Two new drugs for colorectal cancer may offer new hope for late stage patients, and they might hit the market in 2013. Dr. Rich Goldberg, physician-in-chief of the Ohio State University Medical Center and a leader in colorectal cancer research is going to give you the straight facts about these drugs: * What hope might they offer? * What side effects do they cause? * Will either be the right drug for you? About Dr. Goldberg: Dr. Richard Goldberg is an internationally renowned gastrointestinal oncologist and the physician-in-chief at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Institute (OSUCCC-James). He is a member and former chair of the National Cancer Institute Colorectal Task Force and an international leader in evaluating new agents for the treatment of colorectal cancer and researching inherited colorectal cancer syndromes

1. Welcome!
What New Drugs Are On the Way for
Colorectal Cancer?
Part of Fight Colorectal Cancer’s Monthly
Patient Webinar Series
Our webinar will begin shortly
www.FightColorectalCancer.org
877-427-2111

2. 1. Tonight’s speaker: Dr. Richard Goldberg
2. Archived webinars: Link.FightCRC.org/Webinars
3. Follow up survey to come via email. Get a free Blue
Star of Hope pin when you tell us how we did tonight
4. Ask a question in the panel on the right side of your
screen
5. Or call the Fight Colorectal Cancer Answer Line at
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3. Dr. Richard Goldberg
Physician-in-chief at The Ohio State University
Comprehensive Cancer Center
A member and former chair of the National Cancer
Institute Colorectal Task Force
An international leader in evaluating new agents for
the treatment of colorectal cancer and researching
inherited colorectal cancer syndromes

4. New Agents in
Colorectal Cancer
Management
Richard Goldberg
Wexner Medical Center at
The Ohio State University

5. Heterogeneity:
Incidence of Selected Mutations in
Advanced Colorectal Cancers
Study N KRAS NRAS BRAF PI3K Overlapping
Mutation Mutation Mutation Mutation Mutations
Rate Rate Rate Rate
De 747 40% 2.6% 4.7% 14.5% 20% of MT-KRAS
Roock had MT-PI3K
CAIRO 2 559 39.4% N/A 8.7% 9.9% 51% MT-KRAS
had MT-PI3K
COIN 1316 43% 4% 8% N/A 2% MT-KRAS
had MT-NRAS
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

6. In MCRC: Cytotoxics Remain the Nucleus
 First Line:
 5-FU/capecitabine +/- bevacizumab
 FOLFOX +/- bevacizumab
 FOLFIRI +/- bevacizumab
 FOLFIRINOX +/- bevacizumab
 ? Role for EGFR targeted therapy in first line: 80405
 Second Line
 Reciprocal of first line +/- bevacizumab or an EGFR
monoclonal AB
 Third Line:
 KRAS wt: EGFR monoclonal +/- irinotecan
 KRAS mt: no standard therapy
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

7. Drug Development:
The Spotlight is on Biologics
 Repackaging cytotoxics
 Liposome encapsulation: irinotecan or SN-38
 Platinum analogues: pico- or satroplatin
 Exploiting biologics
 Pinpoint a single driving mutation (imatinib & c-kit)
 Drug multiple targets
 Discover a “dirty drug”: exs: regorafinib, BIBF1120
 Combine biologics: ex. Bond 2
 Combine biologics and cytotoxics: ex. Bond 2
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

8. Expression
Center – S. Siena, et al, JNCI, 2009
The Ohio State University Comprehensive Cancer
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

9. Expression
Center – S. Siena, et al, JNCI, 2009
The Ohio State University Comprehensive Cancer
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

10. Expression
Brivinib
Ramucirumab
BIBF 1120
Regorafinib
Perifosine
Center – S. Siena, et al, JNCI, 2009
The Ohio State University Comprehensive Cancer
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

11. Expression
Brivinib
Ramucirumab
BIBF 1120
Regorafinib
Perifosine
Center – S. Siena, et al, JNCI, 2009
The Ohio State University Comprehensive Cancer
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

