• Share
  • Email
  • Embed
  • Like
  • Save
  • Private Content
What's New in Colorectal Cancer Research?
 

What's New in Colorectal Cancer Research?

on

  • 1,731 views

Each summer, the American Society for Clinical Oncology holds the world’s largest conference for cancer researchers, doctors and other medical professionals. Results from clinical trials and other ...

Each summer, the American Society for Clinical Oncology holds the world’s largest conference for cancer researchers, doctors and other medical professionals. Results from clinical trials and other studies are released, which give scientists a fresh look at treatments that may or may not hold great promise in the march toward a cure for cancer.

Dr. Axel Grothey of the Mayo Clinic will explain what science is now telling us about colorectal cancer and how it may impact your treatment in the near future.

Statistics

Views

Total Views
1,731
Views on SlideShare
1,726
Embed Views
5

Actions

Likes
2
Downloads
65
Comments
0

2 Embeds 5

http://nationalfightcrc.org 3
http://fightcolorectalcancer.org 2

Accessibility

Categories

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment
  • SPEAKER NOTESThe large, phase III randomized trial, VELOUR, has enrolled 1226 patients with previously treated metastatic CRC whose disease progressed on an oxaliplatin-based regimen. Patients are randomized to receive either aflibercept plus FOLFIRI or FOLFIRI alone.An important stratification in this trial is patients who have received prior bevacizumab-containing therapy in the front-line setting. In the United States, the majority of patients receive bevacizumab-containing therapy as treatment for their newly diagnosed mCRC.VELOUR has completed accrual of patients.The primary endpoint in this trial is median OS.An interim analysis of the data from VELOUR determined that the trial should continue to final analysis of OS.Final results are expected in late 2011.More details on this trial are available at clinicaltrials.gov (NCT00561470).

What's New in Colorectal Cancer Research? What's New in Colorectal Cancer Research? Presentation Transcript

