1. Best Options Across the Continuum of Care for Patients With Metastatic Colorectal Cancer
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3. Faculty
J. Randolph Hecht, MD Director, Gastrointestinal Oncology Program Professor of Clinical Medicine David Geffen School of Medicine at University of California, Los Angeles Los Angeles, California Jeffrey Meyerhardt, MD, MPH Associate Professor of Medicine Harvard Medical School Clinical Director, Center for Gastrointestinal Cancer Dana-Farber Cancer Institute Boston, Massachusetts
This slide lists the faculty who were involved in the production of these slides.

4. Disclosures
J. Randolph Hecht, MD, has no significant financial relationships to disclose. Jeffrey Meyerhardt, MD, MPH, has disclosed that he has received funds for research support from Biothera, Bristol- Myers Squibb, and Gilead Sciences.
This slide lists the disclosure information of the faculty and staff involved in the development of these slides.

5. Outline Overview of CRC Initial Treatment of Metastatic CRC
Chemotherapy
Biological Agents
Adverse Event Management
Treatment of Metastatic CRC at Progression
Treatment Options
Efficacy
Safety
Biomarkers

6. Overview of CRC
CRC, colorectal cancer.

7. CRC: Epidemiology in 2013 Fourth most common cancer diagnosis in US[1]
Estimated 142,820 new cases in ; 1:1 male:female ratio[2]
Second leading cause of cancer deaths in 2013 (estimated 50,830 deaths)[1]
Steady decrease in age- adjusted incidence rates of distal colon, proximal colon, and rectal cancers in [4]
Death Rates in 2008, per 100,000[3], %
Male
Female
All races
20.2
14.1
White
19.5
13.6
Black
29.8
19.8
Asian/Pacific Islander
13.1
9.6
American Indian/ Alaska Native
18.8
14.6
Hispanic
15.3
10.2
CRC, colorectal cancer.
1. American Cancer Society. Cancer facts & figures Siegel R, et al. CA Cancer J Clin. 2012;62: SEER. Stat fact sheets: colon and rectum. 4. Cheng L, et al. Am Clin Oncol. 2011;34:

8. Colorectal Cancer: Stage at Diagnosis7%
Stage IV
19%
Stage I
24%
Stage III
25%
Stage II
25%
National Cancer Database.

9. Colorectal Cancer: Standard Therapy Algorithm
Stage
Colon
Rectal
I (T1-T2, N0, M0)
Surgery only
II (T3-T4, N0, M0)
Surgery ± chemotherapy
Chemoradiation  surgery  chemotherapy OR
Surgery  chemoradiation + chemotherapy
III (Tany, N+, M0)
Surgery  chemotherapy
IV (Tany, Nany, M1)
Chemotherapy ± surgery
Chemotherapy ±
surgery
NCCN. Clinical practice guidelines in oncology: colon cancer. v

10. Initial Therapy for Metastatic CRC
CRC, colorectal cancer.

11. Should Primary CRC Tumors Be Resected in Metastatic Disease?
What are others doing?
SEER database 2000 ( )
26,754 patients presented with stage IV colorectal cancer
66% had primary tumor resected
CRC, colorectal cancer.
Cook AD, et al. Ann Surg Oncol. 2005;12:

12. Outcomes With Intact Primary Tumor in Synchronous mCRC Receiving CT
Total Cohort (N = 233; 100%)
No primary tumor complication (n = 207; 89%)
Primary tumor complication (n = 26; 11%)
No intervention (n = 152; 65%)
Nonoperative intervention (n = 10; 4%)
Operative intervention (n = 16; 7%)
EBRT, external beam radiation therapy; mCRC metastatic colorectal cancer.
Curative resection (n = 47; 20%)
Stent (n = 7)
Resection (n = 8)
Preemptive resection (n = 8; 3%)
Bypass (n = 1)
EBRT (n = 3)
Ostomy (n = 7)
Poultsides GA, et al. J Clin Oncol. 2009;27:

13. Personalizing Treatment in mCRC: Considerations
Extent of disease
Intent of treatment (palliative vs potentially curative)
Performance score
Age
Comorbid illnesses
Previous adjuvant therapy within 1 yr
Molecular markers
Organ function: hepatic and renal
Risks for toxicity: active CAD/CVD, proteinuria, active bleeding, nonhealed wound, allergy to mAb, neuropathy, IBD, ILD, Gilberts
Convenience
Cost/resources
Patient preferences and goals
CAD, coronary artery disease; CVD, cerebrovascular disease; IBD, inflammatory bowel disease; ILD, interstitial lung disease; KRAS, Kirsten-RAS; mCRC, metastatic colorectal cancer.

