Part 2 Colorectal Cancer Thursday, July 26, 2012 7:30 PM – 8:30 PM ET RTP TV: Emerging Treatment Strategies in Colorectal Cancer

Part 2 — Colorectal Cancer

Thursday, July 26, 20127:30 PM – 8:30 PM ET

RTP TV: Emerging TreatmentStrategies in Colorectal Cancer

Richard M Goldberg, MDProfessor of MedicinePhysician-in-Chief, OSUCCC James Cancer Hospital and Richard J Solove Research InstituteKlotz Family Chair in Cancer ResearchThe Ohio State UniversityColumbus, Ohio

Axel Grothey, MDProfessor of OncologyDepartment of Medical OncologyMayo Clinic Rochester, Minnesota

Neil Love, MDResearch To PracticeMiami, Florida

Agenda — Emerging Treatment Strategies in Colorectal Cancer

• TML Trial (Bevacizumab after progression)

• VELOUR Trial (Aflibercept)

• CORRECT Trial (Regorafenib)

• Tumor Assays in the Adjuvant Setting

– Oncotype DX® Colon Assay: NSABP FLOX Trial

– Coloprint® Assay

– Next Generation Sequencing

• Audience Questions and Cases

Faculty Case: Dr Goldberg

• An 80-year-old man presents with primary rectosigmoid adenocarcinoma and multiple liver, lung and pleural metastases

• PS 2, 30-lb weight loss, massive hepatomegaly

What would be your most likely initial treatment recommendation?

Palliative care only

7%

4%

24%

41%

13%

11%

0% 10%

Other

Fluoropyrimidine alone

Fluoropyrimidine/bevacizumab

Fluoropyrimidine/oxaliplatin/bevacizumab

Fluoropyrimidine/irinotecan/bevacizumab

20% 30% 40% 50%

Patterns of Chemotherapy (CT) Use in a US-Wide Population-Based Cohort of Patients (Pts) with Metastatic Colorectal Cancer (mCRC)

Abrams TA et al.

Proc ASCO 2012;Abstract 3537.

A study of 4,877 consecutive patients with mCRC who received chemotherapy between 2004-2011 in US academic, private and community hospital-based practices

Abrams TA et al. Proc ASCO 2012;Abstract 3537.

Year Treatment (%)

2004 17%

2005 34%

2006 39%

2007 32%

2008 36%

2009 35%

2010 35%

2011 25%

Annual Proportion of Patients Continuing on Bev with Second-Line CT After Receipt of Bev + First-Line CT

Bevacizumab (BEV) plus Chemotherapy (CT) Continued Beyond First Progression in Patients with Metastatic Colorectal Cancer (mCRC) Previously Treated with BEV + CT: Results of a Randomized Phase III Intergroup Study — TML (ML18147)

Arnold D et al. Proc ASCO 2012;Abstract CRA3503.

• Primary endpoint: OS

• Secondary endpoints: PFS, ORR and safety


TML (ML18147) Phase III Study Design

Standard second-line CT

Standard second-line CT

Bevacizumab + standard

second-line CT

R

Progression on bevacizumab + standard first-line CT (either oxaliplatin or irinotecan-based)(n = 820)

CT

(n = 410)

Bev

(n = 409)Hazard

ratio p-value

Median OS 9.8 mo 11.2 mo 0.81 0.0062

OS: ITT Population


CT

(n = 410)

Bev

(n = 409)Hazard

ratio p-value

Median PFS 4.1 mo 5.7 mo 0.68 <0.0001

PFS: ITT Population

TML Trial: Grade 3-5 Adverse Events

CT

(n = 409)

Bev + CT

(n = 401)

Hypertension 1% 2%

Proteinuria — <1%

GI perforation <1% 2%

VTE 3% 5%

ATE <1% <1%

Wound-healing complications <1% <1%

Reverse posterior leukoencephalopathy syndrome — —


Faculty Case: Dr Grothey

• A 65-year-old woman presents with minimally symptomatic adenocarcinoma of the ascending colon and multiple unresectable KRWT liver metastases

What would be your most likely initial treatment recommendation?

