post g.i. asco update: colorectal cancer

Post G.I. ASCO Update:Colorectal Cancer

Ronald Burkes, M.D.

Disclosure of Potential Conflicts of Interest

Dr. Ronald Burkes

Amgen Inc., Eli Lilly and Company, Hoffmann-La Roche, AstraZeneca, Sanofi-Aventis

Advisory board:

Honoraria: Amgen Inc., Eli Lilly and Company, Hoffmann-La Roche, AstraZeneca, Sanofi-Aventis

Speaker: Amgen Inc., Eli Lilly and Company, Hoffmann-La Roche, AstraZeneca

Objective(s) Review what was new and interesting from G.I.

ASCO, 2012 Put these results in perspective Studies to be reviewed:

181 study – FOLFIRI +/- Panitumumab as 2nd-line treatment of mCRC

NCIC CO.20 study – Cetuximab +/-Brivanib in KRAS WT mCRC (3rd-line)

CORRECT trial – BSC +/- Regorafenib in mCRC (4th-line)

XELOXA trial (N016968) – role of adjuvant XELOX for stage III CRC

ACCORD 12 trial – Capox in rectal cancerAssessment of the prognostic and predictive value of

mutant KRAS codons 12 & 13

FOLFIRI +/- Panitumumab as 2nd-line Therapy of mCRC: 181 study

Sobrero GI ASCO (#387), 2012

FOLFIRI + P303

FOLFIRI284

HR/p-value

RR 36% 9.8%PFS (mos) 6.7 4.9 .82/.023OS (mos) 14.5 12.5 .92/.37

Post Rx EGFR MoAb

12% 34%

OS (mos) by ST (2-4 vs 0-1)

16.4 vs 8.4 12.7 .5 vs 1.48

Comments: 181 Final analysis is consistent with the primary analysis There is an improvement in PFS and RR but not OS Not likely to be used as a 2nd-line option since no OS

but may be appropriate for some pts when response is necessary (? still potentially resectable)

Rash/efficacy interaction seems to be important, but not well understood

The inability to mount a skin reaction to an anti- EGFR antibody seems to be associated with a shorter survival → what should we do with patients who don’t develop a rash (should they stop the anti-EGFR MoAb) ?

Brivanib – anti-VEGFR2 inhibitor and also targets fibroblast growth receptors

Cetuximab +/- Brivanib in Refractory KRAS WT mCRC: NCIC CO.20

Siu GI ASCO (#386), 2012

Cetux + Ber376

Cetux + Pl374

HR/p-value

OS (mos) 8.8 8.1 .88/.12PFS (mos) 5 3.4 .72/<.0001

RR 13.6% 7.2% .004DI cetux 57% 83%

AEs (gr3/4) 78% 53%D/C Cetux/Br 8%/22% 4%/3%

Comments: CO.20 PFS and RR benefit but no OS benefit

(primary endpoint!) → no significant x-over Toxicity of the combination may have

confounded efficacy → DI; D/C Rx 20 AEs Potential biological antagonism → PACCE and

CAIRO-2 Unlikely to gain regulatory approval and/or use

in combination with cetuximab Phase III HCC monotherapy trials are ongoing

NB: no PS 2 patients on study

Even

t-f

ree

Prob

abili

ty

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Weeks from Randomization0 8 16 24 32 40 48 56

Hazard ratio=0.54 (95% CI: 0.44, 0.66)

Stratified log-rank testp < 0.000000001

ProgressionProgression--Free SurvivalFree Survival

Panitumumab

BSC

Patients at risk:PanitumumabBSC

231 118 49 31 13 5 1232 75 17 7 3 1 1

Primary Analysis, All Randomized Analysis Set, Central Radiology

BSC +/- Regorafinib in Refractory mCRC: CORRECT Trial (no PS2, no x-over)

Grothey GI ASCO (#385), 2012

Regorafinib505

BSC255

HR/p-value

KRAS mut 54.1% 61.6%

MST (mos) 6.4 5 .77/.0052

PFS (mos) 1.9 1.7 .49/<.00001

RR/DCR 1%/44.8% .4%/15.3% p<.000001

Toxicity H/F, ↑BP, Diarrhea

D/C 20 AEs 8.2% 1%

Comments: CORRECT• OS and PFS benefit

– Statistically significant– Clinically meaningful– Toxicity profile not insiginificant (H/F,

diarrhea, fatigue, ↑BP) but acceptable– Lack of x-over helped achieve endpoints

• Clinical impact– Likely to become an available standard for

refractory mCRC – when??? (unmet need)– Role in PS 2 patients is unknown– Role of continuous dosing is unknown

X-ACT vs XELOXA

Cape Mayo HR/p Bolus Xelox HR/p

N 1004 983 942 944DFS 60.8% 56.7% .88/<.0001(.068) 59.8% 66.1% .8/.0038

OS 71.4% 68.4% .86/<.0001(.06) 70% 75% .83/.038

X-ACT XELOXA

Twelves GI ASCO (#274), 2008

Twelves GI ASCO (#274), 2008

Comments: XELOXA XELOX improves DFS and OS compared to bolus

5-FU in patients with stage III colon cancer (median follow-up of 7 years)

Benefit is less in patients > 70 years XELOX should be considered a treatment option

in the adjuvant therapy of stage III colon cancerq3weeks less infusion time (impact on chemo unit) less need for central lines it is not for everyone – keep a close watch for toxicity

Capecitabine + RT(45) vs Capox + RT (50) in Rectal Cancer: ACCORD 12 Trial

Gerard GI ASCO (#389), 2012

Cape 45299

Capox 50299

DFS (3 yrs) 68.3% 73.7%

OS (3 yrs) 87.6% 88.3%

pCR 13.9% 19.2%

Local recurrence 6.1% 4.7%

Systemic recurrence 25% 21%

Diarrhea gr ¾ 11% 25%

Comments: ACCORD 12 This study introduced 3 changes to the

approach to the pre-operative therapy of rectal cancer

Oxaliplatin increases toxicity (diarrhea) without any significant impact on ypCR (not a radiosensitizer), local or systemic recurrences, DFS and OS

50Gy/5 weeks compatible with surgery and also increased the CRM negative rate

Capecitabine has the same activity as 5-FU

Comments: KRAS Mutation Analysis in mCRCPeeters GI ASCO (#383), 2012

Patients with mCRC that harbor most of the common codon 12 and 13 mutant KRAS alleles are unlikely to benefit from panitumumab therapy

Currently only mCRC patients with WT KRAS tumors should be treated with anti-EGFR MoAbs