cco clinoncjune2011 highlights slides
TRANSCRIPT
June 3-7, 2011Chicago, Illinois
Highlights From the 2011 Clinical Oncology Meeting CCO Independent Conference Coverageof the 2011 ASCO Annual Meeting*
This program is supported by an educational grant fromThis program is supported by educational grants from
*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.
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Faculty
Axel Grothey, MDProfessor, Oncology Mayo Clinic Rochester, Minnesota
John M. Kirkwood, MDProfessor, Medicine, Dermatology, and Translational Science Director, Melanoma and Skin Cancer Program University of Pittsburgh Cancer Institute Pittsburgh, Pennsylvania
Kathy D. Miller, MDAssociate Professor Indiana University Melvin and Bren Simon Cancer Center Indianapolis, Indiana
Craig Reynolds, MDDevelopment Chair US Oncology Lung Cancer Committee US Oncology Ocala, Florida
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Faculty
David I. Quinn, MD, PhDAssociate Professor of Medicine Division of Cancer Medicine and Blood DiseasesThe University of Southern California Medical Director USC Norris Cancer Center and Hospital Los Angeles, California
Robert M. Rifkin, MD, FACPRocky Mountain Cancer Centers Denver, Colorado
Brian I. Rini, MDStaff Physician Department of Solid Tumor Oncology and UrologyCleveland Clinic Taussig Cancer Institute Associate Professor of Medicine CCF/CWRU Lerner College of Medicine Cleveland, Ohio
Nicholas J. Vogelzang, MDChair and Medical Director Developmental Therapeutics CommitteeUS Oncology ResearchComprehensive Cancer Centers of NevadaProfessor of MedicineUniversity of Nevada School of MedicineLas Vegas, Nevada
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Faculty Disclosures
Axel Grothey, MD, has disclosed that he has received contracted research support from Bayer, Daiichi, and Genentech.
John M. Kirkwood, MD, has disclosed that he has received consulting fees from GlaxoSmithKline, Merck, and Morphotek.
Kathy D. Miller, MD, has disclosed that she has received consulting fees and fees for non-CME/CE services from Genentech.
Craig Reynolds, MD, has disclosed that he has received consulting fees from Genentech and Pfizer and fees for non-CME/CE services from Eisai and Eli Lilly.
David I. Quinn, MD, PhD, has disclosed that he has received consulting fees from Astellas, Bayer, Dendreon, Genomic Health, Novartis, Onyx, Johnson & Johnson, and Pfizer.
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Faculty Disclosures
Robert M. Rifkin, MD, FACP, has disclosed that he has received consulting fees from Amgen, Celgene, Cephalon, Millennium, and Onyx.
Brian I. Rini, MD, has disclosed that he has received consulting fees from Aveo, GlaxoSmithKline, and Pfizer and has received research contracts from GlaxoSmithKline and Pfizer.
Nicholas J. Vogelzang, MD, has disclosed that he has received research contracts from Bayer, Johnson & Johnson, and Tokai; has served as a consultant for Amgen, Bayer, Boehringer Ingelheim, Celgene, Cougar, Dendreon, Eisai, Genentech, GlaxoSmithKline, Johnson & Johnson, Mannkind, Novartis, Pfizer, Millennium, and Veridex; has served on speaker bureaus for Arqule, Bayer, Cougar, Dendreon, Eli Lilly, Genentech, Johnson & Johnson, Novartis, Pfizer, Quintiles, Research to Practice, sanofi-aventis, Veridex, and Wilex; and has received grants or support from Algeta, Arqule, Cougar, GlaxoSmithKline, Johnson & Johnson, Mannkind, Novartis, Pfizer, Millennium, Tokai, Veridex, and Wilex.
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Overview of Tumor Types Covered in This Slideset Melanoma
Genitourinary Cancers
Thoracic Cancers
Breast Cancer
Gastrointestinal Cancer
Hematologic Malignancies
Sarcomas
Ovarian Cancer
Melanoma
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BRIM3: Vemurafenib vs Dacarbazine in BRAF V600E–Positive Melanoma
Randomized, nonblinded phase III trial
OS, PFS improved in all prespecified subgroups (age, sex, stage, PS, LDH)
Chapman PB, et al. ASCO 2011. Abstract LBA4.
Patients with untreated, unresectable stage IIIc/IV melanoma and confirmed
BRAF V600E mutation
(N = 675)
Vemurafenib 960 mg PO BID(n = 337)
Dacarbazine 1000 mg/m2 q3w(n = 338)
Outcome Vemurafenib(n = 336)
Dacarbazine(n = 336)
HR (95% CI) P Value
Estimated 6-mo OS, % 84 64 0.37 (0.26-0.55) < .0001
Median PFS, mos 5.3 1.6 0.26 (0.20-0.33) < .0001
ORR, % 48.4 5.5
CR 0.9 0
PR 47.5 5.5
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BRIM3: Safety
Most common toxicities requiring dose modification included arthralgia, rash, fatigue, photosensitivity, and increased LFT values
Discontinuation due to AEs low in vemurafenib and dacarbazine arms (6% vs 4%)
Grade 3/4 Adverse Event, % Vemurafenib(n = 336)
Dacarbazine(n = 282)
Rash 8 0
Increased liver function tests 7 1
Arthralgia 3 < 1
Photosensitivity 3 0
Fatigue 2 2
Nausea 1 2
Neutropenia < 1 8
Cutaneous squamous cell carcinoma 12 < 1
Keratoacanthoma 6 0
Skin papilloma < 1 0
Chapman PB, et al. ASCO 2011. Abstract LBA4.
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MDX-024: Ipilimumab + Dacarbazine vs Dacarbazine in Unresectable Melanoma Phase III trial
Wolchok JD, et al. ASCO 2011. Abstract LBA5.
Patients with previously untreated unresectable stage IIIc/IV melanoma
(N = 502)
Ipilimumab 10 mg/kg q3w for 4 cycles +Dacarbazine 850 mg/m2 q3w for 8 cycles
(n = 250)
Placebo q3w for 4 cycles +Dacarbazine 850 mg/m2 Q3W for 8 cycles
(n = 252)
Wk 24
Ipilimumab10 mg/kg q12w
PlaceboQ12W
Induction Therapy Maintenance Therapy
Est
ima
ted
Su
rviv
al
(%)
504540353025201510
50
47.3
36.3
28.5
17.920.8
12.2
Yr 1 Yr 2 Yr 3
Ipilimumab + DTIC (n = 250)Placebo + DTIC (n = 252)
P = .0009 (HR: 0.72; 95% CI: 0.59-0.87)
mOS, Mos11.29.1
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MDX-024: Median OS, PFS, and Response
*Primary endpoint.
Outcome Ipilimumab + Dacarbazine
(n = 250)
Placebo + Dacarbazine
(n = 252)
HR (95% CI) P Value
Median OS, mos* 11.2 9.1 0.72 (0.59-0.87) .0009
Median PFS, mos 2.8 2.6 0.76 (0.63-0.93) .006
Disease control rate, % 33.2 30.2
CR 1.6 0.8
PR 13.6 9.5
SD 18.0 19.8
PD 44.4 52.0
Median duration of response, mos
19.3 8.1
Wolchok JD, et al. ASCO 2011. Abstract LBA5.
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MDX-024: Safety
Substantially more grade 3/4 adverse events in ipilimumab + dacarbazine arm
Select Adverse Event, %
Ipilimumab + Dacarbazine(n = 247)
Placebo + Dacarbazine(n = 251)
Total Grade 3/4 Total Grade 3/4
Diarrhea 36.4 4.0 24.7 0
Increased ALT 33.2 21.9 5.6 0.8
Increased AST 29.1 18.2 5.6 1.2
Pruritus 29.6 2.0 8.8 0
Rash 24.7 1.2 6.8 0
Colitis 4.5 2.0 0.4 0
Hypothyroidism 1.6 0 0.4 0
Thyroiditis 0.8 0 0 0
Hyperthyroidism 0.4 0 0.4 0Wolchok JD, et al. ASCO 2011. Abstract LBA5.
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EORTC 18991: Long-term PegIFN alfa-2b in Stage III Melanoma Significant RFS benefit of peginterferon sustained at 7.6 yrs of follow-up
Most striking benefit in subset of sentinel-node positive patients with ulcerated primary tumors (improved RFS, DMFS, and OS)
Most common AEs did not worsen as treatment duration increased
Outcome (ITT) 2007 Evaluation 2011 Evaluation
HR (95% CI) P Value HR (95% CI) P Value
RFS 0.82 (0.71-0.96) .01 0.87 (0.76-1.00) .05
DMFS 0.88 (0.75-1.03) .11 0.93 (0.81-1.07) .33
OS 0.98 (0.82-1.16) .78 0.96 (0.82-1.11) .57
Grade 3 Events Occurring in > 5% of Patients, %
PegIFN Maintenance(n = 627)
Observation(n = 629)
Fatigue 14 1
Liver toxicity 10 1
Depression 6 < 1
Eggermont AM, et al. ASCO 2011. Abstract 8506b.
