Colorectal Cancer Research & Treatment News - recap from the May 2014 ASCO conference

Welcome to Fight Colorectal Cancer’s & Colon Cancer Alliance joint Webinar

Research News: Make Sure You Know the Latest News About CRC Research and Treatment

Our webinar will begin shortly.

ABOUT THE COLON CANCER ALLIANCE

Our mission is to knock colon cancer out of the top three cancer killers. We are doing this by

championing prevention, funding cutting-edge research and providing the highest quality patient

support services.

In 2013, the Colon Cancer Alliance:

Today’s Webinar:1. Today’s Speaker: Cathy Eng, M.D. @CathyEngMD

2. Archived Webinars: FightColorectalCancer.org/Webinars

3. AFTER THE WEBINAR: expect an email with links to the material. Also a survey on how we did, receive a Blue Star pin when completed

4. Ask a question in the panel on the RIGHT SIDE of your screen

5. Follow along via Twitter – use the hashtag #CRCWebinar

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Speaker

Cathy Eng, M.D.

Associate Professor in the Department of Gastrointestinal (GI) Medical Oncology at The University of Texas M. D. Anderson Cancer Center. Dr. Eng received her medical degree from Hahnemann University School of Medicine in Philadelphia, PA Dr. Eng is board certified in internal medicine and medical oncology.

Twitter: @CathyEngMD

Department of GI Medical Oncology

CURRENT DEVELOPMENTS IN METASTATIC COLORECTAL CANCER

Cathy Eng, M.D., F.A.C.P.Associate Professor

Associate Medical Director, Colorectal CenterDirector of Network Clinical Research, GI Med Oncology

Co-Chairman, SWOG Rectal SubcommitteeJuly 16, 2014

Cancers of the Colon and RectumInternational Statistics

Cancers of the Colon and RectumInternational Statistics

Jemal et al: Cancer Epidemiol Biomarkers Prev; 19(8) August 2010; Siegel et al: CA Cancer J Clin 2014

Incidence

Mortality

Incidence

Mortality

1.2 Million

609,000

1.2 Million

609,000

WorldwideWorldwide

per annum

USA (2014) USA (2014)

Incidence

Mortality

Incidence

Mortality

136,830

50,310

136,830

50,310

Colorectal cancer is the 3rd most common cancer inmen and the 2nd in women.

Advances in the Treatment of Metastatic Colorectal Cancer

1980 1985 1990 1995 2000 2005

Therapeutic concepts

Palliative CTNeoadjuvant CT

CapecitabineOxaliplatin

Cetuximab

Bevacizumab

Irinotecan5-FU

Panitumumab Targeted therapies

{

5-FU = 5-fluorouracil; CT = chemotherapy.

{Cytotoxic chemotherapies

Ras

OS: 20M

OS: 32 months

AfliberceptRegorafenib

IFL

IFL + be

vacizu

mab

FOLFOX/Cap

eOx

FOLFOX/Cap

eOx +

bev

FOLFIRI

FOLFIRI +

bevac

izumab

mIFL

mIFL + be

vaciz

umab

0

5

10

15

20

25

30

15.6

20.3 19.921.3

23.1

28

17.619.2

First-Line Bevacizumab in mCRC: Overall Survival

*P<0.001; †P = 0.0769.1. Hurwitz H et al. N Engl J Med. 2004;350:2335-2342; 2. Saltz LB et al. J Clin Oncol. 2008;26:2013-2019; 3. Fuchs C et al. J Clin Oncol. 2007;25:4779-4786; 4. Fuchs C et al. J Clin Oncol. 2008;26:689-690;

OS

(m

onth

s)

*

NO169662

AVF2107g1

BICC-C3,4

Approved Anti-VEGF Agents Antiangiogenic agent

Description Target Approval

BevacizumabRecombinant humanized

monoclonal antibody VEGF-A

1st-line mCRC1,2:•FDA 2004•EMEA 20052nd-line mCRC1:•FDA 2006, 2013

Aflibercept Fully human fusion protein

VEGF-AVEGF-B

PIGF

2nd-line mCRC3,4:•FDA 2012•EMEA 2013,•TGA 2013

Regorafinib Small molecule TKI VEGFR-1,2 & 3 PDGFR-b,

TIE-2, FGFR-1, Ret, Kit, & Raf kinases

Salvage5,6:•FDA 2012•CHMP 2013•TGA 2013

CHMP, Committee for Health and Medicine Products; EMEA, European Medicines Agency; FDA, United States Federal Drug Administration, FGFR, fibroblast growth factor receptor; PDGFR, platelet-derived growth factor receptor; PlGF, placental growth factor; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor .

UPDATES IN FIRST-LINE TREATMENT: ANTI- VEGF THERAPY

TRIBE Phase III Study Design

Falcone A. ASCO 2013. Abstract 3505.

Patients

• Unresectable mCRC

• No prior mCRC treatment

• Adjuvant oxali-containing chemotherapy allowed if >12 mo between tx and relapse

Treat to progression

FOLFIRI + Bev (up to 12 cycles)5-FU/LV + Bev (Maintenance)

1:1 Randomization

FOLFOXIRI + Bev (up to 12 cycles)5-FU/LV + Bev (Maintenance)

TRIBE: PFS (ITT Population)


TRIBE: Secondary Endpoint (OS)


TRIBE: Secondary Endpoints

Endpoint FOLFIRI + Bev(n=256)

