Se me pide que sustente mi opinión en un evento en el que la información científica es presentada por otros profesionales...

1. +
Why I choose Everolimus + Exemestane after disease
progression on endocrine therapy in HR+ MBC?
Mauricio Lema Medina

2. +
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

3. +
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.

4. +
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.

5. +
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.

6. +
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.

7. +
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.

8. Mehta RS et al. N Engl J Med 2012;367:435-444.
Kaplan–Meier Curves for Progression-free Survival, According to Treatment
Group.

9. Mehta RS et al. N Engl J Med 2012;367:435-444.
Kaplan–Meier Curves for Overall Survival, According to Treatment Group.

10. 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

11. +
Some argue that there is no
DEFINITIVE evidence of the
superiority of Fulvestrant over
an AI in first-line MBC…

12. +
Some argue that there is no
DEFINITIVE evidence of the
superiority of Fulvestrant over
an AI in first-line MBC…
They are probably RIGHT

13. +
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

14. +
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.

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

16. +
(Almost) ALL patients that
progress after first-line hormonal
therapy for MBC are currently on
an endocrine agent

17. 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
?

18. 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

19. 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 + AI
Restoring endocrine sensitivity

20. 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 + AI
Restoring endocrine sensitivity

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

22. Advanced HR+ MBC
Progressive disease
after an AI
Investigational strategy
2nd-Line Hormonal
agent (ie,
Exemestane/Fulvestra
nt)
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

23. +
Advanced HR+ MBC
Progressive 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

24. 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

25. +
Advanced HR+ MBC
Progressive 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

26. Turner NC et al. N Engl J Med 2015;373:209-219.
Progression-free Survival.
PFS: Fulvestrant 3.7 months

27. +
Advanced HR+ MBC
Progressive 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

28. Baselga J et al. N Engl J Med 2012;366:520-529.
Kaplan–Meier Plot of Progression-free Survival.

29. 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: Stomatitis
Serious: Pneumonitis, hyperglycemia

30. +
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

31. + 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)