  • Welcome! Whats New in Colorectal Cancer Research? Part of Fight Colorectal Cancer’s Monthly Patient Webinar Series Our webinar will begin shortlywww.FightColorectalCancer.org www.CCAlliance.org877-427-2111 877-422-2030
  • MANY THANKS TO OUR PARTNERS AT COLON CANCER ALLIANCE IN SUPPORT AND PROMOTION OF THIS WEBINARwww.FightColorectalCancer.org www.CCAlliance.org877-427-2111 877-422-2030
  • Fight Colorectal Cancer1. Tonight’s speaker: Dr. Axel Grothey2. Archived webinars: Link.FightCRC.org/Webinars3. Follow up survey to come via email. Get a free Blue Star ofHope pin when you tell us how we did tonight.4. Ask a question in the panel on the right side of your screen5. Or call the Fight Colorectal Cancer Answer Line at 877-427-2111 www.FightColorectalCancer.org www.CCAlliance.org 877-427-2111 877-422-2030
  • Fight Colorectal Cancer Upcoming Webinars When Youre Out of Options Dr. Leonard Saltz, MSKCC July 18, 2012 8 - 9:30 PM Eastern time Hospice vs Palliative Care Dr. Jim Meadows, Tennessee Oncology September 19, 2012 8 - 9:30 PM Eastern time Register atwww.FightColorectalCancer.org/awareness/webinars 1-877-427-2111
  • Colon Cancer AllianceNational Conference Friday, July 20, 2012 Colorectal Cancer Diagnosis Under 50 Trends and Implications for the Future Networking Reception Join our Blue Party Saturday, July 21, 2012Redefining Colorectal Cancer Survivorship Live Your Best Life Registration Deadline: Friday, July 13, 2012 Continuing Education Credits Available Learn more at www.ccalliance.org
  • Fight Colorectal CancerDisclaimerThe information and services provided by Fight ColorectalCancer are for general informational purposes only.The information and services are not intended to be substitutesfor professional medical advice, diagnosis, or treatment.If you are ill, or suspect that you are ill, see a doctorimmediately. In an emergency, call 911 or go to the nearestemergency room.Fight Colorectal Cancer never recommends or endorses anyspecific physicians, products or treatments for any condition.www.FightColorectalCancer.org www.CCAlliance.org877-427-2111 877-422-2030
  • Fight Colorectal Cancer Dr. Axel Grothey Professor of Oncology Mayo Clinicwww.FightColorectalCancer.org www.CCAlliance.org877-427-2111 877-422-2030
  • Colorectal CancerUpdates ASCO 2012 Axel Grothey Professor of Oncology Mayo Clinic Rochester
  • Disclosures• Consulting activities (honoraria went to the Mayo Foundation) • Amgen • Bayer • Pfizer • Roche/Genentech • BMS • Imclone/Eli-LillyI WILL include discussion of investigational or off-label use of a product in my presentation.
  • Advances in the Treatment of Stage IV CRC 1980 1985 1990 1995 2000 2005Best supportive care (BSC) 5-FU Irinotecan Capecitabine Oxaliplatin Cetuximab Bevacizumab Panitumumab median overall survival
  • First-line Bevacizumab in Metastatic Colorectal Cancer: OS AVF2107g[1] NO16966[2] BICC-C[3] TREE-2[4] 30 28.0 26.0 27.0 † 23.1 25 * 20.3 19.9 21.3 19.2 20.7 20 17.6 OS (Mos) 15.6 15 10 5 0 *P < .001; †P = .07691. Hurwitz H, et al. N Engl J Med. 2004;350:2335. 2. Saltz LB, et al. J Clin Oncol. 2008;26:2013-2019.3. Fuchs C, et al. ASCO 2007. Abstract 4027. 4. Hochster, et al. ASCO 2006. Abstract 3510.
  • AIO 0504 / Roche ML18147 Multinational European Trial Any-OX Any-IRI + BEV + BEV R R Any-IRI Any-OX Any-IRI Any-OX + BEV + BEVN = 820 Accrual completed May 31, 2010Primary EP: OS
