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TREATMENT FOR RELAPSING PLATINUM SENSITIVE EPITHELIAL OVARIAN CANCER

Sandro Pignata, MD, PhD

Sabrina Chiara Cecere, MD

Uro-Gynecological Department, Division of Medical

Oncology, IRCCS National Cancer Institute “Fondazione G.

Pascale”, Naples, Italy

OVARIAN CANCER (OC) RELAPSE

Despite the best upfront treatment, ovarian cancer has a high incidence

of relapse

About 70–80% of FIGO stage III-IV ovarian cancer patients develop a disease

relapse within 5 years

Yang JC, et al. N Engl J Med. 2003; 349:427-34.

Adapted from: Piccart MJ, et al. Randomised Intergroup Trial of Cisplatin–Paclitaxel Versus Cisplatin–Cyclophosphamide in Women With Advanced Epithelial

Ovarian Cancer: Three-Year Results, J Natl Cancer Inst, 2000, 92, 9 , 699–708, by permission of Oxford University Press

RECURRENT OVARIAN CANCER

(ROC): POPULATION

CHARACTERISTICS

Response to Platinum

Time to RecurrenceResponse to

Further Platinum

Platinum-sensitive 12 mos 30-60%

Platinum-partially sensitive 6-12 mos 25-30%

Platinum-resistant <6 mos <10%

Platinum-refractory No initial response N/A

PRIMARY

THERAPY

0 3 6 12 18 24

Refractory

Resistant

Partially Sensitive

Fully Sensitive

months

THE PLATINUM-FREE INTERVAL

(PFI) TO CLASSIFY OC RELAPSE

Breaking the old and arbitrary categorisation of relapsed OC

Pisano C, et al. Ther Clin Risk Manag. 2009;5:421-426; Gadducci A, et al. Anticancer Res. 2001;21:3525-3533.

Platinum sensitivity is a continous variable

THE PLATINUM-FREE INTERVAL

(PFI) TO CLASSIFY OC RELAPSE


Adapted from Pujade-Lauraine E, et al. Proc Am Soc Clin Oncol. 2002;21: Abstract 829.

Sur

viva

l (da

ys)

0

1000

6–9

800

400

200

600

TFI (months)

12–180–3/Pr 0–3 3–6

Overall survival

Res

pons

e ra

te (

%)

100

80

40

20

60

≥189–12

217

9

90

366

32

166

Response rate

PFS

PFI IS NOT THE ONLY FACTOR TO

CONSIDER IN THE TREATMENT CHOICE

From the Tokyo GCIG OC consensus conference…

PFI revisited

Treatment-free Interval (TFI) vs. Platinum-free Interval (PFI)Leary AF, et al. Ann Oncol. 2017 Apr 1;28(4):718-726.

Fifth Ovarian Cancer Consensus Conference of the

Gynaecologic Cancer InterGroup: recurrent diseaseWilson MK, et al. Ann Oncol 2017;2(4):727–32

«ONE SIZE DOSE DOES NOT

FIT ALL»


• Comorbidities

• Performance status

• Residual toxicities

• Symptoms

• gBRCA

• Histology

• Molecular characterisation

• sBRCA

• HRD status (?)

• Surgery

• Previous treatments (type, number)

• Target maintenance therapy

• TFI

• Availability of treatments

Patient

Tumour

Treatment

What has to be considered for platinum-sensitive

relapse:

Is there a role for surgery at relapse?

Is a platinum-based therapy an option?




relapse: The role of surgery at relapse

Non platinum-based therapy as an option

Platinum-based therapy as an option



PLATINUM-SENSITIVE OC RELAPSE

AGO DESKTOP III (ENGOT-ov20; NCT01166737): Surgery at relapse

Study Design

du Bois A, et al. J Clin Oncol 35, 2017 (suppl; abstract 5501). Presented at ASCO Annual Meeting 2017. Courtesy of Prof A. du Bois.

