new therapies for metastatic breast cancer sigrun hallmeyer, md oncology specialists, sc director,...

New Therapies for Metastatic Breast Cancer

Sigrun Hallmeyer, MDOncology Specialists, SC

Director, Oncology Specialists Research InstituteChair, Cancer Committee ALGH

Primary goals of systemic treatment for metastatic breast cancer

• Prolongation of survival,• Alleviation of symptoms, and • Maintenance / improvement in quality of life, despite associated

treatment toxicity

Local therapies (XRT, surgery) can aid in the achievement of these goals

• Oligometastasectomy associated with 5-10 % long-term DFS • Probable survival improvement with resection of primary breast

malignancy in stage IV patients

Remove Primary

Some theoretical evidence why resection of the primary tumor appears to improve survival:

• ? Ongoing dissemination of disease from the primary

• ? Immunosuppressive or –regulatory effects from primary tumor

• ? Production of growth factors by primary tumor that promote growth of distant disease

AUKhan SA, Stewart AK, Morrow MSOSurgery. 2002;132(4):620 NWMH Chicago

Does aggressive local therapy improve survival in metastatic breast cancer?

• METHODS: Stage IV breast cancer at initial diagnosis in National Cancer Data Base (NCDB) between 1990 and 1993

• RESULTS: n=16,023 patients, – 6861 (42.8%) either no operation or variety of

diagnostic/palliative procedures– 9162 (57.2%) partial (3513) or total (5649) mastectomy

• Free surgical margins improved 3-year survival (26% vs 35%)• Women treated with surgical resection with free margins,

compared with those not surgically treated, had superior prognosis, with a hazard ratio of 0.61 (95% confidence interval 0.58,0.65) even when adjusted for type /amount of distant disease and use of systemic therapy

Impact of Therapy

• Optimal measure of therapeutic efficacy is controversial• Overall survival = gold standard for comparison of therapies

– Requires prolonged follow-up – diluted by the effects of subsequent treatment

• progression-free survival [PFS], time to tumor progression [TTP], or objective response rate [ORR] are suboptimal surrogates for overall survival

• Objective response rates = relative treatment efficacy ≠ clinically meaningful increases in survival

• Symptom relief without measurable disease response and achievement of stable disease are clinically relevant

The impact of new chemotherapeutic and hormone agents on survival in a population-based cohort of women with

metastatic breast cancer

• 2150 patients with a first distant metastases diagnosed during 1 of the 4 cohort intervals were identified– COHORT 1 1991/92– COHORT 2 1994/95– COHORT 3 1997/98– COHORT 4 1999/2001

• Baseline characteristics between cohorts were similar, except a greater proportion of the later cohorts received adjuvant chemotherapy (P < .001), had positive estrogen receptor status (P = .01), and had a longer median time from initial diagnosis to MBC (P < .001)

• Survival got progressively better over time

CancerVolume 110, Issue 5, pages 973–979, 1 September 2007

• 2150 patients with a first distant metastases diagnosed during 1 of the 4 cohort intervals were identified

– COHORT 1 1991/92 438 d– COHORT 2 1994/95 450 d– COHORT 3 1997/98 564 d– COHORT 4 1999/2001 667 d

• In multivariate analysis, the later cohorts were associated independently with improved survival (P = .01 and P < .001, respectively).

• 2150 patients with a first distant metastases diagnosed during 1 of the 4 cohort intervals were identified– COHORT 1 1991/92 438 d– COHORT 2 1994/95 450 d– COHORT 3 1997/98 564 d– COHORT 4 1999/2001 667 d

• In multivariate analysis, the later cohorts were associated independently with improved survival (P = .01 and P < .001, respectively).

