Luis Manso MD PhD
Unidad T Mama y Ginecológicos
Oncología Médica
Hospital 12 de Octubre
AGENDA
• Vía PI3K/AKT/mTOR.
• Alteraciones genéticas en PI3K/AKT:
dependencia oncogénica.
• ER+ breast cancer.
• Her2+ breast cancer.
• TNBC breast cancer.
• Selección, Combinaciones.
Vía PI3K/AKT/mTOR.
Alteraciones genéticas en PI3K/AKT:
dependencia oncogénica
PIK3CA E542K
E545K
H1047R
Mutation: Endometrial 19.8–32.8%
Breast 1.1–2.8%
Exon 9 Exon 20
Alteraciones genéticas en PI3K/AKT:
dependencia oncogénica
Koboldt DC. Nature 2012.
ER+ breast cancer
Interaction between mTOR and ERα
S6K1
mTOR
Growth factors
ERα P
Ser167
Transcription
ER-Responsive Element
E
Cell proliferation *P<.05, 2-tailed paired Student’s t test
Effect of rapamycin and hormonal
therapy on cell proliferation
1. Adapted with permission from Yamnik RL, et al. J Biol Chem. 2009;284(10):6361-6369; 2. Johnston SRD. Clin Cancer Res. 2005;11(2, Suppl.):889S-899S.
- Refractory to previous letrozole or anastrozole, defined as recurrence during or within 12
months after the end of adjuvant treatment or progression during or within 1 month after
the end of treatment for advanced disease.
- Stratified according to the presence of visceral metastasis and previous sensitivity to
endocrine therapy. The latter was defined as at least 24 months of endocrine therapy
before recurrence in the adjuvant setting or a response or stabilization for at least 24
weeks of endocrine therapy for advanced disease.
Pro
gre
ss
ion
-Fre
e S
urv
iva
l, %
EVE+EXE (n/N = 243/364) PBO+EXE (n/N = 165/196)
Censoring Times
PFS Events, n (%) Age < 70 y
Censored, n (%)
Median PFS, mo HR (95% CI)
EVE+EXE Progression 235 (65) 121 (33) 8.11 0.44 (0.36, 0.54) Death 8 (2)
PBO+EXE Progression 163 (83) 31 (16) 4.01 Death 2 (1)
Time, wk
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120
0
20
40
60
80
100
Everolimus Placebo
Number of patients still at risk 364 333 287 247 211 185 153 132 103 77 56 42 29 21 19 10 8 7 1 1 0 196 163 114 83 56 41 31 24 17 12 9 8 5 3 1 1 1 0 0 0 0
A
Pro
gre
ss
ion
-Fre
e S
urv
iva
l, %
EVE+EXE (n/N = 67/121)
PBO+EXE (n/N = 35/43)
Censoring Times
PFS Events, n (%)
Censored, n (%)
Median PFS, mo HR (95% CI)
59 (49) 54 (45) 6.77 0.45 (0.30, 0.68) 8 (7)
35 (81) 8 (19) 1.51 0
0
20
40
60
80
100
Time, wk
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120
B
Everolimus Placebo
Number of patients still at risk 121 103 79 57 46 36 32 26 21 14 10 8 6 3 3 3 2 1 1 0 0 43 27 18 13 11 9 8 6 4 3 1 0 0 0 0 0 0 0 0 0 0
Age ≥ 70 y
EVE+EXE
PBO+EXE
Progression Death
Progression Death
Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo; PFS, progression-free survival; wk, weeks.
Pritchard KI, et al. Clinical Breast Cancer. 2013; 13(6):421-432.
NP
4: 1
60
40
41
10
4 BOLERO-2 (18-mo f/up): PFS Benefits Were Comparable
in Elderly vs Younger Patients
BOLERO-2 (18-mo f/up): PFS Benefits Were Comparable in Patients
With (A) Visceral Metastases, (B) Without Visceral Metastases, and
(C) With Bone-Only Metastases
Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo; PFS, progression-free survival.
Reprinted from Campone M, et al. Eur J Cancer. 2013;49:2621-2632.
