Management of MSI High Solid Tumors and the impact of adding Immunotherapy upon improving survival outcome and response rate. Colorectal and Non Colorectal tumors.

1. Role of Immunotherapy in
MSI High Solid Tumors
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
NEMROCK 23rd Conference
MSD Symposium
Wednesday, 14/03/2018

2. Speaker Disclosures:
Member of Advisory Board, Consultant, and Speaker for:
• Amgen, Astellas, AstraZeneca, Hoffman la Roche, Janssen Cilag,
Merck Serono, Novartis, Pfizer, Mundipharma, Bayer, MSD.

3. Cancer is a complex adaptive system
Host Immune Defenses
Phenotypically Diverse
Tumor Cell Clones
Escape the control
of normal tissue
architecture
The use of host
system to promote
progression
Genome Instability
 emergence of
clonal variants
Invasion
&
Metastases
Evasion of the
Host immune
defenses
Emergence of
drug resistant
tumor cell clones
Quoted from Dr. George Poste; The next Era in Immuno-Oncology, Presentation at Community Oncology
Alliance Annual Meeting, Orlando, FL April 15, 2016

4. A major shift in thinking:
Researchers
Clinicians Authorities
Tissue of
Origin
Molecular
Target
The Lancet Oncology. Vol 18 July 2017, 835.

5. DNA Repair:
A Process Essential to Cell Survival
• Endogenous & Exogenous Stress Each cell sustains
10,000 to 30,000 episodes of DNA damage per day.
• Persistent damage  Genomic Instability (mutation) 
Cancer & Aging.
How long is a piece of DNA?
DNA length per cell 2 meters
Cells per human 2 ˣ 1013
DNA length per human 4 ˣ 1013 meters
Distance from the earth to the sun 1.49 ˣ 1011 meters
Number of return trips to the sun 134

6. Basic DNA Repair Mechanisms:
Lyama & Willson. DNA Repair (Amst). 2013 August ; 12(8): 620–636

7. Basic Unites of Tumorigenesis:
• Microsatellites: Repetitive genetic units (Bases)
 Maintained by MMR system (5 Genes).
• Deficient MMR  MSI  Genomic Instability
 Tumor formation.
• MSI:
– H: instability in > 30% of microsatellite loci.
– L: instability in < 30% of microsatellite loci.
E. Vilar, J. Tabernero, Molecular dissection of microsatellite instable colorectal cancer, Cancer Discov. 3 (5) (2013)
502e511.

8. Pathway of MMR Deficiency in CRC:
Frank A. Sinicrope1,2 and Daniel J. Sargent3. Clin Cancer Res; 18(6) March 15, 2012

9. Slide 4
Presented By Luis Diaz at 2017 Gastrointestinal Cancers Symposium
As Presented by Luis Diaz M.D. in 2017 ASCO Gastrointestinal Cancers Symposium.

10. Slide 6
Presented By Dung Le at 2018 ASCO-SITC Clinical Immuno-Oncology Symposium

11. Test Schemes for MMR-Deficiency by
IHC:
Lee et al. TheOncologist2016;21:1200–1211

12. IHC: MLH1 & PMS2 Deficient
Presented By Dung Le at 2018 ASCO-SITC Clinical Immuno-Oncology Symposium

13. PCR: Microsatellite Instability
Presented By Dung Le at 2018 ASCO-SITC Clinical Immuno-Oncology Symposium

14. NCI Guidelines:
Lee et al. TheOncologist2016;21:1200–1211

15. Features of MSI-H CRC Tumors:
1. More right sided tumor locations.
2. More undifferentiated tumors.
3. More mucoid activity.
4. More lymphovascular invasion.
5. More BRAF mutations
6. More T-Lymphocyte Infiltration.
7. LESS METASTATIC POTENTIAL.
Schwitalle Y, Kloor M, Eiermann S, Linnebacher M, Kienle P, Knaebel HP, Tariverdian M, Benner A, von Knebel Doeberitz M.
Gastroenterology. 2008;134(4):988.