Prediction of OutcomePatient

• Relapse-free interval ≥2 years more favorable than a shorter time to relapse

• Metastases involving the chest wall, bones, or lymph nodes better than hepatic and/or lymphangitic pulmonary

• Patients with lymphangitic lung metastases, bone marrow replacement, carcinomatous meningitis, or significant liver metastases are in visceral crisis worst prognostic group

Prediction of OutcomePathology

• Markers of increased cellular proliferation [IHC staining for the proliferation antigen Ki67] associated with higher chemotherapy response rates

• Gp170 over expression [drug efflux pump, MDR mediator], or mutated p53 gene are less likely to respond to chemotherapy

• Strongest predictors ER, PR and Her2/neu status – Hormone receptor positivity generally more favorable prognosis– ER- and PR-positive tumors have significantly longer survival than single

hormone receptor-positive tumors (ER+/PR- or ER-/PR+)

• Patients with either HER2 overexpression or triple (ER, PR, HER2)-negative metastatic breast cancer have a shorter median survival*– Justifies need for re-biopsy

*Pre-Herceptin included

Prediction of OutcomePathology

• Markers of increased cellular proliferation [IHC staining for the proliferation antigen Ki67] associated with higher chemotherapy response rates

• Gp170 over expression [drug efflux pump, MDR mediator], or mutated p53 gene are less likely to respond to chemotherapy

• Strongest predictors ER, PR and Her2/neu status – Hormone receptor positivity generally more favorable prognosis– ER- and PR-positive tumors have significantly longer survival than single

hormone receptor-positive tumors (ER+/PR- or ER-/PR+)

• Patients with either HER2 overexpression or triple (ER, PR, HER2)-negative metastatic breast cancer have a shorter median survival*– Justifies need for re-biopsy

*Pre-Herceptin included

Prognostic and predicti

Prediction of Response

• ER, PR, Her2/neu important factors in selecting appropriate treatment 2013

• Future is here: molecular sub typing, pathway recognition and mutational analysis

• Target finding and specific therapy development• Melanoma BRAF - vemurafenib• Lung ALK –Crizotinib• CML Ph* - imatinib• NHL CD20 – rituximab• Breast…

Prediction of Response

• ER, PR, Her2/neu important factors in selecting appropriate treatment 2013

• Future is here: molecular sub typing, pathway recognition and mutational analysis

• Target finding and specific therapy development• Melanoma BRAF - vemurafenib• Lung ALK –Crizotinib• CML Ph* - imatinib• NHL CD20 – rituximab• Breast… To Be Determined

Concepts of Chemotherapy Duration

• Optimal duration of chemotherapy for metastatic breast cancer not known

• Trials of extended duration therapy demonstrated improved PFS, but no overall survival

• Prolonged chemotherapy associated with significant increase in toxicity, decreased quality of life.

• Clinical practice: – Fixed time frame (~four to six months) then stop– treating to best response – Treating to progressive disease, as long as

treatment is reasonably well tolerated

Duration of chemotherapy for metastatic breast cancer: a systematic review and meta-analysis of

randomized clinical trials

• Published data from 11 trials (2269 patients) • Patients were randomly assigned to longer versus shorter

duration of chemotherapy • Trial designs heterogeneous, but most compared fixed

number of courses versus treatment until disease progression• Longer duration chemotherapy associated with a statistically

significant 36 percent reduction in the risk of progression, and a significant 9 percent reduction in the risk of death

J Clin Oncol. 2011;29(16):2144

Concept of Sequence

• No clearly defined optimal first-line regimen• Patients with aggressive or symptomatic disease may benefit

from combination chemotherapy regimens or single agents with higher response rates

• Response rates for doxorubicin are higher as first–line therapy than when administered after progression on paclitaxel (41 versus 30 percent)

• Anthracycline/taxane combinations have high RR and improved PFS when compared to non-taxane anthracycline combinations, but also significant toxicity

• OS not significantly affected by the order of administration

Anthracyclines• Doxorubicin• Epirubicin• Pegylated liposomal doxorubicin• MitoxantroneTaxanes• Paclitaxel• Docetaxel• Albumin-bound paclitaxelAnti-metabolites• Capecitabine• Gemcitabine• Methotrexate• PemetrexedOther single agents

