Tumores Genitourinarios

Cancer de Ovario,

hacia la Individualizacion en el Diagnostico y Tratamiento:

Importancia de la Secuencia Terapeutica

Dra. Ana de Juan Ferré, Hospital Universitario Marques de Valdecilla, Santander

Algunos Ejemplos

Diana Tratamiento Tumor

C-KIT Imatinib GIST

EGFR Gefitinib CPNM

ALK Crizotinib CPNM

BRAF Vemurafenib Melanoma

HER2 Trastuzumab Mama

Buscamos…

El tratamiento correcto en el “momento” adecuado (Secuencia)

basado en factores predictores para el paciente apropiado

Guión

“Del cafe para todas” a la Individualizacion

1. Introducción

2. Clasificación molecular e implicaciones

terapéuticas

3. La importancia de la secuencia

4. Conclusiones

Du Bois A,, et al. Cancer 2009

Supervivencia Libre de Enfermedad Supervivencia Global

La mayoría de las pacientes RECAEN

ILP < 6 m

(17%)*

ILP 6-12 m

(23%)*

ILP > 12 m

(55%)*

Según el Tiempo transcurrido desde el último ciclo

con “platino” hasta la progresion

Sensibilidad a Platino

Durante QT

(5%)*

*Du Bois, et al. Cancer 2009, **Colombo PE, et al. Crit Rev Oncol Hematol 2014

0%** <10%** 30%** >60%**

Tratamientos guiados según el ILP

Monoterapia

DLP

Paclitaxel semanal

Gemcitabina

Topotecan

…

ILP < 6 m ILP 6-12 m ILP > 12 m

Combinación con

platino

Carbo + DLP

Carbo + PAC

Carbo + GEM

Combi con platino

Carbo + DLP

Carbo + GEM

Carbo + PAC

Combi sin platino

Trabectedina + DLP

Trabectedina + DLP

Si alergia a Carbo

Valoración cirugía

Monoterapia

Adición de Bevacizumab

O Mantenimiento con Olaparib (BRCAm)

Opciones Terapéuticas

1. Parmar M et al. Lancet 2003

2. González A. Ann Oncol 2005

3. Pfisterer J. J Clin Oncol 2006

4. Pujade-Lauraine E. J Clin Oncol 2010

Study n Prior

taxane 6-12 m Tratamiento PFS OS Tox

ICON 41 802 43% 25% Carboplatin

Carboplatin-Pac

9 m

12 m

24 m

29 m

Alopecia Neuropatía

GEICO

98012 81 87,2% 42,3% Carboplatin

Carboplatin-Pac

8,4 m

12,2 m

17 m

-

Alopecia Neuropatía

AGO-

EORTC3 356 70% 40% Carboplatin

Carboplatin-Gem

5,8 m

8,6 m

17,3 m

18 m Mielotox.

CALYPSO4 973 99% 35% Carboplatin-Pac

Carboplatin-PLD

9,4 m

11,3 m

SPP Mucositis

Plaquetop.

ILP > 6 m: Combinaciones con platino

Metanálisis. Ann Oncol 2013

Mejor la combinación:

-Paclitaxel previo

-ILP

-Número de líneas recibidas

Antiangiogénicos

Estudio OCEANS

Aghajanian C, et al. J Clin Oncol 2012

Data cutoff date: Sep 17, 2010.

Supervivencia Libre de Progresión INV-assessed

GC + PL (n=242)

GC + BV (n=242)

GC + PL (n=242)

GC + BV (n=242)

PFS by INV

Median PFS, mos 8.4 12.4

Stratified analysis, HR (95% CI) 0.484 (0.388 – 0.605)

Log-rank P value <.0001

PFS by IRC

Median PFS, mos 8.6 12.3

Stratified analysis, HR (95% CI) 0.451 (0.351 – 0.580)

Log-rank P value <.0001

ORR and DOR by INV

ORR, % 57 79

Median DOR, mos 7.4 10.4

HR (95% CI) 0.53 (0.41–0.70)

0.0

0.2

0.4

0.6

0.8

1.0

0 6 12 18 24 30

Months

Pro

po

rtio

n p

rogr

essi

on

-fre

e

CI, confidence interval; DOR, duration of response; INV, investigator-assessed; IRC, independent review committee; ORR, objective response rate

