Transcript ASCO 2012 Review: Gynecologic Cancer

ASCO 2012 Review
Gynecologic Cancer
Nelson Teng, M.D., Ph.D.
Director, Gynecologic Oncology
Stanford University School of Medicine
Disclosures
I do not have any conflict of
interest to report
Acknowledgement
Dr. Jakob Dupont, M.D.
Dr. Kathleen Moore, M.D.
Update from ASCO 2012
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Ovarian Cancer
Endometrial Cancer
Cervix / Vulva
Miscellaneous
Up Front Ovarian Treatment
Abstract # 5003
JGOG 3016, NOVEL, Japanese Gynecologic Oncology Group
Long-term follow-up of a randomized trial comparing conventional
paclitaxel and carboplatin with dose-dense weekly paclitaxel and
carboplatin in women with advanced epithelial ovarian, fallopian
tube, or primary peritoneal cancer: JGOG 3016 trial.
.
Noriyuki Katsumata,1 Makoto Yasuda,2 Seiji Isonishi,2 Fumiaki Takahashi,3
Hirofumi Michimae,3 Eizo Kimura,4 Daisuke Aoki,5 Toshiko Jobo,6 Shoji Kodama,7
Fumitoshi Terauchi,8 Hiroshi Tsuda,5 Toru Sugiyama,9 Kazunori Ochiai,2
1Nippon
Medical School Musashikosugi Hospital, Kawasaki; 2The jikei University, Tokyo;
3Kitasato University, Tokyo; 4Kousei General Hospital, Tokyo; 5Keio University, Tokyo;
6Social Insurance Sagamino Hospital, Sagamihara; 7Niigata Cancer Center Hospital,
Niigata; 8Tokyo Medical University, Tokyo; 9Iwate Medical University, Morioka; Japan
JGOG 3016
Conventional TC (c-TC)
• Ovarian Epithelial,
Primary Peritoneal, or
Fallopian Tube cancer
• FIGO Stage II-IV
• Stratfied: residual
disease, stage, and
histology
•
•
•
R
A
N
D
O
M
I
Z
E
Paclitaxel 180mg/m2, day 1
Carboplatin AUC 6.0, day 1
every 21 days for 6-9 cycles
Dose-dense weekly TC (dd-TC)
Paclitaxel 80mg/m2, days 1,8,15
Carboplatin AUC 6.0, day 1
every 21 days for 6-9 cycles
Primary endpoint: PFS
Secondary endpoint: OS
Accrual: 637 pts (2003 Apr.– JGOG
2005
Dec.)
3016,
NOVEL, Japanese Gynecologic
Oncology Group
Katsumata, Lancet 2009; 374: 1331–38
JGOG 3016, NOVEL, Japanese Gynecologic Oncology Group
Characteristics of the patients
Characteristic
Median age, (range)
Conventional TC
(n = 319)
Dose-dense TC
(n = 312)
57 (25-84)
57 (25-87)
Disease, %
Ovarian
Fallopian tube
Primary peritoneal
87
6
8
83
4
12
FIGO stage, %
II
III
IV
17
67
16
20
65
15
Histologic type, %
Serous/ others
Clear-cell/ Mucinous
85
15
83
17
55
45
54
46
Residual disease, % > 1cm
< 1cm
JGOG 3016, NOVEL, Japanese Gynecologic Oncology Group
JGOG3016: Progression-Free Survival
median follow-up period: 6.4 years
dd-TC
c-TC
Treatment n Event, n (%) Median PFS
dd-TC
312
197 (63)
28.2 mos.
c-TC
319
229 (72)
17.5 mos.
P value
HR
95%CI
0.0037
0.76
0.62-0.91
JGOG 3016, NOVEL, Japanese Gynecologic Oncology Group
JGOG3016: Overall Survival
Patients surviving (%)
dd-TC
c-TC
Treatment n Deaths, n (%) Median OS 5-yr survival P value HR 95%CI
dd-TC
312
139 (45)
not reached
58.7%
0.039 0.79 0.63-0.99
c-TC
319
168 (53)
62.2 mos.
