Disease Update: Metastatic Breast Cancer

Transcription

1 Disease Update: Metastatic Breast Cancer Aimee Faso, PharmD, BCOP, CPP Oncology Clinical Specialist, GI/Breast UNC Hospitals and Clinics August 2015 Objectives Identify treatment choices of metastatic breast cancer based on tumor biology Describe the role of HER2 targeted therapies in metastatic breast cancer patients Review agents that target novel pathways in hormone positive metastatic breast cancer Evaluate the evidence for the use of platinums in metastatic breast cancer 1

2 Breast Cancer Is the most common cancer among women worldwide and in American women only second to skin cancers 1.7 million newly diagnosed cases worldwide in 2012 Is the second leading cause of cancer deaths in American women after lung cancer Death rates have been declining since 1989 Believed due to earlier detection and improved treatment (accessed ) cancer key statistics(accessed ) Metastatic Breast Cancer Most common sites of metastasis include bone, brain, lung, and liver It is believed that 6-10% of women present with primary metastatic disease at initial diagnosis It is estimated that up to 30% of women diagnosed with earlier stages of breast cancer will progress to metastatic disease Median survival for metastatic breast cancer is months Survival varies widely depending on tumor subtype, site of metastasis, and burden of disease O Shaughnessy J, et al. The Oncologist. 2005;10 suppl 3: Barinoff J, et al. Eur J Can. 2013;49: ; (accessed ) 2

3 Metastatic Breast Cancer Goals of treatment Prolongation of survival Alleviation of symptoms Maintenance or improvement of Quality of Life Choice of treatment depends on Clinical factors Tumor biology Metastatic Breast Cancer Biologic markers are important for selecting systemic therapy HER2 overexpression HER2 (+) Benefit from HER2 directed therapy Tumor Biology Hormone Receptor Status ER/PR (+) Benefit from hormone therapy Triple negative ER/PR ( ) or hormone refractory Benefit from chemotherapy HER2 Human Epidermal Growth Factor Receptor 2 ER Estrogen Receptor PR Progesterone Receptor 3

4 HER2 (+) Metastatic Breast Ca Timeline of development of HER2 targeted therapies Trastuzumab (Herceptin ) Pertuzumab (Perjeta ) Lapatinib (Tykerb ) Ado Trastuzumab Emtansine (Kadcyla ) HER2 Historical Perspective Trial that demonstrated benefit of HER2 receptor blockade in HER2 (+) metastatic breast cancer Results of chemotherapy in addition to trastuzumab Chemotherapy alone Chemotherapy + Trastuzumab p value Median time to progression 4.6 months 7.4 months p<0.001 Median ORR 32% 50% p<0.001 Median OS 20.3 months 25.1 months p<0.046 ORR Objective Response Rate OS Overall Survival Slamon DJ, et al. N Engl J Med. 2001;344(11):

5 NCCN Guidelines Regimens for HER2 (+) metastatic breast cancer Preferred first line regimens Pertuzumab + Trastuzumab + Docetaxel Pertuzumab + Trastuzumab + Paclitaxel Other first line agents Trastuzumab alone or with: Paclitaxel + Carboplatin Docetaxel Vinorelbine Capecitabine Preferred for trastuzumabexposed disease Ado trastuzumab emtansine Other agents for trastuzumabexposed disease Lapatinib + Capecitabine Trastuzumab + Capecitabine Trastuzumab + Lapatinib Trastuzumab + other agents NCCN. Breast Cancer. v Available at: HER2 (+) Metastatic Breast Ca Teplinsky E and Jhaven K oncology/2014/february 2014/Antibody Drug Conjugatesand T DM1 (accessed ) 5

