2007-2008 Lower GI Overview Chair: Charles D. Blanke, M.D., F.A.C.P. Systemic Therapy Provincial Program Leader, B.C. Cancer Agency Chief, Division of.

2007-2008 Lower GI Overview

Chair: Charles D. Blanke, M.D., F.A.C.P.

Systemic Therapy Provincial Program Leader, B.C. Cancer Agency Chief, Division of Medical Oncology, University of British Columbia

What’s New Re: Large Bowel Malignancy• Update on Systemic Therapy for Metastatic Disease:

Charles D. Blanke, M.D.

• Modern Adjuvant Therapy for Resected Colon Cancer:

John R. Zalcberg, M.D., Ph.D.

• Review of Radiotherapeutic Approaches to Rectal Cancer:

Claus Roedel, M.D.

• Panel Discussion/Questions

ASCO Potential Conflict of Interest Disclosures (Blanke)

• Consultant or Advisory Role: Imclone, Pfizer, Roche, Sanofi, Raven Biotech

• Research Funding: Novartis, Sanofi-Aventis

• Expert Testimony: Private entities

Update on Systemic Therapy for Metastatic Colorectal Cancer

• Background

• What’s New in Chemotherapy Selection

• What’s New in Targeted Therapy (Biologic) Selection

• What’s New in Scheduling

Chemotherapy Offers a Survival Advantage over BSC in mCRC

Scheithauer BMJ 306:752, 1993

5FU: All We had for 40 Years

• Antimetabolite pyrimidine antagonist designed and synthesized 1957

• Most extensively studied and used drug GI oncology

• Poor single-agent response rate (5-18%)

• We can make it better, but not much better-Adding leucovorin improves response rate (23%) and

survival (~10-12 months)

-Giving by infusion improves survival, decreases toxicity

US Approved Agents in mCRCYEAR 1ST LINE SALVAGE

1991 LV

1996, 1998 Irinotecan

2000 Irinotecan

2001 Capecitabine

2002 Oxaliplatin

2004 Oxaliplatin, Bevacizumab

Cetuximab

2006 Bevacizumab, Panitumumab

88

How Much Better Do We Do By Adding a New Drug: Summary Efficacy Data on Irinotecan + 5-

FU/LV

Saltz Douillard

Response Rate 39% 41%

Time to Progression

7 mos 6.7 mos

Overall Survival 14.4 mos 16.8 mos

Saltz N Eng J Med 343:905, 2000 Douillard Lancet 355:1041, 2000

99

How About Oxaliplatin: Summary Phase III Trial of First-Line FOLFOX4 vs. LV5FU2 (Efficacy)

LV5FU2 FOLFOX4 P Value

ORR (%) 22 51 .0001

PFS (mo) 6.2 9.0 .0003

OS (mo) 14.7 16.2 .12

de Gramont J Clin Oncol 18:2938, 2000

1010

Phase III Trial of First-Line FOLFIRI/FOLFOX6

FOLFOX6* FOLFIRI†

FOLFIRI FOLFOX6

Regimens: oxaliplatin* (100 mg/m2) or irinotecan† (180 mg/m2) IV + LV 200 mg/m2 over 2 hours d 1, 5-FU 2,400-3,000 mg/m2 over 46 hours

Primary end point: TTPSecondary end points: ORR, safety

n=113

n=113

Tournigand J Clin Oncol 22:229, 2004

RANDOMIZE

1111

Efficacy

Arm A-FOLFIRI Arm B-FOLFOX P

1st line ORR (%) 56 54 NS

1st line PFS (mo) 8.5 8.0 .26

2nd PFS (mo) 14.2 10.9 .64

Overall Survival (mo) 21.5 20.6 .99

Updated results, multivariate and subgroups analysis confirm improved activity and efficacy for FOLFOXIRI vs. FOLFIRI in the

G.O.N.O. randomized phase III study in metastatic colorectal cancer.

Updated results, multivariate and subgroups analysis confirm improved activity and efficacy for FOLFOXIRI vs. FOLFIRI in the

G.O.N.O. randomized phase III study in metastatic colorectal cancer.

