Current standards and practice changing studies in ...€¦ · Metastatic Breast Cancer (MBC) Landscape 2 HER2+ Triple negative ~15%5 HER=human epidermal growth factor receptor; HR+=hormone

Current standards and practice changing studies in Advanced breast

cancer 2017

Shaheenah Dawood MBBCh, FRCP(Glasgow), FRCP (Edin), FACP, MPH

Consultant Medical Oncologist

April 6th 2018

ESMO, Dubai 2018

Metastatic Breast Cancer (MBC) Landscape

2

HER2+Triple negative

~15%5

HER=human epidermal growth factor receptor; HR+=hormone receptor-positive.1. Early Breast Cancer Trialists’ Collaborative Group, et al. Lancet. 2015;386:1341-1352. 2. O’Shaughnessy J. Oncologist. 2005;10(suppl 3):20-29. 3. National Cancer Institute. SEER cancer statistics review (CSR) 1975-2012. http://seer.cancer.gov/csr/1975_2012/. Accessed April 19, 2016. 4. Mayer M, Grober SE. Silent voices: women with advanced (metastatic) breast cancer share their needs and preferences for information, support, and practical resources. https://www.researchgate.net/publication/274510595_Silent_Voices_Women_with_Advanced_Metastatic_ Breast_Cancer_Share_ Their_Needs_and_Preferences_for_Information_Support_and_Practical_Resources. Accessed April 19, 2016. 5. Howlader N, et al. J Natl Cancer Inst. 2014;106(5):dju055.

Women living with MBC4

HR+

HR+/HER2-~61%5

HR+/HER2+~15%5

HR-/HER2+~9%5

Roughly 20% to 30% of women who have had early

disease will develop advanced or metastatic disease1,2

4% to 9% of all women with breast cancer present with metastatic disease at the time of initial diagnosis3

Improved survival overall and among patients with ER + disease

Questions addressed in 2017

1. Are CDK4/6 inhibitors for everyone ?

1st line hormonal therapy

1st line chemotherapy

Determine sites and extent of disease & symptoms; ER status; HER2 status;

disease free & treatment-free intervals; performance status

No Response

No life-threatening diseaseHormone-responsive

Hormone-unresponsive, orLife-threatening disease

ResponseNo

Response

2nd-line hormonal therapy

2nd-line chemotherapy

Progression

Progression

Progression

Progression

3rd-line hormonal therapy

Response

No Response

3rd-line chemotherapy

Supportive care

Algorithm for Management of Post-menopausal ER+ MBC

Median PFS 3-4 mo

Median PFS 12-15 mo

So many options :Endocrine therapy +/- X in 2017

1. AI + everolimus2. AI + CDK4/6 inhibitor3. Faslodex + CDK4/6 inhibitor4. Faslodex alone5. AI alone6. Tamoxifen

Options

Endocrine therapy alone

- AI

- Fulvestrant

- Tamoxifen

Endocrine therapy +everolimus

Endocrine therapy +palbociclib/Ribociclib/

Abemaciclib

What are your endocrine options in first line endocrine sensitive disease in

2018?

Can we improve upon a median PFS of 10 -12 months afforded by AIs? AT what cost (QOL, AE, price etc..

Important trials to consider in an endocrine sensitive scenario

PALOMA 2

Letrozole 2.5mg odPlacebo

Letrozole 2.5 mg odPalbocilib 125 mg od

Finn et al NEJM 2016Phase IIIPost menopausalNo prior treatment for metastatic diseasePFS 14.5 m vs 24.8 mHR 0.58 (p=<0.0001)

FALCON

Faslodex 500mg IM

ARIMEDEX 1mg od

Ellis et al ESMO 2016Phase IIINo prior endocrine therapy for MBCLargely denovo diseasePFS 16.6 m vs 13.8 mHR 0.797 (significant)

MONALESSA2

Letrozole 2.5mg odPlacebo

Ribociclib 600mg odLetrozole 2.5mg od

Hortobagyi et al NEJM 2016Phase IIILargely denovo disease and >24 m from adj/neoPFS 16 m vs not 25.3m HR 0.56 (significant)

Hortobagyi, et al NEJM 2016, Finn et al NEJM 2016, Ellis et al Lancet oncology 2016, Dickler et al ESMO 2017

MONARCH 3

Letrozole or anastrazolePlacebo

abemaciclib 600mg odLetrozole or anastrazole

Dickler et al ESMO 2017Phase IIILargely denovo disease and >12 m from adj/neoPFS 14.7 m vs not Not reachedHR 0.543 (significant)

SENSITIVE POPULATION




Registration trials of CDK4/6 inhibitors- first line AI sensitive

HR 95% confidence interval

PALOMA 2(palbociclib) 0.58

(0.46,0.72)

MONALEESA 2(ribociclib) 0.58 (0.46,0.70)

MONARCH 3(abemaciclib)

0.54 (0.41,0.72)

Similar efficacy across all CDK4/6 inhibitors: Class effect

Is efficacy and safety of CDK4/6 inhibitors similar among older patients?

