Minimal versus Intense Upfront Systemic Therapy in Metastatic Colorectal Cancer Paulo M. Hoff, MD, FACP Hospital Sirio Libanes Sao Paulo, Brazil Centro de Oncologia

Medical Oncology Treatment Objectives in CRC To cure patients: –Adjuvant chemotherapy –Convert inoperable into operable disease To palliate symptoms: –Reduce tumor volume To prolong survival –Control disease growth

5 – Fluorouracil: 1957 NHNH HN O O F 5-FU 50 years later, fluoropyrimidines remain the backbone of colorectal cancer treatment.

Treatment Options for Advanced Colorectal Cancer in 2006 Six different classes of drugs available: –Fluoropyrimidines 5-FU, FUDR, Capecitabine, UFT, S-1 –Platins Oxaliplatin –Topoisomerase I inhibitors Irinotecan –Direct TS inhibitors Raltitrexed –Anti-VEGF Bevacizumab –Anti-EGFR Cetuximab, Panitumumab

Irinotecan Combination Trials IFL* (n=231) 5-FU/LV (n=226) RANDOMIZE Irinotecan (n=226) Saltz et al. N Engl J Med. 2000;343: Metastatic Colorectal Cancer

Saltz et al. N Engl J Med. 2000;343: Irinotecan Combination Trials: Efficacy Irinotecan + 5-FU/LV5-FU/LVP Value RR (confirmed, %) 39% 21% <.001* PFS (median, mo) OS (median, mo)

Oxaliplatin as Second-Line Treatment for CRC Rothenberg et al. J Clin Oncol. 2003;21: LV5FU2 (n=151) Oxaliplatin (n=156) RANDOMIZERANDOMIZE FOLFOX4 (n=152) Metastatic Colorectal Cancer S/P IFL

Oxaliplatin as Second-Line Treatment for CRC LV5FU2FOLFOX4OxaliplatinP Value RR0%9.9%1.3% <.0001 TTP2.7 mo4.6 mo1.6 mo<.0001 Overall Survival 8.7 mo9.8 mo8.1 mo.07 Rothenberg et al. J Clin Oncol. 2003;21:

N9741: Modified Schema IFL (n=264) IROX (n=264) FOLFOX4 (n=267) Goldberg et al. J Clin Oncol. 2004;22: RANDOMIZERANDOMIZE Metastatic Colorectal Cancer

N9741: Efficacy Results IFL (N=264) FOLFOX (N=267) IROX (N=264) RR (CR + PR)31%45%34% Median TTP (Months) Median OS (Months) Goldberg et al. J Clin Oncol. 2004;22:23-30.

N9741: Second Line Treatment SaltzFOLFOX-4Wasserman CPT-11Oxaliplatin CPT-11 5-FU/LV 5-FU/LV Oxaliplatin N=235N=235N=237 Any59%67%63% CPT-1122%52%28% Oxaliplatin17% 6% 6% 5-FU35%33%45% Other28%20%27%

FOLFOX6 (n=111) FOLFIRI With FOLFOX6 Sequencing Trial in CRC Tournigand et al. J Clin Oncol. 2004;22: FOLFIRI (n=109) RANDOMIZERANDOMIZE FOLFIRI (n=69) FOLFOX6 (n=81) Until progression

RR, % PFS, mo OS, mo FOLFIRI  FOLFOX6 FOLFOX6  FOLFIRI n = 109 n = 81 n = 111 n = 69 Tournigand C et al. J Clin Oncol 2004;22: FOLFIRI With FOLFOX6 Sequencing Trial in CRC

Availability of All Cytotoxic Agents and Survival Grothey A and Sargent D. J Clin Oncol. 2005;23: Patients With 3 Drugs (%) 0 Median OS (months)

5-FU/IRI vs FOLFOXIRI: Falcone et al N = 244 FOLFOXIRI 5-FU/IriDouillard Falcone ASCO 2007 RANDOMIZERANDOMIZE Metastatic Colorectal Cancer

Efficacy 5-FU/IRI N=122 FOLFOXIRI N=122 P-value Response rate (%) 41%66%? PFS (mos)6.9 (BICC = 8.3) OS (mos)16.7 (BICC = 23) Falcone ASCO 2007

Availability of All Cytotoxic Agents and Survival Courtesy of Dr. Goldberg, adapted from Grothey A and Sargent D. J Clin Oncol. 2005;23: Patients With 3 Drugs (%) 0 Median OS (months) * FOLFOXIRI

FU/IRI (42 pts) FOLFOXIRI (39 pts) R0 12%* (5 pts) 36%* (14 pts) * p=0.017 Post-ChemoRx Resections (patients with liver mts only) Falcone ASCO 2007

Phase III Trial With Bevacizumab Therapy in First-Line MCRC Bolus IFL + BV (n = 403) 5-FU/LV + BV (n = 110) Bolus IFL + placebo (n = 412) RANDOMIZE Untreated MCRC Hurwitz H, et al. N Engl J Med 2004;350:2235–42

