Juan Manuel O’Connor, MD

State of the Art:

Colorectal Cancer (CRC)

Objectives

• Review current approaches for the

management and treatment of CRC

• Discuss current challenges/unmet needs in

the treatment

of mCRC

• Review emerging data in the treatment of

mCRC, particularly with anti-angiogenic

therapy

Table of Contents

• Epidemiology

• Treatment of early and metastatic

CRC

– First-, second-, and third-line treatment in

mCRC

– Anti-EGFR and anti-VEGF therapies

• Limited therapeutic options in the

treatment of patients who failed all

standard therapies

• Emerging data in the treatment of

mCRC

Table of Contents

• Epidemiology

• Treatment of early and metastatic

CRC

– First-, second-, and third-line treatment in

mCRC

– Anti-EGFR and anti-VEGF therapies

• Limited therapeutic options in the

treatment of patients who failed all

standard therapies

• Emerging data in the treatment of

mCRC

CRC Is the Third Most Common Cause

Cancer Worldwide1

• There are ≈1,360,000 new cases and ≈690,000 deaths per year worldwide1

• In the US:

– 134,490 new cases and 49,190 deaths in 20162

– Current trends based on data from the SEER CRC registry project that incidence rates

for colon and rectal cancers will increase by 90.0% and 124.2% by 20303

• In Mexico, Central, and South America1:

– ≈47,700 new cases and 25,700 deaths per year

1. Ferlay J et al. Int J Cancer. 2015;136:E359-386.

2. NIH National Cancer Institute Surveillance, Epidemiology, and End Results Program. SEER Stat Fact Sheets: Stomach

Cancer. [Online] http://seer.cancer.gov/statfacts/html/stomach.html [Last accessed May 2016].

3. Bailey CE et al. JAMA Surg. 2015;150:17-22.

cases % ASR

(world)

Cum.

risk

(0-74)

cases % ASR

(world)

Cum.

risk

(0-74)

cases % ASR

(world)

Cum.

risk

(0-74)

1360 9.7 17.2 2.0 746 10.0 20.6 2.4 614 9.2 14.3 1.6

Both sexes Male Female

Estimated new cases (thousands), ASRs (per 100,000) and cumulative risks to age 75 (percent) by sex1

Local Data From Argentina

CRC: Stages at Diagnosis and 5-Year

Survival

SEER, Surveillance, Epidemiology, and End Results Program, NIH/NCI.

http://seer.cancer.gov/statfacts/html/colorect.html. Accessed August 3, 2016.

Table of Contents

• Epidemiology

• Treatment of early and metastatic

CRC

– First-, second-, and third-line treatment in

mCRC

– Anti-EGFR and anti-VEGF therapies

• Limited therapeutic options in the

treatment of patients who failed all

standard therapies

• Emerging data in the treatment of

mCRC

Treatment for Stage 0, I, II, and III Colon and

Rectal Cancer (NCCN & EMSO Treatment Guidelines)

1. Labianca et al. Early colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24;Suppl 6:vi64-vi72; 2. NCCN Clinical Practice

Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.2.2016; 3. Glimelius et al. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-

up. Ann Oncol. 2013;24;Suppl 6:vi81-vi88; 4. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Rectal Cancer V.2.2016.

Stage 0 Local excision, simple

polypectomy, or segmentary

en-bloc resection

Stage II

Stage III

Surgery without adjuvant

chemotherapy

Surgery with adjuvant

FOLFOX or CapeOX,

FLOX,

Capecitabine

Or 5-FU/Leucovorin

Stage I Wide surgical resection and

anastomosis

Colon1,2 Rectal3,4

Local excision by

Total Mesorectal Excision

(TME)

Chemo-radiation

Rectal surgery

Adjuvant chemotherapy

Tri-modal Therapy:

High risk

features

Stage II Colon Cancer

• Current approach, routine care (20% overall

recurrence rate). Treatment cases with high

risk features BUT low level of evidence!

