why i choose everolimus + exemestane (bolero2) after progression on endocrine therapy in hr+ mbc

+

Why I choose Everolimus + Exemestane after disease progression on endocrine therapy in HR+ MBC?

Mauricio Lema Medina

+Scenarios

Visceral Crisis(+) HR(+) Her2(-) MBC Visceral Crisis(-) HR(+) Her2(-) MBC

No prior hormonal therapy De-novo

Prior hormonal therapy (adjuvant / metastatic) Long DFI (>10 years) Short DFI (5-10 years) Very-Short DFI (<12 months)

On adjuvant hormonal therapy

+Scenarios

Visceral Crisis(+) HR(+) Her2(-) MBC (aka) rapidly progressive disease

Lymphangitic lung metastases, Bone marrow replacement, Carcinomatous meningitis, or Significant liver metastases

Visceral crisis should be treated with chemotherapy1

Higher Response Rates with Chemo vs Endocrine (RR=1.25)2

1. Wael H. Management of patients with hormone receptor–positive breast cancer with visceral disease: challenges and treatment options. Cancer Manag Res. 2015; 7: 37–46. 2. Wicken N, Hornbuckle J, Ghersi D. Chemotherapy alone versus endocrine therapy alone for metastatic breast cancer. Cochrane Database Syst Rev 2003;(2):CD002747.

+Scenarios

Visceral Crisis(+) HR(+) Her2(-) MBC Visceral Crisis(-) HR(+) Her2(-) MBC

No prior hormonal therapy De-novo

Endocrine sensitivity: +++ (HR: 0.641) Prior hormonal therapy (adjuvant / metastatic)

Long DFI (>10 years) Endocrine sensitiviy: +++ (HR: 0.591)

Short DFI (5-10 years) Endocrine sensitivity: + (HR: 1.032)

Very-Short DFI (<12 months) (HR: 0.8-1.02,3,4) Endocrine sensitivity: +

On adjuvant hormonal therapy (Speculation) Endocrine sensitivity: +/-1. Robertson JF, Llombart-Cussac A, Rolski J, et al. Activity of fulvestrant 500 mg versus anastrozole 1 mg as first-line treatment for advanced breast cancer: results from

the FIRST study. J Clin Oncol 2009;27:4530-4535. 2. Bergh J, Jonsson PE, Lidbrink EK, et al. FACT: an open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptor-positive postmenopausal breast cancer. J Clin Oncol 2012;30:1919-1925. 3. Di Leo A, Jerusalem G, Petruzelka L, et al. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. 4. Johnston S, Kilburn L, Ellis P, et al. Fulvestrant alone or with concomitant anastrozole vs exemestane following progression on non-steroidal aromatase inhibitor: first results of the SoFEa Trial (CRUKE/03/021 & CRUK/09/007) (ISRCTN44195747). Presented at the 8th European Breast Cancer Conference, Vienna, March 21–24, 2012.

+Scenarios

Visceral Crisis(+) HR(+) Her2(-) MBC Visceral Crisis(-) HR(+) Her2(-) MBC

No prior hormonal therapy De-novo

Endocrine sensitivity: +++ (HR: 0.641)

Cure is highly unlikely in HR+ MBC, therefore, low-toxicity anti-cancer therapy (ie, hormonal) should be preferred over high-toxicity (ie, chemo) except in rapidly progressive disease2

1. 1. Robertson JF, Llombart-Cussac A, Rolski J, et al. Activity of fulvestrant 500 mg versus anastrozole 1 mg as first-line treatment for advanced breast cancer: results from the FIRST study. J Clin Oncol 2009;27:4530-4535, 2. Wicken N, Hornbuckle J, Ghersi D. Chemotherapy alone versus endocrine therapy alone for metastatic breast cancer. Cochrane Database Syst Rev 2003;(2):CD002747.