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BRAF Inhibitor (GSK436) + MEK Inhibitor (GSK212) in BRAF-Mutated Melanoma Phase I/II
GSK436/GSK212 combination therapy generally well tolerated across all doses; treatment-related grade ≥ 3 events occurred in 19% of patients
Skin toxicity incidence compares favorably vs historical data
Active in patients who did not receive previous BRAF inhibitor therapy (n = 71)
Unconfirmed Response, %
GSK436/GSK212 Dose Level
75 mg BID/1 mg QD
(n = 6)
150 mg BID/1 mg QD(n = 22)
150 mg BID/1.5 mg QD
(n = 24)
150 mg BID/2 mg QD(n = 19)
Clinical benefit (CR + PR + SD)
100 95 96 100
Objective response (CR + PR)
67 77 50 74
CR 0 14 0 11
Infante JR, et al. ASCO 2011. Abstract CRA8503.
Genitourinary Cancers
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AXIS: Randomized Phase III Trial, Axitinib vs Sorafenib in Refractory Metastatic RCC Primary endpoint: PFS Treatments generally well
tolerated; similar toxicity
– All-grade hypertension and hypothyroidism more common with axitinib
– All-grade hand-foot syndrome, rash, and alopecia more common with sorafenib
– Discontinuation due to treatment-related AEs
– 3.9% in axitinib group
– 8.2% in sorafenib group
Rini BI, et al. ASCO 2011. Abstract 4503. Reprinted with permission.
1.00.90.80.70.60.50.40.30.20.1
0
PF
S (
Pro
bab
ilit
y)
0 2 4 6 8 10 12 14 16 18 20
Mos
P < .0001 (log-rank)Stratified HR: 0.665(95% CI: 0.544-0.812)
AxitinibSorafenib
mPFS, Mos6.74.7
95% CI6.3-8.64.6-5.6
Pts at Risk, nAxitinib
Sorafenib361362
256224
202157
145100
9651
6428
3812
206
103
11
00
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AXIS: PFS by Prognostic Factors and Baseline Characteristics Authors: data support axitinib as the standard second-line therapy for
advanced RCC
Rini BI, et al. ASCO 2011. Abstract 4503.
AxitinibBenefit
SorafenibBenefit
Baseline Factor n
ECOG PS 1ECOG PS 0
Sunitinib-containing regimenBevacizumab-containing regimenTemsirolimus-containing regimen
Cytokine-containing regimenWhite
NonwhiteMale
FemaleAge < 65Age ≥ 65
MSKCC favorableMSKCC intermediate/poor
AsiaEurope
North AmericaOther region
3273963895924
25154717652320047624730641715235718628
HR (95% CI)0.0 1.0 2.0 3.0
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AXIS: Patient Reported Outcomes on QoL
Composite endpoint: time to deterioration (TTD)*
Patient-reported QoL (FKSI scores) similar for axitinib and sorafenib in AXIS trial
Axitinib associated with 17% reduction in risk of TTD
Authors conclude:
– TTD composite endpoint supports primary efficacy analysis
– Extending PFS in mRCC has QoL value
Cella D, et al. ASCO 2011. Abstract 4504. Reprinted with permission.
1.00.90.80.70.60.50.40.30.20.1
0
Su
rviv
al D
istr
ibu
tio
n F
un
ctio
n
0 2 4 6 8 10 12 14 16 20 24
Time to Composite (Mos)
P = .014†
(HR: 0.829; 95% CI: 0.701-0.981)
AxitinibSorafenib
Median TTD, Mos
3.12.8
95% CI2.8-4.52.7-3.0
18 22
*Death, disease progression, or decrease in FKSI-15 scores.† 1-sided P value.
clinicaloptions.com/oncologyClinical Oncology 2011
COU-AA-301: Final Analysis, Evaluation of CTCs as Efficacy-Response Biomarker Absolute median OS benefit of abiraterone acetate increased from 3.9 to
4.6 mos vs placebo (15.8 vs 11.2 mos, respectively; HR 0.74; 95% CI: 0.638-0.859; P < .0001)
Survival benefit seen regardless of baseline CTC level
Higher CTC conversion rates (from ≥ 5 to < 5) with abiraterone
Scher HI, et al. ASCO 2011. Abstract LBA4517.
CTC Conversion, % AA + Prednisone Placebo + Prednisone
P Value
Wk 4 (n = 422) 42 14 <.0001
Wk 8 (n = 374) 50 17 <.0001
Wk 12 (n = 330) 48 17 <.0001
Median OS, Mos (95% CI) AA + Prednisone(n = 649)
Placebo + Prednisone(n = 323)
Favorable CTC (< 5 cells/ 7.5 mL blood) 22.1 (20.4-24.1) 19.7 (16.7-NE)
Unfavorable CTC (≥ 5 cells/7.5 mL blood) 10.9 (9.9-12.0) 8.2 (7.4-9.3)
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Efficacy-Response Biomarker Panel, Potential Surrogate for OS in mCRPC Biomarker panel developed using pre- and posttreatment
factors strongly associated with OS
Authors suggest the initial biomarker panel with CTC and LDH was strongly associated with survival
Model Factors in Patients With BL CTC ≥ 5
HR (95% CI)* P Value*
Treatment 1.030 (0.773-1.372) .8371
Fold change in LDH 1.252 (1.047-1.497) .0135
Baseline LDH 3.036 (2.276-4.048) < .0001
CTC conversion 0.386 (0.284-0.527) < .0001
Baseline CTC 1.135 (0.987-1.306) .0747
*Adjusted for the biomarker panel.
Scher HI, et al. ASCO 2011. Abstract LBA4517.
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COU-AA-301: Effect of Abiraterone Acetate on Pain Palliation and SREs Nearly one half of COU-AA-301 patients report significant pain at baseline
Pain Interference Abiraterone + Prednisone
(n = 797)
Placebo + Prednisone
(n = 398)
P Value
Palliation, % 59.2 38.0 .0004
Median time to palliation, mos 1.02 3.71 .0009
TTP (25th percentile), mos 9.27 4.57 .0019
Logothetis C, et al. ASCO 2011. Abstract 4520. Reprinted with permission.
155/349(44.4%)
44/163(27.0%)
Pat
ien
ts E
xper
ien
cin
g
Pal
lia
tio
n (
%)
70605040302010
0AA (n = 797) Placebo (n = 398)
Pts
No
t E
xp
erie
nc
ing
P
alli
ati
on
(%
)
100
80
60
40
20
00 3 6 129
Mos
PlaceboAA
Median: 10.25 mos
P = .0010 (log rank)
Median: 5.55 mos
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COU-AA-301: Concluding Efficacy Results
Efficacy Measure Abiraterone + Prednisone
(n = 797)
Placebo + Prednisone
(n = 398)
P Value
Median OS, mos 14.8 10.9 < .0001
Confirmed PSA response, % 29.1 5.5 < .0001
Median radiographic PFS, mos 5.6 3.6 < .0001
Time to first SRE* (25th percentile), days
301 150 < .0001
*SRE defined as one or more of the following: pathologic fracture, spinal cord compression, palliative radiation, bone surgery.
de Bono JS, et al. N Engl J Med. 2011;364:1995-2005. Scher HI, et al. ASCO 2011. Abstract LBA4517. Logothetis C, et al. ASCO 2011. Abstract 4520.
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Cabozantinib, Dual MET/VEGFR TKI, vs Placebo in mCRPC Phase II randomized
discontinuation trial
*At progression, patients on placebo could cross-over to cabozantinib (n = 14).
Lead-in StageCabozantinib
100 mg/day PO(n = 171)
Patients with mCRPC,
measurabledisease, and
mRECIST progression;
rising PSA only, not eligible
SD(n = 31)
12 wksCabozantinib
100 mg/day PO(n = 14)
Placebo daily(n = 17)
Until PD*
Randomization
PR or CR
(n = 79)
Open-Label ExtensionCabozantinib
100 mg/day PO
PD(n = 61)
Discontinue Cabozantinib
Hussain M, et al. ASCO 2011. Abstract 4516.
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Cabozantinib vs Placebo in mCRPC: Efficacy and Safety
Authors: cabozantinib has substantial antitumor activity in progressive mCRPC
– Disease control, Wk 12: 68%
– Measurable disease regression: 74%
– Evidence of improvement on bone scan: 76%
– Pain improvement: 67%
– Moderate but manageable toxicity profile; similar to other TKIs
Hussain M, et al. ASCO 2011. Abstract 4516. Reprinted with permission.
