Recent advances in the

management of metastatic

breast cancer in older adults

Laura Biganzoli

Medical Oncology Dept

New Hospital of Prato

Istituto Toscano Tumori

Italy

Important recent advances in the management of advanced breast cancer

Luminal disease

- mTOR inhibitor

- CDK 4/6 inhibitor

HER2+ disease

- Pertuzumab

- T-DM1

Exemestane

+ placebo

Exemestane (25mg)

+ everolimus (10 mg)

• Post-menopausal

• HR+, HER2− metastatic BC

• Refractory to non-steroidal AIs:

• Recurrence on or ≤12 months after

end of adjuvant treatment with

non-steroidal AI

• Progression on or ≤1 month after

end of treatment with non-steroidal

AI for advanced disease 2:1

RA

ND

OM

IZA

TIO

N

N=485

N=239Primary end point: PFS (on the basis of radiographic studies assessed by the local investigators)

Everolimus= mTOR inhibitor

mTOR, mammalian target of rapamycin

0

20

40

60

80

100

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 50Time, months

Pro

ba

bil

ity

of

Ov

era

ll S

urv

iva

l

EVE+EXE (n/N =267/485)PBO+EXE (n/N =

HR = 0.89 (95% CI, 0.73-1.10)

Log-rank P = .14

Kaplan-Meier medians

EVE+EXE: 30.98 months

PBO+EXE: 26.55 months

Censoring times

232109

248113

266120

279130

292145

311153

330162

347170

373182

399194

414201

429211

448220

471232

485239

EVE+EXEPBO+EXE

No. at risk115

238

3918

5828

9141

11856

15477

19698

216102

00

11

Progression-free Survival

Overall Survival

Piccart M et al, proc. EBCC 2014

** Sepsis (n=2), pneumonia, tumor

hemorrhage, cerebrovascual incident,

renal failure, suicide

SAEs attributed to study treatment

reported in 11% (EE) vs 1% pts (EP)

Median follow-up=18 months

Patients, %

Age <70 years Age ≥ 70 years

Variable E+E (n=364) E+P (n=196) E+E (n=121) E+P (n=43)

Discontinued 81.6 95.9 88.4 95.3

Reasons

- Progressive disease - Pt withdrew consent - Adverse events - Death -- Other

67.0 6.3 6.3 0.80.8

88.8 2.0 4.1 0.5 0.5

46.3 19.017.4 3.32.5

88.4 7.0 0 0 0

On treatment deaths with AE as primary cause, n (exposure adjusted %)

3 (1.3) 1 (1.3) 4 (7.7) 0

• AEs of special interest (all grades) that occurred more

frequently with everolimus than with placebo: stomatitis,

infections, rash, pneumonitis, and hyperglycemia

• Elderly everolimus-treated patients had similar incidence of

these AEs as did younger patients

PALOMA-1/TRIO-18 :Phase 2 Study

N=66

1:1

Part 1

• Post-

menopausal

• ER+, HER2–

BC status

• No prior

treatment for

advanced

disease

R

A

N

D

O

M

I

Z

A

T

I

O

N

Palbociclib 125 mg QDa +

Letrozole 2.5 mg QD

Letrozole 2.5 mg QD

Part 2

N=99

1:1

• Post-

menopausal

• ER+, HER2–

BC with

CCND1

amplification

and/or loss

of p16

• No prior

treatment for

advanced

disease

R

A

N

D

O

M

I

Z

A

T

I

O

N

Palbociclib 125 mg QDa +

Letrozole 2.5 mg QD

Letrozole 2.5 mg QD

Stratification Factors• Disease Site (Visceral vs Bone only vs Other)

• Disease-Free Interval (>12 vs ≤12 mo from end of

adjuvant to recurrence or de novo advanced disease)

aSchedule 3/1

Key Eligibility Criteria• Measurable disease (RECIST 1.0) or bone-only

disease

• ECOG PS of 0 or 1

• Adequate blood counts and organ function

• No prior/current brain metastases

Palbociclib= CDK 4/6 Inhibitor

CDK, Cyclin-Dependent Kinase

Finn et al. AACR 2014

Finn et al. AACR 2014

MBC, metastatic breast cancer; PD, progressive disease

* <6 cycles allowed for unacceptable toxicity or PD; >6 cycles allowed at investigator discretion

Patients withHER2-positive

MBCNo prior

chemotherapy for MBC

(N = 808)

Placebo + trastuzumabn=406

1:1

n=402

Docetaxel*≥6 cycles

recommended

PD

Pertuzumab + trastuzumab

Docetaxel*≥6 cycles

recommended

PD

Baselga et al. N Engl J Med. 2012

CLEOPATRA: trastuzumab and pertuzumab in the 1st-line MBC

Graphical elaboration from text data

Pertuzumab= humanized monoclonal antibody that binds HER2

Baselga et al. N Engl J Med 2012

Median survival Ptz+T+D=56,5 months

15,7 months gain vs Pla+T+D

ESMO 2014

Swain SM et al. Lancet Oncol. 2013

CLEOPATRA: AEs before and after

discontinuation of docetaxel

The safety profile was generally similar in the two groups, with no increase in LVEF dysfunction; the rates of febrile neutropenia and diarrhea of grade ≥ 3 were higher in the pertuzumab group than in the control group

