Treating Advanced Colorectal Cancer: 15 minutes, 13 abstracts Richard M Goldberg MD Professor and Chief of Heme/Onc Lineberger Comprehensive Cancer Center University of North Carolina at Chapel Hill

Topics: Chemotherapy N = 2241 First-line chemotherapy comparisons BICC (Fuchs et al): mIFL, CapeIRI, FOLFIRI Ducreux et al: Xelox to FOLFOX NO 16966 (Cassidy et al): Xelox to FOLFOX GONO (Falcone et al): 5-FU/IRI to FOLFOXIRI Second-line chemotherapy comparisons Rothenberg et al: Xelox to FOLFOX

BICC-C: Fuchs et al: n = 547 FOLFIRI mIFL CapeIRI 1st-line mCRC D O M I Z T 1st-line mCRC N = 1000

Efficacy in 430 Patients mIFL CapeIRI FOLFIRI P-value Response rate (%) 43.3 38.6 47.2 N.S. PFS (mos) 6.0 5.7 8.2 0.01 OS (mos) 17.6 18.9 23.1

Period 1: Progression Free Survival 1.0 Regimen Median PFS (Months) P Value FOLFIRI 8.2 0.01 mIFL 6.0 CapeIRI 5.7 0.9 0.8 0.7 0.6 Progression Free Survival Proportion of 0.5 0.4 0.3 0.2 FOLFIRI mIFL 0.1 CapeIRI 10 20 30 Time (months)

Proportion of Patients Survival Time (months) Period 1: OS as of May 1st, 2007 Regimen Median OS (Months) 1 Year P Value FOLFIRI 23.1 75% -- mIFL 17.6 65% 0.12 CapeIRI 18.9 66% 0.42 1 0.9 0.8 0.7 0.6 Proportion of Patients Who Survived 0.5 0.4 0.3 FOLFIRI 0.2 mIFL 0.1 CapeIRI 10 20 30 40 50 Survival Time (months)

Period 1: Grade 3-4 AEs Nausea 8.8 7.3 18.4 Vomiting 15.6 Diarrhea Adverse Event Grade 3-4 FOLFIRI n = 137 (%) m-IFL CapeIRI n = 141 Nausea 8.8 7.3 18.4 Vomiting 15.6 Diarrhea 13.9 19 47.5 Dehydration 5.8 19.1 Neutropenia 43.1 40.9 31.9 Febrile neutropenia 3.6 12.4 7.1 Hand-foot syndrome 9.9 MI / stroke 0.7 60-day mortality 5.1 3.5

What is currently the best combination of irinotecan and 5-FU? Question answered: What is currently the best combination of irinotecan and 5-FU? FOLFIRI What about toxicity? Beware the CapeIRI regimen used in this study No more IFL, mIFL

Xelox vs FOLFOX: Ducreux et al Equivalence Study N= 306 Randomization FOLFOX6

Efficacy Xelox N=156 FOLFOX6 N=150 P-value Response rate (%) 39% 46% na PFS (mos) 8.8 9.3 OS (mos) 19.9 20.5

Progression-free & Overall survival

Toxicity (n=304) * *p<0.05, Chi-square test * *

Questions Answered: Does XELOX ≈ FOLFOX-6 in terms RR, Median PFS and OS? Yes What about comparative toxicity? XELOX offers significantly less grade 3/4 neuropathy, neutropenia, and febrile neutropenia than FOLFOX-6.

Xelox vs FOLFOX: Cassidy et al Recruitment June 03 – May 04 Recruitment Feb 04 – Feb 05 XELOX n=317 XELOX + placebo n=350 XELOX + bevacizumab n=350 FOLFOX-4 n=317 FOLFOX-4 + placebo n=351 FOLFOX-4 + bevacizumab n=349 n=634 n=1400

Efficacy Xelox N=317 FOLFOX6 P-value Response rate (%) ? na PFS (mos) 8.0 pooled 8.5 OS (mos) 17.7 No bev 18.8

OS for XELOX vs. FOLFOX-4 in the 2-arm part of the study n=317, 262 events Proportion of patients 1.0 XELOX n=317, 250 events 0.9 0.8 0.7 HR = 0.90 [97.5% CI: 0.74–1.10] (ITT) HR = 0.92 [97.5% CI: 0.75–1.13] (EPP) 0.6 0.5 0.4 0.3 0.2 0.1 17.7 18.8 0.0 5 10 15 20 25 30 35 40 45 Months X X/P X/BV F F/P F/BV

Questions Answered: Do XELOX and FOLFOX-4 yield ≈ OS? Yes What about XELOX and FOLFOX-4 toxicities? As expected.