• The Goals: Precise patient selection for

adjuvant treatment. Earlier detection of

recurrence, probably improved survival

The Potential of Circulating Tumour DNA (ctDNA) to Reshape

the Design of Clinical Trials Testing Adjuvant Therapy in

Patients With Early Stage Cancers

Current Approaches to Improve the Management of

Patients With Stage II/III Rectal Cancer

• Total neoadjuvant treatment (both radiation and chemotherapy before

surgery) may help address the undertreatment issue1

• Multiple phase 2 trials show favourable results1

– High rates of clinical response and downstaging; pCR of 15%-33%; no excess

surgical complication rates

• Ongoing phase 3 trial (RAPIDO, NCT01558921)2

– CAPOX and XRT (5.5 weeks)→TME→Optional chemo vs

XRT (1 week)→XELOX (x6)→TME

• Trials testing selective use of one modality (radiation, surgery,

chemotherapy) 1. Schrag. ASCO 2015.

2. https://www.clinicaltrials.gov/ct2/show/NCT01558921?term=RAPIDO&rank=1. Accessed September 1, 2015.

Institution Patients Follow-up

m RCc

Loco-regional failure

DFS OS

Habr-Gama [4] 265 57 71(26.8%) 2/71 (2.8%) 83% (5 yr) 88% (5yr)

Habr-Gama [5] 361 60 99(27.4%) 5/99 (5%) 85% (5yr) 93% (5yr)

Habr-Gama [6] 360 NS 99(27.5%) 6/99 (6%) NS NS

Habr-Gama [7] 173 65 67 (39%) 8/173 (4.6%) 72% (5yr) 96% (5yr)

Maas et al [11] 192 35 21 (11%) 1/21 (5%) 89% (2 yr) 100% (2yr)

Dalton et al. [8] 49 26 12(24%) Bp neg (0%) -- --

Smith et al MSKCC [9]

265 28 32 (12%) 6/32 (19%) 88% (2 yr) 96% (2yr)

S Loria et al. (Argentina)

68 (all RCc) 37 All patients 9/68 (13.2%) 76.3% (5yr) 93.8% (5yr)

Sanchez Loria F et al. Dig Liver Dis. 2016, May 20. [Epub ahead of print].

Non-operative Management (NOM) in

Selected Patients With Rectal Cancer

Treatment of Resectable

Metastatic CRC

Treatment of Resectable Synchronous

Metastatic Colon Cancer (NCCN)

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.2.2016.

Treatment of Unresectable

Metastatic CRC

Approved Targeted Agents for the

Treatment of Unresectable Metastatic CRC

*Approved by FDA in April 2015; by EMA in January 2016.

Modified from Clarke & Hurwitz. J Gastrointest Oncol. 2013;4:253.

VEGFA

VEGFR-1 VEGFR-2

VEGFR-3

VEGFB

PIGF

VEFGA

VEGFC

VEGFD

VEGFC

VEGFD

ziv-Aflibercept

Bevacizumab

FGFR-1 FGFR-2

FGFR-3

PDGFR-a

PDGF FGF

PDGFR-b

EGFR

Cetuximab

Panitumumab

Regorafenib

Angiogenesis

*Ramucirumab

Migration Proliferation Survival Permeability

Table of Contents

• Epidemiology

• Treatment of early and metastatic

CRC

– First-, second-, and third-line treatment

in mCRC

– Anti-EGFR and anti-VEGF therapies

• Limited therapeutic options in the

treatment of patients who failed all

standard therapies

• Emerging data in the treatment of

mCRC

NCCN Guidelines: Recommendations for the

First-line Treatment of Metastatic CRC

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.2.2016.

CT doublet + anti-EGFR

Combination CT + bevacizumab

CT triplet + bevacizumab

CT triplet +/– bevacizumab

CT doublet + biological agent

CT doublet + bevacizumab

Continue maintenance;

or pause Continue maintenance

or pause

Second-line Second-line

Continue

Surgery alone surgery with perioperative

postoperative CT

Patients with clearly resectable metastases

FP + bevacizumab: reduced dose doublet; anti-EGFR

BSC GOAL

Assessment of clinical condition of the patient

Progressive disease Progressive

disease

Surgery

GOAL

Re-evaluation/assessment of response every 2 months Re-evaluation/assessment of response every 2-3 months

Unfit (but may be suitable) Unfit Fita

Cytoreduction (Shrinkage)** Disease Control

OMD

See

figure 2

Cytoreduction

(Shrinkage)

MOLECULAR PROFILE

Disease control (control of progression)