FOLFOXIRI + Bev(n=252) P Value

Response rate 53% 65% 0.006

Complete response 3% 5%

Partial response 50% 60%

R0 secondary surgery

All patients 12% 15% 0.327

Liver-only subgroup 28% 32% 0.823

Overall survival

25.8 months 31.0 months

Unstratified hazard ratio (HR): 0.83 (0.66-1.05) 0.125

Stratified HR: 0.78 (0.63-1.00) 0.054


TRIBE: Grade ≥3 Adverse Events

Patients, %FOLFIRI + Bev

(n=254)FOLFOXIRI + Bev

(n=250) P Value

Serious adverse events (AEs) 19.7 20.4 NR

Fatal AEs 3.5 2.8 NR

Treatment-related deaths 1.6 2.4 NR

Early deaths (<60 days from randomization) 2.3 3.2 NR

Diarrhea 11 19 0.012*

Stomatitis 4 9 0.048*

Neutropenia 20 50 <0.001*

Febrile neutropenia 6 9 0.315

Neurotoxicity 0 5 <0.001*


The Role of Bevacizumab Maintenance Therapy: Chronicity of

Treating Unresectable Disease

CAIRO3: Study Design

Primary endpoint: PFS2 (PFS after re-introduction of bevacizumab + XELOX)

Secondary endpoints: PFS1, OS, TT2PD, ORR, safety

Upon PD1, 60% of patients received bevacizumab + XELOX in arm A and 47% in arm B

Koopman, et al. ASCO GI 2014. Abstract LBA388

Previously untreated

mCRC(n=558)

R

bevacizumab

+ XELOX

(x6)

CRPRSD bevacizumab +

capecitabine (n=279)

Observation (n=279)

bevacizumab + XELOX (n=168)

PD2PD1

PFS2PFS1

TT2PDArm A

Arm B

bevacizumab + XELOX (n=132)

PD2PD1

Median follow-up 48 months (cut-off 060114)

CAIRO3: median PFS1


0 6 12 18 24 30 36

PFS

1 e

stim

ate

1.0

0.8

0.6

0.4

0.2

0

279 84 18 10 7 6 5

Time (months)

Observation

Maintenance

Stratified HR (95% CI)p-value

Median

4.1 months

8.5 months

0.43 (0.36‒0.52) <0.0001

No. at risk:278 173 96 53 36 18 10

4.1 8.5

Induction treatment of 6x cycles bevacizumab + XELOX

prior to randomisation not included (4-5 months)

CAIRO3: median PFS2 (primary endpoint)


8.5 11.7

PFS

2 e

stim

ate

1.0

0.8

0.6

0.4

0.2

0

Time (months)

No. at risk:

0 6 12 18 24 30 36

Observation

Maintenance


Median

8.5 months

11.7 months

0.67 (0.56‒0.81) <0.0001

Induction treatment of 6x cycles bevacizumab + XELOX prior to randomisation not included (4-5 months)

PFS2 = PFS1 for pts in whom bevacizumab + capecitabine is not reintroduced after PFS1 for any reason

279 182 101 37 16 12 7278 206 136 76 46 26 13

CAIRO3: OS


18.1

21.6

0S e

stim

ate

1.0

0.8

0.6

0.4

0.2

0

Time (months)

No. at risk:

0 6 12 18 24 30 36

279 251 198 131 89 61 35

Observation

Maintenance


Median

18.1 months

21.6 months

0.89 (0.73‒1.07) 0.22

278 258 206 159 112 72 39

Median duration of follow-up 48 months

Induction treatment of 6x cycles bevacizumab + XELOX prior to randomisation not included (4-5 months)

Impact of Currently Approved Molecular Markers

Biomarker Development

Review of Definitions: Prognostic marker

Independent of treatment May impact surveillance

Predictive marker Impacts type of treatment provided

Molecular Markers for Anti-VEGF

None identified and validated: Bevacizumab Aflibercept Regorafenib

Anti-EGFR Therapy Predictive: KRAS/NRAS Prognostic: BRAF

KRAS Proto-oncogene First globally utilized predictive marker for

the treatment of MCRC when considering anti-EGFR therapy

30%-50% of all patients MT (exon 2): codons 12, 13, 61, and

rarely 146 KRAS WT does = efficacy of therapy nor

does it indicate duration of response

Copyright © American Society of Clinical Oncology

Khambata-Ford, S. et al. J Clin Oncol; 25:3230-3237 2007

Cetuximab and K-ras modulate signaling through the epidermal growth factor receptor (EGFR) pathway

BRAF MT Serine-threonine kinase belong to the RAF family Mutation also leads to constitutive activation V600E accounts for 90% of mutations Found in < 10 % of all CRC patients Associated with hypermethylation of CpG island. Mutually exclusive with KRAS MT Prognostic but NOT predictive

All studies insufficiently powered to provide sufficient data to determine use of anti-EGFR therapy based on BRAF status.

NRAS Resembles Kras Oncogene < 5% of all mCRC Mutations in codons 12, 13, 61, 117 and

146 Usually codon 61

Mutually exclusive with KRAS

Front-line chemotherapy with anti-EGFR therapy

Update on PRIME Study Phase III

Douillard JY, et al. J Clin Oncol. 2010;28:4697-4705.

Patients• Previously untreated mCRC

• Fluorouracil-based adjuvant chemotherapy allowed if PD occurred ≥6 mo after completion; no oxaliplatin

• Tumor tissue from primary tumor or metastasis available for biomarker analysis

• ECOG PS 0-2

• N=1183Primary endpoint: PFS

Panitumumab 6.0 mg/kg q 2 wkFOLFOX4 q 2 wk

1:1 Randomization

FOLFOX4 q 2 wk

Distribution of mutations in mCRC

RAS wt~50%

KRAS mt (exon 2)

~40%

KRAS mt(non exon 2 KRAS mt) &

NRAS mt~10%

Rare KRAS Mutations

NRAS Mutations

Douillard JY. ASCO 2013. Abstract 3620; Oliner KS. ASCO 2013. Abstract 3511.

