Versión 2 (definitiva): Presentado en la Clínica VIDA en 11.11.2016, por invitación de Jairo Estrada. Versión corregida (se corrigen errores en 3 diapositivas de la versión anterior).

1. Tratamiento inicial de cáncer de mama
en pacientes posmenopáusicas
HR+/Her2- metastásico: una visión
panorámica
Mauricio Lema Medina MD
Clínica de Oncología Astorga / Clínica SOMA, Medellín
Medellín, 11.11.2016

3. @Onconerd

4. 1970s Tamoxifen 20% 26wks38%
ORR CBR PFS/TTF

5. Does chemotherapy increase
response-rate over hormonal
therapy in HR+ aBC?

6. CMF vs Tam
CMF vs Tam + Androgen
FU vs Androgen
AC vs Tam
FACV vs Various
Chemotherapy alone versus endocrine therapy alone for metastatic breast cancer
(Review)
Wilcken N, Cochrane, 2003

7. A Randomized Trial in Postmenopausal Patients With Advanced Breast
Cancer Comparing Endocrine and Cytotoxic Therapy Given
Sequentially or in Combination
ANZBCTG, JCO (1986): 4; 186-193
CR + PR + NC 76% 81% 84%

8. A Randomized Trial in Postmenopausal Patients With Advanced Breast
Cancer Comparing Endocrine and Cytotoxic Therapy Given
Sequentially or in Combination
ANZBCTG, JCO (1986): 4; 186-193

9. Does chemotherapy increase
response-rate over hormonal
therapy in HR+ aBC?
No solid phase III evidence can
support this notion

10. What is the optimal
first-line chemotherapy in aBC?

11. Paclitaxel and epirubicin versus paclitaxel and carboplatin as first-line chemotherapy in
patients with advanced breast cancer: a phase III study conducted by the Hellenic
Cooperative Oncology Group
Fountzilas G, Ann Oncol, 2004
Paclitaxel Epirubicin
Paclitaxel Carboplatin
RMBC
327 patients
Unknown Her2 status
Both ER+ and ER- Endpoint: OS

12. Paclitaxel and epirubicin versus paclitaxel and carboplatin as first-line chemotherapy in
patients with advanced breast cancer: a phase III study conducted by the Hellenic
Cooperative Oncology Group
Fountzilas G, Ann Oncol, 2004
Paclitaxel Epirubicin
Paclitaxel Carboplatin
RMBC
327 patients
Unknown Her2 status
Both ER+ and ER- Endpoint: OS
TTF
Paclitaxel + Carboplatin: 10.8 mo
Paclitaxel + Epirubicin: 8.1
OS
Paclitaxel + Carboplatin
Paclitaxel + Epirubicin
NS: 22-27mo

13. A randomized phase III study comparing three anthracycline-free taxane-based
regimens, as first line chemotherapy, in metastatic breast cancer
Fountzilas G, Breast Cancer Res Treat, 2009
Docetaxel + Gemcitabine q3w
Weekly paclitaxel
RMBC
416 patients
ER+: 65%
Triple negative: 15%
Trastuzumab in 6 patients
Endpoint: OS
OS
Paclitaxel + Carboplatin q3w
OS
Paclitaxel + Carboplatin: 29.9 mo
Docetaxel + Gemcitabine: 26.9 mo
Weekly Paclitaxel: 41.0 mo
p=0.037
PFS
11 mo

14. A randomized phase III study comparing three anthracycline-free taxane-based
regimens, as first line chemotherapy, in metastatic breast cancer
Fountzilas G, Breast Cancer Res Treat, 2009

15. A randomized phase III study comparing three anthracycline-free taxane-based
regimens, as first line chemotherapy, in metastatic breast cancer
Fountzilas G, Breast Cancer Res Treat, 2009
PCb vs Weekly paclitaxel

16. 2009 Weekly paclitaxel 49% 47wks75%
Fountzilas, Breast Cancer Res Treat, 2009
ORR CBR PFS/TTF
ER+/ER-/Her2+

17. What is the optimal
first-line chemotherapy in aBC?
Weekly paclitaxel appears to be
superior to combination agents in
“all-comers” with aBC

19. What is the optimal
first-line single-agent hormonal
therapy in HR+/Her2- aBC?

21. 2001 Tamoxifen 20% 26wks38%
Letrozole 30% 41wks49%
Mouridsen H, JCO, 2001
HR: 0.7
ORR CBR PFS/TTF
ER/PR status unknown in some

22. Mouridsen H, JCO, 2001

26. ESMO-2016, Copenhagen, 7-11 October 2016
Fulvestrant
Anastrozole

27. ESMO-2016, Copenhagen, 7-11 October 2016
A phase 3 trial confirms a phase 2 trial (FIRST).
Fulvestrant appears less effective in visceral metastases.
All patients where hormonotherapy naïve.

