ASCO 2012 ReviewGynecologic Cancer
Nelson Teng, M.D., Ph.D.Director, Gynecologic Oncology
Stanford University School of Medicine
DisclosuresI do not have any conflict of
interest to report
Acknowledgement
Dr. Jakob Dupont, M.D.
Dr. Kathleen Moore, M.D.
Update from ASCO 2012
− Ovarian Cancer
− Endometrial Cancer
− Cervix / Vulva
− Miscellaneous
Up Front Ovarian Treatment
Abstract # 5003
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.
JGOG 3016, NOVEL, Japanese Gynecologic Oncology Group
.
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, NOVEL, Japanese Gynecologic Oncology Group
• Ovarian Epithelial, Primary Peritoneal, or Fallopian Tube cancer
• FIGO Stage II-IV• Stratfied: residual
disease, stage, and histology
Paclitaxel 180mg/m2, day 1 Carboplatin AUC 6.0, day 1 every 21 days for 6-9 cycles
Paclitaxel 180mg/m2, day 1 Carboplatin AUC 6.0, day 1 every 21 days for 6-9 cycles
Paclitaxel 80mg/m2, days 1,8,15 Carboplatin AUC 6.0, day 1 every 21 days for 6-9 cycles
Paclitaxel 80mg/m2, days 1,8,15 Carboplatin AUC 6.0, day 1 every 21 days for 6-9 cycles
RANDOMIZE
• Primary endpoint: PFS• Secondary endpoint: OS• Accrual: 637 pts (2003 Apr.– 2005 Dec.)
JGOG 3016
Katsumata, Lancet 2009; 374: 1331–38
Dose-dense weekly TC (dd-TC)
Conventional TC (c-TC)
Characteristics of the patientsCharacteristic
Conventional TC
(n = 319)
Dose-dense TC
(n = 312)
Median age, (range) 57 (25-84) 57 (25-87)
Disease, % OvarianFallopian tubePrimary peritoneal
8768
83412
FIGO stage, % IIIIIIV
176716
206515
Histologic type, % Serous/ others
Clear-cell/ Mucinous
8515
8317
Residual disease, % > 1cm< 1cm
5545
5446
JGOG 3016, NOVEL, Japanese Gynecologic Oncology Group
JGOG3016: Progression-Free Survival
JGOG 3016, NOVEL, Japanese Gynecologic Oncology Group
Treatment n Event, n (%) Median PFS P value HR 95%CI
dd-TC 312 197 (63) 28.2 mos.0.0037 0.76 0.62-0.91
c-TC 319 229 (72) 17.5 mos.
dd-TCc-TC
median follow-up period: 6.4 years
Treatment n Deaths, n (%) Median OS 5-yr
survivalP
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%
JGOG3016: Overall Survival
JGOG 3016, NOVEL, Japanese Gynecologic Oncology Group
dd-TCc-TC
Patie
nts
sur
vivi
ng (%
)
OS: by residual disease
JGOG 3016, NOVEL, Japanese Gynecologic Oncology Group
Patie
nts
sur
vivi
ng (%
)
Interaction: P = 0.925
HR 0.75 (0.57-0.97), P = 0.0267
Median OS> 1cm, dd-TC (n=174) 51.2 mos. > 1cm, c-TC (n=168) 33.5 mos.
HR 0.76 (0.49-1.19), P = 0.234
< 1cm, dd-TC (n=144) not reached< 1cm, c-TC (n=145) not reached
Median OS
OS: by histologic subtypes
JGOG 3016, NOVEL, Japanese Gynecologic Oncology Group
Patie
nts
sur
vivi
ng (%
)
Interaction: P = 0.483
Clear-cell/ mucinous, dd-TC (n=54) not reachedClear-cell/ mucinous, c-TC (n=48) 62.2 mos.HR 0.92 (0.53-1.61), P = 0.776
Median OS
HR 0.76 (0.59-0.97), P = 0.0252
Serous/ others, dd-TC (n=258) not reached
Serous/ others, c-TC (n=271) 61.2 mos.
