+
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...
+
Scenarios
 Visceral Crisis(+) HR(+) Her2(-) MBC
 (aka) rapidly progressive disease
 Lymphangitic lung metastases,
 B...
+
Scenarios
 Visceral Crisis(+) HR(+) Her2(-) MBC
 Visceral Crisis(-) HR(+) Her2(-) MBC
 No prior hormonal therapy
 De...
+
Scenarios
 Visceral Crisis(+) HR(+) Her2(-) MBC
 Visceral Crisis(-) HR(+) Her2(-) MBC
 No prior hormonal therapy
 De...
+
Scenarios
 Visceral Crisis(+) HR(+) Her2(-) MBC
 Visceral Crisis(-) HR(+) Her2(-) MBC
 No prior hormonal therapy
 De...
+
Scenarios
 Visceral Crisis(+) HR(+) Her2(-) MBC
 Visceral Crisis(-) HR(+) Her2(-) MBC
 No prior hormonal therapy
 De...
Mehta RS et al. N Engl J Med 2012;367:435-444.
Kaplan–Meier Curves for Progression-free Survival, According to Treatment
G...
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 C...
+
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...
+
But, All MUST agree that there
is NO evidence of superiority
of an AI over fulvestrant in
first-line HR+ MBC
Even in tri...
+
Scenarios
 Visceral Crisis(-) HR(+) Her2(-) MBC
 Prior hormonal therapy (adjuvant / metastatic)
 Short DFI (5-10 year...
+ 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 ...
Recent exposure to
endocrine therapy
DECREASES
endocrine sensitivity in
HR+ MBC
(Almost) ALL patients that
progress after ...
Recent exposure to
endocrine therapy
DECREASES
endocrine sensitivity in
HR+ MBC
(Almost) ALL patients that
progress after ...
Recent exposure to
endocrine therapy
DECREASES
endocrine sensitivity in
HR+ MBC
(Almost) ALL patients that
progress after ...
+ Recent exposure to endocrine
therapy DECREASES endocrine
sensitivity in HR+ MBC
Advanced HR+ MBC
Progressive disease
after an AI
Investigational strategy
2nd-Line Hormonal
agent (ie,
Exemestane/Fulvestr...
+
Advanced HR+ MBC
Progressive disease
after an AI
Fulvestrant
Exemestane
R
1. Chia S, Gradishar W, Mauriac L, et al. Doub...
Kaplan-Meier estimates for time to progression (TTP).
Stephen Chia et al. JCO 2008;26:1664-1670
©2008 by American Society ...
+
Advanced HR+ MBC
Progressive disease
after an AI
Palbociclib* +
Fulvestrant
Fulvestrant
R
Turner NC, Ro J, Andre F, et a...
Turner NC et al. N Engl J Med 2015;373:209-219.
Progression-free Survival.
PFS: Fulvestrant 3.7 months
+
Advanced HR+ MBC
Progressive disease
after an AI
Everolimus* +
Exemestane
Exemestane
R
Baselga J, Campone M, Piccart M, ...
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
Le...
+
How to minimize (S)AEs?
 Start with Everolimus 5 mg QD
 Increase to 10 mg QD if no AEs
 Close follow-up during first ...
+ Why I choose Everolimus + Exemestane after
disease progression in HR+ MBC?
 Because…
 It is (a lot) more effective tha...
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Why I choose Everolimus + Exemestane (BOLERO2) after progression on endocrine therapy in HR+ MBC

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Why I choose Everolimus + Exemestane (BOLERO2) after progression on endocrine therapy in HR+ MBC

  1. 1. + Why I choose Everolimus + Exemestane after disease progression on endocrine therapy in HR+ MBC? Mauricio Lema Medina
  2. 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. 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. 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. 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. 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. 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. 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. 9. Mehta RS et al. N Engl J Med 2012;367:435-444. Kaplan–Meier Curves for Overall Survival, According to Treatment Group.
  10. 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. 11. + Some argue that there is no DEFINITIVE evidence of the superiority of Fulvestrant over an AI in first-line MBC…
  12. 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. 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. 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. 15. + Recent exposure to endocrine therapy DECREASES endocrine sensitivity in HR+ MBC
  16. 16. + (Almost) ALL patients that progress after first-line hormonal therapy for MBC are currently on an endocrine agent
  17. 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. 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. 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. 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. 21. + Recent exposure to endocrine therapy DECREASES endocrine sensitivity in HR+ MBC
  22. 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. 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. 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. 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. 26. Turner NC et al. N Engl J Med 2015;373:209-219. Progression-free Survival. PFS: Fulvestrant 3.7 months
  27. 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. 28. Baselga J et al. N Engl J Med 2012;366:520-529. Kaplan–Meier Plot of Progression-free Survival.
  29. 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. 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. 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)

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