0%

59%

10%

16%

0% 10%

Other

Removal of the primary tumor

Chemotherapy

Chemotherapy/bevacizumab

Chemotherapy/EGFR antibody

20% 30% 40% 50% 60%

16%

Impact on Survival of Primary Tumor Resection in Patients with Colorectal Cancer and Unresectable Metastasis

Pooled Analysis of Individual Patients’ Data from Four Randomized Trials

Faron M et al. Proc ASCO 2012;Abstract 3507.

The types of VEGF ligands bound by aflibercept are essentially identical to those bound by bevacizumab

51%

46%

3%

0% 10%

I don’t know

20% 30% 40% 50%

Disagree

Agree

60%

VEGFR-3VEGFR-2VEGFR-1

Endothelial cell

VEGF-A

PP

PP P

PPP

PP

PP

Anti-VEGFantibody

(bevacizumab)

Anti-VEGFR2antibody

(ramucirumab)

Small-molecule inhibitors of VEGFR (regorafenib, PTK-787, AZD2171, motesanib,sunitinib, sorafenib, pazopanib, axitinib, etc)

SolubleVEGF

receptor(aflibercept)

Agents Targeting the VEGF Pathway

Aflibercept

• Soluble fusion protein

• Consists of portion of extracellular 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 more tightly than native receptors

• Half-life in humans ~17 days

Aflibercept

VEGFR-1

VEGFR-2 Fc

IgG

Adapted from Allegra C et al. Proc ASCO 2012;Abstract 3505.

Intravenous (IV) Aflibercept versus Placebo in Combination with Irinotecan/5-FU (FOLFIRI) for Second-Line Treatment of Metastatic Colorectal Cancer (mCRC): Results of a Multinational Phase III Trial (EFC10262-VELOUR)

Van Cutsem E et al. ESMO 2011 13th World Congress on Gastrointestinal Cancer;Abstract O-0024.

• Primary endpoint: OS• Secondary endpoints: PFS, response rate, safety and

immunogenicity

ClinicalTrials.gov, NCT identifier: NCT00561470. Van Cutsem E et al. WCGC 2011;Abstract O-0024.

Patients with mCRC after failure of an oxaliplatin-based regimen in first line(n = 1,226)

Placebo (day 1) + FOLFIRI (q2wk)

(n = 614)

Placebo (day 1) + FOLFIRI (q2wk)

(n = 614)

Aflibercept (4 mg/kg day 1) + FOLFIRI (q2wk) (n = 612)

R

VELOUR: A Phase III Randomized Study with Aflibercept versus Placebo in Combination with FOLFIRI in Second-Line mCRC

Outcome

Placebo + FOLFIRI

(n = 614)

Aflibercept + FOLFIRI

(n = 612)Hazard

ratio p-value

Median OS 12.1 mo 13.5 mo 0.82 0.0032

Median PFS 4.7 mo 6.9 mo 0.76 0.00007

Overall response

11.1% 19.8% — 0.0001

VELOUR: PFS and OS

Van Cutsem E et al. WCGC 2011;Abstract O-0024.

VELOUR Trial: Grade 3/4 Anti-VEGF Associated Events

Placebo + FOLFIRI(n = 605)

Aflibercept + FOLFIRI(n = 611)

Proteinuria 1.2% 7.9%

Hypertension 1.5% 19.4%

Hemorrhage 1.6% 2.9%

VTE

Pulmonary embolism

6.3%

3.5%

7.9%

4.6%

Arterial thromboembolic event

0.5% 1.8%

GI perforation 0.4% 0.5%

Adapted from Allegra C et al. Proc ASCO 2012;Abstract 3505.

