Colorectal Cancer Abstracts Oral Session: 6/6/10

Alan P. Venook, M.D.University of California, San Francisco

Colorectal Cancer Abstracts• MACRO

• COIN

• CLOCC

• HORIZON III

Horizon IIIAZD2171 (Cediranib) – VEGF TKI

• FOLFOX / Bevacizumab v. FOLFOX / AZD2171

• Fails to meet primary end-point

• Abstract withdrawn pending results Horizon II

• 5/28/10 press release: Horizon II negative

• To be submitted to ESMO

Colorectal Cancer Acronyms• MACRO – MAintenance in ColoRectal Cancer

• COIN – Cetuximab and OxaliplatIN

• CLOCC – Chemo and LOcal Therapy for CRC

Colorectal Cancer Acronyms• MACRO – MAintenance in ColoRectal Cancer

• COIN – COmplicated to INterpret

• CLOCC – Chemo and LOcal Therapy for CRC

MACRO TRIALTabernero et al

ProgressionRCapecitabineOxaliplatin

Bevacizumabx6 cycles q3w

Bevacizumabuntil progression

N=480

N=239

N=241

CapecitabineOxaliplatin

Bevacizumabx6 cycles q3w

CapecitabineOxaliplatin

Bevacizumabuntil progression

Primary end-point: PFS

MACRO TRIALTabernero et al

ProgressionRCapecitabineOxaliplatin

Bevacizumabx6 cycles q3w

Bevacizumabuntil progression

N=480

N=239

N=241

CapecitabineOxaliplatin

Bevacizumabx6 cycles q3w

CapecitabineOxaliplatin

Bevacizumabuntil progression

Primary end-point: PFS

MACRO TRIALTabernero et al

ProgressionRCapecitabineOxaliplatin

Bevacizumabx6 cycles q3w

Bevacizumabuntil progression

N=480

N=239

N=241

CapecitabineOxaliplatin

Bevacizumabx6 cycles q3w

CapecitabineOxaliplatin

Bevacizumabuntil progression

Primary end-point: PFS

Clinical Question:• Does Bevacizumab monotherapy substitute for

continuing CAPEOX plus Bevacizumab?

More toxicity with CAPEOX

QOL worse with CAPEOX

Is survival compromised?

Is Bevacizumab active as single agent in colorectal cancer ?

Bevacizumab monotherapy

Bergsland et al, ASCO, 2000

FU/LV +/- bev

Bevacizumab monotherapy

Bergsland et al, ASCO, 2000

PR = 10%

Kabbinavar, JCO,2003

Overall Survival ITT

Patients at risk

Follow-up median months (range) 21.1 (0-40) 20.4 (0-38)

Safety: Treatment-related NCI Grade 3-4* AEs

 

XELOX-BEV N=238 s/a BEV N=238

N % N %

NEUROPATHY SENSORY 59 24.8 18 7.6

DIARRHEA 26 10.9 33 13.9

HAND FOOT SKIN REACTION 29 12.2 16 6.7

FATIGUE 24 10.5 10 4.2

HYPERTENSION 9 3.8 17 7.1

PROTEINURIA 1 0.4 4 1.7

THROMBOSIS 2 0.8 3 1.3

PERFORATION, GI 2 0.8 1 0.4

BLEEDING 1 0.4 1 0.4

OBSTRUCTION/GI . . 1 0.4

CARDIAC ISCHEMIA . . 1 0.4

* Include grade 5

Clinical Question:• Does Bevacizumab monotherapy substitute for

continuing CAPEOX plus Bevacizumab?

Is PFS compromised?

STATISTICS

• Sample Size: 470 patients; 235 per arm– Non-inferiority design – Assuming 10 months as median PFS – Non-inferiority limit of 7.6 m (HR=1.32)– Power = 80%

MACRO Conclusions• This data indicate that a priori specified non-

inferiority cannot be still confirmed, but we can reliably exclude a detriment of larger than 3 weeks in PFS.

• This study suggests that maintenance therapy with single agent BEV is an appropriate option following induction XELOX-BEV in pts with mCRC.

• Further studies evaluating single agent BEV after standard chemotherapy in mCRC are warranted.

Progression Free Survival ITT

LNI: 1.32

Follow-up median months (range) 21.1 (0-40) 20.4 (0-38)

Patients at risk

Progression Free Survival ITT

LNI: 1.32

Follow-up median months (range) 21.1 (0-40) 20.4 (0-38)

Patients at risk

HR: 1.11 (0.89 - 1.37)HR: 1.11 (0.89 - 1.37)

Hazard Ratios

Slope of the survival curve

HR = 1.11

.11 excess hazard over median median of 10 months ≈ 4 weeks

HR = 1.11 (0.89 – 1.37) – 95% confidence intervals

as much as .37 hazard over medianmedian of 10 months ≈ 3.7 months

Conclusions• This data indicate that a priori specified non-

inferiority cannot be still confirmed, but we can reliably exclude a detriment of larger than 3 weeks in PFS.