0
20
40
60
Pro
bab
ility
of
Even
t, %
Pro
bab
ility
of
Even
t, %
80
100
Time, wk Time, wk
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114
EVE+EXE
PBO+EXE
Patients at risk
271 240 192 157 128 107 88 72 52 38 25 22 16 12 11 7 5 4 1 0
135 108 66 44 32 23 18 14 11 8 4 4 3 1 0 0 0 0 0 0
0
20
40
60
80
100
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120
EVE+EXE
PBO+EXE
Patients at risk
214 196 174 147 129 114 97 86 72 53 41 28 19 12 11 6 5 4 1 1 0
104 82 66 52 35 27 21 16 10 7 6 4 2 2 1 1 1 0 0 0 0
A B C
HR=0.47 (95% CI, 0.37-0.60)
Kaplan-Meier medians
EVE+EXE: 6.83 mo
PBO+EXE: 2.76 mo
HR=0.41 (95% CI, 0.31-0.55)
Kaplan-Meier medians
EVE+EXE: 9.86 mo
PBO+EXE: 4.21 mo
Censoring times
EVE+EXE (n/N=122/214)
PBO+EXE (n/N=84/104)
Censoring times
EVE+EXE (n/N=188/271)
PBO+EXE (n/N=116/135) 0
20
40
60
80
100
Time, wk
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108
EVE+EXE
PBO+EXE
Patients at risk
105 95 88 75 72 65 53 47 41 30 20 13 7 6 5 3 2 1 0
46 35 30 24 19 14 12 10 5 3 1 1 1 0 0 0 0 0 0
EVE+EXE (n/N=48/105)
PBO+EXE (n/N=33/46)
Censoring Times
EVE+EXE: 12.88 mo
Kaplan-Meier medians
PBO+EXE: 5.29 mo
HR=0.33 (95% CI, 0.21-0.53)
Pro
gres
sio
n-F
ree
Surv
ival
, %
14
BOLERO-2 (18-mo f/up): Common Adverse Events Were Consistent With the Established Safety Profile of Everolimus
a Adverse events of clinical interest.
Yardley DA, et al. Adv Ther. 2013;30:870-884.
RA
(término preferido)
EVE+EXE (n=482), % PBO+EXE (n=238), %
Grado Grado
Todos 1 2 3 4 Todos 1 2 3 4
Stomatitis 59 29 22 8 0 12 9 2 <1 0
Rash 39 29 9 1 0 7 5 2 0 0
Fatigue 37 18 14 4 <1 27 16 10 1 0
Diarrhea 34 26 6 2 <1 19 14 4 <1 0
Nausea 31 21 9 <1 <1 29 21 7 1 0
Decreased appetite 31 19 10 1 0 13 8 4 <1 0
Weight decreased 28 10 16 1 0 7 3 5 0 0
Cough 26 21 4 <1 0 12 8 3 0 0
Dysgeusia 22 18 4 0 0 6 6 0 0 0
Dyspnea 22 10 6 5 <1 11 8 2 <1 <1
Headache 23 17 6 <1 0 15 13 2 0 0
Arthralgia 21 15 5 <1 0 17 11 5 <1 0
Peripheral edema 21 14 6 1 0 6 5 <1 <1 0
Anemia 21 4 10 7 <1 5 2 2 <1 <1
Epixtasis 17 16 2 0 0 1 1 0 0 0
Vomiting 17 11 6 <1 13 9 3 <1 <1 0
Pyrexia 16 13 3 <1 0 7 5 <1 <1 0
Table 4. Most common adverse events (reported in ≥10% of pacients)
Incidence and Distribution of Grade ≥ 2 Stomatitis and Related Events Over the BOLERO-2 Study Period
Rugo H, et al. St Gallen International Breast Cancer Conference 2013, abstract 274 (poster) and Rugo H, et al. Ann Oncol. Mar 10 [Epub ahead of print].