14. Median Overall Survival in First-Line mCRC: The Golden Age
BSC
~ 4-6 mos
5-FU/LV
12-14 mos
IFL or FOLFIRI
~ mos
19-20 mos
FOLFOX4 or CAPEOX
IFL + Bevacizumab
20.3 mos
BSC, best supportive care; CAPEOX, capecitabine, oxaliplatin; FOLFOX, 5-fluorouracil, leucovorin, oxaliplatin; FOLFIRI, 5-fluorouracil, leucovorin, irinotecan; 5-FU, 5-fluorouracil; IFL, irinotecan, leucovorin, fluorouracil; LV, leucovorin; MCRC, metastatic colorectal cancer; OS, overall survival.
FOLFOX6
21.5 mos
FOLFIRI + Bevacizumab
24 mos 6 12 18 24
Median OS (Mos)
Gallagher DJ, et al. Oncology. 2010;78:
Saltz et al. N Engl J Med. 2000;13:905.
Douillard et al. Lancet. 2000;355:1041.
Goldberg et al. Proc Am Soc Clin Oncol. 2003;22:252. Abstract 1009.
Van Cutsem et al. Proc Am Soc Clin Oncol. 2003;22:255. Abstract 1023.
Tournigand et al. Proc Am Soc Clin Oncol. 2001;20:124a. Abstract 494.
Grothey et al. Proc Am Soc Clin Oncol. 2002;21:129a. Abstract 512.
Hurwitz et al. Proc Am Soc Clin Oncol. 2003;22. Abstract 3646.

15. Modern Chemotherapy for Unresectable mCRC: 50 Yrs of Work
Infusional 5-FU is better than bolus (capecitabine?)
Irinotecan and oxaliplatin: equivalent?
What about FOLFOXIRI?
Almost all the improvement in mCRC survival is due to better cytotoxic therapies, not biologic therapies
FOLFOXIRI, 5-fluorouracil, leucovorin, oxaliplatin, irinotecan; 5-FU, 5-fluorouracil; mCRC, metastatic colorectal cancer.

16. Key First-line Chemotherapy Trials in mCRC: Efficacy
Comparative Regimens
Median PFS, Mos
Median OS, Mos
IFL vs FOLFOX vs IROX[1]
6.9 vs 8.7 vs 6.5
15.0 vs 19.5 vs 17.4
FOLFIRI vs FOLFOX4[2]
7.0 vs 7.0
14.0 vs 15.0
XELOX (CapeOx) vs FOLFOX4[3,4]
7.3 vs 7.7
19.0 vs 18.9
FOLFIRI vs mIFL vs CapeIRI[5]
7.6 vs 5.9 vs 5.8
23.1 vs 17.6 vs 18.9
Bev, bevacizumab; FOLFIRI; fluorouracil, leucovorin, irinotecan; FOLFOX; fluorouracil, leucovorin, oxaliplatin; IFL, fluorouracil, leucovorin, irinotecan; mCRC, metastatic colorectal cancer; NR, not reported; OS, overall survival; PFS, progression-free survival; XELOX, capecitabine, oxaliplatin.
1. Goldberg RM, et al. J Clin Oncol. 2004;22: Colucci G, et al. J Clin Oncol. 2005;23: Cassidy J, et al. J Clin Oncol. 2008;26: Cassidy J, et al. Br J Cancer. 2011;105: Fuchs CS, et al. J Clin Oncol. 2007;25:

17. Phase III Trials of FOLFOXIRI vs FOLFIRI as First-line Therapy for Advanced CRC
RR, %
Median TTP/PFS, Mos
Median OS, Mos
Souglakos
(n = 283)
43.0 vs 33.6
8.4 vs 6.9
21.5 vs 19.5
Falcone
(n = 244)
60 vs 34*
9.8 vs 6.9*
22.6 vs 16.7*
*Statistically significant difference.
CRC, colorectal cancer; FOLFIRI, leucovorin/fluorouracil/irinotecan; FOLFOXIRI, irinotecan/oxaliplatin/fluorouracil/folinate; OS, overall survival; PFS, progression-free survival; RR, response rate; TTP, time to progression.
Souglakos J, et al. Br J Cancer. 2006;94: Falcone A, et al. J Clin Oncol. 2007;25: 17

18. Grade 3/4 Chemotherapy-Associated Toxicities in mCRC: Phase III Experience
Regimen
Neutropenia, %
Diarrhea, %
Neurosensory, %
HFS, %
Capecitabine –
11-15
16-18
CapeOx
5-7
13-15
11-25
2-10
5-FU/LV (infusional)
2-5
21-26
FOLFIRI
10-28
10-14
FOLFOX4
10-59
5-12
4-18
IFL
40-54
23-29
mFOLFOX6
44-47
7-11
25-34
FOLFOXIRI
35-50
20-28
2-6
5-FU, 5-fluorouracil; CapeOx, capecitabine, oxaliplatin; FOLFIRI, 5-fluorouracil, leucovorin, irinotecan; FOLFOX4, 5-fluorouracil, leucovorin, oxaliplatin; HFS, hand-foot syndrome; IFL, irinotecan, 5-fluorouracil, leucovorin; LV, leucovorin; mCRC, metastatic colorectal cancer; mFOLFOX, modified FOLFOX; rIFL, reduced-dose irinotecan, 5-fluorouracil, leucovorin.
Grenon NN, et al. Clin J Oncol Nurs. 2009;13: Souglakos J, et al. Br J Cancer. 2006;94: Falcone A, et al. J Clin Oncol. 2007;25:

