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Il tempo guadagnato, a cosa

dare valore?

Carcinoma mammario:

• Malattia HER 2 -/ER+

Dott.ssa Laura Pisanu

UCO Oncologia

Nuoro

(2)

Epidemiologia

(3)
(4)

Epidemiologia

(5)

Obiettivi terapeutici

(6)

Caratteristiche cliniche:

 Burden tumorale

 Sedi di malattia (viscerale vs non viscerale)

 Grado di compromissione d’organo (lesioni a rischio di morte a breve termine)

 Intervallo libero di malattia

 Precedenti trattamenti adiuvanti e/o per la malattia mts

 Comorbidità e PS

 Preferenze della paziente

Caratteristiche biologiche

 Stato di ER e PgR

 HER 2

 Ki 67

Criteri decisionali

(7)

Criteri decisionali

(8)
(9)
(10)
(11)
(12)

CDK4/6 inhibitors and

Overall Survival

ET-naive/ET- sensitive

(13)

MONALEESA-7 Study Design

Stratification Factors

Liver/lung metastasis (yes/no)

Prior chemotherapy (yes/no)

Combination partner (NSAI/TAM)

Primary endpoint

• PFS (local) Key secondary endpoint

• OS

Select secondary endpoints

• HRQOL

• ORR

• TTDD of ECOG PS

• Safety Pre/perimenopaus

al women a with HR+/HER2− ABC

No prior ET for ABC b

≤ 1 prior CT for ABC

N = 672

Ribociclib 600 mg/day;

3 weeks on/1 week off +

NSAI/TAM c + GOS d n = 335

Placebo

3 weeks on/1 week off +

NSAI/TAM c + GOS d n = 337

ANA, anastrozole; CT, chemotherapy; ECOG PS, Eastern Cooperative Oncology Group performance status; FSH, follicle-stimulating hormone; GOS, goserelin; HRQOL, health-related quality of life; NSAI, nonsteroidal aromatase inhibitor; ORR, objective response rate; TAM, tamoxifen; TTDD, time to definitive deterioration.

a Premenopausal status was defined as either patient had last menstrual period ≤ 12 months or if receiving TAM or toremifene for ≤ 14 days, plasma estradiol and FSH must be in normal premenopausal range or in the case of induced amenorrhea, plasma estradiol and FSH must be in normal premenopausal range. Perimenopausal status was defined as neither premenopausal nor postmenopausal (prior bilateral oophorectomy, age ≥ 60 years, or FSH and plasma estradiol levels in normal postmenopausal range). Patients could not be ≥ 60 years of age. b Patients who received ≤ 14 days of NSAI/TAM ± GOS were allowed. c TAM and NSAI were administered daily orally. TAM dose was 20 mg, LET dose was 2.5 mg. and ANA dose was 1 mg. d GOS 3.6 mg was administered by subcutaneous injection.

First Phase III trial with a CDK4/6

inhibitor exclusively in premenopausal patie nts

Dr Sara Hurvitz

Ran d o m ize d 1 :1

(14)

Patient Disposition at Interim Analysis Data Cutoff

Median follow-up of 34.6 months

Ribociclib + ET (n = 335)

Placebo + ET (n = 337)

All Patients (N = 672) Patients treated, n (%)

Treatment ongoing End of treatment

335 (100) 116 (35) 219 (65)

337 (100) 57 (17) 280 (83)

672 (100) 173 (26) 499 (74) Reason for end of treatment, n(%)

Adverse event Lost to follow-up Physician decision Disease progression Protocol deviation

Patient/guardian decision Death

11(3) 2(< 1) 10 (3) 173 (52)

0 20 (6) 3 (< 1)

13 (4) 0 22 (7) 230 (68)

2 (< 1) 10 (3) 3 (< 1)

24 (4) 2 (< 1) 32 (5) 403 (60)

2 (< 1) 30 (4) 6 (< 1)

Dr Sara Hurvitz

(15)

Overall Survival

1

Dr Sara Hurvitz

5 Ribociclib +

ET

Placebo + ET

Events/N 83/335 109/337

Median OS,

mo Not reached 40.9

HR (95% CI) 0.712 (0.535-0.948)

P value .00973

Kaplan- Meier Estimate

Ribociclib + ET

Placebo + ET

36 months 71.9% 64.9%

42

months 70.2% 46.0%

• ≈ 29% relative reduction in risk of death

• The P value of .00973 crossed the prespecified boundary to claim superior efficacy

Landmark Analysis

(16)

Overall Survival in the NSAI Subgroup

Dr Sara Hurvitz

Ribociclib + ET

Placebo + ET

Events/n 61/248 80/247

Median OS,

mo Not reached 40.7

HR (95% CI) 0.699 (0.501-0.976)

Kaplan- Meier Estimate

Ribociclib + ET

Placebo + ET

36 months 72.2% 64.6%

42 months 69.7% 43.0%

Landmark Analysis

• ≈ 30% relative

reduction in risk of

death

(17)

Overall Survival Subgroup

Analysis

a In patients with no prior chemotherapy in the metastatic setting.