6 HER2 (+) Metastatic Breast Ca Teplinsky E and Jhaven K oncology/2014/february 2014/Antibody Drug Conjugatesand T DM1 (accessed ) Cleopatra Phase III, first line treatment for HER2 (+) metastatic breast cancer HER2 (+) Metastatic Breast Cancer First line therapy (N=808) R Trastuzumab + Pertuzumab + Docetaxel (n=402) Trastuzumab + Placebo + Docetaxel (n=406) Primary endpoint: Progression Free Survival (PFS) Secondary endpoints: OS ORR Safety Study dosing every 3 weeks Pertuzumab/Placebo: 840 mg loading dose, 420 mg maintenance Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance Docetaxel: 75 mg/m 2, escalating to 100 mg/m 2 if tolerated Baselga J, et al. N Eng J Med 2012;366:

7 Cleopatra Baseline characteristics of prior adjuvant or neoadjuvant therapy Baselga J, et al. N Eng J Med 2012;366: Cleopatra Progression Free Survival at Interim Analysis Addition of pertuzumab prolonged PFS by 6.1 months Baselga J, et al. N Eng J Med 2012;366:

8 Cleopatra Overall Survival at Interim Analysis Interim analysis suggested pertuzumab may increase OS but data was immature Baselga J, et al. N Eng J Med 2012;366: Cleopatra Trial Adverse Events (Any Grade) Adverse Event Placebo + Trastuzumab + Docetaxel (%) Baselga J, et al. N Eng J Med 2012;366: Pertuzumab + Trastuzumab + Docetaxel (%) Diarrhea Alopecia Neutropenia Nausea Fatigue Rash Decreased appetite Mucosal inflammation Asthenia Peripheral edema Constipation Febrile neutropenia Dry skin

9 Cleopatra Trial Adverse Events (Any Grade) Adverse Event Placebo + Trastuzumab + Docetaxel (%) Baselga J, et al. N Eng J Med 2012;366: Pertuzumab + Trastuzumab + Docetaxel (%) Diarrhea Alopecia Neutropenia Nausea Fatigue Rash Decreased appetite Mucosal inflammation Asthenia Peripheral edema Constipation Febrile neutropenia Dry skin Cleopatra Adverse Event Adverse Events (Grade 3 or higher) Placebo + Trastuzumab + Docetaxel (%) Pertuzumab + Trastuzumab + Docetaxel (%) Neutropenia Febrile neutropenia Leukopenia Diarrhea LV systolic dysfunction Baselga J, et al. N Eng J Med 2012;366:

10 Cardiotoxicity Cleopatra Left ventricular systolic dysfunction of any grade: Control group = 8.3% Pertuzumab group = 4.4% Left ventricular ejection fraction (LVEF) assessed after baseline - the percent of patients who had a decline of >10 percentage points or LVEF < 50% Control group = 6.6% Pertuzumab group = 3.8% Addition of pertuzumab did not increase rates of cardiac dysfunction Baselga J, et al. N Eng J Med 2012;366: Cleopatra Overall survival reported in final analysis Pertuzumab prolonged overall survival (56.5 months vs months) Swain SM et al. N Engl J Med 2015;372:

11 Cleopatra Final analysis of Cleopatra trial also found: Progression free survival benefit with pertuzumab was maintained 18.7 months vs months (HR=0.68; p< 0.001) No new safety concerns Left ventricular systolic dysfunction of any grade: Control group = 8.6% Pertuzumab group = 6.6% Percent of patients who had a decline of >10 percentage points or LVEF < 50% after baseline Control group = 7.4% Pertuzumab group = 6.1% Swain SM et al. N Engl J Med 2015;372: Cleopatra Summary The addition of pertuzumab to trastuzumab and docetaxel significantly prolonged progression free survival and overall survival when used as first-line treatment for patients with HER2 (+) metastatic breast cancer Combination of HER2 targeted agents did not increase cardiotoxicity 11

12 HER2 (+) Metastatic Breast Ca Ado-trastuzumab emtansine (TDM-1) de Lartigue, J live/2012/june 2012/Antibody Drug Conjugates Guided Missiles Deployed Against Cancerous Cells(accessed (accessed ) EMILIA Patients with advanced breast cancer who were previously treated with trastuzumab and a taxane randomly assigned to T DM1 or lapatinib and capecitabine (N=991) T DM1 Lapatinib + Capecitabine Median PFS 9.6 months 6.4 month Median OS 30.9 months 25.1 months 12 month survival rate 24 month survival rate 85.2% 78.4% 64.7% 51.8% P value HR=.65 p< HR=.682 p= Verma S, et al. N Engl J Med. 2012;367(19):

