Ormonoterapia e associazione con CDK 4/6 inhibitors: quali novità?

“Ormonoterapia e

associazione con CDK 4/6 inhibitors: quali novità?”

Prof. Marina E Cazzaniga UOC Centro di Ricerca Fase 1

ASST Monza & Milano Bicocca School of Medicine and Surgery

Contents

1. Are all the CDK 4/6 created equal?

.. And provide same results?

2. Survival data of randomized clinical trials: the end of the story?

.. Or the begin of new questions?

3. The unanswered questions and the unmet clinical needs

Contents

1. Are all the CDK 4/6 created equal?

2. Survival data of randomized clinical trials: the end of the story?

3. The unanswered questions and the unmet clinical needs

PALOMA-2 MONALEESA-2 MONALEESA-7 MONARCH-3

PFS (HR)

Visceral Non-visceral

Bone-only

0.58

0.63

^{^}

0.50

--

0.56

0.57

^{^^}

-- 0.69

0.43

0.50 -- 0.70

0.54

0.47

^{^^^}

-- 0.58

ORR ^{42.1% 40.7% 35.1% 48.2%}

CBR ^{84.9% 79.6% -- 78%}

First-line setting: CDK 4/6 + AIs (clinical trials)

Finn, 2016; Hortobagyi, 2016; Goetz 2017; Tripathy 2018

Are all the CDK 4/6 created equal ?

(..and are the treated populations similar ?)

^

Not defined

^{^^}

Liver or lung

^^^

Liver or lung

ENDOCRINE RESISTANT

< 12 months from adj 22.3%

ENDOCRINE SENSITIVE

De novo 37%

> 12 months from adj 40%

MAINLY ENDOCRINE SENSITIVE MONALEESA-2

MONARCH-3 MONALEESA-7

ENDOCRINE SENSITIVE + RESISTANT PALOMA-2

ENDOCRINE RESISTANT

< 12 & 12-24 months 5.6%

ENDOCRINE SENSITIVE

De novo 34.1%

> 12 months from adj 60.5%

ENDOCRINE RESISTANT

DFI (from diagnosis) </= 12 months 7%

ENDOCRINE SENSITIVE

De novo 40%

DFI (from diagnosis> 12 months 53%

ENDOCRINE SENSITIVE

No adj 34%

TFI > 36 months 62%

TFI < 36 months 28%

CDK 4/6 inhibitors in a prospective view

PRIMARY ENDOCRINE RESISTANCE (relapse during adj or < 12/24 mos

relapse < 6mos 1L) ENDOCRINE SENSITIVITY

77% 22%

PALOMA-2

100%

MONARCH-3

94.5% ^5.6%

MONALEESA-2

93% ^7%

MONALEESA-7

SECONDARY ENDOCRINE RESISTANCE (relapse > 24 mos

relapse > 6mos 1L)

Median PFS 27.6 mos

Median PFS 28.2 mos

Median PFS 25.3 mos

Median PFS 23.8 mos

Contents

1. Are all the CDK 4/6 created equal?

2. Survival data of randomized clinical trials: the end of the story?

3. The unanswered questions and the unmet clinical needs

4

ABC Global Charter 10 goals for the next 10 years

COMPREHENSIVE NEEDS ASSESSMENT DEFINES MOST URGENT AND ACTIONABLE GOALS Done with (almost) all different stakeholders involved in ABC

1 2

3 4

5

6

7

8

9

10

HELP PATIENTS WITH ABC LIVE LONGER BY DOUBLING ABC MEDIAN OVERALL SURVIVAL BY 2025

ENHANCE OUR UNDERSTANDING ABOUT ABC BY INCREASING THE COLLECTION OF HIGH QUALITY DATA

IMPROVE THE QUALITY OF LIFE (QOL) OF PATIENTS WITH ABC

ENSURE THAT ALL PATIENTS WITH ABC RECEIVE THE BEST POSSIBLE TREATMENTAND CARE BY INCREASING AVAILABILITY OF ACCESS TO CARE FROM A MULTIDISCIPLINARY TEAM

MEET THE INFORMATIONAL NEEDS OF PATIENTS WITH ABC BY USING EASY TO UNDERSTAND, ACCURATE AND UP- TO-DATE INFORMATION MATERIALS AND RESOURCES

ENSURE THAT PATIENTS WITH ABC HAVE ACCESS TO TREATMENT REGARDLESS OF THEIR ABILITY TO PAY IMPROVE COMMUNICATION

BETWEEN HEALTHCARE PROFESSIONALS (HCP) AND PATIENTS WITH ABC THROUGH THE PROVISION OF COMMUNICATION SKILLS TRAINING FOR HCPS

COUNTERACT THE STIGMA AND ISOLATION ASSOCIATED WITH LIVING WITH ABC BY INCREASING PUBLIC UNDERSTANDING OF THE CONDITION

ENSURE THAT PATIENTS WITH ABC ARE MADE AWARE OF AND ARE REFERRED TO NON-CLINICAL SUPPORT SERVICES

HELP PATIENTS WITH ABC CONTINUE TO WORK BY IMPLEMENTING LEGISLATION THAT PROTECTS THEIR RIGHTS TO WORK AND ENSURE FLEXIBLE AND ACCOMMODATING WORKPLACE ENVIRONMENTS

OS: still remains an important aim?