OVA-301: Supervivencia Global Monk BJ, et al. Eur J Cancer 2012

SG

SG ILP > 6 m

SG ILP 6-12 m

Guión

1. Introducción

2. Clasificación molecular e implicaciones

terapéuticas

3. La importancia de la secuencia

4. Conclusiones

Enfermedad Heterogénea: Diferentes Histologías (y alteraciones Moleculares)

Devouassoux-Shisheboran M, et al. Chin J Cancer 2015

Seroso alto grado Endometrioide Seroso bajo grado

Células claras Mucinoso Mucinoso

Mejor Clasificación

Selección

Tratamiento

- Grupo heterogéneo: distinto comportamiento, respuesta a QT… -Permite identificar nuevas dianas y personalizar tratamientos

Tratamientos Dirigidos Banerjee S, et al. Clin Cancer Res 2013

Estudio 19 Mantenimiento con Olaparib tras Respuesta a Platino

Ledermann J, et al. N Engl J Med 2012

Olaparib – Estudio 19: SLP en BRCAm Mantenimiento con Olaparib tras Respuesta a Platino

Ledermann J, et al. Lancet Oncol 2014

Según EMA:

“monotherapy for the maintenance treatment of adult patients with

platinum-sensitive relapsed BRCA-mutated (germline and/or somatic)

high grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer

who are in response (complete response or partial response)

to platinum-based chemotherapy".

Cáncer de Ovario Seroso de bajo Grado

Fase II GOG 239: Selumetinib (inhibidor MEK-1/2)

n= 52 pacientes

Selumetinib 100 mg vo cada 12 horas

58% ≥ 3 líneas de quimioterapia

Respuestas: 1 RC; 7 RP; 34 EE

SLP mediana: 11 meses

Toxicidad: 3 grado 4 (cardiaca, dolor, pulmonar);

46 grado 3 (GI, dermatológica, metabólica)

Análisis exploratorio: respuestas independientes

a las mutaciones RAS/RAF

Farley J, et al. Lancet Oncol 2013

Vía PI3K/AKT: Endometrioides y Células Claras Yap TA, et al. Nat Rev Cancer 2009

PI3K mutación <10% PI3K amplificado 20-40%

AKT mutación <5% AKT amplificado 12-18%

Tothill et al

The Cancer Genome Atlas Research Network. Nature 2011

Subtipos moleculares de CO seroso de alto grado según TCGA

Subtipos moleculares – Implicación pronóstica

Konecny G et al. J Natl Cancer Inst 2014

En los subtipos Proliferativo y

Mesenquimal se mantiene

el beneficio de bevacizumab

Predicción de Respuesta a Bevacizumab

Winterhoff B, et al. ASCO 2014

Guión

1. Introducción

2. Clasificación molecular e implicaciones

terapéuticas

3. La importancia de la secuencia

4. Conclusiones

Cáncer Ovario

Patrón de Recaída Etapa III-IV

1ª Recaída

ILP < 6 m ILP 6-12 m

ILP > 12 m

2ª Recaída

ILP < 6 m

ILP 6-12 m ILP > 12 m

3ª Recaída

ILP < 6 m ILP 6-12 m ILP > 12 m

N Recaída

Secuencia

Cuestiones

1.¿BRCAm?

2.¿Beva previo?

3.¿Respuesta y

toxicidades a

platino?

Quimioterapia Sin Platino: Objetivos

A. Extender el Intervalo Libre de Platino Kavanagh J, et al. J Clin Oncol 1995

Bookman MA. Oncologist 1999

Pignata S, et al. Oncology 2006

Monk BJ, et al. J Clin Oncol 2010

B. Revertir la sensibilidad al platino

C. ¿Por qué es importante la Secuencia?

OVA-301 Supervivencia Global en ILP 6-12 m y Platino Subsiguiente

Poveda A, et al. Cancer Treat Rev 2014

Este análisis genera la hipótesis de que prolongar el tiempo libre de platino

con una combinación sin platino en pacientes con ILP 6-12 meses, puede

aumentar la sensibilidad a platino en el retratamiento

Relapsed ovarian cancer with

progression-free

interval of 6-12 months after

end of last platinum-taxane

therapy

Up to 6 cycles or PD

Follow Up: Until Death

R (1:1

)

