Focus su algoritmi terapeutici

Dipartimento di Scienze Ginecologico-Ostetriche e Scienze

Urologiche Università di Roma “Sapienza”

Dott.ssa Federica Tomao

Algoritmi terapeutici???

Si può perdere di vista l’individualità

del caso

Riduzione delle chance terapeutiche

Ci consentono di standardizzare il

Trattamento con l’ausilio anche degli enti

regolatori (registrazione dei farmaci….)

“Advanced Ovarian Cancer?

a chronic disease with multiple relapses”…….

Giornelli GH et al. Springer Plus 2016

Ovarian Cancer Targeted

Therapy Landscape Overview

In questo scenario le strategie terapeutiche di mantenimento

rappresentano la base per garantire il più lungo periodo libero dai

sintomi legati alla malattia e dalle tossicità legate ai trattamenti.

Aghajanian C et al. JCO 2012; Coleman RL et al. Gynecol Oncol 2015; Ledermann J et al. Lanc Oncol

2014; Ledermann J et al. Lancet. 2016; Marth C et al. EJC. 2017; Monk BJ et al. Lancet Oncol. 2014;

Pujade-Lauraine E et al. J JCO 2014; Mirza MR et al. NEJM 2016; Coleman RL et al. Lancet 2017

L’algoritmo terapeutico alla diagnosi?

La diffusione di malattia e le condizioni della paziente rendono permissiva una

chirurgia citoriduttiva ottimale?

SI NO

LPS, LPTM esplorativa

Fattibilità di un debulking ottimale?

SI NO

PDS

NACT x 3 cicli

Chirurgia citoriduttiva di intervallo*

Chemioterapia di I linea

Valutazione clinica, radiologica e anestesiologica:

*se RC 0 RP o SD

Ulteriori 3 cicli di CT

Algoritmo di trattamento del carcinoma ovarico alla diagnosi

La diffusione di malattia e le condizioni della paziente rendono permissiva una

chirurgia citoriduttiva ottimale?

SI NO

LPS, LPTM esplorativa

Fattibilità di un debulking ottimale?

SI NO

PDS

CBDCA + PTX +/- BEV x 3 cicli

Chirurgia citoriduttiva di intervallo*

CBDCA + PTX +/- BEV x 6 cicli^

(+ BEV in mantenimento)

Valutazione clinica, radiologica e anestesiologica:

^in assenza di controindicazioni specifiche la terapia con BEV è raccomandata

*se RC 0 RP o SD

CBDCA + PTX +/- BEV x 3 cicli^

(+ BEV in mantenimento)

ASPETTANDO I RISULTATI DELLO STUDIO SOLO-1

La Recidiva

Riosposta ai derivati del Platino

Time to recurrenceNuova risposta al

Platino

Platinum-sensibile (PS) >12 months 30-60%

Parzialmente platino-sensibile (PPS) 6-12 months 25-30%

Platino-resistente (PR) < 6 months < 10%

Malattia refrattaria (PD) 0-1 months N/A

III

III-IV

The historical classification of recurrent ovarian cancer according to PFI

has recently been criticized for various reasons…

Platinum sensitivity definition has been defined arbitrarily, based on observational

studies, and a probabilistic partition with the likelihood of response being a

continuous variable.

It can be heavily influenced by the timing of follow-up visits, and the use of CA125

as a trigger leading to further imaging examinations, modalities which have

significantly changed over the time.

Furthermore, improvements in surgical cytoreduction technique and the introduction

of biological agents as maintenance therapy could have modified the natural course

of disease.

