Metastatic Breast Cancer

Transcription

1 Joy M c Carthy, MD, FRCPC Division Chief, Medical Oncology Cancer Care Program, Eastern Health Clinical Associate Professor, Discipline of Oncology, Memorial University of Newfoundland Metastatic Breast Cancer

2 I have participated in advisory boards for Novartis, Amgen, Janssen Biotech and Roche.

3 Objectives To review general principles/standard of care on systemic management of metastatic breast cancer (MBC) Case discussions Discuss major and important toxicities of systemic therapy for MBC Review the evidence supporting treatment options for first, second, and third line therapy

4 In 50 minutes! Not possible. Breast cancer is many different diseases and subtypes. Hormonal therapy is the original targeted therapy so I will mention it. The evidence part will be minimal- you can me at joy.mccarthy@easternhealth.ca if you have any questions Average survival of MBC is 3 years (range is days to 20+ years). ECOG is VERY important (if ECOG >2, chemotherapy will not be helpful)

5 Stage at Diagnosis, 1997 (approximate %) DCIS Unknown Metastatic Locally advanced 6% 3% 6% 18% 39% Negative nodes 28% DCIS = ductal carcinoma in situ Ries LAG, et al. Cancer Ries LAG, et a. SEER Cancer Statistics Review, National Cancer Institute Positive nodes

6 Many women with early stage breast cancer develop recurrent or metastatic disease: Node negative low risk: < 20% Node negative high risk: > 20-30% Node positive: > 30% MBC unlikely to be cured: 5-10% can live >5 years 2-5% long-term survivors

7 Metastatic Breast Cancer Is Not One Disease Rapid disease progression Extensive visceral involvement Resistance to hormonal therapy Resistance to chemotherapy Death within weeks of dx Long, indolent course Bone and soft tissue dz Sensitive to hormonal rx Sensitive to chemotherapy Extended survival (many yrs) Acute Leukemia of Breast Cancer Chronic Lymphocytic Leukemia of Breast Cancer Median survival from dx of MBC is at least 2-3 years, and probably getting longer as new treatments become available that change the natural history of the disease.

8 Unknown host factors?? Heterogeneity of Metastatic Breast Cancer What accounts for the differences? Disease Characteristics Disease-free interval Hormone receptor status HER-2/neu Sites of disease Patient and Treatment Factors Performance status (ECOG) and comorbiditty Prior treatment Response to prior treatment Volume of disease Age

9 GOALS Prolong Survival Progression-free survival Stable disease Improved quality of life Symptom management OPTIONS Local Surgery Radiation RFA Systemic Endocrine therapy Chemotherapy Biological therapy Clinical trials

10 Biopsy first onset metastatic disease- biomarkers can change prove they are mets (ex. new lung nodules) Options : surgery or radiation therapy In general, the likelihood of response to local therapies is higher than that for systemic therapies.? Questions to ask yourself: is the patient in or near a catastrophic situation in the area of local recurrence how widespread is the extent of disease what is the localization of the symptomatic disease

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12 Mrs. S.- Neglected breast cancer/metastatic at onset ER/PR positive Mrs. G. - Her2positive MBC Mrs. M - Triple Negative (ER negative, PR negative, Her2neu negative) MBC

13 77 years old from St. Anthony Widowed, retired teacher. Angina, COPD, HTN More short of breath family brought her to ER

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15 This is NOT an emergency Refer to a surgeon This has been there for as long as patient can remember many many years a few more weeks will NOT make a difference Surgeon MUST request er/pr/her2neu on biopsy (=biomarkers) and results back BEFORE she is seen Need CT/bone scan she had mod pleural effusion, small lung mets and boney mets

16 ER/PR 95/95, her2neu neg Started Denosimab (Xgeva) monthly (Pamidronate is first-line bisphosphonate in those with no private drug coverage) Started letrozole 1 year later.she is doing housework, no SOB and no bony pain (has never had radiation or chemo) Upon failure Tamoxifen, Exemestane (plus or minus Everolimus), Fulvestrant (pure anti-estrogengiven IM) and Megace. Not a chemo candidate due to co-morbidities.

