ASCO Review 2016 Colorectal Cancer

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Updates in Colorectal Cancer
2016
Kristen K. Ciombor, MD, MSCI
Assistant Professor
Division of Medical Oncology

Outline
§ Primary tumor sidedness in colorectal cancer
§  CALGB/SWOG 80405
§ Immunotherapy in colorectal and anal cancer
§  Immunoscore in early stage colon cancer
§  Pembrolizumab in MSI-H mCRC
§  Nivolumab +/- ipilimumab in mCRC
§  Cobimetinib + atezolizumab in MSS mCRC
§  Nivolumab in metastatic anal cancer
2

Primary Tumor
Sidedness in
Colorectal
Cancer (CRC)
3

Impact of primary tumor location on
Overall Survival and Progression Free Survival
in patients with metastatic colorectal cancer:
Analysis of CALGB/SWOG 80405 (Alliance)
A Venook, D Niedzwiecki, F Innocenti, B Fruth, C Greene, BH O’Neil,
J Shaw, J Atkins, LE Horvath, B Polite, JA Meyerhardt, EM O’Reilly,
R Goldberg, HS Hochster, CD Blanke, R Schilsky, RJ Mayer, M Bertagnolli,
HJ Lenz for SWOG and the ALLIANCE

CALGB/SWOG 80405
Chemo + Cetuximab
Chemo + Bevacizumab
1ST LINE
MET / ADVANCED
COLORECTAL
KRAS wt
FOLFIRI
or
FOLFOX
MD choice
ASCO, JUNE, 2014 Chemo + Cetuximab
OS = 32.0 mos
PFS = 11.4 mos
Chemo + Bevacizumab
OS = 31.2 mos
PFS = 11.3 mosN = 1137
CONCLUSION: NO DIFFERENCE
OS better than anticipated in both arms:
Treatment effect and/or Patient selection
All RAS wt
ESMO, SEP, 2014
N = 526

CALGB 80405: Side of primary tumor
Methods
•  Population
–  KRAS wt pts in main analysis
–  Pre-amendment KRAS mut pts
•  Data extraction
–  Study chart, other supporting information if available
•  Side of 1° determination
–  Definitive information:
•  Colonoscopy, surgical or imaging report
Presented by:

Presented by:
80405: Side of Primary Tumors
LEFT
N = 732
(68%)
RIGHT
N = 293
(27%)
TRANSVERSE N = 66
COULD NOT
DETERMINE
N = 46

Bettington, et al. Histopathology. 2013.
Embryology: The origin of the colon
RIGHT COLON
LEFT COLON

80405: Overall Survival by Sidedness
Presented by:
Side N (Events)
Median
(95% CI)
HR
(95% CI)
p
Left 732 (550)
33.3
(31.4-35.7) 1.55
(1.32-1.82)
< 0.0001
Right 293 (242)
19.4
(16.7-23.6)
Right
Left

80405: OS by Sidedness (Bevacizumab)
Presented by:
Side N (Events)
Median
(95% CI)
HR(95% CI) p
Left 356 (280)
31.4
(28.3-33.6)
1.32
(1.05-1.65)

0.01

Right 150 (121)
24.2
(17.9-30.3)
LeftRight

80405: OS by Sidedness (Cetuximab)
Presented by:
Side N (Events)
Median
(95% CI)
HR
(95% CI)
p
Left 376 (270)
36.0
(32.6-40.3)
1.87
(1.48-2.32)

<0.0001

Right 143 (121)
16.7
(13.1-19.4)
Left
Right

80405: Sidedness is Prognostic
Overall Survival (OS)
Presented by:
KRAS wt
N = 1025
Right 1°
Median OS
(mos)
Left 1°
Median OS
(mos)
Hazard Ratio
95% CI
(adjusted*)
P (adjusted*)
All pts 19.4 33.3 1.55 (1.32,1.82) P < 0.0001
Cet 16.7 36.0 1.87 (1.48, 2.32) P < 0.0001
Bev 24.2 31.4 1.32 (1.05, 1.65) P = 0.01
*Adjusted for biologic, protocol chemotherapy, prior adjuvant therapy, prior RT, age, sex,
synchronous disease, in place primary, liver metastases
19.3 MONTHS IS A BIG DIFFERENCE !!