13 TH3RESA Patients previously treated with 2 prior therapies (trastuzumab, lapatinib, taxane) randomly assigned to T DM1 or treatment of physician s choice (N=600) T DM1 Physician s choice* P value ORR 31.3% 8.6% p< Median PFS 6.2 months 3.3 months Median OS (interim analysis) Not yet reached 14.9 months HR=0.528 p< HR=0.552 p= *Single agent chemotherapy, hormonal therapy, or HER2 directed therapy, or a combination of a HER2 directed therapy with a chemotherapy, hormonal therapy, or other HER2 directed therapy. Krop IE, et al. Lancet Oncol ;15(7): Marianne Phase III, double blind, randomized trial HER2 (+) Progressive/ recurrent locally advanced or previously untreated metastatic breast cancer (N=1092) R Trastuzumab + Taxane (n=363) TDM 1 + Pertuzumab (n=367) TDM 1 + Placebo (n=365) Primary endpoint: PFS Secondary endpoints: OS ORR Safety Ellis PA et al. J Clin Onc 2015;33. Abstr

14 TDM 1 found to be non inferior to standard treatment Ellis PA et al. J Clin Onc 2015;33. Abstr 507. HER2 (+) Metastatic Breast Ca Summary HER2 blockade prolongs survival in metastatic breast cancer patients The combination of trastuzumab, pertuzumab and a taxane is the first-line option for previously untreated metastatic breast cancer patients Ado-trastuzumab emtansine should be considered as a second-line or third-line agent 14

15 NCCN Guidelines Endocrine therapy for Stage IV disease Premenopausal patients should have ovarian ablation/suppression and follow postmenopausal recommendations Postmenopausal patients Nonsteroidal aromatase inhibitors Steroidal aromatase inhibitors Everolimus + Exemestane Palbociclib + Letrozole Fulvestrant Tamoxifen or toremifene Megestrol acetate Fluoxymesterone Ethinyl estradiol NCCN. Breast Cancer. v Available at: Breast Cancer Complexity HER2 overexpression Tumor Biology Hormone Receptor Status Triple negative Breast cancer can be defined beyond these 3 subtypes 15

16 Increasing number of potential targets Zardavas, D., et al. Nature Reviews 2013;10: Molecular Subtypes Sandhu, R, et al. Lab Medicine. 2010;41: Luminal A 40% of breast cancers Tend to be ER/PR(+) and HER2 ( ) Slow growing Luminal B 10 20% of breast cancers Tend to be ER/PR (+) and either HER2 ( ) or have high proliferation rates Basal like 10 20% of breast cancers Most are triple negative Most common in BRCA1 gene mutation 16

17 PI3K Pathway Inhibitors There is a high frequency of activating mutations of phosphatidylinositol 3 kinase (PI3K) in luminal A and B breast cancers Cancer genome atlas network. Nature 2012;490:61 70; Atkins MB, et al. Nature Rev Drug Disc 2009;8: PI3K Pathway Inhibitors Everolimus (Afinitor ) inhibits mammalian target of rapamycin (mtor), located downstream from PI3K Aberrant signaling of PI3K/mTOR pathway is also believed to play a role in endocrine resistance Atkins MB, et al. Nature Rev Drug Disc 2009;8: Yamnick RL, et al. FEBS Lett. 2010;584: Yamnick RL et al. J Biol Chem. 2009;284:

18 Bolero 2 Phase III, double blind, randomized trial Post menopausal Hormone receptor (+) HER2 ( ) Unresectable locally advanced or metastatic breast cancer Recurrence or progression after letrozole or anastrozole (N=724) R Everolimus 10 mg po daily + Exemestane 25 mg po daily (n=485) Placebo + Exemestane 25 mg po daily (n=239) Primary endpoint: PFS Secondary endpoints: OR, OS, clinical benefit, safety, QoL Baselga J, et al. N Engl J Med. 2012;366(6): Bolero 2 No difference in OS found: Everolimus + exemestane = 31.0 mo. Placebo + exemestane = 26.6 mo. (p = 0.14) Baselga J, et al. N Engl J Med. 2012;366(6): Piccart M, et al. Ann Oncol 2014;

