Oral Colorectal Presentations: DiscussionAbstracts #4009 - #4011

Cathy Eng, M.D.The University of Texas

M.D. Anderson Cancer CenterMay 31, 2008

Disclosures: • Honararia from Pfizer Oncology• Pharmaceutical sponsored grants for

clinical trial development:– Bristol Myers Squibb – Genentech – Imclone– Novartis– Sanofi~Aventis

Abstracts for Discussion: • Role of Ca/Mg in reducing oxaliplatin-

induced toxicities:– #4009: Adjuvant colon cancer: NCCTG trial

N04C7. (Nikcevich et al)– #4010: Intermittent oxaliplatin administration in

metastatic colorectal cancer: CONcePT trial (Grothey et al)

• Role of combined biologic therapy in metastatic colorectal cancer:– #4011: Capecitabine, oxaliplatin, and

bevacizumab with or without cetuximab in advanced colorectal cancer: CAIRO2 study (Punt et al)

Oxaliplatin-induced neuropathy: • Oxaliplatin is currently approved in the

adjuvant and metastatic treatment of colorectal cancer (CRC)

• Dose-limiting toxicity: peripheral neuropathy– Etiology

• Oxaliplatin metabolite, oxalate, is a chelator of Ca2+ and may alter voltage gated Na+ channels.

– Acute vs. chronic neuropathy• Acute - cold hypersensitivity and muscle contractions

– transient• Chronic – cumulative but reversible

– Impact on quality of life– Impact on dose intensity– No definitive therapies available for prevention or

reduction

MOSAIC: Peripheral Neuropathy

0

10

20

30

40

50

60

DuringTx

6months

1-year 2-year 3-year 4-year

Grade 1

Grade 2

Grade 3

de Gramont et al: ASCO, #4007. 2007

Evaluable patients n=811

Grade 0 84.3%

Grade 1 12.0%

Grade 2 2.8%

Grade 3 0.7%

Ca++/Mg++ Infusion for Prevention of Oxaliplatin Sensory Neuropathy

Gamelin et al. Clin Can Research 10:4055-4061, June 15, 2004

Oxaliplatin With Oxaliplatin Without

Ca/Mg Infusion Ca/Mg InfusionWithdrew from oxaliplatin 4% 31%Acute neurotoxicities (%) 0 9%Neuropathy at end of treatment 20 (P=.003) 45%

Advanced CRCN=161

Ca-gluconate (1 g)Mg-sulfate (1 g)

No Ca/Mg infusion

n=96

n=65

Oxaliplatin/5-FU/LV

Prospective Trials: • U.S.

– N04C7: Ca/Mg in adjuvant colon cancer• Endpoint: Gr 2 sensory neuropathy

– CONcePT: Ca/Mg in treatment naïve metastatic CRC

• Endpoint: Time to treatment failure

• Europe: – Neuroxa: Ca/Mg use in stage III/IV colorectal

cancer receiving FOLFOX4 (Gamelin et al, ISGIO, 2007)

• Endpoint: Rate of acute neuropathy• Preliminary results reported at ISGIO, 2007.

N04C7 Phase III Trial – Original Study Design

• 1g Ca-gluconate and 1g Mg-sulfate in 100 mL D5W over 30 min immediately before and after oxaliplatin (placebo = 100 mL D5W)

Pts to receiveadj. FOLFOX

N=300

Pts to receiveadj. FOLFOX

N=300

IV CaMg

% of Grade 2+ sNT

% of Grade 2+ sNTR

IV placeboIV placebo

Nikevich et al. ASCO, #4009, 2008

N0C47: Salient Points• Phase III placebo-controlled double-blinded trial• Primary endpoint: Grade2 peripheral sensory

neuropathy (PSN)• Secondary endpoints: time to onset and duration

of grade2-3 PSN– Discontinuation of therapy– QOL questionnaires– Duration of therapy– Pharmacogenomics

• Adverse event reporting– NCI CTC v3.0 patient reported outcomes (PRO)– Oxaliplatin specific scale

Neurotoxicity Evaluation

Grade NCI-CTC 3.0 Oxaliplatin-specific scale

I

loss of deep tendon reflexes or paresthesia, including tingling, but not interfering with function

sensory symptoms of short duration

II

objective sensory alteration or paresthesia, including tingling, interfering with function, but not interfering with activities of daily living

sensory symptoms persisting between cycles

IIIsensory alteration or paresthesia interfering with activities of daily living

sensory symptoms causing functional impairment

IVPermanent sensory losses that are disabling -

Inclusion of Patient Reported Outcomes (PRO) with NCI-CTC• Traditionally adverse events are graded by NCI common

toxicity criteria (CTC)– Physician interpretation

• Novel approach to include patient reported AE’s • Advantages:

– Allows patient involvement in documentation of adverse events

• Disadvantages:– May result in additional regulatory paperwork

• Method of collection should be uniform with ease of collection

• Continues to be refined and evaluated

Trotti et al: JCO; 25: 5121-5127, 2007

Combined Oxaliplatin Neurotoxicity Prevention Trial (CONcePT): Original study design

• First-line mCRC, 532 patients• Primary endpoint: time to treatment failure (TTF) of CO vs. IO• Randomization (2x2)

mFOLFOX7 + bevacizumabContinued until Treatment Failure (CO)

mFOLFOX7 + bevacizumabIntermittent Stop-and-Go oxaliplatin

R

+/- IV CaMg

+/- IV CaMg

Grothey et al. ASCO, #4010, 2008

Secondary endpoints: Incidence and severity of pSNRR, PFS, and OS, QOL questionnaires (Quality vs. Quantity)

Notification from Sanofi: June 2007

• Unplanned interim analysis of CONcePT by an independent data monitoring committee (IDMC) as recommended by the CRO suggesting decreased efficacy in the Ca/Mg arms.

• Investigator-determined and unconfirmed radiographic response

• Resulted in the premature closures of N0C47 and CONcePT.

Hochster et al. JCO; 25: 4028-4029

N04C7 Phase III Trial – Study closure

• 1g Ca-gluconate and 1g Mg-sulfate in 100 mL D5W over 30 min immediately before and after oxaliplatin (placebo = 100 mL D5W)

• Data cutoff after 127 days (4M and 7 days)

Pts to receiveadj. FOLFOX

N=300

Pts to receiveadj. FOLFOX

N=300

IV CaMg N=50

% of Grade 2+ sNT

% of Grade 2+ sNTR

IV placeboN=52

IV placeboN=52N=102

N0C47: Development of Grade 2 Peripheral Neuropathy NCI CTC scale: Neurotoxicity Grade

CaMg(N=50)

Placebo(N=52)

P-value(Chi-Square)

Grade 0/1 78% 59% .038

Grade 2+ 22% 41%

Oxaliplatin Scale

Neurotoxicity Grade

CaMg(N=50)

Placebo(N=52)

.018Grade 0/1 72% 49%

Grade 2+ 28% 51%

Conclusions of N0C47:• Study limitations:

– Premature closure of study • Significant differences in development of Gr 2 sNT

– Difference in time to onset in Gr 2 sNT by CTC vs. oxaliplatin scale (P=.0503 vs. P=.0250)

• Emphasizes the differences that exist in capturing AE’s based on diagnostic tools utilized.

– QOL (PRO): Preliminary, final results pending• Acute: Decrease in muscle contractions (P=.012) and trend

in swallowing discomfort (P=.065)• Chronic: Improvement in numbness (P=.021) and trend in

tingling (P=.062)

• Development and duration of Gr 3 sNT: Unknown

Combined Oxaliplatin Neurotoxicity Prevention Trial (CONcePT): Study Closure

First-line mCRC, 532 patientsPrimary endpoint: time to treatment failure (TTF)Randomization (2x2):

mFOLFOX7 + bevacizumabuntil Treatment Failure (CO)

mFOLFOX7 + bevacizumabStop-and-Go oxaliplatin (IO)

+/- IV CaMgR

N= 139N= 139

CONcePT: Interim Analysis of Response

Parameter

CO IO

Placebo Ca2+Mg2+ Placebo Ca2+Mg2+

ITT (n=34)

Eval (n=28)

ITT

(n=35)

Eval (n=31)

ITT (n=36)

Eval (n=31)

ITT (n=35)

Eval (n=28)

Best ORR (N) CR PR SD PD Uneval.

07

1395

06

139-

0101555

011155-

014152 5

014152-

0121157

012115-

ORR, % 95% CI

218.7-37.9

218.3-41.0

2914.6-46.3

3619.2-54.6

3923.1-56.5

4527.3-64.0

3419.1-52.2

4324.5-62.8Odds ratio 95% CI P-value

IO relative to CO 1.96 0.86-4.54 .089

Ca2+Mg2+ relative to placebo 1.29 0.57-2.98 .565

Hochster et al: GI Symposium, #280, 2007

Investigators concluded that Ca/Mg did NOT have a deleterious effect on efficacy

CONcePT: Results• Intermittent oxaliplatin (IO) vs. continuous oxaliplatin (CO)

– Resulted in improved TTF and PFS– Decreased grade ¾ peripheral neuropathy– Less treatment delays and discontinuations