Effects of Prior Bevacizumab Use on Outcomes from the VELOUR Study: A Phase 3 Study of Aflibercept and FOLFIRI in Patients with Metastatic Colorectal Cancer After Failure of an Oxaliplatin Regimen

Allegra C et al. Proc ASCO 2012;Abstract 3505.

Response ratePlacebo + FOLFIRI

Aflibercept + FOLFIRI

Prior bevacizumab 8.4% 11.7%

No prior bevacizumab 12.4% 23.3%

Allegra C et al. Proc ASCO 2012;Abstract 3505.

VELOUR Trial: Response Rates

Phase 2 Randomized, Noncomparative, Open-Label, Study of Aflibercept and Modified FOLFOX6 in the First-Line Treatment of Metastatic Colorectal Cancer (AFFIRM)

Pericay C et al. ESMO 2012 14th World Congress on Gastrointestinal Cancer;Abstract O-0024.

Faculty Case: Dr Goldberg

• A 52-year-old woman who is s/p resection of splenic flexure adenocarcinoma and multiple systemic treatments for bilateral hepatic metastases

• No history of primary liver disease

• Patient is being considered for hepatic resection

What is the minimum % of residual liver required after an R0 resection of the lesions in order to consider surgical removal of hepatic metastases in patients without liver disease?

56%

29%

0%

0% 10%

More than 60%

10%

20%

30%

50%

20% 30% 40% 50% 60%

3%

12%

* Dependent on prior exposure to oxaliplatin

Eligibility (N = 670)

Potentially resectable

hepatic colorectal

metastases

NSABP Protocol Summaries, March 3, 2011.

Closed to accrual 12/16/2011 (total accrual: n = 9)

NSABP-C-11: A Phase III Study Evaluating the Role of Perioperative Chemotherapy for Potentially Resectable Hepatic mCRC

Hepatic resection (mFOLFOX6 or FOLFIRI)* x 12

Hepatic resection (mFOLFOX6 or FOLFIRI)* x 12

(mFOLFOX6 or FOLFIRI)* x 6 hepatic resection

(mFOLFOX6 or FOLFIRI)* x 6

R

Consider the last patient in your practice who died of metastatic colorectal cancer. How many lines of systemic therapy did the patient receive in the metastatic setting?

9%

7%

35%

36%

13%

0% 40%

More than 5

30%20%10%

5

4

3

2

1

0

0%

0%


• A 38-year-old woman with adenocarcinoma of the ascending colon and synchronous widespread metastases

• Over several years she receives multiple lines of systemic treatment, with all approved agents

• Enrolled in CORRECT trial

Grothey A et al. Gastrointestinal Cancers Symposium 2012;Abstract LBA385.

Mode of Action of Regorafenib

• Regorafenib inhibits multiple cell-signaling kinases:

– Angiogenic

• VEGFR1-3, TIE2

– Stromal

• PDGFR-ß, FGFR

– Oncogenic

• KIT, PDGFR, RET

Inhibition of stromal signaling

Inhibition of neoangiogenesis

Inhibition of proliferation

of certain tumor cells

Phase III CORRECT Trial of Regorafenib in Metastatic Colorectal Cancer (mCRC)

Van Cutsem E et al. Proc ASCO 2012;Abstract 3502.

Regorafenib Placebo HR p-value

Median PFS 1.9 mo 1.7 mo 0.49 <0.000001

Median OS 6.4 mo 5.0 mo 0.77 0.0052


CORRECT: Study Design and Survival Outcomes

Pts with refractory metastatic CRC (n = 760)

Regorafenib 160 mg po QD 3/4 wksplus BSC

Regorafenib 160 mg po QD 3/4 wksplus BSC

Placebo po QD 3/4 wksplus BSC

R

CORRECT Trial: Select Grade 3/4 Adverse Events

Regorafenib

(n = 500)

Placebo

(n = 253)

Grade 3 Grade 4 Grade 3 Grade 4

Hand-foot skin reaction 16.6% 0% 0.4% 0%

Fatigue 9.2% 0.4% 4.7% 0.4%

Hypertension 7.2% 0% 0.8% 0%

Diarrhea 7.0% 0.2% 0.8% 0%

Rash/desquamation 5.8% 0% 0% 0%



• 51-year-old man

• Nearly obstructing 8-cm low-grade adenocarcinoma removed from sigmoid colon

• 20 negative nodes, MSS

• Lymphatic invasion but no perineural invasion

Which systemic treatment would you most likely recommend?