• Consistent OS

benefit seen within

subgroups

(18)

MONALEESA-3 Study Design

1L, first line; 2L, second line; ABC, advanced breast cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; ET, endocrine therapy; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; PD, progressive disease; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors; TFI, treatment-free interval.

a Fulvestrant 500 mg intramuscularly every 28 days plus an additional dose on Cycle 1, Day 15.

Slamon DJ, et al. J Clin Oncol. 2018;36:2465-247.

18

Primary end point

• PFS (locally assessed per RECIST version 1.1) Secondary end points

• Overall survival

• Overall response rate

• Clinical benefit rate

• Time to response

• Duration of response

• Time to definitive

deterioration of ECOG PS

• Patient-reported outcomes

• Safety

• Pharmacokinetics

Ribociclib

(600 mg/day;

3 weeks on/1 week off) +

fulvestrant

(500 mg)

a

n = 484

Placebo

+

fulvestrant

(500 mg)

a

n = 242 Stratified by:

• Presence/absence of liver/lung metastases

• Prior endocrine therapy

R a nd om ize d 2 :1

Men and postmenopausal

women with HR+/HER2− ABC

≤ 1 line of prior ET for

advanced disease N = 726

≤ 1 line ET in ABC

TFI ≤ 12 mo and no treatment for ABC TFI > 12 mo + PD on

1L ET for ABC ABC at diagnosis with PD on 1L ET for

ABC Treatmen

t naive for ABC

TFI > 12 mo

De novo ABC

Patient population definitions

= early

relapse

(19)

Patient Disposition

Median follow-up time was 39.4 months

Parameter, n (%) RIB + FUL n = 484

PBO + FUL n = 242

All Patients N = 726

Patients treated 483 (99.8) 241 (99.6) 724 (99.7)

Treatment

ongoing a 121 (25.0) 32 (13.2) 153 (21.1)

End of treatment 362 (74.8) 209 (86.4) 571 (78.7)

Reason for end of treatment

Progressive disease

Adverse event Physician decision Patient/guardian decision

Death

Protocol deviation Technical issue

263 (54.3) 43 (8.9) 28 (5.8) 26 (5.4) 2 (0.4) 1 (0.2)

0

184 (76.0) 9 (3.7) 8 (3.3) 6 (2.5) 1 (0.4) 1 (0.4) 1 (0.4)

447 (61.6) 52 (7.2) 36 (5.0) 32 (4.4) 3 (0.4) 2 (0.3) 1 (0.1)

FUL, fulvestrant; PBO, placebo; RIB, ribociclib.

a At the time of data cutoff: 03 June 2019.

(20)

Overall Survival

The reduction in relative risk of death with RIB was 28%

FUL, fulvestrant; HR, hazard ratio; KM, Kaplan-Meier; NR, not reached; OS, overall survival; PBO, placebo; RIB, ribociclib.

RIB + FUL PBO + FUL

Events/N 167/484 108/242

OS, median

(95% CI), mo NR (42.5-NR) 40.0 (37.0- NR) HR (95% CI) 0.724 (0.568-0.924)

P value 0.00455

Landmark Analysis

• The P value of 0.00455 crossed the prespecified boundary to claim superior efficacy (P < 0.01129)

KM Estimat e

RIB + FUL

PBO + FUL 36

months 67.0% 58.2

% 42

months 57.8% 45.9

%

Ov er al l Su rv iv al , %

RIB + FUL PBO + FUL

0 20 40 60 80 100

484 470 454 444 436 428 414 402 397 389 374 365 348 334 326 309 300 287 237 159 92 41 14 2 0 242 233 227 223 218 213 207 199 194 187 184 174 169 159 155 147 141 134 107 64 37 14 3 0 0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48

No. of patients still at risk Placebo

Ribociclib

Time, months

(21)

Overall Survival by Line of Therapy

OS by line of therapy was consistent with overall population

FUL, fulvestrant; HR, hazard ratio; OS, overall survival; PBO, placebo; RIB, ribociclib.

a This median value may not be estimated reliably due to the last patient on follow-up, who had an event at 45.1 months.

