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Dr Anne-Claire HARDY-BESSARDCentre Armoricain d’Oncologie

CARIO HPCAPlérin France

PHASE I

• Escalade de dose– Cohortes 3-6 patients– Dose de 30 à 400 mg/j– Expansion 15 malades a DMTØ60 patientesØDMT : 300 mg/j

• Partie B : 40 patients à DMT– Ovaire résistant et cancer de prostate

• DLT :– grade 3 fatigue (one patient given 30 mg/day),– grade 3 pneumonitis (one given 60 mg/day), and– grade 4 thrombocytopenia (two given 400 mg/day).

• Common treatment-related toxic effects, predominantly grade 1 or 2 :– anaemia (48%), – nausea (42%), – fatigue (42%), – thrombocytopenia (35%), – anorexia (26%), – neutropenia (24%), – constipation (23%), – Vomiting (20%)

• Pharmacokinetics :– dose proportional and – the mean terminal elimination half-life was 36·4 h ( 32·8-46·0).

• Pharmacodynamic analyses confirmed– PARP inhibition exceeded 50% at doses greater than 80 mg/day– antitumour activity was documented beyond doses of 60

mg/day.

• 8/20 (40%) BRCA1 or BRCA2 mutation carriers with ovariancancer had RECIST partial responses,

• 2/4 (50%) of mutation carriers with breast cancer.

NOVA

Study hypothesis

Niraparib, as a selective PARP1/2 inhibitor, will provide a clinical benefit to all patients who have platinum-sensitive recurrent ovarian cancer who are in response to platinum,

regardless of gBRCA mutation status

The myChoice® HRD test measures DNA damageTelomeric allelic imbalance (TAI) Large-scale state transitions (LST)Loss of heterozygosity (LOH)

Platinium-Sensitive recurrent high grade serous ovarian cancer

Traitement avec 4-6 cycles de platinium-based therapy

Response to platinium treatment

gBRCAmut Non-gBRCAmut

Niraparib 300 mg once daily Placebo

Treat until progression of disease

Niraparib 300 mg once daily Placebo

Treat until progression of disease

Tested at 100 events to achieve p < 0,05

• HRD pos population• Tested at 100 events to achieve p<0.05;• If test was positive then:

• Test overall non-gBRCAmut cohort (p<0.05)

Primary Endpoint : PFS by central, blinded review

Niraparib NEJM. Dec 1. 2016

Characteristic

gBRCAmut Non-gBRCAmutNiraparib(N=138)

Placebo(N=65)

Niraparib(N=234)

Placebo(N=116)

Age - years

Median (min, max)

57.0(36, 83)

58.0(38, 73)

63.0(33, 84)

60.5(34, 82)

ECOG PS0 91 (65.9) 48 (73.8) 160 (68.4) 78 (67.2)1 47 (34.1) 17 (26.2) 74 (31.6) 38 (32.8)

Primary tumor site – n (%)Ovarian 122 (88.4) 53 (81.5) 192 (82.1) 96 (82.8)Primary peritoneal 7 (5.1) 6 (9.2) 24 (10.3) 8 (6.9)Fallopian tube 9 (6.5) 6 (9.2) 18 (7.7) 11 (9.5)

Lines of previous chemo – n (%)

2 70 (50.7) 30 (46.2) 155 (66.2) 77 (66.4)

≥3 67 (48.6) 35 (53.8) 79 (33.8) 38 (32.8)

*One patient received one line of prior therapy.

Treatment

PFSMedian(95% CI)(Month

s)

Hazard Ratio

(95% CI)p-value

% of Patients without

Progression or Death12 mo

18 mo

Niraparib

(N=138)

21.0(12.9, NR)

0.27(0.173, 0.410)

p<0.0001

62%

50%

Placebo

(N=65)

5.5(3.8, 7.2)

16%

16%

PFS was analyzed using a 2-sided log-rank test using randomization stratification factors, and summarized using the Kaplan-Meier methodology. Hazard ratios with 2-sided 95% confidence intervals were estimated using a stratified Cox proportional hazards model, with the stratification factors used in randomization.