My Conclusions• This data indicate that a priori specified non-

inferiority cannot be still confirmed, but we can reliably exclude a detriment of larger than 3 weeks in PFS.

• However, given overall survival results and the QOL associated with the control arm – which reflects excessive oxaliplatin neurotoxicity – PFS less relevant in this analysis

monthsmonths which definitely does not prove non-inferiority

which definitely does not prove non-inferiority

COIN Trial design

.

5FU or capecitabineoxaliplatin

Arm A

CONTINUOUS CT until progression, toxicity or patient choice

5FU or capecitabineoxaliplatin

cetuximab

Arm B

CONTINUOUS CT until progression, toxicity or patient choice

815

815

Maughan et al

For all patientsIncreased non-haematological toxicityNo change in OS or PFS

For KRASwt patientsNo change in OS or PFSIncreased response rate

COIN Trial design

.

5FU or capecitabineoxaliplatin

Arm A

CONTINUOUS CT until progression, toxicity or patient choice

5FU or capecitabineoxaliplatin

cetuximab

Arm B

CONTINUOUS CT until progression, toxicity or patient choice

815

815

Maughan et al

For all patientsIncreased non-haematological toxicityNo change in OS or PFS

For KRASwt patientsNo change in OS or PFSIncreased response rate

Capecitabine / OxalIplatin

Negative

Capecitabine / OxalIplatin

Negative

COIN conclusions• Subgroup analyses suggest that there may be a benefit for

cetuximab in combination with oxaliplatin chemotherapy in patients with– KRAS wildtype tumours, – Limited metastatic disease (0/1 metastatic sites), – Used in combination with infusional 5FU and oxaliplatin

• The differential benefit for choice of fluoropyrimidine and distribution of disease requires validation from other datasets

Mutations in Kras, Nras, Braf: distribution and prognostic significance

BRAF mutation All patientsAny mutationKRAS mutation

KRAS wild-typeAll wild-type

Mutation status:

06

12

Med

ian

PFS

(m

on

ths) Arm A Arm B

06

12

18

Med

ian

OS

(m

on

ths)

57340

268815

367289

45366

297815

362292

01

02

03

04

0

2-y

ear

OS

(%

)

N:

Prognostic effect of mutational status

“All-wt”n=581 (44%)

KRAS-mutn=565 (43%)

NRAS-mutn=50 (4%)

BRAF-mutn=102 (8%)

Totaln=1316 (81%)

554

11

39

102

Population N Arm A Arm B

ITT 1630 815 815

Assessed for mutations

1316 648 668

of which:- KRAS mutation- NRAS mutation- BRAF mutation

565 (43%)50 (4%)

102 (8%)

2681857

2973245

KRAS wt 729 (55%)

367 306

KRAS/NRAS/BRAF-wt“All wild-type”

581 (44%)

289 292

BRAF mutation All patientsAny mutationKRAS mutation

KRAS wild-typeAll wild-type

Mutation status:

06

12

Med

ian

PFS

(m

on

ths) Arm A Arm B

06

12

18

Med

ian

OS

(m

on

ths)

57340

268815

367289

45366

297815

362292

01

02

03

04

0

2-y

ear

OS

(%

)

N:

Prognostic effect of mutational status

BRAF mutation: poorest prognosis

KRAS wt: superior prognosis compared to KRAS mut

Overall Survival:by mutation status: KRAS, NRAS, BRAF

Arm A Arm B Diff.

Median survival:(mo) 20.1 19.9 -0.20

2-year survival rates

40.0% 38.8%

-1.24%

Arm A Arm B Diff.

Median survival: (mo) 14.4 12.7 -1.64

2-year survival rates 21.2% 25.5%

+4.29%

All wild type Any mutation

0.00

0.25

0.50

0.75

1.00

Sur

viva

l

0 6 12 18 24 30 36 42Time (months)

Arm A (OxFp)

Arm B (OxFp + cetux)

HR point estimate = 1.01995% CI = (0.86, 1.20)Χ2 = 0.03; p = 0.86

0 6 12 18 24 30 36 42Time (months)

Arm A (OxFp)

Arm B (OxFp + cetux)

HR point estimate = 1.00495% CI = (0.87, 1.15)Χ2 = 0.00; p = 0.96

Last Conclusion, and not in written abstract• (0/1 metastatic sites),

• Strong prognostic effect of KRAS, BRAF and NRAS mutation status independent of the use of cetuximab

consistent with BRAF data, not conventional wisdom for KRAS

consistent with BRAF data, not conventional wisdom for KRAS

Cetuximab v. BSC 3rd-line:OS by KRAS status in BSC arms

0

0.2

0.4

0.6

0.8

1

0 2 4 6 8 10 12 14 16 18

Time from Randomisation (Months)

Pro

po

rtio

n A

liv

e

Mutated

Wild Type

MutatedWild Type

83 69 42 28 20 13 11 7113 92 69 36 24 17 12 5

HR HR 1.01 1.01 95% CI (0.74,1.37) 95% CI (0.74,1.37)

Log rank p-value: Log rank p-value: 0.970.97

KRAS statusKRAS status MS MS (months)(months)

95% CI95% CI

MutatedMutated 4.64.6 3.6 – 5.53.6 – 5.5

Wild-TypeWild-Type 4.84.8 4.2 – 5.54.2 – 5.5

Karapetis et al, NEJM, 2008

KRAS mutation: Predictive and/or prognostic ?