-12 0 10 20 30 40 50 60
PFS per mRECIST, Post Randomization (Wks)
12-WkLead-in Stage
Pro
po
rtio
n
Pro
gre
ss
ion
Fre
e
1.00
0.75
0.50
0.25
Cabozantinib (n = 14)Placebo (n = 17)
HR 0.13; log-rank P value .0007
mPFS, Wks21 6
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Oral 17,20-lyase inhibitor, TAK-700, in mCRPC: Endocrine Responses Phase II results from phase I/II study designed to evaluate
safety and tolerability of different doses of TAK-700 in men (N = 97) with mCRPC
TAK-700 decreased testosterone to < 2 ng/dL by Wk 12
TAK-700 increased ACTH by Wk 12, but decreased ACTH when combined with prednisone
TAK-700 ± prednisone increased corticosterone by Wk 12
– Increases in corticosterone less with TAK-700 + prednisone compared with TAK-700 alone
Agus DB, et al. ASCO 2011. Abstract 4531.
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TAK-700 in mCRPC: PSA Response and Safety 53% with PSA decreases ≥ 50% at 12 wks
Serious AEs in 25 patients (26%): hypokalemia (n = 3), ARF (n = 3), pneumonia (n = 2), UTI (n = 2), hypotension (n = 2), neutropenia (n = 2), fatigue (n = 2)
TAK-700 active and tolerable given with or without prednisone, suggesting feasibility of a steroid-free regimen
X Previous ketoconazole therapy
Agus DB, et al. ASCO 2011. Abstract 4531. Reprinted with permission.
300 mg BID (n = 23)600 mg BID + prednisone (n = 26)
400 mg BID + prednisone (n = 24)600 mg QD AM (n = 24)
Treatment
275250225200175150125100
25
-25
-75
7550
0
-50
-100-125
PS
A C
han
ge
at
12 W
ks (
%)
x x xx
X x x x xx
x xx x
X x xx x x x x x
clinicaloptions.com/oncologyClinical Oncology 2011
Single-Agent Volasertib in Recurrent, Metastatic Urothelial Cancer (N = 50) Volasertib: potent, selective inhibitor of polo-like kinase; generally well tolerated with favorable
adverse event profile
Outcome All Patients (N = 50)
Dose Escalation to 350 mg
No(n = 27)
Yes(n = 23)
Median response duration, wks (range)
30.1 (12.1-66)
27.1(26.6-27.6)
30.4(12.1-66.0)
Median PFS, wks (range) 6.1 5.9(5.1-6.4)
11.1(5.1-22.1)
3-mo PFS, % 32 22.2 43.5
6-mo PFS, % 22 14.8 30.4
Stadler WM, et al. ASCO 2011. Abstract 4567. Reprinted with permission.
70605040
20
0
-20
-40
-60
-80
30
10
-10
-30
-50
-70
-90
Ma
xim
um
Ch
an
ge
F
rom
Ba
se
lin
e i
n
Tu
mo
r S
ize
(%
)
Best overall response: PD PR SD
clinicaloptions.com/oncologyClinical Oncology 2011
Everolimus generally well tolerated: fatigue, mucositis, and anorexia most common grade 1-2 toxicities
– Grade ≥ 3 adverse events in 29 of 45 (64%) evaluable patients
Potential association between p-4E BP1 expression and PFS at 2 months
Outcome Patients(n = 37)
Median OS, mos (95% CI) 10.3 (7.8-16.1)
Median PFS, mos (95% CI) 3.3 (2.1-3.7)
PFS at 2 mos, % 62
Everolimus in Recurrent Metastatic TCC of the Urothelium (N = 45)
Outcome, n p-4E BP1 Expression by IHC
≤ 1+(n = 12)
≥ 2+(n = 23)
PFS at ≥ 2 mos* 5 17
Progression at < 2 mos 7 6
*P = .08
Milowsky MI, et al. ASCO 2011. Abstract 4606.
Thoracic Cancers
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Status of Actionable Driver Mutations in Lung Adenocarcinoma Tumor Specimens
Lung Cancer Mutation Consortium (LCMC) mutation testing
– Performed in CLIA-certified laboratories at LCMC sites
Physicians used data in real-time to guide therapeutic decisions for patients
– If EGFR mutation: give erlotinib
– If other mutation: recommend trial of agent specific for that target
54% incidence of single driver mutations among samples
– KRAS, EGFR, and EML4-ALK most common
Kris MG, et al. ASCO 2011. Abstract CRA7506. Reprinted with permission.
No mutation detected
KRAS (22%)
EGFR (17%)
EML4-ALK (7%)
Double mutants (3%)
BRAF (2%)
AKT1
NRAS
MEK1
MET AMP
HER2
PIK3CA
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Rosell R, et al. ASCO 2011. Abstract 7503. Reprinted with permission.
EURTAC: Erlotinib vs Chemo in EGFR Mutation-Positive, Stage IIIB/IV NSCLC Phase III; significant benefit in PFS and with erlotinib vs chemotherapy
Erlotinib (n = 86)Chemotherapy (n = 87)
HR: 0.37 (95% CI: 0.25-0.54; log-rank P < .0001)
PF
S P
rob
abili
ty
1.0
0.8
0.6
0.4
0.2
00 3 6 9 12 15 18 21 24 27 30 33
Mos
5.2 9.7
Patients at Risk, nErlotinibChemo
8687
6349
5420
328
215
174
93
71
40
20
20
00
clinicaloptions.com/oncologyClinical Oncology 2011
EURTAC: OS and PFS Across Patient Subgroups No significant difference in OS at interim analysis; data immature with high rate of
crossover (HR = 0.80; 95% CI: 0.47-1.37; P = .4170)
No PFS benefit of erlotinib vs chemotherapy among former smokers
Rosell R, et al. ASCO 2011. Abstract 7503.
0.1 0.2 0.4 0.6 0.81.0 1.5 2.0 4.0
Favors Erlotinib HR Favors Chemotherapy
All< 65 yrs≥ 65 yrs
MaleFemale
PS 0PS 1PS 2
Current smokerFormer smoker
Never smokerExon 19 deletionL858R mutation
HR (95% CI)0.37 (0.25-0.54)0.44 (0.25-0.75)0.28 (0.16-0.51)0.38 (0.17-0.84)0.35 (0.22-0.55)0.26 (0.12-0.59)0.37 (0.22-0.62)0.48 (0.15-1.48)0.56 (0.15-2.15)1.05 (0.40-2.74)0.24 (0.15-0.39)0.30 (0.18-0.50)0.55 (0.29-1.02)
n173858847
1265792241934
12011558
clinicaloptions.com/oncologyClinical Oncology 2011
EURTAC: Response and Safety
CT-treated patients had increased frequency of:
– Grade 3/4 AEs (81% vs 45%)
– Dose modification or interruption due to treatment-related AE (47% vs 23%)
– Discontinuation due to treatment-related AE (14% vs 5%)
– Treatment-related serious AEs (16% vs 7%)
Response Outcome, %
Erlotinib(n = 86)
Chemo(n = 87)
Objective response 58 15
CR 2 0
PR 56 15
Disease control rate 79 66
SD 21 51
PD 7 13
No response assessed
14 22
Rosell R, et al. ASCO 2011. Abstract 7503.
clinicaloptions.com/oncologyClinical Oncology 2011
PARAMOUNT: Maintenance Pem Following Induction With Pem/Platinum Double-blind phase III trial
Patients enrolled (n = 939), eligible for randomization after induction phase (n = 548; 539 randomized)
Reasons patients not randomized: progressive disease (n = 217) adverse event (n = 62), death (n = 56), other (n = 65)
Pemetrexed 500 mg/m2
+ Cisplatin 75 mg/m2
both administered onDay 1 of a 21-day cycle
(n = 939)
Previously untreated
advanced-stagenonsquamous
NSCLC
CR, PR,or SD
Pemetrexed 500 mg/m2 onDay 1 of a 21-day cycle
+ BSC(n = 359)
Placebo on Day 1 of a 21-day cycle
+ BSC(n = 180)
PDBoth arms received folic acid
and vitamin B12 therapy
Induction phase (4 cycles) Maintenance phase (until PD)21-42days
Paz-Ares LG, et al. ASCO 2011. Abstract CRA7510.
clinicaloptions.com/oncologyClinical Oncology 2011
PARAMOUNT: Efficacy, Safety, and QoL
Pem + BSCPlacebo + BSC
1.0
0.8
0.6
0.4
0.2
0.0
0 3 6 9 12 15Mos
Unadjusted HR: 0.62 (95% CI: 0.49-0.79; log-rank P = .00006)
Pts at Risk, nPem + BSC
Placebo + BSC359180
13252
5715
215
40
00
mPFS, Mos4.1 2.8
Improved disease control rate with pemetrexed vs placebo maintenance
– 71.8% vs 59.6%, respectively (P = .009)
Pemetrexed safety profile similar to previous reports
– However, significantly more drug-related serious AEs with pemetrexed vs placebo (8.9% vs 2.8%; P ≤ .05)
No significant difference in health-related QoL between arms
OS data not yet mature
Paz-Ares LG, et al. ASCO 2011. Abstract CRA7510.
clinicaloptions.com/oncologyClinical Oncology 2011
MetMAb + Erlotinib vs Erlotinib Alone in Previously Treated Advanced NCSLC
MetMAb: monovalent antibody to Met
– Prevents Met activation by hepatocyte growth factor
EGFR mutations in study population
– Met diagnostic-positive population: imbalanced on MetMAb arm
– Met diagnostic-negative population: imbalanced on placebo arm
Predefined Met diagnostic-positive population
– Tumor samples with ≥ 50% tumor cells displaying moderate or strong Met staining by IHCSpigel DR, et al. ASCO 2011. Abstract 7505.