2007 A.S.C.O. Annual Meeting

Chicago (USA), June 1-5

A. Falcone1,3, M. Andreuccetti1, I. Brunetti2, S. Ricci2, C. Barbara1, W. Evangelista4, V. Passeri5, S.

Chiara6, G. Allegrini1, G. Masi1

1 U.O. Oncologia Medica, Azienda USL-6, Livorno; 2 U.O. Oncologia Medica, Ospedale S. Chiara, Pisa; 3 Università degli Studi di Pisa, 4 Centro Oncologico ed Ematologico Subalpino, Ospedale S. Giovanni Battista Le Molinette, Torino, 5 Dipartimento di Medicina Sperimentale e Patologia, Oncologia Medica, Università la Sapienza, Roma, 6 Istituto Nazionale per la Ricerca sul Cancro, GenovaITALY

FOLFOXIRI SCHEDULEFOLFOXIRI SCHEDULE

5FU flat continuous infusion3200mg/m2

L-LV 200 mg/m2

Oxaliplatin 85 mg/m2

2 hours

Repeated every 14 days

CPT-11165 mg/m2

48 hours1 hour

FOLFOXIRI vs. FOLFIRI: Summary

FOLFOXIRI FOLFIRI p

Grade 3 diarrhea 20% 12% NA

Grade 3 neutropenia 50% 28% 0.0006

Objective response rate (%) 60 34 <0.001

R0 surgery (%) 15 6 0.033

Median OS (mo) 23.6 16.7 0.042

Clinical Impact of FOLFOXIRI Study

• Not a ton– Not widely used overall, despite modest toxicity and

impressive efficacy– ?Because trial did not include biologics

• Modestly commonly used to downstage potential metastasectomy patients

Starting Point: Common Uses of Biologics Last Year

• First-line metastatic disease: FOLFOX or FOLFIRI + bevacizumab– Median OS IFL +/- bev 15.6 vs. 20.3 months*– No real front-line data oxaliplatin-based rx with bevacizumab (TREE-2)

• Common second-line rx: CPT-11 or FOLFIRI alone or with cetuximab– ORR cetux + CPT-11 vs. cetux: 23% vs. 11%

• Common “late”-line therapy: cetuximab + CPT-11 or panitumumab– Both antibodies offer PFS or OS benefit over BSC

XELOX + placebo n=350

FOLFOX-4 + placebo n=351

XELOX + bevacizumab

n=350FOLFOX-4 + bevacizumab

n=349

XELOX n=317

FOLFOX-4 n=317

Initial 2-arm open-label study

(n=634)

Protocol amended to 2x2 placebo-controlled design after bevacizumab phase III data8 became available (n=1400)

RecruitmentJune 2003 – May 2004

RecruitmentFeb 2004 – Feb 2005

ASCO 2007: XELOX-1 / NO16966 study design

Courtesy Dr. Cassidy

Copyright © American Society of Clinical Oncology

Cassidy, J. et al. J Clin Oncol; 26:2006-2012 2008

XELOX is non-inferior to FOLFOX-4 for Progression-Free Survival (intent-to-treat population)

Chemotherapy with or Without Bevacizumab: Efficacy

Bev + chemorx Chemorx Hazard Ratio

(p value)

PFS (mo.) 9.4 8 0.83

(0.0023)

PFS CapOX (mo.) 9.3 7.4 0.77

(0.0026)

PFS FOLFOX4 (mo.)

9.4 8.6 0.89

(0.1871)

OS (mo.) 21.3 19.9 0.89

(0.077)

Saltz J Clin Oncol 26:2013, 2008 Yellow = significant White = not significant

NO16966 Take-Home Points

• Capecitabine is at least as effective as 5FU, even in combination

• Bevacizumab improves front-line efficacy (PFS) of FPs– Lack of PFS improvement for FOLFOX is interesting– Lack of OS and ORR improvements also interesting– Authors suggested continuing bev until progression important, even if

part of chemorx is dropped (e.g., oxaliplatin)

The CRYSTAL trial: Efficacy and safety of irinotecan and 5-FU/FA with and without cetuximab in the first-line treatment of

metastatic colorectal cancer

Eric Van Cutsem*, M Nowacki, I Lang, S Cascinu,

I Shchepotin, J Maurel, P Rougier, D Cunningham,

J Nippgen, C-H Köhne

*University Hospital Gasthuisberg, Leuven, Belgium

Courtesy Dr. Eric Van Cutsem PASCO 2007

CRYSTAL trial: Study design

Stratification factors: Regions ECOG PS

Populations Randomized patients n=1217 Safety population n=1202 ITT population: n=1198