17 Hormone sensitive disease ECOG 2 Minimal visceral involvement Patient minimally symptomatic Treatment decision : hormonal therapy with aromatase inhibitor (letrozole) and bisphosphonate/osteoclast inhibitor (Pamidronate vs Denosumab) Endocrine therapy preferred over chemotherapy where feasible Less toxicity, better quality of life and good overall response rate: ~50% in first line How do we overcome endocrine resistance? a new paradigmtargeted therapy combined with hormonal therapy (everolimus and exemestane)

18 49 years old developed scab on left breast one year prior to seeking medical attention. Picked at it. Referred to a surgeon biopsy- triple positive - ER 60/PR 30. her 2neu 3+ IHC. CT scan and bone scans negative

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20 This lady- TCH =Taxotere, Carboplatin, Herceptin/Trastuzumab Really has skins mets on contralateral side separate from the primary so metastatic Art of medicine standard of care WAS taxane plus trastuzumab ex: nab-paclitaxel plus trastuzumab and now it is pertuzumab/trastuzumab/taxane.

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22 Mastectomy and AXLND. Tumour was pt4 (9cm with epidermis/muscle involvementmargins clear)n0(0/20)m0 (all skin mets no longer visible). Is she cured? Do we stop at 18 cycles? Almost certain to recur Pertuzumab/Trastuzumab/nab-paclitaxel If >6 months since adjuvant is first line, then TDM1 (Kadcyla)..beyond that no evidence navelbine/trastuzumab then? lapatinib/capecitabine?

23 This 47 year old lady presented with LABC, TNBC that grew very quickly. No risk factors. Completely well FECDOC IV chemo- surgery, minimal partial response (pt4n2m0) 5 months after surgery, cough, SOBOE Went to ER

24 Ct- diffuse lung mets,? Lymphangitic spread Chest wall lesions Next steps?? Within 6 months of neoadjuvant chemo (anthraclines and taxanes would be first line) Doublet vs singlet Options: Capecitabine, Eribulin Gemcitabine/Paclitaxel, Gemcitabline/Cisplatin Others: navelbine, etoposide

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26 Capecitabine- patients choice (tired of IV chemo, wanted oral therapy) Responded initially (RR 30-40%) with improved symptoms 6 months later new liver mets Second Line- Cis/Gem IV both Day 1, 8 responded x 6 cycles then progressed, declined rapidly- not a candidate for further chemo.

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28 For premenopausal women, options include Tamoxifen and estrogen deprivation with or without an AI or pure anti-estrogen (Fulvestrant) For postmenopausal women, options include AI or pure anti-estrogen. Letrozole is preferred first line in postmenopausal women Megace can also be used if the above fail Most women will be offered each of these options in sequence What happens if develops hormone therapy resistance? How to overcome this?

29 Targeted therapy with endocrine therapy to help reverse endocrine resistance A new treatment paradigm.? An alternative to chemotherapy??

30 N = 724 Postmenopausal ER+ Unresectable locally advanced or metastatic BC Recurrence or progression after letrozole or anastrozole R 2:1 Endpoints Primary: PFS (local assessment) EVE 10 mg daily + EXE 25 mg daily (n = 485) Placebo + EXE 25 mg daily (n = 239) Stratification: Sensitivity to prior hormone therapy and presence of visceral metastases Secondary: OS, ORR, QOL, safety, bone markers, PK Abbreviations: BC, breast cancer; ER+, estrogen receptor-positive; EVE, everolimus; EXE, exemestane; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; Ph, phase; PK, pharmacokinetics; QOL, quality of life. Baselga 30 J, et al. N Engl J Med. 2012;366(6):

31 7-mo Follow-up EVE + EXE PBO + EXE 12.5-mo Follow-up EVE + EXE PBO + EXE 18-mo Follow-up EVE + EXE PBO + EXE PFS (Local) PFS (Central) 6.9 mo 2.8 mo 7.4 mo 3.2 mo 7.8 mo 3.2 mo 10.6 mo 4.1 mo 11.0 mo 4.1 mo 11.0 mo 4.1 mo Δ OS events 2.3% 5.4% 6.8% Abbreviations: PFS, progression-free survival; CBR, clinical benefit rate; OS, overall survival; EVE, everolimus; EXE, exemestane Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, Abstract: 9LBA; Hortobagyi G. et al, SABCS 2011 (Abstract #S3-7); Piccart M, et al. ASCO 2012; abstract 559 (poster).

