ASCO 2012 Review Gynecologic Cancer Nelson Teng, M.D., Ph.D. Director, Gynecologic Oncology Stanford...

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

• 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 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

FIGO stage, % IIIIIIV

176716

206515

Histologic type, % Serous/ others

Clear-cell/ Mucinous

Residual disease, % > 1cm< 1cm

JGOG3016: Progression-Free Survival

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

dd-TCc-TC

OS: by residual disease

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

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.

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)

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 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

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

15 mos

Paclitaxel 175 mg/m2

Carboplatin AUC 6

Cytotoxic (6 cycles)

Maintenance(16 cycles)

(CP + PLA → PLA)

Carboplatin AUC 6

PLABEV15 mg/kg

II(CP + BEV→ PLA)

BEV 15 mg/kg

Carboplatin AUC 6

Paclitaxel 175 mg/m2 III(CP + 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)

Time (mos since randomization)

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

Carboplatin AUC 5/6

18 cycles

RN = 1,528a

BEV 7.5 mg/kg q3wks

aDecember 2006 to February 2009.GCIG = Gynecologic Cancer InterGroup.Kristensen et al, 2011.

ICON7 PFS: Updated

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

#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

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

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

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

(77%)(21%)

(1.6%)

(76%)(21%)

(2.4%)

Tumor histology SquamousAdenosquamousAdenocarcinoma

(83%)(2.4%)(14%)

(83%)(3.2%)(13%)

Disease status IVB or persistent1st recurrent2nd recurrent

278218

(21%)(65%)(14%)

248517

(19%) (67%) (13%)

Tumors outside prior irradiation fieldYesNo

(64%)(36%)

(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

(48%)(43%)(0%)(6%)

(57%)(48%)(2%)(8%)

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%)

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

(85.5%)(75.0%)

(76.2%) (45.2%) < 0.0001

Febrile Neutropenia Grade3-4Grade4

(16.0%)(0%)

(7.1%)(0%)

0.0310

Infection Grade3-4Grade4

(4.8%)(0%)

Anemia　 RBC transfusions

Grade3-4 3911

(31.2%)(8.8%)

(44.4%) (8.3%)

Thrombocytopenia 　 Platelet transfusions

Grade3-4 41

(3.2%)(0.8%)

(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)

Overall Survival (www.jcog.jp/en/)

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6

Years after randomization

portio

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 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6

Years after randomization

portio

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

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