Tratamiento inicial de pacientes posmenopáusicas con cáncer de mama HR+/her2- metastásico: Una...

Tratamiento inicial de cáncer de mama en pacientes posmenopáusicas

HR+/Her2- metastásico: una visión panorámica

Mauricio Lema Medina MDClínica de Oncología Astorga / Clínica SOMA, Medellín

Medellín, 11.11.2016

@Onconerd

1970s Tamoxifen 20% 26wks38%

ORR CBR PFS/TTF

Does chemotherapy increase response-rate over hormonal therapy in HR+

aBC?

CMF vs Tam

CMF vs Tam + Androgen

FU vs Androgen

AC vs Tam

FACV vs Various

Chemotherapy alone versus endocrine therapy alone for metastatic breast cancer (Review)

Wilcken N, Cochrane, 2003

A Randomized Trial in Postmenopausal Patients With Advanced BreastCancer Comparing Endocrine and Cytotoxic Therapy Given

Sequentially or in Combination

ANZBCTG, JCO (1986): 4; 186-193

CR + PR + NC 76% 81% 84%

A Randomized Trial in Postmenopausal Patients With Advanced BreastCancer Comparing Endocrine and Cytotoxic Therapy Given

Sequentially or in Combination

ANZBCTG, JCO (1986): 4; 186-193

Does chemotherapy increase response-rate over hormonal therapy in HR+ aBC?

No solid phase III evidence can support this notion

What is the optimal first-line chemotherapy in aBC?

Paclitaxel and epirubicin versus paclitaxel and carboplatin as first-line chemotherapy in patients with advanced breast cancer: a phase III study conducted by the Hellenic

Cooperative Oncology Group

Fountzilas G, Ann Oncol, 2004

Paclitaxel Epirubicin

Paclitaxel CarboplatinRMBC

327 patientsUnknown Her2 statusBoth ER+ and ER- Endpoint: OS

Paclitaxel and epirubicin versus paclitaxel and carboplatin as first-line chemotherapy in patients with advanced breast cancer: a phase III study conducted by the Hellenic

Cooperative Oncology Group

Fountzilas G, Ann Oncol, 2004

Paclitaxel Epirubicin

Paclitaxel CarboplatinRMBC

327 patientsUnknown Her2 statusBoth ER+ and ER- Endpoint: OS

TTF

Paclitaxel + Carboplatin: 10.8 mo

Paclitaxel + Epirubicin: 8.1

OS

Paclitaxel + Carboplatin

Paclitaxel + Epirubicin

NS: 22-27mo

A randomized phase III study comparing three anthracycline-free taxane-based regimens, as first line chemotherapy, in metastatic breast cancer

Fountzilas G, Breast Cancer Res Treat, 2009

Docetaxel + Gemcitabine q3w

Weekly paclitaxel

RMBC416 patientsER+: 65%Triple negative: 15%Trastuzumab in 6 patients Endpoint: OS

OS

Paclitaxel + Carboplatin q3w

OSPaclitaxel + Carboplatin: 29.9 moDocetaxel + Gemcitabine: 26.9 moWeekly Paclitaxel: 41.0 mop=0.037

PFS11 mo



PCb vs Weekly paclitaxel

2009 Weekly paclitaxel 49% 47wks75%

Fountzilas, Breast Cancer Res Treat, 2009

ORR CBR PFS/TTF

ER+/ER-/Her2+

What is the optimal first-line chemotherapy in aBC?

Weekly paclitaxel appears to be superior to combination agents in

“all-comers” with aBC

What is the optimal first-line single-agent hormonal therapy in

HR+/Her2- aBC?

2001 Tamoxifen 20% 26wks38%

Letrozole 30% 41wks49%

Mouridsen H, JCO, 2001

HR: 0.7

ORR CBR PFS/TTF

ER/PR status unknown in some

ESMO-2016, Copenhagen, 7-11 October 2016

Fulvestrant

Anastrozole


A phase 3 trial confirms a phase 2 trial (FIRST).

Fulvestrant appears less effective in visceral metastases.

All patients where hormonotherapy naïve.