32 Stomatitis Infections Noninfectious pneumonitis Skin rash Hyperglycemia Hyperlipidemia Neutropenia Thrombocytopenia Renal dysfunction

33 Characterized by inflammation of the mucous membranes in the mouth, 1 is among the most common oral AEs experienced by patients receiving mtor inhibitors 2 Ulcerated areas in the oral cavity, inner surface of the lips, or tongue 1 Severe cases may be associated with erythema, edema, burning sensation, and occasional bleeding 1 Can cause pain and infections that limit oral intake and affect daily life (eg, interfere with intake of food and fluids, cause difficulty speaking) 1,2 1. Köstler W et al. CA Cancer J Clin. 2001;51: Eisen T et al. J Natl Cancer Inst. 2012;104:

34 Grade Symptoms Management 1 Minimal, normal diet Rinse several times daily with nonalcoholic mouthwash or 0.9% salt water Everolimus Dose Modification No change 2 Symptomatic but can eat and swallow modified diet 3 Symptomatic and unable to adequately eat or hydrate orally 4 Severe (symptoms are life threatening) Topical analgesic mouth treatments (eg, benzocaine, butyl aminobenzoate, tetracaine hydrochloride, menthol or phenol) with or without topical corticosteroids (eg, triamcinolone oral paste)* Avoid agents containing alcohol, hydrogen peroxide, iodine, and thyme derivatives Treat with appropriate medical therapy Same as grade 2 Temporary dose interruption until recovery to grade 1, then re-initiate at same dose If recurs at grade 2, interrupt dose until recovery to grade 1, then reinitiate at a lower dose Hold dose until recovery to grade 1, then restart at reduced dose Discontinue everolimus *Antifungal agents should not be used unless an oral fungal infection is diagnosed, in which case oral topical antifungal agents are preferred. If dose reduction required, the suggested dose is about 50% lower than the dose previously administered 1 Two reductions of everolimus were permitted in the BOLERO-2 trial: an initial reduction to 5 mg daily and a subsequent reduction to 5 mg every other day 2 1- Afinitor Product Monograph. Novartis Pharmaceuticals Canada Inc. 2-Baselga J, et al. N Engl J Med. 2012;366(6): ; 3- Porta C et al. Eur J Cancer. 2011;47:

35 Trastuzumab- Monoclonal antibody again her2 receptor Inhibits signal transduction and cellular growth 20% breast cancers display her2 overexpression 3+IHC or positive FISH for Her2 gene amplification predicts response to treatment using trastuzumab The newest first line targeted agent Pertuzumab- now given with Trastuzumab and Taxane based chemo

36 HER2 Pertuzumab Trastuzumab HER1/3/4 Subdomain IV Trastuzumab: Inhibits ligand-independent HER2 signaling Activates ADCC Dimerization domain Pertuzumab: Inhibits ligand-dependent HER2 dimerization and signaling Activates ADCC ADCC = antibody-dependent cell-mediated cytotoxicity; ECD = extracellular domain

37 CLEOPATRA Study Design Eligibility (n = 808) Centrally confirmed HER2- positive locally recurrent, unresectable or mbc No prior treatment for mbc except 1 hormonal therapy Left ventricular ejection fraction 50% ECOG performance status: 0-1 R n = 402 Pertuzumab + trastuzumab + docetaxel n = 406 Placebo + trastuzumab + docetaxel Primary endpoint: Independently assessed progression-free survival (PFS) Secondary endpoints: Overall survival (OS), objective response rate (ORR) and safety Baselga J et al. N Engl J Med 2012;366(2):

38 OS (%) n at risk Ptz + T + D Pla + T + D HR % CI = 0.56, 0.84 p = Time (months) months Δ 15.7 months Ptz + T + D Pla + T + D 56.5 months ITT population. Stratified by geographic region and neo/adjuvant chemotherapy. CI, confidence interval; Pla, placebo; Ptz, pertuzumab

