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

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 #LBA4003

Thierry 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

FOLFOX + 50Gy Then FOLFOX x 3 cycles 5FU/cisplatin + 50Gy Then 5FU/cisplatin x 2 cycles Primary Endpoint:

Progression Free Survival

Secondary Outcomes

1. CR rate 2. Toxicity 3. Time to treatment failure 4. OS 5. QOL Stratified By: Histology Weight Loss (+/- 10%) PS Center 90% Power to detect 20% increase in 3-year PFS N = 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 Reality of practice – neoadjuvant CRT used to select operable patients NEJM 2012; 388:274-284 J Clin Oncol 30, 2012 (suppl; abstr LBA4003)

A randomized, multicenter trial of epirubicin, oxaliplatin, and capecitabine (EOC) with or without panitumumab in advanced esophagogastric cancer (REAL3).

Abstract #LBA4000

Tom 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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Counterintuitive Observations: OS outcome more extreme than PFS outcome

(n=238) mEOX-P (n=254)

RR in opposite direction of OS results CR 2% 3% PR 40% 43% SD PD Not evaluable

ORR

21% 8% 29%

42%

18% 12% 24%

46%

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Dose Intensity

Median Number of Cycles Dose intensity (% of expected dose) Dose reductions for toxicity Treatment cessation for toxicity Epirubicin Oxaliplatin Capecitabine Panitumumab

EOX 6

89.9% 89.9%

91.0%

36% 18%

EOX-P 5

89.1% 89.6%

86.9%

88.1% 39% 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 #4004

Robert 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 Design

N=940 MMC + 5-FU + XRT

No Maintenance

MMC + 5-FU + XRT

Maintenance

CisP + 5-FU + XRT

No Maintenance

CisP + 5-FU + XRT

Maintenance

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 #4008 Zhenggang 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 Grading

CTCAE v3.0

Grade

Rash: hand-foot skin reaction

1

Minimal skin changes or dermatitis (e.g., erythema) without pain

2

Skin changes (e.g., peeling, blisters, bleeding, edema) or pain, not interfering with function

3

Ulcerative dermatitis or skin changes with pain interfering with function

4

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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/Exclusion Metastatic CRC Not suitable for surgery Front-line Treatment mFOLFOX7 + bev (6-12) XELOX2 + bev (6-12) FOLFIRI + bev (12) No PD

Bevacizumab 7.5 mg/kg q21 days + Erlotinib 150 mg daily Bevacizumab 7.5 mg/kg q21 days Primary Endpoint:

PFS on Maintenance

Secondary Outcomes

1. OS 2. OS from maintenance 3. Duration without chemotherapy 4. RR 5. OS according to KRAS Stratified By: Treatment Regimen 80% Power to detect PFS increase 4.5 to 6.5 mo Anticipated 40% dropout N = 700 (418 evaluable)

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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 #CRA3503

Dirk 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 Registry

Median OS OS Beyond PD

No BBP

19.9 months 9.5 months

BBP

31.8 months 19.2 months JCO 2008; 26:5326-5334.

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

TML Study Design

(AIO KRK 0504, ML18147)

Standard Second Line Chemo + Bevacizumab 2.5 mg/kg/wk Standard Second Line Chemo Primary Endpoint*:

OS from randomization

Secondary Outcomes

1. PFS 2. RR 3. Safety Stratified By: First line chemotherapy First line PFS +/- 9 months Time from last bev dose +/- 45 days PS 90% Power to detect 30% increase in median OS N = 810* * Increased from 572 with endpoint change PFS->OS

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OS PFS

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TML Discussion

TOP LINE RESULTS 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 arms Toxicity is as expected Select Patient Group ?

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 #3505

Carmen 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

VEGFR-1 VEGFR-2 IgG Fc

Aflibercept

Aflibercept KEY FEATURES

Fusion Protein Binds all VEGF-A isoforms, VEGF-B, and PlGF High Affinity: binds VEGF-A and PlGF more tightly than native receptors t 1/2 ~ 17 days

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 Stratified By: PS Prior Bevacizumab

FOLFIRI + Aflibercept 4 mg/kg Q2 weeks FOLFIRI Q2 weeks Primary Endpoint*:

OS from randomization

Secondary Outcomes

1. PFS 2. RR 3. Safety 90% Power to detect OS HR 0.8

N = 1200

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Velour Discussion

TOP LINE RESULTS 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 treatment RR trends higher (up to 23.3%) Toxicity is increased ?

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 #3502

Eric 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 2:1

Regorafenib 160 mg daily 3 weeks on, 1 week off + BSC

N = 760

Placebo 3 weeks on, 1 week off + BSC Primary Endpoint:

OS from randomization

Secondary Outcomes

1. PFS 2. ORR 3. DCR Stratified By: Time from diagnosis to mets Prior anti-VEGF therapy Geographic Region 90% Power to detect 33.3% increase (HR 0.75) 1-sided alpha 0.05

N=690 planned, with 2 interim analysis

OS PFS

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The Evolving Anti-Angiogenic Landscape in CRC Challenges for Integration into Practice

The overall benefit of each of these new observations is modest

Is there a subset with greater benefit?

There is no comparison between them

Bevacizumab versus Aflibercept?

Is regorafenib extended anti-VEGF therapy?

The Way Forward A predictive biomarker Alternate targets