PRIME Biomarker Analysis: Analysis of KRAS/NRAS and BRAF Mutations

RAS and BRAF Status FOLFOX4 Alone Panitumumab + FOLFOX4

KRAS exon 2 (codon 12/13) WTMT

331219

325221

WT KRAS exon 2 tumors tested for RAS and BRAF (n = 321) (n = 320)

WT KRAS exon 2/MT other RAS, n (%) 57 (18) 51 (16)

KRAS exon 3 (codon 61), n (%)WTMT

Failure

306 (95)14 (4)1 (0)

308 (96)10 (3)2 (1)

KRAS exon 4 (codons 117/146), n (%)WTMT

Failure

296 (92)15 (5)10 (3)

288 (90)21 (7)11 (3)

NRAS exon 2 (codons 12/13), n (%)WTMT

Failure

307 (96)14 (4)0 (0)

308 (96)8 (3)4 (1)

NRAS exon 3 (codon 61), n (%)WTMT

Failure

305 (95)14 (4)2 (1)

305 (95)12 (4)3 (1)

NRAS exon 4 (codons 117/146), n (%)WTMT

Failure

313 (98)0 (0)8 (2)

316 (99)0 (0)4 (1)

BRAF exon 15 (codon 600), n (%)WTMT

Failure

280 (87)29 (9)12 (4)

286 (89)24 (8)10 (3)

Oliner J, et al. J Clin Oncol. 2013;31(Suppl): Abstract 3511. Oliner J, et al. Eur J Cancer. 2013;49(Suppl 2): Abstract 2275.

Revised PRIME Consort Diagram

Douillard et al: NEJM, 2013

PRIME: Progression-free survival in patients with (A) Original wild-type (WT) KRAS, (B) Updated All WT RAS, Overall survival in patients with (C)

Original WT KRAS and (D) All WT KRAS

Douillard J et al. JCO 2010;28:4697-4705; NEJM, 2013

©2010 by American Society of Clinical Oncology

D

B

PFS: Wild-Type (WT) KRAS Exon 2 + mutant (MT) Other RAS

Oliner KS. ASCO 2013. Abstract 3511.

OS: Wild-Type (WT) KRAS Exon 2 + mutant (MT) Other RAS

Oliner KS. ASCO 2013. Abstract 3511.

PRIME: Summary and Clinical Implications

About 17% of patients with mCRC harbor mutations beyond KRAS exon 2 mutations

Excluding patients with RAS mutations identifies patients more likely to benefit from anti-EGFR therapy.

Practical interpretation: until an all-RAS test becomes available, EGFR monoclonal antibodies have the potential to be detrimental in patients who may harbor an unrecognized RAS mutation when administered with oxaliplatin-based chemotherapy regimens

Douillard JY. ASCO 2013. Abstract 3620; Oliner KS. ASCO 2013. Abstract 3511.

Treatment choice: Front line chemotherapy with anti-EGFR therapy

or anti-VEGF therapy?

PEAK Phase II Study Design

Schwarzberg et al: JCO, 2014.

Patients• mCRC

• KRAS wild-type

• ECOG PS 0-2

• 1st line therapy; prior adjuvant chemotherapy allowed if completed >6 mo before inclusion

• N=285 Primary Endpoint: PFS

1:1 Randomization

FOLFIRI + Bevacizumab(Bev: 5 mg/kg every 2 weeks)

FOLFIRI + Panitumumab

PEAK: Randomized Phase II (KRAS WT)

FOLFOX/Pmab (N=142)

FOLFOX/Bev (N=143)

Median PFS (95% CI) 10.9 (9.4-13.0) 10.1 (9.0-12.6)

Median OS (95% CI) 34.2 (26.6-NR) 24.3 (21.0-29.2)

ORR (95% CI) 58 (49-66) 54 (45-62)]

Subsequent therapy:Anti EGFR

21% 38%

Anti-VEGF 40% 24%

Schwarzberg et al: JCO 2014

PEAK: Randomized Phase II (KRAS WT and rare RAS WT)

FOLFOX/Pmab (N=88)

FOLFOX/Bev (N=82)

Median PFS (95% CI) 13.0 (10.9-15.1) 9.5 (9.0-12.7)

Median OS (95% CI) 41.3 (28.8-41.3) 28.9 (23.9-31.3)

ORR (95% CI) 64 (52.7-73.6) 61 (49-71.2)

Subsequent therapy:Anti EGFR

22% 37%

Anti-VEGF 40% 33%

Schwarzberg et al: JCO 2014

FIRE-3 Phase III Study Design

Heinemann V. ASCO 2013. Abstract LBA3506.

Patients• mCRC

• KRAS wild-type

• ECOG PS 0-2


• N=592 Primary Endpoint: Response Rate

FOLFIRI + Cetuximab(Cetuximab: 400 mg/m2 loading dose;

250 mg/m2 weekly)

1:1 Randomization


FIRE-3: Overall Response Rate

EndpointFOLFIRI + Cetuximab

FOLFIRI + Bevacizumab

OR P Value

ORR, intent-to-treat (ITT) population (N=592)

62.0% 58.0%1.18

(0.85-1.64)0.183

Complete response 4.4% 1.4%

Partial response 57.6% 56.6%

Stable disease 17.5% 28.8%

Progressive disease 7.1% 5.4%

Not evaluable 13.1% 7.8%

ORR, Evaluable (N=526) 72.2% 63.1%1.52

(1.05-2.19)0.017


FIRE-3: Progression Free Survival

Stintzing S. ASCO 2013. Abstract LBA3506

FIRE-3: Overall Survival


Consort FIRE-3 Diagram

N=592KRAS exon 2 wild-type

ITT population

N=407 (69%)RAS evaluable population

N=65 (16%)‘New’ RAS mutant

N=342RAS wild-type

N= 171 FOLFIRI +Cetuximab

N= 34FOLFIRI

Cetuximab

N= 171 FOLFIRI +

Bevacizumab

N= 31FOLFIRI +

Bevacizumab

N=752mCRC 1st-line

unselected patients

N=58FOLFIRI +Cetuximab

N=55FOLFIRI +

Bevacizumab

N=113KRAS exon 2 mutant

population*

KRAS unknown= 30No treatment= 13

No treatment KRAS mt = 4

Stinzing et al: ESMO, 2013

KRAS Wildtype Exon 2 Additional Subsets

?