Reprinted with permission.
Growth Migration Survival
Noactivity
Met Met
HGF HGF
MetMAb
clinicaloptions.com/oncologyClinical Oncology 2011
MetMAb + Erlotinib vs Erlotinib in Advanced NCSLC: PFS and OS No PFS or OS benefit to adding MetMAb to erlotinib in ITT population MetMAb + erlotinib associated with survival benefits in Met-positive
population
Outcome ITTPopulation(n = 137)
Met Diagnostic-Positive Population
(n = 66)
Met Diagnostic-Negative Population
(n = 62)
MetMAb+ Erlotinib
(n = 69)
Placebo+ Erlotinib
(n = 68)
MetMAb+ Erlotinib
(n = 35)
Placebo+ Erlotinib
(n = 31)
MetMAb+ Erlotinib
(n = 31)
Placebo+ Erlotinib
(n = 31)
Median PFS, mos 2.2 2.6 2.9 1.5 1.4 2.7
HR (95% CI) 1.09 (0.73-1.62) 0.53 (0.28-0.99) 1.82 (0.99-3.32)
P value .69 .04 .05
Median OS, mos 8.9 7.4 12.6 3.8 8.1 15.3
HR (95% CI) 0.80 (0.50-1.28) 0.37 (0.19-0.72) 1.78 (0.79-3.99)
P value .34 .002 .16
Spigel DR, et al. ASCO 2011. Abstract 7505.
clinicaloptions.com/oncologyClinical Oncology 2011
MetMAb: Safety and Met Expression as a Prognostic Factor AE profile in MetMAb + erlotinib arm similar to placebo + erlotinib
– Higher frequency of peripheral edema in MetMAb arm
Met expression associated with worse outcome in placebo + erlotinib arm– 52% of tissue samples found to be Met diagnostic positive
Outcome Placebo + Erlotinib
Met Diagnostic Positive (n = 66)
Met Diagnostic Negative (n = 62)
Median PFS, mos 1.5 2.7
HR (95% CI) 1.71 (0.96-3.02)
P value .06
Median OS, mos 3.8 15.3
HR (95% CI) 2.61 (1.34-5.09)
P value .004Spigel DR, et al. ASCO 2011. Abstract 7505.
clinicaloptions.com/oncologyClinical Oncology 2011
Retrospective Analysis of Crizotinib vs Comparable Controls in ALK+ NSCLC Median OS not yet reached in ALK+ crizotinib-treated patients from phase I study
(N = 82): 1-yr OS: 74%; 2-yr OS: 54%
OS significantly prolonged in ALK+ crizotinib-treated pts vs ALK+ crizotinib-naive controls (clinically and geographically comparable historic controls)
– ALK-positive status did not confer favorable prognosis
OS Outcome ALK+/Crizotinib(n = 30)
ALK+/Control(n = 23)
WT/Control(n = 125)
Median OS, mos NR 6 11
1-yr OS, % 70 44 47
2-yr OS, % 55 12 32
HR vs ALK/control 0.36
P value .004
HR vs WT/control 0.49 1.42
P value .02 .18
Shaw AT, et al. ASCO 2011. Abstract 7507.
clinicaloptions.com/oncologyClinical Oncology 2011
Second-line Amrubicin vs Topotecan in Patients With SCLC (N = 637) Randomized phase III trial
Eligibility: response to platinum-based chemo followed by progression in ≥ 90 days (platinum sensitive) or < 90 days (platinum refractory)
Safety: lower incidence of hematologic events with amrubicin vs topotecan; more FN and infections (specifically pneumonia) observed with amrubicin, which did not translate to increased death
QoL significantly favored amrubicin vs topotecan
Outcome Amrubicin(n = 424)
Topotecan(n = 213)
HR (95% CI) P Value
Median OS, mos 7.5 7.8 0.880 (0.733-1.057) .1701
Platinum sensitive 9.2 9.9 0.936 (0.724-1.211) .6164
Platinum refractory 6.2 5.7 0.766 (0.589-0.997) .0469
Median PFS, mos 4.1 3.5 0.802 (0.667-0.965) .0182
Jotte R, et al. ASCO 2011. Abstract 7000.
clinicaloptions.com/oncologyClinical Oncology 2011
RTOG 0522: Frontline Cisplatin/RT ± Cetuximab in Stage III/IV HNSCC Randomized phase III trial No statistical difference in
2-yr PFS (primary endpoint) or 2-yr OS between treatment arms
– PFS—HR: 1.05 (95% CI: 0.84-1.29; P = .66)
– OS—HR: 0.87 (95% CI: 0.66-1.15; P = .17)
Ang KK, et al. ASCO 2011. Abstract 5500.
63.4
82.6
64.3
79.7
0
20
40
60
80
100
2-Yr PFS 2-Yr OS
Cetuximab + cisplatin/RTCisplatin/RT
Su
rviv
al (
%)
clinicaloptions.com/oncologyClinical Oncology 2011
RTOG 0522: Progression, Safety, and Survival by p16 Status
Risk of distant metastasis at 2 yrs—HR: 0.74 (95% CI: 0.49-1.11; P = .07)
Local-regional progression at 2 yrs—HR: 1.21 (95% CI: 0.92-1.60; P = .92)
Grade 3/4 skin reactions and mucositis ↑ with cetuximab
Late toxicity similar between arms
Survival similar by p16 gene expression
Ang KK, et al. ASCO 2011. Abstract 5500.
24.5
7.6
19.812.0
0
20
40
60
80
100
2-Yr LocoregionalProgression
2-Yr Distant
Metastasis
Cetuximab + cisplatin/RTCisplatin/RT
Rat
e (%
)
clinicaloptions.com/oncologyClinical Oncology 2011
Incidence of Oropharyngeal Cancers Attributed to HPV Infection Oropharyngeal cancer cases from 1984 to 2004 identified in 3
SEER programs (Hawaii, Iowa, and Los Angeles)
From 1998-2004, incidence of HPV-positive oropharyngeal cancers increased by 225%, whereas incidence of HPV-negative oropharyngeal cancers decreased by 50%
Median survival significantly greater for patients with vs without HPV infection (131 vs 20 mos; P < .001)
Survival of all oropharyngeal cancer cases significantly increased over time (P < .001)
Authors suggest that the growing burden of HPV-positive oropharyngeal cancers emphasizes need to evaluate benefit of HPV vaccination for preventing oral HPV infection
Chaturvedi A, et al. ASCO 2011. Abstract 5529.
Breast Cancer
clinicaloptions.com/oncologyClinical Oncology 2011
TBCRC 006: Neoadjuvant Lapatinib + Trastuzumab in HER2-Overexpressing BC Multicenter, phase II: N = 66; n = 64 evaluable for
response
Lapatinib 1000 mg/day + trastuzumab 2 mg/kg/wk (load: 4 mg/kg) for 12 wks followed by surgery
– ER+ disease also treated with letrozole (+ goserelin if premenopausal)
Chang JCN, et al. ASCO 2011. Abstract 505.
Pathologic Response, % All ER Positive ER Negative
pCR* 28 21 40
pCR* + npCR† 53 56 48
*pCR defined as no invasive cancer in breast. †npCR defined as < 1 cm residual disease in breast.
clinicaloptions.com/oncologyClinical Oncology 2011
TBCRC 006 vs Other Neoadjuvant Trials in HER2-Positive Disease
1. Chang JCN, et al. ASCO 2011. Abstract 505. 2. Baselga J, et al. SABCS 2010. Abstract S3-3. 3. Gianni L, et al. SABCS 2010. Abstract S3-2. 4. Untch M, et al. SABCS 2010. Abstract S3-1.