  • Bevacizumab (BEV) plus chemotherapy (CT)continued beyond first progression in patients with metastatic colorectal cancer (mCRC)previously treated with BEV + CT: Results of a randomised phase III intergroup study – TML (ML18147) D Arnold1, T Andre2, J Bennouna3, J Sastre4, P Österlund5, R Greil6 E Van Cutsem7, R von Moos8, I Reyes-Rivera9, B Bendahmane10, S Kubicka11 on behalf of the AIO, GERCOR, FFCD, UNICANCER GI, TTD, GEMCAD and AGMT groups 1Hamburg, Germany; 2Paris, France; 3Nantes, France; 4Madrid, Spain 5Helsinki, Finland; 6Salzburg, Austria; 7Leuven, Belgium; 8Chur, Switzerland 9South San Francisco, USA; 10Basel, Switzerland; 11Reutlingen, Germany
  • ML18147 study design (phase III) Standard second-line CT (oxaliplatin or irinotecan- BEV + standard based) until PD first-line CT (either oxaliplatin or PD Randomize 1:1 irinotecan-based) BEV (2.5 mg/kg/wk) + standard second-line CT (n=820) CT switch: (oxaliplatin or irinotecan- Oxaliplatin → Irinotecan based) until PD Irinotecan → OxaliplatinPrimary endpoint • Overall survival (OS) from randomizationSecondary endpoints • Progression-free survival (PFS)included • Best overall response rate • SafetyStratification factors • First-line CT (oxaliplatin-based, irinotecan-based) • First-line PFS (≤9 months, >9 months) • Time from last BEV dose (≤42 days, >42 days) • ECOG PS at baseline (0/1, 2)Study conducted in 220 centres in Europe and Saudi Arabia
  • Main eligibility criteriaInclusion• Patients ≥18 years with histologically confirmed diagnosis of mCRC• Eastern Cooperative Oncology Group (ECOG) PS 0–2• PD (≥1 measurable lesion according to RECIST v1 assessed by investigator, documented by CT or MRI), ≤4 weeks prior to start of study treatment• Previously treated with BEV plus standard first-line CT, not candidates for primary metastasectomyExclusion• Diagnosis of PD >3 months after last BEV administration• First-line patients with PFS in first-line of <3 months• Patients receiving <3 consecutive months of BEV in first-line
  • Demographic and baseline characteristics: Randomized patients CT BEV + CTCharacteristic (n=411) (n=409)Male, % 63 65Age, median years 63 63ECOG performance status, % 0 43 44 1 52 51 2 5 5First-line PFS, % ≤9 months 56 54 >9 months 44 46First-line CT, % Irinotecan-based 58 59 Oxaliplatin-based 42 41Patients were accrued between February 2006 and June 2010
  • Demographic and baseline characteristics: Randomized patients (cont‟d) CT BEV + CTCharacteristic (n=411) (n=409)Duration from last BEV dose torandomisation, % ≤42 days 77 77 >42 days 23 23Patient populationa, % AIO 32 32 ML18147 68 68Liver metastasis only, % No 71 73 Yes 29 27No. of organs with metastasis, % 1 39 36 >1 61 64 aPatientpopulation refers to sequential enrolment of patients in original AIO study and subsequent enrolment in ML18147 when study was transferred to Roche
  • Second-line chemotherapy during study: Randomized patients CT BEV + CTSecond-line CT regimen, % (n=407) (n=407)Irinotecan-based CT 43 42 FOLFIRI 14 16 LV5FU2 + CPT11 (Douillard regimen1) 7 7 XELIRI 12 12 Other regimens 10 7Oxaliplatin-based CT 57 58 FOLFOX4 / mFOLFOX4 18 19 FOLFOX6 13 16 FUFOX 9 6 XELOX 11 14 Other regimens 6 41. Douillard et al. Lancet 2000;355:1041–7
  • OS: ITT population 1.0 CT (n=410) BEV + CT (n=409) 0.8 Unstratifieda HR: 0.81 (95% CI: 0.69–0.94) p=0.0062 (log-rank test) 0.6 OS estimate Stratifiedb HR: 0.83 (95% CI: 0.71–0.97) 0.4 p=0.0211 (log-rank test) 0.2 9.8 mo 11.2 mo 0 0 6 12 18 24 30 36 42No. at risk Time (months)CT 410 293 162 51 24 7 3 2BEV + CT409 328 188 64 29 13 4 1Median follow-up: CT, 9.6 months (range 0–45.5); BEV + CT, 11.1 months (range 0.3–44.0)aPrimary analysis method; bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last doseof BEV (≤42 days, >42 days), ECOG performance status at baseline (0, ≥1)
