Senthil Kumar: Systemic Management of Advanced/Metastatic HR+, HER2- Breast Cancer

Senthil Kumar, Medical Oncologist at Red Hills Chennai shared a post on X:

“Systemic Management of Advanced/Metastatic HR+, HER2- Breast Cancer

Definitions

Estrogen Receptor (ER) Positive:

≥1% of tumor cells exhibiting ER membrane positivity on IHC.

Menopausal Status

Postmenopausal:

Age >60 years.

Age <60 years with ≥12 months of amenorrhea (in the absence of chemotherapy, tamoxifen, or ovarian suppression).

Prior bilateral oophorectomy.

FSH and estradiol levels consistent with postmenopausal status.

Endocrine-sensitive disease (ESD):

Patients who derived prolonged benefit from endocrine therapy before progression.

Endocrine-resistant disease:

Disease progression within 6 months of adjuvant endocrine therapy or progression on first-line endocrine therapy.

Visceral crisis

Life threatening organ dysfunction due to the disease requiring rapidly efficacious treatment.

First-Line Endocrine Therapy Strategy Preferred Regimen for Most Patients (CDK4/6 Inhibitors + Endocrine Therapy)

 CDK4/6i + AI (Standard-of-Care First-Line)

Ribociclib + AI (MONALEESA-2, MONALEESA-7 trials). Abemaciclib + AI (MONARCH-3 trial).

Palbociclib + AI (PALOMA-2 trial).

Other options ( less preferred )

Single agent AI

single agent fulvestrant

Fulvestrant plus AI

New data

AI plus Capecitabine ( Mecca -1 trial) – suitable for low resource settings

Trial data

PALOMA-2:

Arms: Letrozole ± palbociclib.

PFS: 24.8 vs. 14.5 months; HR 0.58.

OS: No significant difference ( about 54 months )

MONALEESA-2:

Arms: Letrozole ± ribociclib.

PFS: 25.3 vs. 16.0 months; HR 0.57.

OS: 63.9 vs. 51.4 months; HR 0.76.

MONALEESA-7:

Arms: Endocrine therapy (tamoxifen or nonsteroidal AI) + goserelin ± ribociclib.

PFS: 23.8 vs. 13.0 months; HR 0.55.

OS: 59 vs. 48 months; HR 0.76

MONARCH 3:

Arms: Nonsteroidal AI ± abemaciclib.

PFS: 28.2 vs. 14.8 months; HR 0.54.

OS : 67 vs 54 months

FALCON:

Arms: Fulvestrant vs. anastrozole.

PFS: 16.6 vs. 13.8 months; HR 0.80.

OS : no difference ( 45 months )

MECCA 1 TRIAL AI +/- Capecitabine ( OMC) in first line

PFS : 21 vs 12 months favouring AI plus Capecitabine arm

In resource constrained settings where CDK 4/6 inhibitors may not be available , this may be a good option.

A new option for first line in advanced PIK3CA mutated luminal breast cancer

INAVO120 trial Fulvestrant + palbociclib + inavolisib

Addition of inavolisib Doubles the PFS ( 15 vs 7.3 months )

Response is sustained ( PFS 2 – 24 months )

Delays time to chemo.

Biomarker-Driven Selection for Second-Line Therapy (Trial Data) ESR1 Mutation-Positive

EMERALD Trial: ( post 1-2 lines endocrine treatment )

Arms: Elacestrant vs. Standard Endocrine Therapy (Fulvestrant or AI).

PFS: 3.8 vs. 1.9 months (HR 0.55; p=0.0005) in ESR1-mutant patients.

—–

EMBER-3 Trial:

Arms: Imlunestrant ± Abemaciclib.

PFS: 9.4 months ( Imlunestrant + Abemaciclib ) 5.5 months ( Imlunestrant ) 3.8 months ( SOC -ET) Imlunestrant improves PFS as monotherapy in ESR1 mutated patients progressing on first line endocrine therapy ( HR 0.62) Imlunestrant + Abemaciclib gives PFS benefit over Imlunestrant in all patients ( irrespective of ESR1-m status ), median PFS -9.4 months , HR 0.57

—

PIK3CA Mutation-Positive

SOLAR-1 Trial: ( PIK3CA mutated patients , post progression on AI )

Arms: Alpelisib + Fulvestrant vs. Fulvestrant alone.

PFS: 11.0 vs. 5.7 months (HR 0.65; p=0.00065) in PIK3CA-mutant patients.

OS: 39.3 vs. 31.4 months (HR 0.86; p=0.15).

BYLieve Trial: ( PIK3CA mutated patients , post progression on AI + CDK 4/6 inhibitors )

Arms: Alpelisib + Fulvestrant after prior CDK4/6 inhibitor failure.

PFS: about 6 months OS : 21 to 29 months ( across the three cohorts )

—

PIK3CA/AKT1/PTEN Alteration CAPItello-291 Trial:

Arms: Capivasertib + Fulvestrant vs. Fulvestrant alone.

Dose : 400 mg BD 4 days in 3 days off PFS: 7.2 vs. 3.6 months (HR 0.50; p<0.001) in mutation-positive patients.

— BRCA1/2 Mutation-Positive OlympiAD Trial:

Arms: Olaparib vs. Standard Chemotherapy (Capecitabine, Vinorelbine, Eribulin).

PFS: 7.0 vs. 4.2 months (HR 0.58; p<0.001).

OS: 19.3 vs. 17 months (HR 0.90; p=0.513).

ORR –60 %

EMBRACA Trial:

Arms: Talazoparib vs. Standard Chemotherapy.

PFS: 8.6 vs. 5.6 months (HR 0.54; p<0.0001).

OS: 19.3 vs. 19.5 months (HR 0.85; p=0.376).

— No ESR1, BRCA1/2, PIK3CA/AKT/PTEN Mutation

BOLERO-2 Trial:

Arms: Everolimus + Exemestane vs. Exemestane alone.

PFS: 7.8 vs. 3.2 months (HR 0.45; p<0.001).

OS: 31.0 vs. 26.6 months (HR 0.89; p=0.14).

Post-MONARCH Trial: ( favours both ET and cdk inhibitor switch )

Arms: Abemaciclib + Fulvestrant vs. Fulvestrant alone after prior CDK4/6 inhibitor failure.

PFS: 6 vs. 5.3 months 6 months pfs rate 50% vs 37%

MAINTAIN Trial: ( suggests that CDK inhibitor can be continued but ET can be switched )

Arms: Ribociclib + Fulvestrant vs. Fulvestrant alone after prior CDK4/6 inhibitor progression.

PFS: 5.3 vs. 2.8 months (HR 0.57; p=0.006).

EMBER-3 Trial: Imlunestrant plus Abemaciclib is a second line option irrespective of esr1 mutation status

PFS: 9.4 months ( Imlunestrant + Abemaciclib )

Other options

Post first line AI – Fulvestrant plus CDK 4/6 inhibitors may be used Fulvestrant plus everolimus Single agent fulvestrant.”