12. Expression
Brivinib
Ramucirumab
BIBF 1120
Regorafinib
Perifosine
Center – S. Siena, et al, JNCI, 2009
The Ohio State University Comprehensive Cancer
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

13. Targeted Agents
 On the formulary Target
 Bevacizumab VEGF
 Cetuximab EGFR receptor
 Panitumumab EGFR receptor
 On the way to ODAC?
 Regorafenib VEGF, RAF, RET, KIT, PDGFR
 Aflibercept (VEGF trap) VEGF
 Perifosine Akt, JNK, MAPK
 On the radar screen
 Brivinib FGF & VEGF
 Pertuzumab HER-2
 Rilotumumab c-Met (hepatocyte GF)
 Ramucirumab VEGF-2
 BIBF1120 VEGF1-3, PDGF, FGFR
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

14. A drug that works
at the cell surface
AFLIBERCEPT
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

15. Large molecule VEGF inhibitors
PlGF VEGF-A VEGF-C,
VEGF-B VEGF-D
Bevacizumab
Ramucirumab
Aflibercept
(VEGF Trap)
Functions
VEGF-R1 VEGF-R2 VEGF-R3
(Flt-1) (KDR/Flk-1) (Flt-4)
Migration Proliferation Lymphangiogenesis
Invasion, Survival Survival, Permeability
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

16. Aflibercept
• Soluble fusion protein
Aflibercept
• Consists of portion of extracellular
VEGFR-1
domains of human VEGF receptors 1
and 2 fused to human IgG1 Fc portion
• Binds all VEGF-A isoforms, VEGF-B
and PlGF
• High affinity: binds VEGF-A and PlGF
IgG more tightly than native receptors
VEGFR-2 Fc • Half-life in humans ~17 days
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

17. 17
VELOUR
Phase III Trial 2nd Line
VEGF1 &2 and PDGF Decoy
30% of patients had prior BEV
Aflibercept
600 pts
4 mg/kg IV
+ FOLFIRI
mCRC after
failure of an
oxaliplatin R
based regimen
Placebo + FOLFIRI
Stratification factors: 600 pts
Prior bevacizumab (Y/N)
ECOG PS (0 vs 1 vs 2)
PI: Allegra
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

18. Overall Survival - ITT Population
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Cut-off date = February 7, 2011; Median follow-up = 22.28 months
Research Institute

19. Progression Free Survival
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Cut-off date = May 6, 2011 Research Institute

20. Response Rate
Placebo Aflibercept
Evaluable population*, % N = 530 N = 531
Best Overall Response
Complete response 0.4 0
Partial response 10.8 19.8
Stable disease 64.9 65.9
Progressive disease 21.5 10.4
Not evaluable 2.5 4.0
Overall Response Rate
(CR or PR) 11.1 19.8
95% CI 8.5 to 13.8 16.4 to 23.2
p= 0.0001**
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

21. Safety – Most frequent Adverse Events
Safety Population, % of patients Placebo, N = 605 Aflibercept N = 611
All All
Grade 3-4 Grade 3-4
Grades Grades
Diarrhea 56.5 7.8 69.2 19.3
Neutropenia** 56.3 29.5 67.8 36.7
Complicated neutropenia 2.8 5.7
Asthenic conditions (HLT) 50.2 10.6 60.4 16.9
Stomatitis & ulceration (HLT) 34.9 5.0 54.8 13.7
Thrombocytopenia** 33.8 1.7 47.4 3.3
Infections (SOC) 32.7 6.9 46.2 12.3
Decrease appetite 23.8 1.8 31.9 3.4
Weight decreased 14.4 0.8 31.9 2.6
Palmar plantar
4.3 0.5 11.0 2.8
erythrodysaesthesia
Skin hyperpigmentation 2.8 0 8.2 0
Dehydration 3.0 1.3 9.0 4.3
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
** From lab Research Institute

