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Faculty
Axel Grothey, MD
Professor, Oncology Mayo Clinic Rochester, Minnesota
Kathy D. Miller, MD
Associate Professor Indiana University Melvin and Bren Simon Cancer Center Indianapolis, Indiana
John M. Kirkwood, MD
Professor, Medicine, Dermatology, and Translational Science Director, Melanoma and Skin Cancer Program University of Pittsburgh Cancer Institute Pittsburgh, Pennsylvania
Craig Reynolds, MD
Development Chair US Oncology Lung Cancer Committee US Oncology Ocala, Florida
Faculty
David I. Quinn, MD, PhD
Associate Professor of Medicine Division of Cancer Medicine and Blood Diseases The University of Southern California Medical Director USC Norris Cancer Center and Hospital Los Angeles, California
Brian I. Rini, MD
Staff Physician Department of Solid Tumor Oncology and Urology Cleveland Clinic Taussig Cancer Institute Associate Professor of Medicine CCF/CWRU Lerner College of Medicine Cleveland, Ohio
Nicholas J. Vogelzang, MD
Chair and Medical Director Developmental Therapeutics Committee US Oncology Research Comprehensive Cancer Centers of Nevada Professor of Medicine University of Nevada School of Medicine Las Vegas, Nevada
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.
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.
Breast Cancer
Gastrointestinal Cancer Hematologic Malignancies
Sarcomas
Ovarian Cancer
Melanoma
Randomized, nonblinded phase III trial OS, PFS improved in all prespecified subgroups (age, sex, stage, PS, LDH)
Vemurafenib (n = 336) 84 5.3 48.4 0.9 Dacarbazine (n = 336) 64 1.6 5.5 0 HR (95% CI) 0.37 (0.26-0.55) 0.26 (0.20-0.33) P Value < .0001 < .0001
PR
47.5
5.5
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%)
Vemurafenib (n = 336) 8 7 3 3 2 1 <1 12 6 <1 Dacarbazine (n = 282) 0 1 <1 0 2 2 8 <1 0 0
Grade 3/4 Adverse Event, % Rash Increased liver function tests Arthralgia Photosensitivity Fatigue Nausea Neutropenia Cutaneous squamous cell carcinoma Keratoacanthoma Skin papilloma Chapman PB, et al. ASCO 2011. Abstract LBA4.
Placebo q3w for 4 cycles + Dacarbazine 850 mg/m2 Q3W for 8 cycles (n = 252)
47.3 36.3 28.5 17.9 20.8 12.2
mOS, Mos 11.2 Ipilimumab + DTIC (n = 250) 9.1 Placebo + DTIC (n = 252) P = .0009 (HR: 0.72; 95% CI: 0.59-0.87)
Yr 3
Median OS, mos* Median PFS, mos Disease control rate, % CR PR SD PD Median duration of response, mos *Primary endpoint.
.0009 .006
MDX-024: Safety
Substantially more grade 3/4 adverse events in ipilimumab + dacarbazine arm
Ipilimumab + Dacarbazine (n = 247) Placebo + Dacarbazine (n = 251) Select Adverse Event, %
Total
Diarrhea Increased ALT Increased AST Pruritus Rash Colitis Hypothyroidism Thyroiditis Hyperthyroidism 36.4 33.2 29.1 29.6 24.7 4.5 1.6 0.8 0.4
Grade 3/4
4.0 21.9 18.2 2.0 1.2 2.0 0 0 0
Total
24.7 5.6 5.6 8.8 6.8 0.4 0.4 0 0.4
Grade 3/4
0 0.8 1.2 0 0 0 0 0 0
Outcome (ITT)
Observation (n = 629)
1 1 <1
Active in patients who did not receive previous BRAF inhibitor therapy (n = 71)
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)
Unconfirmed Response, %
100
67 0
95
77 14
96
50 0
100
74 11
Genitourinary Cancers
AXIS: Randomized Phase III Trial, Axitinib vs Sorafenib in Refractory Metastatic RCC
Primary endpoint: PFS
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
0 2 4 6 mPFS, Mos Axitinib 6.7 Sorafenib 4.7 95% CI 6.3-8.6 4.6-5.6
PFS (Probability)
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
Pts at Risk, n Axitinib 361 256 202 145 Sorafenib 362 224 157 100
10 12 Mos
64 28 38 12
14
16
18 20
96 51
20 6
10 3
1 1
0 0
Rini BI, et al. ASCO 2011. Abstract 4503. Reprinted with permission.