Incidence of stomatitis and related events was higher in the EVE+EXE arm (59%) vs PBO+EXE arm (12%)
Incidence of new stomatitis/related events (grade ≥ 2) plateaued at wk 6
Most patients (97%; n = 38) with grade 3 stomatitis in the EVE+EXE arm experienced resolution to grade ≤ 1 at median 3.1
wk, and 32 patients (82%) had complete resolution at median 7.4 wk
0
20
40
60
80
100
Time, months 0 2 4 6 8 10 12 14 16 18 20 22 24 26
EVE+EXE
EVE+EXE
PBO+EXE
PBO+EXE
Number of Patients still at Risk 482 307 233 172 134 99 63 39 25 13 10 5 2 0 238 168 115 70 47 33 20 11 7 3 1 1 0 0
Pro
ba
bilit
y o
f E
ve
nt,
%
EVE+EXE (n/N = 160/482)
PBO+EXE (n/N = 7/238)
Censoring Times
~88%
2%
9%
<1%
No AEs (grade 0)
Grade 1
Grade 2
Grade 3
Grade 4
SWISH:Stomatitis prevention in PMW with HR+, HER2- MBC using a DEX based mouth wash
Incidence and Distribution of Grade ≥ 2 Non-infectious Pneumonitis and Related Events Over the BOLERO-2 Study Period
Rugo H, et al. St Gallen International Breast Cancer Conference 2013, abstract 274 (poster) and Rugo H, et al. Ann Oncol. Mar 10 [Epub ahead of print].
Incidence of noninfectious pneumonitis and related events was higher in the EVE+EXE arm (20%) vs
PBO+EXE arm (< 1%)
16 patients (80%) with ≥ grade 3 noninfectious pneumonitis in the EVE+EXE arm experienced resolution
to grade ≤ 1 at median 3.8 wk, and 15 patients (75%) had complete resolution at median 5.4 wk
0
20
40
60
80
100
Time, months
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
EVE+EXE
EVE+EXE
PBO+EXE
PBO+EXE
Number of Patients Still at Risk 482 417 317 242 184 136 94 59 38 21 15 9 3 1 0 238 173 119 72 48 34 21 11 7 3 1 1 0 0 0
EVE+EXE (n/N = 55/482)
PBO+EXE (n/N = 0/238)
Censoring Times
Pro
ba
bilit
y o
f E
ve
nt,
%
~99%
<1%
~79% 9%
7%
4%
<1%
No AEs (grade 0)
Grade 1
Grade 2
Grade 3
Grade 4
BOLERO-2 Biomarker Analyses
Genetic Alterations and Everolimus Efficacy in Hormone Receptor–positive,
HER-2–negative Advanced Breast Cancer: Preliminary Correlative Results
From BOLERO-2
Gabriel Hortobagyi, Martine Piccart, Hope Rugo, Howard Burris III, Mario
Campone, Shinzaburo Noguchi, Alejandra Perez, Ines Deleu, Mikhail
Shtivelband, Louise Provencher, Norikazu Masuda, Shaker Dakhil, Ian
Anderson, David Chen, Amy Damask, Alan Huang, Douglas Robinson,
Rob McDonald, Adnan Derti, Tetiana Taran, Tarek Sahmoud, David
Lebwohl and José Baselga
Presented at ASCO 2013 Abstract LBA509
Patients With No or Single Genetic Alteration in PIK3CA/ PTEN/CCND1 or FGFR1/2 Derive Greater PFS Benefit With EVE
Subgroup Definition Size, %
WT No alteration in PIK3CA AND PTEN AND FGFR1/2 AND CCND1
Minimal
27%
76% Single
Single alteration only in PIK3CA OR PTEN OR FGFR1/2 OR
CCND1
49%
Multiple Two or more alterations in PIK3CA OR PTEN OR FGFR1/2 OR
CCND1 genes Multiple
24%
24%
Subgroup N Events (%) Median
PFS (d) HR* (95%CI)
EVE: WT 43 19 (44%) 356 0.24
(0.11 - 0.54) PBO: WT 18 14 (78%) 203
EVE: Single 76 48 (63%) 214 0.26
(0.16 - 0.43) PBO: Single 35 31 (89%) 77
EVE: multiple 38 27 (71%) 138 0.78
(0.39 - 1.54) PBO: multiple 17 14 (82%) 128
*HR adjusted with imbalanced covariates
Abbreviations: CI, confidence interval; EVE, everolimus; HR, hazard ratio; PBO, placebo;
PFS, progression-free survival; WT, wild type.
