Il carcinoma dell’utero

Gynecologic Oncology Unit Domenica Lorusso

Milan - Italy

IL CARCINOMA DELL’UTERO

PRESENTE E FUTURO DELL’IMMUNO-ONCOLOGIA

Milano 16-17/11/2017

Alexandrov et al. Nature. 2013

DUALISTIC CLASSIFICATION

OF ENDOMETRIAL CANCER

MOLECULAR CHARACTERISTICS OF ENDOMETRIAL CANCER

TGCA, Kandoth et al, Nature 2013

POLE ULTRAMUTATED

(7%) MSI HYPERMUTATED ( 28 %) COPY NUMBER

LOW (39%) COPY NUMBER HIGH (26%)

GENE

ALTERATION 100% mutation in the exonuclease of POLE

MLH1 promoter methylation, few mutation in TP53

and CTNNB1

MSS

Unusual high frequency of CTNNB1

mutations (52%)

Frequent TP 53 mutations (90%) Low PTEN mutation (11%)

MUTATION

RATE Very high

mutation rate High mutation rate Increased PR

expression Amplification of

oncogenes ERB2 and MYC

HISTOTYPE 10% endometrioid About 25% of endometrioid About 50% of

endometrioid 94% serous

12% endometrioid (G1-G2 5%;

G3: 24%)

PROGNOSIS Very good prognosis

(even in G3 tumors) Intermediate prognosis Intermediate

prognosis Bad

prognosis

TCGA Research Network

MUTATIONAL LOAD AND

PROGNOSIS IN ENDOMETRIAL

CANCER

Strickland, K 2016 ASCO Annual Meeting

PD-1 and PD-L1 expression in

endometrial cancer

PEMBROLIZUMAB IN ADVANCED ENDOMETRIAL CANCER:

KEYNOTE 028 STUDY

Phase Ib study

24 pts, 62.4% >2 previous CHT lines

PD-1 inhibitor Pembrolizumab 10 mg/kg q 14 ORR 13.5% (non selected for MSI and POLI) SD: 13.5%

Median Duration of Response 24.6 weeks 6-months PFS 19%

6-months OS 68.8%

Grade 3 AEs: 13.5%

MITO END-3:

Studio multicentrico di fase II, randomizzato di confronto tra Carboplatino/Paclitaxel e Carboplatino/Paclitaxel/Avelumab nel trattamento del carcinoma endometriale

avanzato(FIGO III-IV) o recidivato

DISEGNO DELLO STUDIO

Studio multicentrico di fase II, randomizzato in donne di confronto tra Carboplatino/Paclitaxel vs

Carboplatino/Paclitaxel/Avelumab nel trattamento del carcinoma endometriale avanzato(FIGO III-IV) o recidivato

Campione arruolamento= 120 pts N° centri partecipanti = 20

Durata stimata= 60 mesi

Newly diagnosed or recurrent * EC FIGO stage III-IV

ARM A

Carboplatin AUC5 + Paclitaxel 175mg/mq

q21 days for 6-8cycles

ARM B

Carboplatin AUC5 + Paclitaxel 175mg/mq

q21 days + Avelumab 10mg/kg q21 days for 6-

8cycles

Avelumab 10mg/kg q14 day

until disease progression or

unacceptable toxicity

* prior chemotherapy completed at least 6month prior registration



MITO END 3 protocol

R

1:1

Alexandrov et al. Nature. 2013

Natural History of HPV infection

While persistent infection with high-risk types is considered necessary for the development of cervical cancer, it is not sufficient, as the vast majority of women

with high-risk HPV infection do not develop cancer.

LSIL - Low-grade cervical lesions

HSIL – High- Low-grade cervical lesions

1. Koutsky, Am J Med 1997. 2. Feoli-Fonseca et al. J med Virol 2001. 3. Liaw ET AL. JNCI 1999. 4. Clifford et al. Int Papillomvirus Conference 2004. 5. Globocan 2000. 6.

2. Sawaya et al. NEJM 2003. 7. Mark Schiffman J Natl Cancer Inst Monogr 2003. 8. E.J. Mayeaux. Medscape 2005. 9. CDC Epidemiol Prev Vaccine Prev Dis 2009. 10.