• Eribulin • Etoposide orally• Cyclophosphamide • Cisplatin• Fluorouracil

• Ixabepilone • Irinotecan• VinorelbineHormonal therapy• SERM• AI• Fulvestrant

• Combinations

Chemotherapy combinations• CAF/FAC (cyclophosphamide/doxorubicin/fluorouracil)• FEC (fluorouracil/epirubicin/cyclophosphamide)• AC (doxorubicin/cyclophosphamide)• EC (epirubicin/cyclophosphamide)• AT (doxorubicin/docetaxel; doxorubicin/paclitaxe)• CMF (cyclophosphamide/methotrexate/fluorouracil)• Docetaxel/capecitabine• GT (gemcitabine/paclitaxel)• Ixabepilone/capecitabine

Biologic agents

• Bevacizumab with paclitaxel

HER2-positive disease • Trastuzumab with:• Paclitaxel with or without carboplatin• Docetaxel• Vinorelbine• Capecitabine

• Lapatinib with: – Capecitabine – Paclitaxel– Trastuzumab

• Pertuzumab • T-DM1Triple negative • PARP

• Combinations

Biologic agents

• Pertuzumab • T-DM1 Triple negative • PARP

• Combinations

Biologic agents

• Pertuzumab • T-DM1 Triple negative • PARP

• Eribulin 11/2010• Etoposide orally• Cyclophosphamide • Cisplatin• Fluorouracil

• Ixabepilone 10/2007• Irinotecan• VinorelbineHormonal therapy• SERM• AI• Fulvestrant

• Combinations 06/2012

Biologic agents

• Bevacizumab with paclitaxel 10/2011

• Lapatinib with:

– Capecitabine 03/2007– Paclitaxel– Trastuzumab

• Pertuzumab 06/2012• T-DM1 2013?Triple negative • PARP

Biologic agents

• Lapatinib with:

Avastin• Bevacizumab - mAB against VEGF – inhibits angiogenesis.

As monotherapy in MBC only modest activity (RR 9%) • First Line MBC ECOG trial (E2100), 722 randomly assigned

to bevacizumab and paclitaxel or paclitaxel alone• COMBINATION significantly increased the response rate

(37 versus 21 percent) and PFS (11.8 versus 5.9 months), but no significant increase in median survival (26.7 versus 25.2 months).

Preliminary FDA approval was granted for the combination of first line paclitaxel and bevacizumab

Avastin• Likewise, PFS was increased when bevacizumab was

combined with docetaxel (AVADO) and investigator-selected chemotherapy in the RIBBON-1 (first-line) and RIBBON-2 (second-line) trials

• Pooled analysis of first line treatment from E2100, AVADO, and RIBBON-1 showed significantly improved median PFS (9.2 versus 6.7 months), but not overall survival (26.7 versus 26.4 months)

In November 2011 the FDA revoked the approval due to lack of survival

Biologic agents

• Lapatinib with:

Eribulin

• Non-taxane microtubule inhibitor inhibits the growth phase of the microtubule and arrests the cell cycle at the G2/M phase

Phase II study of eribulin mesylate in patients with MBC previously treated with an anthracycline, a taxane, and capecitabine

• Single-arm, open-label phase II study • Primary end point objective response rate (ORR)• N=269 enrolled patients , median of four prior chemotherapy

regimens, received eribulin for a median of four cycles. • ORR by independent review 9.3%, stable disease (SD) rate 46.5%,

and clinical benefit rate (complete response + PR + SD > or = 6 months) was 17.1%.

• Median duration of response was 4.1 months, and progression-free survival was 2.6 months. Median overall survival was 10.4 months.

• Neutropenia (54%; febrile neutropenia, 5.5%), leukopenia (14%), and asthenia/fatigue (10%; no grade 4); grade 3 neuropathy occurred in 6.9% of patients (no grade 4).