MOLECULAR PROFILE

RAS wt RAS mt BRAF mt RAS wt RAS mt BRAF mt

Summary of Pivotal Trials of Anti-VEGF and Anti-

EGFR Agents in the First-line Treatment of mCRC

Bevaciz, Bevacizumab; Cetux., Cetuximab, Panitum., Panitumumab; IFL, fluorouracil, irinotecan, leucovorin; CT; chemotherapy; WT, wild type; OS,

overall survival; mos, months; HR, hazard ratio; P, P-value. 1. Hurwitz et al. N Engl J Med. 2004;350:2335; 2. Van Cutsem et al. N Engl J Med. 2009;360:1408; 3. Van Cutsem et al. J Clin Oncol. 2015;33:692; 4. Douillard et al. J Clin

Oncol. 2010;28:4697; 5. Douillard et al. N Engl J Med. 2013;369:1023.

Trial Agent Treatment Control OS PFS

(mos) HR P (mos) HR P

AVF2017/A1 Bevaciz. Bevaciz. +

IFL IFL 20.3 vs 15.6 0.66 <0.001 10.6 vs 6.2 0.54 <0.001

CRYSTAL2,3 Cetux. Cetux.

+ FOLFIRI FOLFIRI

28.4 vs 20.2

(RAS WT) 0.69 0.0024 11.4 vs 8.4 0.56 <0.001

PRIME4,5 Panitum. Panitum.

+ FOLFOX4 FOLFOX4

25.8 vs 20.2*

(RAS WT) 0.77 0.009 10.8 vs 9.2 0.72 <0.004

Bold indicates primary endpoint of the clinical trial

NCCN Guidelines: Recommendations for the

Second-line Treatment of Metastatic CRC

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.2.2016.

VEGF Expression Throughout Tumour Life

Cycle1

Pre-clinical data suggest continuous VEGF suppression is key

to achieving and maintaining tumour control2

VEGF = vascular endothelial growth factor

bFGF = basic fibroblast growth factor

TGFβ-1 = transforming growth factor β-1

PD-ECGF = platelet-derived endothelial cell growth factor

Tumour evolution

VEGF

bFGF

TGFb-1

VEGF

bFGF

TGFb-1

PIGF

VEGF

bFGF

TGFb-1

PIGF

PD-ECGF

VEGF

PIGF

PD-ECGF

Pleiotrophin

bFGF

TGFb-1

VEGF

1. Folkman. Cancer: Principles and Practice of Oncology. 7th ed. 2005.

2. Bagri et al. Clin Cancer Res. 2010.

1. Folkman. Cancer: Principles and Practice of Oncology, 7th ed. 2005 2. Bagri et al. Clin Cancer Res 2010 1. Folkman. Cancer: Principles and Practice of Oncology, 7th ed. 2005

2. Bagri et al. Clin Cancer Res 2010 1. Folkman. Cancer: Principles and Practice of Oncology, 7th ed. 2005 2. Bagri et al. Clin Cancer Res 2010

Bevaciz, Bevacizumab; ziv-Aflib., ziv-Aflibercept; Ramucir., Ramucirumab; Panitum., Panitumumab; CT, chemotherapy; OS, overall survival;

PFS, progression-free survival; mos, months; HR, hazard ratio; P, P-value. 1. Bennouna et al. Lancet Oncol. 2013;14:29; 2. Van Cutsem et al. J Clin Oncol. 2012;30:3499-506;

3. Tabernero et al. Lancet Oncol. 2015;16:499; 4. Peeters et al. J Clin Oncol. 2010;28:4706;

5. Peeters et al. Ann Oncol. 2014;25:107.

Summary of Pivotal Trials of Antiangiogenic and Anti-

EGFR Agents in the Second-line Treatment of mCRC

Trial Agent Treatmen

t Contro

l

OS PFS

(mos) HR P (mos) HR P

ML18147/A1 Bevaciz.

Bevaciz. + Switch

CT

Switch CT

11.2 vs 9.8 0.81 0.0062 5.7 vs 4.1 0.68 <0.000

1

VELOUR2 ziv-Aflib.

Ziv-Aflib. + FOLFIRI

FOLFIRI

13.5 vs 12.1

0.817 0.0032 6.9 vs 4.7 0.75

8 0.001

RAISE3 Ramucir.

Ramucir. + FOLFIRI

FOLFIRI

13.3 vs 11.7

0.844 0.0219 5.7 vs 4.5 0.79

3 0.0005

200501814,5 Panitum.