Patients with:

1st relapse

PSROC

AGO Score +ve

R

Cytoreductive surgery with max.

effort for complete resection

Platinum-based combination

therapy strongly recommended

No OP

n=408

Immediate platinum-based

combination therapy

strongly recommended

80 centres in

12 countries

Recruitment

9/2010 – 3/2015

407 of 409 pts

evaluated

(2 screening failures)

OP

allowed

3rd line

PFS by Surgical Outcome

Median PFS (mos)

ΔPFS (mos)

HR (95% CI)

P-value Wald-test

No surgery 14.0 - 1 -

Surgery but with residual tumour

13.7 -0.30.98

(0.71-1.35)0.8952

Surgery with complete resection

21.2 +7.20.56

(0.43-0.72)<0.0001


Surgery at relapse: The new reality

GOG-0213 trial design

Coleman L, et al. J Clin Oncol 36, 2018 (suppl; abstr 5501). Presented at ASCO Annual Meeting 2018.

YES N=107

R

Surgery

No surgery

Women with

recurrent ovarian,

peritoneal primary

or fallopian tube

cancer and a

treatment free

interval ≥6 monthsNO N=567

R

Regimen I

Carboplatin AUC 5

Paclitaxel 175 mg/m2

q 21 days

Regimen II

Carboplatin AUC 5

Paclitaxel 175 mg/m2

Bevacizumab 15 mg/kg

q 21 days

n=674

Maintenance

Bevacizumab 15 mg/kg

q 21 days until

progression or toxicity

precludes further

treatment

Surgical candidate


Surgery at relapse: The new reality

Coleman L, et al. J Clin Oncol 36, 2018 (suppl; abstr 5501). Presented at ASCO Annual Meeting 2018. Courtesy of Prof L. Coleman.

WHEN PLATINUM IS NOT

AN OPTION

• Platinum hypersensitivity

• Progressed or relapsed OC during last platinum

• Residual toxicity (e.g. neurotoxicity,…)

Wilson MK, et al. Ann Oncol 2017;2(4):727–32


AN OPTION

Hypersensitivity, incidence and development

• Incidence seems to be correlated with increased number of cycles

of carboplatin administered, occurring in less than 1% of the patients

during primary treatment but in 8–44% of patients during 2nd or 3rd

line1,2

• The risk of hypersensitivity reactions rises with a longer platinum-free

interval3

• Particular caution is advised in patients receiving:4

More than eight courses of carboplatin

Second platinum dose after reintroduction in second-line chemotherapy

1. Sliesoraitis S, Chikhale PJ. Int J Gynecol Cancer. 2005;15:13-8; 2. Gadducci A, et al. Int J Gynecol Cancer. 2008;18(4):615-20;

3. O´Cearbhaill R, et al. Gynecol Oncol. 2011;116(3):326-31; 4. Markman M, et al. J Clin Oncol.1999;17(4):1141-5.

WHEN PLATINUM IS NOT AN

OPTION: TFIP 6–12 MONTHS

OVA-301 trial

An open-label, multi-centre, randomised Phase 3 study comparing the combination of

PLD and Trabectedin with PLD alone in patients with advanced relapsed ovarian

cancer (ROC)

1. Poveda A, et al. Ann Oncol 2011;22(1):39–48, by permission of Oxford University Press on behalf of the European Society for Medical Oncology (ESMO) ;

2. Reprinted from Eur J Cancer, 2012; 48, Monk BJ, et al. Trabectedin plus pegylated liposomal doxorubicin (PLD) versus PLD in recurrent ovarian cancer: Overall survival analysis,

2361–8; Copyright 2012, with permission from Elsevier. 3. Poveda A, et al. Cancer Treat Rev 2014;40:366–75.