51.1%
JGOG 3016, NOVEL, Japanese Gynecologic Oncology Group
OS: by residual disease
Patients surviving (%)
Median OS
< 1cm, dd-TC (n=144) not reached
< 1cm, c-TC (n=145) not reached
HR 0.76 (0.49-1.19), P = 0.234
Median OS
> 1cm, dd-TC (n=174) 51.2 mos.
> 1cm, c-TC (n=168) 33.5 mos.
HR 0.75 (0.57-0.97), P = 0.0267
Interaction: P = 0.925
JGOG 3016, NOVEL, Japanese Gynecologic Oncology Group
OS: by histologic subtypes
Median OS
Serous/ others, dd-TC (n=258) not reached
Serous/ others, c-TC (n=271)
61.2 mos.
Patients surviving (%)
HR 0.76 (0.59-0.97), P = 0.0252
Median OS
Clear-cell/ mucinous, dd-TC (n=54)not reached
Clear-cell/ mucinous, c-TC (n=48) 62.2 mos.
HR 0.92 (0.53-1.61), P = 0.776
Interaction: P = 0.483
Conclusions
• Dose-dense TC improved long-term PFS and OS in
patients with advanced epithelial ovarian cancer.
• Neither dose-dense nor conventional treatment
seemed effective against clear-cell or mucinous
ovarian carcinoma, which suggests that other
treatment strategies are needed.
JGOG 3016, NOVEL, Japanese Gynecologic
Oncology Group
Dd Taxol in perspective
GOG Protocol 172: Schema
Paclitaxel 135 mg/m2/24 hrs IV
Regimen I
(n = 210)
Cisplatin 75 mg/m2 IV
Every 3 wks for 6 cycles
Regimen II
(n = 205)
Paclitaxel 135 mg/m2/24 hrs IV Day 1
Cisplatin 100 mg/m2 IP Day 2
Paclitaxel 60 mg/m2 IP Day 8
Every 3 wks for 6 cycles

Trial conducted among patients with stage III minimal residual < 1.0 cm
Armstrong D, et al. N Eng J Med. 2006;354:34-43.
Dd Taxol in perspective
GOG 172: Ovarian (Optimal III)
1.0
CDDP (IP) Paclitaxel (IP + IV)
(n = 205)
0.8
24 vs 18 mos PFS
PFS
0.6
0.4
CDDP (IV) Paclitaxel (IV) (n =
210)
0.2
0
0
12
24
36
Mos on Study
48
Copyright ©2006 Massachusetts Medical Society. All rights reserved. Armstrong D, et al. N Engl J Med. 2006;354:34-43.
60
Dd Taxol in perspective
GOG 172: Ovarian (Optimal III)
CDDP (IP) Paclitaxel (IP + IV)
(n = 206)
1.0
0.8
OS
0.6
CDDP (IV) Paclitaxel (IV)
(n = 210)
0.4
66 vs 50 mos survival
0.2
0.0
0
12
24
36
Mos on Study
48
Copyright ©2006 Massachusetts Medical Society. All rights reserved. Armstrong D, et al. N Engl J Med. 2006;354:34-43.
60
GOG 218 Study Schema
Carboplatin AUC 6
Previously Untreated
Epithelial Ovarian,
Primary Peritoneal, or
Fallopian Tube Cancer
 Stage III optimal
(macroscopic)
 Stage III suboptimal
 Stage IV
(N = 1,873)
Paclitaxel 175 mg/m2
R
A
N
D
O
M
I
Z
E
PLA
I
(CP + PLA
→ PLA)
Carboplatin AUC 6
1:1:1
Paclitaxel 175 mg/m2
BEV
15 mg/kg
PLA
Carboplatin AUC 6
Stratification Variables
Paclitaxel 175 mg/m2
 GOG PS
 Stage/debulking status
GOG = Gynecologic Oncology Group; AUC = area under curve;
PS = performance status; CP = carboplatin, paclitaxel; PLA = placebo;
BEV = bevacizumab.
