Oral Colorectal Presentations: Discussion Abstracts #4009 - #4011 Cathy Eng, M.D. The University of...
-
Upload
julie-barker -
Category
Documents
-
view
215 -
download
0
Transcript of Oral Colorectal Presentations: Discussion Abstracts #4009 - #4011 Cathy Eng, M.D. The University of...
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.