5-FU/IRI vs FOLFOXIRI: Falcone et al N = 244 Douillard Randomization FOLFOXIRI

5FU flat continuous infusion FOLFOXIRI Schedule Day 1 Day 2 Day 3 CPT-11 165 mg/m2 Oxaliplatin 85 mg/m2 L-LV 200 mg/m2 5FU flat continuous infusion 3200mg/m2 1 hour 2 hours 48 hours Repeated every 14 days

Efficacy 5-FU/IRI N=122 FOLFOXIRI P-value Response rate (%) 41% 66% ? PFS (mos) 6.9 (BICC = 8.3) 9.9 0.0009 OS (mos) 16.7 23.6 0.042

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

Progression Free & Overall Survival Medians Douillard: 6.9 mos FOLFOXIRI: 9.9 mos P= 0.0009 Medians Douillard: 16.7 mos FOLFOXIRI: 23.6 mos P= 0.042

Grade 3-4 Toxicity (N=122) (N=122) p =0.0006

Survival improves with availability of three active drugs * FOLFOXIRI P=0.0001 Grothey A, Sargent D. J Clin Oncol. 2005;23:9441-9442. 24

Questions Answered/Raised Is FOLFOXIRI more active than 5-FU/IRI? Yes, including better resection rates Is FOLFOXIRI too toxic? Generally not How do 3 drug regimens compare?

Xelox vs FOLFOX 2nd Line: Rothenberg et al N = 627 Randomization FOLFOX

Efficacy Xelox N=313 FOLFOX4 N=314 P-value Response rate (%) 15.3 12.4 na PFS (mos) 4.7 4.8 OS (mos) 11.9 12.6

Progression-free survival Estimated probability XELOX FOLFOX-4 1.0 0.8 0.6 0.4 0.2 4.7 4.8 0 5 10 15 20 25 Months

Overall Survival Estimated probability XELOX FOLFOX-4 1.0 0.8 0.6 0.4 0.2 11.9 12.6 0 5 10 15 20 25 30 35 40 Months

Questions Answered/Raised Does XELOX ≈ FOLFOX-6 in terms RR, Median PFS and OS in second line? Yes Were there any unexpected toxicities? No Do we need another XELOX/FOLFOX study in MCRC? No, 1561 patients reported on in this session MR: I would clarify the first point to state that “Progression-free survival with XELOX is non-inferior to FOLFOX-4 as second-line treatment for MCRC”.

Topics: Biologics N = 5379 Chemotherapy + Bevacizumab EGFR Antibodies: BICC (Fuchs et al): mIFL or FOLFIRI +/- Bev NO 16966 (Saltz et al) Xelox or FOLFOX +/- Bev Schmiegel et al: CapeOx or CapeIri + Bev EGFR Antibodies: Rash/Response Humbet et al: Panitumumab rash/response EVEREST (Tejpar et al) Iri + Cetuximab escalation trial OPUS (Bokemeyer et al) FOLFOX +/- cetuximab

BICC-C Part 2: N= 114 FOLFIRI + Bev Randomization mIFL + Bev

Efficacy mIFL + Bev N=60 FOLFIRI + Bev N=57 P-value Response rate (%) ? PFS (mos) 8.3 11.2 0.28 OS (mos) 19.2 Not reached 0.01

PFS Regimen PFS (Mos) P Value FOLFIRI + BEV 11.2 -- mIFL + BEV 8.3 0.28 1 0.9 0.8 0.7 0.6 Proportion of Subjects Who Did Not Progress 0.5 0.4 0.3 FOLFIRI + Bevacizumab mIFL + Bevacizumab 0.2 0.1 10 20 30 Time to Progression (months)

Proportion of Subjects Who Survived Survival Time (months) Regimen Median OS (Months) 1 Year P Value FOLFIRI+ BEV Not Reached 87% -- mIFL + BEV 19.2 61% 0.01 1 0.9 0.8 0.7 0.6 Proportion of Subjects Who Survived 0.5 0.4 0.3 FOLFIRI + Bevacizumab mIFL + Bevacizumab 0.2 0.1 10 20 30 40 Survival Time (months)

Period 2: Grade 3-4 AEs Nausea 10.7 5.1 Vomiting Diarrhea 11.9 Adverse Event Grade 3-4 FOLFIRI + bevacizumab n = 56 (%) m-IFL + bevacizumab n = 59 (%) Nausea 10.7 5.1 Vomiting Diarrhea 11.9 Dehydration 5.4 1.7 Neutropenia 53.6 28.8 Febrile neutropenia Hand-foot syndrome 3.6 0.0 Hypertension 12.5 MI / stroke 1.8 60-day mortality 6.8

Questions Answered/Raised Does FOLFIRI + bev = mIFL + bev FOLFIRI + bev > mIFL + bev Is a 6.8% 60-day mortality acceptable in PS 0,1 pts? No, but this is a small study with wide confidence intervals What will the OS be for FOLFIRI/Bev? What is the best chemo partner for Bev?