19. Biologic Therapies in First-line Therapy for mCRC
mCRC, metastatic colorectal cancer.

20. The VEGF and VEGF-Receptor Family
PlGF
Ligand
VEGF-A
VEGF-E
VEGF-C
VEGF-D
isoforms
VEGF-B
VEGFR-1s
VEGF-A 165
Extracellular
Intracellular
EGFR, epidermal growth factor receptor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.
VEGFR-1
VEGFR-2
NRP-1
VEGFR-3
Receptor
isoforms
(Flt-1)
(KDR)
(Flt-4)
Lymph angiogenesis
Angiogenesis
tumor metastases
VEGF regulates angiogenesis via interaction with receptor tyrosine kinases
VEGFR-2/KDR and VEGFR-1/Flt-1
Shinkaruk S, et al. Curr Med Chem Anti-Canc Agents. 2003;3: Luttun A, et al. Ann N Y Acad Sci. 2002;979:80-93.

21. First-line Chemotherapy + Bevacizumab in mCRC: Efficacy
Comparative Regimens, Mos
PFS OS
IFL/Bev vs IFL[1]
10.6 vs 6.2
20.3 vs 15.6
FOLFOX4/XELOX/Bev vs FOLFOX4/XELOX[2]
9.4 vs 8.0
21.3 vs 19.9
FOLFOX/Bev vs FOLFIRI/Bev[3]
10.3 vs 10.2
23.7 vs 25.5
Bev, bevacizumab; FOLFIRI; fluorouracil, leucovorin, irinotecan; FOLFOX; fluorouracil, leucovorin, oxaliplatin; IFL, fluorouracil, leucovorin, irinotecan; mCRC, metastatic colorectal cancer; NR, not reported; OS, overall survival; PFS, progression-free survival; XELOX, capecitabine, oxaliplatin.
1. Hurwitz H, et al. N Engl J Med. 2004;350: Saltz LB, et al. J Clin Oncol. 2008;26: Bendell JC, et al. Oncologist. 2012;17:

22. Bevacizumab-Associated Toxicity
Adverse Event
Incidence With Bev Across Indications,[1] %
Comments
Grade ≥ 3 ATE
2.6
Risk of ATE increased in pts 65 yrs of age or older or with ATE history
Grade 3/4 HTN
5-18*
Patients should receive otherwise standard CV prophylaxis and have BP monitored and managed
GI perforations
Grade ≥ 3 hemorrhagic event †
Bev not recommended for pts with serious hemorrhage or recent hemoptysis
Risk of major bleeding does not appear to be increased in pts receiving full-dose anticoagulation tx without other risk factors
Wound complications
15‡
Discontinue 4-8 wks before surgery; resume 6-8 wks postsurgery
ATE, arterial thromboembolic events; Bev, bevacizumab; BP, blood pressure; CV, cardiovascular; GI, gastrointestinal; HTN, hypertension; NSCLC, non-small-cell lung cancer; tx, treatment; VTE, venous thromboembolic events.
*Predominantly grade 3.
†May apply more to NSCLC.
‡When surgery conducted during bev therapy.
Potential for increased VTE risk controversial; increased risk noted in 1 study but not in others.[2,3]
1. Bevacizumab [package insert]. South San Francisco, CA: Genentech; Nalluri SR, et al. JAMA. 2008;300; Hurwitz H, et al. J Clin Oncol. 2011;29:

23. EGFR-Targeted Agents as First-line Therapy in KRAS WT mCRC: Efficacy
Trial
Comparative Regimens
Median PFS, Mos
Median OS, Mos
CRYSTAL[1]
FOLFIRI/Cetux vs FOLFIRI
9.9 vs 8.4
23.5 vs 20.0
OPUS[2]
FOLFOX4/Cetux vs FOLFOX4
8.3 vs 7.2
22.8 vs 18.5
PRIME[3-5]
FOLFOX4/Pmab vs FOLFOX4
9.6 vs 8.0
23.8 vs 19.4
FOLFOX4/Pmab vs FOLFOX4 (KRAS/NRAS WT)
10.1 vs 7.9
26.0 vs 20.2
COIN[6]
FOLFOX/XELOX/Cetux vs FOLFOX/XELOX
8.6 vs 8.6
17.0 vs 17.9
Cetux, cetuximab; EGFR, epidermal growth factor receptor; FOLFIRI; fluorouracil, leucovorin, irinotecan; FOLFOX; fluorouracil, leucovorin, oxaliplatin; mCRC, metastatic colorectal cancer; OS, overall survival; PFS, progression-free survival; Pmab, panitumumab; WT, wild-type; XELOX, capecitabine, oxaliplatin.
Worse PFS outcome with panitumumab + FOLFOX4 in mutant KRAS disease[3]
1. Van Cutsem E, et al. J Clin Oncol. 2011;29: Bokemeyer C, et al. Ann Oncol. 2010;22: Douillard JY, et al. J Clin Oncol. 2010;28: Douillard JY, et al. ASCO Abstract Douillard JY, et al. N Engl J Med. 2013;369: Maughan TS, et al. Lancet. 2011;377:

24. First-line Therapy in KRAS WT mCRC: EGFR- vs VEGF-Targeted mAbs
Trial
Comparative Regimens
PFS, Mos
OS, Mos
PEAK[1]
(N = 285)
mFOLFOX6/Pmab vs mFOLFOX6/Bev
10.9 vs 10.1
NR vs 25.4
FIRE-3[2]
(N = 592)
FOLFIRI/Cetux vs FOLFIRI/Bev
10.0 vs 10.3
28.7 vs 25.0*
*Statistically significant difference.
The primary endpoint of ORR was not significantly different between treatment arms in the FIRE-3 study (62% vs 58%; P = .183)[2]
Bev, bevacizumab; Cetux, cetuximab; EGFR, epidermal growth factor receptor; FOLFIRI; fluorouracil, leucovorin, irinotecan; FOLFOX; fluorouracil, leucovorin, oxaliplatin; mCRC, metastatic colorectal cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; Pmab, panitumumab; VEGF, vascular endothelial growth factor; WT, wild-type; XELOX, capecitabine, oxaliplatin.
1. Schwartzberg LS, et al. ASCO GI Abstract Heinemann V, et al. ASCO Abstract LBA3506.

25. Patients with mCRC and KRAS WT, ECOG PS 0/1
Phase III Trial: First-line CT + Either Cetux or Bev in KRAS-WT mCRC
FOLFOX or FOLFIRI + Bevacizumab q2w
Patients with mCRC and KRAS WT, ECOG PS 0/1
(N = 2900)
FOLFOX or FOLFIRI + Cetuximab q1w
Bev, bevacizumab; Cetux, cetuximab; CT, computed tomography; FOLFIRI; fluorouracil, leucovorin, irinotecan; FOLFOX; fluorouracil, leucovorin, oxaliplatin; mCRC, metastatic colorectal cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; q1w, every week; q2w, every 2 weeks; TTF, time to treatment failure; WT, wild type.
Primary endpoint: OS
Secondary endpoints: ORR, PFS, TTF, duration of response
A third arm with CT + bevacizumab + cetuximab was closed to accrual in September 2009
ClinicalTrials.gov. NCT

26. Anti-EGFR Mab Skin Toxicity
Nearly 100% incidence
STEPP Trial
Pre-emptive rx superior to reactive
Doxycycline 100 mg BID
Topical steroid (1% hydrocortisone cream) applied to face, hands, feet, neck, back, and chest at bedtime
Skin moisturizer applied to face, hands, feet, neck, back, and chest on rising
Sunscreen
Results
Decreased skin toxicity
Decreased diarrhea!
Decreased hypomagnesemia!
Same clinical outcome
BID, twice a day; EGFR, epidermal growth factor receptor; Mab, monoclonal antibody; rx, treatment.
Lacouture ME, et al. J Clin Oncol. 2010;28:

27. Stage IVA Strategies
Surgery to remove primary and liver metastases then adjuvant therapy
Surgery to remove primary tumor, chemotherapy, then surgery for liver lesions
Chemotherapy for a period then surgery together or stepped

28. Neoadjuvant Chemotherapy: Risks/Benefits
New Developments in the Treatment of Colorectal Cancer
Neoadjuvant Chemotherapy: Risks/Benefits
Risks
Early progression precludes surgery
Chemotherapy-associated liver damage
Benefits
Patients progressing on initial therapy have unfavorable tumor biology and resection is likely not to be curative
Renders borderline lesions resectable 28

29. EORTC 40983: FOLFOX4 in mCRC With Resectable Liver Metastases
Phase III study: patients with CRC and resectable liver metastases; WHO/ECOG performance status 0-2
(N = 364)
FOLFOX4
for 6 cycles (12 wks)
(n = 182)
Surgery
FOLFOX4
for 6 cycles (12 wks)
Surgery
(n = 182)
ECOG, Eastern Cooperative Oncology Group; EORTC, European Organization for Research and Treatment of Cancer; FOLFOX4, 5-fluorouracil, leucovorin, oxaliplatin; mCRC, metastatic colorectal cancer; OS, overall survival; PFS, progression-free survival; WHO, World Health Organization.
Primary endpoint: PFS
Secondary endpoints: OS, complete resection
Nordlinger B, et al. Lancet. 2008;371:

30. EORTC: Resectable Liver Metastases PFS
100 80
HR: 0.77 (95.66% CI: ; P = .041)
PFS (%)
+8.1% at 3 yrs 60
36.2% 40
Periop CT
CT, computed tomography scan; EORTC, European Organization for Research and Treatment of Cancer; FOLFOX; fluorouracil, leucovorin, oxaliplatin; OS, overall survival; PFS, progression-free survival. 20
28.1%
Surgery only 1 2 3 4 5 6
Yrs
5-yr OS rate was not significantly different between FOLFOX or surgery alone (51.2% vs 47.8%; P = .34)
Nordlinger B, et al. Lancet. 2008;371: Nordlinger B, et al. Lancet Oncol. 2013;[Epub ahead of print]. 30

