Download Clinical Trials: The Good, Bad and the Ugly

Colorectal Cancer:
The Past, Present, and Future of Cancer Medicine
Christopher Lieu, MD
Director, Colorectal Medical Oncology
University of Colorado Cancer Center
Disclosures
• Consulting
– Merrimack Pharmaceuticals
– Merck Pharmaceuticals
• Data Safety Monitoring Board
– Immune Concepts
What You Need To Know
• Colorectal Cancer 101
• Where have we been?
• Where are we now?
• Where are we going?
Colorectal Cancer 101
Why is Cancer Important?
• 1 in 3 people will GET cancer
• More than 30% of cancer could be prevented mainly
by not using tobacco, having a healthy diet, being
physically active and preventing infections that may
cause cancer (World Health Organization)
• Less than 10% of all cancer is inherited
• The annual cost of treating cancer is $110 billion per
year
*Source: American Cancer Society
Diagnosis/Staging
• Labs
– CBC, CMP, CEA
• Procedures
– Colonoscopy with biopsy
– Flexible sigmoidoscopy with biopsy
• Radiology
–
–
–
–
CT scan
Chest/Abdomen/Pelvis (Chest is controversial)
PET/CT (?)
Liver MRI (?)
http://www.uptodate.com/contents/image?imageKey=GAST%2F83618&topicKey=ON
C%2F2496&rank=1~150&source=see_link&search=colorectal+cancer&utdPopup=true
Factors Influencing Treatment Selection
Tumor
• Resectability
• Biology
• Symptoms
Patient
•
•
•
•
Age
General Health
Other Diseases
Preference
Treatment
• Efficacy
• Toxicity
• Availability
Surgical Resection:
Treatment of choice for early-stage colorectal cancer
Radiation Therapy:
Used prior to surgery or sometimes to treat metastases
Who First Described Cancer?
The first description of cancer?
• 2625 BC
• Egyptian Edwin Smith Papyrus
The Edwin Smith Papyrus
• Egyptian physician, Imhotep, described a “bulging
mass on the breast, large, spreading, and hard”
• Total of 8 cases described
• Treated with cauterization with a tool known as
the “fire drill”
• Therapy: “There is none”
Early descriptions of cancer
• Hippocrates (460 BC – 370 BC) described several
kinds of cancer, referring to them with the Greek
word carcinos (crab)
– The appearance of the cut surface of a solid tumor
with “the veins stretched on all sides as the animal
the crab has its feet”
What causes cancer?
Hippocrates – humoral theory
• 4 humors affected health
–
–
–
–
Blood
Phlegm
Yellow bile
Black bile
• Suggested that an imbalance of these humors
with an excess of black bile could cause cancer
Causes of cancer
• Zacutus Lusitani (1575-1642) and Nicholas Tulp (1593-1674),
doctors in Holland, concluded that cancer was contagious
– Based on breast cancer in members of the same household
• Scottish surgeon John Hunter (1728-1793) suggested that some
cancers might be cured by surgery
– Nearly a century later, development of anesthesia prompted regular
surgery for “movable” cancers that had not spread to other organs
• Virchow (1821-1902) hypothesized that growth could occur in
only two ways: either by increasing cell numbers or by
increasing cell size
– Hyperplasia and hypertrophy
– Cancer was a disease of pathological hyperplasia
Internal Factors
(Genetics,
Hormones,
Decreased Immunity)
External Factors
(Tobacco, Chemical,
Radiation, Viruses)
Initiation
Normal Cells
Promotion
DNA Repair
Progression
Apoptosis / Cell Death
CANCER OVERVIEW
History of Chemotherapy
Where did cancer drugs come from?