Xelox vs FOLFOX+/- Bev: Saltz et al Recruitment Feb 04 – Feb 05 XELOX n=317 XELOX + placebo n=350 XELOX + bevacizumab n=350 FOLFOX-4 n=317 FOLFOX-4 + placebo n=351 FOLFOX-4 + bevacizumab n=349 n=634 n=1400

Efficacy XELOX/FOLFOX N=701 XELOX/FOLFOX + bev N=699 P-value Response rate (%) 49% from GI 47% symposium 0.99 PFS (mos) 8.0 9.4 0.0023 OS (mos) 19.9 20.3 0.076

PFS 1.0 0.8 0.6 0.4 0.2 HR=0.83 [97.5% CI 0.72–0.95] PFS estimate XELOX / FOLFOX-4 + bevacizumab n=699 (513 events) XELOX / FOLFOX-4 + placebo n=701 (547 events) 1.0 0.8 0.6 0.4 0.2 HR=0.83 [97.5% CI 0.72–0.95] p=0.0023 PFS estimate 8.0 9.4 0 5 10 15 20 25 Months

Figure 3. Separation after ~6 months in bevacizumab-containing arms between ‘general’ and ‘on treatment’ PFS XELOX / FOLFOX-4 + bevacizumab XELOX / FOLFOX-4 + placebo 1.0 0.8 0.6 0.4 0.2 ON TREATMENT: HR=0.63 (97.5% CI 0.52–0.75, p<0.0001) PFS estimate When you compare the pooled PFS general and on treatment analysis you can observe that both Avastin curves separate nicely in the begining but the PFS general Avastin curve starts to run parallel around 6 month. This reflects the observed phenomenon that a large group of patients in the 966 trial discontinued treatment at 6 month and was not treated until progression, as recommended in the protocol. GENERAL: HR=0.83 (97.5% CI 0.72–0.95, p=0.0023) 0 5 10 15 20 Months

Figure 4. Overall survival XELOX / FOLFOX-4 + bevacizumab n=699 (420 events) XELOX / FOLFOX-4 + placebo n=701 (455 events) 1.0 0.8 HR=0.89 (97.5% CI 0.76–1.03) p=0.0769 Survival estimate 0.6 0.4 0.2 19.9 21.3 6 12 18 24 30 36 Months

Questions Answered/Raised Does Bevacizumab add to oxaliplatin based regimens? Not as dramatically as in irinotecan studies Should chemotherapy + bev be continued when oxaliplatin must be stopped? Yes, probably Why no difference in response rates? Does this mean we are not optimizing 1st line Rx?

CapeOx + Bev vs CapeIRI + Bev: Schmiegel et al; N= 233 Randomization CapeIRI + Bev

Treatment protocol Arm A: d 1 d 15 q 3wks Oxaliplatin 130mg/m2, 120min i.v. Bevacizumab 7,5 mg/kg i.v. Capecitabine 1000mg/m2 p.o., 2x daily Arm B: (*) Irinotecan 200mg/m2, 30min i.v. 800mg/m2 p.o., 2x daily q 3wks note dose reduction of CapIri compared to previous trials for safety reasons

Efficacy CapeOX + bev N=118 CapeIRI N=115 P-value Response rate (%) 45% 48% na PFS at 6 months (%) 74% 84% OS (mos)

CTC grade 3 and 4 Toxicities (n=229) Related toxicities Arm A (117) [%], 3°/4° Arm B (112) Diarrhoea 16 (16/0) 13 Sensory neuropathy 13 (12/1) Hand-Foot-Syndrome 6 (6/0) 4 (4/0) Vomiting 3 (3/0) 4 (4/0)å Fever 1 Neutropenia 2 (2/0)

Questions Answered/Raised Is 800 mg/m2 bid a better dose for CapeIRI? Likely Final results?