NR=not reachedMirza MR et al. N Engl J Med 2016;375:2154-64

Treatment

PFSMedian(95% CI)(Month

s)

Hazard Ratio

(95% CI)p-value

% of Patients without

Progression or Death12 mo

18 mo

Niraparib

(N=234)

9.3(7.2, 11.2)

0.45(0.338, 0.607)

p<0.0001

41%

30%

Placebo

(N=116)

3.9(3.7, 5.5)

14%

12%

PFS was analyzed using a 2-sided log-rank test using randomization stratification factors, and summarized using the Kaplan-Meier methodology. Hazard ratios with 2-sided 95% confidence intervals were estimated using a stratified Cox proportional hazards model, with the stratification factors used in randomization.

Treatment

PFSMedian(95% CI)(Month

s)

Hazard Ratio

(95% CI)p-value

% of Patients without

Progression or Death12 mo

18 mo

Niraparib

(N=106)

12.9(8.1, 15.9)

0.38(0.243, 0.586)

p<0.0001

51%

37%

Placebo

(N=56)

3.8(3.5, 5.7)

13% 9%

PFS was analyzed using a 2-sided log-rank test using randomization stratification factors, and summarized using the Kaplan-Meier methodology. Hazard ratios with 2-sided 95% confidence intervals were estimated using a stratified Cox proportional hazards model, with the stratification factors used in randomization.

BRCAwt

Treatment

PFSMedia

n(95%

CI)(Month

s)

Hazard Ratio(95%

CI)p-value

% of Patients without

Progression or Death12 mo

18 mo

Niraparib

(N=71)

9.3(5.8, 15.4)

0.38(0.231, 0.628)

p=0.0001

45%

27%

Placebo(N=44)

3.7(3.3, 5.6)

11% 6%

Treatment

PFSMedia

n(95%

CI)(Month

s)

Hazard Ratio(95%

CI)p-value

% of Patients without

Progression or Death12 mo

18 mo

Niraparib

(N=35)

20.9(9.7, NR)

0.27(0.081, 0.903)

p=0.0248

62%

52%

Placebo(N=12)

11.0(2.0, NR)

19%

19%

sBRCAmut

NR=Not reached

Treatment

PFSMedia

n(95%

CI)(Month

s)

Hazard Ratio

(95% CI)p-value

% of Patients without

Progression or Death12 mo

18 mo

Niraparib

(N=92)

6.9(5.6, 9.6)

0.58(0.361, 0.922)

p=0.0226

27%

19%

Placebo(N=42)

3.8(3.7, 5.6)

7% 7%

HRD-positive HRD-negative

Mirza MR et al. N Engl J Med 2016;375:2154-64

Prog

ress

ion–

free

Surv

ival

(%)

HRD ve+

gBRCAm

HRD ve-

0

25

50

75

100

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

Time Since Randomization (months)

gBRCAm

gBRCAwt,HRD ve+gBRCAwt,HRD ve-

gBRCAmut: FOSI

gBRCAmut: EQ-5D-5L

Non-gBRCAmut: FOSI

Non-gBRCAmut: EQ-5D-5L

• Measured using the Functional Assessment of Cancer Therapy –Ovarian Symptom Index (FOSI) and the EQ-5D-5L

• PRO surveys were collected at:• Screening visit• Every other cycle through

cycle 14• Post progression

• Compliance rates were high, and similar between the two treatment arms• Niraparib: FOSI completion

rate ranged from 75.0% to 97.1%

• Placebo: FOSI completion rate ranged from 77.6% to 97.4%

• PROs were similar for niraparib Mirza MR et al. N Engl J Med 2016;375:2154-64

gBRCAmut Non-gBRCAmut

All patientsAge 18 to <65 years

≥65 yearsRace White

Other (including unknown)Region USA and Canada

Europe and IsraelTime to progression before study enrollment 6 to <12 months

≥12 monthsBevacizumab use Yes

NoBest overall response on last platinum regimen Complete response

Partial responseTotal no. of prior platinum regimens 2

>2Cumulative no. of prior chemotherapy regimens 2

>2BRCA BRCA1

BRCA2Confidence LimitHazard Ratio

HR (95% CI)

0.01 0.10 1.00 5.00

HR (95% CI)

0.01 0.10 1.00 5.00

• Chemotherapy-free interval– gBRCAmut: HR 0.26 (22.8 mths vs 9.4 mths; 95% CI: 0.169, 0.414; p<0.0001)– Non-gBRCAmut: HR 0.50 (12.7 mths vs. 8.6 mths; 95% CI: 0.370, 0.666; p<0.0001)

• Time to first subsequent treatment– gBRCAmut: HR 0.31 (21.0 mths vs. 8.4 mths; 95% CI: 0.205, 0.481; p<0.0001)– Non-gBRCAmut: HR 0.55 (11.8 mths vs. 7.2 mths; 95% CI: 0.412, 0.721; p<0.0001)