Group A: PLD 30 mg/m2 as a 1-hour IV infusion + carboplatin AUC 5

30-60 minutes IV day 1 q 4 weeks

Group B*: PLD 30 mg/m2 IV infusion followed by trabectedin 1.1 mg/m2 3-

hour IV day 1 q 3 weeks

At PD, subsequent therapy at investigator discretion

At PD, subsequent platinum rechallenge is mandatory

unless refused by the patient

Estudio INOVATYON: Diseño

*Dexamethasone premedication

Primary Endpoint

• To evaluate OS in patients with relapsed ovarian cancer progressing within 6-12 months after end of last platinum

Sponsor

• MaNGO (Mario Negri Gynecologic Oncology)

Secondary Endpoints

• To evaluate the time from randomization to subsequent chemotherapy and the OS counted from the administration of subsequent chemotherapy

• To evaluate serologic response of CA-125

• Quality of life

• Safety profile, PFS, ORR

Trabectedina: Mecanismo de Acción

is a marine-derived tetrahydroisoquino- line alkaloid (Fig. 1). Trabectedin is ap-proved in combina-tion with pegylated liposomal doxoru-bicin (PLD) for the treatment of plati-num-sensitive, re-current ovarian can-cer in the EU and has been granted orphan drug status for treatment of advanced, recurrent ovarian cancer in the US and Switzerland[3].

Trabectedin + PLD has been shown to be a ben-eficial treatment for recurrent ovarian cancer after failure of platinum-based chemotherapy [3,4].

Trabectedin acts by interacting with the minor groove of double strand DNA, triggering a cascade of events which interfere with tumor cell prolifera-tion by means of multiple effects on both cancer cells and tumor microenvironment (Fig. 2)[5-7].

In vitro and clinical studies have reported that mu-tations in BRCA repair system with functional nu-cleotide-excision repair (NER) machinery induce greater sensitivity to trabectedin.

TRABECTEDIN IN PATIENTS WITH BRCA mutated AND BRCAness PHENOTYPE ADVANCED OVARIAN CANCER: PHASE II PROSPECTIVE MITO-15 STUDYLorusso D1, Ferrandina G2, Pignata S3, Sorio R4, Pietragalla A2, Mosconi A5, Pisano C3, Mangili G6, Masini C7, Artioli G8, Narducci F9, Di Napoli M3, Rigamonti C10, Raspagliesi F1, Scambia G2

1Fondazione IRCCS National Cancer Institute, Milan; 2Catholic University of Rome; 3National Cancer Institute, Naples; 4CRO Aviano; 5University of Perugia; 6San Raffaele Hospital, Milan; 7University of Modena and Reggio Emilia; 8Mirano Hospital; 9Santissima Trinità Sora Hospital; 10PharmaMar Italy

Figure 2. Trabectedin mechanism of action

Presented at ESMO 2014, Madrid, Spain - 26 Sep - 30 Sep 2014

Figure 1. TrabectedinABSTRACT

Trabectedin is a minor groove DNA binding agent with suggested activity in patients with defective homologous recombinant DNA repair. This pro-spective phase II study was designed to evaluate activity of trabectedin in patients with BRCA mu-tated and BRCAness phenotype AOC.

AOC patients with BRCA mutation or BRCAness phenotype (ie, at least 2 previous responses to platinum therapy), were treated with trabectedin. Patients were stratified as platinum-resistant (<3 previous platinum responses) or platinum-sensitive ( 3 previous platinum responses).

A total of 88 patients were evaluable for response after a median follow up of 6 months. Most patients had serous-papillary histology (86%) and 60% were grade 3. Patients were pretreated with a median of 4 chemotherapy lines and received a median of 6 tra-bectedin cycles with a median cumulative dose of 11.0 mg/m2. In the whole population ORR was 41%, median PFS 5.2 months, while median OS was 14.7 months. In the BRCA mutated subgroup, ORR was 52.2%, disease control rate was 73.9% and 21.7% of patients had progressive disease. The most fre-quent grade 3-4 toxicities were neutropenia, leuco-penia, and increase of liver aminotransferases.