Singh H et al, SABCS 2017

Adverse events < 65 years(N=625)

>= 65 yearsN=479)

>70 years(N=280)

Grade 1-2

98% 98% 99%

Grade 3-466% 80% 82%

Grade 5 1% 2% 3%

Grade 3-4 neutropenia

52% 55% 55%

Diarrhea 32% 49% 51%

Is efficacy and safety of CDK4/6 inhibitors similar among older patients?

Severity of adverse events and rates of dose modifications and interruptions higher in those >=65 and > 70 years

Can CDK4/6 inhibitors be safely given among pre menapausal women and in combination with

tamoxifen ?MONALEESA -7

Tripathy D et al, SABCS 2017

Subgroup n (%) Favors ribociclib Favors placebo Hazard ratio 95% CI

All patients 672 (100) 0.553 0.441–0.694

Endocrine therapy

partner

Tamoxifen

NSAI

177 (26)

495 (74)

0.585

0.569

0.387–0.884

0.436–0.743

Age<40 years

≥40 years

186 (28)

486 (72)

0.443

0.590

0.293–0.671

0.449–0.777

Race‡Asian

Non-Asian

198 (29)

413 (61)

0.401

0.657

0.258–0.625

0.492–0.877

ECOG performance status§0

≥1

500 (74)

166 (25)

0.549

0.495

0.417–0.721

0.320–0.765

ER/PgR statusER+ and PgR+

Other

572 (85)

100 (15)

0.574

0.444

0.446–0.739

0.258–0.765

Liver and/or lung involvementNo

Yes

329 (49)

343 (51)

0.642

0.503

0.454–0.907

0.375–0.677

Bone-only diseaseNo

Yes

513 (76)

159 (24)

0.533

0.703

0.415–0.686

0.414–1.194

Prior chemotherapy for advanced

disease

No

Yes

578 (86)

94 (14)

0.566

0.547

0.443–0.724

0.314–0.954

Disease-free interval

≤12

months

>12

months

De novo

36 (5)

366 (54)

270 (40)

0.560

0.615

0.428

0.210–1.490

0.455–0.832

0.287–0.640

PFS subgroup analysis*

• ER, estrogen receptor; PgR, progesterone receptor.*Locally assessed PFS; ‡Non-Asian race includes Caucasian, Black, and Native American;

§ECOG performance status missing for n=6; 1 patient had an ECOG performance status of 2.

0.125 0.25 0.5 1 2 4

Hazard ratio (95% CI)

8

Can addition of a CDK4/6 inhibitor reverse resistance developed by a particular endocrine

therapy

Endocrine therapy A Endocrine therapy B

Endocrine therapy A Endocrine therapy A + CDK4/6

- activity seen with single agent palbo

- PFS of endocrine therapy + palbo = 10.8m – similar to paloma 3

To Reverse Endocrine resistance (TREnd) trial:Phase II, open-label, multicenter, two-stage, non-

comparative trialAim:

• To test the activity and safety of palbociclib in moderately pretreated patients with HR+/HER2–mBC as a single agent and in combination with the same ET received prior to progression

Does everyone need first line combination therapy or is single

agent enough in subsets?

Do we have strong evidence that the combination of CDK4/6

inhibitors + endocrine therapy should always be the up front

option?

Yes!

Are there subgroups who might not benefit from palbociclib: PALOMA 2

Benefit consistent across all subgroups!

Case 138 years old lady

Stage II breast cancerER + / Her2 negative

AC – taxol , surgery, radiationAI /zoladex1 year DFS

3 four liver mets, multiple bone mets

Biopsy : ER +/ HER2 –ve, ki 67 50%

Case 265 years old lady

Stage I ER+/HER2-Tamoxifen

DFS 12 years2 Bone and 1 lung mets

Low volumeLow volume disease

Does everyone need first line combination therapy or is single agent enough

in subsets?