Burger et al, 2010.
Arm
II
(CP + BEV
→ PLA)
III
(CP + BEV
 BEV)
BEV 15 mg/kg
Cytotoxic
(6 cycles)
Maintenance
(16 cycles)
15 mos
Investigator-Assessed PFS
Arm I
Arm II
Arm III
CP + PLA → PLA CP + BEV → PLA CP + BEV  BEV
(n = 625)
(n = 625)
(n = 623)
Median FU: 17.4 mos
Proportion PFS (%)
1.0
Patients with event, n (%)
0.9
Median PFS (mos)
0.8
HR (stratified)
(95% CI)
0.7
One-sided log-rank p value
375 (60)
405 (67)
363 (71)
10.4
11.5
13.9
0.864
0.726
(0.759–0.996) (0.627–0.840)
.0218a
0.6
0.5
0.4
0.3
0.2
CP (arm I)
+ BEV (arm II)
0.1
+ BEV → BEV (arm III)
0
0
ap
2
4
6
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Time (mos since randomization)
value boundary = .0116
PFS = progression-free survival; FU = follow-up; HR = hazard ration; CI = confidence interval.
Burger et al, 2010.
< .0001a
ICON7 Schema
1:1
Carboplatin AUC 5/6
Stratification Variables
Paclitaxel 175 mg/m2
 Stage and extent of debulking:
 I–III debulked ≤ 1 cm
R
N = 1,528a
 Stage I–III debulked > 1 cm
 Stage IV and inoperable stage III
Carboplatin AUC 5/6
Paclitaxel 175 mg/m2
 Timing of intended treatment start
≤ 4 vs. > 4 wks after surgery
 GCIG group
BEV 7.5 mg/kg q3wks
18 cycles
 Academic-led, industry-supported trial to investigate use of BEV
and to support licensing
aDecember
2006 to February 2009.
GCIG = Gynecologic Cancer InterGroup.
Kristensen et al, 2011.
ICON7 PFS: Updated
17.4
19.8
Control
Research
Kristensen et al, 2011.
Cross Trial Comparisons Are Not Legal
but….Subopt CRS
Subopt Data
PFS
OS
JGOG
28.2 (whole group)
51.2
GOG 218
14.1
39.7
ICON 7
15.9
36.6
ICON3
17
36
OVAR3
13
31
GOG 111 (P/T)
18
36
Cross Trial Comparisons Are Not Legal
but….Optimal CRS
Optimal Data
PFS
OS
JGOG
28.2
Not yet reached
GOG 172
20.7
66 mos
GOG 158
20.7
48.7 mos
OVAR 3
26
59
182
29/16
68/40
Maintenance Therapy
Abstract # 5000
Abstract # 5001
LBA5000: Vergote
Ph3: Erlotinib Maintenance if FL EOC
LBA5000: Vergote
Ph3: Erlotinib Maintenance if FL EOC
LBA5000: Vergote
Ph3: Erlotinib Maintenance if FL EOC
LBA5000: Vergote
Ph3: Erlotinib Maintenance if FL EOC
LBA5000: Vergote
Ph3: Erlotinib Maintenance if FL EOC
#5001: Oza
Randomized Ph2 Carbo/Tax +/- Oliparib (PARPi)
#5001: Oza
Randomized Ph2 Carbo/Tax +/- Oliparib (PARPi)
#5001: Oza
Randomized Ph2 Carbo/Tax +/- Oliparib (PARPi)
?
#5001: Oza
Randomized Ph2 Carbo/Tax +/- Oliparib (PARPi)
#5001: Oza
Randomized Ph2 Carbo/Tax +/- Oliparib (PARPi)
Platinum Resistant Disease and Recurrent
Disease NOS
Abstract # 5002 AURELIA
LBA5002: Pujarde-Lauraine
Ph3: Chemo +/- Bevacizumab for Platinum-Resistant EOC
LBA5002: Pujarde-Lauraine
Ph3: Chemo +/- Bevacizumab for Platinum-Resistant EOC
LBA5002: Pujarde-Lauraine
Ph3: Chemo +/- Bevacizumab for Platinum-Resistant EOC
LBA5002: Pujarde-Lauraine
Ph3: Chemo +/- Bevacizumab for Platinum-Resistant EOC
LBA5002: Pujarde-Lauraine
Ph3: Chemo +/- Bevacizumab for Platinum-Resistant EOC
Endometrial Cancer
Abstract # 5004
Prospective assessment of survival,
morbidity and cost associated with
lymphadenectomy in endometrial cancer
Abstract 5004
Dowdy et al.