Finally, the platinum sensitivity definition only applies to chemotherapy, since no

similar relationship has been demonstrated for other agents currently used in the

clinical practice.Tomao F et al., Cancer 2017

Definizione di PFI

Trials in recurrent ovarian cancer should incorporate

-Treatment-free interval (TFI)

TFIp (platinum)

TFInp (non-platinum), TFIb (biological agent to be specified)

-Histological type

-BRCA status (gBRCA, and others including somatic BRCA and HRDa to be

considered as data emerge)

-Type of prior therapy (anti-angiogenic agents, PARP inhibitors, chemotherapy and

others)

-Number of prior lines of chemotherapy (trials should not be limited to second or

third line)

-Presence or absence of symptoms and type (e.g. ascites, abdominal symptoms, pain,

performance status)

-Other factors to be considered: tumour volume and previous surgical outcome 2.

Separate trials are needed for populations with unmet needs:

Medically compromised and/or elderly patients

Multiple lines of prior chemotherapy Wilson MK et al., Ann Oncol 2017

Histotype

Symptoms

Urgent

response

needed?

Treatment

of relapse:

much

more than

PFI!!!

Patient

preference and

expectation

BRCA statusToxicities

N° prior lines

Previous

agents used:

PARP i

Previous

agents used:

BevacizumabFeasibility of

Surgery

Pianificando il trattamento della recidiva….

0-3 Prog 0-3 Non-PD 3-12 Mos 12-18 Mos 18+ Mos

PFS, days 90 176 174 275 339

OS, days 217 375 375 657 957

Response, % 9 24 35 52 62

Day

s

Percen

tage

1000

900

800

700

600

500

400

300

200

100

0

100

90

80

70

60

50

40

30

20

10

0

Pujade-Lauraine E, et al. ASCO 2002

Malattia platino sensibile

courtesy of Vergote I–ESMO 2017-

Il ruolo della chirurgia secondaria

-lo studio Desktop III-

With the highest benefit in patients with RT=0

…and what about BRCAmut patients?

Authors Pts (N°) Regimen Results

PFS (months) OS (months)

Bolis 190 - Carboplatin 300mg/m2q28

vs

-Carboplatin 300mg/m2+Epidoxorubicin

120mg/m2q28

16 vs 20 NS NA

Parmar 802

203 (PPS)

- Carboplatin (AUC-5) or Cisplatin 75mg/m2q21

vs

- Carboplatin (AUC-5) or Cisplatin 50mg/m2 +

Paclitaxel 175mg/m2 (ICON4) or

185mg/m2(AGO-OVAR-2)q21

9 vs 12

p=.00014

24 vs 29 p=.02

Gonzalez-

Martin

81

49 (PPS)

- Carboplatin (AUC-5)q21

vs

- Carboplatin (AUC-5) + Paclitaxel

175mg/m2q21

8.4 vs 12.3 p =.021 18.1 vs NA p=.0021

Pfisterer 356

142 (PPS)

-Carboplatin (AUC-5)q21

vs

- Carboplatin (AUC-4) + Gemcitabine

1000mg/m2 d1,d8q21

5.8 vs 8.6 p=.0031 NS

Alberts 61

26 (PPS)

- Carboplatin (AUC-5)q28

vs

- Carboplatin (AUC-5) + PLD 30mg/m2q28

8 vs 12 p=·0004 18 vs 26 p = .02

Tomao F et al., Cancer 2017

Schemi a base di platino testati nella malattia platino sensibile

Authors Pts (N°) Regimen Results

PFS (months) OS (months)

Pujade-

Lauraine

976 - Carboplatin (AUC-5) + Paclitaxel

175mg/m2q21

vs

- Carboplatin (AUC-5) + PLD 30mg/m2q28

PS

9.4 vs 11.3 (p=.005)

PPS (334 pts)

8.8 vs 9.4 (p=.004)

NS

NS

Aghajanian 484 - Carboplatin (AUC-4) + Gemcitabine

1000mg/m2d1,d8 + placebo q21 for 6-10

cyclesPlacebo until progression

vs

- Carboplatin (AUC-4) + Gemcitabine

1000mg/m2d1,d8 + Bevacizumab 15mg/kg q21

for 6-10 cyclesBevacizumab until progression

PS

8.4 vs 12.4 (p=.0001)

