management of metastatic colorectal cancer

mCRC: The Paradigm of Sequence or

Still Maximum Exposure?Evidence from RCT

Mohamed Abdulla M.D.Prof. of Clinical Oncology

Cairo University

Asyut Annual MeetingMerck Serono LectureLuxor: 22/02/2017

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

Merck Serono, Novartis, Pfizer, Mundipharma, MSD

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.

Median OSMonths

1980s 1990s 2000s BSC 5-FU

Irinotecan1Capecitabine2

Oxaliplatin3Bevacizumab4

Cetuximab5,6BSCPanitumumab7

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

Treatment Lines &

Combinations

mCRC: Can we do better?

Treatment INTENTION

Organ Confined Disease

NAT:Resectable

Or Convertible

Resection for Cure

Progressive Metastatic

Palliative Treatment

OASQoL

Can We Do Better?• Treatment Holidays QoL• Re-challenge (Beyond Progression) Keep on Pressing

The Button Always Response.• Maintenance Therapy Try to Keep What you Achieved.• Triplets versus Doublet +/- Biologics Intensive & Seeking

for Impressive Early Response.

• MDT• Predictive Markers K-RAS Assessment All RAS

Assessment SEQUENCE SMART & STRATEGIC

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

• 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

ORR, %*

PFS, months*

Importance of 1st line treatment decision

1st line1-4 2nd line5–7 3rd line8,9

1 ‡ –22†

2 ‡ –4†

38 ‡ –

69

9 ‡ –13

10 † –

41

4 † –9†

Treatment is most effective in the 1st line1–9 Determining RAS status at diagnosis is crucial for maximizing patient

outcomes and planning the course of treatment

1 .Saltz LB, et al. J Clin Oncol 2008;26:2013–2019; 2. Lenz HJ, et al. ESMO 2014 (Abstract No. 501O); 3. Pericay C, et al. WCGC 2012 (Abstract No. O-0024); 4. Karthaus M, et al. ECC 2013 (Abstract No. 2262); 5. Langer C, et al. ESMO

2008 (Abstract No. 385P); 6. Peeters M, et al. ASCO GI 2014 (Abstract No. LBA387);

7. Cohn A, et al. ASCO 2013 (Abstract No. 3616); 8. Grothey A, et al. Lancet 2013;381:303–312; 9. Price TJ, et al. Lancet Oncol 2014;15:569–579

*Range of results for the targeted treatment arms of key Phase II/III

trials (RAS wt except where indicated;

†KRAS exon 2 wt; ‡unselected)

Predictive Markers

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

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

OAS Dif. = 8.5 ms

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)

Sequence:

Sequence versus Exposure:

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


Bevacizumab47.1%

Cetuximab or Panitumumab

52.2%




Sequence may be more important than Exposure.

Which Treatment Line First?Better Insight:

Heinemann et al. EJC 67 (2016) 11-20. New Era


Heinemann et al. EJC 67 (2016) 11-20.

OAS

PFS

OAR

ETS

Lancet Oncol 2016; 17: 1426–34


Inducing Tumor Shrinkage is essential

Lancet Oncol 2016; 17: 1426–34


Correlation between ETS and increased OS has been consistently observed in 1st line Phase III clinical

trials

• 1. Piessevaux H, et al. J Clin Oncol 2013;31:3764–3775;2. Stintzing S, et al. ESMO 2014 (Abstract No. LBA11); 3. Douillard JY, et al. Eur J Cancer 2015;51:1231–1242;4. Cremolini C, et al. Ann Oncol 2015;26:1188–1194;5. Erbitux SmPC June/2014;6. Heinemann V, et al. Lancet Oncol 2014;15:1065–1075.

*KRAS exon 2 wt population; Cetuximab is approved in patients with RAS wt mCRC.6 Cetuximab is not indicated for the treatment of patients with mCRC whose tumors have RAS mutations or for whom RAS tumor status is unknown.5

**FIRE-3 did not meet its primary endpoint of significantly improving ORR in patients with KRAS (exon 2) wt mCRC based on investigators’ read.6

†Not including the first four months after randomization.

Trial Biomarker status Treatment regimen (n)

OS, months∆OS, mont

hsETS

<20% ETS ≥20%

CRYSTAL1

KRAS exon 2 wt*

FOLFIRI + cetuximab (n=299) 18.6 30.0 11.4

FOLFIRI (n=332) 18.6 24.1 5.5

FIRE-3**2 RAS wt

FOLFIRI + cetuximab (n=157) 20.5 38.3 17.8

FOLFIRI + bevacizumab (n=173) 21.2 31.9 10.7

PRIME3 RAS wt

FOLFOX4 + panitumumab (n=219) 12.6 32.5 19.9

FOLFOX4 (n=221) 15.2 26.0 10.8

TRIBE4 UnselectedFOLFOXIRI + bevacizumab/FOLFIRI + bevacizumab (n=407)

21.9† 31.9† 10.0

Inducing ETS with Cetuximab correlates with symptoms relief and QoL

1. Griebsch I, et al. ASCO GI 2011 (Abstract No. 3626)

16141210

86420

13,2

2,,0

0

5,1

14

1210

8

6

42

0

KRAS wt –Liver-limited

disease cohort

CRYSTAL

7,3

3,1

Patie

nts,

%

OPUS

Patie

nts,

%

KRAS wt-Liver-limited

disease cohort

16.0

KRAS wtP = .22 †KRAS wt

P = .027 †

4,3

Van Cutsem E, et al. J Clin Oncol. 2011;29(4S): Abstract 472.*Fisher’s exact test;†Cochran-Mantel-Haenszel test

