Mutazioni PI3K e mutazioni ER · Placebo + fulvestrant Censoring times 0 2 4 6 8 10 12 14 16 18 20...

Alessandra Fabi

Roma, 25 Maggio 2019

Mutazioni PI3K e mutazioni ER:

quale impatto sull’outcome delle

pazienti con carcinoma

mammario?

San Antonio Breast Cancer Symposium®, December 4-8, 2018

Disclosures

Scientific advisory board, meeting, congress:

Celgene,

Lilly,

Novartis,

Roche,

Pfizer

…

The Importance of the PI3K Pathway in HR+ Breast Cancer

• The PI3K pathway is frequently altered in HR+ breast

cancer and has been implicated in resistance to

endocrine therapies1,2

• Approximately 40% of HR+ breast cancers harbor a

PIK3CA mutation, leading to hyperactivation of the PI3K

pathway3-5

• PI3K signaling has been shown to promote estrogen-

independent growth of ER+ breast cancer cells,6,7 and this

growth is inhibited by the addition of PI3K inhibitors to

antiestrogens8

Figure reprinted by permission from Springer Nature: Nature Reviews Drug Discovery. Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery. Hennessy BT, et al.

Nat Rev Drug Discov. 2005 Dec;4(12):988-1004. © 2005.

1. Miller TW, et al. J Clin Oncol. 2011;29(33):4452-4461. 2. Bosch A, et al. Sci Transl Med. 2015;7(283):283ra51. 3. Mayer IA, et al. Clin Cancer Res. 2017;23(1):26-34. 4. Loi S, et al. Proc Natl Acad Sci U S A.

2010;107(22):10208-10213. 5. Stemke-Hale K, et al. Cancer Res. 2008;68(15):6084-6091. 6. Miller TW, et al. J Clin Invest. 2010;120(7):2406-2413. 7. Crowder RJ, et al. Cancer Res. 2009;69(9):3955-3962. 8. Miller TW, et al.

Cancer Discovery. 2011;1(4):338-351. This presentation is the intellectual property of Dejan Juric. Contact

PI3Kα inhibition increases ERα target-gene expression

Con

trol

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PR

Time (h) of exposure to drug

Rela

tive m

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24h

48h

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Time (h) of exposure to drug

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MCF7

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Fold

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rich

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12

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CREB1 promoter

Bosch et al. Sci Transl Med. 2017

Alteration frequency in ER+/HER2- MBC - BOLERO-2 and The Cancer Genome Atlas (TCGA)

5

Hortobagyi, JCO, 2016

Genomic Alterations Occur in Critical Pathways

• ER positive tumors • PI3K • AKT • mTOR • Erbb2 (HER2) • ESR1 • FGFR

• HER2 positive • PI3K

• Basal (TNBC)

• BRCA • P53 • Genomic Instability

Di Cosimo, S. & Baselga, J. (2010) Nat. Rev. Clin. Oncol

• The principal characteristic of the luminal group is the luminal expression signature, composed of

ESR1, GATA3, FOXA1, XBP1, and cMYB

- the most frequent mutations in the luminal A subtype are PIK3CA (45%), MAP3K1 (13%), GATA3

(13%), TP53 (12%), and CDH1 (9%)

-the most frequent mutations in luminal B tumors are TP53(29%), PIK3CA (29%),GATA3 (13%), and

TTN (12%)

• In addition to TP53 mutations, several other events may intervene in other steps of the same

pathway, including ATM loss and MDM2 amplification

• ESR1mutations (up to 19%) after hormonal treatment => resistance

The no so easy biology of Luminal Tumors

9

Buparlisib plus fulvestrant vs. placebo plus fulvestrant in postmenopausal, HR+/HER2-, advanced breast cancer (BELLE-2)

Baselga, Lancet Oncol 2017

Phase I Dose Escalation Study of Taselisib (GDC-0032), an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors

11 Juric, Cancer Discovery 2017

A Study of Taselisib + Fulvestrant vs. Placebo + Fulvestrant in Participants With Advanced or Metastatic Breast Cancer Who Have Disease Recurrence or Progression During or After AI Therapy (SANDPIPER)

12 Baselga, ASCO 2018

Selective Inhibition of PI3K-alpha Is a Promising Strategy in PIK3CA-Mutated Cancers

• While pan-PI3K and β-sparing inhibitors target

multiple isoforms, alpelisib (BYL719) specifically

targets the α-isoform2

• Alpelisib has demonstrated antitumor activity in

preclinical models harboring PIK3CA alterations2

• In a phase 1b trial, alpelisib + fulvestrant provided a

9.1-mo median PFS in heavily pretreated patients

with ER+ ABC and positive PIK3CA mutation status3

ABC, advanced breast cancer; ER+, estrogen receptor-positive; PFS, progression-free survival; PI3K, phosphatidylinositol 3-kinase.