HR: 0.7

2016 Anastrozole 44% 58wks74%

Fulvestrant 46% 71wks78%

Ellis, ESMO 2016, LBA14_PR

HR: 0.79

FALCON Hormone-naïve

ORR CBR PFS/TTF





HR: 0.7

2016 Anastrozole 44% 58wks74%

Fulvestrant 46% 71wks78%

Ellis, ESMO 2016, LBA14_PR

HR: 0.79

FALCON Hormone-naïve

ORR CBR PFS/TTF


2016 Anastrozole 53wks

Fulvestrant 93wksHR: 0.79

FALCON Non-pulmonary & Non-liver metastases Ellis, ESMO 2016, LBA14_PR

What is the optimal first-line single-agent hormonal therapy in

HR+/Her2- aBC?

Fulvestrant is superior to AIs and displays a remarkable OS in non-

visceral metastatic in de-novo aBC

What about non-hormone naïve progressive HR+/Her2- aBC?

LTED cells exhibit PI3K/mTOR pathway hyperactivation and variable response to E2.

ER+ cell-lines: MCF-7, ZR75-1, MDA-361LTED: Long-term estrogen deprivedControls: Actin / AKTER expression: ERPI3k/mTOR expression: p-S6K/p-AKT https://doi.org/10.1172/JCI41680Miller TW, JCI, 2010

PI3K pathway inhibition suppresses hormone-independent cell growth

ER+ cell-lines: MCF-7, ZR75-1, MDA-361LTED: Long-term estrogen deprivedBEZ235 (Dactolisib): PI3k/mTOR inhibitorRAD0001 (Everolimus): mTOR inhibitorAEW541: IGR-1R inhibitorLapatinib: EGFR/Her2 inhibitor https://doi.org/10.1172/JCI41680Miller TW, JCI, 2010

Anti ER treatment with Fulvestrant induces PI3k pathway activation

Fox EM, Arteaga CL, Miller TW. Frontiers in Oncology, 2012

Hortobagyi GN et al. SABCS 2011;Abstract S3-7.

Postmenopausal, ER-positive locally advanced or metastatic breast cancerProgression on letrozole or anastrozole(n = 724)

R

Everolimus – 10 mg daily+

Exemestane – 25 mg daily

(n = 485)

Placebo+

Exemestane – 25 mg daily

(n = 239)

Stratification: Sensitivity to prior hormonal therapy and presence of visceral metastases

Endpoints:• Primary: Progression-free survival (PFS) by local assessment• Secondary: Overall survival, overall response rate, quality of life,

safety, bone markers, pharmacokinetics

BOLERO-2 Study Design

Patients with primary resistance were those relapsing during or within 6

months of stopping adjuvant AI treatment or progressing within 6

months of starting AI treatment in the metastatic setting

Response and Clinical Benefit

Everolimus + Exemestane

Placebo + Exemestane

Response Clinical Benefit

Perc

ent

12.0%

1.3%

50.5%

25.5%

P < 0.0001

P < 0.0001

Baselga J, et al. N Engl J Med. 2012;366:520-529.

BOLERO-2: Everolimus + Exemestane Improves PFS in HR+ MBC


0 6 12 18 24 30 36 42 48 54 60 66 72 78Wks

Prob

abili

ty o

f Eve

nt (%

)

Everolimus + exemestane(median PFS: 10.6 mos)Placebo + exemestane(median PFS: 4.1 mos)

HR: 0.36 (95% CI: 0.27-0.47;log-rank P < .001)

Patients at Risk, nEverolimusPlacebo

485239

385168

28194

20155

13233

10220

6711

4311

286

183

93

31

20

00

100908070605040302010

0

Central Assessment

BOLERO-2: Final PFS Analysis (18-Mo Follow-up)PFS, Mos EVE + EXE PBO + EXE HR (95% CI) P Value

Local review 7.8 3.2 0.45(0.38-0.54)

< .0001

Central review 11.0 4.1 0.38(0.31-0.48)

< .0001

With visceral mets 6.83 2.76 0.47(0.37-0.60)

--

Without visceral mets 9.86 4.21 0.41(0.31-0.55)

--

Bone-only mets 12.88 5.29 0.33(0.21-0.53)

--

Progression after neo/adj therapy

11.50 4.07 0.39(0.25-0.62)

--

OS data still not mature (HR: 0.77; 95% CI: 0.57-1.04) Most common grade 3/4 AEs were stomatitis (8%), hyperglycemia

(5%), fatigue (4%)


Common Adverse Events

Everolimus + Exemestane

(n = 482)