16. Why not in other tumors?

17. Neoantigens in Cancer:
Dudley et al. Clin Cancer Res; 22(4) February 15, 2016

18. Hypothesis:
• Mutations encode proteins which can be recognized
and targeted by immune system.
• Average tumor has dozens of somatic mutations.
MMR deficient tumors harbor thousands of
mutations.
• MMR deficient tumors are infiltrated by T-Cells.
Presented By Dung Le at 2018 ASCO-SITC Clinical Immuno-Oncology Symposium
PD-1 Blockade  Augment Immune Scenario  Effective in MMR Deficient Tumors?
Histology should not matter

19. Slide 13
Presented By Dung Le at 2018 ASCO-SITC Clinical Immuno-Oncology Symposium

20. Slide 14
Presented By Dung Le at 2018 ASCO-SITC Clinical Immuno-Oncology Symposium

21. MSI-H Among Tumor Types:
Lee et al. TheOncologist2016;21:1200–1211

22. MSI-H Among Tumor Types:
Lee et al. TheOncologist2016;21:1200–1211

23. Lee et al. TheOncologist2016;21:1200–1211

24. Slide 20
Presented By Dung Le at 2018 ASCO-SITC Clinical Immuno-Oncology Symposium

25. Slide 21
Presented By Dung Le at 2018 ASCO-SITC Clinical Immuno-Oncology Symposium

26. Slide 22
Presented By Dung Le at 2018 ASCO-SITC Clinical Immuno-Oncology Symposium

27. Response by Tumor Type: Keynote-016
Presented By E. Chiorean at 2018 ASCO-SITC Clinical Immuno-Oncology Symposium

28. Slide 25
Presented By Dung Le at 2018 ASCO-SITC Clinical Immuno-Oncology Symposium

29. KEYNOTE-164 and 158: Efficacy of Pembrolizumab in Phase 2 KEYNOTE-164 and KEYNOTE-158 Studies of Microsatellite Instability High Cancers<br />
Presented By Dung Le at 2018 ASCO-SITC Clinical Immuno-Oncology Symposium

30. KEYNOTE-164 and KEYNOTE-158: Study Design <br />
Presented By Dung Le at 2018 ASCO-SITC Clinical Immuno-Oncology Symposium

31. Best Overall Response (RECIST v1.1 per IRC) in Patients With MSI-H CRC and MSI-H Non-CRC
Presented By Dung Le at 2018 ASCO-SITC Clinical Immuno-Oncology Symposium

32. Duration of Response (RECIST v1.1 per IRC)<br />Patients With MSI-H CRC
Presented By Dung Le at 2018 ASCO-SITC Clinical Immuno-Oncology Symposium

33. Duration of Response (RECIST v1.1 per IRC)<br />Patients With MSI-H Non-CRC
Presented By Dung Le at 2018 ASCO-SITC Clinical Immuno-Oncology Symposium

34. Slide 41
Presented By Dung Le at 2018 ASCO-SITC Clinical Immuno-Oncology Symposium

35. Overall Survival, Kaplan-Meier Estimate<br />Patients With MSI-H Non-CRC
Presented By Dung Le at 2018 ASCO-SITC Clinical Immuno-Oncology Symposium

36. Nivolumab in mismatch-repair deficient (MMR-d) non-colorectal cancers: NCI-MATCH Trial (Molecular Analysis for Therapy Choice) Arm Z1D
Presented By Dung Le at 2018 ASCO-SITC Clinical Immuno-Oncology Symposium

37. Slide 48
Presented By Dung Le at 2018 ASCO-SITC Clinical Immuno-Oncology Symposium

38. Efficacy analysis
Presented By Dung Le at 2018 ASCO-SITC Clinical Immuno-Oncology Symposium

39. Depth of response
Presented By Dung Le at 2018 ASCO-SITC Clinical Immuno-Oncology Symposium

40. CheckMate-142 Study Design
Presented By Thierry Andre at 2018 Gastrointestinal Cancers Symposium

41. MSI-H CRC Best Response: CheckMate-142
Presented By E. Chiorean at 2018 ASCO-SITC Clinical Immuno-Oncology Symposium

42. MSI-H CRC Best Response: CheckMate-142
Presented By E. Chiorean at 2018 ASCO-SITC Clinical Immuno-Oncology Symposium

43. Progression-Free and Overall Survival
Presented By Thierry Andre at 2018 Gastrointestinal Cancers Symposium

44. FDA Approvals Timeline (Solid Tumors)
Presented By Dung Le at 2018 ASCO-SITC Clinical Immuno-Oncology Symposium

45. • Pembrolizumab accelerated approval is for adult and pediatric patients with
unresectable or metastatic MSI-high/dMMR cancer
– Solid tumors as 2L for patients that have progressed following prior
treatment who have no satisfactory alternative treatment options
– 3L for colorectal cancer patiens that has progressed following treatment
with a fluoropyrmidine, oxaliplatin and irinotecan
Pembrolizumab FDA approvals in
MSI-H solid tumors.

46. Take Home Message:
• Definition of cancer is evolving.
• Therapeutic approvals based on molecular
targets rather than tissue of origin.
• MSI-H and dMMR are associated with
hypermutable tumors and assumed potential
targets for checkpoint inhibitors with concept
extension to non-CRC tumors.
• Pembrolizumab & Nivolumab were approved
recently in solid tumors with MSI-H.
Thank You