Median OS
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 perspectiveGOG Protocol 172: Schema
Trial conducted among patients with stage III minimal residual < 1.0 cm
Armstrong D, et al. N Eng J Med. 2006;354:34-43.
Regimen I(n = 210)
Paclitaxel 135 mg/m2/24 hrs IV
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
Dd Taxol in perspectiveGOG 172: Ovarian (Optimal III)
Copyright ©2006 Massachusetts Medical Society. All rights reserved. Armstrong D, et al. N Engl J Med. 2006;354:34-43.
0
0.2
0.4
0.6
0.8
1.0
PFS
0 12 24 36 48 60Mos on Study
CDDP (IV) Paclitaxel (IV) (n = 210)
CDDP (IP) Paclitaxel (IP + IV)(n = 205)
24 vs 18 mos PFS
Dd Taxol in perspectiveGOG 172: Ovarian (Optimal III)
0.0
0.2
0.4
0.6
0.8
1.0
OS
0 12 24 36 48 60Mos on Study
CDDP (IV) Paclitaxel (IV)(n = 210)
CDDP (IP) Paclitaxel (IP + IV)(n = 206)
66 vs 50 mos survival
Copyright ©2006 Massachusetts Medical Society. All rights reserved. Armstrong D, et al. N Engl J Med. 2006;354:34-43.
GOG 218 Study Schema
Previously Untreated Epithelial Ovarian,
Primary Peritoneal, or Fallopian Tube Cancer
Stage III optimal (macroscopic) Stage III suboptimal Stage IV
(N = 1,873)
Stratification Variables GOG PS Stage/debulking status
RANDOMIZ E
1:1:1
15 mos
Paclitaxel 175 mg/m2
Carboplatin AUC 6
PLA
IArm
Cytotoxic (6 cycles)
Maintenance(16 cycles)
(CP + PLA → PLA)
Carboplatin AUC 6
Paclitaxel 175 mg/m2
PLABEV15 mg/kg
II(CP + BEV→ PLA)
BEV 15 mg/kg
Carboplatin AUC 6
Paclitaxel 175 mg/m2 III(CP + BEV
BEV)
GOG = Gynecologic Oncology Group; AUC = area under curve; PS = performance status; CP = carboplatin, paclitaxel; PLA = placebo; BEV = bevacizumab.Burger et al, 2010.
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
CP (arm I)
Arm I CP + PLA → PLA
(n = 625)
Arm IICP + BEV → PLA
(n = 625)
Arm IIICP + BEV BEV
(n = 623)
Patients with event, n (%) 375 (60) 405 (67) 363 (71)
Median PFS (mos) 10.4 11.5 13.9
HR (stratified)(95% CI)
0.864(0.759–0.996)
0.726 (0.627–0.840)
One-sided log-rank p value .0218a < .0001a
Investigator-Assessed PFS
+ BEV (arm II)+ BEV → BEV (arm III)
Prop
ortio
n PF
S (%
)
Time (mos since randomization)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Median FU: 17.4 mos
ap value boundary = .0116PFS = progression-free survival; FU = follow-up; HR = hazard ration; CI = confidence interval.Burger et al, 2010.
Stratification Variables Stage and extent of debulking:
I–III debulked ≤ 1 cm Stage I–III debulked > 1 cm Stage IV and inoperable stage III
Timing of intended treatment start≤ 4 vs. > 4 wks after surgery
GCIG group
ICON7 Schema
Academic-led, industry-supported trial to investigate use of BEV and to support licensing
Paclitaxel 175 mg/m2
Carboplatin AUC 5/6
Carboplatin AUC 5/6
Paclitaxel 175 mg/m2
18 cycles
RN = 1,528a
BEV 7.5 mg/kg q3wks
1:1
aDecember 2006 to February 2009.GCIG = Gynecologic Cancer InterGroup.Kristensen et al, 2011.