Placebo + Exemestane

(n = 238) All Grades Grade 3/4 All Grades Grade 3/4

Stomatitis 59% 8% 11% <1%Rash 39% 1% 6% 0Fatigue 36% <5% 27% 1%Diarrhea 33% <3% 19% <1%Decreased appetite 30% 1% 12% <1%Nausea 29% <2% 28% 1%Noninfectious pneumonitis 15% 3% 0 0

Hyperglycemia 14% <6% 2% <1%


Bolero-2: OS of Exemestane + Everolimus in mBC

Piccert M, et al. Ann Oncol 2014

2012 Exemestane (E) 1% 17wks25%

Everolimus + E 13% 49wks50%

Baselga, NEJM, 2012

ORR CBR PFS/TTF

Progressing after neoadjuvant therapyCentral review

Royce, M. ESMO (2016), Abstract 2220

BOLERO-4: Phase 2 trial of first-line everolimus (EVE) plus letrozole (LET) in estrogen receptor–positive (ER+), human epidermal growth factor receptor

2–negative (HER2−) advanced breast cancer (BC)


ORR CBR PFS/TTF

2016 Fulvestrant 46% 71wks78%

2001 Letrozole 30% 41wks49%

2012 Eve + Exe 13% 49wks50%


ORR CBR PFS/TTF



2012 Eve + Exe 13% 49wks50%


PALOMA-2: Addition of Palbociclib to Frontline Letrozole Significantly Improves PFS in

Postmenopausal ER+/HER2- Advanced Breast Cancer

PALOMA 2: Study Design • Multicenter, international, double-blind, randomized phase III trial

• Primary endpoint: PFS by investigator• Secondary endpoints: response, OS, safety, biomarkers, pt-reported

outcomes

Postmenopausal women with ER+/HER2- advanced

breast cancer, no prior treatment for advanced

disease, no AI resistance(N = 666)

Stratified by disease site (visceral vs nonvisceral), disease-free interval (de novo metastatic; ≤ 12 mos vs > 12 mos), prior neoadjuvant or adjuvant hormonal therapy (yes vs no)

Palbociclib 125 mg QD (3/1 schedule)+ Letrozole 2.5 mg QD

(n = 444)

Placebo (3/1 schedule)+ Letrozole 2.5 mg QD

(n = 222)

Slide credit: clinicaloptions.comFinn R, et al. ASCO 2016. Abstract 507.

http://www.clinicaloptions.com/oncology

Slide credit: clinicaloptions.com

PALOMA 2: Baseline Characteristics (ITT)

CharacteristicPalbociclib + Letrozole

(n = 444)Placebo + Letrozole

(n = 222)

Median age, yrs (range) 65 yrs or older, %

62 (30-89)41

61 (28-88)36

Race, %White/Black/Asian/other 77/2/15/6 77/1/14/8

ECOG PS, %0/1/2 58/40/2 46/53/1

Disease site, %VisceralNonvisceral

• Bone only

485223

505022

Disease-free interval, %> 12 mos≤ 12 mosDe novo advanced disease

402238

422236

Prior (neo)adjuvant hormonal therapy, % 56 57

Finn R, et al. ASCO 2016. Abstract 507.


PALOMA 2: PFS

• Blinded independent central review confirmed investigator-assessed PFS advantage

• Benefit with palbociclib + letrozole evident across all subgroups


OutcomePalbociclib +

Letrozole (n = 444)

Placebo + Letrozole (n = 222)

HR (95% CI); P Value

Investigator-assessed Number of events, n (%) Median PFS, mos (95% CI)

194 (44)24.8 (22.1-NR)

137 (62)14.7 (12.9-17.1)

0.58 (0.46-0.72); < .000001

Blinded independent central review Number of events, n (%) Median PFS, mos (95% CI)

152 (34)30.5 (27.4-NR)

96 (43)19.3 (16.4-30.6)

0.65 (0.51-0.84);

.0005


Outcome[1] Palbociclib + Letrozole

Placebo + Letrozole OR (95% CI) P Value

ITT populationORR,* % (95% CI)CBR,† % (95% CI)

n = 44442 (37.5-46.9)85 (81.2-88.1)

n = 22235 (28.4-41.3)70 (63.8-76.2)

1.40 (0.98-2.01)2.39 (1.58-3.59)

.0310< .0001

Pts with measurable diseaseORR,* % (95% CI)CBR,† % (95% CI)

n = 33855 (49.9-60.7)84 (80.0-88.0)

n = 17144 (36.9-52.2)71 (63.3-77.5)

1.55 (1.05-2.28)2.23 (1.39-3.56)

.0132

.0003

PALOMA 2: Secondary Endpoints

• Clinical benefit consistent with phase II open-label PALOMA-1 study[2]

Slide credit: clinicaloptions.com

*Confirmed CR + PR. †Confirmed CR + PR + SD ≥ 24 wks.

