What’s New in Biology, Treatment and Clinical Trials for Metastatic

Triple-Negative Breast Cancer

Nancy Lin, MDSusan F. Smith Center for Women’s Cancers

Clinical Director, Breast Oncology Center

Geoffrey Shapiro, MD, PhDDirector, Early Drug Development Center

Dana-Farber Cancer Institute

Outline• Definitions: What is TNBC?

• Treatment: How do we treat TNBC?

• New Directions: What are some approaches being tested in clinical trials?

• Clinical Trials: Which, why, how, when?

• There are three main subtypes of breast cancer

• Within these, there are other ways to further sub-divide breast cancers

• Oncologists use the breast cancer subtype to guide the kinds of treatments to recommend

• Clinical trials often will focus on specific subtypes

Breast Cancer Subtypes

Breast Cancer Subtypes

Breast Cancer Subtypes

ER-positiveHER2-positiveTriple-negative

TALK to your doctor if you are not sure what type of breast cancer you have

“Triple Negative” Breast Cancer (TNBC)

• Defined as negative for estrogen, progesterone, and HER2 receptors

• Represents about 15% of all breast cancer

• More likely to present in younger women and in women of African ancestry

• May be associated with an inherited mutation in BRCA1– National guidelines recommend consideration of genetic testing in women

younger than age 60 with TNBC, regardless of family history– But--most patients with triple negative breast cancer do not carry a

hereditary BRCA1 mutation

Hormonal therapy

Hormonal therapy Chemotherapy Chemotherapy

Chemotherapy Chemotherapy Chemotherapy

Herceptin + perjeta +

chemotherapyTDM1 Lapatinib +

CapecitabineHerceptin +

chemotherapyHerceptin +

chemotherapy

Hormone receptorpositive

Triple-negative

HER2-Positive

*Note, these are just examples. Each patient is different and treatment is tailored accordingly.

How Do We Treat Metastatic Breast Cancer?

Chemotherapy for Metastatic TNBC

Many active and tolerable chemotherapy choices

• Order of chemotherapy does not appear to influence survival

• Choose chemotherapy based on:– Activity level seen in clinical trials– Amount of active cancer/need for rapid response– Prior treatments– Route of administration (pills versus IV)– Side effect profile– BRCA 1/2 status– Other health problems

• Blood counts, neuropathy, diabetes, heart problems, liver function

Choice of Chemotherapy in Metastatic TNBC

Drug Route Hair loss Diarrhea Neuropathy Hand foot

redness

Effect on blood counts

Paclitaxel (Taxol)

IV weekly2 or 3 wks in a row Then off 1

wk

Yes No Yes No +

Capecitabine (Xeloda)

Oral twice daily2 wks in a rowThen off 1 wk

No Yes No Yes +

Eribulin(Halaven)

IV weekly2 wks in a rowThen off 1 wk

Sometimes No Yes No ++

Choice of Chemotherapy in Metastatic TNBC:One example

•What chemotherapies have been given previously? How long ago?•Able to take and absorb pills?•How is the liver function?•How important is avoidance of hair loss?•Any baseline neuropathy and how severe?

Is all TNBC the same?

ER-negative, PR-negativeHER2-negative

Heterogeneity of TNBC

TNBC is not just one disease—Different subtypes likely have different “Achilles’ heels”

VEGF

EGFR

PTEN loss

BRCA1-

Basal-like

AR

Immuneinfiltrate

Many Approaches Under Evaluation for TNBC in Clinical Trials

Pathway/Drug type Drugs in development

DNA repair PARP inhibitors (olaparib, rucaparib, veliparib), platinum agents (cisplatin, carboplatin)

PI3K/Akt/mTOR PI3K inhibitors (buparlisib, taselisib, GDC0941, AZD8186, many others); Akt inhibitors (GDC0068, others), mTOR inhibitors (everolimus, others)

Androgen (testosterone) signaling

Anti-androgens (bicalutamide, enzalutamide)

Immune CTLA4 blockade (ipilumumab), PD1/PD-L1 blockade (nivolumab, pembrolizumab, atezolizumab),

Antibody-drug conjugates IMMU-132, SGN-LIV1A, PF06647263, CDX-011

Cell cycle Dinaciclib, seleciclib

Chk1 GDC0575

Bromodomain TEN-101, GSK525762

Heat shock (stress) Ganetespib, others

Angiogenesis Ramucirumab, cedirinib

Targeting DNA repair

Environmental Insults Cause DNA Damage

Cross-linkingagents

Cross-links

DNA Damage leads to mutations that can contribute to development of cancer

Chemotherapy and radiation used in cancer treatment also damage DNA

Normal Cells Cancer cells

Six normal DNA repair pathways

++++++Cancer cells are often deficient in one or more DNA repair pathway

−+++++

Cancer cells may become hyper-dependent on a second DNA repair pathway

Six normal DNA repair pathways

Normal cells

One defective pathway leads to hyper-dependence on a second pathway

Cancer cells

+ + + + + + −++ + + +

The status of the six DNA Repair Pathways can drive treatment decisions (Precision