28. 2001 Tamoxifen 20% 26wks38%
Letrozole 30% 41wks49%
Mouridsen H, JCO, 2001
HR: 0.7
2016 Anastrozole 44% 58wks74%
Fulvestrant 46% 71wks78%
Ellis, ESMO 2016, LBA14_PR
HR: 0.79
FALCON Hormone-naïve
ORR CBR PFS/TTF
ER/PR status unknown in some

29. 2001 Tamoxifen 20% 26wks38%
Letrozole 30% 41wks49%
Mouridsen H, JCO, 2001
HR: 0.7
2016 Anastrozole 44% 58wks74%
Fulvestrant 46% 71wks78%
Ellis, ESMO 2016, LBA14_PR
HR: 0.79
FALCON Hormone-naïve
ORR CBR PFS/TTF
ER/PR status unknown in some
2016 Anastrozole 53wks
Fulvestrant 93wks
HR: 0.79
FALCON Non-pulmonary & Non-liver metastases Ellis, ESMO 2016, LBA14_PR

30. What is the optimal
first-line single-agent hormonal
therapy in HR+/Her2- aBC?
Fulvestrant is superior to AIs and
displays a remarkable OS in non-
visceral metastatic in de-novo aBC

31. What about non-hormone naïve
progressive HR+/Her2- aBC?

32. LTED cells exhibit PI3K/mTOR pathway
hyperactivation and variable response to E2.
ER+ cell-lines: MCF-7, ZR75-1, MDA-361
LTED: Long-term estrogen deprived
Controls: Actin / AKT
ER expression: ER
PI3k/mTOR expression: p-S6K/p-AKT https://doi.org/10.1172/JCI41680Miller TW, JCI, 2010

33. PI3K pathway inhibition suppresses hormone-
independent cell growth
ER+ cell-lines: MCF-7, ZR75-1, MDA-361
LTED: Long-term estrogen deprived
BEZ235 (Dactolisib): PI3k/mTOR inhibitor
RAD0001 (Everolimus): mTOR inhibitor
AEW541: IGR-1R inhibitor
Lapatinib: EGFR/Her2 inhibitor
https://doi.org/10.1172/JCI41680Miller TW, JCI, 2010

34. Anti ER treatment with Fulvestrant induces
PI3k pathway activation
Fox EM, Arteaga CL, Miller TW. Frontiers in Oncology, 2012

35. Hortobagyi GN et al. SABCS 2011;Abstract S3-7.
Postmenopausal, ER-
positive locally
advanced or metastatic
breast cancer
Progression on letrozole
or anastrozole
(n = 724)
R
Everolimus – 10 mg daily
+
Exemestane – 25 mg daily
(n = 485)
Placebo
+
Exemestane – 25 mg daily
(n = 239)
Stratification: Sensitivity to prior hormonal therapy and presence of visceral metastases
Endpoints:
• Primary: Progression-free survival (PFS) by local assessment
• Secondary: Overall survival, overall response rate, quality of life,
safety, bone markers, pharmacokinetics
BOLERO-2 Study Design

36. Patients with primary resistance were
those relapsing during or within 6
months of stopping adjuvant AI
treatment or progressing within 6
months of starting AI treatment in the
metastatic setting

37. Response and Clinical Benefit
Everolimus + Exemestane
Placebo + Exemestane
Response Clinical Benefit
Percent
12.0%
1.3%
50.5%
25.5%
P < 0.0001
P < 0.0001
Baselga J, et al. N Engl J Med. 2012;366:520-529.