Study and Treatment Pts, n pCR,* %
TBCRC 006[1]
Lapatinib + trastuzumab for 12 wks 66 28
NeoALTTO[2]
Lapatinib 18 wks with paclitaxel added for last 12 wksTrastuzumab 18 wks with paclitaxel added for last 12 wksLapatinib + trastuzumab 18 wks with paclitaxel added for last 12 wks
455154149152
24.729.551.3
NeoSphere[3]
Trastuzumab + docetaxel for 12 wksPertuzumab + docetaxel for 12 wksTrastuzumab + pertuzumab + docetaxel for 12 wksTrastuzumab + pertuzumab for 12 wks
10796
107107
29.024.045.816.8
Geparquinto (GBG 44)[4]
Lapatinib + epirubicin/cyclophosphamide → docetaxel for 24 wks Trastuzumab + epirubicin/cyclophosphamide → docetaxel for 24 wks
615308307
35.250.4
*No invasive cancer in breast.
clinicaloptions.com/oncologyClinical Oncology 2011
NCIC CTG MAP.3: Placebo vs Exemestane to Prevent BC in Postmenopausal Women Double-blind phase III trial
Primary endpoint: incidence of invasive breast cancer
Annual incidence rate of invasive breast cancer
– Exemestane: 0.19% (95% CI: 0.08-0.30)
– Placebo: 0.55% (95% CI: 0.36-0.73)
– HR: 0.35 (95% CI: 0.18-0.70; P = .002)
Significant reduction in risk of invasive breast cancer with exemestane observed in patients with ER+, PgR+, and/or HER2-negative disease
– Investigators: findings should be interpreted with caution given small number of events
Incidence of DCIS and precancerous benign lesions also reduced
Goss PE, et al. ASCO 2011. Abstract LBA504. Goss, PE, et al. N Engl J Med. 2011;364:2381-2391.
clinicaloptions.com/oncologyClinical Oncology 2011
NCIC CTG MAP.3: Safety
No increase in incidence of SAEs with exemestane over 3 yrs, including fractures, osteoporosis, CV toxicity, or second malignancies
Authors conclude: exemestane is an option for prevention of breast cancer in postmenopausal women
Goss PE, et al. ASCO 2011. Abstract LBA504. Goss, PE, et al. N Engl J Med. 2011;[Epub ahead of print].
Adverse Event (All Grades), % Exemestane (n = 2240) Placebo (n = 2248) P Value
Hot flashes 40 32 < .0001
Joint pain 30 27 .04
Fatigue 23 21 .03
Vaginal dryness 16 15 .68
Arthritis 11 9 .01
Depression 11 10 .96
Insomnia 10 8 .04
Muscle pain 7 9 .01
Nausea 7 5 .04
Diarrhea 5 3 .002
clinicaloptions.com/oncologyClinical Oncology 2011
SWOG S0221: Cont. Wkly AC + Filgrastim vs q2w AC + Pegfilgrastim as Adjuvant Tx Phase III; current analysis compares continuous wkly AC + G vs AC q2w
Budd GT, et al. ASCO 2011. Abstract 1004.
Patients with stage I-III, node-positive or high-risk node-negative invasive
breast cancer who underwent surgical
resection
(N = 2716)
AC q2w*(n = 1375)
AC + G†
(n = 1341)
Paclitaxel 175 mg/m2 +Pegfilgrastim q2w for 6 cycles
Paclitaxel 175 mg/m2 +Pegfilgrastim q2w for 6 cycles
Paclitaxel 80 mg/m2/wkfor 12 cycles
Paclitaxel 80 mg/m2/wkfor 12 cycles
*AC q2w: doxorubicin 60 mg/m2 + cyclophosphamide 600 mg/m2 + pegfilgrastim, q2w for 6 cycles.†AC + G: doxorubicin 24 mg/m2 + cyclophosphamide 60 mg/m2 PO + granulocyte-colony stimulating factor (ie, filgrastim) on Days 2-7, wkly for 15 cycles.
clinicaloptions.com/oncologyClinical Oncology 2011
SWOG S0221: DFS
Primary endpoint: DFS First interim analysis: lower 99.5% CI boundary of 0.82 crossed in AC + G arm, resulting in futility of AC + G vs AC q2w
– DSMB recommended halting randomization to AC wkly
Study still ongoing to assess whether weekly paclitaxel superior to q2w paclitaxel
Budd GT, et al. ASCO 2011. Abstract 1004. Reprinted with permission.
DF
S
Yrs Since Registration
AC q2w (n = 1342; 183 events)AC + G (n=1320; 202 events)
HR = 1.15 (95% CI: 0.95-1.41) P = .16
0 2 4 6 8
0
0.25
0.50
0.75
1.00
5-Yr DFS, %8279
0.50
clinicaloptions.com/oncologyClinical Oncology 2011
SWOG S0221: Safety
Toxicity profiles of AC + G vs AC q2w differed
Budd GT, et al. ASCO 2011. Abstract 1004.
Grade 3/4 Adverse EventDuring AC Segments, %
AC + G AC q2w P Value
Anemia 5.25 9.6 < .001
Leukopenia 15.0 20.0 .001
Neutropenia 23.0 26.0 .09
Thrombocytopenia 3.4 2.8 .6
InfectionFebrile neutropeniaNonneutropenic
2.02.7
6.02.9
< .001.84
CardiotoxicityDuring AC segmentsDuring AC and paclitaxel segments
0.40.5
1.12.2
.046< .001
Mucositis 8.2 2.0 < .001
Dermatologic/hand-foot syndrome 17.0 2.0 < .001
clinicaloptions.com/oncologyClinical Oncology 2011
Phase III: Addition of Iniparib (BSI-201) to Gemcitabine/Carboplatin in mTNBC Coprimary endpoints: OS and PFS
O’Shaughnessy J, et al. ASCO 2011. Abstract 1007. Reprinted with permission.
1.0
PF
S P
rob
abil
ity
0 2 4 6 80
Mos 10 12 14 16
0.8
0.6
0.4
0.2
OS
Pro
bab
ilit
y0 2 4 6 8
0
1.0
Mos10 12 14 16
0.8
0.6
0.4
0.2
Outcome, Mos GCI (n = 261) GC (n = 258) HR (95% CI) P Value
Median PFS 5.1 4.1 0.79 (0.65-0.98) .027
Median OS 11.8 11.1 0.88 (0.69-1.12) .28
clinicaloptions.com/oncologyClinical Oncology 2011
Addition of Iniparib (BSI-201) to Gemcitabine/Carboplatin in mTNBC Addition of iniparib to GC in patients with mTNBC did not significantly
improve OS or PFS vs GC alone[1]
– OS findings may be confounded by 96% cross-over from control to experimental arm
– Results in contrast with those of previous phase II study[2]
ORR also similar with iniparib + GC vs GC alone: 34% vs 30%[1]
Exploratory analyses suggest iniparib may confer benefits in patients receiving iniparib + GC in second- and third-line settings[1]
– Confirmatory study needed
Biomarker analyses under way to identify potential patient subgroups that may benefit from iniparib
1. O’Shaughnessy J, et al. ASCO 2011. Abstract 1007. 2. O’Shaughnessy J, et al. N Engl J Med. 2011;364:205-214.
clinicaloptions.com/oncologyClinical Oncology 2011
AMG 386 + Paclitaxel + Bevacizumab for First-line Tx of HER2-Negative Advanced BC Double-blind, randomized phase II study; primary endpoint: PFS comparison
of blinded arms– AMG 386: recombinant peptide-Fc fusion protein that binds and neutralizes effects
of Ang1 and Ang2 to inhibit angiogenesis
Dieras V, et al. ASCO 2011. Abstract 544. Reprinted with permission.
100
PF
S (
%)
80
60
40
20
00 5 10 15 20 25 30
Mos
mPFS, Mos11.39.2
12.2
AMG 386 10 mg/kg qw + P + Bev (n = 56)AMG 386 3 mg/kg qw + P + Bev (n = 57)Placebo qw + P + Bev (n = 58)
HR for AMG 386 10 mg/kg vs placebo: 0.984 (80% CI: 0.720-1.344; P = .946)
HR for AMG 386 3 mg/kg vs placebo: 1.119 (80% CI: 0.821-1.524; P = .642)
clinicaloptions.com/oncologyClinical Oncology 2011
AMG 386 3 mg/kg
AMG 386 10 mg/kg
Placebo Open-LabelAMG386 10 mg/kg
+ Paclitaxel
CR
Pat
ien
ts (
%)
PR
SD
PD
NE/NA
12.2 2.4 10.9
10.2
2.4 4.8
13
26.5
24.431
30.4
49
63.4
59.541.3
2 7.3 4.3
0
20
40
60
80
100
+ Paclitaxel + Bevacizumab
cORR:51%
cORR:70.7%
cORR:59.5%
cORR:45.7%
Dieras V, et al. ASCO 2011. Abstract 544.