  • Subgroup analysis of OS: ITT populationCategory Subgroup n HR (95% CI)All All 819 0.81 (0.69–0.94)Patient populationa AIO 260 0.86 (0.67–1.11) ML18147 559 0.78 (0.64–0.94)Gender Female 294 0.99 (0.77–1.28) Male 525 0.73 (0.60–0.88)Age <65 years 458 0.79 (0.65–0.98) ≥65 years 361 0.83 (0.66–1.04)ECOG performance status 0 357 0.74 (0.59–0.94) ≥1 458 0.87 (0.71–1.06)First-line PFS ≤9 months 449 0.89 (0.73–1.09) >9 months 369 0.73 (0.58–0.92)First-line CT Oxaliplatin-based 343 0.79 (0.62–1.00) Irinotecan-based 476 0.82 (0.67–1.00)Time from last BEV ≤42 days 630 0.82 (0.69–0.97) >42 days 189 0.76 (0.55–1.06)Liver metastasis only No 592 0.81 (0.67–0.97) Yes 226 0.79 (0.59–1.05)No. of organs 1 307 0.83 (0.64–1.08)with metastasis >1 511 0.77 (0.64–0.94) HR 0 1 2aPatient population refers to sequential enrolment of patients in original AIO and subsequent enrolment in ML18147 whenstudy was transferred to Roche. All patients listed under AIO were included in primary analysis
  • PFS: ITT population 1.0 CT (n=410) BEV + CT (n=409) 0.8 PFS estimate Unstratifieda HR: 0.68 (95% CI: (0.59–0.78) 0.6 p<0.0001 (log-rank test) Stratifiedb HR: 0.67 (95% CI: 0.58–0.78) 0.4 p<0.0001 (log-rank test) 0.2 4.1 mo 5.7 mo 0 0 6 12 18 24 36 Time (months)No. at riskCT 410 119 20 6 4 0BEV + CT 409 189 45 12 5 2aPrimary analysis method; bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last doseof BEV (≤42 days, >42 days), ECOG performance status at baseline (0, ≥1)
  • Best overall response: Measurable disease population CT BEV + CTOutcome (n=406) (n=404)Respondersa, n (%) 16 (3.9) 22 (5.4) p-value 0.3113Complete response, n (%) 2 (<1) 1 (<1)Partial response, n (%) 14 (3) 21 (5)Stable disease, n (%) 204 (50) 253 (63)Disease control rate, n (%) 220 (54) 275 (68) p-valueb <0.0001PD, n (%) 142 (35) 87 (22)Missingc, n (%) 44 (11) 42 (10)aPatientswith a best overall response of confirmed complete or partial responsebThis analysis was not prespecifiedcIncludes „not-evaluable‟ or „no tumour assessment‟ following baseline visit
  • Grade 3–5 adverse events (incidence ≥2%) in any arm: Safety population CT BEV + CTAdverse event, % (n=409) (n=401)Neutropenia 13 16Leukopenia 3 4Diarrhoea 8 10Vomiting 3 4Nausea 3 3Abdominal pain 3 4Subileus <1 2Asthenia 4 6Fatigue 2 4Mucosal inflammation 1 3Dyspnoea 3 2Pulmonary embolism 2 3Polyneuropathy 2 3Neuropathy peripheral 2 1Hypokalaemia 2 2Decreased appetite 2 1
  • Adverse events of special interest to BEV: Safety population CT BEV + CT (n=409) (n=401)Patients, % All grades Grade 3–5 All grades Grade 3–5AEs of special interest to BEV 21 6 41 12 Hypertension 7 1 12 2 Proteinuria 1 – 5 <1 Bleeding/haemorrhage 9 <1 26 2 Abscesses and fistulae – – 1 <1 GI perforation <1 <1 3 2 Congestive heart failure <1 <1 <1 – VTE 4 3 6 5 ATE 1 <1 <1 <1 Wound-healing <1 <1 1 <1 complications RPLS – – – – ATE: arterial thromboembolic events; GI: gastrointestinal; RPLS: reverse posterior leukoencephalopathy syndrome; VTE: venous thromboembolic events
  • Conclusions• First randomized clinical trial that prospectively investigated the impact of continued VEGF inhibition with BEV beyond first progression• Study confirms that continuing BEV beyond first progression while modifying CT is beneficial for patients with mCRC and leads to a significant improvement in OS and PFS• This provides a new second-line treatment option for patients who have been treated with BEV + standard CT in first line while maintaining an acceptable safety profile• Findings indicate a potential new model for treatment approaches through multiple lines and this is currently being investigated in other tumour types