FOLFIRI

irinotecan (180 mg/m2) + 5-FU 400 mg/m2 bolus + 2400 mg/m2 as 46-hr continuous infusion) + FA every 2 weeks

Cetuximab + FOLFIRI

Cetuximab IV 400 mg/m2 on day 1, then 250 mg/m2 weekly+ irinotecan (180mg/m2) + 5-FU (400 mg/m2 bolus + 2400 mg/m2 as 46-hr continuous infusion)+ FA every 2 weeks

RUntreated EGFR-expressing metastatic CRC

Courtesy Dr. Van Cutsem

CRYSTAL Trial: SummaryFOLFIRI FOLFIRI + Cetuximab Odds Ratio/HR

(p value)

Grade 3/4 Diarrhea (%) 10.5 15.2 --

Grade 3 Skin Toxicity (%) 0.2 18.7 --

ORR (%) 38.7 46.9 (0.0038)

Median PFS (mo)* 8.0 8.9 0.851

(0.0479)

RO Resection Rate (%) 1.5 4.3 3

(0.0034)

*Primary objective

2424

CRYSTAL Take-Home Points•Cetuximab improves efficacy of FOLFIRI

•Cetuximab works in first-line rx of metastatic CRC

•Cetuximab can be used as part of “conversion therapy”

•Not shown: EGFR Ab may not work in patients with mutant ras*

-We may need to start testing patients before using cetux or panitum

-Current national trials in CRC may need to be modified

*ASCO plenary 2008!

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The Kitchen and Bathroom Sinks: “FOLFOXIRI” with Bev or Cetuximab

•GI Symposium 2008: Phase II trial of FOLFOXIRI + bev in first-line mCRC (Masi et al.)

-23% grade 3 neutropenia; 83% ORR!

•Same : FOLFIRINOX + cetux in first-line mCRC (Samalin et al.)-3/14 DLT (1 toxic death); 57% ORR (14% CR!)

•Stay tuned

•Be careful

2626

CAUTION! Emerging Concerns About Combining Chemotherapy and Two Biologics

• PACCE1 (chemorx + bev +/- panitumumab): Worse PFS for oxali/bev/pan and CPT/bev/pan vs. drug/bev alone

– Lots more toxicity and toxic deaths for combos, too

• CAIRO-22 (Capox + bev +/- cetuximab): Statistically significantly worse PFS with both antibodies

– More rash and diarrhea; no major increase in deaths

• Is there a negative interaction between EGFR- and VEGF-directed antibodies?

• What about C80405 (current phase III Intergroup study)?

1GI Symp 2008 2ASCO 2008

SCHEDULING: CAIRO study CKTO 2002-07

Arm A Arm B

Randomize

capecitabine

capecitabine +oxaliplatin

irinotecancapecitabine +

oxaliplatin

capecitabine +irinotecan1st line

2nd line

3rd line

Courtesy Punt, PASCO 2007

Median overall survival

Combination treatment 17.4 months (15.2-19.2)

----------- Sequential treatment 16.3 months (14.3-18.2)

p = 0.33

Updated Lancet 370:105, 2007

2929

Thoughts on Scheduling: 2007-08

•> 1 study has suggested starting out with one drug is OK-Combinations still significantly favored by most oncologists

•Chemoholidays now mandatory with wide-spread use of FOLFOX-Optimox-21 suggested 7 month improvement in OS with use of maintenance chemotherapy instead of full holiday (p = 0.0545)

1ASCO 2007

3030

Update on Systemic Therapy for Metastatic Colorectal Cancer: Conclusions

After a 10-year explosion of new drugs, we have been bereft of new agents

Questions still remain re: the optimal chemo- and biologic regimens in first and second-line settings

More aggressive combinations seem to lead to greater downsizing of tumor

-May equal greater rates of resectability and thus cure

3131

Update on Systemic Therapy for Metastatic Colorectal Cancer: Conclusions (cont.)

• Capecitabine may be substituted for 5FU, alone or in combination regimens

• Don’t combine antibodies off study

• The jury remains out on initial combinations versus sequential single-agent therapies

• Selecting agents based on genetic testing is here (ras)!