P = .15* P = .35*

5,6

R0 RESECTIONS IN RANDOMIZED TRIALS WITH CETUXIMAB

FOLFIRI ERBITUX FOLFIRI ERBITUX FOLFOX4 ERBITUX FOLFOX4 ERBITUXN = 350 + FOLFIRI N = 72 + FOLFIRI N = 97 + FOLFOX4 N = 23 + FOLFOX4

N = 316 N = 68 N = 82 N = 25

1. Folprecht G et al. Lancet Oncol 2010; 11(1): 38-47.

Higher Resection Rates correlates with Prolonged OS and PFS

Phase III TAILOR study: open-label, randomized ,1st line FOLFOX-4 ± Erbitux in patients with RAS wild-type metastatic colorectal cancer (RAS wt mCRC)

3

First prospective Phase III analysis to assess the efficacy and safety of Erbitux plus FOLFOX versus FOLFOX alone as 1st line therapy in RAS wt mCRC

Endpoints• Primary:

PFS • Key secondary:

OS, ORR, safety/tolerability

1st line, RAS wt mCRC

R1:1

Arm A:Erbitux + FOLFOX-4

Arm B:FOLFOX-4 alone

Treatment until

progressive disease or

unacceptable toxicity*

IRC, independent review committee; HR, hazard ratio; OS, overall survival; ORR, overall response rate*In the case of non-PD treatment discontinuation, tumor assessment was to be continued

FOLFOX-4: • Oxaliplatin 85 mg/m2 Day 1, every 2 weeks• Folinic acid 200 mg/m2 Day 1 and Day 2, every 2 weeks• 5-FU 400 mg/m2 bolus, then 22h continuous infusion of 600 mg/m2/day Day 1

and Day 2, every 2 weeks

Erbitux: • 400 mg/m2 Day 1, then 250 mg/m2/week

Qin S, et al. WCGC 2016 (Abstract no. O-025)

35

GORTEC 2007-021TAILOR

Confirms Erbitux as a Standard of care for all patients with RAS wt mCRC, with consistent benefit in combination with standard CT regimens

PFS: 9.2 vs 7.4 months1

HR: 0.69p=0.004

• ORR: 61.1% vs 39.5%1

OR: 2.41 p=<0.001

• OS: 20.7 vs 17.8 months1

HR: 0.76 p=0.02

SOC, standard of care; CT, chemotherapy; PFS, progression-free survival; HR, hazard ratio; OS, overall survival; ORR, overall response rate

6

31% decrease in the risk of disease progression1

• 24% reduction in the risk of death1

• 61% ORR is consistent with previous studies2,3

1. Qin S, et al. WCGC 2016 (Abstract no. O-025)2. Van Cutsem E, et al. J Clin Oncol 2015;33:692–700;

3. Bokemeyer C et al. Eur J Cancer 2015;51:1243–1252

Significant benefit with Erbitux + FOLFOX versus FOLFOX aloneacross all efficacy endpoints1

Tumor location in CRC

ESMO updates

37

FIRE-3No difference in outcomes

between arms in right-sided tumors, but conclusions are

limited by small sample size & imbalances

38.3

38

CRYSTALNo significant difference in outcomes between arms in

right-sided tumors, but conclusions are limited by small

sample sizeNumerical

increase in ORR compared with

CT alone

In RS, patients in the Erbitux arm had poorer PS, larger

tumors, and more frequent prior adjuvant therapy,

compared with CT alone

28.7

39

CALGB/SWOG 80405

Longer PFS with bevacizumab vs Erbitux, but no difference in OS between arms, in right-sided tumors; conclusions limited by small

sample size

Data for patients with right-sided tumors are inconclusive due to:

• Small patient numbers• Unreported baseline characteristics,

treatment dose, treatment duration and subsequent therapies

39.3

~30% of patients

40

Conclusion

~70% of patients

Median OS >38 months!

• Over 10 months more than bev + CT (FIRE-3)

• 7 months more than bev + CT (CALGB 80405)

• 7 month more than CT (crystal)

Bad prognosis regardless of

therapySmall sample size ,

premature data

LEFT RIGHT

Anti-EGFR agents

1. Erbitux SmPC June/2014;2. Imai K, Takaoka A. Nat Rev Cancer 2006;6:714–727; 3. Vectibix SmPC February/2015.

Human constant domains

Mouse variable domains

Human constant and variable domains

Cetuximab1,2 Panitumumab2,3

Chimeric monoclonal IgG1 antibody

Fully human monoclonal IgG2 antibody

Differences in molecular structure

Potent ADCC Less ADCC

Take Home Message:• Better insight to decide for first line treatment.• Growing evidence of 1st line Anti-EGFR MCA as SOC in All-RAS wild

type patients (Resection or OAS).• Availability of 2nd line data from major RCT emphasized the survival

advantage of 1st line Anti-EGFR based combination therapy.• Emphasizing ETS as an endpoint to predict Survival, Resectability

and Symptom Relief.• Data for tumor location needs more validation, with retrospective

data favoring anti-EGFR for left sided tumors.• Immunogenic response to Cetuximab needs to be highlighted in

the era of immunotherapy.

Thank You

management of metastatic colorectal cancer

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