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Nuevas vías de señalización en cáncer de mama

Miquel Àngel Seguí Palmer


While the use of endocrine monotherapyremains an effective treatment option formany women, both in the first and secondline settings, the usefulness of endocrinetherapy over time becomes limited bychanges in tumor biology and consequentendocrine resistance.

Increasing understanding of thecomplexity of endocrine receptorsignaling and interactions with multiplesignaling pathways provide a frameworkfor the development and evaluation ofnew agents for use in combination withstandard endocrine therapy.

Emerging targeted agents against breast cancer under clinical development


• Selection of patients with advanced breast cancer asappropriate for endocrine manipulation according tohormone receptor status is a successful strategy.

• Unfortunately, the emergence of resistance is inevitableand subsequent treatment is not well defined.

• Numerous mechanisms have been implicated in thedevelopment of resistance; central among them is theactivation of compensatory signaling pathways.


Evolution of the clonal architecture of ER-positive MBC under the pressure of endocrinetreatment is promoted by several escape mechanisms which result in the expansion of resistantclones, clinically overt disease progression, need for cytotoxic chemotherapy and death.

These mechanisms include:

• Acquisition of ESR1 mutations

• Loss of ER expression

• Imbalances between positive and negative coregulators

• Overexpression of growth factors

• Enhanced crosstalk withcompensatory pathways

Osborne CK, Schiff R. Annu Rev Med. 2011


Targetable genomic alterations under clinical investigation or withpotential clinical relevance in metastatic ER+HER2– breast cancers

Turner NC, et al. Lancet 2016


Key Pathways of Endocrine Resistance

ESR1 mutations


1. PI3K/Akt/mTOR Pathway

2. Inhibition of CDK4/6

3. PI3K/Akt/mTOR Pathway + Inhibition of CDK4/6

4. SERDs

5. HDAC Inhibitors

6. Immune Checkpoint Inhibition


Most frequently mutated signalingpathway in breast carcinoma

PI3K activation is associated with bothde novo and also acquired endocrineresistance.

PI3K/Akt/mTOR Pathway

mTORC1 inhibitors Everolimus

Temsirolimus

Dual mTORC1/2 inhibitors AZD2014

TAK-228 (MLN0128)

Pan-PI3K inhibitors BKM120 (Buparlisib)

XL-147 (SAR245408)

PX-866

PKI-587 (Gedatolisib)

GDC-0941(Pictilisib)

PI3K inhibitors Wortmannin

LY294002

BYL719 (alpelisib)

GDC-0032 (Taselisib)

BAY 80-6946 (Copanlisib)

NK-1117

Dual PI3K/mTOR inhibitors BEZ235

BGT226

PF-4691502

GDC-0980

XL-765

AKT inhibitors MK2206



mTORC1 inhibitorsEverolimusBOLERO-2TAMRADPrRECOG 0102BOLERO-4BOLERO-6




BOLERO-4: Phase 2 Trial of First-Line Everolimus Plus Letrozole in Estrogen

Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative

Advanced Breast Cancer. (NCT01698918)

Royce M, et al. JAMA Oncol. 2018




BOLERO-6: A Phase II Study of Everolimus in Combination With

Exemestane Versus Everolimus Alone Versus Capecitabine in Advance

Breast Cancer. (NCT01783444)




BOLERO-6: A Phase II Study of Everolimus in Combination With Exemestane Versus

Everolimus Alone Versus Capecitabine in Advance Breast Cancer. (NCT01783444)

Jerusalem G et al. JAMA Oncol. 2018



Dual mTORC1/2 inhibitors

AZD2014MANTA

TAK-228C31006


MANTA: A Randomized Study of AZD2014 in Combination With Fulvestrant in

Metastatic or Advanced Breast Cancer.

(NCT02216786)

Primary Outcome Measures:

• Progression free survival



AZD2014MANTA

TAK-228C31006




AZD2014MANTA

TAK-228C31006

Schmid P et al. SABCS 2017


The PI3K pathway with respective PI3K inhibitors


Serious (grade 3 or higher) toxicity was reported in 77.3% receiving buparlisib and 61% of those receivingpictilisib in the BELLE-2 and FERGI trials, respectively.

The most commonly observed adverse events are elevated liver function enzymes, rash and hyperglycemia.Psychiatric disorders such as anxiety and depression have also been noted in patients receiving buparlisib.