31. Neurotoxicity Study of CaMg vs CaMg/ Placebo vs Placebo in Colon Cancer: Results
Time to Grade 2 Oxaliplatin-Induced Neuropathy
100 90 80 70 60
Without Grade 2 Neuropathy (% of Patients) 50 40 30
CaMg/CaMg Placebo/placebo CaMg/placebo 20
CaMg, calcium and magnesium; IV, intravenous. 10
P = .9721 1 2 3 4 5 6 7 8 9 10 11 12
Cycle
Pts at Risk, n CaMg/CaMg Placebo/Placebo CaMg/Placebo
IV CaMg did not prevent oxaliplatin-induced neuropathy
Loprinzi CL, et al. ASCO Abstract 3501.

32. New Developments in the Treatment of Colorectal Cancer
Strategies to Consider for Continuation of Therapy (First or Later Lines)
Increasing number of patients have good disease control for prolonged periods
Most trials for new therapies or combinations treat until progression of disease or treatment-limiting toxicities
Strategies for patients with good disease control
Continuous therapy until progression or toxicities
Maintenance therapy
Treatment holidays 32

33. Treatment Holidays: GISCAD Trial
RANDOM I ZAT I ON
FOLFIRI
x 2 mos
Break x 2 mos then FOLFIRI
x 2 mos
EVALUATE
Previously untreated mCRC
CR, PR, SD
2:1
FOLFIRI
x 2 mos
FOLFIRI
x 4 mos
CR, complete response; FOLFIRI, leucovorin/fluorouracil/irinotecan; mCRC, metastatic colorectal cancer; PR, partial response; SD, stable disease.
Progression: Off Trial
Labianca R, et al. Ann Oncol. 2011;22:

34. Treatment Holiday: GISCAD TrialOS
PFS
Events
145
143
Totals
146
147
Events
145
143
Totals
146
147
Continuous arm
Intermittent arm
100
100
Continuous arm
Intermittent arm 80 80 60 60
Patients (%)
Patients (%) 40 40 20 20
OS, overall survival; PFS, progression-free survival. 6 12 18 24 30 36 6 12 18
Mos
Mos
Pts at Risk, n
Continuous
146
130 95 60 39 19 10
146 75 25 10
Intermittent
147
124
101 68 43 29 13
147 70 27 9
Labianca R, et al. Ann Oncol. 2011;22:

35. OPTIMOX Studies: Maintenance or Treatment Holiday
FOLFOX 4 until progression
OPTIMOX1[1]
Maintenance therapy
(n = 620)
FOLFOX 7
FOLFOX 7
sLV5FU2
mFOLFOX 7
mFOLFOX 7
OPTIMOX2[2]
Chemotherapy-free interval
(n = 202)
FOLFOX, 5-fluorouracil, leucovorin, and oxaliplatin; mFOLFOX, modified 5-fluorouracil, leucovorin, and oxaliplatin; sLV5FU2, simplified leucovorin plus bolus and infusional fluorouracil.
sLV5FU2
mFOLFOX 7
mFOLFOX 7
Chemotherapy-Free Interval
1. Tournigand C, et al. J Clin Oncol. 2006;24: Chibaudel B, et al. J Clin Oncol. 2009;27:

36. OPTIMOX Studies: Results
OPTIMOX1 (maintenance vs continuous therapy)
No significant difference in duration of disease control, PFS, or OS
OPTIMOX2 (treatment holiday vs maintenance therapy)
Significantly better duration of disease control and PFS with maintenance therapy
No significant difference in OS
OS, overall survival; PFS, progression-free survival.
Tournigand C, et al. J Clin Oncol. 2006;24: Chibaudel B, et al. J Clin Oncol. 2009;27:

37. Maintenance Bevacizumab: MACRO Trial
Capecitabine +
Oxaliplatin +
Bevacizumab
x 6 cycles q3w
(n = 239)
Capecitabine +
Oxaliplatin +
Bevacizumab
until progression
Patients with newly diagnosed
mCRC and ECOG PS ≤ 2
ECOG, Eastern Cooperative Oncology Group; mCRC, metastatic colorectal cancer; PS, performance score; q3w, every 3 weeks.
Capecitabine +
Oxaliplatin +
Bevacizumab
x 6 cycles q3w
(n = 241)
Bevacizumab
until progression
Diaz-Rubio E, et al. Oncologist. 2012;17:15-25. 37