21

First line Early relapse + second line

RIB + FUL PBO + FUL Events/N 102/237 60/109 OS, median,

mo 40.2 32.5

HR (95% CI) 0.730 (0.530-1.004) RIB + FUL PBO + FUL

Events/N 63/237 47/128 OS, median,

mo

Not

reached 45.1

a

HR (95% CI) 0.700 (0.479-1.021)

RIB + FUL

PBO + FUL

RIB + FUL PBO + FUL

O ver al l Su rv iv al , % O ver al l Su rv iv al , %

237 231 222 218 213 210 199 188 184 179 172 167 158 152 145 135

109 103 98 97 93 90 88 83 81 78 77 72 69 63 61 59 54 49 35 23 15 6

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48

129 122 94 63 36 17 7 1 0 1 0 0 0

20 40 60 80 100

No. of patients still at risk Placebo

Ribociclib

Time, months No. of patients still at risk

237 229 222 217 214 210 207 206 205 202 194 190 182 174 173 166 163 157 138 92 54 22 6 1 0 128 126 122 121 119 116 113 110 106 104 99 97 93 91 85 84 82 70 40 21 8 2 0 0 Placebo

Ribociclib

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 Time, months

0

20

40

60

80

100

(22)

Progression-Free Survival: Overall Population

Descriptive analysis of PFS consistent with primary report

FUL, fulvestrant; HR, hazard ratio; PBO, placebo; PFS, progression-free survival; RIB, ribociclib.

RIB + FUL PBO + FUL

Pr o gr es si o n -Fr ee Su rv iv al , %

RIB + FUL PBO + FUL Events/N 283/484 193/242 PFS, median,

mo 20.6 12.8

HR (95% CI) 0.587 (0.488-0.705)

484 403 364 346 323 305 282 258 239 225 205 198 181 174 159 156 149 127 92 65 29 11 4 0

6 2 1 0

242 195 168 156 144 134 116 106 98 88 82 68 62 59 51 47 45 41 21 13

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 0

20 40 60 80 100

No. of patients still at risk Placebo

Ribociclib

Time, months

(23)

Progression-Free Survival by Line of Therapy

Median PFS for RIB + FUL is now reached in first line (33.6 months)

FUL, fulvestrant; HR, hazard ratio; PBO, placebo; PFS, progression-free survival; RIB, ribociclib.

First line

RIB + FUL

PBO + FUL

RIB + FUL

PBO + FUL

P ro g re ssi o n -F re e S u rvi va l, % P ro g re ssi o n -F re e S u rvi va l, %

RIB + FUL PBO + FUL

Events/N 167/237 95/109

PFS, median,

mo 14.6 9.1

HR (95% CI) 0.571 (0.443-0.737) RIB + FUL PBO +

FUL

Events/N 112/237 95/128

PFS, median,

mo 33.6 19.2

HR (95% CI) 0.546 (0.415-0.718)

237 204 187 178 171 164 157 147 140 132 125 123 117 113 102 101 98 84 63 44 20 7 2 9 5 1 1

0 128 109 99 91 88 85 78 75 70 62 58 52 48 45 41 38 37 33 17 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 0

20 40 60 80 100

No. of patients still at risk Placebo

Ribociclib

Time, months

237 189 168 160 144 134 119 105 93 87 74 69 58 56 52 50 47 41 27 19 9

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46

3 3 1 1 109 82 66 62 53 46 35 28 25 23 21 14 12 12 8 8 7 7 0 0

4 2 0 0

20 40 60 80 100

No. of patients still at risk Placebo

Ribociclib

Time, months

Early relapse + second

line

(24)

CDK4/6 inhibitors and

Overall Survival

ET-Resistance

(25)

PALOMA-3 study design 1

Placebo (3 wks on/1 wk off)

+ Fulvestrant

(500 mg IM Q4W)

Palbociclib (125 mg QD;

3 wks on/1 wk off) +

Fulvestrant

(500 mg IM Q4W)

• Visceral metastases

• Sensitivity to prior hormonal therapy

• Pre/peri- vs postmenopausal 2:1 Randomization

N=521

Stratification:

n=347

n=174

• HR+, HER2– ABC

• Pre/peri-* or postmenopausal

• Progressed on prior endocrine therapy:

– On or within 12 months adjuvant – On therapy for ABC

• ≤1 prior chemotherapy regimen for advanced cancer

• Patients must have progressed on prior AI therapy if postmenopausal or TAM if pre/perimenopausal.