Pan-PI3K inhibitors

BuparlisibBELLE 2BELLE 3

PictilisibFERGI

Baselga J, et al. Lancet Oncol. 2017; Di Leo A, et al. Lancet Oncol. 2018


PI3K inhibition for ER+ breast cancer: limitations and possible solutions



PI3K inhibitors

Alpelisib

Taselisib


SOLAR-1: Study Assessing the Efficacy and Safety of Alpelisib Plus Fulvestrant

in Men and Postmenopausal Women With Advanced Breast Cancer Which

Progressed on or After Aromatase Inhibitor Treatment. (NCT02437318)


PI3K inhibitors

AlpelisibPIKNICSOLAR-1BYLieve

TaselisibLORELEIPOSEIDONSANDPIPER



PI3K inhibitors



SANDPIPER Study: A Study Of Taselisib + Fulvestrant Versus

Placebo + Fulvestrant In Patients With Advanced or Metastatic

Breast Cancer Who Have Disease Recurrence or Progression

During or After Aromatase Inhibitor Therapy. (NCT02340221)


• Progression free survival

Baselga J et al. ASCO. 2018



PI3K inhibitors



SANDPIPER Study: A Study Of Taselisib + Fulvestrant Versus Placebo + Fulvestrant In Patients With Advanced or

Metastatic Breast Cancer Who Have Disease Recurrence or Progression During or After Aromatase Inhibitor Therapy.

(NCT02340221)

Baselga J et al. ASCO. 2018


PI3K/Akt/mTOR Pathway + Inhibition of CDK4/6Preclinical work aiming to understand resistance to CDK4/6inhibition, has suggested that HR BC cells quickly adapt toCDK4/6 inhibition by activation of PI3K. Thus, by targetingthe CDK4/6/retinoblastoma and the PI3K/Akt/mTOR-axiswe might be able to overcome or prevent resistance toCDK4/6 inhibitors.

Herrera-Abreu MT et al. Cancer Res 2016


Available efficacy and safety data from triplet therapy clinical studies in patients with HR+, HER2 advanced breast cancer.

PI3K/Akt/mTOR Pathway + Inhibition of CDK4/6

Phases Ib/II Palbociclib+Everolimus+Exemestane(NCT02871791)Ribociclib+Everolimus+Exemestane(NCT01857193)Ribociclib+Everolimus+Exemestane(NCT02732119)

Palbociclib + Taselisib / Pictilisib(PIPA, NCT02389842)Palbociclib + AZD2014(PASTOR, NCT02599714)Ribociclib + Alpelisib + Letrozole)(NCT01872260)

Abemaciclib+Everolimus+Exemestane(NCT02057133)

• Early trials combining CDK4/6 inhibitors, PI3K or mTOR inhibitors, andendocrine therapy have shown encouraging signs of clinical activity.

• However, further research is needed to help understand the extent oftreatment benefit from triplet therapy and where this strategy will fit inthe treatment sequence for patients with HR+ breast cancer.

Cortes J. et al. Cancer Treat Rev 2017






TRINITI1: Study of Ribociclib With Everolimus + Exemestane in HR+ HER2-

Locally Advanced/Metastatic Breast Cancer Post Progression on CDK 4/6

Inhibitor.


• Phase I: Maximum Tolerated Dose (MTD) and/or the Recommended Phase II

Dose for the triplet combination.

• Phase II: Clinical Benefit Rate (CBR) among subjects receiving triplet therapy






TRINITI1: Study of Ribociclib With Everolimus + Exemestane in HR+ HER2-

Locally Advanced/Metastatic Breast Cancer Post Progression on CDK 4/6

Inhibitor.

Moulder S et al. AACR 2018


Selective ER Downregulators (SERDs) are competitive ER⍺ antagonists that alsoinduce a conformational shift of the receptor that results in ubiquitination andsubsequent degradation of ER⍺, via the ubiquitin-proteasome system.

SERDs

• A mechanism of resistance that hasbeen recently suggested is thedevelopment of ESR1 mutations.

• Early BC samples showed a lowpresence of ESR1 mutations in 0.5%and of ESR1 amplification in 2.5% ofthe cases. In contrast, ESR1mutations have been reported in20-50% of recurrent or MBC after ETwith AIs.


Theoretically, a strategy of completely or nearly completelydestroying the ER, may lead to a more effective inhibition of highlyER-dependent tumors.

The recognition that ERα remains a viable target even in the settingof endocrine resistance and the limitations of fulvestrant led to thesearch for a new generation of orally bioavailable highly selectiveSERDs.