Panitum. + FOLFIRI

FOLFIRI

14.5 vs

12.5 0.92 0.37 6.4 vs 3.7 0.58 0.014

Bold indicates primary endpoint of the clinical

trial

Current Management of

Third-line mCRC

NCCN Guidelines: Recommendations for the

Third-line Treatment of Metastatic CRC

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.2.2016.

*In combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy.

1. Grothey et al. Lancet Oncol. 2013;381:303; 2. Karapetis et al. N Engl J Med. 2008;359:1757;

3. Amado et al. J Clin Oncol. 2008;26:1626.

Summary of Pivotal Trials of Targeted Agent

in the Third-line Treatment of mCRC

Trial Agent Treatment Control OS PFS

CORRECT1 Regoraf.* Regorafenib

+ BSC BSC 6.4 vs 5.0 0.77 0.0052 1.9 vs 1.7 0.49 <0.001

NCIC CO.172* Cetux. Cetux. BSC 9.5 vs 4.8

(RAS WT) 0.55 <0.001 3.7 vs 1.9 0.40 <0.001

Amado et al.3 Panitum. Panitum. + BSC

BSC 8.1 vs 7.6

(RAS WT) 0.67 0.004 2.8 vs 1.7 0.45 <0.001

Anti-EGFR Therapies in the

Treatment of mCRC

The ErbB Family in CRC

ErbB = proto-oncogene B of the avian erythroblastosis virus.

1. Saletti P et al. Gastrointestinal Cancer: Targets and Therapy. 2015;5:21-38; 2. Stczen H et al. Oncotarget. 2015;6:15065-15076;

3. Kavuri SM et al. Cancer Discov. 2015;8:832-841; 4. Beji A et al. Clin Cancer Res. 2012;18:956-68;

5. Jaiswal BS et al. Cancer Cell. 2013;23:603-617; 6. Williams CS et al. Carcinogenesis, 2015;36:710-718.

EGFR (ErbB1)

• Overexpression in CRC: 35-50%1

• Overexpression is associated with poor prognosis1

HER2 (ErbB2)

• Overexpression in CRC: 18%2

• Somatic mutations and gene amplification in CRC: 7%3

ErbB3

• Overexpression in CRC: 11-21%4,5

• Overexpression is associated with worse survival4

ErbB4

• Overexpression in CRC: 17%6

• Levels of mRNA were increased at all tumour stages6

• Overexpression associated with tumourigenesis6 Adapted from Yarden and Pines 2012.1

Impaired

TKI domain

No known ligand

The Majority of mCRC Patients Are Not

Suitable for EGFR-targeted Therapies

• RAS (KRAS, NRAS) and

BRAF mutations predict lack of

response to anti-EGFR therapy1-3

• The majority of mCRC patients (≈56%)

harbour mutant KRAS/NRAS or BRAF1-4

– Only 44% of these patients are RAS and

BRAF wild type and suitable for

anti-EGFR-containing therapy

• However, even RAS- and BRAF-wt

status in CRC does not ensure

responsiveness to anti-EGFR agents,

suggesting additional determinants of

sensitivity3

1. NCCN Clinical Guidelines. V3.2015; 2. Cancer Genome Atlas Network. Nature. 2012;487:330;

3. Fakih. J Clin Oncol. 2015;33;1809-24; 4. Bettegowda et al. Sci Transl Med. 2014;6:224ra24.

Frequency of KRAS, RAS and BRAF

mutations in mCRC

Development of Treatment-related Resistance Is a Major

Issue in Patients With KRAS- and or BRAF-wt mCRC

• Emergence of RAS and BRAF mutations during

anti-EGFR treatment as mechanism of resistance1-4

– Majority of patients with RAS and BRAF WT disease

will test positive for one or more KRAS, NRAS, or

BRAF mutations in the cDNA or on repeat tumour

biopsy before or at the time of anti-EGFR resistance2

– RAS mutations seen in up to 60% of tumour samples

biopsied at the time of resistance to anti-EGFR

therapy3,4

– In a study of 24 objective responders to

anti-EGFR therapy who subsequently progressed, 23

developed a detectable mutation involving the MAPK

pathway. The majority of these were RAS- or BRAF-

activating mutations2

1. Fakih. J Clin Oncol. 2015;33;1809-24; 2. Bettegowda et al. Sci Transl Med. 2014;6:224ra24;

3. Misale et al. Nature. 2012;486:532; 4. Diaz et al. Nature. 2012;486:537.

Current Approaches to Overcome Resistance to

EGFR-targeted Agents in mCRC

• Inhibition of RAS signalling pathway in

patients with BRAF V600 mutations

– Dabrafenib + trametinib1

ORR: 7%

mPFS: 3.5 months

– Panitumumab + dabrafenib2

ORR: 10%

mPFS: 10.1 months

– Panitumumab + dabrafenib + trametinib2

ORR: 26%

mPFS: 9.0 months

– Encorafenib + cetuximab3

ORR: 22%

mPFS: 4.2 months (Median OS: 12.4 mo)