? ?

EXON 1 EXON 2 EXON 3 EXON 4

EXON 2 EXON 3 EXON 4

KRAS

NRAS

12 13

12 13

61 146

59 61 117 146

wt

? ?

EXON 1

EXON 15EXON 11BRAF

600?

?

Heinemann V, et al. J Clin Oncol. 2013;31(Suppl): Abstract LBA3506.

Eventsn/N (%)

Median(months)

95% CI

― FOLFIRI + Cetuximab 91/171(53.2%)

33.1 24.5 – 39.4

― FOLFIRI + Bevacizumab 110/171(64.3%)

25.6 22.7 – 28.6

HR 0.70 (95% CI: 0.53 – 0.92)p (log-rank)= 0.011

FIRE-3: Overall survival RAS* all wild-type

0.012 24 36 48 60 72

months since start of treatment

171171

No. at risk

128127

7168

3926

209

61

0.75

1.0

0.50

0.25

0.0

Pro

ba

bil

ity

of

su

rviv

al

Δ = 7.5 months

* KRAS and NRAS exon 2, 3 and 4 wild-typeStinzing et al: ESMO, 2013

FIRE-3 Update: Overall Survival by All-RAS Mutation Status

Study Population FOLFIRI + Cetuximab


HR P Value

ITT (N=592) 28.7 months 25.0 months 0.77 0.017

RAS WT (n=342) 33.1 months 25.6 months 0.70 0.011

RAS MT (n=65) 16.4 months 20.6 months 1.20 0.57

BRAF MT (n=48) 12.3 months 13.7 months 0.87 0.65

Stintzing S. European Cancer Conference 2013. Abstract LBA17.

FIRE-3: Summary and Clinical Implications

Current data limitations No central assessment of response OS data continues to mature

Practical impact EGFR antibodies added to FOLFIRI can be

considered a viable option in first-line, KRAS wild-type mCRC


CALGB/SWOG 80405: PHASE III TRIAL OF FOLFIRI OR FOLFOX WITH BEVACIZUMAB OR

CETUXIMAB FOR PATIENTS W/ KRAS WILD TYPE UNTREATED METASTATIC ADENOCARCINOMA

OF THE COLON OR RECTUM

A Venook, D Niedzwiecki, HJ Lenz, F Innocenti, M Mahoney, B O’Neil, J Shaw, B Polite, H Hochster, R Goldberg, R Mayer,

R Schilsky, M Bertagnolli, C Blanke ALLIANCE and SWOG

CALGB / SWOG 80405: FINAL DESIGN

N = 1140

1° Endpoint: Overall Survival

Chemo + Cetuximab

Chemo + Bevacizumab

mCRC1st-line

KRAS wild type(codons 12,13)

STRATA:FOLFOX/FOLFIRI

Prior adjuvantPrior XRT

FOLFIRIor

FOLFOX

MD choice

CALGB/SWOG 80405: Eligibility Criteria

• Untreated Metastatic CRC• Tumor KRAS wild type codons 12 & 13• > 12 months since adjuvant therapy• ECOG 0-1 • Preserved organ function

AT ENROLLMENT• CHOOSE: FOLFOX or FOLFIRI• INTENT: Palliative or Part of strategy to resect

all metastases

CALGB/SWOG 80405: Statistics

Assumption: OS: 22 mos to 27.5 mos

Δ 5.5 months 90% power to detect HR of 0.80 (2-sided α=0.05)

ACCRUAL GOAL = 1140 (1137)

Estimate 326 eligible pre-amendment (333) KRAS wild type, single biologic arm

Estimate 814 post-amendment (804)

Actual

CALGB/SWOG 80405: Overall Survival

Arm N (Events)OS (m)

Median95% 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)

CALGB/SWOG 80405: Overall SurvivalFOLFOX Subgroup

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

FOLFOX + Cetux 426 (277) 30.1 26.6-34.8

FOLFOX + Bev 409 (290) 26.9 24.7–30.0

P=0.09HR 0.9 (0.7-1.0)

CALGB/SWOG 80405: Overall SurvivalFOLFIRI Subgroup

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

FOLFIRI + Bev 150 (81) 33.4 27.3-41.3

FOLFIRI + Cetux 152 (98) 28.9 25.6-34.2

P=0.28HR 1.2 (0.9-1.6)

CALGB/SWOG 80405: Grade 3-4 Toxicities

Toxicity Chemo + Bev N = 534 (%)

Chemo +Cetux N = 547 (%)

Total Grade 3 278 (52) 295 (54)

Hematologic 142 (26.6) 150 (27.4)

Non-Hem 234 (43.8) 259 (47.3)

Total Grade 4 66 (12.4) 75 (13.7)

Total Grade 5 7 (1.3) 3 (0.5)

Neuropathy Gr ≥ 3 71 (14) 68 (12)

Rash Gr 3 0 40 (7)

Diarrhea Gr ≥ 3 45 (8) 59 (11)

Hypertension Gr ≥ 3 35 (7) 3 (1)

GI Events Gr ≥ 3 10 (2) 2 (0.5)

CALGB/SWOG 80405: Data Pending

Response Rate Duration of therapy / dose intensity Analysis special subsets:

Patients rendered NED Patients recur after adjuvant therapy

Details 2nd and later treatments Concordance KRAS analysis: local v. central

Anti-EGFR versus Bevacizumab Trials

FIRE CALGB/SWOG

80405PEAK

Number of patients 592 1137 285

Chemotherapy backbone FOLFIRI FOLFOX or FOLFIRI FOLFOX

Primary endpoint Response rate Overall survival PFS

Anti-EGFR Cetuximab Cetuximab Panitumumab

KRAS selection Codon 12/13 Codon 12/13 Codon 12/13

Expanded RAS available to date Yes No Yes

Response rate (anti-EGFR v anti-VEGF; %) 62 v 58 N/A 58 v 54

Median PFS (anti-EGFR v anti-VEGF; months) 10.0 v 10.3 10.4 v 10.8 10.9 v 10.1

Median Overall survival (anti-EGFR v anti-VEGF; months) 28.7 v 25.0 * 29.9 v 29.0 34.2 v 24.3 *

* Statistically significant

2nd line Anti-Angiogenic Options

ML18147 (TML): Continuing Bevacizumab Beyond Progression

A randomized, open-label phase III intergroup study

Standard second-line CT (oxaliplatin or irinotecan based) until PD

(n = 411)

BEV 2.5 mg/kg/wk + standard second-line CT (oxaliplatin or

irinotecan-based) until PD(n = 409)

Progressive mCRC after BEV + standard first-line CT (either oxaliplatin or

irinotecan based)(n = 820)

Bennouna J, et al. Lancet Oncol. 2013;14:29-37.

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)

Primary endpoint: OS

ML18147 (TML): Continuing Bevacizumab Beyond Progression Increases OS (ITT)

OS

(%

)

MosCT (n = 410)BEV + CT (n = 409)

100

80

60

40

20

00 6 12 18 24 30 36 42 48

9.8 mos 11.2 mos

Unstratified* HR: 0.81 (95% CI: 0.69-0.94; log-rank P = .0062)

Stratified† HR: 0.83 (95% CI: 0.71-0.97; log-rank P = .0211)

*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.

100

80

60

40

20

0

PF

S (

%)

0 6 12 18 24 30 36 42

Mos

Unstratified* HR: 0.68 (95% CI: 0.59-0.78; log-rank P < .0001)

Stratified† HR: 0.67 (95% CI: 0.58-0.78; log-rank P < .0001)

4.1

mo

5.7 mo

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

1234567

1234567

VEGF TrapKd = 0.5 pM

Fc

VEGFR-1Kd 10-30 pM

VEGFR-2Kd 100-300 pM

Holash J, et al. Proc Natl Acad Sci U S A. 2002;99:11393-11398.

EFC10262: VELOURPhase III Trial 2nd Line FOLFIRI +/-

VEGF-TRAP (Aflibercept)

Stratification factors:Prior bevacizumab (Y/N)ECOG PS (0 vs 1 vs 2)

1:1

mCRC afterfailure of an oxaliplatin

based regimenR

600 pts Aflibercept 4 mg/kg IV+ FOLFIRI q 2 weeks

600 pts Placebo + FOLFIRIq 2 weeks

68

30% of patients had prior BEVPrimary endpoint: OSPI: Allegra et al

VELOUR Study: Survival Results

Van Cutsem E, et al. J Clin Oncol. 2012;30:3499-3506.

OS

(%

)

100

80

60

40

20

0

Mos

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Stratified HR: 0.817 (95.34% CI: 0.713-0.937; log-rank P = .0032)

Placebo/FOLFIRIMedian: 12.06 mos

Aflibercept/FOLFIRIMedian: 13.50 mos

PF

S (

%)

100

80

60

40

20

0

Mos

0 3 6 9 12 15 18 21 24 27 30

Stratified HR: 0.758 (95% CI: 0.661-0.869; log-rank P < .0001)



Overall Survival: Stratified by Previous Bevacizumab; ITT Population

Tabernero J, et al. Eur J Cancer. 2013;[Epub ahead of print].

OS

(%

)

100

80

60

40

20

0

Mos

0 3 6 9 12 15 18 21 24 27 30 33 36 39

HR: 0.862 (95.34% CI: 0.673-1.104)



Pts at Risk, n PlaceboAFL

187186

170178

138150

115121

8189

5459

3736

2222

1313

Previous Bevacizumab

OS

(%

)

100

80

60

40

20

0

Mos

0 3 6 9 12 15 18 21 24 27 30 33 36 39

HR: 0.788 (95.34% CI: 0.699-0.927)



Pts at Risk, n PlaceboAFL

427426

403388

347348

286295

205222

139157

94112

6582

3862

No Previous Bevacizumab

Treatment of heavily pretreated metastatic colorectal cancer

Regorafenib (BAY 73-4506), an oral multikinase inhibitor targeting multiple tumor pathways1-3

1. Wilhelm SM et al. Int J Cancer 2011.2. Mross K et al. Clin Cancer Research 2012.3. Strumberg D et al. Expert Opin Invest Drugs 2012.