Breast Cancer Res Treat 2013

Safety data

• Diarrhoea, fatigue, asthenia, decreased appetite,

vomiting and dysgeusia were reported more frequently in

patients aged ≥ 65 years in both treatment arms

• Neutropenia and febrile neutropenia were reported less

frequently in the older age group (dose of docetaxel reduced

more frequently and median number of cycles lower in ≥65)

Febrile neutropenia (especially in the younger

subgroup) and diarrhea (especially in the older

subgroup)

Peripheral neuropathy only in patients aged ≥ 65 (8%)

AEs grade ≥ 3 reported more frequently in the pertuzumab arm

EMILIA Study Design

• Stratification factors: World region, number of prior chemo regimens for MBC or

unresectable LABC, presence of visceral disease

• Primary endpoints: PFS by independent review, OS, and safety

1:1

HER2-positive LABC or MBC (N=980)

• Prior taxane and trastuzumab

• Progression on metastatic treatment or within 6 months of adjuvant treatment

PDT-DM1

3.6 mg/kg q3w IV

Capecitabine 1000 mg/m2 PO bid, days 1–14, q3w

+ Lapatinib

1250 mg/day PO qd

PD

Verma S. et al N Engl J Med. 2012

Trastuzumab emtansine (T-DM1) = antibody–drug conjugate in which

trastuzumab is chemically linked to the emtansine

PFS benefit was consistently observed

across clinically relevant subgroups, with

a less definitive benefit among patients

aged ≥ 75 years (n=25) and those with

non visceral or non measurable disease

EMILIA - Adverse EventsGrade ≥3 AEs With Incidence ≥2%

Cap + Lap(n=488)

T-DM1(n=490)

Adverse Event All Grades, % Grade ≥3, % All Grades, % Grade ≥3, %

Diarrhea 79.7 20.7 23.3 1.6

Hand-foot syndrome 58.0 16.4 1.2 0.0

Vomiting 29.3 4.5 19.0 0.8

Neutropenia 8.6 4.3 5.9 2.0

Hypokalemia 8.6 4.1 8.6 2.2

Fatigue 27.9 3.5 35.1 2.4

Nausea 44.7 2.5 39.2 0.8

Mucosal inflammation 19.1 2.3 6.7 0.2

Thrombocytopenia 2.5 0.2 28.0 12.9

Increased AST 9.4 0.8 22.4 4.3

Increased ALT 8.8 1.4 16.9 2.9

Anemia 8.0 1.6 10.4 2.7

Verma S. et al N Engl J Med. 2012

Rates of grade 3 or 4 adverse events were higher with lapatinib plus capecitabine than with T-DM1 (57% vs. 41%). The incidences of thrombocytopenia and increased serum aminotransferase levels were higher with T-DM1, whereas the incidences of diarrhea, nausea, vomiting, and palmar–plantar erythrodysesthesiawere higher with lapatinib plus capecitabine

Recent advances in the management of metastatic breast cancer in older adults

• Patient’ age should not limit the access to new

treatment options;

• Close monitoring and proactive management of

toxicities should clearly be undertaken

• Difficult to translate the results of these trials,

conducted in selected patients, to the overall

population of older adults, especially to those

with comorbidities and increased susceptibility to

adverse events

Back up

Patients, %

Age <70 years Age ≥ 70 years

Variable E+E (n=364) E+P (n=196) E+E (n=121) E+P (n=43)

Discontinued 81.6 95.9 88.4 95.3

Reasons

- Progressive disease - Pt withdrew consent - Adverse events - Death -- Other

67.0 6.3 6.3 0.80.8

88.8 2.0 4.1 0.5 0.5

46.3 19.017.4 3.32.5

88.4 7.0 0 0 0

On treatment deaths with AE as primary cause, n (exposure adjusted %)

3 (1.3) 1 (1.3) 4 (7.7) 0

Safety data

• Diarrhoea, fatigue, asthenia, decreased appetite, vomiting and dysgeusia were reported more frequently in patients aged ≥ 65 years in both treatment arms.

• Neutropenia and febrile neutropenia were reported less frequently in the older age group.

Febrile neutropenia and

diarrhea in both age

groups

Peripheral neuropathy

only in ≥ 65

Ten most common grade ≥ 3 adverse events (AE) Most common grade ≥ 3 AEs in the pertuzumab arm

Ann Oncol 2014; The Breast 2014

The decision to treat must take into

account the relevant toxicities

associated with this combination and

should be made on a case-by-case

basis

Finn et al. AACR 2014

PFS benefit was consistently observed

across clinically relevant subgroups, with

a less definitive benefit among patients

aged ≥ 75 years (n=25) and those with

non visceral or non measurable disease