• Remains an active area of research and

clinical development

EGFR

RAS

BRAF

MEK

ERK

Proliferation, Survival, etc

Anti-EGFR

Dabrafenib

Encorafenib

Trametinib

1. Corcoran et al. J Clin Oncol. 2014;32(suppl;abstr 3517).

2. Atreya et al. J Clin Oncol. 2015;33(suppl; abstr 103).

3. Tabernero et al. J Clin Oncol. 2016; 34(suppl; abstr 3544).

Anti-EGFR vs Anti-VEGF

Therapies in the Treatment of

mCRC

Anti-EGFR vs Anti-VEGF in the First-line

Treatment of mCRC

1.Schwartzberg et al. J Clin Oncol.2014;32:2240; 2.Heinemann V et al. Lancet.

Oncol. 2014;15:1065; 3. Stintzing S et al. Ann Oncol.2014;25:abstr LBA11.

Trial Regimen Primary endpoint Secondary endpoints

Post-PD treatment

PEAK trial1

KRAS-wt: N=285 RAS-wt: N=170

FOLFOX + panitum

vs FOLFOX + bev

KRAS-wt: PFS: 10.9 (panitum) vs 10.1 mos (bev)

(HR, 087; P=0.353)

RAS-wt: PFS: 13 (panitum) vs 9.5 mos (bev)

(HR, 0.65; P=0.029)

KRAS-wt: OS: 34.2 (panitum) vs

24.3 mos (bev) (HR, 0.62, P=0.009)

RAS-wt:

OS: 41.3 (panitum) vs 28.9 mos (bev)

(HR, 0.63; P=0.058)

Anti-EGFR : Bev arm: 38%

Panitum arm: 21%

FIRE-3 trial2,3

KRAS-wt: N=592 RAS-wt: N=400

FOLFIRI + cetux vs

FOLFIRI + bev

KRAS-wt: ORR (independent):

66.5% (cetux) vs 55.6%

(OR, 1.18; P=0.18)

RAS-wt: ORR (independent): 72% (cetux) vs 56%

(OR, 2; P=0.003)

KRAS-wt:* OS:

28.7 (cetux) vs 25 mos (bev)

(HR, 0.77; P=0.017)

RAS-wt:* OS:

33.1 (cetux) vs 25 mos (bev)

(HR, 0.7; P=0.0059)

Cetuximab-arm: 78% received

2nd-line treatment

Bev-arm: 76% received

2nd-line treatment

*No significant difference in median PFS between the arms.

1.Venook et al. J Clin Oncol. 2014;32(suppl 5s; abstr LBA3).

2. Lenz et al. Ann Oncol. 2014;25(abstr 5010).

3. Venook et al. Ann Oncol. 2014;25:(abstr LBA10).

4. Senellart et al. J Clin Oncol. 2016; 34 (suppl; abstr 3537).

Anti-EGFR vs Anti-VEGF in the First-line

Treatment of mCRC (cont’d)

Trial Regimen Primary endpoint Secondary endpoints Post-PD

treatment

CALGB 80405)1-3

KRAS-wt: N=1,137 RAS-wt: N=526

FOLFOX or FOLFIRI + cetux

vs FOLFOX or

FOLFIRI + bev

KRAS-wt: OS: 29.9 (cetux) vs 29 mos (bev) (HR, 92; P=0.30)

RAS-wt:

OS: 30.8 (cetux) vs 30.3 mos (bev)

(HR, 0.9; P=0.40)

KRAS-wt: PFS: 10.4 (cetux) vs 10.8

mos (bev) (HR, 1.04, P=0.55)

RAS-wt:

PFS: 10.9 (cetux) vs 11.4 mos (bev)

(HR, 1.1; P=0.31)

