luis manso md phd unidad t mama y ginecológicos oncología ... · unidad t mama y ginecológicos...

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.