German bombing at Bari, Italy
December 2, 1943
• Fisherman and residents
began to complain of the
whiff of burnt garlic and
horseradishes in the breeze
• Thousands of servicemen
and Italian civilians lost
their lives in the weeks
following the bombing
• One of the ships that was
bombed was the US Liberty
ship John Harvey, which
was carrying a secret load
of 2,000 M47A1 mustard
gas bombs
The Bari Incident
• Autopsies revealed that white blood cells had vanished in
the blood of men and women who initially survived the
bombing
• The Chemical Warfare Service was created to study war
gases
• Two scientists, Louis Goodman and Alfred Gilman were
contracted to study nitrogen mustard
Goodman and Gilman
• Animal studies
– Injected nitrogen mustard intravenously into rabbits
and mice
– Normal WBCs and bone marrow disappeared without
the toxic vesicant actions
• In 1942, they persuaded a thoracic surgeon, Gustaf
Lindskog, to treat a 48-year-old male with lymphoma
with ten doses of IV mustard, causing a remission
• Goodman and Gilman published their findings in
1946
Sidney Farber
• Born in 1903 (the 3rd of 14 children)
• Pediatric pathologist
• The 1940s saw an explosion of therapeutics to
treat illnesses with the advent of penicillin
• Interested in developing an anti-leukemic drug to
treat children with leukemia
Sidney Farber
• Lucy Wills observed that folic acid
could restore the normal genesis of
blood in nutrient-deprived patients
• Farber’s 1st clinical trial was to inject
folic acid into children with leukemia
• Farber found that folic acid actually
accelerated the progression of
leukemia
Sidney Farber
• In September 6, 1947, Farber began to inject
pteroylaspartic acid (PAA – anti-folate) into a twoyear-old male with leukemia
– No effect was noted, and the patient continued to
worsen
• On December 28, Farber received a newer version of
the anti-folate called aminopterin
• WBC began to drop to nearly 1/6th of its peak value
• The patient began walking again and his spleen and
liver returned to normal size
• Ten of sixteen patients had responded to
aminopterin
• Five children remained alive 4-6 months after
diagnosis
Sidney Farber
Early Cancer Therapy
• When cancer was confined to a local site, it was
understood that a cancer could potentially be cured
• William Halsted at Johns Hopkins pioneered the
radical mastectomy in the 1890s
• The discovery of x-rays in the early 1900s lead to
radiation being used to kill tumor cells at local sites
– Emil Grubbe (21-year-old medical student) gave an
elderly woman with breast cancer radiation using an
improvised x-ray tube
Case Presentation – Colorectal Cancer
• 62-year-old male presents with rectal bleeding
• Colonoscopy reveals a malignant appearing
mass in the sigmoid colon
• Staging CT reveals hypodensities in the liver
concerning for metastases
Case Presentation – Colorectal Cancer
Standard of Care Treatment until 2000
• Treatment: 5-fluorouracil
• Response rate = 10-15%
• Overall survival = 8-12 months
Where are we now?
The current state of Colorectal Cancer Therapy
Childhood ALL: Improvements in Survival
100
1996-2000
(n=3421)
%
1989-1995
(n=5121)
80
S
u
r
v
i
v
a
l
1983-1988
(n=3711)
60
1978-1983
(n=2984)
1975-1977
(n=1313)
40
1972-1975
(n=936)
20
1970-1972
(n=499)
1968-1970
(n=402)
0
0
2
4
6
8
Years from Study Entry
10
12
Slide courtesy of Lia Gore, MD
General Themes of Treatment
- Some patients with stage IV disease are cured using
multi-disciplinary approaches
- surgery, chemo, ablation, radiation
- Combination therapy is generally well-tolerated
- Biologics have added incremental (and somewhat
disappointing) benefit
- Era of personalized therapy began with KRAS
Surgical Resection of Liver Tumors
Radiofrequency Ablation (RFA)
High frequency
alternating current
Ionic vibration &
heat generation
45°C: Protein
denaturation
70°C: Thermal
coagulation
100°C: Tissue
desiccation
Adapted from Minami Y, Kudo M. Int J Hepatol. 2011;doi:10.4061/2011/104685.