Yes But….Perhaps not necessarily in all patients!


Exploratory sub group analysis MONARCH -3

Patients with long treatment free interval or bone only disease single agent endocrine

therapy upfront may be sufficient


In the absence of clinical trial data perhaps certain criteria can help select patients that will do well with AI alone:

1. Long DFI2. low volume disease3. Non visceral mets4. Low grade5. Less aggressive biology

The absolute benefit of CDK 4/6 inhibitors maybe less ?

Biomarkers we have in the clinic!

ER PR HER2

In the clinic tomorrow what do we do ?

Use clinical features and your clinical acumen !

BOLER0-2

Exemestane 25mgPlacebo

Exemestane 25mg +Everolimus 10mg

MONARCH 2

Faslodex 500mg IMPlacebo

Faslodex 500mg IMAbemaciclib 150mg bd

PALOMA 3

Faslodex 500mg IMPlacebo

Faslodex 500mg IMPalbocilib 125mg od

Piccart et al SABCS 2012- updated analysisPhase IIIProgressed on AIApprox 80% received ttt for MBCPFS 3.2 m vs 7.8 mHR 0.45 (95%CI 0.38-0.54,p <0.0001)

Cristofanilli M et al Lancet oncology 2016Phase IIIPeri/post menapausalProgressed on prior endocrine therapyOne prior line of chemo allowedPFS 4.6 m vs 11.2 mHR 0.42 (p<0.0001)

RESISTANT POPULATION

RESISTANT POPULATION

GW Sledge et al ASCO 2017Phase IIIPeri/Post menopausalProgressed on prior endocrine therapyPFS 9.3m vs 16.4 mHR 0.553 (p<0.0001)

Important phase III trials in second line setting and beyond

RESISTANT POPULATIONApproximately 5-7 month improvement if PFS

Piccart et al NEJM 2012Sledge et al ASCO 2017

Turner et al 2015

2nd Line Endocrine Therapy: BOLERO, PALOMA, MONARCH

BOLERO-2PALOMA-3

MONALESSA-2

MONARCH -2

Piccart et al NEJM 2012Sledge et al ASCO 2017

Turner et al 2015

First line therapy with CDK4/6 associated with more rapid

response


1. Are CDK4/6 inhibitors for everyone ?2. Can we improve on anti HER2 therapy in the advanced setting?

Pivotal Combination Trial of First-Line Chemotherapy Trastuzumab

in MBC

Treatment Response rate

Time to Progression(months)

Median survival (months)

Chemotherapy 32% 4.6 20.3

Chemotherapy+

Trastuzumab50% 7.4 25.1

Difference 18% 2.8 4.8

Slamon et al. N Engl J Med. 2001;344:783.

Estimated life-years saved with trastuzumab in first-line

HER2-positive mBC (1999–2013)

Danese M, et al. ASCO 2013 (Abstract 625).

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 20130

50,000

75,000

100,000

125,000

150,000

175,000

200,000

25,000

Calendar year

Cum

ulative

life-years

save

d

Upper limit

Lower estimate

Mean estimate

Anti –HER2

Trastuzumab lapitinib Pertuzumab TDM-1 Niratinib

Plethora of anti –HER 2 agents available: Major advances over the past 15 years

Important trials to consider in the HER2 positive metastatic setting

CLEOPATRA

Trastuzumab +Docetaxel

Trastuzumab + Pertuzumab+ Docetaxel

Swain et al NEJM 2015Phase IIINo prior treatment for metastatic diseasePFS 12.4 m vs 18.7 mHR 0.68 (p=<0.0001)OS 40.8 m vs. 56.5 m

TH3RESA

Physician Choice

TDM-1

Krop et al Lancet oncology 2017Phase III>=2 prior anti HER2 lines of therapy60% >= lines of therapyPFS 3.3 m vs 6.2 mHR 0.55 (p=<0.0001)

EMILIA

Lapatinib +XELODA

TDM-1

Dieras et al Lancet oncology 2017Phase IIIPrior taxane/trastuzumabProgression on metastatic therapyPFS 6.4 m vs 9.6 mHR 0.65 (p=<0.0001)OS 25.9 vs. 29.9m HR 0.75 p =0.0003

1st line therapy

Questions in the first line setting

CLEOPATRA




Is there a role for TDM-1 in the first line setting ?