Phase III Trial of Bevacizumab in First-Line MCRC IFL + Placebo (n=411) IFL + Bevacizumab (n=402)P Value ORR (%) CR PR Hurwitz H, et al. N Engl J Med 2004;350:2235–42

Median PFS (months) IFL + placebo: 6.2 (95% CI: 5.6–7.7) IFL + Bevacizumab: 10.6 (95% CI: 9.0–1.0) HR=0.54 (95% CI: 0.45–0.66) p<0.001 Probability of being progression-free PFS (months) IFL + Bevacizumab IFL + placebo Phase III trial : PFS Hurwitz H, et al. N Engl J Med 2004;350:2335–42

Median survival (months) IFL + placebo: 15.6 (95% CI: 14.3–17.0) vs IFL + Bevacizumab: 20.3 (95% CI: 18.5–24.2) HR=0.66 (95% CI: 0.54–0.81) p<0.001 Probability of survival Survival (months) IFL + Bevacizumab IFL + placebo Hurwitz H, et al. N Engl J Med 2004;350:2335–42 Phase III trial : Survival

FOLFIRI (n=144) R mIFL (n=141) XELIRI (n=145) Feb 2003 – April 2004 Initial design n=430 FOLFIRI+Bev. mIFL+Bev. (n=60) (n=57) May 2004 – Dec 2004 n=117 Primary endpoint: PFS Trial of Bevacizumab plus FOLFIRI/mIFL (BICC-C): design Protocol amended due to approval of bevacizumab Amended design R * Celecoxib data not shown Fuchs et al, ASCO 2007

BICC Efficacy in 430 Patients mIFLCapeIRIFOLFIRIP-value Response rate (%) N.S. PFS (mos) OS (mos) N.S. Fuchs et al, ASCO 2007

Adverse Event Grade 3-4 FOLFIRI n = 137 (%) m-IFL n = 137 (%) CapeIRI n = 141 (%) Nausea Vomiting Diarrhea Dehydration Neutropenia Febrile neutropenia Hand-foot syndrome day mortality Period 1: Grade 3-4 AEs Fuchs et al, ASCO 2007

Period 2: Efficacy mIFL + Bev N=60 FOLFIRI + Bev N=57 P-value Response rate (%) ??? PFS (mos) OS (mos)19.2Not reached0.01 Fuchs et al, ASCO 2007

Progression Free Survival Proportion of Subjects Who Did Not Progress RegimenPFS (Mos) P Value FOLFIRI + BEV mIFL + BEV Time to Progression (months) FOLFIRI + Bevacizumab mIFL + Bevacizumab Fuchs et al, ASCO 2007

Overall Survival Survival Time (months) Regimen Median OS (Months)1 Year P Value FOLFIRI+ BEVNot Reached87%-- mIFL + BEV19.261%0.01 Proportion of Subjects Who Survived FOLFIRI + Bevacizumab mIFL + Bevacizumab Fuchs et al, ASCO 2007

E3200: Phase III Trial of Bevacizumab in Second-Line Metastatic CRC FOLFOX4 BV monotherapy FOLFOX4 + BV Previously IFL Treated Metastatic CRC (n=880) Giantonio, ASCO 2005

E3200: Efficacy 4.8 P < vs. BV 3.0%9.2%21.8% P < vs. FOLFOX RR P < vs. FOLFOX PFS (months) Bevacizumab P = vs. FOLFOX OS (months) 271 FOLFOX4FOLFOX4 + bevacizumab Giantonio BJ et al. ASCO 2005

Phase III Trial of Bevacizumab With Oxaliplatin-Based Therapy in CRC Primary end point: PFS Previously untreated MCRC (N=1600) XELOX FOLFOX4 + Placebo + Bevacizumab (7.5 mg/kg, q3w) + Bevacizumab (5 mg/kg, q2w) Saltz L, et al. ASCO 2007

Efficacy XELOX/FOLFOX N=701 XELOX/FOLFOX + bev N=699 P-value Response rate (%) 49%47%0.99 PFS (mos) OS (mos) Saltz L, et al. GI ASCO 2007

Overall survival HR=0.89 (97.5% CI 0.76–1.03) p= XELOX / FOLFOX-4 + bevacizumabn=699 (420 events) XELOX / FOLFOX-4 + placebon=701 (455 events) Months Survival estimate Saltz L, et al. ASCO 2007

Cetuximab in Colorectal Cancer “Bond Trial” Irinotecan pre-treated EGF-R positive Metastatic CRC Cetuximab and Irinotecan 218 patients Cetuximab 111 patients * 577 patients screened 329 patients included in a 2:1 randomization PD Cunningham et al. NEJM 2004;351:

Cetuximab Combination Therapy “BOND” Trial IRI/Cx Cx Assessment(n=218)(n=111)P-value Response Rate 22.9%10.8%0.007 TTP 4.1 mo. 1.5 mo.<0.001 (Median) Survival (Median) 8.6 mo. 6.9 mo.0.48 Cunningham et al. NEJM 2004;351: Cetuximab may circumvent irinotecan resistance