4%

17%

50%

11%

7%

0% 10%

Other

20% 30% 40% 50%

Capecitabine/oxaliplatin

5-FU/oxaliplatin

Capecitabine

5-FU

None 11%


• 51-year-old man

• Nearly obstructing 8-cm low-grade adenocarcinoma removed from sigmoid colon

• 20 negative nodes, MSS

• Lymphatic invasion but no perineural invasion

• Recurrence Score® = 45 (17%-20% ROR)

Which systemic treatment would you most likely recommend?

2%

15%

63%

7%

11%

0%

Other

70%

Capecitabine/oxaliplatin

5-FU/oxaliplatin

Capecitabine

5-FU

None 2%

60%50%40%30%20%10%

Validation of the 12-Gene Colon Cancer Recurrence Score (RS) in NSABP C07 as a Predictor of Recurrence in Stage II and III Colon Cancer Patients Treated with 5FU/LV (FU) and 5FU/LV+Oxaliplatin (FU+Ox)

O’Connell M et al. Proc ASCO 2012;Abstract 3512.

Five-Year Recurrence Risk by Recurrence Score (RS)

5-FU 5-FU + Ox

Stage II

Low RS 7% 12%

Int RS 8% 10%

High RS 23% 9%

Stage IIIA/B

Low RS 19% 17%

Int RS 30% 19%

High RS 43% 31%

Stage IIIC

Low RS 41% 38%

Int RS 48% 40%

High RS 67% 59%

O’Connell M et al. Proc ASCO 2012;Abstract 3512.

Effect of the 12-Gene Colon Cancer Assay Results on Treatment Recommendations in Patients with Stage II Colon Cancer

Cartwright TH et al. Proc ASCO 2012;Abstract 3626.

A web-based survey of 116 primarily community-based, US medical oncologists who ordered ≥3 Oncotype DX assays for patients with Stage II colon cancer since January 2010.

Impact of 12-Gene Recurrence Score (RS) on Treatment Recommendations

Rx plan before RS Rx plan after RS

Observation

(N = 40)

Non-oxaliplatin CT (n = 4)

Oxaliplatin CT (n = 5)

Non-oxaliplatin CT

(N = 19)Observation (n = 6)

Oxaliplatin CT

(N = 33)

Observation (n = 8)

Non-oxaliplatin CT (n = 4)

23% intensity

34.6% intensity

Overall, 27 out of 92 treatment plans (29%) changed after RS obtained

Cartwright TH et al. Proc ASCO 2012;Abstract 3626.

The PARSC Trial, a Prospective Study for the Assessment of Recurrence Risk in Stage II Colon Cancer (CC) Patients Using ColoPrint

Salazar R et al.GI Cancers Symposium 2012;Abstract 678.

Use of Next-Generation Sequencing (NGS) to Detect a Novel ALK Fusion and a High Frequency of Other Actionable Alterations in Colorectal Cancer (CRC)

Ross JS et al. Proc ASCO 2012;Abstract 3533.

Schedule of Events

Thursday, September 13Renal Cell Carcinoma

Thomas E Hutson, DO, PharmD Robert J Motzer, MD

Thursday, October 11Advanced Prostate CancerChristopher J Logothetis, MD A Oliver Sartor, MD

Documents

Part 2 Colorectal Cancer Thursday, July 26, 2012 7:30 PM – 8:30 PM ET RTP TV: Emerging Treatment Strategies in Colorectal Cancer