ECOG PS 1 ECOG PS 0 Sunitinib-containing regimen Bevacizumab-containing regimen Temsirolimus-containing regimen Cytokine-containing regimen White Nonwhite Male Female Age < 65 Age 65 MSKCC favorable MSKCC intermediate/poor Asia Europe North America Other region
327 396 389 59 24 251 547 176 523 200 476 247 306 417 152 357 186 28
0.0 1.0 2.0 HR (95% CI) 3.0
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 *Death, disease progression, or decrease in FKSI-15 scores. has QoL value
1-sided
P value.
Median OS, Mos (95% CI) Favorable CTC (< 5 cells/ 7.5 mL blood) Unfavorable CTC ( 5 cells/7.5 mL blood)
Wk 8 (n = 374)
Wk 12 (n = 330)
50
48
17
17
<.0001
<.0001
HR (95% CI)*
Treatment Fold change in LDH Baseline LDH CTC conversion 1.030 (0.773-1.372) 1.252 (1.047-1.497) 3.036 (2.276-4.048) 0.386 (0.284-0.527)
P Value*
.8371 .0135 < .0001 < .0001
Baseline CTC
*Adjusted for the biomarker panel.
1.135 (0.987-1.306)
.0747
AA (n = 797)
Placebo (n = 398)
Pain Interference
P Value
Palliation, %
Median time to palliation, mos TTP (25th percentile), mos
59.2
1.02 9.27
38.0
3.71 4.57
.0004
.0009 .0019
Median OS, mos Confirmed PSA response, % Median radiographic PFS, mos
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.
SD (n = 31)
*At progression, patients on placebo could cross-over to cabozantinib (n = 14). Hussain M, et al. ASCO 2011. Abstract 4516.
PD (n = 61)
Discontinue Cabozantinib
0.25
10
60
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
xx x
Xxx
x x
x x
Xx x
xx x
xxx
Treatment
300 mg BID (n = 23) 600 mg BID + prednisone (n = 26) X Previous ketoconazole therapy
Agus DB, et al. ASCO 2011. Abstract 4531. Reprinted with permission.
PD
PR
SD
Outcome
Dose Escalation to 350 mg No (n = 27) 27.1 (26.6-27.6) 5.9 (5.1-6.4) 22.2 14.8 Yes (n = 23) 30.4 (12.1-66.0) 11.1 (5.1-22.1) 43.5 30.4
Median response duration, wks (range) Median PFS, wks (range) 3-mo PFS, % 6-mo PFS, %
Stadler WM, et al. ASCO 2011. Abstract 4567. Reprinted with permission.
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
Outcome, n
PFS at 2 mos*
Progression at < 2 mos *P = .08 Milowsky MI, et al. ASCO 2011. Abstract 4606.
5
7
17
6
Thoracic Cancers
Kris MG, et al. ASCO 2011. Abstract CRA7506. Reprinted with permission.
0.6
0.4 0.2 0 0 3
5.2
9.7
12
15 18 Mos
21
24
27
30
33
54 20
32 8
21 5
17 4
9 3
7 1
4 0
2 0
2 0
0 0
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)
Favors Erlotinib HR Favors Chemotherapy Rosell R, et al. ASCO 2011. Abstract 7503.
79
21 7 14
66
51 13 22
21-42 days
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)
Paz-Ares LG, et al. ASCO 2011. Abstract CRA7510.
0.6
6 Mos
57 15
9
21 5
12
4 0
15
0 0
No significant difference in healthrelated QoL between arms OS data not yet mature
MetMAb
Met
Met
Spigel DR, et al. ASCO 2011. Abstract 7505. Reprinted with permission.