+Scenarios

Visceral Crisis(+) HR(+) Her2(-) MBC Visceral Crisis(-) HR(+) Her2(-) MBC

No prior hormonal therapy De-novo

Endocrine sensitivity: +++ (HR: 0.641) Prior hormonal therapy (adjuvant)

Long DFI (>10 years) Endocrine sensitiviy: +++ (HR: 0.591)

Likelihood of response to an endocrine agent is similar to the de-novo patient (and similar considerations)2

1. 1. Robertson JF, Llombart-Cussac A, Rolski J, et al. Activity of fulvestrant 500 mg versus anastrozole 1 mg as first-line treatment for advanced breast cancer: results from the FIRST study. J Clin Oncol 2009;27:4530-4535, 2. Wicken N, Hornbuckle J, Ghersi D. Chemotherapy alone versus endocrine therapy alone for metastatic breast cancer. Cochrane Database Syst Rev 2003;(2):CD002747.

+Scenarios

Visceral Crisis(+) HR(+) Her2(-) MBC Visceral Crisis(-) HR(+) Her2(-) MBC

No prior hormonal therapy De-novo

Endocrine sensitivity: +++ (HR: 0.641) Prior hormonal therapy (adjuvant)

Long DFI (>10 years) Endocrine sensitiviy: +++ (HR: 0.591)

Best 1st-line hormonal agent: FULVESTRANT (500) +/- Aromatase inhibitor1,2

1. Robertson JF, Llombart-Cussac A, Rolski J, et al. Activity of fulvestrant 500 mg versus anastrozole 1 mg as first-line treatment for advanced breast cancer: results from the FIRST study. J Clin Oncol 2009;27:4530-4535, 2. Mehta RS, et al. Combination anastrozol and fulvestrant in metastatic breast cancer. New Engl J Med 2012; 367: 435-444.

Mehta RS et al. N Engl J Med 2012;367:435-444.

Kaplan–Meier Curves for Progression-free Survival, According to Treatment Group.

Mehta RS et al. N Engl J Med 2012;367:435-444.

Kaplan–Meier Curves for Overall Survival, According to Treatment Group.

Kaplan-Meier plot for time to progression.

John F.R. Robertson et al. JCO 2009;27:4530-4535

©2009 by American Society of Clinical Oncology

+Some argue that there is no DEFINITIVE evidence of the superiority of Fulvestrant over an AI in first-line MBC…

+Some argue that there is no DEFINITIVE evidence of the superiority of Fulvestrant over an AI in first-line MBC…

They are probably RIGHT

+But, All MUST agree that there is NO evidence of superiority of an AI over fulvestrant in first-line HR+ MBC

Even in trials with sub-optimal fulvestrant dosing

+Scenarios

Visceral Crisis(-) HR(+) Her2(-) MBC Prior hormonal therapy (adjuvant / metastatic)

Short DFI (5-10 years) Endocrine sensitivity: + (HR: 1.032)

Very-Short DFI (<12 months) (HR: 0.8-12,3,4) Endocrine sensitivity: +

On adjuvant hormonal therapy (Speculation) Endocrine sensitivity: +/-

1. Robertson JF, Llombart-Cussac A, Rolski J, et al. Activity of fulvestrant 500 mg versus anastrozole 1 mg as first-line treatment for advanced breast cancer: results from the FIRST study. J Clin Oncol 2009;27:4530-4535. 2. Bergh J, Jonsson PE, Lidbrink EK, et al. FACT: an open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptor-positive postmenopausal breast cancer. J Clin Oncol 2012;30:1919-1925. 3. Di Leo A, Jerusalem G, Petruzelka L, et al. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. 4. Johnston S, Kilburn L, Ellis P, et al. Fulvestrant alone or with concomitant anastrozole vs exemestane following progression on non-steroidal aromatase inhibitor: first results of the SoFEa Trial (CRUKE/03/021 & CRUK/09/007) (ISRCTN44195747). Presented at the 8th European Breast Cancer Conference, Vienna, March 21–24, 2012.