MARIANNEPhase III

Trastuzumab +Taxane

TDM-1 + Placebo

TDM-1 + Pertuzumab

Perez et al , ASCO 2017

Addition of P clearly superior

Role of TDM-1 in the first line setting has yet to be defined!

HER-2 POSITIVE MBC: 1st line

The standard 1st line therapy for patients previously untreated with anti-HER-2 therapy is the combination of CT + trastuzumab and pertuzumab, because it has proven to be superior to CT + trastuzumab in terms of OS in this population. (LoE: 1 A) (86%)

HER-2 POSITIVE MBC: 1st line

For patients previously treated (in the (neo)adjuvant setting) with anti-HER-2 therapy, the combination of CT + trastuzumab and pertuzumab is an important option for 1st

line therapy. (LoE: 1 A) (76%)

Few (88) of these pts were treated in the Cleopatra trial and all with trastuzumab-free interval > 12 months.


CLEOPATRA




Do all women with HER2 positive MBC require chemotherapy? Can we de escalate therapy?

60 years old womanMBC HER2 positiveER / PR positiveOne liver metBone metsStage IV denovo

TANDEM

Trastuzumab +Anastrazole

Anastrazole

Kaufmann et al JCO 2009Phase IIINo prior treatment for metastatic diseasePFS 5.6 m vs 3.6 mp=0.006)


T + AI/Doc

P+T+ AI/DOC

Improvment

HR

TANDEM 5.6m

PERTAIN 15.8 m 18.09 2.29m 0.65

CLEOPATRA (ALL)

12.4m 18.7 6.3m 0.68

CLEOPATRA (HR+)

0.73

Authors concluded that PERTAIN met its primary end point:P+T+AI was superior to T +AI

PERTAIN (Phase II)

ALTERNATIVE: Study Design

Authors conclusion: LAP+TRAS+ AI an effective

alternative option in patients not intended for

chemotherapy


CLEOPATRA




60 years old womanMBC HER2 positiveER / PR positiveOne liver metBone metsStage IV denovo

YES : PFS prolongation, less toxicityNO: No OS benefit, response rates higher with THP

Consider in patients with limited tumor burden or those not considered candidates for chemotherapy?


Should we use endocrine therapy+dual blockade for ER+/HER2+ disease?

For highly selected patients* with ER+/HER-2+ MBC, for whom ET is chosen over CT, ET should be given in combination with anti-HER-2 therapy (either trastuzumab or lapatinib) since the combination provides PFS benefit (i.e. “time without CT”) compared to ET alone. (LoE: 1 A) (72%)

The addition of anti-HER-2 therapy to ET in the 1st line setting has not led to a survival benefit but long-term follow was not collected in the available trials.In addition, this strategy is currently being directly compared with CT + anti-HER2 therapy.

ER + / HER-2+ MBC

* Defined in the manuscript


CLEOPATRA




TH3RESA

Physician Choice

TDM-1


EMILIA

Lapatinib +XELODA

TDM-1


1st line therapy

2nd line therapy

Verma S, et al. N Engl J Med 2012Dieras et al , Lancet oncology, 2017

3.2m improvement in PFS

4m improvement in OS

EMILIA Trial


CLEOPATRA




TH3RESA

Physician Choice

TDM-1


EMILIA

Lapatinib +XELODA

TDM-1


1st line therapy

2nd line therapy

Beyond 2nd line therapy

11

2013

PFS by Investigator Assessment

Median follow-up: TPC, 6.5 months; T-DM1, 7.2 months.

Unstratified HR=0.521 (P<0.0001).

198 120 62 28 13 6 1 0

404 334 241 114 66 27 12 0

TPC

T-DM1

No. at risk:Time (months)

1412108642

0.0

0.2

0.4

0.6

0.8

1.0

0

Pro

po

rtio

n p

rog

ressio

n-f

ree

TPC

(n=198)

T-DM1

(n=404)

Median (months) 3.3 6.2

No. of events 129 219

Stratified HR=0.528 (95% CI, 0.422, 0.661)

P<0.0001

3 months benefit PFS,

Krop et al, Lancet Oncology 2017

6.9 m improvement in OS

TH3RESA: A Phase III Trial of T-DM1 vs TPC

- 60-65% had > 4 lines of therapy- 80% of patients on the TPC arm

received trastuzumab based regimen


1. Are CDK4/6 inhibitors for everyone ?2. Can we improve on adjuvant anti HER2 therapy?3. Can we improve therapy in the realm of TNBC?