1. Andre F, et al. ESMO 2018. Abstract LBA3 [oral]. 2. Fritsch C, et al. Mol Cancer Ther. 2014;13(5):1117-1129. 3. Juric D, et al. JAMA Oncol. 2018;In press.

This presentation is the intellectual property of Dejan Juric. Contact [email protected] for permission to reprint and/or distribute.

mailto:[email protected]

Phosphatidylinositol 3-Kinase a–Selective Inhibition With Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human Study (BYL719X2101)

14

Juric, JCO 2018



SOLAR-1: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial (NCT02437318)1

Primary endpoint

• PFS in PIK3CA-mutant cohort

(locally assessed)

Secondary endpoints include

• OS (PIK3CA-mutant cohort)

• PFS (PIK3CA-non-mutant cohort)

• PFS (PIK3CA mutation in ctDNA)

• PFS (PIK3CA-non-mutant in ctDNA)

• ORR/CBR (both cohorts)

• Safety

Men or postmenopausal women

with HR+, HER2– ABC

• Recurrence/progression on/after prior AI

• Identified PIK3CA status

(in archival or fresh tumor tissuea)

• Measurable disease or

≥ 1 predominantly lytic bone lesion

• ECOG performance status ≤ 1

(N = 572)

1:1, stratified by presence of

liver/lung metastases and prior

CDK4/6 inhibitor treatment

ALP 300 mg PO QD

+ FUL 500 mg IMb

n = 169

PBO

+ FUL 500 mg IMb

n = 172

R

PIK3CA-non-mutant

cohort (n = 231)

ALP 300 mg PO QD

+ FUL 500 mg IMb

n = 115

PBO

+ FUL 500 mg IMb

n = 116

R

PIK3CA-mutant

cohort (n = 341)

• The primary endpoint included all randomized patients in the PIK3CA-mutant cohort; PFS was analyzed in the PIK3CA-non-mutant cohort as a proof of concept

• Safety was analyzed for all patients who received ≥ 1 dose of study treatment, in both cohorts

15

Primary Endpoint: Locally Assessed PFS in the PIK3CA-mutant Cohort1,a

16

Data cut-off:

Jun 12, 2018

ALP + FUL

(n = 169)

PBO + FUL

(n = 172)

Number of PFS events, n (%) 103 (60.9) 129 (75.0)

Progression 99 (58.6) 120 (69.8)

Death 4 (2.4) 9 (5.2)

Censored 66 (39.1) 43 (25.0)

Median PFS (95% CI) 11.0 (7.5-14.5) 5.7 (3.7-7.4)

HR (95% CI) 0.65 (0.50-0.85)

One-sided P value 0.00065

CI, confidence interval; HR, hazard ratio; PFS, progression-free survival. a Mutation status determined from tissue biopsy.

1. Andre F, et al. ESMO 2018. Abstract LBA3 [oral].



PFS by Line of Therapy in the PIK3CA-mutant Cohorta

Second-line (n = 161) Defined as patients whose disease progressed > 1 year after (neo)adjuvant ET and while on or after 1 line of ET for ABC or patients with newly diagnosed ABC whose disease progressed while on or after 1 line of ET

17

ALP + FUL

(n = 79)

PBO + FUL

(n = 82)

Events, n (%) 50 (63.3) 65 (79.3)

Median PFS, mo 10.9 3.7

HR, (95% CI) 0.61 (0.42-0.89)

0

20

40

60

80

100

Even

t-fr

ee p

rob

ab

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y (%

)

Alpelisib + fulvestrant Placebo + fulvestrant

Censoring times

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Time (months)

30

ABC, advanced breast cancer; CI, confidence interval; ET, endocrine therapy; HR, hazard ratio; PFS, progression-free survival. a Mutation status determined from tissue biopsy.