4.8
AMG 386 + Paclitaxel + Bevacizumab for First-line Tx of HER2-Negative Advanced BC
Gastrointestinal Cancer
clinicaloptions.com/oncologyClinical Oncology 2011
Panitumumab + Rilotumumab or Ganitumab for mCRC With WT KRAS Rilotumumab: fully human HGF mAb Ganitumab: fully human IGF-1R mAb Phase Ib: DLT assessed Phase II: randomized comparison
Primary endpoint: ORR Probability that combination better
than panitumumab alone– Panitumumab + rilotumumab: 93%
– Panitumumab + ganitumab: 63%
Eng C, et al. ASCO 2011. Abstract 3500.
Response, % Panitumumab + Rilotumumab*
(n = 48)
Panitumumab + Ganitumab*
(n = 46)
Panitumumab + Placebo* (n = 48)
ORR 31 22 21
CR 0 0 0
PR 31 22 21
SD 40 39 35
PD 23 33 33
*Panitumumab dosed at 6 mg/kg, rilotumumab dosed at 10 mg/kg, and ganitumab dosed at 12 mg/kg; all doses administered q2w.
clinicaloptions.com/oncologyClinical Oncology 2011
Panitumumab + Rilotumumab or Ganitumab: Adverse EventsGrade 3/4 Adverse Event,* %
Panitumumab + Rilotumumab (n = 48)
Panitumumab + Ganitumab (n = 46)
Panitumumab + Placebo (n = 48)
Any 71 63 52
Rash 29 13 8
Acneiform dermatitis 15 11 10
Hypomagnesemia 4 15 2
Abdominal pain 4 7 6
Anemia 0 0 8
Constipation 0 0 6
Acne 4 0 0
Asthenia 0 4 0
Diarrhea 4 2 0
Fatigue 4 2 2
Paronychia 4 2 2
Skin toxicity 2 4 0
*Occurring in > 2% of patients in any treatment arm.
Eng C, et al. ASCO 2011. Abstract 3500.
clinicaloptions.com/oncologyClinical Oncology 2011
Impact of KRAS G13D Mutation in CRYSTAL and OPUS Trials CRYSTAL and OPUS: improved efficacy with addition of
cetuximab to first-line chemotherapy in KRAS WT mCRC[1]
– Patients with KRAS mutated mCRC experienced either no benefit or worse outcomes with cetuximab + first-line chemotherapy
KRAS G13D mutated cells sensitive to cetuximab[2]
In pooled exploratory analysis of CRYSTAL and OPUS, KRAS G13D mutation associated with poor prognosis in chemotherapy alone arms from each trial[3]
– PFS HR for KRAS G13D vs other mutations: 1.54 (P = .0847)
– OS HR for KRAS G13D vs other mutations: 1.39 (P = .0988)
1. Bokemeyer C, et al. ASCO 2010. Abstract 3506. 2. De Roock W, et al. JAMA. 2010;304:1812-1820. 3. Tejpar S, et al. ASCO 2011. Abstract 3511.
clinicaloptions.com/oncologyClinical Oncology 2011
Impact of KRAS G13D Mutation in CRYSTAL and OPUS Trials Significant treatment interaction observed for KRAS G13D vs KRAS
other mutations
– PFS: P < .0001; OS: P = .0201; response: P < .0001
Similar treatment effects for KRAS G13D mutations and KRAS WT
*HR for PFS and OS outcomes; OR for response rate outcomes; HR < 1 favors chemotherapy + cetuximab and HR > 1 favors chemotherapy alone; OR < 1 favors chemotherapy alone and OR > 1 favors chemotherapy + cetuximab.
Tejpar S, et al. ASCO 2011. Abstract 3511.
HR or OR* in Pooled Analysis (95% CI)
KRASWT
KRAS G13D KRAS G12V KRASOther Muts
Median PFS 0.66(0.55-0.80)
0.60(0.32-1.12)
1.55(0.94-2.56)
1.37(1.02-1.84)
Median OS 0.81(0.69-0.94)
0.80(0.49-1.30)
1.10(0.75-1.62)
1.16(0.91-1.48)
Response rate 2.17(1.64-2.86)
2.41(0.90-6.45)
0.54(0.26-1.12)
0.58(0.36-0.91)
clinicaloptions.com/oncologyClinical Oncology 2011
NSABP R-04: Neoadjuvant Capecitabine and Oxaliplatin for Rectal Cancer Phase III trial; patients with
resectable stage II/III rectal cancer randomized to 1 of 4 arms
– 5-FU: n = 477
– 5-FU + oxaliplatin: n = 329
– Capecitabine: n = 472
– Capecitabine + oxaliplatin: n = 330
All pts received neoadjuvant radiation in addition to CT
Primary endpoint: locoregional relapse rate (data not yet mature)
Outcome, % 5-FU Capecitabine P Value
pCR 18.8 22.2 .12
SD 20.7 23.0 .62
SSS 61.2 62.7 .59
5-FU vs capecitabine
Outcome, % No Oxaliplatin
Oxaliplatin P Value
pCR 19.1 20.9 .46
SD 23.0 19.2 .48
SSS 63.6 60.4 .28
Oxaliplatin vs no oxaliplatin
– More grade 3/4 diarrhea with oxaliplatin vs no oxaliplatin: 15.4% vs 6.6% (P = .0001)
Roh MS, et al. ASCO 2011. Abstract 3503.
clinicaloptions.com/oncologyClinical Oncology 2011
CLASSIC: Adj. XELOX vs Observation After D2 Dissection of Gastric Cancer Primary endpoint: 3-yr DFS
– All pts in trial Asian; phase III
XELOX given for 8 cycles
3-yr DFS benefit maintained across subgroups: disease stage, age, nodal status
Nearly twice as many patients in observation vs XELOX arm experienced disease recurrence
– XELOX: 18.1%
– Observation: 30.1%
Trend toward prolonged OS with XELOX vs observation (median follow-up: 34.4 mos)
– HR: 0.74 (95% CI: 0.53-1.03; P = .0775)
Bang Y, et al. ASCO 2011. Abstract LBA4002. Reprinted with permission.
1.0
0.8
0.6
0.4
0.2
00 6 12 18 24 30 36 42 48
Mos
74%
60%
HR: 0.56 (95% CI: 0.44-0.72;P < .0001)
XELOX (n = 520)Observation (n = 515)
No. leftXELOX
Observation520515
443414
410352
333286
246209
166147
7458
3022
106
clinicaloptions.com/oncologyClinical Oncology 2011
Adjuvant XELOX vs Observation After D2 Dissection of Gastric Cancer: AEs AEs markedly higher in XELOX vs observation arms
– All grades: 99% vs 52%; grade 3/4: 54% vs 6%; serious AEs: 14% vs 7%
AEs in XELOX Arm, % XELOX (n = 496)
All Grades Grade 3/4
Nausea 66 8
Neutropenia 60 22
Peripheral neuropathy 56 2
Diarrhea 47 2
Vomiting 39 7
Thrombocytopenia 26 8
Hand-foot syndrome 19 1
Stomatitis 12 < 1
Cardiac disorders 2 < 1
Bang Y, et al. ASCO 2011. Abstract LBA4002.
clinicaloptions.com/oncologyClinical Oncology 2011
BSC ± Second-line Chemotherapy in Pretreated Advanced Gastric Cancer Phase III Korean trial
Chemotherapy: docetaxel or irinotecan; continued until PD, toxicity, or study withdrawal
Primary endpoint: OS
No significant difference in OS with docetaxel vs irinotecan (P = .114)
OS benefit maintained across patient subgroups
Park SH, et al. ASCO 2011. Abstract 4004. Reprinted with permission.
OS
Pro
bab
ility
0
0.2
0.4
0.6
0.8
1.0
Mos
Median f/u: 17 mos (95% CI: 16-18 mos)
Log rankP = .009
0 6 12 18
SLC + BSCBSC alone
Median5.1 mos3.8 mos
95% CI4.0-6.23.0-4.6
clinicaloptions.com/oncologyClinical Oncology 2011
BSC ± Second-line Chemotherapy in Pretreated Advanced Gastric Cancer: AEs Similar incidence of all-cause death within 30 days of
randomization regardless of treatment
– Docetaxel: n = 1
– Irinotecan: n = 1
– BSC alone: n = 2
Park SH, et al. ASCO 2011. Abstract 4004.