22. Safety – Anti-VEGF Associated Events
Safety population, % of Placebo N = 605 Aflibercept N = 611
patients
Grouped Term, PT All Grade Grade 3/4 All Grade Grade 3/4
Proteinuria* 40.7 1.2 62.2 7.9
Hypertension 10.7 1.5 41.4 19.3
Haemorrhage 19.0 1.7 37.8 2.9
Epistaxis 7.4 0 27.7 0.2
GI origin 5.1 1.0 10.0 2.0
Dysphonia (PT) 3.3 0 25.4 0.5
Headache (PT) 8.8 0.3 22.3 1.6
Venous thromboembolic event 7.3 6.3 9.3 7.9
Pulmonary embolism 3.5 3.5 4.7 4.7
Arterial thromboembolic event 1.5 0.5 2.6 1.8
Fistula (GI origin) 0.3 0.2 1.1 0.3
Wound healing 0.8 0 0.5 0.3
GI perforation 0.5 0.3 0.5 0.5
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

23. Deaths During Study Treatment
Placebo Aflibercept
% – Safety Population
N = 605 N = 611
Number of deaths within 30d from last dose 3.1 4.9
Disease progression 2.1 2.3
Adverse events: 1.0 2.6
Infections (sepsis and neutropenic sepsis) 0.5 0.7
Death/sudden death 0.3 0.3
Pulmonary embolism 0 0.2
GI hemorrhage (duodenal ulcer) 0 0.2
GI disorders (inflammation/obstruction) 0 0.3
Respiratory disorders 0.2 0.3
Other** 0 0.7
**Other: dehydration (2pts), metabolic encephalopathy (1pt), hypovolemic shock (1pt)
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

24. Discontinuation of Study Treatment
ITT Population Placebo Aflibercept
% N = 614 N = 612
Discontinued study treatment 97.4 96.9
Disease progression 71.2 49.8
Adverse event 12.1 26.6
Patient request 7.0 12.6
Investigator decision 3.4 3.3
Metastatic surgery 1.6 2.0
Other causes* 2.1 2.6
Study treatment ongoing 1.8 2.3
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

25. A drug that hits
A cell surface receptor
RAMUCIRUMAB
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

26. 26
Phase III Trial 2nd Line
Targets VEGFR-2
Projected completion date 8/2014
Primary EP: OS
525 pts Ramucirumab IV
+ FOLFIRI q 2 weeks
mCRC after
failure
FP/oxaliplatin R
+ BEV regimen
525 pts Placebo + FOLFIRI
q 2 weeks
PIs: Tabernero, Grothey
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

27. A drug being compared
To bevacizumab with
chemotherapy
BIBF 1120
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

28. 28
Phase II Trial First Line
Targets , VEGF, PDGF, FDGF
Presented at ESMO 9/11
Primary EP: OS
63 pts BIBF1120
+ mFOLFOX6
mCRC R
Bevacizumab
63 pts + mFOLFOX6
Van Cutsem
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

29. Efficacy/Toxicity
FOLFOX + FOLFOX +
Bevacizumab BIBF1120
No. of patients 63 63
ORR 53.7% 61.2%
PFS at 9 mos 69% 63%
Median OS N.A. N.A
GI toxicity, G>3 29.3 % 11.8%
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

30. A drug that hits
multiple internal targets
REGORAFINIB
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

31. Mode of action of regorafenib
 Regorafenib inhibits
multiple cell-signaling
kinases:
 Angiogenic
 VEGFR1–3, TIE2
 Stromal
 PDGFR-β, FGFR
 Oncogenic
 KIT, PDGFR, RET
The Ohio State University Comprehensive Cancer
Center – Wilhelm SM et al. Int J Cancer 2011
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

32. 32
CORRECT Trial
Targets VEGF, TIE2, RAF, Ret, c-Kit
Primary EP: OS
505 pts Regorafinib po
+ BSC
mCRC after
failure of all R
standard Rx
Placebo
255 pts
+ BSC
PI: Grothey
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

33. Overall survival (primary endpoint)
Primary endpoint met prespecified stopping criteria at interim analysis
(1-sided p<0.009279 at approximately 74% of events required for final analysis)
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

