The Immunotherapy Journey for Colorectal Cancer

Bao Lam, MD

W. Joost Lesterhuis, John B. A. G. Haanen & Cornelis J. A. Punt

Nature Reviews Drug Discovery 10, 591-600 (August 2011)

2015 - The Revolution of Immunotherapy in CRC Began

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

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.

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.

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.

Mellman Immunity 2013

Complex Immune Matrix

Basis for Immune Therapy – Immune Escape

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

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

MSI-high Colorectal CancerAnti-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

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

• Personalized • Translational Oncology

Hope Rising