Grade 3/4 AE, % SLC + BSC BSC Alone (n = 62)Docetaxel
(n = 66)Irinotecan
(n = 60)
Fatigue 17 20 27
Anorexia 6 5 10
Nausea 5 3 6
Diarrhea 3 8 5
Stomatitis 6 2 2
Hematologic Malignancies
clinicaloptions.com/oncologyClinical Oncology 2011
COMFORT-II (Phase III): Ruxolitinib in Myelofibrosis Ruxolitinib (INCB18424): potent and selective JAK1/2 inhibitor
Primary endpoint: 35% reduction in spleen volume by MRI at Wk 48
Patients with myelofibrosis and
≥ 2 IPSS risk factors
(N = 219)
Ruxolitinib 15 or 20 mg PO BID
(n = 146)
Best Available Therapy (BAT)(n = 73)
Ruxolitinib extension or crossover if
disease progression*
Harrison CN, et al. ASCO 2011. Abstract LBA6501.
≥ 35% Reduction in Spleen Volume, % (95% CI)
Ruxolitinib(n = 146)
BAT(n = 73)
P Value
Wk 24 31.9 (24.4-40.2) 0 (0-5) < .0001
Wk 48 28.5 (21.3-36.6) 0 (0-5) < .0001
*Progression defined as splenectomy or 25% spleen volume increase from baseline or on-study nadir.
clinicaloptions.com/oncologyClinical Oncology 2011
COMFORT-II: Survival and QoL
PFS, LFS, and OS did not significantly improve with ruxolitinib treatment Ruxolitinib associated with improvement in symptoms and functioning
Mean Change in EORTC QLQ-C30 Scores From Baseline to Wk 48
Ruxolitinib(n = 69)
BAT(n = 28)
Global health status or QoL 9.1 (n = 66) 3.4 (n = 27)
Role functioning 9.9 -5.4
Select symptoms common to myelofibrosis
Loss of appetite -8.2 9.5
Insomnia -12.3 (n = 68) 6.0
Dyspnea -6.3 4.8
Pain -1.9 3.0
Fatigue -12.8 0.4
Harrison CN, et al. ASCO 2011. Abstract LBA6501.
clinicaloptions.com/oncologyClinical Oncology 2011
COMFORT-II: Safety and Conclusions
Grade 3/4 anemia (mostly grade 3) and thrombocytopenia (mostly grade 1/2) more common with ruxolitinib treatment
Results of phase III COMFORT-I[1] trial (N = 308) comparing ruxolitinib vs placebo similar to COMFORT-II[2]
– At Wk 24, 42% of ruxolitinib-treated patients had ≥ 35% reduction in spleen volume vs 0.7% of placebo-treated patients: OR: 134.4 (95% CI: 17.97-1005; P < .0001)
– Significantly more ruxolitinib-treated patients had ≥ 50% decrease in total symptom score vs placebo (46% vs 5%, respectively; P < .0001)
– As with COMFORT-II OS not statistically different between treatment arms (60-wk OS: 93.5% ruxolitinib vs 90.9% placebo)
Authors suggest ruxolitinib may be a significant improvement over currently available treatments for MF
1. Verstovsek S, et al. ASCO 2011. Abstract 6500. 2. Harrison CN, et al. ASCO 2011. Abstract LBA6501.
clinicaloptions.com/oncologyClinical Oncology 2011
CLASSIC I: Clofarabine + Cytarabine vs Cytarabine in Relapsed/Refractory AML Poor prognosis for older patients (older than 55 yrs of age) with
relapsed or refractory AML
Efficacy Outcome, % Clofarabine + Cytarabine(n = 162)
Cytarabine Alone (n = 157)
P Value
4-mo EFS 38 17 < .0001
ORR 47 23 < .0001
CR 35 18 .0005
Faderl S, et al. ASCO 2011. Abstract 6503.
OS not significantly different between treatment arms
– Median OS: 6.6 mos for clofarabine + cytarabine vs 6.4 mos for cytarabine alone: HR: 1.00 (95% CI: 0.78-1.28; P = .9951)
Clofarabine + cytarabine associated with 47% reduced risk of events (progression or death): HR: 0.63 (95% CI: 0.49-0.80; P = .0001)
clinicaloptions.com/oncologyClinical Oncology 2011
Decitabine vs SC or Cytarabine in Older Patients With Newly Diagnosed AML Open-label phase III trial; at protocol-defined clinical cutoff (396
deaths), median OS not statistically longer with decitabine (7.7 vs 5.0 mos; HR: 0.85; 95% CI: 0.69-1.04; P = .108)
Decitabine demonstrated significant benefit in OS for pts 75 yrs or older, de novo AML diagnosis, bone marrow blast > 30%, intermediate risk cytogenetics, ECOG PS 2
Higher response rates found with decitabine treatment vs either SC or low-dose cytarabine
> 50% of pts with treatment-related grade 3/4 adverse event; rates similar between decitabine and cytarabine treatment (low with SC)
Response, % Decitabine(n = 242)
Treatment Choice
(n = 243)
Low-Dose Cytarabine(n = 215)
Supportive Care
(n = 28)
CR + CR with incomplete platelet recovery 17.8* 7.8* 8.4 3.6
Thomas XG, et al. ASCO 2011. Abstract 6504.
*P = .001; OR: 2.5 (95% CI 1.40-4.78).
clinicaloptions.com/oncologyClinical Oncology 2011
SWOG 9704: ASCT After R-CHOP in Pts With Advanced High-Risk Diffuse NHL Pts (N = 253) with ≥ PR after induction with CHOP ± R for 5 cycles
Randomized to R-CHOP for 1 cycle + ASCT or R-CHOP for 3 cycles
Higher incidence of grade 3/4 adverse events observed with ASCT
ASCT significantly prolonged PFS in patients with advanced high-intermediate or high IPI diffuse NHL
In exploratory analysis, significantly greater proportion of pts with a high IPI score had 2-yr PFS and OS with ASCT in first remission vs those with CHOP ± rituximab alone
Outcome, % CHOP ± R for 1 Cycle + ASCT(n = 125)
CHOP ± R for 3 Cycles (n = 128)
HR (95% CI) P Value
2-yr PFS 69 56 1.72 (1.18-2.51) .005
2-yr OS 74 71 1.24 (0.81-1.91) .16
Stiff PJ, et al. ASCO 2011. Abstract 8001.
clinicaloptions.com/oncologyClinical Oncology 2011
Frontline R-MegaCHOEP and ASCT vs R-CHOEP-14 in B-Cell Lymphoma Younger (age < 61 yrs) high-risk pts (N = 262) with aggressive disease
Randomized to 8 cycles R-CHOEP-14 vs 4 cycles R-MegaCHOEP with ASCT
75% of pts achieved CR/CRu with no benefit of R-MegaCHOEP + ASCT over R-CHOEP-14
Grade 3/4 AEs more common with R-MegaCHOEP
R-MegaCHOEP followed by ASCT not superior R-CHOEP-14Outcome at Yr 3, % R-CHOEP-14 x 8 Cycles(n = 130)
R-MegaCHOEP + ASCT x 4 Cycles
(n = 132)
P Value
EFS 69.5 61.4 .140
aaIPI 2 75.5 63.5 .051
PFS 73.7 69.8
OS 84.6 77.0 .081
aaIPI 2 91.0 77.1 .013
Schmitz N, et al. ASCO 2011. Abstract 8002.
clinicaloptions.com/oncologyClinical Oncology 2011
R-HDT vs R-CHOP-14 as First-line Treatment for Younger Pts With DLBCL
CHOP-14 + Rituximab 375 mg/m2
on Day 1(n = 156)
HDT + Rituximab 375 mg/m2
on Day 1(n = 156)
Adults (60 yrs of age or younger)
with DLBCL
(N = 312)
Stratified by center and age-adjusted IPI
4 cycles; evaluation
PET negR-CHOP-14
4 cycles
PET pos
PET neg
R-DHAP x 3BEAM
BEAM + ASCT
Le Gouill S, et al. ASCO 2011. Abstract 8003.
clinicaloptions.com/oncologyClinical Oncology 2011
R-HDT vs R-CHOP-14: Results
Numerically more patients in R-CHOP-14 treatment arm PET-negative at intermediate evaluation compared with patients in R-HDT arm
ORR 88% for both treatment arms
Authors conclude that R-CHOP-14 for 8 cycles could become new standard in patients who are PET negative after 4 cycles
3-Yr Survival, % CHOP-14 + Rituximab(n = 156)
HDT + Rituximab(n = 156)
P Value
EFS 56 41 .03
Age-adjusted IPI 0-1 57 46 .3
Age-adjusted IPI 2-3 56 37 .06
PFS 81 79 .9
OS (median not reached) 85 82 NS
Le Gouill S, et al. ASCO 2011. Abstract 8003.