80405: Overall Survival by Sidedness and Biologic
Presented by:
31.4 (28.3-33.6)
36.0 (32.6-40.3)
24.2 (17.9-30.3)
16.7 (13.1-19.4)

Summary of Primary Tumor Sidedness in mCRC
§ Patients with R-sided primaries had much worse
outcomes than pts with L-sided primaries,
independent of biologic arm (prognostic)
§ 1st line cetuximab and bevacizumab have different
treatment effects in sidedness subgroups
§ Sidedness is likely a surrogate for tumor biology
§ Future trials to stratify patients by primary sidedness
§ Remember: this is a retrospective ad hoc analysis;
these results will factor in when making tx decisions
but this is not the whole story
14

Immunoscore in
Early Stage
Colon Cancer
15

Presented By Jerome Galon at 2016 ASCO Annual Meeting

Summary of Immunoscore in Early Stage Colon CA
§ Time to recurrence was significantly longer in patients
with stage I/II/III colon cancer and high immunoscore
§ Immunoscore is significant in multivariate analyses in all
cohorts (TS, IVS, EVS)
§ Potential identification of a high-risk stage II group
§ Immunoscore predicts TTR, DFS and OS
§ How much is microsatellite instability contributing?
§ Future immune-based assay for cancer: TNM-Immune?
22

Pembrolizumab
in MSI-H mCRC
23

Presented By Dung Le at 2016 ASCO Annual Meeting

Summary of Pembrolizumab in MSI-H mCRC
§ PD-1 blockade with pembrolizumab is highly active
in dMMR mCRC
§ Complete and durable responses are seen in >50%
of patients
§ 18% have reached the two year mark on tx and
patients are under surveillance
§ Next/current trials: single agent pembrolizumab in 1st
line MSI-H mCRC, adjuvant trial, pembro + FOLFOX
32

Nivolumab +/-
Ipilimumab in
mCRC
33

Nivolumab ± Ipilimumab in Treatment of Patients With Metastatic Colorectal Cancer With and Without High Microsatellite Instability: CheckMate 142 Interim Results
Presented By Michael Overman at 2016 ASCO Annual Meeting

Ipilimumab and Nivolumab Mechanisms of Action

Phase 2 CheckMate 142 Study Design: Microsatellite Stable (MSS) Cohort

Phase 2 CheckMate 142 Study Design: MSI-H Cohort

Investigator-Assessed Best Overall Response in Patients With MSI-H Receiving Nivolumab Monotherapy

Investigator-Assessed Best Overall Response in Patients With MSI-H Receiving Nivolumab + Ipilimumab

Best Reduction in Target Lesion Size in Patients With MSI-H

OS in Patients With MSI-H Nivolumab ± Ipilimumab in Metastatic CRC

Treatment-Related Adverse Events in ≥ 15% of Patients With MSI-H

Summary of Efficacy in Patients With MSS Nivolumab ± Ipilimumab in Metastatic CRC

Summary of Nivo +/- Ipi in mCRC
§ Nivolumab monotherapy and nivo + ipi showed
encouraging activity in MSI-H mCRC (interim analysis)
§ Responses were durable in MSI-H patients
§ Tolerable safety profiles but increasing toxicities with
combination therapy, consistent w/ observations in
other solid tumors
§ Need final analysis prior to next trials
44

Cobimetinib +
Atezolizumab in
MSS mCRC
45

Clinical activity and safety of cobimetinib and atezolizumab in colorectal cancer
Presented By Johanna Bendell at 2016 ASCO Annual Meeting

Atezolizumab: An Anti-PDL1 Antibody

PD-L1 and MEK Inhibition: A Rational Combination

Phase Ib Dose Escalation and Cohort Expansion Study (NCT01988896)

Safety Summary

Safety: Treatment-related AEs

Efficacy: Confirmed Objective Response

Efficacy: Change in Tumor Burden

Efficacy: Duration of Treatment and Response

Summary of Cobi + Atezo in MSS mCRC
§ Cobimetinib + atezolizumab was fairly tolerated in
pts with refractory MSS mCRC
§ Combination therapy resulted in higher clinical
response rate (17%) and 6-month OS (72%) than
expected with either agent alone
§ Cobi may sensitize tumors to atezo by increasing
MHC I expression on tumor cells, promoting
intratumoral CD8 T cell accumulation
§ Next/current trial: Phase Ib expansion and phase III
trial both ongoing
56