Details not provided

UCGI 25 A4

Afatinib + Cetuximab N=51 Cetuximab N=24

Afatinib + Cetuximab

vs Cetuximab

Non progression rate at 6 months

17% (7.7-30.8)

(afa/cetu) vs

20,8% (7.1-42.2) (cetu alone)

mPFS 4.1 vs 2.7

OS

13.6m vs 13.4m

ORR 26.0% vs 8.3%

Table of Contents

• Epidemiology

• Treatment of early and metastatic

CRC

– First-, second-, and third-line treatment in

mCRC

– Anti-EGFR and anti-VEGF therapies

• Limited therapeutic options in the

treatment of patients who failed all

standard therapies

• Emerging data in the treatment of

mCRC

Emerging Data in the Treatment of

Patients With mCRC Who Failed ≥3

Lines of Prior Therapies

Phase 3 Trial of Regorafenib Monotherapy for

Previously Treated mCRC (CORRECT Trial)

Median Overall Survival:

6.4 vs 5.0 mos.

Median Progression-Free Survival:

1.9 vs 1.7 mos.

Grothey et al. Lancet. 2013;381:303.

Safety of Regorafenib in

Relapsed/Refractory CRC: AEs

Regorafenib

n=500 (%)

Placebo

n=253 (%)

Discontinued study due to AEs 42 (8) 7 (3)

Dose modification 333 (67) 57 (23)

Dose reductions 188 (38) 8 (3)

Dose interruptions 304 (61) 55 (22%)

Treatment-related AEs (grade ≤3)

Overall 253 (51) 31 (12)

AEs of higher incidence (Regorafenib vs placebo)

Hand-foot skin reaction 83 (17) 1 (<1)

Fatigue 46 (9) 12 (5)

Hypertension 36 (7) 2 (1)

Diarrhoea 35 (7) 2 (1)

Rash or desquamation 29 (6) 0

Hypophosphataemia 19 (4) 1 (<1)

Oral mucositis 15 (3) 0

Thrombocytopaenia 13 (3) 1 (<1)

Anaemia 12 (2) 0

Hyperbilirubinaemia 10 (2) 2 (1)

Proteinuria 7 (<1) 1 (<1)

Voice change 1 (<1) 0

Nausea 2 (<1) 0

Vomiting 3 (1) 0

Fever 4 (1) 0

Grothey et al. Lancet. 2013;381:303.

Phase 3 Trial of TAS-102 in Relapsed/Refractory

mCRC (RECOURSE Trial)

Mayer et al. N Engl J Med. 2015;372:1909.

Overall Survival:

7.1 vs 5.3 mos.

Progression-Free Survival:

2.0 vs 1.7 mos.

Based on OS improvement, TAS-102 received approval from the FDA

(Sept 2015), and by the EMA (April 2016)

Safety of TAS-102 in

Relapsed/Refractory CRC: AEs

Mayer et al. N Engl J Med. 2015;372:1909.

TAS-102

n=533 (%)

Placebo

n=265 (%)

Discontinued study due to AEs 19 (4) 4 (2)

Dose reduction 73 (14%)

Treatment-related AEs (grade ≤3)

Overall 370 (69) 137 (52)

AEs of higher incidence (TAS-102 vs placebo)

Neutropaenia 200/528 (38) 0

Leukopaenia 113/528 (21) 0

Anaemia 96/528 (18) 8/263 (3)

Thrombocytopaenia 27/528 (5) 1/263 (<1)

Febrile neutropaenia 20 (4) 0

Nausea 10 (2) 3 (1)

Vomiting 11 (2) 1 (<1)

Diarrhoea 16 (3) 1 (<1)

Nintedanib: An Oral Triple Angiokinase

Inhibitor

• Simultaneously inhibits multiple angiokinases

at low nanomolar concentrations (IC50)1-3

– VEGFR-1, -2, and -3

– PDGFR-a/b

– FGFR-1, -2, and -3

• Demonstrated high antiangiogenic and anti-

tumour activity as monotherapy or in combined

regimens in multiple preclinical models

including bevacizumab-resistant CRC

xenograft3

• Long-term treatment with nintedanib does not

induce EMT in multiple preclinical models2

1. Hilberg et al. Cancer Res. 2008;68-4774; 2. Kutluk Cenik et al. Mol Cancer Ther. 2013;12:992;

3. Mésange et al. Oncotarget. 2014;5:4709.

Nintedanib is approved in the European union (EU) under the brand name VARGATEF® for use

in combination with docetaxel in adult patients with locally advanced, metastatic or locally

recurrent NSCLC of adenocarcinoma tumour histology after first-line chemotherapy. Registration

conditions differ internationally, please refer to locally approved prescribing information.