Correlation Between Response Rate and Prior Treatment Subgroups Combination n/N (%) Monotherapy n/N (%) Prior regimens 17/41 (17.1)5/27 (18.5) 220/79 (25.3)5/41 (12.2) ≥323/98 (23.5)2/43 (4.7) Prior oxaliplatin yes30/135 (22.2)6/71 (8.5) no20/83 (24.1)6/40 (15.0)

The BOND II Trial RANDOMIZERANDOMIZE Bevacizumab + Cetuximab Bevacizumab + Cetuximab + Irinotecan CRC patients who progressed on irinotecan (any line) Saltz et al, ASCO 2005

The BOND II Trial Best response on study –CBI (n= 41)PR = 37% –CB (n=40)PR = 20% Median time to tumor progression: –Cetux/Bev/IRI 7.9 months –Cetux/Bev5.6 months Saltz et al, ASCO 2005

CALGB Intergroup Trial mFOLFOX6 or FOLFIRI Bevacizumab Cetuximab Bevacizumab + Cetuximab RANDOMIZERANDOMIZE

Panitumumab Phase III Trial in First Line Metastatic CRC: PACCE RANDOMIZE FOLFOX or FOLFIRI + Bevacizumab + Panitumumab FOLFOX or FOLFIRI + Bevacizumab Previously untreated CRC patients N=1000 PACCE: Panitumumab Advanced Colorectal Cancer Evaluation Press release reported lack of benefit in experimental arm

First Line Trials: Caveats for Survival as Endpoint Randomization Drug A Drug A + B Crossover to B not encouraged Classic Randomization Drug A Drug A + B Crossover to B mandatory Practical

The FOCUS Trail Drug A until it fails… …then B until it fails “staged single agents” A Drug A until it fails… …then add drug B until both fail “staged combination” B Drugs A + B together until both fail “1 st -line combination” C

A: FU until it fails, then change to Ir “3 rd drug” salvage OxCap IrCap OxCap IrCap B (ir) : FU until it fails, then add Ir B (ox) : FU until it fails, then add Ox C (ir) : FU+Ir from the start, until it fails C (ox) : FU+Ox from the start, until it fails patients Focus Design Seymour et al ASCO 2005

Overall survival PlanFirst 2 drugs scheduleMedian OS AFU then Ir13.9 B(ir) B(ox) FU then FU/Ir FU then FU/Ox C(ir) C(ox) 1 st -line FU/Ir 1 st -line FU/Ox Seymour et al ASCO 2005

FOCUS Summary Use of sequential chemotherapy, with deferred use of combinations, appears as effective as using the combination upfront; HOWEVER… Sequential single agents appears to be inferior than single agent followed by an appropriate combination Questions remain regarding exposure to all agents Not all agents should be used alone

CAIRO: Trial Profile Arm A Arm B Randomize capecitabine N=397 capecitabine + oxaliplatin N=143 (36%) irinotecan N=251 (62%) capecitabine + oxaliplatin N=213 (53%) capecitabine + irinotecan N=398 1 st line 2 nd line 3 rd line Courtesy of Punt et al, ASCO 2007

Median Overall Survival Combination treatment 17.4 months ( ) Sequential treatment 16.3 months ( ) p = 0.33 Courtesy of Punt et al, ASCO 2007

Who, What, How Definitions Intense therapy: –Implies early use of more complex combinations –Is not the same as piling all active drugs together Minimal therapy: –Seeks to minimize toxicity and perhaps cost –It is not the same as sequential monotherapy –It is not minimalist therapy

Who, What, How Who should get upfront intense therapy? –Depends on what you call intense therapy! –Patients who may become resectable with a good response –Patients whose quality of life may improve with a tumor response –Patients who are unlikely to get second and third line treatment regimens (e.g., aggressive tumors)

Who, What, How Who should get upfront minimal therapy? –Reserved for patients with little hope for a curative surgery –Patients who have relatively indolent disease, and who can expect to receive additional lines of therapy –Patients with good quality of life who are not interested in trading it for improvements in the therapy’s efficacy

Chemotherapy for CRC Summary Doublets are more active than single agents, and triplets may be even better Use of combinations of agents, in some sequence, results in better response rates, resection rates, time to progression, and overall survival However, the agents do not all need to be used upfront Judicious use of combination therapy, in an appropriate sequence, is indicated for most patients

How Should We Use the Available Drugs Good activity by itself –5-FU/LV –Capecitabine –UFT –Irinotecan –Raltitrexed Better used in combination –Oxaliplatin FOLFOX / XELOX IROX –Bevacizumab 5-FU Oxaliplatin Irinotecan Cetuximab –Cetuximab Irinotecan FOLFOX / XELOX –Panitumumab?

The Building Block Strategy 5-FU + LV 5-FU + Oxaliplatin Irinotecan + Cetuximab Capecitabine Irinotecan 5-FU + Bevacizumab Capecitabine + Oxaliplatin Panitumumab

Conclusion Treatment objectives are often different Patients are different Tumor biology and behavior is variable 1 Why should the treatment be the same ? We desperately need studies to learn how to match the correct treatment with the appropriate patient 1 O’Connell et al Abst. 4009, ASCO 2007