Laparoscopic RFA of Liver
mCRC Outcomes Have Improved With the
Evolution of Treatment Options
Months
30
25
Median OS
20
15
10
5
0
1980s
1990s
2000s
BSC
5-FU
Irinotecan1
Capecitabine2
Oxaliplatin3
Bevacizumab4
Cetuximab5,6
Panitumumab7
Aflibercept8
Regorafenib9
1. Cunningham D, et al. Lancet. 1998;352(9138):1413-1418. 2. Van Cutsem E, et al. Br J Cancer. 2004;90(6):1190-1197.
3. Rothenberg M, et al. J Clin Oncol. 2003;21(11):2059-2069.
4. Hurwitz H, et al. N Engl J Med. 2004;350(23):2335-2342. 5. Cunningham D, et al. N Engl J Med. 2004;351(4):337-345.
6. Van Cutsem E, et al. N Engl J Med. 2009;360(14):1408-1417.
7. Van Cutsem E, et al. J Clin Oncol. 2007;25(13):1658-6164. 8. Van Cutsem E et al. J Clin Oncol. 2012;30(28):34993506. 9. Grothey A, et al. Lancet. 2013;381(9863):303-312.
Overview of EGFR and VEGFR Growth Signaling Pathways
Tumor Cell
Endothelial Cell
VEGF
EGFR
Targeted by cetuximab
and panitumumab
KIT
PDGFR-β
VEGFR
Targeted by
bevacizumab
and
aflibercept*
Targeted by
ramucirumab
RAS
Pl3K
RAF
BRAF
AKT
MEK
mTOR
ERK
ONCOGENESIS
ANGIOGENESIS
TUMOR MICROENVIRONMENT
*aflibercept also targets PIGF
EGFR, epidermal growth factor receptor; PDGFR, platelet-derived growth factor
receptor;
VEGFR, vascular endothelial growth factor receptor.
Krasinskas et al, 2011; Sitohy et al, 2012; Bendardaf et al, 2008; Kitadai et al,
2006; Jayson et al, 2005; FDA News Release.
11 FDA Approved Drugs for Colorectal Cancer
“Cytotoxics”
1. 5-Fluorouracil (5-FU)
2. capecitabine
3. TAS-102
4. irinotecan
5. oxaliplatin
Mechanism
-> pyrimidine analog
-> oral 5-FU pro-drug
-> 5-FU drug with metabolism inhibitor
-> topoisomerase I inhibitor
-> 3rd generation platinum
“Biologics/Targeted”
1. cetuximab
2. panitumumab
3. bevacizumab
4. ziv-aflibercept
5. regorafenib
6. ramucirumab
Mechanism
-> antibody against EGFR
-> antibody against EGFR
-> antibody against VEGF
-> VEGF trap
-> tyrosine kinase inhibitor
-> antibody against VEGFR2
VEGF= Vascular Endothelial Growth Factor
EGFR= Epidermal Growth Factor Receptor
Colorectal Cancer is Expensive
•
•
•
•
•
•
•
•
•
•
5-FU (500 mg/m2)
Leucovorin (500 mg/m2)
Capecitabine (2000 mg/m2/day)
Irinotecan (180 mg/m2) / generic
Oxaliplatin (85 mg/m2) / generic
Bevacizumab (5 mg/kg)
Cetuximab (250 mg/m2)
Panitumumab (6 mg/kg)
Aflibercept (4 mg/kg)
Regorafenib (160 mg, 3/1)
$6
$85
$3,250
$2,300 / $480
$4,190 / $590
$2,560
$5,120
$4,360
$5,380
$5,650
1997: 6 months of 5-FU/LV costs ~$500
2016: 35 months of therapy with combinations costs >$425,000
Recent “progress” in colorectal cancer
Progression-Free
Survival 1.9 vs. 1.7
months
Grothey et al. 2012 GI Cancers Symposium (LBA385)
Current Cancer Treatment Strategy:
One-size-fits-all
Where are we going?