Altogether, data suggest that trabectedin represents a valid treatment option in patients with platinum-sensitive AOC and documented BRCA mutation or BRCAness phenotype after multiple platinum lines.

INTRODUCTION

Patients with advanced ovarian cancer (AOC) have a poor prognosis; however BRCA-like tumors are particularly sensitive to DNA-damaging agents such as platinum agents, because of impaired BRCA-mediated DNA repair mechanisms[1,2].

BRCA1/2 mutations detected in germline can be predictive of somatic mutations, as it increases the probability of complete BRCA dysfunction leading to genetic instability and tumorigenic mutations.

In the whole AOC population germline BRCA mu-tations are present in 15-24% of patients. Trabectedin (Yondelis®, PharmaMar, Madrid, Spain)

CONCLUSIONS

This study shows an increased percentage of BRCA 1/2 mutations in the BRCAness phenotype compared to published data in AOC patients.

BRCAness profile and, in particular, a history of higher number of previous responses to platinum, is associated with increased responses to trabectedin compared to published data (ORR: 37%, n=189)[8].

Clinical response was higher although non-statistically significant in patients carrying germline BRCA 1/2 mutations. Overall sur-vival was significantly higher in patients with mutated versus wild type germline BRCA.

In this clinical study NER polymorphisms did not correlate with responses to trabectedin. These results point towards an improved response to trabectedin in BRCA1/2 mutated patients. The fact that germline mutations

do not necessarily translate into somatic mutations, and that BRCA driven HR is not the only repair mechanism available in tumor cells, can limit the sensitivity of germline BRCA mutations as predictive factors in this study.

6 months

follow-up

100 enrolled

patients

88 evaluable

patients

46 PR

42 PS

RESULTS

2

Treatment

Patients

Stratification≥

Patients ORR CR PR SD DCR PD PFS OS

N N (%) N (%) N (%) N (%) [ORR + N (%) (median, (median,

SD] N (%) months) months)

PR (46) 15 (32.6) 0 15 (32.6) 12 (26.1) 27 (58.7) 19 (41.3) 2.7 9.7

PS (42) 21 (50) 4 (9.5) 17 (40.5) 10 (23.8) 31 (73.8) 11 (26.2) 6* 18.5**

Tot. 88 36 (41) 4 (9.5) 32 (36.4) 22 (25) 58*** (66) 30 (34) 5.2 14.7

CR, complete response; DCR, disease control rate; ORR, overall response rate; OS, overall survival; PD, progres- sive disease; PFS, progression-free survival; PR, partial response. *PR vs PS, p = 0.012; **PR vs PS, p = 0.041; ***PR vs PS, p = 0.088

We hypothesize that trabectedin will be an effective treatment in pa-tients with BRCAness phenotype, and its activity further enhanced in those carring BRCA 1/2 mutations. Efficacy could also be affected by the presence of different NER related germline polymorphisms.

AIM

Evaluate activity of trabectedin in patients with BRCA mutated and BRCAness phenotype AOC.

Assess germline mutations of BRCA 1 and 2. Evaluate activity of trabectedin according to BRCA and single nu-cleotide polymorphisms (SNPs) in DNA repair genes (XPD, XPG and ERCC1) mutations.

PATIENTS AND METHODS

Prospective phase II study (EudraCT n. 2011-001298-17).

Response to trabectedin according to BRCA mutational status

BRCA N ORR DCR PD PFS 3-years

status (CR + PR) (ORR + SD) N (%) (months) OS (%)

N (%) N (%)

WT 43 17 (39.5) 27 (62.8)* 14 (32.5) 4.5 66.7**

Mutated 23 12 (52.2) 17 (73.9) 5 (21.7) 4.5 83.0

*p = 0.51; **p = 0.041

Response to trabecteding according to mutations of SNPs in DNA repair

genes (XPD, XPG and ERCC1)

SNPs CR + PR + SD PD P value

N (%) N (%)

ERCC1 C118T

WT (n = 26) 16 (61.5) 8 (30.7) 0.8

MUT (n = 49) 33 (67.3) 14 (28.5)

