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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
Arnold D et al. Proc ASCO 2012;Abstract CRA3503.
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
Arnold D et al. Proc ASCO 2012;Abstract CRA3503.
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 — —
Arnold D et al. Proc ASCO 2012;Abstract CRA3503.
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%
Faculty Case: Dr Grothey
• 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
Van Cutsem E et al. Proc ASCO 2012;Abstract 3502.
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%
Van Cutsem E et al. Proc ASCO 2012;Abstract 3502.
Faculty Case: Dr Grothey
• 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%
Faculty Case: Dr Grothey
• 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