Biochemicalactivity

Regorafenib IC50 mean ± SD nmol/l (n)

VEGFR1 13 ± 0.4 (2)

Murine VEGFR2 4.2 ± 1.6 (10)

Murine VEGFR3 46 ± 10 (4)

TIE2 311 ± 46 (4)

PDGFR-β 22 ± 3 (2)

FGFR1 202 ± 18 (6)

KIT 7 ± 2 (4)

RET 1.5 ± 0.7 (2)

RAF-1 2.5 ± 0.6 (4)

B-RAF 28 ± 10 (6)

B-RAFV600E 19 ± 6 (6)

Regorafenib

Sorafenib

Randomized Phase III Regorafenib (BAY 73-4506) vs. BSC (CORRECT Trial)

Multitargeted TKI of VEGFR-2, TIE-2 90% powered to detect a 33.3% % (HR=0.75; regorafenib/placebo)

difference in OS Primary endpoint: OS Secondary endpoints: PFS and RR

RPlacebo PO QD

Cycle = 28 Days

Patients with refractory mCRC

N= 760

Regorafenib 160 mg QD x 21 days

Grothey et al: Lancet. 2013 Jan 26;381(9863):303-12

CORRECT: OS (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)

Grothey et al: Lancet. 2013 Jan 26;381(9863):303-12

Phase III TAS-102 (RECOURSE)

Patients• Pretreated mCRC

• ECOG PS 0-1

• N=800

Primary endpoint: OS

TAS-102

2:1 Randomization

Placebo

Yoshino et al: World GI Congress, 2014

RECOURSE RESULTS:

Improved median OS was 7.1 months for TAS-102 vs. 5.3 months for placebo (hazard ratio 0.68).

TAS-102 also improved PFS compared to placebo (hazard ratio 0.48), which was a secondary endpoint.

Likely submitted for expedited FDA approval

Yoshino et al: World GI Congress, 2014

Should all RAS WT patients receive anti-EGFR therapy

front-line?

New EPOC Study: Chemotherapy ± Cetuximab in Operable KRAS-WT mCRC

Original EPOC study showed 8% PFS benefit to addition of neoadjuvant FOLFOX to surgery in mCRC patients with operable liver metastases[1]

New EPOC study evaluated addition of cetuximab to standard neoadjuvant chemotherapy in mCRC[2]

Primary endpoint: PFS

Secondary endpoints: OS, preop response, pathologic resection status, periop safety, QoL, cost-effectiveness

Patients with resectable KRAS WT mCRC with liver mets

(N = 621)

Neoadjuvant Chemotherapy*(randomized n = 134;

primary analysis n = 116)

Neoadjuvant Chemotherapy* + Cetuximab

(randomized n = 137;N = 117)

1. Nordlinger G, et al. Lancet. 2008. 2. Primrose JN, et al. ASCO 2013. Abstract 3504.

*CAPOX, OxMdG, IrMdG

New EPOC: Neoadjuvant Chemotherapy ± Cetuximab in Operable KRAS-WT mCRC: PFS

Median PFS significantly worse with cetuximab: 14.1 months vs 20.5 months with chemotherapy alone

Study stopped at predefined futility analysis

Immature data, but more events unlikely to change result

Primrose JN, et al. ASCO 2013. Abstract 3504.

Pro

po

rtio

n p

rog

res

sio

n f

ree 1.00

0.75

0.50

0.25

0.00

0 6 12 18 24 30 36 42 48 54 60

Time to progression or death (months)

HR: 1.49 (95% CI: 1.04-2.12); P = .030

Number at riskChemo alone

Chemo + Cetuximab 116

117

89

87

65

54

38

24

23

15

12

5

5

3

2

2

1

1

1

0

0

0

Chemo aloneChemo + cetuximab

Why did the new EPOCH study fail?

KRAS is a predictive marker of potential benefit for the use of EGFR inhibition.

Cetuximab does not have a role in the adjuvant setting N0147: FOLFOX +/- cetuximab failed to demonstrate

an improvement in DFS in stage III colon cancer 3-yr DFS: 74.6% vs 71.5% with the addition of

cetuximab (HR, 1.21; 95% CI, 0.98–1.49; P=.08)

Is it the combination of FOLFOX and cetuximab?

Alberts et al: JAMA. Apr 4, 2012; 307(13): 1383–1393.

http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=22474202

Upcoming: Liver-Only Trials

BOS-2 (EORTC 40091): Phase II KRAS WT Resectable Liver Mets

RANDOMIZE

FOLFOX

• First-line mCRC

• N=360

FOLFOX + bevacizumab

FOLFOX + panitumumab

Study amended: Wild-type KRAS tumors only

Primary Endpoint: PFS

http://www.clinicaltrials.gov/ct2/show/NCT01508000?term=BOS-2&rank=1

BOS -3 (EORTC-1207) Phase II/III Study Design (Pending)

http://www.clinicaltrials.gov/ct2/show/NCT01646554?term=BOS-2&rank=2

Patients• mCRC

• KRAS MT

• ECOG PS 0-1


Primary endpoint: PFS

FOLFOX + Aflibercept(Aflibercept: 4 mg/m2)

1:1 Randomization

FOLFOX

Up and Coming: Novel Agents

Treat until disease progression or intolerable toxicity

• Important inclusion criteria: - Metastatic or loc. adv. unresectable gastric or GEJ* adenocarcinoma - Progression after 1st line platinum/fluoropyrimidine based chemotherapy• Stratification factors: - Geographic region, - Measurable vs non-measurable disease, - Time to progression on 1st line therapy (< 6 mos vs. ≥ 6 mos)

Ramucirumab 8 mg/kg day 1&15+ Paclitaxel 80 mg/m2 day 1,8 &15 of a 28-day cycleN = 330

Placebo day 1&15 + Paclitaxel 80 mg/m2 day 1,8 &15N = 335

SCREEN

RANDOMIZE

Survival and safety follow-up

RAINBOW: Gastric Cancer

Wilke et al: ASCO GI 2014

1:1

RAINBOW: Overall SurvivalHR (95% CI) = 0.807 (0.678, 0.962)

Stratified log rank p-value = 0.0169

RAM + PTX PBO + PTX

Patients / Events 330 / 256 335 / 260

Median(mos) (95% CI) 9.63 (8.48, 10.81) 7.36 (6.31, 8.38)

6-month OS 72% 57%

12-month OS 40% 30%

RAM + PTX 330 308 267 228 185 148 116 78 60 41 24 13 6 1 0

PBO + PTX 335 294 241 180 143 109 81 64 47 30 22 13 5 2 0

No. at risk

Censored

Δ mOS = 2.3 months

Treat until disease progression or intolerable toxicity

• Important inclusion criteria: - Progression after 1st line FOLFOX based chemotherapy• Closed to enrollment, results pending