PFS1 OS2,3


AN OPTION

The post hoc analysis of the OVA-301 trial: TFIP 6-12 months T+PLD a

valid option in BRCA mutated ROC

BRCA1-mutated patients

treated with T+PLD

showed longer PFS and

OS compared to PLD

BRCA1mut may predict improved outcome to T + PLD treatment

Monk BJ, et al. Effect of BRCA1 and XPG mutations on treatment response to trabectedin and pegylated liposomal doxorubicin in patients with advanced ovarian cancer: exploratory

analysis of the phase 3 OVA-301 study. Ann Oncol 2015;26(5):914–20. by permission of Oxford University Press on behalf of The European Society for Medical Oncology (ESMO).


Platinum-based combination PARP inhibitors

Carboplatin + gemcitabine + bevacizumab bevacizumab

maintenance (for bevacizumab naïve)

Platinum-based combination + bevacizumab bevacizumab

maintenance (for bevacizumab pre-treated in first line)

WHEN PLATINUM IS AN OPTION


All the platinum based combinations are equivalent in terms of

efficacy, with different toxicity profiles

CARBO AUC5 + PLD 30 mg/m²

CARBO AUC4 d1+ GEM 1000 mg/m²

d1,8 q21d

CALYPSO/ AGO OV 2.9

AGO OV 2.5

Haematologic toxicity, hypersensibility

Palmoplantar erythrodysesthesia, mucositis, thrombocytopenia

CARBO AUC5 + TAX 175 mg/m² q21d ICON 4/AGO OV 2.2 –

GEICO 0104

Alopecia, neurotoxicity, haematologic toxicity, hypersensibility

META-ANALYSIS COMBINATION

THERAPY VS. MONOTHERAPY

Carbo/paclitaxel, carbo/PLD, carbo/gemcitabine

Orlando M, et al. ASCO 2007, Abstract 5524; Pfisterer J, et al. J Clin Oncol. 24: 4699-4707, 2006; Parmar MK, et al. Lancet 361: 2099-2106, 2003.

Combination chemotherapy appears to improve ORR, PFS, and OS when compared to

monotherapy in the management of ROC

Endpoint Odds ratio combo/mono (95% CI) P value

ORR (n=1730, 8 studies) 1.42 (1.1601.74) 0.001

PFS at 2 years (n=2234, 7 studies) 0.67 (0.52-0.89) 0.004

PFS at 1 year 0.69 (0.57-0.84) 0.000

OS at 2 years (n=2315, 8 studies) 0.80 (0.067-0.95) 0.012*



Carboplatin + Gemcitabine + bevacizumab bevacizumab


platinum-based combination + bevacizumab bevacizumab



Sensitivity analysis: PFS by blinded independent central review (BICR)

Key secondary endpoints:

Time to first subsequent therapy or death (TFST), time to second progression

(PFS2), time to second subsequent therapy or death (TSST), overall survival (OS)

Safety, health-related quality of life (HRQoL*)

Patients

BRCA1/2 mutation

Platinum-sensitive relapsed

ovarian cancer

At least 2 prior lines of

platinum therapy

CR or PR to most recent

platinum therapy

SOLO2/ENGOT-OV21:

STUDY DESIGN

*Primary endpoint for HRQoL was trial outcome index (TOI) of the

FACT-O (Functional Assessment of Cancer Therapy – Ovarian)

Presented by Pujade-Lauraine E, at SGO 2017 Annual Meeting.

R

Olaparib tablets

300 mg bid n=196

Placebo

n=99

2:1

Primary endpoint

Investigator-assessed

PFS

Pro

gre

ssio

n-f

ree

surv

ival

(%

)

Months since randomisation

Olaparib

(n=196)

Placebo

(n=99)

Events (%) 107 (54.6) 80 (80.8)

Median PFS, months 19.1 5.5

Median follow-up was 22.1 months in the olaparib group and 22.2 months for placebo

PFS BY INVESTIGATOR

ASSESSMENT

Reprinted from The Lancet Oncol, 18(9), Pujade-Lauraine E, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian

cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial, 1274–84. Copyright 2017, with

permission from Elsevier.