39 Select adverse events (Grade 3) Pertuzumab (n = 407) Placebo (n = 397) Neutropenia 48.9% 45.8% Febrile neutropenia 13.8% 7.6% Leukopenia 12.3% 14.6% Diarrhea 7.9% 5.0% Peripheral neuropathy 2.7% 1.8% Left ventricular systolic dysfunction 1.2% 2.8% Baselga J et al. N Engl J Med 2012;366(2):

40 Breast Cancer Res Treat (2012) 135:347

41 Breast Cancer Res Treat (2012) 135:347

42 No evidence to guide treatment of the rash from pertuzumab Treatment of the papulopustular rash from EGFR inhibitors may be similar a tetracycline antibiotic (doxycycline or minocycline) and a topical corticosteroid may be effective For mild cases treatment with a topical corticosteroid or a topical antibiotic, such as clindamycin or dapsone,may be of benefit Breast Cancer Res Treat (2012) 135:347

43 Taxane average 6-8 cycles Study treatment cycles 15 in control group (range 1 to 50) 18 in pertuzumab group (range 1 to 56) Continue trastuzumab and pertuzumab until PD Treatment at progression could include trastuzumab but not pertuzumab 5-10% may have complete response No data to guide when to stop anti-her2 therapy with prolonged response

44 Approved by Health Canada April st line therapy for HER2 positive MBC In combination with trastuzumab and docetaxel Initial dose 840 mg IV over 60 minutes day 1 alone, docetaxel and trastuzumab day 2 Then 420 mg IV over 30 to 60 minutes day 1 with other drugs cycle 2 and beyond if tolerated Re-load if held > 6 weeks

45 No dose reduction recommended Hold dose or discontinue if toxicity May continue after chemotherapy stopped If stop trastuzumab, stop pertuzumab Use cardiotoxicity algorithm Caution if EF < 50% or significant cardiac history Has not been studied with hepatic impairment No adjustment for mild renal impairment

46 The addition of Pertuzumab to standard taxane and trastuzumab leads to a clinically and statistically significant improvement in PFS and OS (15.7 m on 70 months FU) There was no additional cardiac toxicity seen However there were increased rates of diarrhea and febrile neutropenia pcodr approved can use any Taxane (we use nab-paclitaxel)

47 TDM1 Other options- Xeloda/Trastuzumab, Navelbine/Trastuzumab where do they fit in the age of Dual-Her blockade? (Pertuzumab and Trastuzumab)

48 S Verma, 1 D Miles, 2 L Gianni, 3 IE Krop, 4 M Welslau, 5 J Baselga, 6 M Pegram, 7 D-Y Oh, 8 V Diéras, 9 E Guardino, 10 L Fang, 10 MW Lu, 10 S Olsen, 10 K Blackwell 11 1 Sunnybrook Odette Cancer Center, Toronto, Canada; 2 Mount Vernon Cancer Center, Northwood, UK; 3 San Raffaele Hospital, Milan, Italy; 4 Dana-Farber Cancer Institute, Boston, MA, USA; 5 Medical Office Hematology, Aschaffenburg, Germany; 6 Massachusetts General Hospital, Boston, MA, USA; 7 University of Miami Sylvester Comprehensive Cancer Center, Miami, FL, USA; 8 Seoul National University College of Medicine, Seoul, Korea; 9 Institut Curie, Paris, France; 10 Genentech, Inc, South San Francisco, CA, USA; 11 Duke Cancer Institute, Durham, NC, USA

49 Trastuzumab-specific MOA Antibody-dependent cellular cytotoxicity (ADCC) Inhibition of HER2 signaling Inhibition of HER2 shedding HER2 T-DM1 Emtansine release Inhibition of microtubule polymerization Lysosome P P P Internalization Nucleus Adapted from LoRusso PM, et al. Clin Cancer Res 2011.

