Join us for this exciting webinar to get all the research updates from this year’s Gastrointestinal Cancers Symposium (GI ASCO).

1. GI ASCO 2019 UPDATE

2. TODAY’S WEBINAR
 SPEAKER(S)
 Dustin Deming M.D.
 Nataliya Uboha M.D., Ph.D
 QUESTIONS
 Ask a question in the panel on the RIGHT SIDE of your
screen
 WEBINAR ARCHIVE
 FightCRC.org/webinar
 TWEET ALONG
 Follow along via Twitter – use the hashtag #CRCWebinar

3. RESOURCES
TABOO-TY PODCAST MINI MAGAZINES YOUR GUIDE IN THE FIGHT

4. FIGHTCOLORECTALCANCERDISCLAIMER
The information and services provided
by Fight Colorectal Cancer are for
general informational purposes only.
The information and services are not
intended to be substitutes for
professional medical advice,
diagnoses or treatment.
If you are ill, or suspect that you are ill,
see a doctor immediately. In an
emergency, call 911 or go to the
nearest emergency room.
Fight Colorectal Cancer never
recommends or endorses any specific
physicians, products or treatments for
any condition.

5. Dr.DustinDeming
Dr. Deming is a gastrointestinal oncologist
and colorectal cancer laboratory researcher
at UW Carbone Cancer Center. He has a
focus in the treatment of colon, rectal and
anal cancers. He aims his research to
fundamentally change the way in which we
treat gastrointestinal cancers to a more
personalized approach.
Dr. Uboha is an assistant professor in the
Department of Medicine at the University of
Wisconsin School of Medicine and Public Health,
Madison, WI. She specializes in gastrointestinal (GI)
malignancies.
Dr.NataliyaUboha

6. GI ASCO 2019
Update
Dustin Deming and Nataliya Uboha
GI Medical Oncologists

7. Outline
• Updates in targeted therapies – Dusty Deming
• Standard of Care testing
• NTRK
• BRAF
• HER2
• Updates in immunotherapies – Nataliya Uboha
• Immunotherapy for MMR deficient CRC (MSI-H)
• Immunotherapy in MMR proficient CRC (MSS)
• Immunoscore as a validated prognostic marker

8. Molecular Testing for Metastatic CRC
• Current standard is to test for: KRAS, NRAS, BRAF and MMR/MSI
status
• Current reasons to test: To determine potential sensitivity to anti-
epidermal growth factor receptor antibodies (cetuximab and
panitumumab) and also immunotherapy

9. NTRK
(Amatu, et al. ESMO Open, 2016)

10. Larotectinib Response

11. Gastrointestinal Stromal Tumor
with an NTRK Fusion

12. Summary
• FDA has recently approved larotrectinib for NTRK fusion cancer
regardless of histology
• Routine testing can identify patients with these alterations though
they are present in a fairly rare subtype of CRC

13. BRAF Mutant Colorectal Cancer

14. Clinical Characteristics
• More common in female and elderly
• Right-sided predominance with larger primary
tumors
• Associated with:
• MMR deficiency
• High grade
• Peritoneal disease
• Metastatic lymph node involvement

15. BRAF V600E – Prognostic Implications
(Cremolini, et al., Lancet, 2015)

16. Not All BRAF Mutations are Created Equally
(Jones, JCO, 2017)

17. In Vitro Kinase Activity
(Jones, JCO, 2017)

18. First-line treatment for BRAF V600E mCRC
• Only a third of patients go on to second-line
therapy
• FOLFOXIRI + Bevacizumab (TRIBE and CHARTA
studies)
• FOLFOX or FOLFIRI +/- Bevacizumab
(Seligmann, Ann Oncol, 2017; Cremolini, Lancet, 2015; Schnoll, ASCO, 2017)