NOVA STUDY

Phase III trial of maintenance therapy with Niraparib in recurrent

platinum-sensitive high-grade serous ovarian cancer

Non-gBRCAmut

gBRCA mut

Niraparib 300 mg QD

N=234

Placebo

N=116

Primary endpoint

BICR-assessed PFS in 3 predefined

cohorts

gBRCA

Overall Non-gBRCA

Non-gBRCA HRD+

Key secondary endpoints

PRO, chemotherapy-free interval;

time to first subsequent

treatment; PFS2; time to second

subsequent treatment; OS; safety

Exploratory analysis

Non-gBRCA mut cohort:

PFS stratified by HRD/BRCA status

HRD positive, sBRCA mut

HRD-positive BRCA wt

HRD-negative

Patient stratification

Time to disease progression on penultimate platinum-based therapy

Bevacizumab with last or penultimate chemotherapy

CR/PR during last platinum regimen

N=553

Relapsed high-grade serous

histology or known gBRCA

mut

≥2 prior regimens of

platinum-based

chemotherapy

Responded to last platinum

regimen; remains in

response and enrolled within

8 weeks of completion of

last platinum regimen

No measurable lesion

>2 cm

R 2:1

Mirza MR, et al. N Engl J Med 2016;375:2154–2164.

Niraparib 300 mg QD

N=138

Placebo

N=65

R 2:1

NOVA TRIAL: MAINTENANCE

NIRAPARIB IN PLATINUM-SENSITIVE HGOC

1º Endpoint: BICR assessed PFS

Niraparib

(n=138) Placebo (n=65)


HR=0.27

95% CI 0.17, 0.41

P<0.001

Niraparib

(n=234) Placebo (n=116)


HR=0.45

95% CI 0.34, 0.61

P<0.001

From N Engl J Med, Mirza MR, et al, Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer, 375, 2154–64. Copyright © 2016,

Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

BRCA wt (n=115)sBRCA mut (n=47)

HRD positive HRD negative

100

0

25

50

75

0 2 4 6 8 10 12 14 16 18 20 22 24

92 73 54 35 26 22 11 8 3 3 3 2 1

42 35 19 11 7 6 2 2 0


Pro

gre

ssio

n-f

ree

surv

ival

(%

)

Niraparib

Placebo

No. at Risk

Hazard ratio 0.58 (95% CI 0.36–0.92)

P=0.02

Placebo

Niraparib

100

0

25

50

75

0 2 4 6 8 10 12 14 16 18 20 22 24

71 58 46 38 29 25 21 12 7 6 4 2 1

44 32 19 12 7 6 3 2 0


Pro

gre

ssio

n-f

ree

surv

ival

(%

)

Niraparib

Placebo

Placebo

No. at Risk

Hazard ratio 0.38 (95% CI 0.23–0.63)

P<0.001

Niraparib

100

0

25

50

75

0 2 4 6 8 10 12 14 16 18 20 22 24

35 32 29 26 23 21 19 17 9 8 7 2 1

12 9 7 4 4 3 1 1 1


Pro

gre

ssio

n-f

ree

surv

ival

(%

)

Niraparib

Placebo

No. at Risk

Hazard ratio 0.27 (95% CI 0.08–0.90)

P=0.02

Placebo

Niraparib

1 1 1 1

(n=134)

Niraparib (n=71) Placebo (n=44)

PFS median (95% CI) (Months) 9.3 (5.8–15.4) 3.7 (3.3–5.6)

Hazard ratio (95% CI); P value 0.38 (0.231–0.628); P=0.0001

% of patients without progression

or death at 12 mo45% 11%




PFS median (95% CI) (Months) 20.9 (9.7–NR) 11.0 (2.0–NR)







PFS median (95% CI) (Months) 6.9 (5.6–9.6) 3.8 (3.7–5.6)






NOVA EXPLORATORY ANALYSIS

PFS in non-gBRCA mut subgroups

From N Engl J Med, Mirza MR, et al., Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer, 375, 2154–64. Copyright © 2016, Massachusetts

Medical Society. Reprinted with permission from Massachusetts Medical Society; Mirza MR, et al. Ann Oncol. 2016;27(Suppl 6): Abstract LBA3_PR.