Options

Immunotherapy PARP inhibitorsNovel

chemotherapeutic approaches and agents

Improving therapy among patients with TNBC

Cohort A N=170

Previously treated

Cohort BN=52

First line therapyPDL-1 +

ORR 4.7%

(regardless of PDL-1)23%

DCR7.6%

PDL1 + = 9.5%PDL1 - = 4.7%

23%

DOR 6.3m 8.4m

PFS 2.0m 2.1m

OS

8.9mNot reached among

responders and thosewith stable disease

NR

Keynote 086: Phase II trial pembrolizumabmonotherapy among patients with metastatic TNBC

Adams S, et al. ASCO 2017

Combination of Immune-and Chemotherapy in TNBC

Nab-Paclitaxel + anti-PD-L1 (atezolizumab)

ORR 66.7%(unconfirmed 88.9%)

1st line Patients

ORR 25% / 28.6%(unconf. 75% / 43%)

2nd/≥3rd line Patients

PDL1<1% (n = 7)

PDL1 ≥1% (n = 9)

Unknown (n = 8)

ORR 57.1% 77.8% 75%

SD 42.9% 22.2% 0

PD 0 0 25%

Adapted from Adams S, et al. SABCS 2015

Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer: Results from the I-SPY 2 Trial

Nanda R, et al. ASCO 2017

Options




Robson M et al NEJM 2017

OlympiAD:Phase III trial of olaparib monotherapy versus chemotherapy for patients with HER2 negative metastatic

breast cancer and a germline BRCA mutation

PFS7.0 months vs. 4.2 months

Benefit among pts with TNBC

Benefit among pts who had not

received prior platinum

Benefit among pts with BRCA 1

mutation

Litton J et al SABCS 2017

EMBRACA: Phase 3 trial comparing talazoparib to physician choice of therapy in patients with advanced

breast cancer a germline BRCA-mutation


HR=0.54, p<0.0001

Whole cohort CNS met Subgroup


EMBRACA OlympiAD

PARP inhibitorTalazoparib Olaparib

Phase III III

Patient numbers 431 302

Time from adjuvant or neoadjuvant platinum

6 months 12 months

Previous platinum 16% 29%

No of chemotherapy regimensfor MBC

Up to 3 Up to 2

CNS mets 15% Not reported

Improvement in PFS 3m 2.8m

HR+ HR 0.47HR= 0.82 (not significant)

TNBC HR 0.60 HR= 0.43

Improvement in PFS in the CNS group

4.1m Not reported

Difference between the two?

Options




Median (95% CI): 5.5 months (4.8, 6.6)85/110 (77%) number of events

Number at risk

106 60 18 10 6

Months

Pro

gre

ssio

n-f

ree S

urv

ival

(%)

0

20

40

60

80

100

0 4 8 12 16

Median (95% CI): 12.7 months (10.8, 13.6)71/110 (64%) deaths reported

Months

Overa

ll S

urv

ival

(%)

20

40

60

80

100

0

0 3 6 9 12 15 18 21 24

Number at risk

110 93 83 60 37 19 15 12 9

Progression-free survival Overall survival

Scituzumab Govitecan (IMMU-132), an Anti-Trop-SN-38 Antibody-Drug Conjugate, as >=3rd line therapeutic Option for Patient with relapased/refractory metastatic triple-negative breast cancer

(mTNBC)

• Sacituzumab govitecan demonstrated significant clinical activity as ≥3rd-line therapy in patients with relapsed/refractory mTNBC

– Confirmed ORR*: 34% ; clinical benefit rate (6 months)*: 45%

• ASCENT Phase III study is recruiting and has a primary completion date as end of 2019

Bardia A et al, SABCS 2017

Clinical pearls in the metastatic settingHR +/ HER2 negative : Pre and post menapausal

CDK4/6 upfront

CDK4/6 / affinitor second line

Future : addition of immunotherapy

BRCA + : PARP

TNBC

Chemotherapy

BRCA + : PARP

HER2 +

Trastuzumab+ Pertuzumab

TDM-1Trastuzumab+lapatinib

Thank You!

Shaheenah Dawood MBBCh, FRCP(glasgow), FACP, MPH, CPH

Consultant Medical Oncologist

[email protected]

Documents

Current standards and practice changing studies in ...€¦ · Metastatic Breast Cancer (MBC) Landscape 2 HER2+ Triple negative ~15%5 HER=human epidermal growth factor receptor; HR+=hormone