Cardoso, ESMO 2018

Evolution of OS over time

Observed Overall Survival From Diagnosis of Metastatic Disease All Patients

Period 2008 2009 2010 2011 2012 2013

Median OS (95% CI)(yrs)

3.12 [2.92-3.31]

2.94 [2.78-3.09]

3.09 [2.94-3.24]

3.23 [3.02-3.48]

3.09 [2.89-3.25]

3.29 [3.09-ND]

Median FU for the whole cohort is 4.05 yrs [95 CI: 3.98-4.12]

Delaloge et al, ASCO 2017, Gobbini et al, EJC 2018

National cohort of 19.898 MBC pts diagnosed between

01/2008 and 12/2016 and treated in 18 Comprehensive

Cancer centers

Overall Survival data – the end of the story?

OVERALL SURVIVAL Monarch-2 Overall Survival MONALEESA-3

The relative reduction in 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)

Pvalue 0.00455

Landmark Analysis

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

KM Estimate

RIB + FUL

PBO + FUL

36 months 67.0% 58.2%

42 months 57.8% 45.9%

OverallSurvival,%

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 00 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

SlamonD et al. ESMO 2019 LBA

MONALEESA-3 Study D esign 1L, first line; 2L, second l ine; ABC, advanced brea st cancer; ECOG PS, Easte rn Cooperative Oncology Group performance stat us;ET, endocrine therapy; HER2 , human epidermal grow th factor receptor 2; HR, hormone receptor; PD, p rogressive disease; PFS, p rogression- free survival; RECIST, Res ponse Evaluation Criteria in Solid Tumors; TFI, trea tment-free interval. Slamon DJ, et al. J Clin On col. 2018;36:2465-247.

Primary end point • PFS (locally assesse d per RECIST version 1.1) Secondary end point s • Overall survival • Overall response rate • Clinical benefit rate • Time to response • Duration of response • Time to definitive deterioration of ECOG PS • Patient-reported outc omes • Safety • Pharmacokinetics

Ribociclib (600 mg/day; 3 weeks on/1 week o ff) + fulvestrant (500 mg) a n = 484 Placebo + fulvestrant (500 mg) a n = 242

Stratified by: •Presence/absence of liver/lung metastases •Prior endocrine therapy

Ra nd

om iz

ed 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

Treatment naive for ABC

TFI > 12 mo De novo ABC

Patient population de finitions = early relapse Slamon D et al. ESMO 20 19 LBA

Only endocrine-resistant

OS data: the end of the story?

OVE RAL L SU RVIV AL ( ITT) 9

−

Abs olut e im prov eme nt in me dian OS in t he p albo cicli b ar m v s th e pl aceb o ar m w as 6 .9 m onth s.

0 6 12 18 24 30 36 42 48 54 Tim e (M onth )

0 10

20

30

40

50

60

70

80

90 100

_{Overall Survival Probability (%)}

Palb ocic lib+ Fulv estr ant (N= 347 ) Me dia n O S=3 4.9 mon ths 95 % C I (2 8.8, 40 .0) Pla ceb o+F ulve stran t (N= 174 ) Me dia n O S=2 8.0 mon ths 95 % C I (2 3.6, 34 .6) Strat ified HR= 0.8 14 95% CI (0.64 4, 1 .02 9) 1-s ide d p= 0.04 29 Uns trati fied HR= 0.7 91 95% CI (0.62 6, 0 .99 9) 1-s ide d p= 0.02 46 347 321 286 247 209 165 148 126 17 PA L+FU L 174 155 135 115 86 68 57 43 7 PB O+ FU L

Nu mb er o f pat ien ts a t ris k

HR=0.81, -19% deaths

OVE RAL L SU RVI VAL BY SU BGR OUP S 10 ESR 1=es troge n rec eptor 1; N E=no t esti mabl e; PI K3CA =pho spha tidylin osito l 3-ki nase , cata lytic s ubun it alp ha. *Pres pecif ied s tratifi catio n fac tors.

†

ESR 1 and PIK3 CA d ata w ere fr om a subs et of patie nts w ho ha d circ ulatin g tum or DN A sam ples and w ho w ere teste d for the m utatio ns.