ARIEL-3

Phase 3, randomised, double-blind study of rucaparib vs. placebo

following response to platinum-based chemotherapy for recurrent

ovarian carcinoma study design

Patient eligibility

High-grade serous or endometrioid epithelial OC, primary peritoneal, or fallopian tube cancers

Sensitive to penultimate platinum

Responding to most recent platinum (CR or PR)*

Excludes patients without assessable disease following second surgery

CA-125 within normal range

No restriction on size of residual tumour

ECOG PS ≤1

No prior PARP inhibitors

Placebo BIDn=189

Rucaparib 600 mg BIDn=375

*CR (defined by RECIST) or PR (defined by RECIST and/or a GCIG CA-125 response [CA-125 within normal range]) maintained until entry to ARIEL3 (≤8

weeks of last dose of chemotherapy). †ATM, ATR, ATRX, BARD1, BLM, BRIP1, CHEK1, CHEK2, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG,

FANCI, FANCL, FANCM, MRE11A, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C, RAD51D, RAD52, RAD54L, RPA1.,BID.

R 2:1

Stratification

HRR gene mutation status by NGS analysis:

BRCA1 or BRCA2

Non-BRCA HRR gene†

None of the above

Response to recent platinum

CR

PR

Progression-free interval after penultimate platinum

6 to ≤12 months

>12 months

ARIEL3

Investigator-Assessed Progression-Free Survival

BRCA mutant HRD ITTMedian(months) 95% CI

Rucaparib

(n=236)

13.6 10.9–16.2

Placebo

(n=118)

5.4 5.1–5.6

HR, 0.32;

95% CI, 0.24–0.42;

P<0.0001

Median(months) 95% CI

Rucaparib

(n=375)

10.8 8.3–11.4

Placebo

(n=189)

5.4 5.3–5.5

HR, 0.36;

95% CI, 0.30–0.45;

P<0.0001

At risk (events)

Rucaparib 130 (0) 93 (23) 63 (46) 35 (58) 15 (64) 3 (67) 0 (67)

Placebo 66 (0) 24 (37) 6 (53) 3 (55) 1 (56) 0 (56)

Rucaparib, 48% censored Placebo, 15% censored

At risk (events)

Rucaparib 236 (0) 161 (55) 96 (104) 54 (122) 21 (129) 5 (134) 0 (134)

Placebo 118 (0) 40 (68) 11 (95) 6 (98) 1 (101) 0 (101)


At risk (events)

Rucaparib 375 (0) 228

(111)

128

(186)

65 (217) 26 (226) 5 (234) 0 (234)

Placebo 189 (0) 63 (114) 13 (160) 7 (164) 2 (167) 1 (167) 0 (167)


Median(months) 95% CI

Rucaparib

(n=130)

16.6 13.4–22.9

Placebo

(n=66)

5.4 3.4–6.7

HR, 0.23;

95% CI, 0.16–0.34;

P<0.0001

Reprinted from The Lancet, Vol.390, Nº10106, Coleman RL, et al., The Lancet,, Rucaparib maintenance treatment for recurrent ovarian carcinoma after response

to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial, p1949-1961. Copyright 2017, with permission from Elsevier.



Carboplatin + gemcitabine + bevacizumab bevacizumab maintenance

(for bevacizumab naïve)

Platinum-based combination + bevacizumab bevacizumab maintenance (for

bevacizumab pre-treated in first line)



Bevacizumab in platinum-sensitive relapsed OC: the OCEANS trial

Epithelial ovarian, primary peritoneal, or fallopian tube cancer.