FOLFIRI + Ramucirumab 8 mg/kg

N = 525

FOLFIRI + PlaceboN = 525

SCREEN

RANDOMIZE

Endpoint: OS

Phase III: FOLFIRI +/- Ramucirumab

1:1

http://clinicaltrials.gov/show/NCT01183780, accessed 2/16/14

http://clinicaltrials.gov/show/NCT01183780

MET/HGF Signaling Pathway

Raghav and Eng, Colorectal Cancer, 2012

AMG-102

ARQ-197

MetMab

Prior CMET/HGF Agents: AMG-102:

Randomized phase II study Fulfilled primary endpoint of RR

ARQ-197 Randomized phase II study

No difference in PFS

Problems Cmet expression is not uniformly accepted.

Prior studies largely had tumors from the colon or rectum not metastatic site. Higher cmet expression is noted in sites of metastatic disease

Cmet amplification may be a better marker but rare (< 20% of all pts)

Van Cutsem, Eng et al: Clin Can Res, June 2014; Eng et al: ASCO, Abs #3508, June 2013

Phase II – MetMab ACCOMPLISH

Bendell et al: J Clin Oncol 30, 2012 (suppl; abstr TPS3640)

Primary Endpoint: PFS

Final results: Pending

AMG-337: Schema

PI’s: Raghav and Eng (MDACC)

ETA: Fall 2014

Primary Objectives Evaluate efficacy of AMG-337 in MET amplified mCRC, refractory to anti-EGFR therapy.

Secondary Objectives: Evaluate duration of efficacy of AMG-337 in MET amplified mCRC, refractory to prior anti-EGFR therapy, on treatment with AMG-337.

Evaluate survival outcomes in patients with MET amplified mCRC, refractory to prior anti-EGFR therapy, after treatment with AMG-337.

Evaluate safety and toxicity of AMG-337 in patients with mCRC.

Other Upcoming/Ongoing Trials Aflibercept

Different than bevacizumab? Biomarker study underway (Canada) Phase I/II: X-TRAP capecitabine + aflibercept, (N=60) Phase II: Maintenance (N=69) Phase II Rectal cancer: MDACC (PI’s: Dasari and Eng) Phase II: Appendiceal CA (PI: Eng) Phase II: ALIVE-C of FOLFOXIRI +/- Aflibercept (I Chau) in surgically

unresectable liver mets Regorafenib

Biomarkr studies: Korea Phase II: FOLFOX + Regorafenib (N=54)

Primary endpoint: RR (closed to enrollment) Phase III COAST trial: Maintenance Regorafenib vs. placebo following

adjuvant chemotherapy (N=750) Primary endpoint: DFS

Rare Population Subsets

BRAF MT Serine-threonine kinase belong to the RAF family Mutation also leads to constitutive activation V600E accounts for 90% of mutations Found in < 10 % of all CRC patients Associated with hypermethylation of CpG island. Mutually exclusive with KRAS MT Prognostic but NOT predictive

All studies insufficiently powered to provide sufficient data to determine use of anti-EGFR therapy based on BRAF status.

Single agent BRAF inhibitor in mCRC

Single agent vemurafenib Refractory mCRC N=21

1 partial response Median PFS was 3.7M

Kopetz et al: ASCO 2010, Abs #3534

TRIBE Phase III Study Design


Patients

• Unresectable mCRC

• No prior mCRC treatment

• Adjuvant oxali-containing chemotherapy allowed if >12 mo between tx and relapse

Treat to progression

FOLFIRI + Bev (up to 12 cycles)5-FU/LV + Bev (Maintenance)

1:1 Randomization

FOLFOXIRI + Bev (up to 12 cycles)5-FU/LV + Bev (Maintenance)

MOLECULAR CHARACTERISTICS

TRIBE: PFS Subgroup Analyses


FIRE-3 Phase III Study Design


Patients• mCRC

• KRAS wild-type

• ECOG PS 0-2


• N=592 Primary Endpoint: Response Rate

FOLFIRI + Cetuximab(Cetuximab: 400 mg/m2 loading dose;

250 mg/m2 weekly)

1:1 Randomization


FIRE-3 Update: Overall Survival by All-RAS Mutation Status

Study Population FOLFIRI + Cetuximab


HR P Value

ITT (N=592) 28.7 months 25.0 months 0.77 0.017

RAS WT (n=342) 33.1 months 25.6 months 0.70 0.011

RAS MT (n=65) 16.4 months 20.6 months 1.20 0.57

BRAF MT (n=48) 12.3 months 13.7 months 0.87 0.65

Stintzing S. European Cancer Conference 2013. Abstract LBA17.

Poor prognostic indicator

PHASE 1B STUDY OF VEMURAFENIB IN COMBINATION

WITH IRINOTECAN AND CETUXIMAB IN PATIENTS WITH BRAF-MUTATED

METASTATIC COLORECTAL CANCER

David S. Hong1, Van Morris2, Badi El-Osta1, Siqing Fu1, Michael Overman3, Sarina Piha-Paul1, Bryan Kee3, Ralph Zinner1, David Fogelman3, Imad Shureiqi3, Funda Meric-

Bernstam1, Scott Kopetz3

1Investigational Cancer Therapeutics, 2Cancer Medicine-Fellowship, 3Gastrointestinal Medical Oncology

The University of Texas MD Anderson Cancer Center

Introduction Vemurafenib (V), an oral kinase inhibitor specific to the

mutated V600 isoform of BRAF FDA approved in melanoma In vitro data in CRC cell lines has shown that blockade

of mutated BRAF by vemurafenib triggers compensatory activation of EGFR [Prahallad, 2012].