• PFS 2 (data are immature)– gBRCAmut: HR 0.48 (25.8 mths vs. 19.5 mths; 95% CI: 0.280, 0.821; p=0.0062)– Non-gBRCAmut: HR 0.69 (18.6 mths vs.15.6 mths; 95% CI: 0.494, 0.964; p=0.0293)

uOverall survival (data are immature)• <20% patient deaths in either treatment arm; HR 0.73 (95% CI, 0.480 to 1.125; p=0.1545)

Event — no. (%)Niraparib(N=367)

Placebo(N=179)

Thrombocytopeniaa 124 (33.8) 1 (0.6)

Anemiab 93 (25.3) 0

Neutropeniac 72 (19.6) 3 (1.7)

Fatigued 30 (8.2) 1 (0.6)

Hypertension 30 (8.2) 4 (2.2)

*There were no Grade 5 events. aThrombocytopenia=thrombocytopenia and decreased platelet count. No grade 3 or 4 bleeding events were associated with thrombocytopenia; bAnemia=anemia and decreased hemoglobin counts; cNeutropenia=neutropenia, decreased neutrophil count, and febrile neutropenia; dFatigue=fatigue, asthenia, malaise, and lethargy.

MDS/AML occurred in 5 of 367 (1.4%) in patients who received niraparib and 2 of 179 (1.1%) in patients who received placebo.

Event — no. (%)

Dose Reductions

(N=367)

Events That Occurred After

Cycle 3(N=296)

DoseDiscontinuation

s (N=367)Thrombocytopeniaa 148 (40.3) 7 (2.4) 12 (3.3)

Anemiab 68 (18.5) 50 (16.9) 5 (1.4)

Neutropeniac 32 (8.7) 8 (2.7) 7 (1.9)

Fatigued 20 (5.4) 9 (3.0) 12 (3.3)

Hypertension 5 (1.4) - 1

aThrombocytopenia=thrombocytopenia and decreased platelet count. No grade 3 or 4 bleeding events were associated with thrombocytopenia; bAnemia=anemia and decreased hemoglobin counts; cNeutropenia=neutropenia, decreased neutrophil count, and febrile neutropenia; dFatigue=fatigue, asthenia, malaise, and lethargy.

Mandatory dose reductions for hematology laboratory abnormalities were required for thrombocytopenia, anemia, and neutropenia

Any Grade Grade 3/4 Any Grade

gBRCAmut: FOSI

gBRCAmut: EQ-5D-5L

Non-gBRCAmut: FOSI

Non-gBRCAmut: EQ-5D-5L

• Measured using the Functional Assessment of Cancer Therapy –Ovarian Symptom Index (FOSI) and the EQ-5D-5L

• PRO surveys were collected at:• Screening visit• Every other cycle through cycle 14• Post progression

• Compliance rates were high, and similar between the two treatment arms• Niraparib: FOSI completion rate

ranged from 75.0% to 97.1%• Placebo: FOSI completion rate

ranged from 77.6% to 97.4%• PROs were similar for niraparib

compared with placebo

AMM POUR TOUTES LES PATIENTES EN RECIDIVE

PLATINE SENSIBLE

AMM POUR TOUTES LES PATIENTES EN RECIDIVE

PLATINE SENSIBLE

Création de TESARO

QUADRA

24

HRD=homologous recombination deficiency; ITT=intent-to-treat; mITT=modified intent-to-treat; PARPi=PARP inhibitor.

Key ObjectivesTo evaluate the safety and clinical activity of niraparib treatment in the tBRCAmut (both germline and somatic) subgroup ofpatients according to their platinum responsiveness.To evaluate clinical activity of niraparib treatment in the subgroup of patients with HRDpos platinum-sensitive disease.Secondary objectives The assessment of efficacy in the intent-to-treat (ITT) population, and a planned subgroup analysis based on BRCA and HRD tumor status, and response to last platinum-based therapy.

• 1. Bruchim I, et al. Eur J Obstet Gynecol Reprod Biol. 2013, 2. Hanker, LC, et al. Annals Oncol. 2012, 3. Domchek, et al. Gyn Oncol. 2016, 4. Matulonis, UA, et al. Annals Oncol. 2016, 5. Konecny. SGO Annual Meeting 2017, 6. Moore, KN, et al. ASCO Annual Meeting, 2018. Abstract #5514.

