Mary Ann Machol was diagnosed with inoperable stage 4 colorectal cancer in 2013. After undergoing chemotherapy, her cancer progressed and she had no further options until she enrolled in a clinical trial testing the immunotherapy drug pembrolizumab. She responded well to the drug, experiencing reduced pain and weight gain. Her tumors began shrinking, classifying her as a partial responder. Immunotherapy is showing promise for treating gastrointestinal cancers like colorectal cancer. Several clinical trials are exploring immunotherapy drugs alone and in combination for MSI-high and non-MSI-high colorectal cancer, with some patients experiencing responses or stable disease.

2. The Immunotherapy Journey for
Colorectal Cancer
Bao Lam, MD

3. W. Joost Lesterhuis, John B. A. G. Haanen & Cornelis J. A. Punt
Nature Reviews Drug Discovery 10, 591-600 (August 2011)

4. 2015 - The Revolution of Immunotherapy in CRC Began

5. The Real Face of Colon Cancer
MARY ANN MACHOL, diagnosed with stage 4 colorectal cancer, has responded well to immunotherapy.
[PHOTO BY JULIE CHESHIRE (JULIECHESHIRE.COM)]
The Next Frontier: The Promise
of Immunotherapy in
Gastrointestinal Cancers In the
oncology world,
gastrointestinal cancers may be
the next in line to realize the
promise of immunotherapy.
by Arlene Weintraub;
March 24, 2016
CURE MAGAZINE

6. The Real Face of Colon Cancer
• Mary Ann Machol was 44 in 2013 when she learned she had inoperable stage 4
colorectal cancer — a difficult diagnosis that left her with no choice but to
undergo the harsh three-drug chemotherapy regimen known as FOLFOX. The
cocktail (consisting of leucovorin, fluorouracil and oxaliplatin) helped shrink her
tumors, but then she was diagnosed with uterine cancer, and had to stop all
treatments. After undergoing surgery to remove her uterus, Machol, who lives in
the San Francisco Bay area, was put on a different chemotherapy regimen for the
colorectal cancer.

7. The Real Face of Colon Cancer
• By the end of 2014, Machol had run out of options. Then she learned about a trial
at Stanford University involving a drug that stimulates the immune system to fight
off cancer. The drug, Keytruda (pembrolizumab), from Merck, was already on the
market and being used successfully in melanoma and certain lung cancer patients.
In March 2015, Machol was accepted into the trial and began receiving infusions
of Keytruda every two weeks.

8. The Real Face of Colon Cancer
• “After the second dose, I started feeling better,” Machol says. “I had been in
severe pain — on high doses of morphine around the clock, bedridden and
sleeping 16 to 20 hours a day. Then, all of a sudden, I was cutting back on the
morphine. I was down to about 100 pounds because I couldn’t eat, but by
summer I had gained all my weight back.” Machol’s tumors are shrinking,
classifying her as a partial responder to the drug so far. She will remain in the trial
through 2017.

9. Mellman Immunity 2013
Complex Immune Matrix

10. Basis for Immune Therapy – Immune Escape

11. Potential Modalities as Monotherapy or Combinatorial Strategies
Folfox/Folfiri
Anti-EGFR
VEGF/R inhibitors
STAT3 inhibitor
Bruton’s Tyrosine Kinase
Anti-Chemokine Receptor
Epigenetics
CSF1R inhibitor
JAK inhibitor
Pi3K delta
MEK inhibitor
ERK inhibitor
IDO inhibitor
TNF superfamily
CRISPR
Anti-GITR
CEACAM1
LAG 3
BET inhibitor
IL-10
TIGIT
STING
Vaccines
Radiation

12. MSI-high Colorectal Cancer
Anti-PD1 (pembrolizumab)
• Small phase 2 study at Johns
Hopkins University
• MSI-high (N=28) and non-MSI-
high colorectal (N=25) cancer
• 57% of patients with MSI-high CRC
had a response and 32% had
stable disease
• 0% of patients with MSI-high CRC
had a response
Dung Le, ASCO 2016

13. MSI-high Colorectal Cancer
Anti-PD-L1 (Atezolizumab) +
Anti-VEGF (Bevacizumab)
Atezolizumab and bevacizumab combination
therapy showed anti-tumor activity in pre-
treated patients with dMMR/MSI-H mCRC
– Small (N=10) phase Ib with safety as primary
endpoint
– 3 patients (30%) had a response and 6
patients (60%) had stable disease
H. Hochster. GI ASCO 2017

14. Non MSI-high Colorectal Cancer Anti-
PD-L1 (Atezolizumab) +
MEKi (Cobimetinib)
• Atezolizumab and Cobimetinib
combination therapy showed anti-
tumor activity in pre-treated
patients with MSS mCRC
• Small (N=23) exploratory study
• 17% of patients had a response;
22% had stable disease
Bendell. ASCO 2016

15. • Personalized
• Translational Oncology

16. Hope Rising