ASCO Update 2012:Gastrointestinal Malignancies

Thomas J. Semrad MD, MASAssistant 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

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

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)

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.

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

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?

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

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)

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

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)

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

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

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^

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

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

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.

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

? ?

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

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

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? ?

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

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