Medicine)Cancer Status Clinical Decision

One pathway is defective Use a chemotherapy drug that requires that pathway for repair

Pathway is restored and the cancer becomes resistant

Use a chemotherapy drug + an inhibitor of the restored pathway to re-sensitize the cancer (combination treatment)

One pathway is defective and the cancer is hyper-dependent on a second pathway

Use an inhibitor of the second pathway

TNBC may be defective in the homologous recombination (HR) repair pathwayCancer Status Clinical Decision

HR pathway is defective (inherited or acquired BRCA mutation)

Sapacitabine or cisplatin damage DNA in a way that requires HR for repair; cancer cells defective in HR are highly sensitive to these agents

HR pathway is restored and the cancer becomes resistant

Use sapacitabine or cisplatin + a 2nd drug that disrupts HR (e.g. CDK inhibitor, HSP90 inhibitor, PI3-Kinase inhibitor)

Cell defective in the HR pathway become hyper-dependent on a second pathway called alt-NHEJ

Alt-NHEJ requires the PARP enzyme.A PARP inhibitor blocks alt-NHEJ and is lethal to an HR-defective cancer cell.

Basis of Use of PARP inhibitors in HR-deficient breast cancer (BRCA-mutated)

Concept of Synthetic Lethality

Cancer Status Inhibition of PARP1 Repair Status Cellular Outcome

HR-proficient (BRCA WT)

– PARP repairs SSBs Cancer and Normal Cell Survival

HR-proficient + HR (BRCA1/2) repairs DSBs

Cancer and Normal Cell Survival

HR-deficient (BRCA mutated)

– PARP repairs SSBs Cancer and Normal Cell Survival

HR-deficient(BRCA mutated)

+ HR is defectiveAlt-NHEJ cannot compensateNo Repair

Normal Cell SurvivalCancer Cell Death

DNA Damage Single-Strand Break Double-Strand Break

Concept of Synthetic Lethality has translated to positive clinical outcomes in patients treated with a PARP

inhibitor (olaparib)

Platinum Agents and Breast Cancer

• Include the drugs cisplatin and carboplatin

• DNA cross-linking agents—so there is reason to believe they may be especially effective in patients with BRCA ½ mutations and/or with triple negative breast cancer

• These drugs are active in breast cancer in general….but the questions is:

Platinum Agents and Breast Cancer

• Include the drugs cisplatin and carboplatin

• DNA cross-linking agents—so there is reason to believe they may be especially effective in patients with BRCA ½ mutations and/or with triple negative breast cancer

• These drugs are active in breast cancer in general….but the questions is:

How does platinum chemotherapy comparewith other chemotherapy drugs?

TNT Trial

Metastatic TNBCOrBRCA ½ associated breast cancer

Platinum chemotherapy

Taxane chemotherapy

Tutt et al, SABCS 2014

PARP Inhibitors•Tumors of BRCA 1/2+patients lose 2important ways to repair DNA whentreated with a PARP inhibitor

•Multiple trials testingPARP vs chemo inBRCA 1/2 carriers

•Trials combining PARPwith other drugs inBRCA 1/2 non-carriers

Phase 3 Trials Ongoing

Inherited BRCA 1 orBRCA2 mutation

Up to 2 previous typesof chemotherapy for MBC

PARP inhibitor

Choice of standard chemotherapy -Capecitabine -Vinorelbine -Eribulin -Gemcitabine (allowed in BRAVO and EMBRACA)Olaparib – OLYMPIAD – NCT02000622

Niraparib – BRAVO – NCT01905592

BMN673 – EMBRACA – NCT01945775

Completed accrual, awaiting results

Accruing

Accruing

Targeting the Androgen Receptor

Androgen Receptor Function: The Basics

Testosterone

AndrogenReceptor

Androgen Receptor Function: The Basics

Testosterone

AndrogenReceptor

DNA

Targeting AR in the Clinic

• Bicalutamide– 21% had stable disease > 6 months

• Enzalutamide– 20% of patients had stable disease > 6 months– “PredictAR” gene signature sorted patients to those with

average disease control 2 months vs 10 months– Phase III study (ENDEAR) to be launched will compare Taxol vs enza vs combination of Taxol + enza for

predictAR+ve patients

Gucalp et al, CCR 2013; Traina et al, ASCO 2015

Modulating the immune system

The Immunity Cycle

APC-T Cell Interaction

B7-CTLA-4 interaction is an immune checkpoint. CTLA-4 antibodies (e.g. ipilimumab) produced the first prolongation in survival in patients with advanced melanoma

The Immunity Cycle

T-Cell – Tumor Cell Interaction

Adaptive Immune Resistance

• PD-1 – PD-L1 interaction is an immune checkpoint.• PD-1 or PD-L1 antibodies re-activate the T cells in order to attack the cancer cells• PD-1 antibodies: Opdivo (nivolumab), Keytruda (pembrolizumab)• PD-L1 antibody: Tecentriq (atezolizumab)• Drugs approved for melanoma, lung cancer, renal cell cancer, bladder cancer

Durability of Responses is driving the excitement for this anti-cancer strategy

Data in > 1800 melanoma patients treated with ipilimumab

aKaplan-Meier estimate.Analysis cut-off date: November 10, 2014.