2525

26

27

28

• The continuum of clinical activity according to platinum sensitivity in patientswith tumors bearing BRCA mutations was further demonstrated byprogression-free survival (PFS) analysis.

• The mPFS was 6.3 months (95% CI 5.4, 8.2) overall. In comparison, PFS inpatients with platinum-sensitive, -resistant and –refractory disease was 11.0months (95% CI 5.5, NE), 5.4 months (95% CI 1.8, 10.1), and 5.7 months (95% CI1.8, NE), respectively

28

AVANOVA

Niraparib 100–300 mg qd + BEV 15 mg/kg q3w

• High-grade serous/ endometrioid PS ROC or BRCAm OC

• Measurable diseasePrimary endpoint: safety & tolerabilitySecondary endpoints: Define Phase 2 dose, PK, PD, ORR

Mirza M, et al. ESMO 2017, abstract 953P

• 3/12 patients BRCA1/2m (germline and tumour)

• 4/12 patients HRD positive (including 3 with BRCA1/2m)

• Recommended phase 2 regimen: niraparib 300 mg/day + BEV 15 mg/kg q3w

• Main toxicities were haematological (one case of grade 4 thrombocytopenia meeting criteria for DLT)

• 50% ORR (CR in 8%); 92% CBR; median PFS 11.3 months

PRIMA

Endpoint assessment

Niraparib 200 or 300 mg

daily*

PlaceboDaily

High risk for progressive disease ovarian cancer stage III or IV and achieved a CR or PR following front line platinum-based

chemotherapy

Progression-free survival (PFS) by central radiologic reviewPrimary Endpoint

2:1 Randomization• Neoadjuvant chemotherapy administered: Yes or No

• Best response to 1st platinum therapy: CR or PR

• HRD status: positive or negative/not determined

Stratification Factors

*Starting dose of 200 mg used for patients <77kg or

with baseline platelet count <150,000/uL

• Body weight <77 kg or baseline platelet count <150,000/μLexperienced grade ≥3 thrombocytopenia at higher rates and were more likely to be dose reduced.

• Importantly, efficacy was not compromised in patients who received a dose reduction.

0

20

40

60

80

100

<77 kg or <150,000/uL

≥77kg and ≥150,000/uL

Inci

denc

e (%

)

Grade 3/4 thrombocytopenia in

NOVA

35

High-grade serous or endometrioid or high-grade predominantly serous or endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer that is stage III or IV according to FIGO criteriaMust be randomized within 12 weeks of the first day of the last cycle of chemotherapySurgical criteria: • All stage IV patients• Stage III patients treated with neoadjuvant chemotherapy • Stage III disease who have visible residual disease after primary debulking

surgeryChemotherapy criteria*: • Must have had ≥6 and ≤9 cycles of platinum-based therapy • Must have had ≥2 postoperative cycles of platinum-based therapy following

interval debulking surgery Patients must agree to undergo central tumor HRD testing

*Bevacizumab not allowed during maintenance

*†Anemia events included anemia and hemoglobin decrease.‡Neutropenia events included neutropenia, febrile neutropenia, and neutrophil count decrease.

Hematological toxicities Grade

Pre-amendment, fixed starting dose

300 mg QD(Pooled niraparib &

placebo)

Post-amendment, individualized starting dose

300 + 200 mg QD(Pooled niraparib

& placebo)

N=480 N=247

ThrombocytopeniaAny grade, n (%) 164 (34.2) 50 (20.2)≥Grade 3, n (%) 110 (22.9) 22 (8.9)Grade 4, n (%) 76 (16.5) 8 (3.2)

Platelet count decrease

Any grade, n (%) 91 (19) 34 (13.8)≥Grade 3, n (%) 51 (10.6) 12 (4.9)Grade 4, n (%) 26 (5.4) 6 (2.4)

Anemia† Any grade, n (%) 229 (47.7) 77 (31.2)≥Grade 3, n (%) 101 (21.0) 27 (10.9)

Neutropenia‡ Any grade, n (%) 148 (30.8) 57 (23.1)≥Grade 3, n (%) 75 (15.6) 23 (9.3)

Symptomatic TEAEs

Pre-amendment, fixed starting

dose300 mg QD

(Pooled niraparib & placebo)

Post-amendment,

individualized starting dose

300 + 200 mg QD(Pooled niraparib

& placebo)

