Colon Cancer UpdatesData from ASCO GI - 2016

Mohamed Abdulla M.D.Prof. of Clinical Oncology

Cairo University

MERCK – Symposium NEMROCK 24/04/2016

Adopted from Keynote Presentation by

David Cunningham ASCO GI 2016

Member of Advisory Board, Consultant, and Speaker for:• Amgen, Astellas, AstraZeneca, Hoffman la Roche, Janssen Cilag,

Merck Serono, Novartis, Pfizer, Mundipharma• The content of this presentation does not relate to any product of a

commercial interest

Speaker Disclosures:

Basic Facts:

• 2nd & 3rd most common cancer in females & males.• 1.4 million new case and 694000 deaths.• Males > Females.• Lowest rates in Africa & South Central Asia.• Low SES 30% increased risk.• Rising incidence < 50 years Left sided colon &

rectal, symptomatic & advanced Poor outcome.• Sporadic > Hereditary.

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016; 66:7. Ahnen DJ, Wade SW, Jones WF, et al. The increasing incidence of young-onset colorectal cancer: a call to action. Mayo Clin Proc 2014; 89:216.

Aspirin Colon Cancer Prevention:

• Aspirin reduces adenoma and CRC in General Population and HNPCC.

• Prevents recurrence in mutated PIK3CA patients.

Liao et al, n engl j med 367;17 nejm.org october 25, 2012

Adjuvant Chemotherapy for Stage III Colon Cancer

Adjuvant Chemotherapy for Stage II Colorectal Cancer

Assessing risk/ benefit in stage II patients

Follow up for stage II/III disease following curative treatment

Systemic Therapy for Advanced Disease:

• No predictive biomarker for chemotherapy.• Monotherapy for less fit/elderly patients.• Doublets & Triplets for higher response rates.• FOLFOX, CAPEOX, FOLFIRI Similar Efficacy.• All RAS Wild Tumors (50%) benefit from EGFR inhibition. • No biomarker to select for inhibition of angiogenesis.• Triplets may be the best option for BRAF mutated tumors.• Duration of therapy is usually 6 months or induction for 3-4

months followed by maintenance or de-escalation of doses.• Maximum Exposure or Sequence of Administration?

Choice of Systemic Therapy:

5-Fu/LV

Capecitabine

OxaliplatinIrinotecan

Bevacizumab

CetuximabPanitumumab

AfliberceptRegrafinib

TAS 102

Survival Improvement

Treatment Lines &

Combinations

Daily Treatment Scenarios:

Maximum Exposure:• Advancing Cancer Chronic

Disease.• Survival All Active Agents.• Sequence isn’t important

Sequence:• Predictive Markers • Upfront Massive Attack.• Late still wining cards

• Survival Improvement is modest in 2n & 3rd Lines.• Losing an Active Agent Out of Upfront Treatment.

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

Predictive Markers:

OPUS, COIN, CRYSTAL, PRIME, 20050181, PICCOLO, 20020408, FIRE -3, PEAK

KRAS WT: Impact of All RAS Testing:1. PFS

Sorich et al. Annals of Oncology 26: 13–21, 2015

KRAS WT: Impact of All RAS Testing:2. OAS

Sorich et al. Annals of Oncology 26: 13–21, 2015

KRAS WT: Impact of All RAS Testing:

• Panitumumab and Cetuximab are EQUIVALENT in OAS and PFS in All RAS WT.

• EUIVALENCE regardless the backbone of chemotherapy.

• Anti-EGFR mAb third-line mono- therapy was estimated to have significantly greater benefit than first-/second-line anti-EGFR mAb therapy in combination with chemotherapy with respect to PFS (P = 0.002), but not OS (P = 0.66)

Sorich et al. Annals of Oncology 26: 13–21, 2015

CRYS

TAL5

COIN

3

PRIM

E4

NO

RDIC

VII2

CO.1

79

4088

N01

471

PFS for EGFR inhibitors improves across lines of therapy in KRAS wild-type patients:

Haza

rd ra

tio

1. Alberts, et al. JAMA 2012; 2. Tveit, et al. JCO 2012; 3. Maughan, et al. Lancet 2011 4. Douillard, et al. ASCO 2011; 5. Van Cutsem, et al. JCO 2011; 6. Langer, et al. ESMO 2008

7. Sobrero, et al. ASCO GI 2012; 8. Amado, et al. JCO 2008; 9. Karapetis, et al. NEJM 2008

First line Second line Salvage (single agent)

Adjuvant

1.2

1.0

0.8

0.6

0.4

0.2

0

Stud

y 18

17

EPIC

6

Albert Sobrero , WCGIC 2012

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

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 IIIUntreated mCRC

N = 592

Bevacizumab + FOLFIRI

Cetuximab + FOLFIRI

CALGB-804053

Phase IIIUntreated mCRC

N = 1200

Bevacizumab + FOLFIRI or FOLFOX

Cetuximab + FOLFIRI or FOLFOX

No Hypothesis

OAS

ORR

DP

FIRE-3 Trial: FOLFIRI + Either Cetuximab or Bevacizumab 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

CALGB/SWOG 80405: Overall Survival

Arm N (Events)OS (m)Median

95% CI

Chemo + Cetux 578 (375) 29.9 27.0-32.9

Chemo + Bev 559 (371) 29.0 25.7-31.2

P=0.34HR 0.925 (0.78-1.09)

CALGB/SWOG 80405: Progression-Free Survival(Investigator Determined)

Arm N (Events)PFS (m)Median 95% CI

Chemo + Bev 559 (498) 10.8 9.7-11.4

Chemo + Cetux 578 (499) 10.4 9.6-11.3

P=0.55 HR 1.04 (0.91 -1.17)

100 –

90 –80 –

70 –

60 –

50 –

40 –

30 –20 –

10 –

0 –

CALGB/SWOG 80405: Quality of Life and Symptoms

Venook A, et al. J Clin Oncol. 2014;32(Suppl): Abstract LBA3.

Baseline Week 6 Month 3 Month 6 Month 9

Scor

e(0

-100

sca

le; h

ighe

r sco

res

repr

esen

t be

tter Q

OL)

P = .0546

EORTC global QoL DSQL skin satisfaction100 –

90 –

80 –70 –

60 –

50 –

40 –

30 –20 –

10 –

0 –Baseline Week 6 Month 3 Month 6 Month 9

P<.0001

BevacizumabCetuximab

Chemo/bevacizumab Chemo/cetuximab

Sequence:

Sequence: All RAS WT:

1st Line Chemo + Anti-VEGF

2nd Line Chemo + Anti-VEGF

3rd Line Chemo + Anti-EGFR

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

Sequence versus Exposure:

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

Sequence versus Exposure:

Bevacizumab47.1%

Cetuximab or Panitumumab

52.2%

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

Sequence versus Exposure:

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

Sequence may be more important than Exposure.

The Art of Today:

• Significant improvement of OAS among patients with mCRC over time.

• Predictive Factors if available are mandatory (All RAS).• Although all treatment options are valid, Sequence of

administration might be more important than exposure (RAS WT).

• Anti-EGFR is a reasonable and more appealing alternative to Anti-VEGF in 1st line treatment of RAS WT.

• Still more research is awaited for better insight.

Is systemic therapy always the best option?

Oligo-metastatic disease at presentation

Treatment options for Oligo-metastases

Slide 24

Progression in our understanding of CRC subtypes

Liquid Biopsy: circulating tumour DNA (ctDNA)

Taking ctDNA into the adjuvant setting

Conclusions

Thank You