Metastatic Colorectal Cancer Treatment Platform Algorithm in 2017

Mohamed Abdulla M.D.Prof. of Clinical Oncology

Head of Gastrointestinal Malignancies UnitCairo University

KIOW 3rd EditionKhartoum – Corinthia Hotel25/11/2017

Member of Advisory Board, Consultant, and Speaker for:

• Amgen, Astellas, AstraZeneca, Hoffman la Roche, Janssen Cilag, Merck Serono, Novartis, Pfizer, Mundipharma, MSD, Ely Lilly.

• This Presentation does not relate to any pharmaceutical of commercial interest.

Speaker Disclosures:

Colon Cancer:Basic Facts & Figures:• 2nd & 3rd most common cancers in females and males.

• 9% of cancer related deaths.

• 90% occurring around the age of 40 – 50 years.

• OAS for entire patients = 65%.

• Metastatic disease: 5-year OAS = 10%.

• Organ limited metastatic disease (Metastatectomy):

5-year OAS > 40%

• Median survival of metastatic disease > 35 months.

• Improved OAS with exposure to all available drugs.

• Unified global treatment algorhytm is still controversial.

uptodate.com Accessed 01/11/2017

Egypt Demographics:

Gender Lower Egypt2009 - 2011

Middle Egypt2009

Upper Egypt2008

Males 2.9% 2.1% 2.48%

Females 2.3% 2.3% 2.08%

Incidence Rates/100000 Population: Colon Cancer

Year 2013 2015 2020 2025 2050

Number 2862 3055 3608 4465 8585

Estimated Number of New Cases Over Time:

Ibrahim et al. Journal of Cancer Epidemiology. Volume 2014, Article ID 437971, 18 pages

Median OSMonths

1980s 1990s 2000s

BSC 5-FUIrinotecan1

Capecitabine2

Oxaliplatin3

Bevacizumab4

Cetuximab5,6

Panitumumab7 Aflibercept8

Regorafenib9

30

25

20

15

10

5

0

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):3499-3506. 9. Grothey A, et al. Lancet. 2013;381(9863):303-312.

mCRC: Improved Survival Over Time:

Choice of Systemic Therapy:Old Dogma:

5-Fu/LV

Capecitabine

OxaliplatinIrinotecan

Bevacizumab

CetuximabPanitumumab

AfliberceptRegrafinib

Ramucirumab

TAS 102

Survival Improvement

Can We Do Better?

• Patient Stratification• MDT• Predictive Markers K-RAS Assessment All RAS

Assessment SEQUENCE SMART & STRATEGIC• Tumor Location & Biology Different Behavior & Outcome • Role of Immunotherapy

1. Patient Stratification:mCRC

Oligometastatic

Symptomatic Asymptomatic

Progressive Metastatic

Cure 1. Symptom Relief2. Extension of QoL

1. R.R.2. Shrinkage

Predictive Markers

IntensiveEffectiveToxicity

Well ToleratedSurvival ++

King GT et al. THE AMERICAN JOURNAL OF HEMATOLOGY/ONCOLOGY. VOL. 12, NO. 10. OCTOBER 2016

2. MDT: A Mandatory Practice

Munro et al. BMC Cancer (2015) 15:686

MDT: A Mandatory Practice

3. Predictive Biomarkers:Daily Treatment Scenarios: Exposure:

• Advancing Cancer Chronic Disease.

• Survival All Active Agents.

• Sequence isn’t important

Sequence:

• Predictive Markers

• Upfront Massive Attack.

• Late still wining cards

Khattak et al. Clinical Colorectal Cancer, Vol. 14, No. 2, 81-90 a 2015

Survival Advantage is Modest in 2nd & 3 Lines

Don’t Lose The Most Active Agent out of 1st Line

Parameter 1st Line 2nd Line 3rd Line

OOR (%) 38 - 69 10 - 41 1 - 22

PFS (ms) 9 - 13 4 - 9 2 - 4

First Head-to-Head Comparisons of First-Line Bevacizumab Versus EGFR Inhibitors in KRAS WTmCRC

1. Schwartzberg LS, et al. J Clin Oncol. 2014;32(21):2240-2247. 2. Heinemann V, et al. Lancet Oncol. 2014;15(10):1065-1075.3. Venook A, et al. J Clin Oncol. 2014;32(Suppl): Abstract LBA3.