PPS

7.4 vs 12.5 (p=NA)

NS^

NS

Tomao F et al., Cancer 2017

Platinum-Based Strategies in

Recurrent, Platinum-Sensitive Disease

Interval since last chemotherapy,

months

Carboplatin + PLD

(466 pts)

Carboplatin + PTX

(507 pts)

Median 15.2 15.0

6-12 161 35 183 36.1

>12 305 65 324 63.9

Carboplatin + Paclitaxel vs Carboplatin +

PLD (the CALYPSO trial) -976 pts-

Experimental arm: PLD (30 mg/m2) p1q28 and carboplatin (AUC5) p1q28

Multivariate analysis according to baseline

characteristics

Therap

y free

interval

No HR 95% CI P

6-12 342 1.00 0.48 to

0.65

<.001

>12 617 0.56

Pujade-Lauraine E et al., JCO 2010

9.4 vs 11.3 (p=.005) in

PS

8.4 vs 12.4 (p=.0001)

in PPS

Carboplatin + Gemcitabine with or without

Bevacizumab (the OCEANS study) -976 pts-

Time to recurrence since last platinum

based therapy

Beva (242) Beva (242)

6-12 (months) 102 42.1 100 41.3

>12 (months) 140 57.9 142 58.7

The PARP-Inhibitors ERA

0

200

400

600

800

1000

1977-1987 1987-1997 1997-2007 2007-2017

N° of publication on Parp-Inhibitors

N° of publication

(PUBMED)

82% risk reduction of progression

0Time from randomization (months)

0

1.0

Pro

po

rtio

n o

f p

ati

ents

pro

gre

ssio

n-f

ree

3 6 9 12 15

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

Olaparib BRCAm

Placebo BRCAm

Ledermann J et al,

Lancet Oncol, 2012

Ledermann J et al,

Lancet Oncol, 2014

HR=0.18

95% CI (0.11, 0.31); P<0.00001

Olaparib: dallo Studio 19 al SOLO 2

100

90

80

70

60

50

40

30

20

10

0

Pro

gre

ssio

n-f

ree

surv

iva

l (%

)

Months since randomization

0 3 6 9 12 15 18 21 24 27 30 33

Olaparib

Placebo

30.25.5 19.1

HR=0.25

95% CI: 0.18-0.35, p<0.0001

HR=0.30

95% CI: 0.22-0.41, p<0.0001

PFS by investigator and central assessments in BRCA mut population

11.2 months vs 4.3 months

Phase III study (2:1)

Objective: efficacy of maintenance treatment with Niraparib

after platinum-based therapy

553 Pts affected by platinum-sensitive disease

PFS: 21.0 vs 5.5 months PFS: 12.9 vs 3.8 months PFS: 9.3 vs 3.9 months

P<0.001 P<0.001 P<0.001

Mirza MR et al., New Eng J Med, 2016

Niraparib

Study HR

NOVA 0.27

Study 19 0.18

Oza 0.21

Solo2 0.25

Study HR

Study 19 0.62

Oza 1.28

Solo2 0.80

Study HR

NOVA 0.45

Study 19 0.54

Oza 0.77

Study HR

Study 19 0.83

P<0.00001

P=0.03

P=0.0006

P=0.38

BRCA mut

wt

PFS

PFS

OS

OS

Hematologic adverse events

(Study 19 vs SOLO 2)

All grades Grade ≥3

Olaparib

(n=195)

Placebo

(n=99)

Olaparib

(n=195)

Placebo

(n=99)

Anemia* 85 (43.6) 8 (8.1) 38 (19.5) 2 (2.0)

Neutropenia* 38 (19.5) 6 (6.1) 10 (5.1) 4 (4.0)

Thrombocyto

penia*27 (13.8) 3 (3.0) 2 (1.0) 1 (1.0)

MDS/AML: 4 cases in olaparib group

(2.1%), including one case of CMML; 4 cases

in placebo group (4.0%)

All grades Grade ≥3

Olaparib

(n=136)

Placebo

(n=128)

Olaparib

(n=136)

Placebo

(n=128)

Anaemia29

(21%)7 (5%) 7 (5%)* 1 (<1%)

Neutropenia 7 (5%) 5 (4%) 5 (4%)† 1 (<1%)

Adverse events (any grade) in ≥10% of patient

overall and grade ≥3 events in ≥3% of patients in

either treatment group.