Nintedanib is not approved in other indications.

BIBF 1120

Antitumour Activity of Nintedanib in mCRC

• Primary endpoint: PFS rate at 9 months

Nintedanib

(150 or 200 mg bid)

+

mFOLFOX6

Bevacizumab

(5 mg/kg q2wks)

+

mFOLFOX6

• Confirmed mCRC

(adenocarcinoma)

• Previously

untreated patients

• ECOG PS ≤2

• Adequate organ

functions

N=126

R

A

N

D

O

M

I

S

E

2:1

n=85

n=41

Van Cutsem E et al. Ann Oncol. 2015 Aug 12. pii:mdv286. [Epub ahead of print]

mFOLFOX6= oxaliplatin 85 mg/m2, I-leucovorin 200 mg/m2 or d,I-leucovorin 400 mg/m2,

5-FU bolus 400 mg/m2 followed by 2400 mg/m2, every 2 weeks

Study design

62,1 63,5

70,2

56,1

0

10

20

30

40

50

60

70

80

PFS (9 mos) ORR

Nint + mFOLFOX Bev + mFOLFOX

*

*Confirmed ORs

Activity

Where Do We Go From Here?

How Do We Further Improve Patient

Outcomes?

Identification of Potentially Novel Targetable

Driver Mutations in mCRC Analysis of 224 tumour and normal pair tissue samples

Cancer Genome Atlas Network. Nature. 2012;487:330-337.

NATURE MEDICINE ADVANCE ONLINE PUBLICATION

1

Right-Sided CRC Different From Left-Sided

CRC

• Left-sided primary tumours

are associated with longer

survival, versus right-sided

primary tumours

– Even in KRAS-mutated

tumours, tumours originating

from the left side are

associated with better

survival

• Location may help predict

optimal treatment decision

Venook A et al. ASCO 2016. Abstract 3504.

Rationale for Immunotherapeutic Approaches for

Mismatch Repair Deficient CRC

• The genomes of microsatellite instability high (MSI-H)

tumours harbour thousands of mutations which if

expressed as proteins can potentially be recognised

by the immune system and foreign antigens

• This abundance of mutant-associated neo-antigens

results in the tumour appearing foreign to the host

immune system

• This results in a inflamed microenvironment with very

high expression of immune checkpoints

• Treatments of these tumours with anti-PD-1/PD-L1

therapy unlocks a potent anti-tumour response in MSI-

H malignancies Dung et al. J Clin Oncol. 34, 2016 (suppl; abstr 103).

Ongoing Clinical Trials With Immune

Checkpoint Inhibitors in MSI-High CRC

Link JT et al. Cancer J. 2016;22(3):190-5.

Phase 2 Trial of Pembrolizumab in Patients With

Microsatellite Instability-High (MSI-H) Tumours

Dung et al. J Clin Oncol. 2016;34(suppl; abstr 103).

FDA has granted Breakthrough Therapy Designation to pembrolizumab for the treatment

of patients with microsatellite instability high (MSI-H) mCRC (Nov 2015)

Anti-PD-1/PD-L1 in mCRC: The Need to Identify the Right Patient Population

Nivolumab and Ipilimumab in mCRC +/– High

Microsatellite Instability (CheckMate 142 Interim Results)

NCT02060188

Overman et al. J Clin Oncol. 2016;34(suppl; abstr 3501).

Patients with MSI High

Nivolumab and Ipilimumab in mCRC +/– High

Microsatellite Instability (CheckMate 142 Interim Results)

NCT02060188

Overman et al. J Clin Oncol. 2016;34(suppl; abstr 3501).