ERCC1 C8092

WT (n = 37) 23 (61.3) 12 (32.4) 0.6

MUT (n = 38) 26 (69.3) 10 (26.3)

XPG ASP1104HIS

WT (n = 47) 30 (63.8) 15 (32) 0.6

MUT (n = 28) 19 (67.8) 7 (25)

XPD ASP312ASN

WT (n = 26) 15 (57.6) 9 (34.6) 0.4

MUT (n = 49) 34 (69.4) 13 (26.5)

XPD LYS751GLN

WT (n = 29) 16 (55) 11 (38) 0.2

MUT (n = 46) 33 (72) 11 (24)

Email address: kettalorusso@libero.it

Platinum-resistant Platinum-sensitive

28%

60%

12%

26%

41%33%

WT Mutated Unknown WT Mutated Unknown

Platinum-resistant Platinum-sensitive

28%

60%

12%

26%

41%33%

WT Mutated Unknown WT Mutated Unknown

BRCA mutation data available for 66 pts: 43 wild type, 12 BRCA 1 mutated,

11 BRCA 2 mut

References1. Baumann KH, Wagner U, du Bois A. The changing landscape of therapeutic strategies

for recurrent ovarian cancer. Future Oncol 2012;8:1135-47.

2. Rigakos G, Razis E. BRCAness: finding the Achilles heel in ovarian cancer. Oncologist

2012;17(7):956-62.

3. Carter NJ, Keam SJ. Trabectedin: a review of its use in soft tissue sarcoma and ovarian

cancer. Drugs 2010;70(3):355-76.

4. Del Campo JM, Muñoz-Couselo E, Diaz de Corcuera I, Oaknin A. Trabectedin

combined with liposomal doxorubicin in women with relapsed ovarian cancer. Expert Rev Anticancer Ther

2010;10(6):795-805.

5. D’Incalci M, Galmarini CM. A review of trabectedin (ET-743): a unique mechanism of action. Mol Cancer Ther

2010;9(8):2157-63.

6. Germano G, Frapolli R, Matteo S, et al. Antitumor and anti-inflammatory effects of trabectedin on human myxoid

liposarcoma cells. Cancer Res 2010;70:2235-44.

7. Allavena P, Signorelli M, Chieppa M, et al. Anti-inflammatory properties of the novel antitumor agent Yondelis

(trabectedin): inhibition of macrophage differentiation and cytokine production. Cancer Res 2005;65(7):2964-71.

8. Del Campo JM, Sessa C, Krasner CN, et al. Trabectedin as single agent in relapsed advanced ovarian cancer:

results from a retrospective pooled analysis of three phase II trials. Med Oncol 2013;30:435-45.

ESMO_Poster.indd 1 23/09/14 16.03

BRCA

NER

Sequence Effect Hypothesis: May Trabectedin Resensitize Ovarian Cells to Next Platinum?

NER-deficient cell – sensitive to

platinum, reduced sensitivity to

trabectedin

Solid tumor NER-proficient cell – sensitive to

trabectedin, reduced sensitivity to platinum

26

Treatment with

platinum Trabectedin

Tumor at relapse Tumor after platinum Increased sensitivity to Pt

PFS and OS by BRCA1 Genotypes in Treatment Groups

BRCA1mut may predict improved outcome to T + PLD treatment

Monk B, et al. Ann Oncol. 2015

OVA 301: Trabectedina en pacientes con BRCA mutado

BRCA1-mutated patients

treated with T + PLD showed

longer PFS and OS

compared to PLD.

Guión

1. Introducción

2. Clasificación molecular e implicaciones

terapéuticas

3. La importancia de la secuencia

4. Conclusiones

La Clasificación y el Tratamiento del CO está cambiando

Mejor Clasificación Mejor Selección Biomarcadores Tratamiento dirigido

Conclusiones

1. Enfermedad Heterogénea

1. Las opciones terapéuticas dependen del tipo

tumoral, de las características del paciente y de los

tratamientos previos (respuestas y toxicidades)

Identificación de factores predictores/biomarcadores

2. La secuencia Trabectedina-DLP Platino permite

incrementar el intervalo libre de platino y

posiblemente revertir resistencias