* 1 patient with a grade 4 adverse event.

† 3 patients with a grade 4 adverse event.

Study 19

SOLO 2

Grade III-IV advers events:

Trombocytopenia (in 33.8%),

Anemia (in 25.3%),

Neutropenia (in 19.6%)

Whereas in NOVA study…

L’ algoritmo terapeutico del carcinoma ovarico recidivante?

SI NO

Mutazione patogenetica di BRCA1-2

Chemioterapia con CBDCA associato a:

PTX

PLD

Gemcitabina

Chemioterapia con CBDCA associato a:

PTX

PLD

Gemcitabina

RC, RP o SD

SI NO

Olaparib Chemioterapia di III linea

RC, RP o SD

SI NO

Niraparib Chemioterapia di III linea

Malattia platino-sensibile con intervallo

libero ≥ 12 mesi dopo BEV in I linea

L’algoritmo terapeutico del carcinoma ovarico recidivante?

SI NO

Mutazione patogenetica di BRCA1-2

Chemioterapia con CBDCA associato a:

PTX

PLD

Gemcitabina

Chemioterapia con CBDCA associato a:

Gem + BEV (con BEV in mantenimento)

PTX

PLD

Gemcitabina

RC, RP o SD

SI NO

Olaparib Chemioterapia di III linea

RC, RP o SD

SI NO

Niraparib Chemioterapia di III linea

Malattia platino-sensibile con intervallo

libero ≥ 12 mesi (pz BEVA naïve)

A)

B) CBDCA+ Gem + BEV (con BEV in mantenimento) soprattutto se ascite o high tumor load

0-3 Prog 0-3 Non-PD 3-12 Mos 12-18 Mos 18+ Mos

PFS, days 90 176 174 275 339

OS, days 217 375 375 657 957

Response, % 9 24 35 52 62

Days

Percentage

1000

900

800

700

600

500

400

300

200

100

0

100

90

80

70

60

50

40

30

20

10

0

Pujade-Lauraine E, et al. ASCO 2002

Malattia parzialmente platino sensibile

Tra 6-12: Platino o no?

No platinum based when PFI < 6 m

Monk et al EJC, 2012

Furthermore:

Longer time to

new treatment

(Kaye S et al.,

2011)

longer OS in

patients treated

successively with

platinum based

strategy

(Colombo N et

al., 2011)

PLD-Trabectedina

Yondelis+PLD =

22.4 months

PLD=

16.4 months

INOVATYON

Randomization

(strata: ECOG, Measurable disease, PFI)

PLD 30 mg/m2 1 hour i.v. +

Carboplatin AUC 5 q4weeks

Up to 6 cycles or progression

Relapsed ovarian cancer

with platinum-free interval (PFI) of 6-12 months

PLD 30 mg/m2 1 hour i.v. +

Trabectedin 1.1 mg/m2 q3weeks

Up to 6 cycles or progression

3rd line chemotherapy: at

investigator discretion

3rd line chemotherapy: platinum

rechallenge

…and the accrual is completed….

L’ algoritmo terapeutico del carcinoma ovarico recidivante?