50 HER2-positive LABC or MBC (N=980) Prior taxane and trastuzumab Progression on metastatic treatment or within 6 months of adjuvant treatment 1:1 T-DM1 3.6 mg/kg q3w IV Capecitabine 1000 mg/m 2 PO bid, days 1 14, q3w + Lapatinib 1250 mg/day PO qd PD PD Stratification factors: World region, number of prior chemo regimens for MBC or unresectable LABC, presence of visceral disease Primary endpoints: PFS by independent review, OS, and safety Key secondary endpoints: PFS by investigator, ORR, DOR Statistical considerations: Hierarchical statistical analysis was performed in pre-specified sequential order: PFS by independent review OS secondary endpoints PFS analysis: 90% power to detect HR=0.75; 2-sided alpha 5% OS analyses: 80% power to detect HR=0.80; 2-sided alpha 5%

51 Proportion surviving % 85.2% Median (months) No. of events Cap + Lap T-DM Stratified HR=0.682 (95% CI, 0.55, 0.85); P= Efficacy stopping boundary P= or HR= % 51.8% Time (months) No. at risk: Cap + Lap T-DM Data cut-off July 31, 2012; Unstratified HR=0.70 (P=0.0012).

52 Cap + Lap (n=488) T-DM1 (n=490) Adverse Event All Grades, % Grade 3, % All Grades, % Grade 3, % Diarrhea Hand-foot syndrome Vomiting Neutropenia Hypokalemia Fatigue Nausea Mucosal inflammation Thrombocytopenia Increased AST Increased ALT Anemia ALT, alanine aminotransferase; AST, aspartate aminotransferase.

53 Cardiac dysfunction AEs, a n (%) All grades Grade 3 Lowest post-baseline LVEF value, n (%) 45% 40 to <45% <40% LVEF <50% and 15-point decrease from baseline, n (%) Cap + Lap (n=488) 15 (3.1) 2 (0.4) (n=461) 454 (98.5) 4 (0.9) 3 (0.7) (n=445) 7 (1.6) T-DM1 (n=490) 9 (1.8) 1 (0.2) (n=482) 476 (98.8) 3 (0.6) 3 (0.6) (n=481) 8 (1.7) a Includes preferred terms decreased ejection fraction and left ventricular dysfunction ; Does not include cardiac AEs (e.g. myocardial infarction, atrial fibrillation).

54 Trastuzumab emtansine (KADCYLA) approved by Health Canada Sept 2013 for HER2+ MBC approved by pcodr Prior taxanes and trastuzumab Prior treatment for MBC unless relapsed within 6 months of adjuvant therapy Improved OS by approx. 6 months compared to Lapatinib/Capecitabine Progression beyond TDM1? Unknown.

55 Chemo - only option as systemic therapy No hormonal therapy No targeted agents Can also use these options for HR positive disease if not response to hormonal theraoy and/or extensive burden of disease Can also use these options in Her2neu+ MBC IF EF decreased significantly and/or progressed despite at least 2 lines of Her2neu+ therapies.

56 Drug Class Agents Mechanism of Action Antracyclines Antimetabolites Antimicrotubule agents Platinum analogues Doxorubicin, Epirubicin Capecitabine, Gemcitabine Paclitaxel, Docetaxel, Ixabepilone Eribulin Vinorelbine DNA intercalation and induction of cell death Inhibits processes required for DNA synthesis Stabilizes microtubules by inhibiting the shortening of microtubule Inhibits microtubules by suppressing microtubule growth at the plus end Inhibits microtubules by inhibiting the polymerization of tubulin dimers and depolymerization Carboplatin, Cisplatin Induces DNA adduct formation and cell death

57 Line of CT Total (n) HR+(month s) TNBC (months) HER2+ (months) 1 st nd rd th th th Seah DS et al. Proc ASCO 2012;Abstract 6089

58 First-Line Second-Line Doxorubicin 35-50% %1 Epirubicin 52-68% 28% Paclitaxel 29-63% % Docetaxel 47-65% % Capecitabine 25% %1 Gemcitabine 23-37% %1 Vinorelbine 40-44% % 1Esteva F et al, Oncologist 2001 (6):

59 Combination therapy uses the concept of nonoverlapping resistance mechanisms Higher response rate, longer TTP/PFS, only marginal improvement of OS (2-3 months) Increased toxicity Balancing survival and quality of life Therapy with serial single agents is reasonable and often preferred, especially in 2 nd, 3 rd, and 4 th line treatment nab-paclitaxel is our preferred first line agent (QOL and RR).