HR (95 % CI)

PA L+F UL Med ian OS (95 % CI)

PBO +FUL Med ian OS (95 % CI) Inter act ion PV alu e Sub gro up Pat ien ts, n (% )

All randomized patients, ITT, stratified All randomized patients, ITT, unstratified Sensitivity to previous hormonal therapy* Yes No Site of metastatic disease* Visceral Nonvisceral Menopausal status at study entry* Pre/peri Post Prior chemotherapy Metastatic treatment None Prior lines of therapy in metastatic setting 0 1 2 −3 ESR1 mutation status† Positive Negative PIK3CA mutation status† Positive Negative

521 (100) 521 (100) 410 (78.7) 111 (21.3) 311 (59.7) 210 (40.3) 108 (20.7) 413 (79.3) 177 (34.0) 130 (25.0) 114 (21.9) 225 (43.2) 131 (25.1) 51 (9.8) 106 (20.3) 289 (55.5) 133 (25.5) 262 (50.3)

0.81 (0.64–1.03) 0.79 (0.63–1.00) 0.72 (0.55–0.94) 1.14 (0.71–1.84) 0.85 (0.64–1.13) 0.69 (0.46–1.04) 1.07 (0.61–1.86) 0.73 (0.57–0.95) 0.91 (0.63–1.32) 0.68 (0.41–1.15) 0.70 (0.43–1.14) 0.86 (0.60–1.22) 0.76 (0.48–1.22) 0.64 (0.29–1.40) 0.69 (0.43–1.12) 0.85 (0.61–1.19) 0.74 (0.48–1.14) 0.84 (0.59–1.18) 34.9 (28.8–40.0) 34.9 (28.8–40.0) 39.7 (34.8–45.7) 20.2 (17.2–26.4) 27.6 (24.4–31.2) 46.9 (39.3–NE) 38.0 (24.4–NE) 34.8 (28.8–40.1) 25.6 (21.4–30.1) 46.2 (36.5–NE) 36.1 (27.6–43.7) 38.0 (27.7–46.5) 30.0 (23.0–40.1) 34.8 (26.1–NE) 35.6 (23.6–42.0) 36.5 (28.0–43.1) 28.6 (25.3–39.3) 38.8 (28.9–44.5) 28.0 (23.6–34.6) 28.0 (23.6–34.6) 29.7 (23.8–37.9) 26.2 (17.5–31.8) 24.7 (20.8–31.8) 35.4 (24.6–NE) 38.0 (22.2–NE) 27.1 (22.8–32.1) 26.2 (20.0–37.5) 29.7 (22.8–NE) 24.7 (19.5–34.6) 33.8 (23.5–41.4) 24.3 (20.0–29.7) 27.1 (5.3–NE) 24.6 (19.7–33.0) 31.8 (22.8–39.1) 22.2 (15.7–29.5) 33.0 (24.3–41.6)

0.12 0.44 0.25 0.66 0.88 0.60 0.64 0.250.50 In favor of PAL+FULIn favor of PBO+FUL

0.751.001.251.501.752.00

Paloma-3

•S TO P A CC EP TIN G P FS BE NE FIT AL ON E A S T HE M AIN GO AL •O S M US T B E A T L EA ST A C O- PR IM AR Y •I NV EST IN LE SS BU T “ BIG GE R” (S UF FIC IEN TLY PO WE RE D) TR IAL S •C OL LEC T P OS T-P RO GR ESS ION DA TA •U SE RE AL W OR LD DA TA

Cardoso, ESMO 2018

Phase III MONALEESA-7 Trial of Premenopausal Patients With HR+/HER2− Advanced Breast Cancer Treated With Endocrine Therapy ± Ribociclib: Overall Survival Results

Presented By Sara Hurvitz at 2019 ASCO Annual Meeting

Overall Survival

Presented By Sara Hurvitz at 2019 ASCO Annual Meeting

Overall Survival Subgroup Analysis

Presented By Sara Hurvitz at 2019 ASCO Annual Meeting

MONALEESA-7

CDK 4/6 inhibitors in a prospective view

PRIMARY ENDOCRINE RESISTANCE (relapse during ad or < 12j) ENDOCRINE

SENSITIVITY

SECONDARY

ENDOCRINE RESISTANCE

77% 22%

PALOMA-2

100%

MONARCH-3

94.5% ^5.6 _%

MONALEESA-2

93% ^7%

MONALEESA-7

21% 79%

PALOMA-3

25% 73%

MONARCH-2

60%

26% 73%

MONALEESA-3

•S TO P A CC EP TIN G P FS BE NE FIT AL ON E A S T HE M AIN GO AL •O S M US T B E A T L EA ST A C O- PR IM AR Y •I NV EST IN LE SS BU T “ BIG GE R” (S UF FIC IEN TLY PO WE RE D) TR IAL S •C OL LEC T P OS T-P RO GR ESS ION DA TA •U SE RE AL W OR LD DA TA

Cardoso, ESMO 2018

How can we read these data?