Inhibition of EGFR combined with vemurafenib results in synergistic cytotoxicity in preclinical models, which is further augmented by irinotecan [Yang 2012].

The safety and efficacy of the combination in patients with BRAF-mutated advanced malignancies have not been studied.

Objectives Primary Objectives

To define the maximum tolerated dose (MTD) of vemurafenib when used in combination with cetuximab and irinotecan

To define the safety profile of this combination Expansion phase with BRAF (+) KRAS (-) cancers

To determine the antitumor activity of this combination in patients with metastatic colorectal cancer (CRC)

To determine the antitumor activity of this combination in patients with non-CRC advanced solid malignancies

Secondary Objectives To evaluate clinical response signals of the combination To assess pharmacodynamics (PD) profile of the combination

Hong et al: ASCO 2014

Phase 1, single institution study of vemurafenib with irinotecan and cetuximab

• Histologically confirmed metastatic or advanced solid tumors

• BRAF V600E mutation

• Measurable disease by RECIST 1.1

• ≥ 18 years old

• ECOG ≤ 2

• Adequate organ function

• Informed consent

Key Eligibility Criteria Key Exclusion Criteria

• KRAS 12 or 13 mutation

• Treatment for tumor control within 3 weeks with investigational drug, 2 weeks with cytotoxic agent given weekly, or 5 half- lives of biological targeted agent

• Uncontrolled medical illness

• Pregnant, lactating, or breastfeeding


Patient baseline characteristicsCharacteristic N = 12

Age, median (range)

64.8 (42.5-73.2)

Gender

Male 7 (58%)

Female 5 (42%)

Caucasian 12 (100%)

ECOG PS

0 1 (8%)

1 10 (83%)2 1 (8%)

Lines of priortherapy, median(range)

2 (1-4)

Characteristic N = 12

Site of primary tumor

Colon/rectum 11 (92%)

Appendix 1 (8%)

Prior treatmentexposures

Irinotecan 8 (67%)

Cetuximab 5 (33%)

Vemurafenib 1 (8%)

Microsatellite status 10 tested

MSS 8 (80%)

MSI 2 (20%)


Adverse Events by CTCAE version 4.0

Preferred termsGrade 1/2

AEsGrade ≥ 3

AEs

Nausea 9 (75%) 0

Anemia 8 (67%) 1 (8%)

Diarrhea 8 (67%) 3 (25%)

Fatigue 8 (67%) 1 (8%)

Rash 8 (67%) 0

Anorexia 6 (50%) 0

Myalgia 5 (42%) 0

Vomiting 5 (42%) 0

Leukopenia 3 (25%) 0

Mucositis 3 (25%) 0

Preferred terms Grade 1/2 AEs

Grade ≥ 3 AEs

Alopecia 2 (17%) 0

Arthralgia 2 (17%) 1 (8%)

Dyspnea 2 (17%) 0

Cramping 1 (8%) 0

Dysgeusia 1 (8%) 0

Fever 1 (8%) 0

GERD 1 (8%) 0

HTN 1 (8%) 0

Hypoalbuminemia 1 (8%) 0

Weight Loss 1 (8%) 0


Responses by RECIST 1.1 in all restaged patients

*


Prior to starting trial End of Cycle 4(1st restaging)

69 y/o male with metastatic BRAFV600E refractory to FOLFOX after first restaging on Vemurafenib+Irinotecan and Cetuximab had a 41% decrease By RECIST1.1


Months on Study (N=12)


Response to Therapy 12 patients were enrolled onto the study before the

4/15/2014 cutoff for data analysis. 9 are evaluable.

Partial response or stable disease was noted in all 8 patients with colorectal cancer who underwent restaging scans after treatment initiation. Historic response rates for either vemurafenib or

irinotecan+cetuximab in BRAFmut CRC patients are <10%

For the 8 colorectal cancer patients who have undergone restaging, the response rate was 50%. (95% CI of 16 to 85%)


SWOG S1406: a randomized phase II study of irinotecan and cetuximab with or without vemurafenib in BRAF-

mutant metastatic colorectal cancer

BRAFV600E-mutated metastatic colorectal cancer

1-2 lines of prior systemic treatment

No prior EGFR monoclonal antibody

KRAS/NRAS wild-type

Arm 1: Irinotecan + Cetuximab

Arm 2: Irinotecan + Cetuximab + Vemurafenib

R Optional crossover to

arm 2 at progression

Endpoints

Primary: Progression-free survival

Secondary:Overall survival

ORR by RECIST 1.1

Grade 3/4 Toxicity

N=39

N=39

Target activation June 15 with Central IRB. Open through CTSU for all cooperative groups.

PI: Kopetz

Is there a role for immunotherapy?

Computed Tomographic (CT) Scans of the Chest Showing Tumor Regression in a Metastatic Melanoma Patient Who Received the Concurrent Regimen of Nivolumab and Ipilimumab.

Wolchok JD et al. N Engl J Med 2013;369:122-133.

BMS CA209142 study: NCT02060188

MSI-H: MDACC PI - Overman

Conclusions: Many treatment options are available to patients but

limitations remain for KRAS MT patients. Controversy remains whether all RAS WT tumor types

may have more benefit for OS if an anti-EGFR therapy is provided in the front-line setting.

However, provision of anti-EGFR therapy in the setting of a RAS MT can be detrimental Many institutions utilize outside sites for tissue processing Need a readily available panel with all RAS mutations

With categorization based on molecular marker analysis, it is likely more “rare” subgroups will be identified.

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Colorectal Cancer Research & Treatment News - recap from the May 2014 ASCO conference

Health & Medicine

Transcript of Colorectal Cancer Research & Treatment News - recap from the May 2014 ASCO conference