asco update 2012: gastrointestinal malignancies
DESCRIPTION
ASCO Update 2012: Gastrointestinal Malignancies. Thomas J. Semrad MD, MAS Assistant Professor of Medicine Division of Hematology/Oncology. Disclosure. Speaker’s Bureau: Novartis Consulting: Amgen, Genomic Health Research Funding: Novartis, Millenium , NCI. ASCO 2012: Non-Colorectal Topics. - PowerPoint PPT PresentationTRANSCRIPT
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ASCO Update 2012:Gastrointestinal Malignancies
Thomas J. Semrad MD, MASAssistant Professor of Medicine
Division of Hematology/Oncology
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Disclosure
• Speaker’s Bureau: Novartis
• Consulting: Amgen, Genomic Health
• Research Funding: Novartis, Millenium, NCI
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ASCO 2012: Non-Colorectal Topics
Esophagogastric Cancer– Locoregional Disease: Alternative to cisplatin / 5-
fluorouracil chemoradiation– Advanced Disease: Another negative trial of a
biologic in unselected patients
Anal Cancer– Timing of response assessment
HCC– Optimizing supportive care
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Phase III randomized trial of definitive chemoradiotherapy (CRT) with FOLFOX or cisplatin and fluorouracil in esophageal cancer (EC): Final results of the PRODIGE
5/ACCORD 17 trial.
Abstract #LBA4003Thierry Conroy, Marie-Pierre Galais, Jean Luc Raoul, Olivier Bouche, Sophie Gourgou-Bourgade, Jean-Yves Douillard, Pierre-Luc Etienne, Valérie Boige, Isabelle Martel-Lafay, Pierre Michel, Carmen Llacer-Moscardo, Jocelyne Berille, Laurent Bedenne,
Antoine Adenis
J Clin Oncol 30, 2012 (suppl; abstr LBA4003)
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Chemoradiation in Esophageal Cancer
RTOG 85-01• median survival
– 14 months vs. 9 months• 5 year survival
– 27% vs. 0%
• Local failure 45%• Major toxicity 20%
NEJM 1992; 326: 1593-8.
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Prodige 5 – ACCORD 11 Study Design
Unresectable Esophageal Cancer
• AdenoCa or SCCa • No Prior Treatment• No weight loss > 20%• No tracheal invasion or
TE fistula
N = 267
Primary Endpoint: Progression Free Survival
Secondary Outcomes1. CR rate2. Toxicity3. Time to treatment
failure4. OS5. QOL
FOLFOX + 50GyThen
FOLFOX x 3 cycles
5FU/cisplatin + 50GyThen
5FU/cisplatin x 2 cycles
Stratified By:HistologyWeight Loss (+/- 10%)PSCenter
90% Power to detect 20% increase in 3-year PFSN = 266 planned (144 events)
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Prodige 5 – ACCORD 11 Efficacy
PFS
OS
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Conclusion
• FOLFOX is not superior to 5-FU/cisplatin for definitive chemoradiation treatment for unresectable esophageal cancer
• This trial will be used to demonstrate clinical efficacy of definitive FOLFOX chemoradiation
• How does this compare to weekly carboplatin / paclitaxel?
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Which Regimen?
• Carbo/Taxol – CROSS– Neoadjuvant Study
(reduced radiation dose)
– pCR rate ~30%– Effective in both SCCa and
adenoCa– What is the systemic
efficacy?
• FOLFOX – Prodige 5– Inoperable study– Not superior to cisplatin/5-
FU– Mostly SCCa, but used
often in advanced adenoCa– More systemic therapy
NEJM 2012; 388:274-284 J Clin Oncol 30, 2012 (suppl; abstr LBA4003)
Reality of practice – neoadjuvant CRT used to select operable patients
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A randomized, multicenter trial of epirubicin, oxaliplatin, and capecitabine (EOC) with or without panitumumab in advanced
esophagogastric cancer (REAL3).
Abstract #LBA4000Tom Samuel Waddell, Ian Chau, Yolanda Barbachano, David Gonzalez de Castro, Andrew Wotherspoon, Claire Saffery, Gary
William Middleton, Jonathan Wadsley, David Raymond Ferry, Wasat Mansoor, Tom David Lewis Crosby, Fareeda Y Coxon, David Smith, Justin S. Waters, Timothy Iveson, Stephen Falk, Sarah Slater, Alicia Frances Clare Okines, David Cunningham
J Clin Oncol 30, 2012 (suppl; abstr LBA4000)
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REAL-3 Background
NEJM 2008;358:36-46. Gastric Cancer 2012;15:252-264.