1.09 (0.73-1.62)
0.53 (0.28-0.99)
1.82 (0.99-3.32)
Outcome
Placebo + Erlotinib
Met Diagnostic Positive (n = 66) Met Diagnostic Negative (n = 62) 2.7 1.71 (0.96-3.02) .06 3.8 2.61 (1.34-5.09) .004 15.3
Median PFS, mos HR (95% CI) P value Median OS, mos HR (95% CI) P value
Spigel DR, et al. ASCO 2011. Abstract 7505.
1.5
OS Outcome
ALK+/Crizotinib (n = 30)
ALK+/Control (n = 23)
WT/Control (n = 125)
NR
70 55 0.36 .004 0.49 .02
6
44 12
11
47 32
1.42 .18
7.5
9.2 6.2 4.1
7.8
9.9 5.7 3.5
0.880 (0.733-1.057)
0.936 (0.724-1.211) 0.766 (0.589-0.997) 0.802 (0.667-0.965)
.1701
.6164 .0469 .0182
No statistical difference in 2-yr PFS (primary endpoint) or 2-yr OS between treatment arms
PFSHR: 1.05 (95% CI: 0.84-1.29; P = .66) OSHR: 0.87 (95% CI: 0.66-1.15; P = .17)
24.5
20 0
19.8 7.6
Breast Cancer
*pCR defined as no invasive cancer in breast. npCR defined as < 1 cm residual disease in breast.
Chang JCN, et al. ASCO 2011. Abstract 505.
pCR,* % 28
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
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].
Pegfilgrastim q2w for 6 cycles 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) Paclitaxel 80 mg/m2/wk for 12 cycles
AC + G (n = 1341)
Paclitaxel 175 mg/m2 + Pegfilgrastim q2w for 6 cycles Paclitaxel 80 mg/m2/wk for 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. Budd GT, et al. ASCO 2011. Abstract 1004.
0.75
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
0.50
5-Yr DFS, % AC q2w (n = 1342; 183 events) 82 AC + G (n=1320; 202 events) 79 HR = 1.15 (95% CI: 0.95-1.41) P = .16
DFS
0.25
Study still ongoing to assess whether weekly paclitaxel superior to q2w 8 paclitaxel
Budd GT, et al. ASCO 2011. Abstract 1004. Reprinted with permission.
AC q2w
9.6 20.0 26.0 2.8 6.0 2.9 1.1 2.2 2.0 2.0
P Value
< .001 .001 .09 .6 < .001 .84 .046 < .001 < .001 < .001
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. OShaughnessy J, et al. ASCO 2011. Abstract 1007. 2. OShaughnessy J, et al. N Engl J Med. 2011;364:205-214.
20
31
10.2 12.2 2.4 2.4 24.4 4.8 4.8 13 10.9
Placebo
Gastrointestinal Cancer
Primary endpoint: ORR Probability that combination better than panitumumab alone
Panitumumab + rilotumumab: 93%
Response, %
ORR CR PR
SD PD
40 23
39 33
35 33
*Panitumumab dosed at 6 mg/kg, rilotumumab dosed at 10 mg/kg, and ganitumab dosed at 12 mg/kg; all doses administered q2w. Eng C, et al. ASCO 2011. Abstract 3500.
Anemia
Constipation Acne Asthenia Diarrhea Fatigue Paronychia Skin toxicity Eng C, et al. ASCO 2011. Abstract 3500.
0
0 4 0 4 4 4 2
0
0 0 4 2 2 2 4
8
6 0 0 0 2 2 0
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)
*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.
5-FU vs capecitabine
Outcome, % pCR SD 5-FU 18.8 20.7 Capecitabine 22.2 23.0 P Value .12 .62
SSS
61.2
62.7
.59
Oxaliplatin vs no oxaliplatin
More grade 3/4 diarrhea with oxaliplatin vs no oxaliplatin: 15.4% vs 6.6% (P = .0001)
Outcome, % pCR SD SSS No Oxaliplatin 19.1 23.0 63.6 Oxaliplatin 20.9 19.2 60.4 P Value .46 .48 .28
All pts received neoadjuvant radiation in addition to CT Primary endpoint: locoregional relapse rate (data not yet mature)
Roh MS, et al. ASCO 2011. Abstract 3503.
