GAP Filling or Bridging
1. Development of metrics that measure specific outcomes in a specific
population , ie E...
What do we know so far?
163
Overall, the evidence describing outpatient palliative care’s
benefit is stronger for QoL, resource utilization outcomes, ...
Future Directions :Theme:If Earlier is Better,
How is it better? Re EAOCRC
1. Improved Symptom management both short and
l...
Center for Young Onset
Colorectal Cancer
Andrea Cercek, MD
Assistant Attending
Section Head, Colorectal Oncology
Co-Direct...
Center for Young Onset Colorectal Cancer:
A Coordinated Clinical and Research Program
GI Oncology
Gastroenterology
Colorec...
Survivorship Care : Living Beyond Cancer
Essential components of Survivorship Care:
Long-term follow-up / Surveillance
L...
Young-Onset Colorectal Cancer Care at
Dana-Farber Cancer Institute
Kimmie Ng, MD, MPH
Karen Fasciano, PsyD
Early Age Onset...
Mission
• Clinical Care
−Provide expert, compassionate, and multidisciplinary care to patients
with young-onset colorectal...
Integration of Psychosocial Care:
Young Adult Program /Young-Onset
Colorectal Cancer Program
• Enhance coping skills and p...
Support & Connection
Family Support Program
Young-Onset Colorectal Cancer Care at
Dana-Farber Cancer Institute
Kimmie Ng, MD, MPH
Karen Fasciano, PsyD
Early Age Onset...
Mission
• Clinical Care
−Provide expert, compassionate, and multidisciplinary care to patients
with young-onset colorectal...
Integration of Psychosocial Care:
Young Adult Program /Young-Onset
Colorectal Cancer Program
• Enhance coping skills and p...
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
5th Annual Early Age Onset Colorectal Cancer Summit - Session IV
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5th Annual Early Age Onset Colorectal Cancer Summit - Session IV

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5th Annual Early Onset Colorectal Cancer Summit - Session IV : Timely, Effective, Quality of Life Preserving State of the Art Treatment