38. MACRO: Overall Survival (ITT)
XELOX-Bev
Bev
Patients, n
239
241
Events, n (%)
175 (73)
174 (7%)
Censored, n (%)
64 (27)
67 (28)
Median (95% CI)
23.2 (19.79,-26.01)
19.99 ( )
1.00
0.75
0.50
HR: 1.05 (95% CI: )
Survival Probability
Bev, bevacizumab; ITT, intention to treat; XELOX, capecitabine, oxaliplatin.
0.25
XELOX-Bev
Bev 3 6 9 12 15 18 21 24 27 30 33 36 39
Mos
Patients at Risk, n
XELOX-Bev
239
227
208
191
170
146
120 85 60 40 23 13 6 2
Bev
241
226
210
193
159
132
101 77 54 39 26 19 8
Diaz-Rubio E, et al. Oncologist. 2012;17:15-25. 38

39. Therapy After Disease Progression

40. What About Continuing Angiogenesis Inhibition After First-line Therapy?
Bevacizumab
ziv-aflibercept

41. E3200: Bevacizumab in Second-line Therapy for mCRC
Stratified by ECOG performance score 0 vs 1 or 2; previous XRT
Arm A
FOLFOX4 + Bevacizumab
(n = 286)
Patients with previously treated mCRC; no previous bevacizumab
(N = 820)
Arm B
FOLFOX4
(n = 291)
5-FU, 5-fluorouracil; ECOG, Eastern Cooperative Oncology Group; FOLFOX4, 5-fluorouracil, oxaliplatin, leucovorin; IV, intravenously; LV, leucovorin; mCRC, metastatic colorectal cancer; q2w, every 2 weeks; XRT, external-beam radiotherapy.
Arm C
Bevacizumab
(n = 243)
FOLFOX4
Oxaliplatin 85 mg/m2 on Day 1 q2w
5-FU 400 bolus/600 mg/m2 IV on Days 1 and 2 q2w
LV 200 mg/m2 on Days 1 and 2 q2w
Bevacizumab
10 mg/kg on Day 1 q2w
Giantonio BJ, et al. J Clin Oncol. 2007;25:

42. E3200: FOLFOX + Bev Improves OS in Previously Treated mCRC
1.0
0.8
0.6
Probability
0.4
HR: 0.76 A vs B: P = B vs C: P =.95
0.2
Bev, bevacizumab; FOLFOX4, 5-fluorouracil, oxaliplatin, leucovorin; mCRC, metastatic colorectal cancer; OS, overall survival. 6 12 18 24 30 36
OS (Mos)
Total, n
Dead, n
Alive, n
Median, Mos
A: FOLFOX4 + bevacizumab
286
254 32
12.9
B: FOLFOX4
291
264 27
10.8
C: Bevacizumab
243
219 24
10.2
Giantonio BJ, et al. J Clin Oncol. 2007;25:

43. ML18147 (TML): Continuing Bevacizumab Beyond Progression
A randomized, open-label phase III intergroup study
Stratified by first-line CT (oxaliplatin or irinotecan based), first-line PFS (≤ 9 or > 9 mos), time from last BEV dose (≤ 42 or > 42 days),
ECOG PS at baseline (0/1 or 2)
Standard second-line CT (oxaliplatin or irinotecan based) until PD
(n = 411)
Progressive mCRC after BEV + standard first-line CT (either oxaliplatin or irinotecan based) (n = 820)
5-FU, 5-fluorouracil; BEV, bevacizumab; CT, chemotherapy; ECOG PS, Eastern Cooperative Oncology Group performance status; mCRC, metastatic colorectal cancer; OS, overall survival; PD, progressive disease; PFS, progression-free survival.
BEV 2.5 mg/kg/wk + standard second-line CT (oxaliplatin or irinotecan-based) until PD
(n = 409)
Primary endpoint: OS
Bennouna J, et al. Lancet Oncol. 2013;14:29-37.

44. ML18147 (TML): Continuing Bevacizumab Beyond Progression Increases OS (ITT)
Unstratified* HR: 0.81 (95% CI: ; log-rank P = .0062)
Unstratified* HR: 0.68 (95% CI: ; log-rank P < .0001)
100
100 80 80
Stratified† HR: 0.83 (95% CI: ; log-rank P = .0211)
Stratified† HR: 0.67 (95% CI: ; log-rank P < .0001) 60 60
OS (%)
PFS (%) 40 40 20 20
4.1 mo
9.8 mos
11.2 mos
5.7 mo
CT, chemotherapy; BEV, bevacizumab; ECOG, Eastern Cooperative Oncology Group; ITT, intent to treat; OS, overall survival; PFS, progression-free survival; PS, performance score.
Mos
Mos
CT (n = 410)
BEV + CT (n = 409)
*Primary analysis method. †Stratified by first-line CT (oxaliplatin based, irinotecan based), first-line PFS (≤ 9 mos, > 9 mos), time from last dose of BEV (≤ 42 days, > 42 days), ECOG PS at baseline (0, ≥ 1).
Bennouna J, et al. Lancet Oncol. 2013;14:29-37.