60 Novel microtubule inhibitor Halichondria okadai MTD 2 mg/m 2 DLT neutropenia t 1/2 = 46.5 hours

61 Eligibility (n = 762) Locally recurrent or mbc 2-5 prior chemotherapies 2 for advanced disease Prior anthracyclines and taxanes Progression 6 months of last chemotherapy Neuropathy Grade 2 ECOG 2 R 2: 1 Eribulin mesylate (n=508) 1.4 mg/m 2, 2-5 min IV D1, 8 q21 days Treatment of Physician s Choice (TPC) (n=254) Any monotherapy (chemotherapy, hormonal, biological)* or supportive care only** * Approved for cancer treatment ** Or palliative treatment or radiotherapy according to local practice Twelves C et al. Proc ASCO 2010;Abstract CRA1004.

62 % of patients treated with chemotherapy Total patients = 247 % of patients n = 61 Vinorelbine n = 46 n = 44 n = 38 Gemcitabine Capecitabine Taxanes n = 24 n = 25 Anthracyclines Other chemo n = 9 Hormonal No patient received best supportive care or biological therapies only Taxanes: paclitaxel, docetaxel, nanoparticle albumin-bound (nab) paclitaxel; Anthracyclines: doxorubicin, liposomal doxorubicin, mitoxantrone Twelves C et al. Proc ASCO 2010;Abstract CRA1004.

63 Endpoint Eribulin TPC Hazard ratio p- value OS (n = 508, 254) 13.1 mo 10.6 mo PFS* (n = 508, 254) Independent review (ITT) Investigator review (ITT) 3.7 mo 3.6 mo 2.2 mo 2.2 mo ORR (CR+PR) (n = 468, 214) Independent review (ITT) Investigator review (ITT) 12.2% 13.2% 4.7% 7.5% CBR (CR+PR+SD) (n = 468, 214) Independent review (ITT) Investigator review (ITT) 22.6% 27.8% 16.8% 20.1% * PFS in per-protocol population was significant for independent (p = 0.02) and investigator (p < 0.001) reviews Twelves C et al. Proc ASCO 2010;Abstract CRA1004.

64 Hematologic events Neutropenia Leukopenia Anemia Febrile neutropenia Non-hematologic events Asthenia/fatigue Peripheral neuropathy Nausea Dyspnea Mucosal inflammation Hand-foot syndrome Eribulin (n = 503) 21.1% 11.7% 1.8% 3.0% 8.2% 7.8% 1.2% 3.6% 1.4% 0.4% Grade 3 Grade 4 TPC (n = 247) 14.2% 4.9% 3.2% 0.8% 10.1% 2.0% 2.4% 2.4% 2.0% 3.6% Eribulin (n = 503) 24.1% 2.2% 0.2% 1.2% 0.6% 0.4% TPC (n = 247) 6.9% 0.8% 0.4% 0.4% % 0 0 Twelves C et al. Proc ASCO 2010;Abstract CRA1004.

65 Overall 35% patients reported PN 5% discontinued therapy due to neuropathy Phase II trials 25-26% grade 1/2 and 5-7% grade 3 Phase II randomized trial eribulin vs. ixabepilone n=127 MBC patients, grade <2 neuropathy 33.3% vs. 48% all grades neuropathy 9.8% vs. 22% grade 3

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67 First line taxane or anthracycline (we prefer Nab-Paclitaxel- RR50-60%, no pre/post meds) Second line- FEC60 or Capecitabine (for TNBC- Cis/Gem- good data for second line use) Third line- Capecitabine or Eribulin 4th line and beyond- Navelbine, Etoposide Need a doublet (fast progression?) Gem/Taxol or Cis/Gem. Capecitabine doublets with taxanes/anthracyclines- very toxic. I don t use them.

68 There is no standard systemic therapy in the treatment of MBC If possible, endocrine therapy should be considered The choice of single or polychemotherapy and of the specific agents depends on patients PS, organ function and the extent of disease involvement Combination treatments have led to prolongation in survival, but higher toxicity Molecular targeted therapies in combination with chemotherapy represent the most promising developments in the treatment of MBC

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