19 Bolero 2 Most Common Grade 3/4 Adverse Effects Everolimus + Exemestane Exemestane alone Grade 3 Grade 4 Grade 3 Grade 4 Stomatitis 8% 0% 1% 0% Dyspnea 4% 0% 1% <1% Anemia 5% 1% <1% <1% Hyperglycemia 4% <1% <1% 0% Pneumonitis 3% < 1% 0% 0% Baselga J, et al. N Eng J Med, 2012;366: Bolero 2 Genetic sequencing identified genetic pathways harboring the most genetic alterations: PIK3CA (48%) Identified in about 1/3 of ER (+) tumors CCND1 (31%) TP53 (23%) FGFR1 (18%) Unable to identify a subset of patients most likely to benefit from mtor inhibitor Hortobagyi GN, et al. J Clin Oncol 31, 2013 (suppl; abstr LBA509) 19

20 CDK 4/6 Inhibitor CDK 1 Cyclin B M G0 Cell cycle transition is coordinated by complexes formed between cyclins and CDKs Cyclin D CDK 4/6 G2 G1 Rb P EF2 CDK 2 Cyclin A Cyclin B CDK 2 S Cadoo, KA, et al. Breast Ca. 2014;6: Cyclin A CDK 2 CDK=Cyclin Dependent Kinase Rb=Retinoblastoma tumor suppressor gene product EF2=Elongation Factor 2 CDK 4/6 Inhibitor CDK 1 Cyclin B M G0 Palbociclib Cyclin D CDK 4/6 G2 G1 Rb P EF2 Cyclin A CDK 2 Cyclin B CDK 2 S Cyclin A CDK 2 Palbociclib is a selective inhibitor of CDK 4 and 6 Cadoo, KA, et al. Breast Ca. 2014;6:

21 Paloma 1 Phase II, open label, first line treatment for advanced breast cancer Post menopausal Estrogen receptor (+) HER2 ( ) Advanced Breast Cancer N=165 R Letrozole 2.5 mg po daily + Palbociclib 125 mg po daily 3wks on/1 wk off (n=84) Letrozole 2.5 mg po daily (n=81) Primary endpoint: PFS Secondary endpoints: OR, Clinical benefit, Duration of response, OS Finn RS, et al. Lancet Oncol. 2015;16: Paloma 1 Median Progression Free Survival Palbociclib + Letrozole = 20.2 months Letrozole Only = 10.2 months Finn RS, et al. Lancet Oncol. 2015;16:

22 Paloma 1 Subgroup analysis for Progression Free Survival Finn RS, et al. Lancet Oncol. 2015;16: Paloma 1 Subgroup analysis for Progression Free Survival Favors combination Finn RS, et al. Lancet Oncol. 2015;16:

23 Paloma 1 Most Common Adverse Effects Palbociclib + Letrozole Letrozole alone Grade 1 2 Grade 3 4 Grade 1 2 Grade 3 4 Neutropenia* 20% 54% 4% 1% Leukopenia 24% 19% 3% Fatigue 36% 4% 22% 1% Anemia 29% 6% 5% Alopecia 22% 3% 0% Pulmonary embolism 5% *No cases of neutropenic fever were reported Finn RS, et al. Lancet Oncol. 2015;16: Paloma 3 Phase III, second line treatment for advanced breast cancer Pre/Peri or Post menopausal Hormone receptor (+) HER2 ( ) Advanced Breast Cancer Progressed on prior endocrine therapy (N=165) R Palbociclib 125 mg po daily 3wks on/1 wk off + Fulvestrant* (n=347) Placebo + Fulvestrant* (n=174) Primary endpoint: PFS Secondary endpoints: OR, OS, Duration of response *Fulvestrant 500 mg IM Cycle 1 Day 1 and 15, then 500 mg IM monthly Turner NC et al. J Clin Onc 2015;33. Abstr LBA502.; Turner NC, et al. N Eng J Med 2015; 373(3):