clinicaloptions.com/oncologyClinical Oncology 2011
CORAL: Induction Therapy With R-ICE vs R-DHAP in Relapsed DLBCL Pts with CD20+ relapsed DLBCL randomized to salvage
with R-ICE vs R-DHAP each followed by BEAM and ASCT; pts with at least a PR randomized to observation or maintenance rituximab therapy for 1 yr
At a median follow-up of 45 mos, mobilization-adjusted ORR comparable after induction therapy
– 51.5% for R-ICE vs 56.5% for R-DHAP
– Fewer AEs with R-ICE
EFS and OS comparable between R-ICE and R-DHAP
– EFS: 29% vs 33%, respectively
– OS: 48% vs 51%, respectivelyGisselbrecht C, et al. ASCO 2011. Abstract 8004.
clinicaloptions.com/oncologyClinical Oncology 2011
CORAL: Rituximab Maintenance Therapy vs Observation in Relapsed DLBCL EFS, PFS, and OS comparable with rituximab
maintenance vs no additional therapy
Median PFS longer for females vs males in rituximab maintenance arm
– Not reached vs 25.3 mos (P = .0044)
Survival After Maintenance Therapy, Mos
Maintenance Rituximab(n = 122)
No Additional Therapy(n = 120)
P Value
Median EFS 57.6 58.2 .7435
Median PFS 57.6 58.2 .8314
Median, mos Not reached 62.9 .7547
Gisselbrecht C, et al. ASCO 2011. Abstract 8004.
clinicaloptions.com/oncologyClinical Oncology 2011
MM-015: SPM With MPR-R vs MPR vs MP in Elderly Pts With Newly Diagnosed MM
Patients (N = 459) aged 65 yrs or older randomized to MPR followed by maintenance lenalidomide vs MPR vs MP
Median PFS significantly prolonged in MPR-R arm (31 mos) vs MPR (14 mos) and MP (13 mos) arms
– Risk of PD reduced 60% in MPR-R arm vs MP (HR: 0.395; P < .001)
– No significant difference in OS among 3 treatment arms at median follow-up of 30 mos
8.0
5.9
2.6
4.7
3.3
0.7
3.32.6
2.0
0
2
4
6
8
10
MPR-R MPR MP
Total invasive SPMs
Hematologic malignancies
Solid tumors
Inci
den
ce
of
SP
Ms
(%)
Palumbo AP, et al. ASCO 2011. Abstract 8007.
Risk for PD or death greater than risk for SPM in each treatment arm
clinicaloptions.com/oncologyClinical Oncology 2011
BiRD: SPM With Continuous Lenalidomide as First-line Therapy for MM Patients (N = 72) with newly diagnosed MM
Efficacy with 6 yrs of follow-up
– ORR: 90%; CR/near CR: 53%
– 2-yr EFS: 97.2%; 4-yr OS: 82%
Incidence of SPM following first-line treatment with BiRD: 11 of 68 pts (16%) with no cases of AML/MDS
Incidence of invasive cancer comparable to that of general population of similar age (SEER 2003-2007)
– Patients initially treated with BiRD: 2.85 per 100 person-yrs
– General population: 2.1 per 100 person-yrsRossi AC, et al. ASCO 2011. Abstract 8008.
clinicaloptions.com/oncologyClinical Oncology 2011
MM-009/MM-010: Risk of SPM With LEN + DEX in Relapsed/Refractory MM Patients (N = 704) with relapsed/refractory MM randomized to
lenalidomide/dex vs placebo/dex
Incidence of invasive SPM (1.71 per 100 person-yrs) with lenalidomide/dex treatment; comparable to SEER data
No cases of AML; MDS: n = 2; solid tumors: n = 6 (heterogeneous)
Noninvasive nonmelanoma skin cancer reported in 11 patients receiving lenalidomide/dex and 2 patients receiving placebo/dex
Significantly longer median TTP or development of SPM with lenalidomide/dex vs placebo/dex (HR: 0.355; 95% CI: 0.292-0.431; P < .001)
Significantly longer median OS with lenalidomide/dex vs placebo/dex (HR: 0.607; 95% CI: 0.459-0.803; P < .001)
Dimopoulos MA, et al. ASCO 2011. Abstract 8009.
clinicaloptions.com/oncologyClinical Oncology 2011
SPM Following Multiple Myeloma
Potential bias in evaluating SPM
– Reporting of SPM varies between treatment arms
– Often survival differences between treatment arms
– Differences in study design
Mechanism of SPM in MM currently unknown
Clinicians should weigh the demonstrated benefits of therapy with the risk of SPM
Landgren O. ASCO 2011. Discussant. Reprinted with permission.
Proposed Model for SPM Following MM
Treatment of MM
Secondmalignancy
Behavioralfactors
MM related factors
Host relatedfactors
Environmentalfactors
Sarcomas
clinicaloptions.com/oncologyClinical Oncology 2011
SUCCEED: Ridaforolimus Maintenance in Patients With Metastatic Sarcoma Double-blind phase III trial
Ridaforolimus: oral rapamycin analogue with potent activity against mTOR
Primary endpoint (PFS) significantly prolonged vs placebo
Patients with metastatic sarcoma who had attained
CR, PR, or SD from previous standard
chemotherapy
(N = 711)
Ridaforolimus 40 mg PO QD for 5 days/wk(n = 347)
Placebo PO QD for 5 days/wk(n = 364)
Disease progression
or unacceptable
toxicity
Outcome, IRC Assessment Ridaforolimus(n = 347)
Placebo (n = 364)
HR P Value
Median PFS, wks 17.7 14.6 0.72 .0001
PFS rate, %
3 mos 70 54
6 mos 34 23
Chawla SP, et al. ASCO 2011. Abstract 10005.
clinicaloptions.com/oncologyClinical Oncology 2011
SUCCEED: OS, Response, and Safety
Clinical benefit (CR + PR + SD ≥ 4 mos) significantly improved
Ridaforolimus safety profile consistent with that of other mTOR inhibitors
≥ 1 grade ≥ 3 AEs more common with ridaforolimus vs placebo (64% vs 26%)
Grade ≥ 3 events occurring more often with ridaforolimus included thrombocytopenia, stomatitis, anemia, hyperglycemia, infections, and diarrhea
Outcome Ridaforolimus(n = 347)
Placebo (n = 364)
HR P Value
Median OS, mos 21.4 19.2 0.88 .2256
Clinical benefit, % 40.6 28.6 -- .0009
Best target lesion response, mean tumor size %
-1.3 +10.3 -- < .0001
Chawla SP, et al. ASCO 2011. Abstract 10005.
Ovarian Cancer
clinicaloptions.com/oncologyClinical Oncology 2011
OCEANS: Bev + Carboplatin/Gemcitabine in Recurrent Ovarian Cancer
Population Median PFS, Mos HR (95% CI) P Value
Bev + CG(n = 242)
Placebo + CG(n = 242)
Investigator assessed 12.4 8.4 0.484(0.388-0.605)
< .0001
IRC assessed 12.3 8.6 0.451 (0.351-0.580)
< .0001
Aghajanian C, et al. ASCO 2011. Abstract LBA5007.
Platinum-sensitive recurrent OC*
Measurable diseaseECOG 0/1No previous chemo forrecurrent OCNo previous Bev
(n = 484)
PL q3w until progression
Bev 15 mg/kg q3w until progression
CG + PL
CG + Bev
CG for 6 (up to 10) cycles
C AUC 4
G 1000 mg/m2 Days 1 & 8
C AUC 4
G 1000 mg/m2 Days 1 & 8
*Epithelial ovarian, primary peritoneal, or fallopian tube cancer.
clinicaloptions.com/oncologyClinical Oncology 2011
OCEANS: OS, Response, and Safety
In interim analysis, trend toward improved OS; final OS results awaited
Safety profile of bev + carbo/gem consistent with other trials; serious AEs and more common with addition of bevacizumab
Similar incidence of ≥ grade 3 neutropenia in both arms; ≥ grade 3 hypertension and ≥ grade 3 proteinuria more common in bev arm
Aghajanian C, et al. ASCO 2011. Abstract LBA5007.
Outcome Bev + CG(n = 242)
Placebo + CG(n = 242)
HR (95% CI) P Value
Objective response, % 78.5 57.4 -- < .0001
CR 17 9
PR 61 48
Median duration of response, mos
10.4 7.4 0.534(0.408-0.698)
< .0001
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Data From Chicago!Capsule Summaries of all the key data presented at the 2011 conference
Expert Analyses panel discussions exploring the clinical implications of these key data
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