• The use of Ca/Mg had no impact on:– TTF or PFS– Within IO vs. CO arms:

• No notable differences: – Grade ¾ peripheral neuropathy– Delays or discontinuations

• Neurotoxicity by PRO:– Acute neuropathy:

• Improved with intermittent oxaliplatin vs. continuous oxaliplatin• No benefit with Ca/Mg vs. placebo

– Chronic neuropathy:• Benefit noted with both intermittent oxaliplatin use and the use of

Ca/Mg

Other Methods to Reduce Neuropathy:

Treatment PhaseReduction in

pSNRisk of

Toxicities

Ca/Mg III Inconclusive None

Gabapentin II Equivocal Yes

Carbamezapine II Equivocal Yes

Glutamine II Possibly Yes

Xaliproden III Pending -

OPTIMOX 1 III Yes Less

FLOX regimen III Yes Yes

Saif et al. Ther Clin Risk Manag. 2005 December; 1(4): 249–258

Wang et al. The Oncologist; 12:312-319, 2007

De Gramont et al. JCO. Vol 24, No 3 (January 20), 2006: pp. 394-400

Kuebler et al: JCO Jun 1 2007: 2205-2211.

Conclusions of CONcePT:• Relevance of neuropathy on QOL • Impact on current practice?

– Continuous vs. Intermittent oxaliplatin• Use of intermittent oxaliplatin fared better• Standard of care?

– Still not widely adopted– Must be on patient by patient basis

– Ca/Mg: • Appears to have no impact on efficacy • Reduces the incidence of chronic neuropathy but not acute

– Palliative setting vs. adjuvant setting?» Physician variability

• Consideration of use should be physician dependent

• Future approaches: – Xaliproden (EFC5505): pending– Pharmacogenomics

Efficacy of Combined Biologic Therapy?

CAIRO2

Rationale for CAIRO2: • Inhibition of two common but independent

pathways (VEGF and EGFR) in CRC may result in increased efficacy.

• Promising results of BOND2 in heavily pretreated patient mCRC pts.

• In contrast, data from the Panitumumab Advanced Colorectal Cancer Evaluation Study (PACCE) demonstrated decreased efficacy at risk of increased toxicity.

• CAIRO2: Early safety data of first 400 patients noted no increased toxicities.

Hecht et al: GI Cancers Symposium; Abs#273, 2008Saltz et al. JCO: 25; 4557-4568, 2007

Tol et al: Annals of Onc; 19: 734–738, 2008

PACCE: Panitumumab Advanced Colorectal Cancer Evaluation: Study

SchemaPanitumumab 6 mg/kg Q2W

Ox-CTBevacizumab

Ox-based CT(eg, FOLFOX)

N = 800Inv choice

Iri-basedCT(eg, FOLFIRI)

N = 200Inv choice

Ox-CTBevacizumab

Panitumumab Panitumumab 6 mg/kg Q2W6 mg/kg Q2W

Iri-CTIri-CTBevacizumabBevacizumab

Iri-CTIri-CTBevacizumabBevacizumab

RANDOMIZE

1:1

1:1

SCREENING

1º endpoint: PFS

Hecht et al: 9th World Congress on GI Cancers, Barcelona 2007

PACCE: Overall Inferior Results of Combined Biologic Therapy

FOLFOX/Bev/Pmab

(N=407)

FOLFOX/Bev(N=405)

Grade 3/4 Toxicities 53/28 (81%) 51/18 (69%)

PFS (M) 9.0 (HR = 1.29) 10.5

OS (M) 18.6 (HR = 1.44) NA

Hecht et al: 9th World Congress on GI Cancers, Barcelona 2007

Phase III Trial Design of CAIRO2

RRAANNDDOOMMII

Z Z E E

Arm A: Capecitabine / Oxaliplatin/Bevacizumab

Cycle >> 7: Capecitabine/Bevacizumab

Arm B: Capecitabine / Oxaliplatin/Bevacizumab

+weekly Cetuximab

Cycle >> 7: Capecitabine/Bevacizumab

+ weekly Cetuximab

Treatment naïve, surgically

unresectable patientsN= 755

1º Endpoint: PFS

2º Endpoints: RR, OS, toxicities, and QOL

Response rate: q3 cycles

CAIRO2: Inferior PFS for Combined Biologic Therapy

CapeOX/Bev CapeOx/Bev + Cetux

P-value

n= 368 n=368

Median PFS (M) (95% CI)

10.7 (9.7-12.5)

9.6 (8.5-10.7)

.018 HR 1.21

(1.03-1.45)

Median OS (M)(95% CI)

20.4 (18.1-26.1)

20.3(17.9-21.6)

.21 HR 1.15

(0.93-1.43)