  • Large molecule VEGF inhibitors PlGF VEGF-A VEGF-C, VEGF-B Bevacizumab VEGF-D RamucirumabAflibercept(VEGF Trap) Functions VEGF-R1 VEGF-R2 VEGF-R3 (Flt-1) (KDR/Flk-1) (Flt-4) Migration Proliferation Lymphangio- Invasion Survival genesis Survival Permeability
  • 28 EFC10262: VELOUR Phase III Trial 2nd Line FOLFIRI +/- VEGF-TRAP (Aflibercept) Aflibercept 4 mg/kg 600 pts IV + FOLFIRI q 2 weeks mCRC after failure of an oxaliplatin R 1:1 based regimen Placebo + FOLFIRI Stratification factors: 600 pts q 2 weeks Prior bevacizumab (Y/N) ECOG PS (0 vs 1 vs 2)PIs: Allegra, Van Cutsem 30% of patients had prior BEV
  • VELOUR Study• Overall results • Adding aflibercept to FOLFIRI in mCRC patients previously treated with an oxaliplatin-based regimen resulted in significant OS and PFS benefits OS PFS Van Cutsem E et al. ESMO/WCGC 2011, Barcelona, Abstract O-0024.
  • Overall Survival:Stratified by Prior Bevacizumab – ITT Population
  • Progression-Free Survival:Stratified by Prior Bevacizumab – ITT Population
  • Response Rates
  • Safety – Most frequent AEs, with ≥ 5% difference in incidence between treatment arms, excluding anti-VEGF class events Placebo, N = 605 Aflibercept N = 611 Safety Population, % of patients 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 leading AEs to treatment discontinuation: 4.3 0.5 11.0 2.8 erythrodysaesthesia AFL: 26.6% Skin hyperpigmentation 2.8 0 8.2 0 Dehydration PL: 12.1% 3.0 1.3 9.0 4.3 Van Cutsem, et al. WCGC 2011
  • Cytokine increase on BEV therapy Kopetz et al., JCO 2010
  • Regorafenib – A Multi-Kinase Inhibitor Cellular Phosphorylation Assays IC50 nM VEGFR-2 Phosphorylation, 293 Cells 8 TIE2-Receptor Phosphorylation, CHO Cells 31 PDGFR-β Phosphorylation, Aortic SM Cells 90 mVEGFR3 Phosphorylation, 293 Cells 150Mutant RET Phosphorylation, Thyroid TT Cells 10Mutant c-KIT Phosphorylation, GIST 882 Cells 20 FGF-10 FGFR MCF-7 Cells 150-300 MAPK ERK-P HCC, HepG2 Cells 500 Cell Proliferation Assays IC50 nM VEGF/HuVEC (2% FCS) BrdU 4 bFGF/ HuVEC (2% FCS) BrdU 120 PDGFBB/Aortic SM (0.1% BSA) BrdU 121 Thyroid TT RET C643W (10% FCS) 33 GIST 882 KIT K642E (10% FCS) 45 Breast, MDA MB 231 (10% FCS) 570 Melanoma, A375 (10% FCS) 900 HCC HepG2 (10% FCS) 560
  • CORRECT study design R Regorafenib + BSC Primary A 160 mg orally once daily N 3 weeks on, 1 week off Endpoint: D O OS mCRC after M 90% power to standard I 2:1 Z detect 33.3% therapy A increase T I (HR=0.75), with Placebo + BSC O 1-sided overall 3 weeks on, 1 week off N a=0.025• Multicenter, randomized, double-blind, placebo-controlled, phase III • 2:1 randomization • Strat. factors: prior anti-VEGF therapy, time from diagnosis of mCRC, geographical region• Global trial: 16 countries, 114 active centers • 1,052 patients screened, 760 patients randomized within 10 months• Secondary endpoints: PFS, ORR, DCR• Tertiary endpoints: duration of response / stable disease, QOL, pharmacokinetics, biomarkers
  • Overall survival (primary endpoint) Regorafenib Placebo 1.00 Median 6.4 mos 5.0 mos Survival distribution function 95% CI 5.9–7.3 4.4–5.8 0.75 Hazard ratio: 0.77 (95% CI: 0.64–0.94) 1-sided p-value: 0.0052 0.50 0.25 Placebo N=255 Regorafenib N=505 0 0 50 100 150 200 250 300 350 400 450 Days from randomization Primary endpoint met prespecified stopping criteria at interim analysis(1-sided p<0.009279 at approximately 74% of events required for final analysis)