45. ziv-Aflibercept (VEGF-Trap)
Fully human fusion protein and soluble recombinant decoy VEGF receptor consisting of
VEGFR-1 Ig domain 2
VEGFR-2 Ig domain 3
Human IgG1 Fc
Stronger binding than bevacizumab
Blocks VEGF and PlGF
t1/2: ~ 17 days
The Structure of VEGF Trap Fc
VEGF Trap Kd = 0.5 pM
PlGF, placental growth factor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.
VEGFR-1 Kd pM
VEGFR-2 Kd pM
Holash J, et al. Proc Natl Acad Sci U S A. 2002;99:

46. Phase III VELOUR Study: FOLFIRI ± ziv-Aflibercept as Second-line Therapy in mCRC
Stratified by previous bevacizumab (yes vs no),
ECOG PS (0 vs 1 vs 2)
FOLFIRI + ziv-Aflibercept 4 mg/kg q2w
(n = 612)
Patients with mCRC progressing on first-line oxaliplatin-based chemotherapy* (planned N = 1226)
FOLFIRI + Placebo q2w
(n = 614)
*30% had previous bevacizumab.
ECOG, Eastern Cooperative Oncology Group; FOLFIRI, fluorouracil/leucovorin/irinotecan; mCRC, metastatic colorectal cancer; ORR, overall response rate; OS, overall survival; q2w, once every 2 weeks; PFS, progression-free survival; PS, performance status.
Primary endpoint: OS
Secondary endpoints: PFS, ORR, safety, immunogenicity
No correlatives
Van Cutsem E, et al. J Clin Oncol. 2012;30: ClinicalTrials.gov. NCT

47. VELOUR Study: Survival Results
Stratified HR: (95.34% CI: ; log-rank P = .0032)
Stratified HR: (95% CI: ; log-rank P < .0001)
100
100 80 80 60 60
Aflibercept/FOLFIRI Median: mos
OS (%)
PFS (%)
Aflibercept/FOLFIRI Median: 6.90 mos 40 40
FOLFIRI, fluorouracil/leucovorin/irinotecan; mCRC, metastatic colorectal cancer; OS, overall survival; PFS, progression-free survival. 20
Placebo/FOLFIRI Median: mos 20
Placebo/FOLFIRI Median: 4.67 mos 3 6 9 12 15 18 21 24 27 30 33 36 39 3 6 9 12 15 18 21 24 27 30
Mos
Mos
Van Cutsem E, et al. J Clin Oncol. 2012;30:

48. Overall Survival: Stratified by Previous Bevacizumab; ITT Population
No Previous Bevacizumab
100
HR: (95.34% CI: )
100
HR: (95.34% CI: ) 80 80 60 60
OS (%)
Aflibercept/FOLFIRI Median: 12.5 mos
OS (%)
Aflibercept/FOLFIRI Median: 13.9 mos 40 40 20
Placebo/FOLFIRI Median: 11.7 mos 20
Placebo/FOLFIRI Median: 12.4 mos
AFL, aflibercept; FOLFIRI, fluorouracil/leucovorin/irinotecan; ITT, intent to treat. 3 6 9 12 15 18 21 24 27 30 33 36 39 3 6 9 12 15 18 21 24 27 30 33 36 39
Mos
Mos
Pts at Risk, n Placebo AFL
Pts at Risk, n Placebo AFL
81 89
54 59
37 36
22 22
13 13
94 112
65 82
38 62
Tabernero J, et al. Eur J Cancer. 2013;[Epub ahead of print].

49. Increased Incidence of Adverse Events During Therapy With ziv-Aflibercept
Increased Grade 3/4 AEs in Aflibercept Arm, %
FOLFIRI + Aflibercept
(n = 611)
FOLFIRI + Placebo
(n = 605)
Any
83.5
62.5
Diarrhea
19.3
7.8
Asthenia
16.9
10.6
Stomatitis/ulceration
13.7
5.0
Infection
12.3
6.9
Palmar-plantar erythrodysesthesia
2.8
0.5
Anti-VEGF–associated events
Hypertension
1.5
Hemorrhage
2.9
1.7
Arterial thromboembolic events
1.8
Venous thromboembolic events
7.9
6.3
Neutropenia
36.7
29.5
Complicated neutropenia
5.7
Thrombocytopenia
3.3
AEs, adverse events; FOLFIRI, fluorouracil/leucovorin/irinotecan; VEGF, vascular endothelial growth factor.
Van Cutsem E, et al. J Clin Oncol. 2012;30:

50. Second-line Therapy With EGFR-Targeted mAbs in mCRC
Trial
Comparative Regimens
PFS, Mos
OS, Mos
EPIC[1]
Irinotecan/Cetux vs Irinotecan
4.0 vs 2.6*
10.7 vs 10.0
181[2]
FOLFIRI/Pmab vs FOLFIRI
5.9 vs 3.9*
14.5 vs 12.5
SPIRITT[3]
FOLFIRI/Pmab vs FOLFIRI/Bev
7.7 vs 9.2
18.0 vs 21.4
*Statistically significant difference.
Bev, bevacizumab; Cetux, cetuximab; EGFR, epidermal growth factor receptor; FOLFIRI; fluorouracil, leucovorin, irinotecan; OS, overall survival; mCRC, metastatic colorectal cancer; PFS, progression-free survival; Pmab, panitumumab.
1. Sobrero AF, et al. J Clin Oncol. 2008;26: Peeters M, et al. J Clin Oncol. 2010;28: Hecht JR, et al. ASCO Abstract 335.