SI NO

Mutazione patogenetica di BRCA1-2

Chemioterapia con CBDCA associato a:

PTX

PLD

Gemcitabina

Chemioterapia con CBDCA associato a:

PTX

PLD

Gemcitabina

RC, RP o SD

SI NO

Olaparib Chemioterapia di III linea

RC, RP o SD

SI NO

Niraparib Chemioterapia di III linea

Malattia platino-sensibile con intervallo

libero tra 6 e 12 mesi

A)

B) PLD + Trabectedina

C) CBDCA+ Gem + BEV (con BEV in mantenimento) soprattutto se ascite o high tumor load

0-3 Prog 0-3 Non-PD 3-12 Mos 12-18 Mos 18+ Mos

PFS, days 90 176 174 275 339

OS, days 217 375 375 657 957

Response, % 9 24 35 52 62

Day

sP

ercentag

e

Pujade-Lauraine E, et al. ASCO 2002

1000

900

800

700

600

500

400

300

200

100

0

100

90

80

70

60

50

40

30

20

10

0

Malattia Platino Refrattaria/Resistente

QOL

Studi di fase III sull’uso di combinazioni

vs singoli agenti nella malattia

refrattaria/resistenteAuthor N pts Drugs RR (%) PFS

(median)

OS (median) Note

Buda 2004 212 PTX vs

PTX+EPI

46.9

37.4

6.0 m

6.0 m

14.0 m

12.0 m

Increased toxicity

in the combination

arm

Bolis 1999 81 PTX vs

PTX+EPI

17.1

34.2

NR

NR

18

10(2-year OS)

Increased toxicity

in the combination

arm

Sehouli 2008 502 TPT vs

TPT+ VP 16 vs

TPT +GEM

27.8

36.1

31.6

7.0 m

7.8 m

5.3 m

17.2 m

17.8 m

15.2 m

Increased toxicity

in the combination

arm

Vergote 2010 125 PLD vs

CAN+PLD

12.3

8.3

3.7 m

5.6 m

NR

NR

Increased toxicity

in the combination

arm

Monk 2010 242 PLD vs

PLD + ET743

12.2

13.4

4.0 m

3.7 m

12.4 m

14.2 m

Increased toxicity

in the combination

arm

Lortholary

2012

165 PTX w vs

CBDA + PTX w vs

TPT w

35

37

39

3.7 m

4.8 m

5.4 m

19.9 m

15.2 m

18.6 m

Increased toxicity

in the combination

arm

Aurelia

Pujade-Lauraine E, et al. JCO, 2014

Paclitaxel cohort

Poveda AM et al., JCO 2015

Bevacizumab nella malattia

Platino-resistente

L’algoritmo terapeutico del carcinoma ovarico recidivante?

Malattia platino-refrattaria (progressione durante la I linea)

Monochemioterapia con:

PTX settimanale

PLD

Gemcitabina

Topotecan

Incoraggiata l’inclusione e lo sviluppo di trials clinici

Best supportive care

L’ algoritmo terapeutico del carcinoma ovarico recidivante?

Malattia platino-resistente Intervallo libero <6 mesi)

Monochemioterapia con:

PTX settimanale

PLD

Gemcitabina

Topotecan

Incoraggiata l’inclusione e lo sviluppo di trials clinici

The BAROCCO

Study

• Italian multicenter randomized phase II study of weekly

paclitaxel vs. Cediranib-Olaparib with continuous schedule vs.

Cediranib-Olaparib with intermittent schedule in patients with

platinum resistant high grade epithelial ovarian, fallopian tube, or

primary peritoneal cancer.

• SPONSOR: Mario Negri Gynaecology Oncology Group

(MaNGO)

• PI: Prof.ssa Nicoletta Colombo, Istituto Europeo di Oncologia

• SUPPORT: AstraZeneca

v

Algoritmi terapeutici???

In uno scenario in cui le opzioni terapeutiche si sono ampliate notevolmente,

applicare un algoritmo terapeutico è di grande ausilio per garantire alle nostre

pazienti la miglior strategia terapeutica…

SENZA DIMENTICARE L’IMPORTANZA DI FARE RETE PER

INCENTIVARE L’ARRUOLAMENTO DELLE STESSE NEI PROTOCOLLI

DI RICERCA