ICON7 PFS: Updated
17.4
19.8Control
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 # 5000Abstract # 5001
LBA5000: VergotePh3: Erlotinib Maintenance if FL EOC
LBA5000: VergotePh3: Erlotinib Maintenance if FL EOC
LBA5000: VergotePh3: Erlotinib Maintenance if FL EOC
LBA5000: VergotePh3: Erlotinib Maintenance if FL EOC
LBA5000: VergotePh3: Erlotinib Maintenance if FL EOC
#5001: OzaRandomized Ph2 Carbo/Tax +/- Oliparib (PARPi)
#5001: OzaRandomized Ph2 Carbo/Tax +/- Oliparib (PARPi)
?
#5001: OzaRandomized Ph2 Carbo/Tax +/- Oliparib (PARPi)
#5001: OzaRandomized Ph2 Carbo/Tax +/- Oliparib (PARPi)
#5001: OzaRandomized Ph2 Carbo/Tax +/- Oliparib (PARPi)
Platinum Resistant Disease and Recurrent Disease NOS
Abstract # 5002 AURELIA
LBA5002: Pujarde-LaurainePh3: Chemo +/- Bevacizumab for Platinum-Resistant EOC
LBA5002: Pujarde-LaurainePh3: Chemo +/- Bevacizumab for Platinum-Resistant EOC
LBA5002: Pujarde-LaurainePh3: Chemo +/- Bevacizumab for Platinum-Resistant EOC
LBA5002: Pujarde-LaurainePh3: Chemo +/- Bevacizumab for Platinum-Resistant EOC
LBA5002: Pujarde-LaurainePh3: Chemo +/- Bevacizumab for Platinum-Resistant EOC
Endometrial Cancer
Abstract # 5004
Prospective assessment of survival, morbidity and cost associated with lymphadenectomy in endometrial cancer
Abstract 5004Dowdy 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
Dedes, K. J. et al. (2010) Emerging therapeutic targets in endometrial cancer Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2010.216
Dysregulated Signaling Pathways
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
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(www.jcog.jp/en/)
Multicenter (30 specialized institutions), Randomized Phase III Trial
Stage IVB, persistent or recurrent cervical cancer; not amenable to curative surgery / radiotherapy
RANDOMIZE*
Standard arm: TPPaclitaxel 135 mg/m2 24h d1Cisplatin 50 mg/m2 2h d2
every 21 days for 6 cycles
Experimental arm: TCPaclitaxel 175 mg/m2 3h d1Carboplatin AUC 5 1h d1
* Balancing factors: •Tumors outside of the prior irradiation field
(yes or no)•PS 0-1 or 2•SCC or non-SCC•Institution
Key Eligibility CriteriaI. 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 therapya) 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(www.jcog.jp/en/)
25253 patients enrolled and randomly
assigned
25253 patients enrolled and randomly
assigned
127 assigned to
TP
127 assigned to
TP
126 assigned to
TC
126 assigned to
TC4 ineligible 5 ineligible
25Maximum 6 cycles of treatment until disease progression or unacceptable
toxicity
25Maximum 6 cycles of treatment until disease progression or unacceptable
toxicity123 efficacy
analysis 125 safety
analysis
123 efficacy analysis
125 safety analysis
121 efficacy analysis
126 safety analysis
121 efficacy analysis
126 safety analysis
2/21/2006 ~ 11/20/2009
Patient Characteristics(www.jcog.jp/en/)
Characteristic TP (n=127) TC (n=126)
No. of patients (%)
Median age [ range ] 53 yr [29-74] 53 yr [22-72]
Performance status (ECOG) 012