51. Patients With Wild-Type KRAS Patients With Mutant KRAS
KRAS as a Biomarker for Panitumumab Response in Previously Treated mCRC
Patients With Wild-Type KRAS
Patients With Mutant KRAS
100
Pmab + BSC
100
BSC alone
Median in Wks
Mean in Wks
Pmab + BSC
Events, n/N (%)
BSC alone
Median in Wks
Mean in Wks 80
115/124 (93)
12.3
19.0 80
Events, n/N (%)
114/119 (96)
7.3
9.3
76/84 (90)
7.4
9.9 60 60
95/100 (95)
7.3
10.2
HR: 0.45 (95% CI: ; stratified log-rank test: P < .0001)
PFS (%)
PFS (%) 40
HR: 0.99 (95% CI: ) 40
BSC, best supportive care; mCRC; metastatic colorectal cancer; PFS, progression-free survival; Pmab, panitumumab. 20 20 4 8 12 16 20 24 28 32 36 40 44 48 52 4 8 12 16 20 24 28 32 36 40 44 48 52
Wks
Wks
Amado RG, et al. J Clin Oncol. 2008;26: 51

52. Latest Evidence on the Clinical Utility of Other Biomarkers in mCRC
KRAS G13D[1]
Mixed data on prognostic and predictive value
No benefit with anti-EGFR in analyses of large randomized trials
BRAF[2,3]
Prognostic of poor outcome
Mixed data on predictive value; not seen in first-line trials
Expanded RAS analysis[4,5]
~ 10% of KRAS 12/13 WT tumors have other RAS mutations
KRAS exons 3, 4
NRAS exons 2,3,4
No benefit with anti-EGFR Mab
EGFR, epidermal growth factor receptor; Mab, monoclonal antibody; mCRC; metastatic colorectal cancer; WT, wild type.
1. Peeters M, et al. J Clin Oncol. 2013; 31: Richman SD, et al. J Clin Oncol. 2009;27: Van Custem E, et al. J Clin Oncol. 2011;29: Peeters M, et al. Clin Cancer Res. 2013;19: Douillard JY, et al. N Engl J Med. 2013;369:

53. Arm A: Regorafenib 160 mg PO QD + BSC
CORRECT: Regorafenib After Progression on All Available Std Therapy in mCRC
Arm A: Regorafenib 160 mg PO QD + BSC
3 wks on, 1 wk off
(n = 505)
Patients with progression after all available standard therapy
(N = 760)
2:1
Arm B: Placebo + BSC
3 wks on, 1 wk off
(n = 255)
BSC, best supportive care; mCRC, metastatic colorectal cancer; OS, overall survival; PO, orally; QD, daily; Std, standard.
Primary endpoint: OS
Approximately 50% of patients with ≥ 4 systemic therapies
All patients had received bevacizumab
Grothey A, et al. Lancet. 2013;381:

54. CORRECT: Overall Survival
100 50 25 75
100 50 25 75
HR: 0.77 (95% CI: ; P = .0052)
HR: 0.49 (95% CI: ; P < )
OS (%)
PFS (%)
Placebo (n = 255)
Regorafenib (n = 505)
Placebo (n = 255)
Regorafenib (n = 505)
OS, overall survival; PFS, progression-free survival.
Mos From Randomization
Mos From Randomization
Regorafenib
Placebo
Median, mos
6.4
5.0
IQR
Regorafenib
Placebo
Median, mos
1.9
1.7
IQR
Primary endpoint met prespecified stopping criteria at second interim analysis (1-sided P ≤ at approximately 74% of events required for final analysis)
Grothey A, et al. Lancet. 2013;381:

55. CORRECT: Toxicities Occurring in ≥ 10% of Patients
Adverse Event
Regorafenib (n = 500)
Placebo (n = 253)
All Grades
Grade 3
Grade 4
Hand–foot skin reaction 47 17 8
< 1
Fatigue 9 28 5
Hypertension 7 6 1
Diarrhea 34
Rash/desquamation 26 4
Anorexia 30 3 15
Oral mucositis 27
Thrombocytopenia 13 2
Fever 10
Nausea 14 11
Dose modification due to adverse event in 67% of patients receiving regorafenib vs 23% of patients receiving placebo.
Grothey A, et al. Lancet. 2013;381:

56. New Developments in the Treatment of Colorectal Cancer
Summary
Colorectal cancer is a common disease; treatment advances in increments throughout the past decade
Molecular personalization limited for metastatic disease
Personalization should also consider patient goals, preferences, comorbidities, performance status
Despite new drugs and advances during past 10 yrs, progress has slowed; consider and offer clinical trials

57. Go Online for More CCO Coverage of CRC!
Capsule Summaries of all the key data Additional CME-certified slideset on CRC with expert faculty commentary on all the key studies
clinicaloptions.com/oncology