Presentation on theme: "Part 2 Colorectal Cancer Thursday, July 26, 2012 7:30 PM – 8:30 PM ET RTP TV: Emerging Treatment Strategies in Colorectal Cancer."— Presentation transcript:
Part 2 Colorectal Cancer Thursday, July 26, 2012 7:30 PM – 8:30 PM ET RTP TV: Emerging Treatment Strategies in Colorectal Cancer
Richard M Goldberg, MD Professor of Medicine Physician-in-Chief, OSUCCC James Cancer Hospital and Richard J Solove Research Institute Klotz Family Chair in Cancer Research The Ohio State University Columbus, Ohio Axel Grothey, MD Professor of Oncology Department of Medical Oncology Mayo Clinic Rochester, Minnesota Neil Love, MD Research To Practice Miami, 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. YearTreatment (%) 200417% 200534% 200639% 200732% 200836% 200935% 201035% 201125% 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 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 ratiop-value Median OS9.8 mo11.2 mo0.810.0062 OS: ITT Population Arnold D et al. Proc ASCO 2012;Abstract CRA3503. CT (n = 410) Bev (n = 409) Hazard ratiop-value Median PFS4.1 mo5.7 mo0.68<0.0001 PFS: ITT Population
TML Trial: Grade 3-5 Adverse Events CT (n = 409) Bev + CT (n = 401) Hypertension1%2% Proteinuria<1% GI perforation<1%2% VTE3%5% ATE<1% Wound-healing complications<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 dont know 20%30%40%50% Disagree Agree 60%
VEGFR-3VEGFR-2VEGFR-1 Endothelial cell VEGF-A P P P P P P P P P P P P Anti-VEGF antibody (bevacizumab) Anti-VEGFR2 antibody (ramucirumab) Small-molecule inhibitors of VEGFR (regorafenib, PTK-787, AZD2171, motesanib, sunitinib, sorafenib, pazopanib, axitinib, etc) Soluble VEGF 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 13 th 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 ratiop-value Median OS12.1 mo13.5 mo0.820.0032 Median PFS4.7 mo6.9 mo0.760.00007 Overall response 11.1%19.8%0.0001 VELOUR: PFS and OS Van Cutsem E et al. WCGC 2011;Abstract O-0024.
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 rate Placebo + FOLFIRI Aflibercept + FOLFIRI Prior bevacizumab8.4%11.7% No prior bevacizumab12.4%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 14 th 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% 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%
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.
RegorafenibPlaceboHRp-value Median PFS1.9 mo1.7 mo0.49<0.000001 Median OS6.4 mo5.0 mo0.770.0052 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 wks plus BSC Regorafenib 160 mg po QD 3/4 wks plus BSC Placebo po QD 3/4 wks plus BSC R
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) OConnell M et al. Proc ASCO 2012;Abstract 3512.
Five-Year Recurrence Risk by Recurrence Score (RS) 5-FU5-FU + Ox Stage II Low RS7%12% Int RS8%10% High RS23%9% Stage IIIA/B Low RS19%17% Int RS30%19% High RS43%31% Stage IIIC Low RS41%38% Int RS48%40% High RS67%59% OConnell 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 RSRx 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 13 Renal Cell Carcinoma Thomas E Hutson, DO, PharmD Robert J Motzer, MD Thursday, October 11 Advanced Prostate Cancer Christopher J Logothetis, MD A Oliver Sartor, MD