J Clin Oncol. 2010 Sep 1;28(25):3922-8

Graph (eligible population, response by independent review) showing change in tumor size from baseline to nadir (each bar represents a patient; n = 250; 19 patients did not have

assessable tumor measurements after the baseline assessment).

Cortes J et al. JCO 2010;28:3922-3928

Biologic agents

• Lapatinib with:

Ixabepilone

• Mechanism of Action: Epothilone B analog; binds to the beta-tubulin subunit of the microtubule, arresting the cell cycle at the G2/M phase and inducing apoptosis.

• Activity in taxane-resistant cells has been demonstrated

Ixabepilone

• Phase II study, 126 patients with MBC previously treated with an anthracycline, a taxane, and capecitabine

• median of three prior chemotherapy regimens• ORR by independent review was 11.5% • 50% of patients achieved SD (14.3% achieved SD ≥ 6

months)• CBR was 25%. • Peripheral neuropathy was reported by 60% of patients

(13% grade 3, 1% grade 4), • 79% neutropenia (31% grade 3, 23% grade 4). Febrile

neutropenia was reported in four patients.J Clin Oncol. 2007 Aug 10;25(23):3421-7. Epub 2007 Jul 2.

Best response from baseline in radiographic measurements of target lesions.

Denduluri N et al. JCO 2007;25:3421-3427

Biologic agents

• Lapatinib with:

TYKERB Inhibits Tyrosine Kinase Intracellularly

• Crosses the cell membrane and intracellularly binds to the receptor’s TK domain2

• Directly inhibits TK phosphorylation3

• Stops ensuing signal transduction that results in malignant behavior3

As a small molecule, TYKERB1:

1. TYKERB [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2010.2. Rowinsky EK. The Oncologist. 2003;8(suppl 3):5-17.3. Xia W et al. Oncogene. 2002;21:6255-6263.

RANDOMIZE

EGF100151 Study Study Design

Patients on treatment until progressionor unacceptable toxicity, then followedfor survival

• Lapatinib 1250 mg po qd continuously + Capecitabine 2000 mg/m2/d po days 1-14 q 3 wk

•Capecitabine 2500 mg/m2/d po days 1-14 q 3 wk

•Progressive, HER2+ MBC or LABC

•Previously treated with anthracycline, taxane and trastuzumab*

•No prior capecitabineStratification:•Disease sites•Stage of disease

•Progressive, HER2+ MBC or LABC

•Previously treated with anthracycline, taxane and trastuzumab*

•No prior capecitabineStratification:•Disease sites•Stage of disease

*Trastuzumab must have been administered for metastatic disease.

Data on File, GlaxoSmithKline. Geyer C, et al. NEJM 2006;355:2733-2743.

Therapy with Lapatinib Resulted in a Significant Improvement in Time to Progression (2 of 2)

CapecitabineLapatinib + Capecitabine

0.00762P value (log-rank, 1-sided)

126 121Progressed or died18.3 23.9Median TTP, wk

201198No. of pts

0.72 (0.56, 0.92)Hazard ratio (95% CI)

Investigator Assessment

2012 ASCO Chicago

Lapatinib plus Trastuzumab

• Dual targeting of HER2 may be synergistic• Phase III trial, N=296 patients with MBC with disease progression following ≥1

prior trastuzumab-containing therapy• regimens randomly assigned to treatment with lapatinib alone or in

combination with trastuzumab • Combination of lapatinib and trastuzumab resulted in:

– Improved PFS (HR 0.74, 95% CI 0.58-0.94; median, 11 versus 8 weeks)– Improved OS (HR 0.74, 95% CI 0.57-0.97; median, 14 versus 10 months

J Clin Oncol. 2010;28(7):1124.