3. Edward E. Partridge. Medscape 2006. 11. Kenneth A Alexander. Medscape 2007.

Normal

HPV infection

Precancer (LSIL)

Cervical Cancer

Infection

Clearance >90%

Progression 10%

Regression 70%

Invasion

Within 1 year

>10 years

Precancer (HSIL)

Progression 30% Regression 30 %

Up to 5 years

Transient infection

Persistent infection

PROPOSED CARCINOGENESIS MODEL

OF HPV INDUCED CERVICAL CANCER

Effectiveness of HPV Vaccination Tested in Several Pubblications

21 HPV prevalence

Cervical disease Genital Wart

*Studio che associa I dati di effectiveness allo stato vaccinale. ^b Dal 1 febbraio 2016il programma di vaccinazione infantile è passato al vaccino bivalente.⁴²

c Meta-analisi dei dati da 20 studi in 9 paesi (Stati Uniti, Australia, Inghilterra, Scozia, Nuova Zelanda, Svezia, Danimarca, Canada, Germania), includendo sia il vaccino quadrivalente che il bivalente.²⁵

Introduction of HPV vaccination

New Zealand Denmark^b Sweden

United States Germany Australia Canada Czech Republic

Belgium

2006 2007 2008

Fairley Sex Transm Infect⁷

2009

Brotherton Lancet²⁷ Donovan Lancet Infect Dis⁹

Oliphant NZMJ¹⁰ Read Sex Transm Infect⁸

2011

Bauer Am J Public Health¹² Leval J Infect Dis¹¹

* Powell Vaccine²⁸

* Tabrizi J Infect Dis³⁶

2012

*Baldur-Felskov Cancer Causes Control³⁰

*Baldur-Felskov JNCI⁴

Chow BMJ²¹

*Crowe BMJ³¹

Deleré BMC Infect Dis³⁹ Harrison PLoS One²²

*Mahmud J Clin Oncol³²

*Tabrizi Lancet Infect Dis³⁸

Liu Sex Transm Infect²³ Wilson Sex Transm Infect²⁰

2014

*Herweijer Int J Cancer³⁵

* Markowitz Pediatrics⁴¹ 2016

Smith J Infect Dis²⁴

*Smith Pediatrics³³

*Drolet^c

Lancet Infect Dis²⁵

*Petráš Vaccine²⁶

*Dominiak-Felden PLoS One⁶

*Dunne J Infect Dis⁴⁰

*Hariri Vaccine³⁴

2015 Ali

BMC Infect Dis¹⁶

Ali BMJ¹⁷ Baandrup Sex Transm Dis¹³

*Blomberg Clin Infect Dis¹⁴

Flagg Am J Public Health¹⁸

*Gertig BMC Med²⁹ *Leval JNCI³

Markowitz J Infect Dis³⁷ Mikolajczyk Sex Transm Dis¹⁵

Nsouli-Maktabi MSMR¹⁹

2013

Curtesy of Merck

Great Worldwide Experience in Use of HPV Vaccines

1. Garland SM, Kjaer SK, Muñoz M, et al. Clin Infect Dis. 2016;63(4):519–527.

2. Ali H, Guy RJ, Wand H, et al. BMC Infect Dis. 2013 Mar 18;13:140.

3. Baandrup L, Blomberg M, Dehlendorff C, et al. 2013;40(2):130–135.

4. Drolet M, Bénard É, Boily MC, et al. Lancet Infect Dis. 2015;15(5):565–580.

5. Baldur-Felskov B, Dehlendorff C, Munk C, et al. J Natl Cancer Inst. 2014;106(3):djt460.

6. World Health Organization. http://www.who.int/vaccine_safety/committee/topics/hpv/GACVS_Statement_HPV_12_Mar_2014.pdf. Accessed June 8, 2016.

7. European Medicines Agency. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-

_Procedural_steps_taken_and_scientific_information_after_authorisation/human/000703/WC500021147.pdf. Accessed June 8, 2016.

8. European Centre for Disease Prevention and Control. http://ecdc.europa.eu/en/publications/Publications/20120905_GUI_HPV_vaccine_update.pdf. Accessed June 8, 2016.

9. Centers for Disease Control and Prevention. http://www.cdc.gov/vaccinesafety/vaccines/hpv-vaccine.html. Accessed June 8, 2016.

More than 205 million doses adminstered since 2006. ¹

Level A evidence suggested the impact of HPV vaccines in reducing HPV –related lesions and their safety ^2–5

Ongoing monitoring ensures safety of HPV vaccines. ^6–9

Curtesy of Merck

High Effectiveness of HPV vaccination ^a on high-grade cervical dysplasia ^1-3

46 ^%

(95% CI; 33%-57%)

Decrease in CIN2/3+

prevalence in women having HPV-V vs non-vaccinate Aged 11-27 yrs.

(3 doses)

73 ^%

(95% CI; 0.10-0.67)

Decrease in CIN2/3+

prevalence in women having HPV-V vs non- vaccinate

Girls born in 1993-1994 ( ≥1 dose)

75 ^%

(95% CI; 0.18-0.35)

Decrease in CIN2/3+

prevalence in women having HPV-V vs non- vaccinate

Aged less than 17 yrs (3 doses).

aVOR (1–incidence rate ratios, odds ratio, o hazard ratio)*100.

CIN2/3+= cervical intraepithelial neoplasia grade 2 o 3 or cancer .