PREDICTIVE – response to therapy• KRAS mutation predicts non-response to EGF-R antibodies

PROGNOSTIC – outcome independent of treatment• NO:

– 3rd line Cetuximab / Panitumumab monotherapy trials– CAIRO-2 – 1st line oxaliplatin / bevacizumab +/- cetuximab stage IV– PACCE – 1st line chemo / bevacizumab +/- panitumumab stage IV

• YES:– RASCAL – stage III colon cancer– FOCUS – 1st line sequential treatment stage IV– COIN – 1st line oxaliplatin / cetuximab stage IV

• MAYBE:– CRYSTAL – 1st line FOLFIRI / cetuximab stage IV

KRAS mutation: Predictive and/or prognostic ?

PREDICTIVE – response to therapy• KRAS mutation predicts non-response to EGF-R antibodies

PROGNOSTIC – outcome independent of treatment• NO:

– 3rd line Cetuximab / Panitumumab monotherapy trials– CAIRO-2 – 1st line oxaliplatin / bevacizumab +/- cetuximab stage IV– PACCE – 1st line chemo / bevacizumab +/- panitumumab stage IV

• YES:– RASCAL – stage III colon cancer– FOCUS – 1st line sequential treatment stage IV– COIN –

• MAYBE:– CRYSTAL – 1st line FOLFIRI / cetuximab stage IV

N0147 – later in this sessionN0147 – later in this session

My conclusions

• KRAS not prognostic 3rd line– May reflect selection of patients:

• KRAS mutant patients who proceed to a 3rd line study may be a subset not representative of the KRAS mutant patients in general

• If KRAS status is prognostic, then– Current studies may need to be stratified for

KRAS status and analyzed for KRAS prognostic status

– Past study results may be in question because of the uncertain KRAS distribution

CALGB/SWOG 80405

Untreatedadvancedor mCRCN =1142

Bevacizumabfollowed by

FOLFOX or FOLFIRIq 2 wks

Cetuximabfollowed by

FOLFOX or FOLFIRIq 2 wks

Accrual 6/2/10 = 606

Screenfor

eligibility

Sendtumortissue

block toSWOGPCO

RandomizePatients

w/Wild type

K-ras tumor

RegisterPatient

CLOCC 40004 Ruers et al

Randomi z e

RF + chemotherapy ± additional resection

Patients with unresectable CRC liver metastases

N=152Chemotherapy good response resectionN = 119

Local Therapy for Liver Tumors- BUT DO THEY IMPROVE OUTCOMES ?

• Hepatic Intra-arterial chemotherapy• Trans-arterial chemoembolization• Isolated hepatic perfusion• Radio-frequency Ablation• Ablation

– Cryo, microwave, ultrasound, irreversible electroporation

• External radiotherapy• Internal radiation

Key details

Unresectable “incurable” liver metastases

No extrahepatic disease Prior chemotherapy allowed as long as at least SD

Primary objective:

To demonstrate a 30-month OS >38% in RF + chemotherapy arm Fleming design, power of 90% and 1 sided type I error of 10%

07

Primary end point: 30 months Overall Survival

TreatmentPatients

(N)

ObservedEvents

(O)Hazard Ratio

(95% CI)P-Value

(Log-Rank)Median (95% CI)

(Years)

% at 30 months (95% CI)

Chemo 59 39 1.00 0.2176 3.38 (2.46, 4.18)

58.56 (44.82, 69.99)

RF +Chemo

60 31 0.74 (0.46, 1.19)

3.78 (2.76, N) 63.83(50.10,74,71)

Primary end point: 30-month OS in RFA + chemo >38% met in BOTH ARMS

My Conclusions

• RFA + chemotherapy with FOLFOX (+ bevacizumab) is safe and feasible

• Patients with liver-only metastases do appreciably better than patients with other sites of disease

• It is tough / impossible to accrue to studies randomizing patients with liver-only disease to this kind of intervention because it is offered in the community

• This important clinical and cost-economics question is unlikely to ever be addressed in a randomized trial

Colorectal Cancer Abstracts: Comments and Conclusions

• Well-done and well-presented• Europeans get studies done• Americans: studies are under-powered• Important clinical questions

– Maintenance Bevacizumab– Patient selection – Role for RFA debulking

• Did not get conclusive answers because…

Colorectal Cancer Abstracts: Comments and Conclusions• What may be new:

– KRAS MAY be prognostic

• What we knew and still know:– Pts with liver-only metastases do well with or

without RFA and RFA will continue to be done

• What we still do not know:– Bevacizumab as maintenance– What the message is from the COIN trial

• What we need to do now:– Go back to the drawing board