34. Progression-free survival
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

35. Overall response and disease control rates
Regorafenib Placebo
Best response, %
N=505 N=255
Complete response 0 0
Partial response 1.0 0.4
Stable disease 43.8 14.9
Progressive disease 49.5 80.0
Disease control rate, %* 44.8 15.3
*DCR = PR + SD; p<0.000001
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

36. Drug-related, treatment-emergent adverse events
occurring in ≥10% of patients at any grade
Regorafenib Placebo
Adverse event, %
N=500 N=253
All Grade Grade Grade All Grade Grade Grade
grades 3 4 5 grades 3 4 5
Hand–foot skin reaction 46.6 16.6 0 0 7.5 0.4 0 0
Fatigue 47.4 9.2 0.4 0 28.1 4.7 0.4 0
Hypertension 27.8 7.2 0 0 5.9 0.8 0 0
Diarrhea 33.8 7.0 0.2 0 8.3 0.8 0 0
Rash/desquamation 26.0 5.8 0 0 4.0 0 0 0
Anorexia 30.4 3.2 0 0 15.4 2.8 0 0
Mucositis, oral 27.2 3.0 0 0 3.6 0 0 0
Thrombocytopenia 12.6 2.6 0.2 0 2.0 0.4 0 0
Fever 10.4 0.8 0 0 2.8 0 0 0
Nausea 14.4 0.4 0 0 11.1 0 0 0
Bleeding 11.4 0.4 0 0.4 2.8 0 0 0
Voice changes 29.4 0.2 0 0 5.5 0 0 0
Weight loss 13.8 0 0 0 2.4 0 0 0
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

37. Summary of CORRECT
 Overall survival:
 6.4 vs 5.0 months, HR=0.77, p=0.0052
 Progression-free survival:
 1.9 vs 1.7 months, HR=0.49, p<0.000001
 Disease control rate (PR + SD):
 44.8% vs 15.3%, p<0.000001
 Main treatment-related adverse events:
 fatigue, hand–foot skin reaction, diarrhea, poor
appetite, voice changes, hypertension, oral mucositis,
and rash/peeling skin
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

38. A drug that apparently
didn’t make it
PERIFOSINE
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

39. Perifosine
 Oral alkylphospholipid
 Inhibition of multiple signal transduction
pathways
 AKT inhibition
 NF- B inhibition
 Activation of apoptotic pathway via JNK
 Selective tumor cell accumulation and potential
disruption of membrane asymmetry
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

40. Perifosine: Mechanism of Action
Selective tumor cell accumulation and
potential disruption of membrane
asymmetry
Activates Prevents
apoptotic JNK AKT recruitment
pathway of AKT to the
Apoptosis Cell growth cell
and Survival membrane
Inhibition of Modulates the
NF- CDK 2
chemoresistance cell cycle via
Cellular Stress Cell Cyclep21
and Survival
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

41. 41
Perifosine
Targets PI3K & akt Pathway and NF-kB
Primary EP: OS
20 pts Perifosine po
+ capecitabine
after
failure of all R
standard Rx
18 pts Capecitabine
Bendell, J Clin Oncol, 33:3394-4400, 2011
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

42. Results: Response
 35 / 38 Patients evaluable for efficacy
 3 placebo patients not evaluable: 2 off for toxicity at d 14, 46; 1 off at d 4 for other disease
All Evaluable: n = 35
CR PR Duration of Response SD > 12 Weeks SD or >*
Group n
N (%) N (%) (months) N (%) N (%)
CR: 34
P-CAP 20 1 (5%) 3 (15%) 11 (55%) 15 (75%)
PR: 21, 19, 11
CAP 15 0 1 (7%) PR: 7 5 (33%) 6 (40%)
*p = 0.036
5-FU Refractory: n = 25
PR Duration of Response SD > 12 Weeks SD or >*
Group n
N (%) (months) N (%) N (%)
P-CAP 14 1 (7%) 19 months 8 (57%) 9 (64%)
CAP 11 0 - 3 (27%) 3 (27%)
*p = 0.066
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