The future of Colorectal Cancer Therapy
BRAF inhibition in Melanoma
BRAF Inhibition in Melanoma
Wagle et al. J Clin Oncol. 2011.
BRAF Inhibition in Melanoma
Wagle et al. J Clin Oncol. 2011.
Cancer signaling is complex!
Vigil
etet
al.al.Nature
2010.
Vigil
NatureRev
Rev Cancer
Cancer 2010.
Advances in Understanding the Genetic
Landscape of Cancer
• On average, there are
~70 genes mutated per
cancer
• However, < 20
pathways will actually
drive cancer
development
• Most mutations are
harmless
Wood et al. Science 2007.
Roadmap of Precision Oncology
Wnt is upregulated in MEK-resistant CRC cell lines
Spreafico et al. Clin Can Res 2013.
Targeting MEK and WNT Inhibits Growth in a
KRAS Mutant CRC PDX
Spreafico et al. Clin Can Res 2013.
Immunotherapy 101
Hallmarks of Cancer
http://www.researchcancerimmunotherapy.com/images/overview/
evading-immune-destruction/hallmark-cancer.png
Types of Immune Therapy
Cytokine
Therapy
eg. IL-2, IFN
Immune
Checkpoint Blockade
eg. CTLA-4, PD1
Vaccine Therapies
eg. sipuleucel-T
PD-1 and PD-L1 Function as Immune Checkpoints:
Prevents Activation
http://directorsblog.nih.gov/2015/06/09/a-surprisingmatch-cancer-immunotherapy-and-mismatch-repair/
Number of mutations vary by cancer
Alexandrov et al. Nature 2013; 500(1).
Clinical Activity of Anti-PD-1 Therapy:
Melanoma
Baseline: April 13, 2012
April 9, 2013
72-yr-old male with symptomatic progression after bio-chemotherapy, HD IL-2, and ipilimumab
UCLA Health. Reproduced with permission.
Clinical Activity of Anti-PD-1 Therapy:
Lung Cancer
http://www.cancerresearch.org/CRI/media/Content/Strategy%20a
nd%20Impact/Timeline/2012-anti-PD-1-lung-cancerresponse.jpg?width=697&height=402&ext=.jpg
Microsatellite Unstable CRC
MSI-high CRC
The Importance of Mismatch Repair
Wakamatsu et al. J Bio Chem 2010;285: 9762-9769
MSI-high tumors have more mutations
What about immunotherapy for microsatellite
stable colorectal cancer?
Clinical activity and safety of cobimetinib and
atezolizumab in colorectal cancer
Johanna Bendell,1 Tae Won Kim,2 Boon Cher Goh,3 Jeffrey Wallin,4 Do-Youn Oh,5 Sae-Won Han,5
Carrie Lee,6 Matthew D. Hellmann,7 Jayesh Desai,8 Jeremy Lewin,9 Benjamin J. Solomon,10 Laura Q.