Response rate (CR+PR)*

44% 42% .602

* 660 patients were evaluable for response

Phase III Trials of Combined Biologic Therapy with Negative Impact on PFS

0 6 12 18 24 30

months from randomization

0.0

0.2

0.4

0.6

0.8

1.0

Prog

ress

ion

free

sur

viva

l pro

babi

lity

Arm A (without cetuximab)

Arm B (with cetuximab)

CAIRO2

Months

PACCE

HR=1.44 (95% CI: 1.13-1.85)P =.004

HR=1.21 (95% CI: 1.03-1.45)P =.018

Hecht et al; World GI Cancer, Barcelona, 2007

0 4 12

16

208

FOLFOX/Bev

FOLFOX/Bev+Pmab

9.6 vs. 10.7 M

9.6 vs. 11.1 M

Panitumumab vs. BSC: Panitumumab vs. BSC: Impact of KRas on PFS (WT vs. Impact of KRas on PFS (WT vs. Mutant) Mutant)

Amado et al. JCO; Apr 1;26(10):1626-34, 2008

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Weeks

36 38 40 42 44 46 48 50 52

115/124 (93) 12.3 19.0

114/119 (96) 7.3 9.3

Pmab + BSC (WT)

BSC Alone (WT)

Events/N (%)Median

In WeeksMean

In Weeks

WT: HR = 0.45 (95% CI: 0.34–0.59)Stratified log-rank test, p < 0.0001

Pro

po

rtio

n w

ith

PF

S

Pmab + BSC (MT) 76/84 (90) 7.4 9.9

CAIRO2: Impact of KRas on PFS and OS

Wild type Mutant P value

Progression-free survival

CapeOx/Bev 10.7 12.5 .92

CapeOx/Bev+C 10.5 8.6 .47

P value .10 .043

Overall survival

CapeOx/Bev 23 24.9 0.90

CapeOx/Bev+C 22.2 19.1 0.52

P value .49 .35

Phase II OPUS: Impact of KRas on FOLFOX +/- Cetuximab

Bokemeyer et al: ASCO, #4000, 2008

Wild-Type MutantFOLFOX +

CFOLFOX FOLFOX + C FOLFOX

RR (%)

61 (n=61)

37 (n=73)

33 (n=52)

49 (n=47)

P=.01 P=.11

PFS (M)

7.7 (n=61)

7.2 (n=73)

5.5 (n=52)

8.6 (n=47)

HR:0.57 P=.02 HR:1.83 P=.02

Conclusions from CAIRO2: • Combined biologic therapy

(anti-VEGF/EGFR) is of NO added benefit in RR or OS and negatively impacts PFS.

• KRas status did not appear to have any impact on outcome in PFS or OS within either arm.

• However, of those patients with KRas mutant tumors, the use of cetuximab resulted in inferior PFS than the standard chemotherapy regimen alone.

CAIRO2: Unanswered Questions of Impact of KRas

Wild type Mutant P value

Progression-free survival

CapeOx ? ? ?

CapeOx + C ? ? ?

CapeOx/Bev 10.7 12.5 .92

CapeOx/Bev+C 10.5 8.6 .47

P value .10 .043

Future of Combined Biologic Therapy:

**Two negative Phase III trials of combined anti-VEGF and EGFR therapy

Impact on existing trials:• U.S. Cooperative group trials:

– CALGB/SWOG 80405: Front-line– SWOG 0600: Second-line

• Impact on 10 other existing trials?

Proposed CALGB/SWOG 80405 Design

Untreatedadvancedor mCRC

N = ?

Bevacizumabfollowed by

FOLFOX or FOLFIRIq 2 wks

Cetuximabfollowed by

FOLFOX or FOLFIRIq 2 wks

Cetuximabfollowed by

Bevacizumabfollowed by FOLFOX

or FOLFIRI q 2 wks

mCRC = metastatic colorectal cancer

Open-label Phase III Study

Screenfor

eligibility

Sendtumortissue

block toSWOGPCO

RandomizePatients

w/Wild type

K-ras tumor

RegisterPatient

Accrual as of May 22, 2008 = 1386

Courtesy of Alan Venook, M.D.

Future of Combined Biologic Therapy:

• **The use of combined biologic therapy (anti-VEGF/EGFR) should only be conducted as part of a clinical trial

• Indicates that our understanding of both VEGF and EGFR pathways is not fully understood.

• Role of KRas?– Evidence to support its role as a predictive marker– *Must be considered when proposing anti-EGFR

therapy– To date, the use of anti-EGFR therapy in KRas

mutant tumors in combination with chemotherapy negatively impacts PFS and possibly RR.