• All patients who were pre/perimenopausal at study entry received goserelin during the study.

• Sensitivity to prior hormonal therapy was defined as documented clinical benefit (CR, PR, or SD ≥24 weeks) to ≥1 prior hormonal therapy regimen in the metastatic setting or at least 24 months of adjuvant hormonal therapy before recurrence.

Mod. da Cristofanilli M, et al. ESMO 2018 (Abstract LBA2_PR)

(26)

Overall survival in PALOMA-3 (ITT)

Median 0S, months (95% CI) Palbociclib+Fulvestrant (N=347) 34.9 (28.8–40.0) Placebo+Fulvestrant (N=174) 28.0 (23.6–34.6)

Time (months)

O veral l sur vi val p ro b ab ili ty (% )

Stratified HR=0.81 95% CI (0.64–1.03) 1-sided p=0.043 Unstratified HR=0.79 95% CI (0.63–1.00) 1-sided p=0.025

Absolute improvement in median OS in the palbociclib arm versus the placebo arm was 6.9 months

Metastatic HR+/HER2- BC

Mod. da Cristofanilli M, et al. ESMO 2018 (Abstract LBA2_PR)

(27)

Overall survival by sensitivity to prior ET

HR=0.72

95% CI (0.55–0.94) 1-sided p=0.008

Months

Ov e ra ll su rv iv al p ro b ab ili ty ( % )

In patients with sensitivity to prior ET, absolute improvement in median OS in the palbociclib arm versus the placebo arm was 10.0 months

Median OS, months (95% CI) Palbociclib+Fulvestrant (N=274) 39.7 (34.8–45.7) Placebo+Fulvestrant (N=136) 29.7 (23.8–37.9)

PATIENTS WITH SENSITIVITY TO PRIOR ET

HR=1.14

95% CI (0.71–1.84) 1-sided p=0.70

Months

Ov e ra ll su rv iv al p ro b ab ili ty ( % )

Median OS, months (95% CI) Palbociclib+Fulvestrant (N=73) 20.2 (17.2–26.4) Placebo+Fulvestrant (N=38) 26.2 (17.5–31.8)

PATIENTS WITHOUT SENSITIVITY TO PRIOR ET

Metastatic HR+/HER2- BC

Mod. da Cristofanilli M, et al. ESMO 2018 (Abstract LBA2_PR)

(28)

MONARCH 2: Overall survival of abemaciclib plus fulvestrant in patients with HR+, HER2- advanced

breast cancer

• HR+, HER2- ABC

• Pre/peri- 

a

or postmenopausal

• ET resistant:

– Relapsed on neoadjuvant or on/within 1 yr of adjuvant ET – Progressed on first-line ET for

ABC

• No chemo for ABC

• No more than 1 ET for ABC

• ECOG PS ≤ 1

abemaciclib (n=446): 150 mg

b

  BID (continuous schedule)

fulvestrant: 500 mg 

c

Primary endpoint:

Investigator-assessed PFS Secondary endpoint:

Overall survival

Exploratory analysis:

Time to chemotherapy (TTC) placebo (n=223): BID

(continuous schedule) fulvestrant: 500 mg 

c

Ran d o m iz a tio n

2 :1 N=669

7Cardoso et al. Breast. 2017;35:203-217; 8Cardoso et al. Ann Oncol. 2017;28(12):3111

a Required to receive GnRH agonist

b Dose reduced by protocol amendment in all new and ongoing patients from 200 mg to 150 mg BID after 178 patients enrolled

c  Fulvestrant administered per label

Abbreviations: N, number of patients in population; n, number of patients

Stratification factors:

• Metastatic site (visceral, bone only, or other)

• ET resistance (primary or secondary)  7,8

• Data cut-off: 20 June 2019

• Median follow-up: 47.7 months

• 17% patients (abemaciclib arm) vs 4% (placebo arm)

remained on treatment

(29)

Overall Survival

(30)

Overall Survival by Stratification Factors

30

Site of Metastases

Visceral: lung, liver, pleural, or peritoneal (in the presence or absence of bone metastases)

Bone Only: only in bone

Other: other soft tissue sites (in the presence or absence of bone metastases) Endocrine Resistance (ESO-ESMO guidelines)