Patients with MSI High

Testing for Circulating Tumour DNA

Potential Applications of Liquid Biopsy

• Assess clonal changes in RAS over time

– Mutated clones that emerge with treatment can regress

with withdrawal

• Monitor response over time

– Complement radiologic assessments or alternative to

imaging for earlier evaluation

• Individualise treatment

– Withdraw treatment at resistance and rechallenge if

clones regress

– Select more specific pathway blockers

Summary/Conclusion

• Management of CRC involves multimodality strategies

combining surgery, radiation therapy, and chemotherapy

• Neoadjuvant/adjuvant chemotherapy for Stage II/III is an area of

active study particularly in rectal cancer

• Significant advances have been made over the last two decades

in the treatment of mCRC

• Immunotherapy has shown promising results with checkpoint

inhibitors in mismatch repair-deficient tumours and is being

evaluated in combination with chemotherapy and monoclonal

antibodies

• However, a number of challenges still remain (eg, treatment-

emergent resistance, the need for better tolerated, and effective

therapy in later-line settings)

• More efforts are needed to better understand the underlying

disease mechanisms of mCRC and to identify novel, targetable

driver mutations in order to improve disease management

THANK YOU FOR YOUR

ATTENTION!

BACKUP SLIDES

Different Classes of CRC-Associated

Molecular and Cellular Biomarkers

Aghagolzadeh P et al. World J Gastroenterol. 2016; 22(25): 5678-5693.

Poner diapo de correlación con clasif

molecular

Ongoing Trials With Anti-PD-1 Agents in

mCRC

Trial Study Title Treatment 1° Endpoint Status

Phase 2 NCT02437071

Assess the Efficacy of Pembrolizumab

Plus Radiotherapy or Ablation in

Metastatic Colorectal Cancer Patients

Combination Radiation Therapy or Ablation Plus Pembrolizumab

Response Rate Recruiting

Phase 2 NCT02375672

Study of Pembrolizumab in Combination With Chemotherapy for Patients With Advanced Colorectal Cancer

Combination FOLFOX6 Chemotherapy with Pembrolizumab

PFS Recruiting

Phase 2 NCT02260440

A Phase 2 Study of Pembrolizumab in

Combination With Azacitidine in Subjects

With Chemo-refractory Metastatic CRC

Combination Azacitidine with Pembrolizumab

Response Rate Recruiting

Phase 1/2 NCT02318901

Pembrolizumab and Monoclonal Antibody Therapy in Advanced Cancer

Combination of Pembrolizumab with Trastuzumab, ado-Trastuzumab

emtansine, or Cetuximab RP2D Recruiting

Phase 1/2 NCT02268825

Phase I/IIA Study MK-3475 With

Chemotherapy in Patients With

Advanced GI Cancers (MK-3475 GI)

Combination FOLFOX6 Chemotherapy with Pembrolizumab

Safety Recruiting

Phase 1/2 NCT02327078

A Study of the Safety, Tolerability, and

Efficacy of INCB24360 Administered in

Combination With Nivolumab in Select

Advanced Cancers

Combination with INCB24360 (IDO1

Inhibitor) with Nivolumab

Phase 1: Safety (DLT)

Phase 2: Response Rate & Overall Survival

Recruiting

Phase 1/2 NCT02423954

Study of Nivolumab Plus Chemotherapy

in Patients With Advanced Cancer

(NivoPlus)

Combination of Nivolumab with Temsirolimus or Irinotecan or Irinotecan plus Capecitabine

RP2D Recruiting

PFS, Progression free survival; RP2D, Recommended phase 2 dose; DLT, dose limiting toxicities.

www.clinicaltrials.gov. Accessed Sept. 3, 2015.

Ongoing Trials With Anti-PD-1 Agents in

MMR and MSI-high mCRC

Trial Study Title Treatment 1° Endpoint Status

Phase 2

NCT02460198

Study of Pembrolizumab as

Monotherapy in Participants

With Previously-Treated Locally

Advanced Unresectable or

Metastatic Colorectal Cancer

(KEYNOTE-164)

Pembrolizumab

Monotherapy

Response Rate Recruiting

Phase 2

NCT01876511

Phase 2 Study of MK-3475 in

Patients With Microsatellite

Unstable (MSI) Tumors

Pembrolizumab

Monotherapy

IR-PFS &

Response Rate

Recruiting

Phase 1/2

NCT02060188

A Study of Nivolumab and

Nivolumab Plus Ipilimumab in

Recurrent and Metastatic Colon

Cancer (CheckMate 142)

Nivolumab Alone or

in Combination with

Ipilimumab

Response Rate Recruiting

IR-PFS, immune-related progression free survival

www.clinicaltrials.gov. Accessed September 3, 2015.