38. BOLERO-2: Everolimus + Exemestane
Improves PFS in HR+ MBC
Baselga J, et al. N Engl J Med. 2012;366:520-529.
0 6 12 18 24 30 36 42 48 54 60 66 72 78
Wks
ProbabilityofEvent(%)
Everolimus + exemestane
(median PFS: 10.6 mos)
Placebo + exemestane
(median PFS: 4.1 mos)
HR: 0.36 (95% CI: 0.27-0.47;
log-rank P < .001)
Patients at Risk, n
Everolimus
Placebo
485
239
385
168
281
94
201
55
132
33
102
20
67
11
43
11
28
6
18
3
9
3
3
1
2
0
0
0
100
90
80
70
60
50
40
30
20
10
0
Central Assessment

39. BOLERO-2: Final PFS Analysis (18-Mo
Follow-up)PFS, Mos EVE + EXE PBO + EXE HR (95% CI) P Value
Local review 7.8 3.2 0.45
(0.38-0.54)
< .0001
Central review 11.0 4.1 0.38
(0.31-0.48)
< .0001
With visceral mets 6.83 2.76 0.47
(0.37-0.60)
--
Without visceral mets 9.86 4.21 0.41
(0.31-0.55)
--
Bone-only mets 12.88 5.29 0.33
(0.21-0.53)
--
Progression after
neo/adj therapy
11.50 4.07 0.39
(0.25-0.62)
--
 OS data still not mature (HR: 0.77; 95% CI: 0.57-1.04)
 Most common grade 3/4 AEs were stomatitis (8%), hyperglycemia
(5%), fatigue (4%)
Baselga J, et al. N Engl J Med. 2012;366:520-529.

40. Common Adverse Events
Everolimus +
Exemestane
(n = 482)
Placebo +
Exemestane
(n = 238)
All Grades Grade 3/4 All Grades Grade 3/4
Stomatitis 59% 8% 11% <1%
Rash 39% 1% 6% 0
Fatigue 36% <5% 27% 1%
Diarrhea 33% <3% 19% <1%
Decreased appetite 30% 1% 12% <1%
Nausea 29% <2% 28% 1%
Noninfectious
pneumonitis
15% 3% 0 0
Hyperglycemia 14% <6% 2% <1%
Baselga J, et al. N Engl J Med. 2012;366:520-529.

41. Bolero-2: OS of Exemestane + Everolimus
in mBC
Piccert M, et al. Ann Oncol 2014

42. 2012 Exemestane (E) 1% 17wks25%
Everolimus + E 13% 49wks50%
Baselga, NEJM, 2012
ORR CBR PFS/TTF
Progressing after neoadjuvant therapy
Central review

43. Royce, M. ESMO (2016), Abstract 2220
BOLERO-4: Phase 2 trial of first-line everolimus (EVE) plus letrozole (LET) in
estrogen receptor–positive (ER+), human epidermal growth factor receptor
2–negative (HER2−) advanced breast cancer (BC)

44. Royce, M. ESMO (2016), Abstract 2220
BOLERO-4: Phase 2 trial of first-line everolimus (EVE) plus letrozole (LET) in
estrogen receptor–positive (ER+), human epidermal growth factor receptor
2–negative (HER2−) advanced breast cancer (BC)

45. Royce, M. ESMO (2016), Abstract 2220
BOLERO-4: Phase 2 trial of first-line everolimus (EVE) plus letrozole (LET) in
estrogen receptor–positive (ER+), human epidermal growth factor receptor
2–negative (HER2−) advanced breast cancer (BC)

46. Royce, M. ESMO (2016), Abstract 2220
BOLERO-4: Phase 2 trial of first-line everolimus (EVE) plus letrozole (LET) in
estrogen receptor–positive (ER+), human epidermal growth factor receptor
2–negative (HER2−) advanced breast cancer (BC)

47. 1970s Tamoxifen 20% 26wks38%
ORR CBR PFS/TTF
2016 Fulvestrant 46% 71wks78%
2001 Letrozole 30% 41wks49%
2012 Eve + Exe 13% 49wks50%

48. 1970s Tamoxifen 20% 26wks38%
ORR CBR PFS/TTF
2016 Fulvestrant 46% 71wks78%
2001 Letrozole 30% 41wks49%
2012 Eve + Exe 13% 49wks50%
2009 Weekly paclitaxel 49% 47wks75%