0 8 16 24 32 40 48 56

Time, weeks

ResponderNonresponder

CRPRSDPD

PD after CR, PR, or SDLast doseTreatment ongoing

Best overall response

A Phase Ib Study of Pembrolizumab (MK-3475,anti-PD-1 Ab)in Patients With Advanced Triple-Negative Breast Cancer.

Nanda et al.

Overall response rate 18.5%

Median time to response 17.9 weeks

Median duration of response not yet reached

Nanda et al, JCO 2016

Challenges in Breast Cancer I:Weak activation of T Cells

Strategy: Stimulate anti-tumor immunity

• Chemotherapy• Radiation• PARP inhibitors• Combinations

with other immunotherapy agents

Atezolizumab (anti-PDL1) + nab-Paclitaxel

Adams S, et al. SABCS 2015

Best Overall Response

1L (n=9)

2L (n=8)

3L+ (n=7)

All patients(n=24)

ORR(95% CI)

CR PR

67%(30, 93)

11%78%

25%(3, 65)

075%

29% (4, 71)

043%

42%(22, 63)

4%67%

SD 11% 25% 29% 21%

PD 0 0 29% 8%

Challenges in Breast Cancer II:Complexity of the Immune Microenvironment

Anti-TumorT Cell

Several other cell types may prevent activation and proliferation of the T cells (CD8 cells)capable of killing tumor cells.Strategy: Administer agents capable of disabling T-Regs MDSCs or of reprogramming macrophages

Challenges in Breast Cancer III:Other Immune Checkpoints Turn off T Cells in

addition to PD-1 – PD-L1

Strategy:Anti-LAG-3 and Anti-TIM-3 antibodies

Summary of Additional Immune Targets

Antibody-Drug Conjugates

Antibody Drug Conjugates

1. Antibody that recognizes a marker on tumor cells that is not/less present on normal cells

2. Linker that is stable in circulation but releases the drug in target cells

3. Potent drug designed to attack the cancer cell when internalized and released

Antibody Drug Conjugates

Tumor cell

Antibody Drug Conjugates

Tumor cell

Antibody Drug Conjugates

Tumor cell

Antibody Drug Conjugates

Tumor cell

Antibody Drug Conjugates

Tumor cell

Antibody Drug Conjugates in Development for TNBC

• IMMU-132– Target: Trop2– Phase 1/2 trial completed, phase III trial planned

• CDX-011– Target: TPNMB– Phase 2 completed, phase 3 trial ongoing

• SGN-LIV1A– Target: LIV-1– Ph1 in breast ca ongoing

• PF-06647263– Target: EFNA4– Phase 1 in breast cancer ongoing 53

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Prior chemotherapies = 4 (median; range=1-11)

IMMU-132

54

Objective response = 15/49 = 31%Disease control = 37/49 = 76%Clinical benefit ratio [CR+PR+(SD ≥4 mo)] = 63%*

15 May 2015

Bardia et al

How Can We Make Progress?Support Clinical Trials!

• “One reason I chose to participate in a clinical trial was to help women with triple-negative breast cancer. It is thanks to women who have enrolled in clinical trials that we have the treatments that give us hope.”

– Natalia (LBBC, Guide to Understanding TNBC)

Clinical Trials: FAQs• When should I consider a clinical trial?

– Clinical trials may be an option for you as early as the first treatment you receive for metastatic breast cancer, but may also be an option further into the course of your disease.

– If you are interested in trials, getting connected early to a treatment team who can help identify potential trials for you is key.

• Will I have to pay more to be on a trial?– All normal procedures are billed to insurance; anything beyond normal care is paid for by the

trial. There should be no “upcharge” for being in a trial

• Is being on a trial busy?– Each trial is different and has a different schedule

• Will I know what medicine I am getting? I don’t want a placebo.– In most trials, both patient and provider know exactly what treatment is being given. – Some larger trials use randomization and placebos, and in some cases neither patient nor

provider know identity of study drug. – But in almost every trial with placebo, at minimum a patient receives best standard of care.

How to learn about trials?• Know what subtype of breast cancer you have

• Learn about your family history and consider BRCA testing

• Talk to your doctor and/or nurse

• Consider receiving care and/or consultation in a center with a focus on clinical trials

• Consider on-line resources

Advanced TNBC: Conclusions• TNBC is unique compared to other types of breast cancer

• Not all TNBC is the same

• Chemotherapy works for TNBC, and there are a number of standard options

• No single best target has been identified so far; however, TNBC is an area of very active research; many exciting new agents and approaches in the pipeline

• Speak to your provider about whether a trial is an option for you

• Future progress depends on.....Making every woman count!