1. Finn R, et al. ASCO 2016. Abstract 507. 2. Finn RS, et al. Lancet Oncol. 2015;16:25-35.


PALOMA 2: Safety

AEs (All Causality), % Palbociclib + Letrozole (n = 444) Placebo + Letrozole (n = 222)Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4

Any AE 99 62 14 95 22 2Hematologic AE in ≥ 15% of pts in either arm Neutropenia* 80 56 10 6 1 < 1 Leukopenia* 39 24 1 2 0 0 Anemia* 24 5 < 1 9 2 0 Thrombocytopenia* 16 1 < 1 1 0 0

Nonhematologic AE in ≥ 25% of pts in either arm Fatigue 37 2 0 28 < 1 0 Nausea 35 < 1 0 26 2 0 Arthralgia 33 1 0 34 0 0 Alopecia 33 0 0 16 0 0 Diarrhea 26 1 0 19 1 0 Cough 25 0 0 19 0 0 Headache 21 < 1 0 26 2 0 Hot flush 21 0 0 31 0 0

*Includes clustered MedDRA-preferred terms.

Finn R, et al. ASCO 2016. Abstract 507. Slide credit: clinicaloptions.com


PALOMA 2: AE Summary

• Most AEs resulting in d/c reported as single events, most commonly neutropenia with palbociclib (1.6%) or fatigue with placebo (0.9%)

• One on-study, treatment-related death because of pulmonary embolism/respiratory failure in placebo arm


Outcome, % Palbociclib + Letrozole (n = 444)

Placebo + Letrozole (n = 222)

Serious AE 19.6 12.6

Serious AE occurring in ≥ 1% of ptsFebrile neutropeniaPulmonary embolism

1.60.9

01.4

AE-related discontinuation 9.7 5.9

AE-related death 2.3 1.8


PALOMA 2: Conclusions• First-line palbociclib + letrozole significantly improved median PFS vs

placebo + letrozole in women with ER+/HER2- advanced breast cancer– Median PFS improved by > 10 mos compared to placebo

• 24.8 mos vs 14.5 mos, HR: 0.58 (95% CI: 0.46-0.72; P < .0001)

• Palbociclib clinical benefit observed in all prespecified subgroups• Palbociclib well tolerated with neutropenia, leukopenia the most

frequently reported AEs• PALOMA-2[1] data confirm PALOMA-1[2] results and constitute the longest

median PFS improvement to date in the front-line setting in advanced ER+ breast cancer

Slide credit: clinicaloptions.com1. Finn R, et al. ASCO 2016. Abstract 507.2. Finn RS, et al. Lancet Oncol. 2015;16:25-35.


2016 Letrozole (L) 35% 61wks70%

Palbociclib + L 42% 103wk85%

Baselga, NEJM, 2012

ORR CBR PFS/TTF

PALOMA-2


ORR CBR PFS/TTF



2012 Eve + Exe 13% 49wks50%


2016 Letrozole (L) 35% 61wks70%

Palbociclib + L 42% 103wk85%

Hormone-resistant

Hormone-naïve

Non-HR+ included

Gets better with time

Unavailable

>77 mo in 1st/2nd Line

HR+/Her2- aBC

What’s needed?Sprint

Marathon

Hormone-naïve

Hormone-resistant

Neither

Where does the patient belong

In short…

Hormone-naïve

Sprint Hormone-resistant

Neither

Paclitaxel / anti-CDK4 + AI / Fulvestrant

Paclitaxel / probably anti-CDK4 + AI / Fulvestrant / AI

Paclitaxel / anti-CDK4 + AI / Fulvestrant / AI

ie, visceral crisis

Hormone-naïve

Marathon Hormone-resistant

Neither

Fulvestrant / Anti-CDK4 + AI / AI / Paclitaxel

Eve + Exe / Paclitaxel / probably CDK4i + AI / Fulvestrant

CDK4i + Letrozole / probably Fulvestrant / probably Eve + Let / Paclitaxel

ie, low-risk disease

Approx 10% of patients

Approx 90% of patients

@Onconerd

Tratamiento inicial de pacientes posmenopáusicas con cáncer de mama HR+/her2- metastásico: Una...

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