OPUS: Bokemeyer et al, N = 337 Phase II “Superiority trial” FOLFOX Randomization FOLFOX + Cetuximab

Efficacy FOLFOX N=168 + cetuximab N=169 P-value Response rate (%) 35.7% 45.6% na PFS OS (mos)

Questions Answered/Raised Does the addition of cetuximab to FOLFOX increase the response rate? Yes, by 10% How do we integrate this with Acrobat? This is a larger study and likely more reliable

Association of skin toxicity severity with clinical outcomes and health-related quality of life with panitumumab Y Humblet, M Peeters, S Artale, A Hendlisz, B Neyns, A Sobrero, M Wolf, M Woolley, R Amado, E Van Cutsem

Skin Toxicity & Outcomes with P-Mab: Humblet et al, N = 391 BSC Randomization Panitumumab + BSC

OS by Worst Skin Tox & mDLQI Score Patients with worst grade of 2-4 had better overall survival vs those with a worst grade of 1

Questions Answered/Raised Does rash correlate with outcomes? From this exploratory analysis improved PFS, overall survival, and HRQOL were associated with worse skin toxicity. Can we find a predictive marker for EGFR antibody response that does not require treatment? Amphiregulin, heregulin?

cetuximab dose escalation Not eligible for randomization EVEREST: Tejpar at al Arm A standard cetuximab regime (250 mg/m2/w) Cetuximab (400 mg/m2initial dose then 250 mg/m2/w) + irinotecan (180 mg/m2 q2w) Day 22 Screening Randomization Arm B cetuximab dose escalation (dose increases of 50 mg/m2 q2w up to maximum 500 mg/m2/w) Not eligible for randomization Arm C standard cetuximab regime (250 mg/m2/w)

Efficacy Standard dose N=45 Escalated dose N=44 P-value Response rate (%) 16% 30% Not done PFS (mos) 3.9 4.8 OS (mos) 10.0 8.6

Toxicity Standard dose N=45 Escalated dose N=44 Diarrhea 11% 23% Low Mg 2% 9% Grade≥ 2 rash 36% 57%

Questions Answered/Raised Can Cetuximab be escalated to doses of up to 500 mg/m2/week? Yes Is it useful? Higher RR, longer PFS, OS no better Is it practical? Can we find a predictive biomarker?

Topics: Miscellaneous Brite registry (Grothey et al) Bev after 1st progression Confirm 2 (Kohne et al) FOLFOX +/- PTK787 RTOG 0315 (Zachariah et al) Octreotide for chemo/rads diarrhea

The BRITE Registry: Grothey et al, N=1953 OBJECTIVES To evaluate the association between exposure to BV beyond 1st PD (BBP) and survival beyond 1st PD in an exploratory analysis in BRiTE Evaluable Evaluable Patients Patients (N=1953) (N=1953) Median follow-up time 19.6 mo 1 1 st st Progression* Progression* (n=1445) (n=1445) BV and No treatment CT/Biologics No Post-PD treatment No BBP CT/Biologics BBP (n=181) (n=486) (n=778) (n=531) (n=642) (n=253) BBP=bevacizumab beyond 1st PD

A previous report: median OS = 27.1 months Figure 2. Definition of Survival Beyond 1st PD OS OS TTP TTP BV start BV start 1st 1 st Progression Progression Death Death Survival beyond 1st PD Survival beyond 1 st PD A previous report: median OS = 27.1 months 1st line PFS median = 10.1 months

Figure 4. Kaplan-Meier Estimates by Subgroups Based on Treatment Post-1st PD A) Survival Beyond 1st PD B) Overall Survival A B

Questions Answered/Raised What does the data suggest? That OS with bev continuation exceeds that observed in comparable groups How useful is registry data? It is hypotheses generating (iBET study) Is this enough evidence to sway practice? Should it be?

CONFIRM 2 (2nd Line PTK 787): Koehne et al N = 852 FOLFOX4 Randomization FOLFOX4 + PTK787

Overall OS & PFS

PFS & OS in High LDH Patients

Questions Answered/Raised Is PTK useful when added to FOLFOX in this setting? No What does an elevated LDH mean? Should investigators lead or participate in Phase III trials that skip Phase II?

Octreotide for Radiation Related Diarrhea: Zachariah et al, N = 218 Chemo + RT Randomization Chemo + RT + Octreotide

Questions Answered/Raised Does octreotide help in this setting? No

Summary N= 7620 Patients FOLFIRI best irinotecan regimen Xelox ≈ FOLFOX 1st and 2nd line 3 Strategies pushed the OS >23 months GONO: FOLFOXIRI > 5-FU/IRI (not FOLFIRI) BICC: FOLFIRI + Bev Brite: bevacizumab continuation How to optimize bev/oxaliplatin regimens? How to optimize doses of biologics?