24 Adverse Events of Paloma 3 Trial Palbociclib + Fulvestrant Placebo + Fulvestrant Adverse Event (%) Any grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4 Any Adverse Event Neutropenia Leukopenia Anemia Thrombocytopenia Fatigue Nausea Headache 21 < Upper Resp Infect 19 < Diarrhea Constipation Alopecia Turner NC et al. J Clin Onc 2015;33. Abstr LBA502. Turner NC, et al. N Eng J Med 2015; 373(3): Adverse Events of Paloma 3 Trial Palbociclib + Fulvestrant Placebo + Fulvestrant Adverse Event (%) Any grade Grade 3 Grade 4 Any Grade Grade 3 Grade 4 Any Adverse Event Neutropenia Leukopenia Anemia Thrombocytopenia Fatigue Nausea Headache 21 < Upper Resp Infect 19 < Diarrhea Constipation Alopecia Turner NC et al. J Clin Onc 2015;33. Abstr LBA502. Turner NC, et al. N Eng J Med 2015; 373(3):

25 Paloma 3 Progression Free Survival Turner NC et al. J Clin Onc 2015;33. Abstr LBA502. Turner NC, et al. N Eng J Med 2015; 373(3): Paloma 3 Summary of Key Secondary Endpoints Palbociclib + Fulvestrant (n=347) % of patients Placebo + Fulvestrant (n=174) % of patients p value ORR CBR CBR Clinical Benefit Rate = (complete response + partial response + stable disease > 24 weeks) Turner NC et al. J Clin Onc 2015;33. Abstr LBA502. Turner NC, et al. N Eng J Med 2015; 373(3):

26 Palbociclib Summary Palbociclib improved PFS in women with hormone positive, HER 2 negative advanced breast cancer When used as first line treatment in combination with letrozole (Paloma-1) When used as second line treatment in combination with fulvestrant (Paloma-3) Overall survival results are pending NCCN Guidelines Chemotherapy Regimens for Metastatic Breast Cancer Preferred Single Agents Doxorubicin Pegylated liposomal doxorubicin Paclitaxel Capecitabine Gemcitabine Vinorelbine Eribulin Other Single Agents Cyclophosphamide Carboplatin Docetaxel Albumin bound paclitaxel Cisplatin Epirubicin Ixabepilone Chemotherapy Combinations FAC (Fluorouracil, doxorubicin, cyclophosphamide) FEC (Fluorouracil, epirubicin, cyclophosphamide) AC (Doxorubicin, cyclophosphamide) EC (Epirubicin, cyclophosphamide) CMF (Cyclophosphamide, methotrexate, fluorouracil) Docetaxel + Capecitabine Gemcitabine + Paclitaxel Gemcitabine + Carboplatin Paclitaxel + Bevacizumab NCCN. Breast Cancer. v Available at: 26

27 Triple Negative Breast Cancer Trial (TNT) Phase III, first line treatment for triple negative metastatic breast cancer Triple negative or BRCA 1/2 (+) Metastatic or locally advanced breast cancer First line therapy (N=376) R Docetaxel 100 mg/m2 q3weeks x 6 cycles (n=188) Carboplatin AUC 6 q3weeks x 6 cycles (n=188) Primary endpoint: ORR Secondary endpoints: PFS, OS, toxicity BRCA1/2=Breast Cancer Susceptibility Gene 1 and 2 Crossover upon progression allowed for both arms Tutt A, et al. San Antonio Breast Cancer Symposium 2014; Abstract S3 01 Triple Negative Breast Cancer Trial (TNT) Results Carboplatin Arm Docetaxel Arm N Age 55.7 years 54.9 years BRCA 1/2 mutation 9% 6.4% Febrile Neutropenia 2% 25% Neuropathy (grade 3 4) 1% 6% ORR 31.4% 35.6% Median PFS Median OS 3.1 months [95% CI: mo] 12.4 months [95% CI: mo] 4.5 months [95% CI: mo] 12.3 months [95% CI: mo] Tutt A, et al. San Antonio Breast Cancer Symposium 2014; Abstract S