9827
2
(77%)(21%)
(1.6%)
96 27
3
(76%)(21%)
(2.4%)
Tumor histology SquamousAdenosquamousAdenocarcinoma
1063
18
(83%)(2.4%)(14%)
1054
17
(83%)(3.2%)(13%)
Disease status IVB or persistent1st recurrent2nd recurrent
278218
(21%)(65%)(14%)
248517
(19%) (67%) (13%)
Tumors outside prior irradiation fieldYesNo
8146
(64%)(36%)
7650
(60%)(40%)
Patient Characteristics(www.jcog.jp/en/)
Characteristic TP (n=127) TC (n=126)No. of patients (%)
Prior platinum chemotherapy Yes Cisplatin Carboplatin OthersNo
6154
07
66
(48%)(43%)(0%)(6%)
(52%)
7260
210
54
(57%)(48%)(2%)(8%)
(43%)
Platinum-free interval < 6 months≥ 6, < 12≥ 12 None
20202166
(16%)(16%) (17%) (52%)
13243554
(10%)(19%) (28%) (43%)
Treatment Compliance(www.jcog.jp/en/)
TP (n=127) TC (n=126)No. of patients (%)
Completed protocol treatment 90 (70.9%) 91 (72.2%)
Discontinued protocol treatment due to:Progressive diseaseAdverse events (AEs) Patient refusal not related to AEsDeathsOthers
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%)
Relative dose intensity (median) PaclitaxelCisplatin
97.8%98.4%
PaclitaxelCarboplatin
99.8%99.9%
Hematologic Toxicities(www.jcog.jp/en/)
Toxicity (Grade) TP (n=125)
TC (n=126)
P-value**
No. of patients (%)
Neutropenia* Grade3-4Grade4
10693
(85.5%)(75.0%)
96 57
(76.2%) (45.2%) < 0.0001
Febrile Neutropenia Grade3-4Grade4
200
(16.0%)(0%)
90
(7.1%)(0%)
0.0310
Infection Grade3-4Grade4
60
(4.8%)(0%)
60
(4.8%)(0%)
1.000
Anemia RBC transfusions
Grade3-4 3911
(31.2%)(8.8%)
5623
(44.4%) (8.3%)
Thrombocytopenia Platelet transfusions
Grade3-4 41
(3.2%)(0.8%)
318
(24.6%)(6.3%)
** Fisher’s exact test* n=124 due to missing data
Non-Hematologic Toxicities(www.jcog.jp/en/)
Toxicity TP (n=125) TC (n=126)Grade2 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
Myalgia
Neuropathy (Motor)
Neuropathy (Sensory)
10.4%
6.4%
3.2%
14.4%
0.8%
0.8%
0.8%
0%
20.6%
14.3%
5.6%
22.2%
1.6%
2.4%
2.4%
4.8%
Overall Survival (www.jcog.jp/en/)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6
Years after randomization
Pro
portio
n
Arm N Events Median(m)[95% CI]
1-yrOS
2-yrOS
3-yrOS
TP 123 106 18.3 m[16.1-22.9] 72.4% 38.8% 18.3%
TC 121 98 17.5 m[14.2-20.3] 67.6% 31.5% 21.3%
#stratified Cox regression with “tumors outside prior irradiation field[yes/no]” as strata
HR: 0.994 [90% CI: 0.789-1.253 (<1.29)]non-inferiority one-sided p = 0.032#
Progression-free Survival(www.jcog.jp/en/)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6
Years after randomization
Pro
portio
n
Arm N Events Median(m)[95% CI]
1-yrPFS
2-yrPFS
3-yrPFS
TP 123 115 6.9 m[5.7-7.9] 17.2% 7.38% 5.53%
TC 121 113 6.2 m[5.5-7.2] 16.5% 8.26% 6.43%
#unstratified Cox regression
HR: 1.041 [95% CI: 0.803-1.351]non-inferiority one-sided p = 0.053#
Forest Plots of the HRs for OS (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)non-inferiority one sided p=0.838
HR 0.69 (95% CI : 0.47-1.02)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.
(www.jcog.jp/en/)
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