43. Kaplan-Meier plot of time to progression (TTP) in (A) all evaluable patients and (B) evaluable
fluorouracil-refractory patients.
Bendell J C et al. JCO 2011;29:4394-4400
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
©2011 by American Society of Clinical Oncology Research Institute

44. Kaplan-Meier plot of overall survival (OS) in (A) all evaluable patients and (B) evaluable
fluorouracil-refractory patients.
Bendell J C et al. JCO 2011;29:4394-4400
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
©2011 by American Society of Clinical Oncology Research Institute

45. Efficacy
perifosine+
Capecitabine capecitabine P-value
No. of patients 18 20
ORR (%) 7% 20% n.s.
TTP (wks) 10.1 27.5 p< 0.001
Median OS (mo) 6.5 15.1 p< 0.006
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

46. 46
X-Pect Phase III Study:
Completed Enrollment 7/11
Primary EP: OS
215 pts Perifosine po
+ capecitabine
mCRC after
failure of all R
standard Rx
215 pts Capecitabine
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

47. Press release 4/12:
Did not meet survival endpoint
Details pending
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

48. Conclusions
 Patients with resectable disease at presentation are
potentially curable
 Some with unresectable disease are too
 Combination chemotherapy +/- biologics are
standard in fit patients
 We are still learning how to best exploit out tools
 We have a number of new drugs coming
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

49. Another drug that apparently
didn’t make it
BRIVINIB
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

50. PHASE III RANDOMIZED TRIAL OF CETUXIMAB +
EITHER BRIVANIB OR PLACEBO IN PATIENTS
WITH METASTATIC, CHEMOTHERAPY
REFRACTORY, K-RAS WILD-TYPE COLORECTAL
CARCINOMA:
THE NCIC CLINICAL TRIALS GROUP AND AGITG
CO.20 TRIAL
LL Siu, JD Shapiro, DJ Jonker, CS Karapetis, JR Zalcberg, J Simes,
F Couture, MJ Moore, TJ Price, J Siddiqui, LM Nott, D Charpentier, W
Liauw, M Sawyer, M Jefford, NM Magoski, A Haydon, I Walters, D Tu, CJ
O’Callaghan
GI ASCO 2012, Abstract 386
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

51. Schema
Targets VEGF and FGF
Brivanib
R +
1° endpoint:
A Cetuximab Overall Survival
N
n = 376
D
Last pt randomized:
O February 10, 2011
M Placebo
I Median follow-up:
Z + 19 months
E Cetuximab
n = 374
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

52. Combining targeted agents
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

53. A RANDOMIZED, PHASE IB/II TRIAL OF
RILOTUMUMAB
OR GANITUMAB
WITH PANITUMUMAB
VS PMAB ALONE
IN PATIENTS WITH WILD-TYPE KRAS
METASTATIC COLORECTAL CANCER
C Eng, E Van Cutsem, E Nowara, A Świeboda-Sadlej, NC. Tebbutt,
Mitchell, I Davidenko, KS Oliner, L Chen, J Huang, I McCaffery,
E Loh, D Smethurst, J Tabernero
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

54. Primary Endpoint:
Objective Response Rate
Panitumumab Panitumumab
Panitumumab
+ Rilotumumab + Ganitumab
+ Placebo
(AMG 102) (AMG 479)
(n = 48)
(n = 48) (n = 46)
Objective Response - n (%) 10 (21) 15 (31) 10 (22)
Complete Response (CR) 0 (0) 0 (0) 0 (0)
Partial Response (PR) 10 (21) 15 (31) 10 (22)
Stable Disease (SD) 17 (35) 19 (40) 18 (39)
Progressive Disease (PD) 16 (33) 11 (23) 15 (33)
Unevaluable/Not done 5 (10) 3 (6) 3 (6)
Disease control rate - % (95% CI) 56 (41-71) 71 (56-83) 61 (45-75)
Duration of response - median months 3.7 (3.6-NE) 5.1 (3.7-5.6) 3.7 (3.6-5.8)
(95% CI)
Posterior probability of Odds Ratio > 1 0.93 0.63
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