N=480 N=247

NauseaAny grade, n (%) 226 (47.1) 86 (34.8)

≥ Grade 3, n (%) 5 (1.0) 2 (1)

VomitingAny grade, n (%) 84 (17.5) 23 (9.3)

≥ Grade 3, n (%) 4 (0.8) 0

FatigueAny grade, n (%) 144 (30.0) 57 (23.1)

≥ Grade 3, n (%) 6 (1.25) 3 (1.2)

Hypertension*Any grade, n (%) 59 (12.3) 16 (6.5)

≥ Grade 3, n (%) 18 (3.8) 1 (0.4)

InsomniaAny grade, n (%) 95 (19.8) 28 (11.3)

≥ Grade 3, n (%) 5 (1.0) 0

NIQOL

TOPACIO

ASCO 2018 - D’après Kostantinopoulos P et al., abstr. 106, actualisé

Niraparib + pembrolizumab chez des patientes atteintes d’un cancer de l’ovaire en rechute résistante ou réfractaire

5% had been treated with 3 or more prior lines of chemotherapy, 97% with prior taxane, 63% received prior bevacizumab, and 29% were platinum refractory.

The majority (77%) did not have a BRCA mutation BRCA sauvage, n (%) 48 (77)

HRD–, n (%) 32 (52)

PD-L1+, n (%) 35 (57)

Congrès américain d’oncologie clinique 2018 - D’après Kostantinopoulos P et al., abstr. 106, actualisé

Intérêt de l’association niraparib + pembrolizumab chez des patientes atteintes d’un cancer de l’ovaire en rechute résistante ou réfractaire

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110

Sujets

907050

3010

-10-30-50-70-90

-30

tBRCA mutéHRD+HRD–/inconnuSous traitementPD-L1+*

*********************************

HRD (déficit en recombinaison homologue)

(n = 60, 2 patientes non évaluables)

• ORR: 25% • Disease control rate : 68%;

• ORR was 24% in the platinum refractory population.

• Response rates were not dependent on biomarker status; – 26% (9/34) in patients without a tumor BRCA mutation – 29% (7/24) in patients with HRD-negative tumors.

FIRST

Treatment21 days cycle

x 5 cycles

MaintenanceUp to 3 years

Newly diagnosed stage III/IV advanced ovarian cancer

N= 720-960

Cycle 1: Carboplatin + paclitaxel

± bevacizumab

Randomization

Carboplatin + Paclitaxel + TSR-042

Double placebo

+/- Bevacizumab

+/- Bevacizumab

Carbo + Paclitaxel+ Placebo

Carbo + Paclitaxel+ Placebo

Placebo (TSR-042) + Niraparib

TSR-042 + Niraparib

Primarydebulkingsurgery

Intervaldebulkingsurgery

OR

• Leading Group: GINECO• Chair: AC Hardy-Bessard

Ø High grade epithelial OC except mucinous adenocarcinomaØ All patients with neo adjuvant chemotherapyØ All patients with FIGO IVØ After primary debulking surgery :

Ø All patients with FIGO high grade stage III without complete resection

Ø All patients with FIGO high grade stage III with complete resection and high risk defined by Aggregate 5 cm extra-pelvic disease during PDS

Ø Concurrent bevacizumab use (investigator choice; yes vs no)

Ø HRR (homologous Recombinant Repair) and BRCAmstatus based on ctDNA with tumorsample as back-upü BRCAmut, ü BRCAwt HRR+ ü BRCAwt HRRneg / inconclusive

Ø FIGO Stage III with residual < 1 cm at PDS versus others

Ø PFS investigator RECIST 1.1

• SOLO1 positif chez patientes mutées

Treatment21 days cycle

x 5 cycles

MaintenanceUp to 3 years

Newly diagnosed stage III/IV advanced ovarian cancer

Cycle 1: Carboplatin + paclitaxel ± bevacizumab

Randomization

Carboplatin + Paclitaxel + TSR-042

Double placebo

+/- Bevacizumab

+/- Bevacizumab

Carboplatin + Paclitaxel + TSR-042

Carbo + Paclitaxel+ Placebo

Placebo (TSR-042)

+ Niraparib

TSR-042 + Niraparib

+/- Bevacizumab

+/- Bevacizumab

BRCAmut BRCAwt

Carbo + Paclitaxel+ Placebo

Carbo + Paclitaxel+ Placebo

Placebo (TSR-042)

+ Niraparib

TSR-042 + Niraparib