  • Progression-free survival (secondary endpoint) 1.00 Regorafenib PlaceboSurvival distribution function Median 1.9 mos 1.7 mos 95% CI 1.9–2.1 1.7–1.7 0.75 Hazard ratio: 0.49 (95% CI: 0.42–0.58) 1-sided p-value: <0.000001 0.50 Placebo N=255 0.25 Regorafenib N=505 0 0 50 100 150 200 250 300 350 Days from randomization
  • Drug-related, treatment-emergent adverse events occurring in ≥10% of patients at any grade Regorafenib PlaceboAdverse event, % N=500 N=253 All Grade Grade Grade All Grade Grade Grade grades 3 4 5 grades 3 4 5Hand–foot skin reaction 46.6 16.6 0 0 7.5 0.4 0 0Fatigue 47.4 9.2 0.4 0 28.1 4.7 0.4 0Hypertension 27.8 7.2 0 0 5.9 0.8 0 0Diarrhea 33.8 7.0 0.2 0 8.3 0.8 0 0Rash/desquamation 26.0 5.8 0 0 4.0 0 0 0Anorexia 30.4 3.2 0 0 15.4 2.8 0 0Mucositis, oral 27.2 3.0 0 0 3.6 0 0 0Thrombocytopenia 12.6 2.6 0.2 0 2.0 0.4 0 0Fever 10.4 0.8 0 0 2.8 0 0 0Nausea 14.4 0.4 0 0 11.1 0 0 0Bleeding eventsAdverse 11.4 0.4 0 0.4 2.8 0 0 0leading to permanentVoice changes 29.4 0.2 8.2%0 0 5.5 0 1.2%0 0Tx discontinuationWeight loss 13.8 0 0 0 2.4 0 0 0
  • Take-Home Messages: OptimizedMedical Therapy of Advanced CRC1. Identify the goal of therapy • For most patients gain of time and maintaining QOL is more important • Strength of BEV – duration of therapy matters • RR only matters for • conversion therapy of liver metastases or • if patient is symptomatic from his tumor burden
  • Take-Home Messages: OptimizedMedical Therapy of Advanced CRC2. Treat to progression – and beyond Be mindful about toxicities, stop oxaliplatin before neurotoxicity develops • Some select patients can have CFI3. Expose patients to all potentially active agents • These agents are the oncologist‟s tools to keep patients alive • Use fluoropyrimidine-based combinations as default backbone, reserve sequential single agent therapy for select patients4. We finally have new active agents in CRC: Aflibercept and regorafenib
  • Bevacizumab vs EGFR Antibodies in Advanced CRC - SimplifiedAgent Strength WeaknessBevacizumab • Delay in tumor • Limited single progression agent activity • Gain in time • Weak effect on RR • Toxicity profile (per RECIST)EGFR • Single agent activity • Gain in time toantibodies • Consistent increase progression in RR moderate • Activity independent • Toxicity profile of line of therapy • Negative predictive marker available
  • Example of Continuum of Care FOLFOX-BEV KEY POINTS x8 • For elderly patients consider start of sequence with FP+/- FP-BEV BEV Until PDif TTP of FP-BEV • First-line oxaliplatin-based >6 mos therapy needs to be “optimoxed” FOLFOX-BEV • Sequences of FOLFOX -> FOLFIRI or FOLFIRI -> FOLFOX FOLFIRI-BEV are interchangeable if KRAS wt • BEV beyond progression (BBP) supported by phase III (Irino-) EGFR results mAb • EGFR mAb retain their activity in later lines of Regorafenib therapy
  • Advances in the Treatment of Stage IV CRC 1980 1985 1990 1995 2000 2005 2010 2015 BSC 35 5-FU 30 Irinotecan Capecitabine 25 OxaliplatinOS (months) Cetuximab 20 Bevacizumab Panitumumab 15 Aflibercept 10 Regorafenib 5 median overall survival 0 1980 1985 1990 1995 2000 2005 2010 2015
  • COST of CARE The Elephant in the Room PRESENTED BY:
  • Fight Colorectal Cancerwww.FightColorectalCancer.org www.CCAlliance.org877-427-2111 877-422-2030
  • Fight Colorectal Cancer CONTACT US Fight Colorectal Cancer 1414 Prince Street, Suite 204 Alexandria, VA 22314 (703) 548-1225 Toll-Free Answer Line: 1-877-427-2111 www.FightColorectalCancer.orgEmail us: Info@FightColorectalCancer.org