Aghajanian C, et al. J Clin Oncol 30(17), 2012:2039–45

CG + placebo

CG + bevacizumab

Bevacizumab 15 mg/kg q3w until progression

Placebo

q3w until progression

n=484

Platinum-sensitive recurrent

OC

Measurable disease

ECOG 0/1

No prior chemo for recurrent

OC

No prior bevacizumab

CG for 6 (up to 10) cycles

CBDCA AUC 4

GEM 1000 mg/m2 d1, 8

CBDCA AUC 4

GEM 1000 mg/m2 d1, 8

Stratification variables:

Platinum-free interval (6-12 vs. >12 months)

Cytoreductive surgery for recurrent disease (yes vs. no)


OCEANS trial: PFS and OS results

1. Aghajanian C, et al. J Clin Oncol, 30(17), 2012:2039–45. Reprinted with permission. © 2012 American Society of Clinical Oncology;

2. Reprinted from Gynecol Oncol 139(1), Aghajanian C, et al. Final overall survival and safety analysis of OCEANS, a phase 3 trial of chemotherapy with or

without bevacizumab in patients with platinum-sensitive recurrent ovarian cancer, 10–6. Copyright 2015, with permission from Elsevier.

Primary analysis of PFS1 Final OS2



Carboplatin + gemcitabine + bevacizumab bevacizumab


Platinum-based combination + bevacizumab bevacizumab




Bevacizumab beyond progression in platinum-sensitive bevacizumab

pre-treated relapsed OC: the MITO-16/MaNGO OV-2 trial design

CG + placebo

CG + bevacizumab

Avastin 15 mg/kg q3w

1:1

Stage IIIB-IV EOC, FT or PPC

progressing or recurring at

least 6 months after front-line

chemotherapy plus avastin

(n≈400)

Until PD

Carboplatin

PLD or gemcitabine or paclitaxel

Carboplatin

PLD or gemcitabine or paclitaxel

Primary endpoint

PFS

x6-8

cyc

les

Pignata S, et al. J Clin Oncol 36, 2018 (suppl; abstr 5506). Presented at ASCO Annual Meeting 2018.


MITO-16B/MaNGO OV-2B trial: PFS results

PFS Investigator assessed (Primary endpoint)

Standard Experimental Log Rank P

No. of events 161 143

Median PFS 8.8 months 11.8 months <0.001

HR* (95% CI) 0.51 (0.41-0.65)

*Adjusted by: Age, PS, centre size, bevacizumab at relapse, chemo

backbone, residual disease at initial surgery


Treatment algorithm

THIRD LINE

BRCA mutated or WT

Platinum based treatment

MAINTENANCE


FOURTH LINE

SECOND LINE

Pld + trabectedin

Carbo-gem

+ bevacizumab

Bevacizumab

Platinum based ct

Olaparib/ niraparib


Olaparib/ niraparibPld + trabectedin

Platinum based ct

TFIp 6-12 months

Radiologic

CR or PR

If TFIp 6-12 months consider

Platinum free interval is not the only parameter to be considered to select treatment

for recurrence. Other parameters including biology, pathology and previous target

maintenance therapy need to be taken into account.

Recurrent OC patients are classified for being candidate or not to a platinum

re-treatment.

Indication for surgery must be assessed although final results of trials are still

pending.

Platinum combination chemotherapy is more effective than single agent platinum.

In patients who respond to a platinum based therapy, PARP-i maintenance is effective

in prolonging PFS, with higher effect in BRCA mutated patients.

Platinum based therapy plus bevacizumab prolongs PFS compared to chemo

alone, both in patients who are bevacizumab naive or bevacizumab pre-treated.

Bev-containing regimens given in preference to patients at high risk of quick

progression and large bulk of disease.

In patients with TFI between 6–12 months, not candidate for platinum,

trabectedine-PLD should be considered.

CONCLUSIONS

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