Biologic agents

• Lapatinib with:

E-Journal ASCO 2010

mABDimerization Inhibitor

Antibody-DrugConjugate

Pertuzumab plus Trastuzumab

• CLEOPATRA Phase III trial, n=808 women with HER2-positive metastatic breast cancer

• First-line treatment with trastuzumab, docetaxel with randomization to pertuzumab versus placebo

• Significant improvement in median PFS (19 versus 12 months)• Trend towards improvement in OS• Significant improvement in ORR (80 versus 69%)• Similar rates of left ventricular dysfunction (1 versus 2 percent)

N Engl J Med. 2012 Jan;366(2):109-19. Epub 2011 Dec 7

Overall Survival.

Baselga J et al. N Engl J Med 2012;366:109-119.

Biologic agents

• Lapatinib with:

• Pertuzumab 06/2012• T-DM1 2013 ?Triple negative • PARP

Biologic agents

• Lapatinib with:

• Pertuzumab 06/2012

• T-DM1 02/21/2013Triple negative • PARP

• Trastuzumab emtansine: antibody-drug conjugate composed of trastuzumab, a thioether linker, and a derivative of the antimitotic agent, maytansine

• EMILIA: phase III trial, n=978 patients with HER2-positive breast cancer previously treated with trastuzumab and a taxane, and randomly assigned to treatment with T-DM1 or the combination of capecitabine plus lapatinib

• Improved PFS (10 versus 6 months)• Improved median OS (31 versus 25 months) • Improvement in the ORR (44 versus 31%)• Most common toxicity with T-DM1 was thrombocytopenia (13

versus 0.2 % with XL), LVEF decline to <50% was low (2 percent/each arm)

2012 ASCO Chicago

Not commercially available at this time

Now commercially available at your

oncologists office - $96,000/course

KADCYLA

PARP Inhibitors• Inhibitors of poly (adenosine diphosphate-ribose)

polymerase (involved in the molecular events leading to cell recovery from DNA damage)

• particularly useful in BRCA-mutated breast cancer (majority triple negative, defective DNA repair mechanism)

• not commercially available , but several in clinical trials

PARP Inhibitors• Olaparib (400 mg po bid) was administered to women with BRCA1-

and/or BRCA2-deficient, advanced breast cancer (>50 percent triple-negative) in single arm study – ORR 41 percent – PFS of 5.7 months, – fatigue, nausea, and vomiting. – A separate study found olaparib had no activity outside of patients with

BRCA mutations

• Veliparib (ABT-888) was tested in combination with temozolomide (alkylating agent) in 41 women with advanced triple-negative breast cancer – any activity concentrated only among patients with BRCA mutations, in

whom the overall response and clinical benefit rates were 37.5 and 62.5 percent, respectively.

• Iniparib failed to show any activity in large (n=519) phase III trial with triple negative breast cancer, cytotoxicity probably not driven by PARP inhibition

Biologic agents

• Lapatinib with:

• Pertuzumab 06/2012• T-DM1 02/2013Triple negative • PARP

Potential Cross-Talk Between Signal Transduction and Endocrine Pathways1

SOSRASRAF

Basaltranscription

machineryp160

ERE ER target gene transcription

ER CBPER

Pp90RSK

MAPK P

Cellsurvival

Cytoplasm

Nucleus

PPPPPP

Cellgrowth

Plasmamembrane

EGFR / HER2IGFRGrowth factorEstrogen

Letrozole

TYKERB

1. Adapted from Johnston S. Clin Cancer Res. 2005;11:889S-899S.

Lapatinib Combined With Letrozole Versus Letrozole and Placebo as First-Line

Therapy for Postmenopausal Hormone Receptor-Positive Metastatic Breast

Cancer1

Stephen Johnston, John Pippen, Jr, Xavier Pivot, Mikhail Lichinitser,Saeed Sadeghi, Veronique Dieras, Henry Leonidas Gomez, Gilles Romieu, Alexey

Manikhas, M. John Kennedy, Michael F. Press, Julie Maltzman, Allison Florance, Lisa O'Rourke, Cristina Oliva, Steven Stein, Mark Pegram

