Immunotherapy shows promise for colorectal cancer (CRC) patients with microsatellite instability-high (MSI-H) tumors. MSI-H tumors have a higher number of mutations and immune cell infiltrate that make them more visible to immunotherapy. Clinical trials have found response rates of 30-40% for pembrolizumab in metastatic MSI-H CRC patients. Ongoing trials are exploring combination therapies targeting immune checkpoints like PD-1 and CTLA-4 for MSI-H CRC. Immunotherapy may provide an effective treatment option for this patient subgroup.

1. Immunotherapy for Colorectal
Cancer
Michael Overman, MD
MD Anderson Cancer Center
Gastrointestinal Medical Oncology

2. Immune Infiltrate and Prognosis in Primary CRC:
Immunoscore
JCO 2006 Pages et al., NEJM 2005 Pages et al.
411 stage I and II CRC

3. Deficient mismatch repair (dMMR) or microsatellite instability-
high (MSI-H)
Tejpar BJC 2009; Koopman BJC 2009
• Mutations in MMR (inherited) or loss of MMR by methylation
(acquired) results in microsatellite instability (MSI)
– Increased duplication of tandem dinucleotide repeats (microsatellites)
– Resulting increased mutations rate and higher risk of colon cancer
– Unique clinicopathological features (lymphocytic infiltrate, Crohn’s-like
reaction, varigated histology, poor differentiation, right sided)
Anti-CD3
MSI-high CRC
≈3% HNPCC
≈12% sporadic

4. Universal Testing for HNPCC
1158 (31.5)
992(27)
2125 (57.8)
2394(65.2)
3671(100)
No Tested (%)
Moreira et al. JAMA 2012
Revised Bethesda criteria:
1. CRC <50y/o
2. Synchronous, metachronous CRC or other HNPCC cancer
3. CRC with MSI-high histology in <60y/o
4. CRC in ≥1 1st-degree relative with hnpcc cancer with 1 cancer diagnosed <50yrs
5. CRC in ≥2 1st or 2nd-degree relatives with hnpcc cancer regardless of age
Jerusalem criteria: all CRC <70 years old

5. dMMR or MSI-H Have Better Outcomes (Prognostic Effect)
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5
Years
%DiseaseFree
HR: 0.51 (0.29-0.89)
p=0.009
Untreated (N=515)
MSI-H 80%
MSS 56%
5 yr DFS
Sargent, et al. ASCO 2008 and ASCO 2014; Tejpar BJC 2009; Koopman BJC 2009
Stage MSI-H
II 22%
III 12%
IV 3.5%
5-year OS HR 95% OS P-value
dMMR pMMR
Stage II
Surgery alone
(n=307)
90% 78% 0.27 0.10 - 0.74 0.011
Stage III
Surgery alone
(n=264)
59% 54% 0.69 0.35 – 1.36 0.283
ACCENT
database
14 phase III
adjuvant
studies

6. Metastatic MSI-high CRC
Retrospective reivew of 55
metastatic MSI-H pts from
MDACC + Royal Melbourne
Hospital, Australia
– 14 BRAF V600E (25%)
Goldstein + Overman AoO 2014
BRAF V600E

7. Somatic mutation frequencies CRC
Nature
2012
Colon
TCGA

8. CRC TCGA
Nature 2012
Colon TCGA

9. Mutational Rates Across Tumors
Lawrence Nature 2013

10. Schreiber et al. Science 2011
Tumor Antigens:
Differentiation (melanocyte differentiation antigens…)
Overexpressed (HER-2…)
Viral (HPV proteins…)
Cancer/testis (MAGE, NY-ESO-1…)
Mutational (p53…)
Immunity and Cancer

11. Matsushita A et al. Nature (2012); 482 (7385); 400-4
Immunogenic
methylcholantherene-
induced sarcoma cell
lines from Rag2-/- mice
demonstrate ≈20% tumor
rate in naïve wildtype
mice
Spectirn β-2 R913L
mutation predicted and
cloned from TIL
MHC class I