Nivolumab in
Metastatic Anal
Cancer
57

NCI9673: A Multi-Institutional ETCTN
Phase II Study of Nivolumab in Refractory
Metastatic Squamous Cell Carcinoma of
the Anal Canal (SCCA)
V. Morris1, K. Ciombor2, M.E. Salem3, H. Nimeiri4, S. Iqbal5, P. Singh6, B. Polite7,
D. Deming8, E. Chan9, J.L. Wade10, T.S. Bekaii-Saab2, H.E. Uronis11, M.G. Pasia1, G. Bland1,
R.A. Wolff1, A. Ohinata1, C. Ohaji1, J.E. Rogers1, P. Sharma1, C. Eng1
1The University of Texas MD Anderson Cancer Center, Houston, TX; 2The Ohio State University Comprehensive Cancer Center,
Arthur G. James Cancer Hospital, Columbus, OH; 3Lombardi Comprehensive Cancer Center, Georgetown University, Washington,
DC; 4Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; 5University of Southern California/
Norris Comprehensive Cancer Center, Los Angeles, CA; 6Washington University, Siteman Cancer Center, St. Louis, MO; 7The
University of Chicago, Chicago, IL; 8University of Wisconsin Hospitals and Clinics, Madison, WI; 9Vanderbilt University Medical
Center, Nashville, TN; 10Cancer Care Center of Decatur, Decatur, IL; 11Duke University Medical Center, Durham, NC

•  Approximately 80-95% of cases
are linked to infection with human
papillomavirus (HPV).
•  The role of HPV in the
tumorigenesis of SCCA provides
rationale for the use of immune
checkpoint blockade agents as a
novel therapy for treatment of
patients with a virally driven
disease.
Presented by: Cathy Eng, MD
Rationale for Nivolumab in Metastatic SCCA:
Morris VK et al. The Oncologist, 2015, Sarup-Hansen E et al. J Clin Oncol ,2014

NCI#9673: Phase II Design of Nivolumab in Metastatic SCCA
Patients with metastatic squamous cell carcinoma of the anal canal
- Treated with at least one prior therapy for metastatic disease
- No prior immune therapies received as part of cancer treatment
12 patients treated initially with nivolumab
3mg/kg IV every 2 weeks
Patients will be followed for best response
using RECIST criteria 1.1
0 responses ≥1 response
Stop trial
Expand trial to include 25
additional patients with
metastatic SCCA
* HIV+ patients allowed
•  Rapid enrollment in < 6 months
•  Closed to enrollment as of 11/01/15
•  Simon Optimal, two-
stage phase II study,
Ho: p ≤ 0.05 and an
alternative hypothesis
Ha: p ≥ 0.20,
•  α = 0.10 and a β = 0.10

Primary Endpoint: Response Rate
Response Rate N (%)
CR 2 (5.4%)
PR 7 (18.9%)
SD 17 (45.9%)
PD 8 (21.6%)
Unevaluable 3 (8.1%)
ORR (ITT, N=37) 9 (24.3%)
ORR (Evaluable,
N=34) 9 (26.5%)
Data cutoff date: 5/15/16

-1 0 0
-9 0
-8 0
-7 0
-6 0
-5 0
-4 0
-3 0
-2 0
-1 0
0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
8 0
9 0
1 0 0
P a tie n t
%targetlesionreduction
frombaselinebyRECIST1.1
P ro g re s s iv e D is e a s e
S ta b le D is e a s e
P a rtia l R e s p o n s e
P R
P D
NCI#9673: Response Rate
N=37 (ITT)
N=34 (evaluable
for RR)
2 CR’s
7 PR’s
Patients
CR

NCI#9673 Toxicities of Therapy
Toxicity (N=37) Grade (%)
1 2 3 4
Fatigue 17 (46) 7 (19) 1 (3) -
Anemia 13 (35) 11 (30) 2 (5) -
Rash 8 (22) 2 (5) 1 (3) -
Constipation 8 (22) 2 (5) - -
Diarrhea 8 (22) - - -
Anorexia 5 (14) 4 (11) - -
Weight loss 5 (14) 1 (3) - -
Arthralgia 3 (8) 3 (8) - -
Hyperglycemia 3 (8) 1 (3) - -
Lymphedema 1 (3) 1 (3) - -
Pneumonitis - 1 (3) - -
Nausea 2 (5) - - -
Hypothyroidism 1 (3) 1 (3) 1 (3) -

Summary of Nivolumab in Anal Cancer
§ First prospective phase II trial completed in refractory
mSCC of anal canal; <6 month accrual
§ Encouraging response rates in a “rare” cancer with
few treatment options for metastatic disease
§ Nivolumab was well tolerated, even in HIV+ patients
§ Future trial: amendment of NCI 9673—pilot of
nivolumab + ipilimumab
64

Thank You
To learn more about Ohio State’s cancer
program, please visit cancer.osu.edu or
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65

ASCO Review 2016 Colorectal Cancer

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