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EOX (n=238)
mEOX-P (n=254)
CR 2% 3%
PR 40% 43%
SD 21% 18%
PD 8% 12%
Not evaluable 29% 24%
ORR 42% 46%
Counterintuitive Observations:OS outcome more extreme than PFS outcome
RR in opposite direction of OS results
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Dose Intensity
EOX EOX-PMedian Number of Cycles 6 5Dose intensity Epirubicin 89.9% 89.1%(% of expected dose) Oxaliplatin 89.9% 89.6%
Capecitabine 91.0% 86.9%Panitumumab - 88.1%
Dose reductions for toxicity 36% 39%Treatment cessation for toxicity 18% 18%
J Clin Oncol 30, 2012 (suppl; abstr LBA4000)
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Take Home Points
• No evidence of benefit for the addition of panitumumab to EOX
• Inferior OS may be due to inferior dose intensity of the experimental regimen
• RR was not a good surrogate for survival outcomes, and OS worse than PFS
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Optimum time to assess complete clinical response (CR) following chemoradiation (CRT) using mitomycin (MMC) or cisplatin (CisP), with or without maintenance
CisP/5FU in squamous cell carcinoma of the anus: Results of ACT II.
Abstract #4004Robert Glynne-Jones, Roger James, Helen Meadows, Rubina Begum, David Cunningham, John Northover, Jonathan A.
Ledermann, Sandra Beare, Latha Kadalayil, David Sebag-Montefiore
J Clin Oncol 30, 2012 (suppl; abstr 4004)
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ACT II Factorial DesignN=940
MMC + 5-FU + XRTNo Maintenance
CisP + 5-FU + XRTNo Maintenance
MMC + 5-FU + XRTMaintenance
CisP + 5-FU + XRTMaintenance
1. MMC vs. Cisplatin
2. Maintenance vs. No Maintenance
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Timing of CR Assessment
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Message: Be patient with response assessment
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A randomized controlled phase II study of the prophylactic effect of urea-based cream on the hand-foot skin reaction associated
with sorafenib in advanced hepatocellular carcinoma.
Abstract #4008Zhenggang Ren, Kangshun Zhu, Haiyan Kang, Minqiang Lu, Zengqiang Qu, Ligong Lu, Tianqiang Song, Weiping Zhou, Hui
Wang, Weizhu Yang, Xuan Wang, Yongping Yang, Lehua Shi, Yuxian Bai, Sheng-Long Ye
J Clin Oncol 30, 2012 (suppl; abstr 4008)
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HFSR GradingCTCAE v3.0
Grade 1 2 3 4
Rash:hand-foot skin
reaction
Minimal skin changes or
dermatitis (e.g.,erythema)
without pain
Skin changes (e.g.,
peeling, blisters,bleeding,
edema) or pain,not interfering
withfunction
Ulcerative dermatitis orskin changes
with paininterfering with
function
_
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ASCO 2012: Colorectal Topics
Maintenance– Combining Anti-VEGF and Anti-EGFR therapy
Anti-Angiogenic Therapy– Bevacizumab Beyond Progression– Aflibercept in Second Line– A new multi-targeted agent in advanced disease
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Bevacizumab (Bev) with or without erlotinib as maintenance therapy, following induction first-line chemotherapy plus Bev in patients with metastatic colorectal cancer (mCRC): Efficacy and
safety results of the International GERCOR DREAM phase III trial.
Abstract #LBA3500^Christophe Tournigand, Benoit Samson, Werner Scheithauer, Gérard Lledo, Frédéric Viret, Thierry Andre, Jean François
Ramée, Nicole Tubiana-Mathieu, Jérôme Dauba, Olivier Dupuis, Yves Rinaldi, May Mabro, Nathalie Aucoin, Ahmed Khalil, Jean Latreille, Christophe Louvet, David Brusquant, Franck Bonnetain, Benoist Chibaudel, Aimery De Gramont
J Clin Oncol 30, 2012 (suppl; abstr LBA3500^
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Combined anti-VEGF and anti-EGFR
• CAIRO2 • PACCE
N Engl J Med 2009;360:563-72. JCO 2009;27:5672-5680
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OPTIMOX3 – DREAM Schema
Inclusion/ExclusionMetastatic CRCNot suitable for surgery
Front-line TreatmentmFOLFOX7 + bev (6-12)XELOX2 + bev (6-12)FOLFIRI + bev (12)
Primary Endpoint: PFS on Maintenance
Secondary Outcomes1. OS2. OS from maintenance3. Duration without
chemotherapy4. RR5. OS according to KRAS
Bevacizumab 7.5 mg/kg q21 days
+Erlotinib 150 mg daily
Bevacizumab 7.5 mg/kg q21 days
Stratified By:Treatment Regimen
80% Power to detect PFS increase 4.5 to 6.5 moAnticipated 40% dropoutN = 700 (418 evaluable)
No PD
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Conclusion
The combination of EGFR- and VEGF-targeted agents is not dead*
*But should not (yet) be used in routine clinical practice
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Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first progression in patients with metastatic colorectal cancer (mCRC)
previously treated with BEV plus CT: Results of a randomized phase III intergroup study (TML study).
Abstract #CRA3503Dirk Arnold, Thierry Andre, Jaafar Bennouna, Javier Sastre, Pia J. Osterlund, Richard Greil, Eric Van Cutsem, Roger Von Moos,
Irmarie Reyes-Rivera, Belguendouz Bendahmane, Stefan Kubicka
J Clin Oncol 30, 2012 (suppl; abstr CRA3503
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BRiTE RegistryNo BBP BBP
Median OS 19.9 months 31.8 months
OS Beyond PD 9.5 months 19.2 months
JCO 2008; 26:5326-5334.