28 Triple Negative Breast Cancer Trial (TNT) Results Carboplatin Arm Docetaxel Arm N Age 55.7 years 54.9 years BRCA 1/2 mutation 9% 6.4% Febrile Neutropenia 2% 25% Neuropathy (grade 3 4) 1% 6% ORR 31.4% 35.6% Median PFS Median OS 3.1 months [95% CI: mo] 12.4 months [95% CI: mo] 4.5 months [95% CI: mo] 12.3 months [95% CI: mo] No difference between use of docetaxel or carboplatin Tutt A, et al. San Antonio Breast Cancer Symposium 2014; Abstract S3 01 Triple Negative Breast Cancer Trial (TNT) Results Carboplatin Arm Docetaxel Arm N Age 55.7 years 54.9 years BRCA 1/2 mutation 9% 6.4% Febrile Neutropenia 2% 25% Neuropathy (grade 3 4) 1% 6% ORR 31.4% 35.6% Median PFS Median OS 3.1 months [95% CI: mo] 12.4 months [95% CI: mo] 4.5 months [95% CI: mo] 12.3 months [95% CI: mo] Significant difference in adverse effects between the two groups Tutt A, et al. San Antonio Breast Cancer Symposium 2014; Abstract S

29 Triple Negative Breast Cancer Trial (TNT) Results Carboplatin Arm Docetaxel Arm N Age 55.7 years 54.9 years BRCA 1/2 mutation 9% 6.4% Febrile Neutropenia 2% 25% Neuropathy (grade 3 4) 1% 6% ORR 31.4% 35.6% Median PFS Median OS 3.1 months [95% CI: mo] 12.4 months [95% CI: mo] 4.5 months [95% CI: mo] 12.3 months [95% CI: mo] BRCA 1/2 Mutated Cohort ORR 68% 33% Median PFS 6.8 months [95% CI: mo] 3.1 months [95% CI: mo] Tutt A, et al. San Antonio Breast Cancer Symposium 2014; Abstract S3 01 Triple Negative Breast Cancer Trial (TNT) Results Carboplatin Arm Docetaxel Arm N Age 55.7 years 54.9 years BRCA 1/2 mutation 9% 6.4% Febrile Neutropenia 2% 25% Neuropathy (grade 3 4) 1% 6% ORR 31.4% 35.6% Median PFS Median OS 3.1 months [95% CI: mo] 12.4 months [95% CI: mo] Tutt A, et al. San Antonio Breast Cancer Symposium 2014; Abstract S months [95% CI: mo] 12.3 months [95% CI: mo] BRCA 1/2 Mutated Cohort ORR 68% 33% Median PFS 6.8 months [95% CI: mo] 3.1 months [95% CI: mo] Patients with BRCA 1/2 had greater response to carboplatin 29

30 TN Breast Ca Summary Carboplatin as well as docetaxel can be considered for upfront treatment Patients with triple negative BRCA1/2 metastatic breast cancer may gain more benefit from a platinum agent Immunotherapy Future Directions? Pembrolizumab 10 mg IV q2 weeks Anti-programmed cell death protein-1 (PD-1) inhibitor Phase I trial in 27 women with metastatic triple negative breast cancer 18.5% had an objective response 25.9% had stable disease Selective PI3K inhibitors ER/PR (+) cancers HER2 (+) cancers Nanda, R. et al. San Antonia Breast Cancer Symposium 2014; Abstract S

31 Conclusions Treatment of metastatic breast cancer is determined by the tumor biology HER2 directed therapies prolong survival in patients with HER2 (+) metastatic breast cancer Agents that target novel pathways provide alternative treatment options for hormone positive metastatic breast cancer in the first line and second line settings When possible, single agent chemotherapy is the preferred treatment in triple negative breast cancer including taxanes and platinums Disease Update: Metastatic Breast Cancer Questions? 31