+Recent exposure to endocrine therapy DECREASES endocrine sensitivity in HR+ MBC

+(Almost) ALL patients that progress after first-line hormonal therapy for MBC are currently on an endocrine agent

Recent exposure to endocrine therapy

DECREASES endocrine sensitivity

in HR+ MBC

(Almost) ALL patients that progress after first-line

hormonal therapy for MBC are currently on an endocrine

agent

?

Recent exposure to endocrine therapy

DECREASES endocrine sensitivity

in HR+ MBC

(Almost) ALL patients that progress after first-line

hormonal therapy for MBC are currently on an endocrine

agent

?Rapidly progressive disease (ie, visceral

crisis)Chemo

Recent exposure to endocrine therapy

DECREASES endocrine sensitivity

in HR+ MBC

(Almost) ALL patients that progress after first-line

hormonal therapy for MBC are currently on an endocrine

agent

?Non-Rapidly

progressive disease

Chemo

2nd-line hormonal

mTOR + AIRestoring endocrine sensitivity

Recent exposure to endocrine therapy

DECREASES endocrine sensitivity

in HR+ MBC

(Almost) ALL patients that progress after first-line

hormonal therapy for MBC are currently on an endocrine

agent

?Non-Rapidly

progressive disease

Chemo

2nd-line hormonal

mTOR + AIRestoring endocrine sensitivity

+Recent exposure to endocrine therapy DECREASES endocrine sensitivity in HR+ MBC

Advanced HR+ MBCProgressive disease

after an AI

Investigational strategy

2nd-Line Hormonal agent (ie,

Exemestane/Fulvestrant)

R

1. Chia S, Gradishar W, Mauriac L, et al. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol 2008;26:1664-1670. 2. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012;366:520-529. 3. . Turner NC, Ro J, Andre F, et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med 2015;373:209-219

+

Advanced HR+ MBCProgressive disease

after an AI

Fulvestrant

Exemestane

R

1. Chia S, Gradishar W, Mauriac L, et al. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol 2008;26:1664-1670.

EFECT

Kaplan-Meier estimates for time to progression (TTP).

Stephen Chia et al. JCO 2008;26:1664-1670

©2008 by American Society of Clinical Oncology

PFS: Both arms 3.7 months

+

Advanced HR+ MBCProgressive disease

after an AI

Palbociclib* + Fulvestrant

Fulvestrant

R

Turner NC, Ro J, Andre F, et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med 2015;373:209-219

*cdk4 inhibitor

PALOMA3

Turner NC et al. N Engl J Med 2015;373:209-219.

Progression-free Survival.

PFS: Fulvestrant 3.7 months

+

Advanced HR+ MBCProgressive disease

after an AI

Everolimus* + Exemestane

Exemestane

R

Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012;366:520-529.

* mTOR inhibitor

BOLERO2

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

Kaplan–Meier Plot of Progression-free Survival.

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

Adverse Events Irrespective of Relationship to Study Treatment (with at Least 10% Incidence in the Everolimus–Exemestane

Group).

>5% grade 3: StomatitisSerious: Pneumonitis, hyperglycemia

+How to minimize (S)AEs?

Start with Everolimus 5 mg QD Increase to 10 mg QD if no AEs

Close follow-up during first 2-3 months Q2W labs x2, Q1M x2

Glycemia LFTs

Q2W visit x2, Q1M x2

Early topical steroids for mouth ulcers Early detection of pneumonitis

Cough Dyspnea Pulmonary infiltrates

+Why I choose Everolimus + Exemestane after disease progression in HR+ MBC?

Because… It is (a lot) more effective than a single agent hormonal

therapy Adverse side-effects can be minimized Less toxic than chemotherapy There is no more effective therapy available in Colombia

Let’s have this discussion again when anti cdk4 agents are available in Colombia… (Then, we will talk about money)