1. Johnston S et al. J Clin Oncol. 2009;27:5538-5546.

Progression-Free Survival: HER2+ Population1

Letrozole(n=108)

Letrozole + TYKERB(n=111)

Median PFS, months 3.0* 8.2†

Hazard ratio (95% CI) 0.71 (0.53, 0.96)

P value 0.019

Time From Randomization (Months)

*13 weeks (95% CI; 12.0, 23.7) Letrozole.†35.4 weeks (95% CI; 24.1, 39.4) letrozole + TYKERB2.

1. Johnston S et al. J Clin Oncol. 2009;27:5538-5546.2. TYKERB [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2010.

TYKERB +Letrozole

Improvement in PFS vsLetrozole

Progression-Free Survival: HER2+ Population1

Letrozole(n=108)

Letrozole + TYKERB(n=111)

Median PFS, months 3.0* 8.2†

Hazard ratio (95% CI) 0.71 (0.53, 0.96)

P value 0.019

Time From Randomization (Months)

*13 weeks (95% CI; 12.0, 23.7) Letrozole.†35.4 weeks (95% CI; 24.1, 39.4) letrozole + TYKERB2.

TYKERB +Letrozole

Improvement in PFS vsLetrozole

Overall Response Rate

Response Rate: HER2+ Population (n=219)1,2

P = 0.021

f Pati

14.8%2

(95% CI; 8.7, 22.9)

Letrozole Letrozole + TYKERB

27.9%2

(95% CI; 19.8, 37.2)

Fulvestrant and AI

Step up Hormonal Therapy

mTORMammalian TargetOfRapamycin

AI plus mTOR

• Exemestane plus everolimus • BOLERO-2 trial n=724 women with MBC who

progressed on anastrazole• Patients randomly assigned to exemestane alone or

exemestane plus everolimus • Combination :

– Improvement in PFS (median, 7.8 versus 3.2 months) – Higher ORR (13.6 versus 1.7 percent)

• Stomatitis (8%), dyspnea (4%), noninfectious pneumonitis (3%), and elevated liver enzymes (3%)

SABCS 12/2011; NEJM 2/9/2012

Kaplan–Meier Plot of Progression-free Survival.

Baselga J et al. N Engl J Med 2012;366:520-529.

Biologic agents

• Lapatinib with:

• Pertuzumab 06/2012• T-DM1 02/ 2013Triple negative • PARP

Conclusions• Metastatic breast cancer is biologically, pathologically and

molecularly very heterogeneous disease• Local therapies including surgical resection of the primary

malignancy have impact on outcome• A “whole stable” of hormonal, chemotherapeutic and

targeted agents is at our disposal – duration and sequence of therapy remains undefined

• New drugs are being developed in rapid pace, sometimes outpacing our approval safeguards

• Combinations of “old drugs” and “old with new” drugs can have significant impact on outcome

Conclusions continued

• Overall Survival assessment becomes increasingly difficult to use as study endpoint, but surrogate markers of efficacy have severe limitations

• Despite these challenges, significant progress has been made not only in terms of longevity, but also QOL for the many women affected by MBC

• As our understanding of the inner workings of breast cancer cells improves, we discover the possibility for true targeted and personalized therapies

• Once these are defined and optimized, it is truly believable that MBC can become a curable condition

• As our understanding of the inner workings of breast cancer cells improves, we discover the possibility for true targeted and personalized therapies

• Once these are defined and optimized, it is truly believable that MBC can become a curable condition

Fall down 7 times

Get up 8

Thank you.

Sigrun Hallmeyer, MDOncology Specialists, SC

Director, Oncology Specialists Research InstituteChair, Cancer Committee ALGH

Phone 847-268-8200shallmeyer@oncmed.net

new therapies for metastatic breast cancer sigrun hallmeyer, md oncology specialists, sc director,...

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