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

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Primary Tumor Sidedness in Colorectal Cancer (CRC)

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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 mos N = 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:


(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)

Left Right

80405: OS by Sidedness (Cetuximab)

Presented by:


(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

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Immunoscore in Early Stage Colon Cancer

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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?

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Pembrolizumab in MSI-H mCRC

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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

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Nivolumab +/- Ipilimumab in mCRC

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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

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Cobimetinib + Atezolizumab in MSS mCRC

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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

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Nivolumab in Metastatic Anal Cancer

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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

01 02 03 04 05 06 07 08 09 0

1 0 0

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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

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ASCO Review 2016 Colorectal Cancer

Healthcare

Transcript of ASCO Review 2016 Colorectal Cancer