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

  1. 1. 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
  2. 2. 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.
  3. 3. 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
  4. 4. 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
  5. 5. 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
  6. 6. 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 Dos Santos Fernandes,Chatila, Cercek ASCO 2018, ESMO 2018
  7. 7. 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 Dos Santos Fernandes,Chatila, Cercek ASCO 2018, ESMO 2018
  8. 8. Mutation burden Young Onset vs Average Onset Wilcoxon rank sum test P-value: 0.17 P-value: 0.09 Cercek, Chatila unpublished data
  9. 9. Mutation burden by primary tumor location: YO vs AO ** ** Cercek, Chatila unpublished data
  10. 10. Genomic Differences in MSS mCRC: EO vs AO * 20q Amp Alteration Frequencies:Young vs Average Onset Cercek, Chatila unpublished data
  11. 11. Pathway alterationsEarly Onset Average Onset Cercek, Chatila unpublished data
  12. 12. 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
  13. 13. Survival Analyses • Young onset patients have significantly better survival. 65 Dos Santos Fernandes,Chatila, Cercek ASCO 2018, ESMO 2018
  14. 14. Survival differences Young Onset vs Average Onset Yaeger R, et al Cancer Cell 2018 17-35 50+ 35-45 Cercek, Chatila unpublished data
  15. 15. 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
  16. 16. 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
  17. 17. 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)
  18. 18. 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 Cercek, Stadler manuscript submitted Cercek, Stadler manuscript submitted
  19. 19. 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) Cercek, Stadler manuscript submitted
  20. 20. What are the effects of treatment on young patients? • Longitudinal sexual health and fertility • Psychological impact • Bone health • Cardiac toxicities • Potential overtreatment • Surveillance intervals
  21. 21. 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
  22. 22. 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
  23. 23. 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
  24. 24. 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
  25. 25. 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
  26. 26. 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
  27. 27. 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
  28. 28. 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
  29. 29. 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
  30. 30. 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
  31. 31. 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
  32. 32. Research is Needed to Understand: • Biology of young onset CRC • Epidemiology • Diagnosis • Treatment strategies • Survivorship/psychosocial outcomes • Surveillance • Prevention/screening
  33. 33. 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 Hepatobiliary Surgery •Peter Kingham Radiation Oncology •Carla Hajj •John Cuaron •AbrahamWu •Chris Cane SocialWork •Hadley Maya •Anne Martin Psychology/Psychiatry •Andrew Edelstein •Katherine Duhamel Integrative Medicine •Gary Deng Nutrition Survivorship • ZanaCorrea Administration • Lerie Palmaira • Mindy Sovel • Michelle Karlin • KellyTurner
  34. 34. 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
  35. 35. Datamonitor 2018 (US) Young Onset CRC Newly Diagnosed Cases by Age 2170
  36. 36. 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.
  37. 37. 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
  38. 38. 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
  39. 39. 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
  40. 40. ASSISTED REPRODUCTIVE FERTILITY PRESERVATION TECHNIQUES Options Mature Oocyte Freeze Embryos Sperm Freeze Mature Oocytes Freeze Tissue Donor oocytes Ovarian Transposition Ovary with Oocytes
  41. 41. 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
  42. 42. 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
  43. 43. 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
  44. 44. 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
  45. 45. 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
  46. 46. OOCYTE CRYOPRESERVATION • 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
  47. 47. OOCYTE CRYOPRESERVATION 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
  48. 48. 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
  49. 49. 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
  50. 50. Thank you Dr. Nicole Noyes nnoyes@northwell.edu
  51. 51. 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
  52. 52. Disclosures ● Bayer ● BMS ● Merck ● Roche ● Taiho
  53. 53. Discussion Points ● What can we learn from prior IMT trials in mCRC? ● Impact factors? ○ TMB ○ Immunoscore ● Are all immunotherapeutic oncologic agents equivalent? ● Ongoing trials
  54. 54. Treatment of MSI-H mCRC
  55. 55. 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
  56. 56. 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 Overman et al: JCO, 2018
  57. 57. 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 Nivolumab + ipilimumab 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 Nivolumab + ipilimumab 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 Overman et al: JCO, 2018
  58. 58. Lenz et al: LBA 18, ESMO 2018
  59. 59. Lenz et al: LBA 18, ESMO 2018 Checkmate 142: Nivo/Ipi Front-Line mCRC
  60. 60. Lenz et al: LBA 18, ESMO 2018 Checkmate 142: Nivo/Ipi Front-Line mCRC
  61. 61. 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
  62. 62. 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
  63. 63. Treatment of MSI-S mCRC
  64. 64. 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
  65. 65. 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%
  66. 66. CCTG CO.26 Study Schema: Presented By Eric Chen at 2019 Gastrointestinal Cancer Symposium Primary endpoint: OS
  67. 67. Results: efficacy Presented By Eric Chen at 2019 Gastrointestinal Cancer Symposium
  68. 68. Results: overall survival Presented By Eric Chen at 2019 Gastrointestinal Cancer Symposium
  69. 69. Case: 70yoF, unresected colon to lung, MSS, KRAS mutant Presented By Eric Chen at 2019 Gastrointestinal Cancer Symposium
  70. 70. Nov 2018 January 2019 Anecdotal Case: IMT in MSI-S patient
  71. 71. Other IMT non-anti-PD-1/PD-L1 approaches
  72. 72. 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)
  73. 73. - 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
  74. 74. What other diagnostic tools are there for identifying a possible role for IMT in MSI-S patients?
  75. 75. 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
  76. 76. 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
  77. 77. ESMO: Development of TMB as a Standard Diagnostic Tool Chan et al: Ann of Onc, 2019
  78. 78. 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
  79. 79. 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?
  80. 80. 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
  81. 81. 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
  82. 82. Emerging Targeted Therapies
  83. 83. 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
  84. 84. 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
  85. 85. NCCN Guidelines: BRAF mutant CRC
  86. 86. BEACON CRC Phase 3 Study Design
  87. 87. RAS: Difficult to target due to redundancies and cross-talk in MAPK pathway
  88. 88. 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
  89. 89.  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)
  90. 90. 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
  91. 91. 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
  92. 92. 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.
  93. 93. ↑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
  94. 94. 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
  95. 95. 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
  96. 96. 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.
  97. 97. Selected clinical trials of ICIs in combination with molecularly targeted agents in patients with CRC.
  98. 98. 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
  99. 99. Clinical trials of combination ICIs and radiotherapy in CRC patients.
  100. 100. 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
  101. 101. Indoleamine 2,3 dioxygenase - Kynurenine Pathway Pathway Therapeutic Target Agent ICI Study 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
  102. 102. Colony Stimulating factor 1 receptor (CSF1R) Pathway Pathway Therapeutic Target Agent ICI Study Colony-stimulating factor 1 receptor CSF1R inhibitor Cabiralizumab Nivolumab NCT02777710 NCT02452424 NCT02829723 NCT02880371
  103. 103. Lymphocyte Activation Gene-3 (LAG3; CD223) Pathway Therapeutic Target Agent ICI Study 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.
  104. 104. 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)
  105. 105. 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
  106. 106. 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
  107. 107. 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
  108. 108. 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
  109. 109. 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
  110. 110. What do we know so far? 163
  111. 111. 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
  112. 112. 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
  113. 113. 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
  114. 114. 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
  115. 115. 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
  116. 116. 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
  117. 117. 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
  118. 118. 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
  119. 119. Support & Connection
  120. 120. Family Support Program
  121. 121. 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
  122. 122. 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
  123. 123. 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

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