12. Corbiere et al. Can Res 2012; Robbins J Exp Med 1996; Gaudin et al. J Immun 1999
Peptide In silico HLA nM
affinity
A0201
SLFEGIDFYT 11
SLFEGIDIYT 18
A2403
SYLDSGIHS 5646
SYLDSGIHF 6
A0201
ILDKVLVHP 16730
ILDKVLVHL 42

13. BMS-936550
RR: 0/18 CRC
Tremelimumab
RR: 1/45 CRC
(response duration 15m)
Nivolumab
RR: 0/19 CRC
Nivolumab
RR: 1/14 CRC
(response duration >21m, MSI-H pt)
Immune Checkpoint Agents in CRC

14. CMS 400 MSI-high CRC patient

15. Immune Escape Mechanisms in MSI-high CRC
Llosa et al. Cancer Discovery 2014
Invasive FrontStroma
TIL

16. Le DT, et al. NEJM. 2015: 372: 2509-20.
Pembrolizumab 10 mg/kg every 14 days

17. Pembrolizumab: Response Rate

18. Pembrolizumab: Additional
Efficacy Endpoints
CEA response Progression-free survival

19. Immune Infiltrate
PDL1 expression
CD8 density
CD8 density and response

20. Ongoing Anti-PD1 or Anti-PDL1 Clinical Trials
with MSI-high CRC Subsets
• NCT01876511: Phase 2 study of MK-3475 in patients with microsatellite unstable (MSI) tumors
– MSI-high CRC, MSS CRC, MSI-high non-CRC
• NCT02060188: A study of nivolumab and nivolumab plus ipilimumab in recurrent and metastatic
colon cancer (CheckMate 142)
– MSI-high CRC, MSS CRC
• NCT02227667: Evaluate the Efficacy of MEDI4736 in Immunological Subsets of Advanced Colorectal
Cancer
– MSI-high CRC, TIL high CRC
• NCT02404411: phase I/II study of PDR001 in patients with advanced malignancies
– MSI-high CRC, other tumors
• NCT01633970: A phase 1b study of MPDL3280A (an engineered anti-PDL1 antibody) in
combination with bevacizumab and/or chemotherapy in patients with advanced or metastatic solid
tumors
– MSI-high CRC, other tumors
• A phase 1, open-label study of GSK3174998 administered alone and in combination with
anticancer agents including Pembrolizumab in subjects with selected advanced solid tumors
– MSI-high CRC, other tumors

21. Immune checkpoint in melanoma
Ipilimumab in advanced melanoma
Wolchok et al. Lancet Oncol 2010
Nivolumab/Ipilimumab: Chort 2a (n=16):
Nivolumab 3mg/kg + ipilimumab 1mg/kg
Clinical benefit of 73%
G3/4 immmune Aes: 11
Wolchok et al. NEJM 2013
What about combo data in
MSI-high CRC?
Nivolumab in frontline
melanoma
Robert et al. NEJM 2014

22. CheckMate 142 Study Design
Responses seen
Limited activity

23. Nivolumab single agent
MSI-High CRC
Pre-rectal Xrt Pre-tx Restaging at 4months
Cap/xrt to
rectum Nivolumab
Pre-tx Restaging at 4months
Nivolumab
Patient #1
Patient #2

24. Nivolumab single agent
MSI-High Gastric Cancer
Pre-tx
11/13/2013
Restaging
6/10/2015

25. Conclusion
• Test for MSI-high
– As universal testing approach for HNPCC
– For prognostic relevance in stage II
– For clinical trial options in metastatic patients
• Clinical trials of immune-checkpoints in MMR
deficient (MSI-high) CRC should be engaged upon
• Targeting PD1/L1 and/or CTLA-4 have
demonstrated limited to no activity in MMR
proficient CRC