A#5004: LND
• Prospective database over 10 years
• Starting in 2000 – all surgeons stopped
performing LND for patients found to be low
risk on frozen section
• Costs and morbidity data collected
A#5004: LND in Endometrial Cancer
• 1415 patients in database
• 385 met Mayo low risk criteria
(<2cm,G1,superficial invasion)
– 28% of entire cohort
– 34% of endometrioid cancers
• Hyst +/- BSO and:
– LND omitted in 305 (79%)
Outcome
LND no (n=305)
LND yes (n=80)
P
OS
92%
94%
0.72
PFS
98%
96%
0.64
CSS
99%
97%
0.32
• Metastatic LN indentified in a single patient
who underwent LND (1.3%)
– Staged d/t extensive LVSI on frozen section
• 11 recurrences total
– 6 vaginal, 1 peritoneal, 1 liver/peritoneal, 1
inguinal, 1 brain, 1 lung
• No recurrences in pelvic/para-aortic LN
• Cause specific survival 99% with 0.3% +LN
• Cost benefit analysis demonstrated lower cost
associated with no LND. Cost for upstaged low
risk per case $439,990 (laparoscopy)
$327,866 (laparotomy)
• Weaknesses – extrapolation of Mayo frozen
section criteria across departments
Dysregulated Signaling Pathways
Dedes, K. J. et al. (2010) Emerging therapeutic targets in endometrial cancer
Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2010.216
A#5025 Phase II trial of temsirolimus and bevacizumab for initial
recurrence of endometrial cancer Einstein et al
• Eligible patients endometrial cancer patients at time of first
recurrence
• Temsirolimus 25mg IV q week + bevacizumab 10 mg day 1, 8
• First stage accrual N=26
– 73% had prior RT
– 20% PR
– 48% progression free at 6 months
– An additional 5 pts were enrolled with best response of SD
– The combination did not achieve efficacy assumptions and
the study was closed.
Cervix and Vulvar Cancer
(www.jcog.jp/en/)
JGOG 0505 trial
A randomized, phase III trial of
paclitaxel plus carboplatin (TC) versus paclitaxel plus cisplatin
(TP) in stage IVB, persistent or recurrent cervical cancer
Ryo Kitagawa, Noriyuki Katsumata,
Taro Shibata, Toru Nakanishi,
Sadako Nishimura, Kimio Ushijima,
Masashi Takano, Toyomi Satoh,
Hiroyuki Yoshikawa, Toshiharu Kamura (PI)
(www.jcog.jp/en/)
Trial Design
Multicenter (30 specialized institutions), Randomized Phase III Trial
Stage IVB, persistent or
recurrent cervical cancer;
not amenable to curative
surgery / radiotherapy
* Balancing factors:
•Tumors outside of the prior
irradiation field
(yes or no)
•PS 0-1 or 2
•SCC or non-SCC
•Institution
R
A
N
D
O
M
I
Z
E
*
Standard arm: TP
Paclitaxel 135 mg/m2 24h d1
Cisplatin 50 mg/m2 2h d2
every 21 days for 6 cycles
Experimental arm: TC
Paclitaxel 175 mg/m2 3h d1
Carboplatin AUC 5 1h d1
(www.jcog.jp/en/)
Key Eligibility Criteria
I.
Histologically proven uterine cervical cancer
II.
Newly diagnosed stage IVB (including persistent) or recurrent (1st, 2nd)
III. SCC, adenocarcinoma or adenosquamous cell carcinoma
IV. One of the following; not amenable to curable therapy
a) at least one metastatic lesion beyond pelvic cavity
b) at least one localized lesion inside of the prior irradiation field
V.