49. PALOMA-2: Addition of Palbociclib
to Frontline Letrozole Significantly
Improves PFS in Postmenopausal
ER+/HER2- Advanced Breast Cancer

50. PALOMA 2: Study Design
• Multicenter, international, double-blind, randomized phase III trial
• Primary endpoint: PFS by investigator
• Secondary endpoints: response, OS, safety, biomarkers, pt-reported
outcomes
Postmenopausal women
with ER+/HER2- advanced
breast cancer, no prior
treatment for advanced
disease, no AI resistance
(N = 666)
Stratified by disease site (visceral vs nonvisceral),
disease-free interval (de novo metastatic; ≤ 12 mos vs > 12 mos),
prior neoadjuvant or adjuvant hormonal therapy (yes vs no)
Palbociclib 125 mg QD (3/1 schedule)
+ Letrozole 2.5 mg QD
(n = 444)
Placebo (3/1 schedule)
+ Letrozole 2.5 mg QD
(n = 222)
Slide credit: clinicaloptions.comFinn R, et al. ASCO 2016. Abstract 507.

51. Slide credit: clinicaloptions.com
PALOMA 2: Baseline Characteristics (ITT)
Characteristic
Palbociclib + Letrozole
(n = 444)
Placebo + Letrozole
(n = 222)
Median age, yrs (range)
65 yrs or older, %
62 (30-89)
41
61 (28-88)
36
Race, %
White/Black/Asian/other 77/2/15/6 77/1/14/8
ECOG PS, %
0/1/2 58/40/2 46/53/1
Disease site, %
Visceral
Nonvisceral
• Bone only
48
52
23
50
50
22
Disease-free interval, %
> 12 mos
≤ 12 mos
De novo advanced disease
40
22
38
42
22
36
Prior (neo)adjuvant hormonal therapy, % 56 57
Finn R, et al. ASCO 2016. Abstract 507.

52. PALOMA 2: PFS
• Blinded independent central review confirmed investigator-
assessed PFS advantage
• Benefit with palbociclib + letrozole evident across all
subgroups
Slide credit: clinicaloptions.comFinn R, et al. ASCO 2016. Abstract 507.
Outcome
Palbociclib +
Letrozole
(n = 444)
Placebo +
Letrozole
(n = 222)
HR
(95% CI);
P Value
Investigator-assessed
 Number of events, n (%)
 Median PFS, mos (95% CI)
194 (44)
24.8 (22.1-NR)
137 (62)
14.7 (12.9-17.1)
0.58
(0.46-0.72);
< .000001
Blinded independent central review
 Number of events, n (%)
 Median PFS, mos (95% CI)
152 (34)
30.5 (27.4-NR)
96 (43)
19.3 (16.4-30.6)
0.65
(0.51-0.84);
.0005

53. Outcome[1] Palbociclib +
Letrozole
Placebo +
Letrozole
OR (95% CI) P Value
ITT population
ORR,* % (95% CI)
CBR,† % (95% CI)
n = 444
42 (37.5-46.9)
85 (81.2-88.1)
n = 222
35 (28.4-41.3)
70 (63.8-76.2)
1.40 (0.98-2.01)
2.39 (1.58-3.59)
.0310
< .0001
Pts with measurable disease
ORR,* % (95% CI)
CBR,† % (95% CI)
n = 338
55 (49.9-60.7)
84 (80.0-88.0)
n = 171
44 (36.9-52.2)
71 (63.3-77.5)
1.55 (1.05-2.28)
2.23 (1.39-3.56)
.0132
.0003
PALOMA 2: Secondary Endpoints
• Clinical benefit consistent with phase II open-label PALOMA-1 study[2]
Slide credit: clinicaloptions.com
*Confirmed CR + PR. †Confirmed CR + PR + SD ≥ 24 wks.
1. Finn R, et al. ASCO 2016. Abstract 507.
2. Finn RS, et al. Lancet Oncol. 2015;16:25-35.