PEAK1

Phase II

Untreated –Unresectable mCRC

N = 285

Bevacizumab + mFOLFOX6

Panitumumab + mFOLFOX6

FIRE-32

Phase III

Untreated mCRC

N = 592

Bevacizumab + FOLFIRI

Cetuximab + FOLFIRI

CALGB-804053

Phase III

Untreated mCRC

N = 1200

Bevacizumab +

FOLFIRI or FOLFOX

Cetuximab

+ FOLFIRI or FOLFOX

No Hypothesis

OAS

ORR

DP

FIRE-3 Trial: FOLFIRI + Either Cetuximab orBevacizumab in KRAS WT mCRC

Heinemann V, et al. Lancet Oncol. 2014;15(10):1065-1075.

HR 0.77P .011

Parameter Chemo + CET Chemo + Bev P

ORR (%) 62 58 .183

PFS (ms) 10 10.3 .547

OAS Dif. = 8.5 ms

Anti-EGFR or Anti-VEGF/R in RAS-Wild mCRC: Evidence from Literature:

Modest et al. J Clin Oncol 33. © 2015 by American Society of Clinical Oncology

CALGB 80405: OAS

Alan P. Venook, MD et al. JAMA June 20, 2017 Volume 317, Number 23

80405: (KRAS WT) Overall Survival by Sidedness

Presented by:ASCO ANNUAL MEETING ‘16

SideN

(Events)

Median

(95% CI)

HR

(95% CI)p

Left 732 (550)33.3

(31.4-35.7) 1.55

(1.32-1.82)

<

0.0001Right 293 (242)

19.4

(16.7-23.6)

Petrelli et al. Jama Oncology. 2017 Vol 3 Number 2

66 RCT = 1437846 Colon Cancer Patients

Location as an Independent Prognostic Factor:

Right versus Left Colon:Why different disease entities?

Different:• Blood Supply• LN Drainage

1. Embryologic Origin2. Blood Supply & Nodal Drainage

3. Microbiome Difference

4. Precancerous Lesions.

6. Histopathology & Natural History

5. Consensus Molecular Subtypes.

Stintzing et al. European Journal of Cancer 84 (2017) 69e80

3. Microbiome Difference:

Right Colon Cancer Left Colon Cancer

Prevotella, Pyramido-bacterium, Selenomonas and Peptostreptococcus.

Fusobacterium, Escherichia-Shigellaand Leptotrichia

Escherichia coli phylogroup B2. Helicobacter pylori infection

Dense Bacterial Aggregates

1. E-Cadherin2. IL-63. STAT3

Cellular Proliferation

Invasion of Colonic Mucous LayerProinflammatory Genes

Flemer et al. Tumour-associated and non-tumour- associated microbiota in colorectal cancer. Gut 2017;66(4): 633e43.

4. Pre-Neoplastic Lesions:

Lee et al. JNCCN—Journal of the National Comprehensive Cancer Network. Volume 15 Number 3. March 2017

Lee et al. JNCCN—Journal of the National Comprehensive Cancer Network. Volume 15 Number 3. March 2017

Molecular Alterations in CRC:

Molecular Alterations in CRC:

Stintzing et al. European Journal of Cancer 84 (2017) 69e80

Molecular Alterations in CRC:

Stintzing et al. European Journal of Cancer 84 (2017) 69e80

5. Consensus Molecular Subtypes (CMS):

RIG

HT

CO

LON

LEFT

CO

LON

BETTER OUTCOME

WORSE OUTCOME

Guinney et al. Nature Medicine. 21,1350-1356 (2015)Lee et al. JNCCN—Journal of the National Comprehensive Cancer Network. Volume 15 Number 3. March 2017.

Right Versus Left Sided Colon Cancer OAS & Anti-EGFR:

Jhonathan et al. Ther Adv Med Oncol 2017, Vol. 9(8) 551–564

Jhonathan et al. Ther Adv Med Oncol 2017, Vol. 9(8) 551–564

Right Versus Left Sided Colon Cancer PFS & Anti-EGFR:

mCRC: “Different Goals on Subsequent Treatments”

Vogel et al. Cancer Treatment Reviews 59 (2017) 54–60

Treatment Goals

“Maintain QoL Across Treatment Journey”

1st & 2nd

Subsequent Therapies

OAS ORR Shrinkage

3rd Line

PFS

First Line Options

Combination Therapy

Second Line Options

Combination Therapy

Third Line Options

Good PS & Sypmt. Monotherapy or Re-challenge

Poor PS or Asympt. BSC

Beyond combination therapy in first and second line – A heterogeneous situation

(5-Fu/Leucovorin or Cape) +/- Oxaliplatin+/- Irinotecan +/- Anti-EGFR or VEGF/R

Chemo or Anti-EGFR

Vogel et al. Cancer Treatment Reviews 59 (2017) 54–60

2nd Line & Beyond Treatment Options:Basic Principles:

Previously Received Treatment & Clinico-Molecular Pattern

Change the Backbone of Chemotherapy

Beyond progression Same Biologic (TML, E3200, SPIRIT)

2nd Line Approved Biologics (Aflibercept & Ramucirumab) + Chemotherapy

Clinical Trial & BSC

VEGF/R Directed Therapy in 2nd L or Later

Second-

line

VEGF

Last-line

multi VEGF TKI

TML18147 E3200 VELOUR RAISE CORRECT

BEV in First-line All patients No patients Yes / No All patientsAll patients

(+ EGFR,

if KRAS wildtype)

2nd

Line

CTh

FOLFRI or

FOLFOX FOLFOX FOLFIRI FOLFIRI Last line BSC

VEGF inhibitor Bevacizumab Bevacizumab Aflibercept Ramucirumab Regorafenib

OS11.2 v 9.8 mo

HR 0.81

P = .0062

12.9 v 10.8 mo

HR 0.75

P = .0011

13.5 v 12.1 mo

HR 0.82

P = .003

11.7 vs. 13.3 mo

HR 0.84

P = .022

6.4 vs. 5.0 mo

HR 0.77

P = .0052

Bennouna J, et al. Lancet Oncol. 2013;14(1):29-37. Giantonio BJ, et al. J Clin Oncol. 2007;25(12):1539-

1544. Van Cutsem E, et al. J Clin Oncol.

2012;30(28):3499-3506. Tabernero J, et al. Lancet Oncol. 2015;16(5):499-508. Grothey A, et al. Lancet.

2013;381:303-312.

1st Line 2nd Line 3rd Line

3rd Line Treatment Options:

Previous Treatment

& PS

Irinotecan +

Anti-EGFR

Anti-EGFR

TAS 102

Regorafinib

BSC

Clinical Trial

Vogel et al. Cancer Treatment Reviews 59 (2017) 54–60

Factors Affecting Treatment Selection in 3L of mCRC:• Patient-related factors (e.g. comorbidities) as

well as patient preferences and motivation, which becomes more important in this setting

• Disease-related factors (e.g. molecular characteristics, tumor- related symptoms, growth dynamics and manifestation)

• Treatment-related factors (e.g. availability, toxicity and safety profile)

• Prior treatment toxicity, efficacy and characteristics (e.g. discontinuation before progression) of combination chemotherapies

Vogel et al. Cancer Treatment Reviews 59 (2017) 54–60

3rd Line Data:

Vogel et al. Cancer Treatment Reviews 59 (2017) 54–60

Treatment Platform:

Jhonathan et al. Ther Adv Med Oncol 2017, Vol. 9(8) 551–564

Basic Unites of Tumorigenesis:

• Microsatellites: Repetitive genetic units Maintained by MMR system (5 Genes).

• Deficient MMR MSI Genomic Instability Tumor formation.

• MSI:

– H: instability in > 30% of microsatellite loci.

– L: instability in < 30% of microsatellite loci.

E. Vilar, J. Tabernero, Molecular dissection of microsatellite instable colorectal cancer, Cancer Discov. 3 (5) (2013) 502e511.

Slide 4

Presented By Luis Diaz at 2017 Gastrointestinal Cancers SymposiumAs Presented by Luis Diaz M.D. in 2017 ASCO Gastrointestinal Cancers Symposium.

Features of MSI-H Tumors:

1. More right sided tumor locations.

2. More undifferentiated tumors.

3. More mucoid activity.

4. More lymphovascular invasion.

5. More T-Lymphocyte Infiltration.

6. More BRAF mutations

7. LESS METASTATIC POTENTIAL.

Schwitalle Y, Kloor M, Eiermann S, Linnebacher M, Kienle P, Knaebel HP, Tariverdian M, Benner A, von Knebel Doeberitz M. Gastroenterology. 2008;134(4):988.

Role of Anti-PD-1 Therapy in mCRC:

Nivolumab in Patients With DNA Mismatch Repair Deficient/Microsatellite Instability High Metastatic Colorectal Cancer: Update From CheckMate 142

Presented By Luis Diaz at 2017 Gastrointestinal Cancers Symposium

Slide 18

Presented By Luis Diaz at 2017 Gastrointestinal Cancers Symposium

Best Reduction in Target Lesion Size <br />in Patients With MSI-H

Presented By Luis Diaz at 2017 Gastrointestinal Cancers Symposium

The Art of Today:

• The landscape of treating mCRC is expanding.

• Proper stratification & MDT implementation are pre-requisites of effective therapeutic approach.

• Molecular subtyping and location are the most crucial factors in deciding treatment algorithm.

• More options are readily available for treatment beyond first line.

• Immunotherapy knowledge curve is steeply rising 1st line treatment option.