No bilateral hydronephrosis or serum creatinine <1.2 mg/dL
VI. No more than one prior platinum regimen including chemoradiotherapy
VII. No prior chemotherapy with taxanes
VIII. Age: ≥ 20, ≤ 75
IX. Performance status (ECOG): 0-2
X.
Written informed consent
(www.jcog.jp/en/)
Endpoints
Primary endpoint
•Overall survival (OS)
Secondary endpoints
•Progression-free survival (PFS)
•Response rate (RECIST v1.0)
•Adverse events (CTCAE v3.0)
•The proportion of non-hospitalization periods as a
surrogate for quality of life (QoL)
(www.jcog.jp/en/)
Trial Profile
25253
patients enrolled and randomly assigned
2/21/2006 ～ 11/20/2009
127 assigned to TP
126 assigned to TC
4 ineligible
5 ineligible
25Maximum 6 cycles of treatment
until disease progression or unacceptable toxicity
123 efficacy analysis
125 safety analysis
121 efficacy analysis
126 safety analysis
(www.jcog.jp/en/)
Patient Characteristics
TP (n=127)
Characteristic
TC (n=126)
No. of patients (%)
Median age [ range ]
Performance status (ECOG)
1
2
0
Tumor histology
Adenosquamous
Adenocarcinoma
Squamous
Disease status
1st recurrent
2nd recurrent
IVB or persistent
Tumors outside prior irradiation field
Yes
No
53 yr
[29-74]
53 yr
[22-72]
98
27
2
(77%)
(21%)
(1.6%)
96
27
3
(76%)
(21%)
(2.4%)
106
3
18
(83%)
(2.4%)
(14%)
105
4
17
(83%)
(3.2%)
(13%)
27
82
18
(21%)
(65%)
(14%)
24
85
17
(19%)
(67%)
(13%)
81
46
(64%)
(36%)
76
50
(60%)
(40%)
(www.jcog.jp/en/)
Patient Characteristics
TP (n=127) TC (n=126)
Characteristic
No. of patients (%)
Prior platinum chemotherapy
Yes
54
0
7
Cisplatin
Carboplatin
Others
No
Platinum-free interval
≥ 6, < 12
≥ 12
None
61
< 6 months
(48%)
72
(43%)
(0%)
(6%)
60
2
10
(57%)
(48%)
(2%)
(8%)
66
(52%)
54
(43%)
20
20
21
66
(16%)
(16%)
(17%)
(52%)
13
24
35
54
(10%)
(19%)
(28%)
(43%)
(www.jcog.jp/en/)
Treatment Compliance
TP (n=127)
TC (n=126)
No. of patients (%)
Completed protocol treatment
90
(70.9%)
91
(72.2%)
Discontinued protocol treatment due
to:
Progressive disease
Adverse events (AEs)
Patient refusal not related to AEs
Deaths
Others
19
15
2
0
1
(15.0%)
(11.8%)
(1.6%)
(0%)
(0.8%)
21
12
1
1
0
(16.7%)
(9.5%)
(0.8%)
(0.8%)
(0%)
Dose reduction
37
(29.1%)
31
(24.6%)
97.8% Paclitaxel
98.4% Carboplatin
99.8%
99.9%
Relative dose intensity (median)
Paclitaxel
Cisplatin
(www.jcog.jp/en/)
Hematologic Toxicities
TP
(n=125)
Toxicity (Grade)
TC
(n=126)
Pvalue**
No. of patients (%)
Neutropenia*
Grade3-4
Grade4
106
93
(85.5%)
(75.0%)
Febrile Neutropenia
Grade3-4
Grade4
20
0
(16.0%)
(0%)
9
0
(7.1%)
(0%)
0.0310
Infection
Grade3-4
Grade4
6
0
(4.8%)
(0%)
6
0
(4.8%)
(0%)
1.000
Anemia
RBC transfusions
Grade3-4
39
11
(31.2%)
(8.8%)
56 (44.4%)
23 (8.3%)
Thrombocytopenia