55. Progression-Free Survival
Panitumumab ± Rilotumumab (AMG 102)
(AMG 102)
Panitumumab ± Ganitumab (AMG 479)
(AMG 479)
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

56. Adverse Events
(Any Grade in 20% or Grade 3/4 in 2 Patients)
Panitumumab Panitumumab
Panitumumab
+ Rilotumumab + Ganitumab
+ Placebo
(AMG 102) (AMG 479)
(n = 48)
(n = 48) (n = 46)
AE (Preferred term) - % Any Grade Grade 3/4 Any Grade Grade 3/4 Any Grade Grade 3/4
Any AE 94 52 98 71 100 63
Rash 52 8 58 29 48 13
Acneiform dermatitis 33 10 35 15 26 11
Pruritus 25 0 21 0 28 2
Skin fissures 17 0 15 2 26 0
Paronychia 15 2 31 4 20 2
Dry skin 15 0 23 2 22 0
Acne 0 0 8 4 11 0
Skin toxicity 0 0 2 2 4 4
Constipation 25 6 10 0 13 0
Decreased appetite 17 2 21 2 20 2
Abdominal pain 15 6 10 4 9 7
Diarrhea 10 0 15 4 26 2
Hypomagnesemia 21 2 29 4 41 15
Fatigue 21 2 10 4 17 2
Anemia 17 8 4 0 2 0
Asthenia 15 0 8 0 13 4
AE, adverse event
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

57. Combinations Also on the Radar Screen
Agent(s) Target(s)
 Bortezomib + cetuximab NFk-B, EGFR
 Pertuzumab + cetuximab closed, toxicity
 Rilotumumab + panitumumab HGF, EGFR
 Ganitumab + panitumumab IGFR, EGFR
 IMC-A12 + cetuximab IGFR, EGFR
 Sorafenib + bevacizumab raf, VEGF
 Erlotinib + panitumumab EGFR
 Everolimus + cetuximab mTOR + EGFR
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

58. Cominations Also on the Radar Screen
Agent(s) Target(s)
 AZD6244 + cetuxumab MEK, EGFR
 BEZ235 + MEK 162 PI3-k, MEK
 BKM120 + MEK162 PI3-k, MEK
 Decitabine + panitumumab DNA methyltransferase
 Simvistatin + panitumumab Turpenes + EGFR
 Imprime PGG + cetuximab Immunity + EGFR
 EMD 525797 + cetuximab Integrin + EGFR
 Dasatinib + cetuximab BCR/ABL + EGFR
 Lenalidomide + cetuximab Apoptotic + EGFR
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

59. Modulating BRAF
 Downstream of RAS
 A potential target for patients with k-RAS mt tumors
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

60. The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

61. BRAF Inhibitors: In early testing
 Vemurafenib (PLX-4032)
 Dabrafenib (GSK2118436)
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

62. Conclusions
 Multiple targeted agents are in development
 It is likely that combinations will be more effective
than single agents
 Agents may work in specific subsets of CRC patients
who can be identified by genetic profiling
 It appears the lean years in CRC drug development
may be over
The Ohio State University Comprehensive Cancer
Center –
Arthur G. James Cancer Hospital and Richard J. Solove
Research Institute

63. Thanks for your
attention!
Questions?

64. UPCOMING WEBINARS
MANAGING YOUR SYMPTOMS AND TREATMENT SIDE
EFFECTS
MAY 16, 2012
8-9:30 PM EASTERN TIME
WHAT'S NEW IN COLORECTAL CANCER RESEARCH?
JUNE 20, 2012
8 - 9:30 PM EASTERN TIME
WHEN YOU'RE OUT OF OPTIONS
JULY 18, 2012
8 - 9:30 PM EASTERN TIME