1. Crowe E et al. BMJ. 2014;348:g1458. 2. Baldur-Felskov B et al. J Natl Cancer Inst. 2014;106:djt460. 3.

Herweijer E et al. Int J Cancer. 2016;138:2867–2874

HPV Vaccination Prevents Recurrent Cervical Disease

LLO immuno-mechanism of action

Preclinical and early clinical evidence

PD-L1 expression in Cervical Cancer

CCO Independent Conference Coverage*

of the 2016 ASCO Annual Meeting, June 3-7, 2016

KEYNOTE-028: Pembrolizumab in PD-L1+ Advanced Cervical

Cancer

*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.

This activity is supported by educational grants from Amgen, Ariad, Bayer Healthcare Pharmaceuticals, Celgene Corporation, Genentech, Incyte, Merck, and Taiho Pharmaceuticals.

KEYNOTE-028: Study Design

 Primary endpoints: ORR (RECIST v1.1), safety

 Secondary endpoints: PFS, OS, response duration

Slide credit: clinicaloptions.com Frenel JS, et al. ASCO 2016. Abstract 5515.

* ≥ 1% of tumor or stromal cells with membranous PD-L1 expression by IHC assay using 22C3 antibody.

†

Response assessment every 8 wks for 6 mos, then every 12 wks.

‡

Clinically stable pts could remain on pembrolizumab until PD confirmed by second scan ≥ 4 wks later.

Pts with PD after discontinuing pembrolizumab could receive up to 1 yr additional treatment if no other anticancer therapy received.

PD-L1+* metastatic or unresectable cervical cancer; ECOG PS 0/1;

failure of or ineligibility for standard therapy;

measurable disease (RECIST v1.1)

(N = 24)

CR, PR, or SD: treat for 24 mos or until PD ^‡ or intolerable toxicity Confirmed PD ^‡ or unacceptable toxicity: discontinue pembrolizumab

Pembrolizumab 10 mg/kg IV Q2W

Response

assessment

Slide credit: clinicaloptions.com

KEYNOTE-028 : Baseline Characteristics

Characteristic Pts (N = 24)

Median age, yrs (range) 41 (26-62)

Race, white/Asian/not specified, % 63/4/33

ECOG PS of 1, % 75

Histology, %

 Squamous cell carcinoma

 Adenocarcinoma

96 4 Metastatic stage, %

 MX

 M0

 M1

 Unknown

4 25 63 8

Prior radiotherapy, % 96

Prior lines of therapy for advanced disease,%

 1

 2

 ≥ 3

38 25 38

Prior platinum, % 96

Prior bevacizumab, % 42

Frenel JS, et al. ASCO 2016. Abstract 5515.

KEYNOTE-028: Response

 38% of pts had decreased tumor size

 Median time to response: 8 wks (range: 8-36 wks)

 Median response duration: 26 wks (range: 18-52 wks)

Slide credit: clinicaloptions.com Frenel JS, et al. ASCO 2016. Abstract 5515.

Response by RECIST v1.1 Criteria and Investigator Review*

Pembrolizumab (N = 24)

n % 95% CI

ORR ^† 4 17 5-37

 PR 4 17 5-37

SD 3 13 3-32

PD 16 67 45-84

No assessment ^‡ 1 4 < 1-21

*All pts with evaluable disease who received ≥ 1 dose pembrolizumab.

No CRs.

Pt had no postbaseline

response evaluation.

Longitudinal Change From Baseline in Tumor Size (RECIST v1.1, Investigator Review)

0 8 16 24 32 40 48 56 64 72 -100

-80 -60 -40 -20 0 20 40 60 80 100

-30% decrease +20% increase

Time, weeks

Chan ge From Baseline, %

Data cutoff date: Feb 17, 2016.

Patients who received ≥1 dose of pembrolizumab, had a baseline scan with measurable disease per RECIST v1.1, and a post-baseline assessment are included (n = 21).

Non responder Responder

Who are

these pts?

KEYNOTE-028: Safety

 Median follow-up: 43 wks (range: 6-92 wks)

 No treatment-related grade 4 AEs or mortality

 Treatment-related discontinuations: 1 grade 3 Guillain-Barre syndrome, 1 grade 3 colitis

Slide credit: clinicaloptions.com Frenel JS, et al. ASCO 2016. Abstract 5515.

AE Any Grade Occurring in ≥ 2 Pts, %

Pts (N = 24)

Any 75

Pyrexia 17

Rash 13

Fatigue 8

Asthenia 8

Constipation 8

Diarrhea 8

Dry mouth 8

Anemia 8

Proteinuria 8

Dry skin 8

Pruritus 8

Grade 3 AEs Occurring in ≥ 1 Pt, %

Pts (N = 24)

Any 21

Rash 8

Neutropenia 4

Colitis 4

Guillain-Barre syndrome 4

Proteinuria 4

Ongoing Trials in Cervical cancer

Conclusions

• Immunotherapy appears promising the the treatment of endometrial and cervical cancer

• The best setting (adjuvant, locally advanced or metastatic disease) and the best

combination (chemotherapy, chemoradiation, maintenance) need to be defined

• The ongoing trials will clarify if, who, when,

how