19. ORR DCR Ref
Nivolumab (n=12) 25% - Overman, JCO, 2018
Nivolumab and
Ipilimumab (n=29)
55% 79% Overman, JCO, 2018
BRAF V600E MMR deficient
Second-line Treatment

20. EGFR Feedback Signaling
(Corcoran, et al., Cancer Discovery, 2018)

21. Vemurafenib, Cetuximab, Irinotecan

22. Vemurafenib, Cetuximab, Irinotecan

23. n RR PFS Ref
Encorafenib,
binimetinib,
cetuximab
30 48 8 Van Cutsem, GI
ASCO, 2018
Triplet BRAF Targeted Therapy

24. Summary
• BRAF V600 mutant cancers are a distinct subtype of CRC with unique
clinical characteristics and a poor prognosis
• Current treatment strategies include chemotherapy and targeted
therapies.
• Anti-PD1 therapies should be used in the setting of mismatch repair
deficiency.

25. HER2-Amplified CRC Background
• ~5% of mCRC have amplification of
HER2
• Copy number greater than 10 or 3+
IHC
• High copy number tumors typically
less likely to have concomitant
alterations in RAS/RAF

26. Trastuzumab and Pertuzumab in CRC
34 patients
Response Rate 38%
Median Duration of
Benefit
10.3 months
(Hurwitz, et al., GI ASCO, 2017)

27. First-line Treatment with Single Agent Trastuzumab

28. Summary
• HER2 amplified CRC is a new subtype of CRC
• There are non-cytotoxic chemotherapy containing options for
patients with HER2-amplified CRC
• Multiple on-going studies are examining the subtype of CRC
• S1613 – Trastuzumab/Pertuzumab vs Cetuximab/Irinotecan
• Genentech - My Pathway

29. Targeted Therapy Conclusion
• There are new targeted treatment options for patients with subtypes
of CRC
• NTRK mutations and HER2-amplification should be added to standard
of care KRAS/NRAS/BRAF and MMR testing for all patients with
metastatic CRC

30. Immune Checkpoint Inhibitors: Taking the Breaks Off
Immune System
Adapted from https://www.cancer.gov/images/cdr/live/CDR774646-750.jpg

31. Benefits of Immunotherapy
• Overall better tolerated than chemotherapy.
• Those who respond tend to respond for a long time.
• However, most patients with colorectal cancer are resistant to
these agents.
• Microsattelite unstable tumors are the only one to show
significant response.
• Extensive ongoing research to optimize benefits in MSI-H tumors
and to make MSS tumors more sensitive to these drugs.

32. What is MSI-H CRC?
• MSI-H tumors lack proteins that correct mistakes in DNA.
• These tumors tend to accumulate DNA errors.
• MSI-H tumors can result from familial deficiency of these proteins
(Lynch syndrome) or can be acquired (i.e, new, sporadic).
• Frequency of MSI-H CRC:
• Stage II 22%, Stage III 12%, Stage IV 3.5 %
• All CRC tumors should be tested for MSI at the time of diagnosis,
regardless of stage!

33. Adapted from GI ASCO 2019 presentation of M. Overman

34. FDA Approvals for MSI-High CRC
• Pembrolizumab: approved for MSI-H or dMMR colorectal cancer
following progression on a fluoropyrimidine, oxaliplatin, and
irinotecan (Nov 2015)
• Nivolumab: FDA approved for MSI-H CRC (alone or with ipilimumab)
after chemo progression (Aug 2017)
• Ipilimumab: FDA approved for MSI-H CRC to be used in combination
with nivolumab, after chemo progression (Jul 2018)

35. Should Immunotherapy be used in first line?
COMMIT Study Design (NCT02997228)-ongoing
mFOLFOX6/Bevacizumab
(Arm 1: Control)
Atezolizumab
(Arm 2: Single Agent)
mFOLFOX6/Bevacizumab +
Atezolizumab
(Arm 3: Combination)
R MSI-High CRC
 No prior treatments
 N=347

36. What about Adjuvant Immunotherapy for Stage III
MSI-H CRC?
Adapted from presentation by Frank Sinicrope at GI ASCO 2019

37. Adapted from presentation by Frank Sinicrope at GI ASCO 2019

38. Limited Activity of Immunotherapy Against MSS
CRC
Adapted from presentation by Overman at GI ASCO 2019

40. Immunotherapy Agents
• Durvalumab: anti-PDL1 antibody
• Tremelimumab: anti-CTLA4
• These agents have been combined safely in other
studies.