Platelet transfusions
Grade3-4
4
1
(3.2%)
(0.8%)
31 (24.6%)
8 (6.3%)
* n=124 due to missing data
96 (76.2%)
57 (45.2%)
< 0.0001
** Fisher’s exact test
(www.jcog.jp/en/)
Non-Hematologic Toxicities
Toxicity
TP (n=125)
Grade2
TC (n=126)
Grade3-4
Grade2
Grade3-4
Creatinine
7.2%
2.4%
4.8%
0%
Allergy
0.8%
0.8%
3.2%
0%
Fatigue
17.6%
4.0%
15.9%
7.9%
Alopecia
64.8%
-
69.0%
-
Nausea / Vomiting
29.6%
7.2%
19.8%
3.2%
Diarrhea
8.0%
1.6%
4.0%
1.6%
Arthralgia
10.4%
0.8%
20.6%
1.6%
Myalgia
6.4%
0.8%
14.3%
2.4%
Neuropathy (Motor)
3.2%
0.8%
5.6%
2.4%
14.4%
0%
22.2%
4.8%
Neuropathy (Sensory)
(www.jcog.jp/en/)
Overall Survival
1.0
0.9
Arm
N
Events
TP
123
106
TC
121
98
0.8
1-yr
OS
2-yr
OS
3-yr
OS
72.4%
38.8%
18.3%
67.6%
31.5%
21.3%
HR: 0.994 [90% CI: 0.789-1.253 (<1.29)]
non-inferiority one-sided p = 0.032#
0.7
Proportion
Median(m)
[95% CI]
18.3 m
[16.1-22.9]
17.5 m
[14.2-20.3]
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
5.5
6
Years after randomization
#stratified Cox regression with “tumors outside prior irradiation field[yes/no]” as strata
(www.jcog.jp/en/)
Progression-free Survival
1.0
0.9
Arm
N
Events
TP
123
115
TC
121
113
Median(m)
[95% CI]
6.9 m
[5.7-7.9]
6.2 m
[5.5-7.2]
1-yr
PFS
2-yr
PFS
3-yr
PFS
17.2%
7.38%
5.53%
16.5%
8.26%
6.43%
0.8
HR: 1.041 [95% CI: 0.803-1.351]
non-inferiority one-sided p = 0.053#
Proportion
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
5.5
6
Years after randomization
#unstratified
Cox regression
Forest Plots of the HRs for OS
(www.jcog.jp/en/)
(www.jcog.jp/en/)
Effects on OS of Prior Platinum
Without prior platinum (n=117)
With prior platinum (n=127)
HR 1.57 (95% CI：1.06-2.32)
HR 0.69 (95% CI：0.47-1.02)
non-inferiority one sided p=0.838
non-inferiority one sided p=0.0008
(www.jcog.jp/en/)
Summary
• In patients with stage IVB, persistent or recurrent cervical cancer, TC
was not inferior in terms of OS to TP.
– HR 0.99 (multiplicity adjusted 90% CI: 0.79-1.25);
non-inferiority p=0.032
– PFS; HR 1.04 (95％ CI: 0.80-1.35)
– Particularly preferable in patients with platinum-free interval ≥6 mo.
• On the contrary, TP was superior to TC in patients without prior
platinum (mainly cisplatin-based chemoradiotherapy).
• Both TP and TC were well tolerated.
• TP was associated with more frequent febrile neutropenia, creatinine
elevation, and nausea/vomiting.
• TC was associated with more frequent arthralgia, myalgia, and
neuropathy, but the proportion of non-hospitalizations was higher.
Thanks
Targeting PTEN/PI3KCa/MTOR
• mTOR inhibitors: Early Results
Agent
N
RR(%)
CBR (%)
Duration of
SD
(median)
Temsirolimus
19
25
82
8.7
Temsirolimus
27
7
51
3.5
Deferolilmus
45
7
33
<4
Everolimus
35
0
43
4.5