Endocrine sensitive patients Endocrine resistant patients

ALP + FUL

(n = 20)

PBO + FUL

(n = 19)

ALP + FUL

(n = 68)

PBO + FUL

(n = 70)

Events, n (%) 11 (55.0) 9 (47.4) 40 (58.8) 55 (78.6)

Median PFS, mo 22.1 19.1 9.0 4.7

HR, (95% CI) 0.87 (0.35-2.17) 0.69 (0.46-1.05)

First-line (n = 177) Defined as patients whose disease progressed ≤ 1 year after (neo)adjuvant ET (endocrine resistant) or whose disease progressed > 1 year after (neo)adjuvant ET (endocrine sensitive) (later excluded after protocol amendment)

ALP + FUL

(n = 88)

PBO + FUL

(n = 89)

Events, n (%) 51/88 (58.0) 64/89 (71.9)

Median PFS, mo 11.0 6.8

HR, (95% CI) 0.71 (0.49-1.03)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

0

20

40

60

80

100

Even

t-fr

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ab

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y (%

)

Alpelisib + fulvestrant Placebo + fulvestrant

Censoring times

Time (months)


ctDNA, circulating tumor DNA; HR, hazard ratio; PFS, progression-free survival; QD, once daily.


Locally Assessed PFS by Tissue or Plasma ctDNA-determined Mutation Status

ALP + FUL PBO + FUL

HR Event n/N

(%) Median

PFS Event n/N

(%) Median

PFS

Patients with PIK3CA

mutation: tissue 103/169 (60.9) 11.0 129/172 (75.0) 5.7 0.65

Patients with PIK3CA

mutation: plasma 57/92 (62.0) 10.9 75/94 (79.8) 3.7 0.55

Patients without PIK3CA

mutation: tissue 49/115 (42.6) 7.4 57/116 (49.1) 5.6 0.85

Patients without PIK3CA

mutation: plasma 92/181 (50.8) 8.8 103/182 (56.6) 7.3 0.80

Number of patients still at risk

92 87 80 77 68 61 54 52 44 43 41 38 34 31 29 24 23 19 18 16 9 8 6 2 2 1 1 1 0

94 90 58 53 42 41 37 34 30 30 26 22 20 19 18 14 14 11 10 9 6 6 5 2 2 1 1 1 0 Placebo + ful

Alpelisib + ful

Time (months)

0

20

40

60

80

100

Even

t-fr

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rob

ab

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)

Alpelisib + fulvestrant

Placebo + fulvestrant

Censoring times

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

18

PIK3CA mutant patients determined by ctDNA


19

Mouse models with targeted inactivating mutation in the p110-delta subunit of PI3K (PI3K p110-delta D910A/D910A) revealed defects in B and T-cell signaling, macrophage function and chronic colitis

Okkenhaug et al., Science, 2002

Uno et al., Gastroenterology, 2010

Courtesly by Dejan Juric.

Non-responding tumors also demonstrate sustained or increased levels of phospho-RB: the future developments

Vora, Cancer Cell, 2014

20


Combined inhibition PI3K-alpha and CDK4/6 is synergistic


Vora, Cancer Cell, 2014

21


Although CDK4/6 have dramatically improved outcomes in patients with ABC, new treatment strategies are needed disease progression eventually occurs1

• Resistance to CDK4/6 inhibitors may occur through multiple mechanisms, including CCNE1 amplification, Rb loss, and ER-signaling1-5

• The PI3K pathway is frequently mutated in breast cancer, with approximately 40% of HR+ breast cancers expressing mutated PIK3CA2

– Upregulation of PI3K/mTOR has been noted after prolonged CDK4/6 inhibitor exposure in preclinical studies1,3

• Preclinical evidence suggests that inhibition of PI3K/AKT/mTOR pathway in combination with endocrine therapy is effective in CDK4/6 resistant breast cancer cells3,4

Disease Progression on CDK4/6 Inhibitor + ET Potential Mechanisms of Resistance

1. Cortex J, et al. Cancer Treat Rev. 2017; 2. Herrara-Abreau MT, et al. Cancer Res. 2016;76(8):2301-2313; 3. O’Brien NA, et al. AACR 2017. Abstract 4150 [poster]; 4. Lenihan C, et al. SABCS 2016. Abstract P3-03-12 [poster]; 5. Turner

NC, et al. AACR 2018. Abstract CT039 [poster].

23

CLEE011X2107 TREATMENT-RELATED ADVERSE EVENTS

This presentation is the intellectual property of Dejan Juric. Contact [email protected] for permission to reprint and/or distribute. 24


Improving therapeutic window of PI3K inhibitors

Mathijssen, Nat Rev Clin Oncol. 2014

25


Take of Message

•PI3K mutations are frequent

•Selective PI3Kα inhibitors active in phase III in tumors with PI3Kα mutations

•Adaptive activation of ER occurs upon PI3k pathway inhibition

•SERDs and PI3Kα inhibitors in combination are very active Registration trials under way

• Progression after CDK4/6 Inhibitors: promise of PI3K inhibithors

•Tumor evolution under selective pressure to be addressed

Roma, 25 Maggio 2019

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