41. Adapted from presentation by E. Chen at GI ASCO 2019

42. Adapted from presentation by E. Chen at GI ASCO 2019

43. Is this practice changing?
• No, but encouraging to see a positive signal!
• However, this positive signal needs to be confirmed in a more
robust study (i.e. blinded, larger number of patients, more
vigorous statistical design).
• This study allows for 10% false positive rate.
• Need more information on subsequent therapies.
• Correlative studies are critical: it is key to learn what makes
some MSS tumors respond to immunotherapy, so that we can
learn how we can make other MSS tumors respond.

44. Radiation May Augment Responses to Immunotherapy
• Radiation Induced Changes in Immune Microenvironment
Sharabi et al, Lancet Oncology 2015; 16: e498-509

45. Phase Ib study of Pembrolizumab in Combination with
Stereotactic Body Radiotherapy for MSS Resectable Liver
Metastatic Colorectal Cancer
Open to accrual at University of Wisconsin, PI Dr. D. Deming, NCT02837263

46. Adverse Events
(presented at ASCO GI, 2019)
Based on our data so far, this
approach is feasible. No
unexpected toxicities identified.

47. NSABP-FR2: Phase 2 study of durvalumab and
Chemoradiation for Stage II-IV Rectal Cancer
(ongoing)
George et al, poster presentation at GI ASCO 2019

49. Mlecnik, et al., Immunity, 2016
• Innate immune response to the tumor.
• Immunoscore is an indicator of tumor
recurrence beyond MSI status.
Potential clinical use:
• Can we use this score to guide
treatment of stage II colon cancer?
• Can it help us decide who needs chemo
after resection?
What is the Immunoscore?

51. Immunoscore Evaluation in High Risk Stage II CRC
• 1130 patients with resected stage II CRC
• 630 high-risk, 500 low-risk
• No chemotherapy
• High risk defined as:
• Poorly differentiated histology
• Less than 12 lymph nodes resected
• T4 tumors
• Lymphovascular or perineural invasion
• Bowel obstruction or perforation

54. So should it be used in clinical practice?
• Not yet.
• Immunoscore is a prognostic marker for colorectal cancer.
• It has never been shown that a treatment change based on
the immunoscore result benefits patients.
• At this time, there is no role for it in clinical practice.
• Prospective randomized studies are needed.

55. Summary
• Immunotherapy has is very active against MSI-H tumors
• There are ongoing trials evaluating the role of these agents during earlier
lines of treatment (stage III, first-line metastatic).
• Immonotherapy has limited activity against MSS, and recent studies have
been disappointing.
• New combination strategies (such as with radiation) may augment activity
of these agents again MSS CRC. Early trials are ongoing.
• Immunoscore evaluates how innate immunity reacts to tumor. It has been
shown to correlate with recurrence risk in stage II CRC. It is not ready for
use in clinical practice.

56. Clinical Trial Finder

57. Our Dedicated Supporters
(Cathy Wingert CRC Research Fund)

58. Q
&
A
SNAP A #STRONGARMSELFIE
In 2018, up to $55,000 will be donated thanks to our
sponsors: Bayer, Fujifilm, Myriad Genetics and Taiho
Oncology!
Flex a “strong arm” & post it to Twitter or Instagram using the
hashtag #StrongArmSelfie

59. CONTACT US
CALL TOLL FREE
1.877.427.2111