54. PALOMA 2: Safety
AEs (All Causality), %
Palbociclib + Letrozole (n = 444) Placebo + Letrozole (n = 222)
Any Grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4
Any AE 99 62 14 95 22 2
Hematologic AE in ≥ 15% of pts in either arm
 Neutropenia* 80 56 10 6 1 < 1
 Leukopenia* 39 24 1 2 0 0
 Anemia* 24 5 < 1 9 2 0
 Thrombocytopenia* 16 1 < 1 1 0 0
Nonhematologic AE in ≥ 25% of pts in either arm
 Fatigue 37 2 0 28 < 1 0
 Nausea 35 < 1 0 26 2 0
 Arthralgia 33 1 0 34 0 0
 Alopecia 33 0 0 16 0 0
 Diarrhea 26 1 0 19 1 0
 Cough 25 0 0 19 0 0
 Headache 21 < 1 0 26 2 0
 Hot flush 21 0 0 31 0 0
*Includes clustered MedDRA-preferred terms.
Finn R, et al. ASCO 2016. Abstract 507. Slide credit: clinicaloptions.com

55. PALOMA 2: AE Summary
• Most AEs resulting in d/c reported as single events, most commonly
neutropenia with palbociclib (1.6%) or fatigue with placebo (0.9%)
• One on-study, treatment-related death because of pulmonary
embolism/respiratory failure in placebo arm
Slide credit: clinicaloptions.comFinn R, et al. ASCO 2016. Abstract 507.
Outcome, % Palbociclib +
Letrozole (n = 444)
Placebo +
Letrozole (n = 222)
Serious AE 19.6 12.6
Serious AE occurring in ≥ 1% of pts
Febrile neutropenia
Pulmonary embolism
1.6
0.9
0
1.4
AE-related discontinuation 9.7 5.9
AE-related death 2.3 1.8

56. PALOMA 2: Conclusions
• First-line palbociclib + letrozole significantly improved median PFS vs
placebo + letrozole in women with ER+/HER2- advanced breast
cancer
– Median PFS improved by > 10 mos compared to placebo
• 24.8 mos vs 14.5 mos, HR: 0.58 (95% CI: 0.46-0.72; P < .0001)
• Palbociclib clinical benefit observed in all prespecified subgroups
• Palbociclib well tolerated with neutropenia, leukopenia the most
frequently reported AEs
• PALOMA-2[1] data confirm PALOMA-1[2] results and constitute the longest
median PFS improvement to date in the front-line setting in advanced ER+
breast cancer
Slide credit: clinicaloptions.com
1. Finn R, et al. ASCO 2016. Abstract 507.
2. Finn RS, et al. Lancet Oncol. 2015;16:25-35.

57. 2016 Letrozole (L) 35% 61wks70%
Palbociclib + L 42% 103wk85%
Baselga, NEJM, 2012
ORR CBR PFS/TTF
PALOMA-2

58. 1970s Tamoxifen 20% 26wks38%
ORR CBR PFS/TTF
2016 Fulvestrant 46% 71wks78%
2001 Letrozole 30% 41wks49%
2012 Eve + Exe 13% 49wks50%
2009 Weekly paclitaxel 49% 47wks75%
2016 Letrozole (L) 35% 61wks70%
Palbociclib + L 42% 103wk85%
Hormone-resistant
Hormone-naïve
Non-HR+ included
Gets better with time
Unavailable
>77 mo in 1st/2nd Line

60. ESMO-2016, Copenhagen, 7-11 October 2016

61. HR+/Her2- aBC
What’s needed?
Sprint
Marathon
Hormone-naïve
Hormone-resistant
Neither
Where does the
patient belong
In short…

62. Hormone-naïve
Sprint Hormone-resistant
Neither
Paclitaxel / anti-CDK4 + AI / Fulvestrant
Paclitaxel / probably anti-CDK4 + AI / Fulvestrant / AI
Paclitaxel / anti-CDK4 + AI / Fulvestrant / AI
ie, visceral crisis
Hormone-naïve
Marathon Hormone-resistant
Neither
Fulvestrant / Anti-CDK4 + AI / AI / Paclitaxel
Eve + Exe / Paclitaxel / probably CDK4i + AI / Fulvestrant
CDK4i + Letrozole / probably Fulvestrant / probably Eve + Let
/ Paclitaxel
ie, low-risk disease
Approx 10% of patients
Approx 90% of patients

63. @Onconerd