Chow,11 Wilson H. Miller Jr,12 Justin Gainor,13 Keith Flaherty,13 Jeffrey Infante,1 Meghna Das Thakur,4
Paul Foster,4 Edward Cha,4 Yung-Jue Bang5
1Sarah
Cannon Research Institute/Tennessee Oncology, Nashville, TN; 2Asan Medical Center, Seoul, South Korea; 3Cancer
Science Institute of Singapore, National University of Singapore, Singapore; 4Genentech, Inc., South San Francisco, CA; 5Seoul
National University Hospital, Seoul, South Korea; 6UNC Lineberger Comprehensive Cancer Center, University of North Carolina –
Chapel Hill, North Carolina; 7Memorial Sloan Kettering Cancer Center, New York, NY; 8Royal Melbourne Hospital, University of
Melbourne, Melbourne, VIC, Australia; 9Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada; 10Peter
MacCallum Cancer Center, Melbourne, VIC, Australia; 11University of Washington, Seattle, WA; 12Segal Cancer Center and Jewish
General Hospital, McGill University, Montreal, QC, Canada; 13Massachusetts General Hospital, Boston, MA
Bendell J, et al. Cobimetinib and atezolizumab in CRC. ASCO 2016
PD-L1 and MEK Inhibition: A Rational Combination
• MEK inhibition alone can result in intratumoral T-cell accumulation and MHC I upregulation, and
synergizes with an anti-PDL1 agent to promote durable tumor regression1
Class I MHC
CD8+ T cell
per tumor cell
Tumor volume (mm3)
P = 0.0024
Control
Anti-PDL1
MEKi (38963)
MEKi + anti-PDL1
ND
MEKi
ND
MEKi
Day
• To examine the possible benefits of MEK inhibition with an anti-PDL1 agent, we evaluated cobimetinib
+ atezolizumab in patients with advanced solid tumors
MHC, major histocompatibility complex; ND, no drug (vehicle alone).
CT26 (KRASmt) CRC models. 1. Ebert et al. Immunity 2016.
65
Bendell J, et al. Cobimetinib and atezolizumab in CRC. ASCO 2016
Maximum SLD Reduction
From Baseline, %
Efficacy: Change in Tumor Burden
50
40
PD PD
PD PD
20
0
-20
TC3
PD PD
PD
PD-L1 IC status
PD
NA
PD
IC0
PD PD SD
SD SD PD SD SD PR PR PR PR
IC1
IC2
IC3
-40
TC
TC TC TC
0
0 NA 0
-60
-80
•
•
4 patients had partial responses (confirmed per RECIST v1.1)
•
Tumor volume reduction was not associated with PD-L1 status: TC3 (n = 1; PD), TC0 (n = 18), NA (n = 4)
MSI status of CRC patients was examined by NGS-based scoring: 3 of 4 responders were mismatch-repair
proficient (not MSI-H); 1 responder had unknown MSI status and was not evaluable
PD-L1 IHC status on tumor cells (TC) and tumor-infiltrating immune cells (IC) defined as: TC3 = TC ≥ 50% PD-L1+ cells; IC3 = IC ≥ 10% PD-L1+ cells; TC2 = TC ≥ 5% and < 50% PD-L1+
cells; IC2 = IC ≥ 5% and < 10% PD-L1+ cells; TC1 = TC ≥ 1% and < 5% PD-L1+ cells; IC1 = IC ≥ 1% and < 5% PD-L1+ cells; TC0 = TC < 1% PD-L1+ cells; IC0 = IC < 1% PD-L1+ cells.
NA, not available; NGS, next generation sequencing. Efficacy-evaluable patients. 2 patients missing or unevaluable are not included. Data cut-off February 12, 2016.
66
Bendell J, et al. Cobimetinib and atezolizumab in CRC. ASCO 2016
Efficacy: Change in Tumor Burden Over Time
Change in Sum of Longest Diameters
from Baseline, %
PD
SD
PR/CRa
Discontinued atezolizumab
New lesion
•
Median duration of response
was not reached (range: 5.4 to
11.1+ mo)
•
Responses are ongoing in 2 of 4
responding patients
Time on Study (mo)
aConfirmed
per RECIST v1.1. CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
Efficacy-evaluable patients. 2 patients missing or unevaluable are not included. Data cut-off February 12, 2016.
67
Bendell J, et al. Cobimetinib and atezolizumab in CRC. ASCO 2016
There are many
checkpoints that
regulate immune
responses!
Pardoll DM. Nat Rev Can 2012;12.
Wrap-Up
• Treatment for colorectal cancer has improved dramatically
– Unprecedented progress in the last decade
• Targeted therapies and immunotherapies will change the
way we treat colorectal cancer in the future
– Finding targets to give the right drugs to the right patients
• Research being performed across the world will change
the way we think about and treat colorectal cancer
Questions