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TML Study Design(AIO KRK 0504, ML18147)
Metastatic CRC
• Front line chemo (either oxaliplatin- or irinotecan-based) + bevacizumab
• Progression within 4 wks• Not surgical candidate• Front-line PFS > 3 months• PD within 3 months of bev
N = 820
Primary Endpoint*: OS from randomization
Secondary Outcomes1. PFS2. RR3. Safety
Standard Second Line Chemo
+ Bevacizumab 2.5 mg/kg/wk
Standard Second Line Chemo
Stratified By:First line chemotherapyFirst line PFS +/- 9 monthsTime from last bev dose +/- 45 daysPS
90% Power to detect 30% increase in median OSN = 810*
* Increased from 572 with endpoint change PFS->OS
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OS
PFS
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TML Discussion
OS 9.8 -> 11.2 months (+1.4 months), HR 0.81 (95% CI 0.69 – 0.94)PFS 4.1 -> 5.7 months (+1.6 months), HR 0.68 (95% CI 0.59 – 0.78)
RR low (~5%) in both armsToxicity is as expectedSelect Patient Group
TOP LINE RESULTS
UNANSWERED QUESTIONS
1. Is it worth it? 2. Third line? Thirteenth line?3. Aflibercept? -> See next abstract
? ?
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Effects of prior bevacizumab (B) use on outcomes from the VELOUR study: A phase III study of aflibercept (Afl) and FOLFIRI in patients (pts) with
metastatic colorectal cancer (mCRC) after failure of an oxaliplatin regimen.
Abstract #3505Carmen Joseph Allegra, Radek Lakomy, Josep Tabernero, Jana Prausová, Paul Ruff, Guy Van Hazel, Vladimir Mikhailovich
Moiseyenko, David R Ferry, Joseph J McKendrick, Eric Van Cutsem
J Clin Oncol 30, 2012 (suppl; abstr 3505
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Aflibercept
Fusion Protein
Binds all VEGF-A isoforms, VEGF-B, and PlGF
High Affinity: binds VEGF-A and PlGF more tightly than native receptors
t1/2 ~ 17 days
Aflibercept
VEGFR-1
VEGFR-2 Fc
IgG
KEY FEATURES
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VELOUR Study Design
Metastatic CRC• Front line oxaliplatin- based chemo
• Relapse within 6 months adjuvant FOLFOX
• Not surgical candidate• Front-line PFS > 3 months• PD within 3 months of last bevacizumab
N = 1200
Primary Endpoint*: OS from randomization
Secondary Outcomes1. PFS2. RR3. Safety
FOLFIRI+
Aflibercept 4 mg/kgQ2 weeks
FOLFIRIQ2 weeks
Stratified By:PSPrior Bevacizumab
90% Power to detect OS HR 0.8N = 1200
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Velour Discussion
OS 12.1 -> 13.5 months (+1.4 months), HR 0.82 (95% CI 0.71 – 0.94)PFS 4.7 -> 6.9 months (+2.2 months), HR 0.76 (95% CI 0.58 – 0.99)
No apparent interaction with prior bevacizumab treatmentRR trends higher (up to 23.3%)
Toxicity is increased
TOP LINE RESULTS
UNANSWERED QUESTIONS
1. Is it worth it? 2. How to sequence with bevacizumab?
-> See prior abstract? ?
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Phase III CORRECT trial of regorafenib in metastatic colorectal cancer (mCRC).
Abstract #3502Eric Van Cutsem, Alberto F. Sobrero, Salvatore Siena, Alfredo Falcone, Marc Ychou, Yves Humblet, Olivier Bouche, Laurent Mineur, Carlo Barone, Antoine Adenis, Josep Tabernero, Takayuki Yoshino, Heinz-Josef Lenz, Richard M. Goldberg, Daniel J.
Sargent, Frank Cihon, Andrea Wagner, Dirk Laurent, Axel Grothey
J Clin Oncol 30, 2012 (suppl; abstr 3502)
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CORRECT Study Design
Metastatic CRC• Chemorefractory (oxaliplatin, irinotecan, 5-FU)
• EGFR Ab refractory (KRAS WT)
•PS 0-1
N = 760
Primary Endpoint: OS from randomization
Secondary Outcomes1. PFS2. ORR3. DCR
Regorafenib 160 mg daily3 weeks on, 1 week off
+BSC
Placebo3 weeks on, 1 week off
+BSC
Stratified By:Time from diagnosis to metsPrior anti-VEGF therapyGeographic Region
90% Power to detect 33.3% increase (HR 0.75) 1-sided alpha 0.05
N=690 planned, with 2 interim analysis
2:1
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OS
PFS
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The Evolving Anti-Angiogenic Landscape in CRC
The overall benefit of each of these new observations is modestIs there a subset with greater benefit?
There is no comparison between themBevacizumab versus Aflibercept?
Is regorafenib extended anti-VEGF therapy?
Challenges for Integration into Practice
A predictive biomarkerAlternate targets
The Way Forward