ER+ breast cancer
OPPORTUNE
2 wks
The primary end point was change in Ki-67.
OPPORTUNE
mean percentage
suppression
of Ki-67 was 83.8% (95%
CI, >79.0%)
mean percentage
suppression
of Ki-67 was 66.0%
(95% CI,<75.4%)
P = .004
OPPORTUNE
GeparQuattro, GeparQuinto , GeparSixto, NeoALTTO, CHERLOB
PIK3CA mutation rate 20% aprox
The prognostic impact of PIK3CA mutations cannot be attributed to a specific
mutation, nor to mutation(s) in a specific exon, based on the available dataset
182 mutations detected overall (32%)
Exon 7: 12; exon 9: 39; exon 20: 131
Pla+T+D Ptz+T+D
PIK3CA status Patients, n Events
Median, months Patients, n Events
Median, months
HR (95% CI)
Mut 90 63 8.6 86 45 12.5 0.64
(0.43, 0.93)
WT 191 101 13.8 190 83 21.8 0.67
(0.50, 0.89)
Overall 406 242 12.4 402 191 18.5 0.62
(0.51, 0.75)
CLEOPATRA
Shorter median PFS observed with mutated
PIK3CA while treatment effect is maintained
Mut, mutated; WT, wild-type
Baselga J. SABCS 2012; JCO Nov 2014
Lancet Oncol 2014
BOLERO-3: Primary endpoint progression-free survival by local assessment
Lancet Oncol 2015
BOLERO-1: Primary endpoint progression-free survival by local assessment
HR -
NeoPHOEBE: Neoadjuvant Trastuzumab + BKM120 in Combination With
Weekly Paclitaxel in HER2-positive Primary Breast Cancer (NeoPHOEBE)
ClinicalTrials.gov: NCT01816594
Buparlisib (100 mg/day) or Buparlisib (80 mg/day) Population
(N = 220)
• Adult women with HER2+,
untreated primary non-
inflammatory BC
• Known PIK3CA mutation
status
• ECOG PS ≤1
PBO + TRAS (4 mg/kg) loading dose then 2 mg/kg for 6 wks
or
TRAS (2 mg/kg/week) and PAC (80 mg/m2)/week for 12 wks
PIK3CA mutant or wild-type
[wt] 1:1
NeoPhobe: Phase II, randomized, double-blind, placebo-controlled, parallel-cohort study
Objectives
•To determine the MTD, safety and activity of alpelisib (BYL719) in combination with T-DM1 in HER2+ MBC who progressing on prior T-DM1 therapy
Methodology
Results
Phase I study of alpelisib and T-DM1 in trastuzumab-refractory HER2+ MBC
Jain (Abstract # 588)
Conclusions
ALP + T-DM1 treatment was safe, well tolerated, and clinically efficacious in pts with HER2+ MBC who progressed on prior T-DM1 therapy
A further phase II study is planned
Poster
Phase I, 3+3 dose expansion study
cohort 11
BYL719 300mg PO q day
cohort 2
BYL719 350mg PO q day
cohort 33
BYL719 400mg PO q day
+
cohort 1
BYL719 250mg PO q day
N = 15
• HER2+ locally advanced and MBC
• Disease progressed on
trastuzumab and/or taxane-
containing regimens in the
metastatic setting or within 6
months in the adjuvant setting
• ECOG PS ≤ 2
Response
assesments4
• MTD, safety and
efficacy
• PK/PD evaluation
T-DM1
(3.6 mg/kg
IV q cycle2)
FOLLOW UP5
Most common AEs (≥40%)
AEs, n (%) Gr 1/2 Gr 3
AST increased 11 (73) -
Nausea 8 (53) -
Fatigue 8 (53) -
Hyperglycemia 7 (47) 2 (13)
Maculopapular rash - 6 (40)
1.Starting dose = cohort 1; 2.1 cycle = 21 days; 3. An expansion cohort of 10 patients will be treated at the MTD; 4.Treatment continued until progression, excessive toxicity, or patient preference;
5.Once off treatment, patients will be followed every 3 months until disease progression or initiation of next therapy; * Additional 7 patients will be enrolled; AE, adverse events; AST, aspartate
aminotransferase; DLT, dose-limiting toxicity; ECOG PS, Eastern Cooperative Oncology Group performance status; HER2+, human epidermal growth factor receptor 2 positive; MTD, maximum
tolerated dose; MBC, metastatic breast cancer; PK, pharmacokinetics; PD, pharmacodynamics; PFS, progression free survival; PO, Orally; T-DM1, ado-trastuzumab emtansine
In cohort 1, no grade 3 or higher AEs were reported
The MTD for alpelisib was established as 250 mg daily
The median PFS in whole population was 8.4 months
No prior TDM-1 vs Prior TDM-1: 9.8 mo vs 5.6 mo
Figures: Progression-free Survival
TNBC breast cancer
- PTEN loss and activating PI3K pathway (TCGA samples).
