L’oncologo

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 therapies ^1,2

• Approximately 40% of HR+ breast cancers harbor a PIK3CA mutation, leading to hyperactivation of the PI3K pathway ^3-5

• 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 antiestrogens ⁸

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

Control

BYL

MK 0

1 2 3

Luciferase assay MCF-7

Relative ERa transcriptional activity

**

** Control 4h 8h

12h 24h

48h 0.0

0.5 1.0 1.5 2.0 2.5

PR

Time (h) of exposure to drug

Relative mRNA levels

**

**

**

**

Control 4h 8h

12h 24h

48h 0.0

0.5 1.0 1.5 2.0 2.5

GREB1

Time (h) of exposure to drug

Relative mRNA levels **

**

**

**

MCF7

0 0,5 1 1,5 2 2,5 3 3,5 4 4,5

Fold Enrichment

PR promoter

0 2 4 6 8 10 12

Fold Enrichment

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

Juric, Cancer Discovery 2017 11

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)

Baselga, ASCO 2018 12

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-isoform

• Alpelisib has demonstrated antitumor activity in preclinical models harboring PIK3CA alterations

• 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 status

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.

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

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

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 tissue

)

• Measurable disease or

≥ 1 predominantly lytic bone lesion

• ECOG performance status ≤ 1

1:1, stratified by presence of liver/lung metastases and prior

CDK4/6 inhibitor treatment

ALP 300 mg PO QD + FUL 500 mg IM

n = 169 PBO + FUL 500 mg IM

n = 172 R

PIK3CA-non-mutant

cohort (n = 231)

ALP 300 mg PO QD + FUL 500 mg IM

n = 115 PBO + FUL 500 mg IM

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 Cohort ^1,a

16

Data cut-off:

Jun 12, 2018

ALP + FUL (n = 169)

PBO + FUL (n = 172)

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].

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

PFS by Line of Therapy in the PIK3CA-mutant Cohort ^a

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

Event-free probability (%)

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.

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

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

Event-free probability (%)

Alpelisib + fulvestrant Placebo + fulvestrant Censoring times

Time (months)

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

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

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

Event-free probability (%)

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

Courtesly by Dejan Juric. 20

Combined inhibition PI3K-alpha and CDK4/6 is synergistic

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

Vora, Cancer Cell, 2014

21

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

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

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

breast cancers expressing mutated PIK3CA

–

Upregulation of PI3K/mTOR has been noted after prolonged CDK4/6 inhibitor exposure in preclinical studies

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

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

Courtesly by Dejan Juric. 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

Grazie!