7,8

Primary: relapse while on the first 2 years of adjuvant ET, or PD within first 6 months of 1st line ET for MBC, while on ET

Secondary: relapse while on adjuvant ET but after the first 2 years, or relapse within 12 months of completing adjuvant ET, or PD ≥ 6 months after initiating ET for MBC, while on ET

7Cardoso et al. Breast. 2017;35:203-217; 8Cardoso et al. Ann Oncol. 2017;28(12):3111

(31)

Overall Survival by Resistance to Endocrine Therapy

a

Interaction P-value: 0.588 31

(32)
(33)

Exploratory Analysis: Time to Chemotherapy a

© 2019 Eli Lilly and Company

33

aTime to chemotherapy was analyzed from randomization to initiation of first post discontinuation chemotherapy (censoring patients who died prior to initiation of chemotherapy)

(34)

Progression-Free Survival 2

RIB + FUL demonstrated a 10-month improvement in PFS2:

Monaleesa 3-trial

FUL, fulvestrant; HR, hazard ratio; PBO, placebo; PFS2, time to first progression on next-line therapy or death; RIB, ribociclib.

a The first documented progression on next-line treatment was based on investigator assessment of progressive disease.

34 RIB + FUL

PBO + FUL

Pr o gr es si o n -Fr ee Su rv iv al 2 , %

484 470 454 436 422 403 380 353 338 327 313 298 279 264 253 235 226 216 180 126 73 34 11 2 0 0 0 9 2

242 232 224 216 207 197 182 168 160 146 139 128 122 113 109 103 95 85 70 40 21

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 0

20 40 60 80 100

Number of patients still at risk Placebo

Ribociclib

Time, months RIB + FUL PBO + FUL

Events/N 217/484 141/242 PFS2, median,

mo 39.8 29.4

HR (95% CI) 0.670 (0.542 - 0.830)

PFS2 = time from randomization to disease progression on the first new systemic

antineoplastic therapy after discontinuation of

study treatment or death from any cause

a

(35)

484 462 418 395 383 371 350 332 316 297 287 279 263 249 241 223 215 207 175 121 70 34 12 2 0 8 2 0 0 242 228 198 191 181 174 165 149 143 134 126 116 109 102 96 88 83 79 67 39 20

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 0

20 40 60 80 100

No. of patients still at risk Placebo

Ribociclib

Time, months

Time to First Chemotherapy

Time to first chemotherapy was longer with RIB + FUL:

monaleesa -3 trial

FUL, fulvestrant; HR, hazard ratio; NR, not reached; PBO, placebo; RIB, ribociclib; TTC, time to first chemotherapy.

35 RIB + FUL PBO + FUL

Events/N 182/484 115/242

TTC, median,

mo NR 29.5

HR (95% CI) 0.696 (0.551-0.879) N o t Yet R ecei ved C h em o th er ap y, % RIB + FUL

PBO + FUL Landmark analysis

KM Estimat e

RIB + FUL

PBO + FUL 36

months 57.4% 45.2

% 42

months 56.4% 43.7

%

(36)

Progression-Free Survival 2:

MONALEESA 7-TRIAL

Dr Sara Hurvitz

Ribociclib +

ET Placebo + ET

Events/n 126/335 161/337

Median PFS2,

mo Not reached 32.3

HR (95% CI) 0.692 (0.548-0.875)

Kaplan- Meier Estimate

Ribociclib + ET

Placebo + ET

36 months 58.4% 46.2%

42 months 54.6% 37.8%

PFS 2: time from randomization to progression on the next line of therapy or death

Landmark Analysis

(37)

Safety

(38)

Conclusioni

 La terapia ormonale con inibitori delle cicline è il trattamento standard per le donne con carcinoma mammario metastatico ER +/Her 2 –

• Gli inibitori di CDK4/6 hanno dimostrato un vantaggio sia in PFS che in OS determinando una riduzione del rischio di morte di circa il 30% nei diversi studi

• Il prolungamento della PFS2 e del tempo all’inizio della chemioterapia portano ad una migliore qualità di vita.

1L, first line; ABC, advanced breast cancer; CDK4/6, cyclin-dependent kinase 4/6; ET, endocrine therapy; FUL, fulvestrant; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; NR, not reached; OS, overall survival; PBO, placebo; PFS, progression-free survival;

PFS2, time to first progression on next-line therapy; RIB, ribociclib.

38

Riferimenti

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