In particular, ER degraders may have a particular advantage in tumorswith ESR1 mutations, which may emerge after estrogen deprivationstrategies, but could potentially be less of a problem as a mechanismof resistance if ER is degraded.

SERDs


SERDs Antitumor activity of GDC-0810 in a tamoxifen-resistant breast cancer xenograft model.

Joseph JD et al. Elife 2016


SERDs

GDC-0810GDC-0927LSZ102

HydranGea: A Phase II, Open Label, Randomized

Study of GDC0810 Versus Fulvestrant in

Postmenopausal Women With Advanced or

Metastatic ER+ /HER2 Breast Cancer Resistant to

Aromatase Inhibitor Therapy.

(NCT02569801)

n=71


• PFS for all participants and for subset of participants

with Estrogen Receptor (ESR)1 mutations.

An Open label,Phase Ia/Ib/IIa Study of GDC0810

Single Agent or in Combination With Palbociclib

and/or an LHRH Agonist in Women With Locally

Advanced or Metastatic Estrogen Receptor Positive

Breast Cancer.

(NCT01823835)

n=195


• Phase Ib: RP2D of GDC0810 When Used in Combination

With Palbociclib and/or LHRH.

• Phase IIa: Percentage of Participants With Confirmed

Objective Tumor Response of GDC0810.

An Open Label, Phase I Study of GDC0927 in

Postmenopausal Women With Locally Advanced or

Metastatic Estrogen Receptor Positive Breast

Cancer.

(NCT02316509)

n=90


• Maximum Tolerated Dose (MTD)/Recommended Phase II

Dose (RP2D) of GDC0927.

• Percentage of Participants With Adverse Events

Phase I/Ib Trial of LSZ102 Single Agent or

LSZ102 + LEE011 or LSZ102 + BYL719 in ER+

Breast Cancers.

(NCT02734615)

n=152


• Incidence of dose limiting toxicities (DLTs)

• Safety and tolerability of LSZ102 at the recommended dose

for expansion


HDAC Inhibitors

Phase II ENCORE 301

Yardley DA, et al. J Clin Oncol. 2013


HDAC Inhibitors

Etinostat

E2112: Exemestane With or Without Entinostat in Treating Patients With Recurrent

Hormone Receptor Positive Breast Cancer That is Locally Advanced or Metastatic

(NCT02115282)


• OS

• PFS


Immune Checkpoint Inhibition

Anti PD-1Pembrolizumab

Anti PD-L1Durvalumab


Goel X et al. Nature 2017; Deng X et al. Cancer Discovery 2017


Pembrolizumab, Letrozole, and Palbociclib in Treating Patients With Stage IV Estrogen

Receptor Positive Breast Cancer With Stable Disease That Has Not Responded to

Letrozole and Palbociclib.

(NCT02778685)





ULTIMATE: Durvalumab and Endocrine Therapy in ER+/Her2- Breast Cancer

After CD8+ Infiltration Effective Immune Attractant Exposure.

(NCT02997995)


• pathological Complete Response

The first cohort patients will receive

tremelimumab (3 mg/kg, single infusion) as

immune attractant





• Endocrine resistance in patients with HR-positive breast carcinoma continues to represent anoncological challenge.

• Efforts at elucidating the molecular mechanisms of endocrine resistance have revealed anumber of targets that act downstream or upstream the ER or that crosstalk with it.

• Alterations in the PI3K signaling pathway are among the most frequent somatic mutations inER-positive breast carcinomas, which are associated with endocrine resistance. NumerousPI3K inhibitors are currently undergoing preclinical and clinical development.

• Notable successes include agents targeting mTOR and CDK4/6 in combination with endocrinetherapy, whereas failures include the disappointing performance of pan-PI3K inhibition.PI3K⍺ inhibitors ??.

• Similarly, efforts to develop next-generation SERDs combining improved oral bioavaliabilitywith enhanced ER targeting, HDAC Inhibitors and Immune Checkpoint Inhibition, appearspromising.

Take home messages (1)


• We need to better identify which patients are most likely to derive themost benefit from combination therapy, and design efficient clinicaltrials that take into account ER-positive disease biology and timing ofadditional intervention to modulate endocrine response.

• Defining populations with a specific alteration in a given signallingpathway could improve the likelihood of benefit from a targeted agent,limit unnecessary exposure to toxicity and allow the sustainability ofthese newer treatments.

Take home messages (2)

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