EN D OC R INE R ESIS TAN C E

PFS IMPROVEMENT MONALEESA-3

12.8 mos MONARCH-2

9.3 mos PALOMA-2

4.6 mos P2

11.2 mos

M2 16.4 mos

ML2

20.5 mos

Control Arm Performance - Endocrine resistant

PAL OM A-3 3 PFS dat a of fulv estr ant + CD K 4/ 6 in hibi tor P has e III tria ls in ET pret reat ed 1. S lam onD et a l JCO 201 8;36 :246 5-72 ; 2. Sled ge G W e t al JCO 201 7;35 :287 5-84 ; 3. Turn er N et a l. Ne w E ngl J Me d 20 16

MON AR CH -2 2 MON ALEESA -3 1 Leve l of p retre atme ntinc rease sand PFS in co ntrol arm decre ases

PFS1 2.8m onths PFS 9.3m onths PFS 4.6 m onths

LET’S TRY TO PUT DATA IN THE RIGHT PERSPECTIVE

Ov era ll S urv iva l by Lin e o f T her apy OS by lin e o f th era py wa s c ons iste nt wit h o ver all pop ula tio n

FUL, fulvestrant; HR, hazard ratio; OS, overall survival; PBO, placebo; RIB, ribociclib. aThis median value may not be estimated reliably due to the last patient on follow-up, who had an event at 45.1 months.9

Firs t lin e Ea rly re lap se + s ec on d li ne RI B + FU L PB O + FU L Ev en ts/ N 10 2/237 60 /10 9 OS , m ed ian , m o 40 .2 32 .5 HR (95 % CI ) 0.730 (0.530 -1.004) RI B + FU L PB O + F UL Ev en ts/ N 63 /23 7 47 /12 8 OS , m ed ian , mo Not rea ch ed 45 .1

a

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

RI B + F UL PB O + F UL RI B + F UL PB O + F UL

Ov er al l Su rv iv al ,

%

Ov er 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 pa tien ts s till at r isk Pla ceb o Rib oci clib

Tim e, mo nth s No . of pa tien ts s till at r isk 237 229 222 217 214 210 207 206 205 202 194 190 182 174 173 166 163 157 138 92 54 22 0 6 1 128 126 122 121 119 116 113 110 106 104 99 97 93 91 85 84 82 70 40 21 8 2 0 0 Pla ceb o Rib oci clib

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 Tim e, m on ths

0 20

40

60

80 100

OVERALL SURVIVAL

Alltogether these trials have established a very important thing:

finally, in 2019 OS of HR+ ABC patients has improved!

Contents

1. Are all the CDK 4/6 created equal?

2. Survival data of randomized clinical trials: the end of the story?

3. The unanswered questions and the unmet clinical needs

Cardoso, ESMO 2018

Ca n w e id en ti fy w hi ch p at ie nt s be ne fit a nd /o r w hi ch o ne s do n ot be ne fit fr om E T + CD K4 /6 i? Is it b et te r t o us e a CD K4 /6 i i n 1 st lin e or 2 nd lin e (in p re vi ou s ET ex po se d or E T- na ïv e pa ti en ts )? W ill th er e be a ro le fo r “ co nt in ui ng b ey on d pr og re ss io n” ?

PALOMA-2 STEPP Analysis CI=confidence interval; STEPP=Subpopulation Treatment Effect Pattern Plot; TFI=treatment-free interval.

U N CO N FI RM ED P RO BL EM : P RO G RE SS IO N A FT ER C D K4 /6 i I S FA ST ER ? M O RE P O ST -P RO G RE SS IO N D AT A N EE D ED

HERMIONE-7 STUDY

An exploratory, Phase 2, single arm trial evaluating the activity and safety of Abemaciclib+ Aromatase Inhibitors (AIs) after 1st-line

treatment with High-Dose Fulvestrant (HD-FUL) in Hormone-

Receptor-Positive (HR+), Human-Epidermal-Growth-factor-negative (HER2-) advanced breast cancer patients

HD-FUL ABEMA + AIs

Approved September 12, 2019 Centres: 39

HERMIONE-8 STUDY

Prospective evaluation of Ribociclib activity and safety in a real-world setting

Approved September 06, 2018

Centres: 27

Conclusions

1. Are all the CDK 4/6 created equal?

PROBABLY YES, BUT DIFFERENT POPULATIONS ENROLLED MAKE THE PICTURE A BIT CONFUSING

2. Survival data of randomized clinical trials: the end of the story?

NOT YET, MORE DATA ARE NEEDED, ESPECIALLY IN ENDOCRINE-SENSITIVE PTS

3. The unanswered questions and the unmet clinical needs

LOTS OF TRIALS ONGOING, WE WILL WAIT FOR RESULTS