- PDX models TNBC -> Inh mTOR/AKT (Xu S, Mol Cancer Ther. 2013).
- Ph 1 single-agent BKM102, 1 PR en TNBC (Bendell J, JCO 2013).
- RB, MYC, TP53 limit the antitumor activity of PI3K inh.
Selección, Combinaciones
http://www.selleckchem.com/PI3K.html
Alpelisib Breast Cancer Program Overview
Combination Neo-adjuvant mBC
Letrozol
Fulvestrant
TAM +
goserelin
T-DM1
CBYL719A2201: Letrozole ± BKM120
or BYL719 (Phase II)
Registration Trial 43
CBYL719XUS03T Letrozole + BYL719
(Phase Ib)
CLEE011X2107:
Letrozole + LEE011 ±BYL719
(Phase I/II)
CBYL719X2101 Fulvestrant+ BYL719
(Phase I) CLEE011X2108:
Fulvestrant + LEE011
± BKM120 or BYL719 (Phase I/II) SOLAR-1
Fulvestrant ± BYL719 (Phase III) (1/2L)
B-YOND:
TAM + Goserelin with
BKM120 or BYL719 (Phase Ib)
BYL719 + T-DM1
(Phase Ib)
Ph I study of BYL719 (Alpelisib) plus fulvestrant in
PIK3CA-altered and wild type (wt) ER+/HER2− mBC
Efficacy summary
The estimated median PFS was longer in the PIK3CA-altered group compared with the PIK3CA WT group (8.3 months vs 4.7 months), HR 0.28 (95% CI: 0.13–0.57; p<0.001).
In the PIK3CA-altered and PIK3CA WT group, 54.0% and 41.9% of patients were censored, respectively.
CBYL719X2101/NCT01219699.
Janku, F. et al. SABCS Abstract #PD5-5; December 2014
PI3KCA-altered
PI3KCA WT
Kaplan–Meier Plot for Patients With
PIK3CA-altered and PIK3CA WT, ER+,
HER2–, Locally Advanced or Metastatic
Breast Cancer
Selección, Combinaciones
- The BET family of proteins consists
of 4 members, BRD2-4.
- They contain two tandem
bromodomains (BRD).
- Facilitate the recruitment of
transcription factors and chromatin
organizers required in transcription
initiation and elongation.
Conclusiones
- PI3K/AKT pathway is the most frecuently mutated network in human cancer.
- The diversity of alterations in this pathway (p110, p85, AKT, mTOR, PTEN, etc.) provides multiple molecular targets for therapy.
- In ER+ breast cancer addition of everolimus to exemestane prolongs PFS in patients with HR+, HER2– breast cancer after a nonsteroidal aromatase inhibitor. Median 7.8 vs 3.2 months HR = 0.45, P < .0001.
- Biomarkers that identify PI3K-dependent cancers are not yet known.
- On-target toxicities manageable but not insignificant. Should be avoidable by PIK3CA-mutant-specific inhibitors??.
- The benefit of these drugs will require development of rational combinations.