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%
0
0
No. left XELOX 520 443 410 333 246 166 74 Observation 515 414 352 286 209 147 58
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)
Vomiting
Thrombocytopenia Hand-foot syndrome Stomatitis Cardiac disorders
Bang Y, et al. ASCO 2011. Abstract LBA4002.
39
26 19 12 2
7
8 1 <1 <1
6 Mos
12
18
Park SH, et al. ASCO 2011. Abstract 4004. Reprinted with permission.
Irinotecan (n = 60) 20 5 3 8 2
17 6 5 3 6
Hematologic Malignancies
*Progression defined as splenectomy or 25% spleen volume increase from baseline or on-study nadir. Harrison CN, et al. ASCO 2011. Abstract LBA6501.
Role functioning
Select symptoms common to myelofibrosis Loss of appetite Insomnia Dyspnea
9.9
-5.4
Pain
-1.9
3.0
Fatigue -12.8 0.4 PFS, LFS, and OS did not significantly improve with ruxolitinib treatment Ruxolitinib associated with improvement in symptoms and functioning
Harrison CN, et al. ASCO 2011. Abstract LBA6501.
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.
Clofarabine + cytarabine associated with 47% reduced risk of events (progression or death): HR: 0.63 (95% CI: 0.49-0.80; P = .0001)
Faderl S, et al. ASCO 2011. Abstract 6503.
> 50% of pts with treatment-related grade 3/4 adverse event; rates similar between decitabine and cytarabine treatment (low with SC)
Thomas XG, et al. ASCO 2011. Abstract 6504.
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
Outcome, % CHOP R for 1 Cycle + ASCT (n = 125) 69 74 CHOP R for 3 Cycles (n = 128) 56 71 HR (95% CI) P Value .005 .16
Higher incidence of grade 3/4 adverse events observed with ASCT ASCT significantly prolonged PFS in patients with advanced highintermediate 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
Stiff PJ, et al. ASCO 2011. Abstract 8001.
Outcome at Yr 3, %
.140 .051
4 cycles; evaluation
PET neg
R-CHOP-14 4 cycles
CHOP-14 + Rituximab 375 mg/m2 on Day 1 (n = 156) HDT + Rituximab 375 mg/m2 on Day 1 (n = 156)
PET pos
R-DHAP x 3 BEAM
PET neg
BEAM + ASCT
56
81 85
37
79 82
.06
.9 NS
Authors conclude that R-CHOP-14 for 8 cycles could become new standard in patients who are PET negative after 4 cycles
Le Gouill S, et al. ASCO 2011. Abstract 8003.
.7435 .8314
Median, mos
Not reached
62.9
.7547
MM-015: SPM With MPR-R vs MPR vs MP in Elderly Pts With Newly Diagnosed MM
Risk for PD or death greater than risk for SPM in each treatment arm
Total invasive SPMs 10 Incidence of SPMs (%) 8 6 4.7 4 2 0.7 0 MPR-R MPR MP 3.3 3.3 2.6 2.6 2.0 8.0 5.9 Hematologic malignancies Solid tumors
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
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-yrs
Rossi AC, et al. ASCO 2011. Abstract 8008.
Behavioral factors
Second malignancy
MM related factors
Clinicians should weigh the demonstrated benefits of therapy with the risk of SPM
Sarcomas
Patients with metastatic sarcoma who had attained CR, PR, or SD from previous standard chemotherapy (N = 711)
Placebo (n = 364)
14.6 54 23
HR
0.72
P Value
.0001
Ridaforolimus (n = 347)
21.4
Placebo (n = 364)
19.2
HR
0.88
P Value
.2256
Clinical benefit, %
Best target lesion response, mean tumor size %
40.6
-1.3
28.6
+10.3
---
.0009
< .0001
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
Chawla SP, et al. ASCO 2011. Abstract 10005.
Ovarian Cancer
Platinum-sensitive recurrent OC* Measurable disease ECOG 0/1 No previous chemo for recurrent OC No previous Bev
(n = 484)
CG + PL
CG + Bev
G 1000 mg/m2 Days 1 & 8 Bev 15 mg/kg q3w until progression CG for 6 (up to 10) cycles
Population
HR (95% CI)
P Value
12.4 12.3
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.
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