New Treatment Options for Breast Cancer

New Treatment Options for Breast Cancer Brandon Vakiner, PharmD., BCOP Clinical Pharmacy Specialist - Oncology The University of Iowa Hospitals and Clinics Assistant Professor (Clinical) University of Iowa College of Pharmacy

Disclosures Brandon Vakiner reports no relevant financial disclosures

Objectives Discuss recently published literature regarding breast cancer (BC) treatment Review recently FDA-approved breast cancer treatments Name Mechanism of Action (MOA) Adverse Effects Place in Therapy Review relevant studies

Everolimus (Afinitor): BOLERO-2 724 pts randomized in a 2:1 ratio to everolimus 10 mg/day plus exemestane 25 mg/day vs. exemestane plus placebo Hormone-receptor positive, HER-2 negative advanced breast cancer Recurrence or progression while receiving previous therapy with a nonsteroidal aromatase inhibitor in the adjuvant setting or to treat advanced disease (or both) Primary end point: progression-free survival (PFS) based on radiographic studies Secondary: overall survival (OS), overall response rate Baselga J, et al. NEJM. 2012;366:520-9

BOLERO-2 Results Median PFS by investigator assessment 7.8 months for patients receiving everolimus 3.2 months for patients receiving placebo [HR 0.45 (95 percent CI: 0.38-0.54), p < 0.0001] Objective response rates 12.6 percent in patients receiving everolimus 1.7 percent in patients receiving placebo Interim analysis of OS conducted at 46% of expected events was not statistically significant [HR=0.77 (95 percent CI: 0.57, 1.04)] Final analysis of OS is expected to occur in June 2014

Tamoxifen: ATLAS & attom ATLAS Adjuvant Tamoxifen: Longer Against Shorter From 1996 2005, randomized 6846 women with ER+ disease already taking tamoxifen to stop after 5 years or continue to 10 years 12894 women were evaluated for safety evaluation attom adjuvant Tamoxifen Treatment offers more? From 2001 2005, 6,953 women with ER+ (n=2755), or ER untested (4198, estimated 80% ER+ if status known) invasive BC from 176 UK centers randomized to stop tamoxifen after 5 years of or continue to year 10 Davies C, et al. Lancet. 2013;381: 805 16 Gray RJ, et al. J Clin Oncol (Meeting Abstracts). 2013; 31(18): suppl 5

ATLAS Continuing reduced: Risk for BC recurrence (617 vs 711; P =.002), BC mortality (331 vs 397 deaths; P =.01) Overall mortality (639 vs 722 deaths; P =.01) Continuing increased risk for endometrial CA (relative risk [RR], 1.74) & for pulmonary embolism (RR, 1.87). attom Continuing reduced: BC recurrences (28% vs 32%; P =.003) BC mortality (392 vs 443 deaths after recurrence; 21% vs 24%; P =.06) Non-BC mortality was little affected (457 vs 467 deaths, rate ratio 0.94 [0.82-1.07]) Endometrial cancers RR=2.20 (1.31-2.34, p<0.0001)

The HER Family http://www.cancer.gov/ncicancerbulletin/archive/2009/011309/page6. Accessed 10/7/13

HER2 & HER3 HER2 gene is amplified & overexpressed in about 25% of BC, leading to more aggressive disease HER2 not only important in development of BC but drives progression & metastasis in its advanced stages HER3 is frequently overexpressed in BC with HER2 overexpression, and increased expression of HER3 synergistically increases transforming potency of HER2 HER2 HER3 signaling complex is highly effective in activating the PI3K/Akt pathway Hsieh AC, Moasser MM. Br J Cancer. 2007;97:453-457

Pertuzumab injection (Perjeta, Genentech) Humanized monoclonal antibody that binds HER2 at a different epitope than trastuzumab Combined with trastuzumab & docetaxel for treatment of HER2-positive (HER2+) metastatic breast cancer who haven t received prior anti-her2 therapy or chemotherapy for metastatic disease Initial dose: 840 mg over 60 minutes Maintenance: 420 mg over 30 60 minutes every 3 weeks Mix & Monitoring are the same as trastuzumab Perjeta IV injection [package insert]. South San Francisco, CA: Genentech Inc.; June 2012

Mechanism of Action http://www.perjeta.com/hcp/moa;jsessionid=4ad2bb455625af520c646832274f9e64.gxe501b-m2. Accessed 3/11/13.

Randomized 808 patients with HER2+ metastatic BC to firstline treatment with: Placebo + trastuzumab + docetaxel (control group) Pertuzumab + trastuzumab + docetaxel (pertuzumab group) Primary end pt: PFS (independently assessed) Secondary end pts: OS, PFS (investigator assessed), objective response rate, & safety

Pertuzumab: CLEOPATRA Increased median PFS 12.4 months docetaxel & trastuzumab 18.5 months docetaxel, trastuzumab and pertuzumab Toxicity greater in pertuzumab group: Any Grade: diarrhea, rash, dry skin, mucositis, febrile neutropenia Grade 3 or higher: febrile neutropenia & diarrhea Combination showed no increased rates of cardiac dysfunction Strong trend for increased OS Baselga J, et al. NEJM. 2012;366:109-19

In the intention-to-treat population, 267 patients died by data cutoff (05/14/12) 154 (38%) of 406 in the placebo group 113 (28%) of 402 in the pertuzumab group Median OS was 37.6 months (95% CI 34 3 NE [not estimable]) in the placebo group but had not been reached (95% CI 42 4 NE) in the pertuzumab group (hazard ratio 0 66, 95% CI 0 52 0 84; p=0 0008)

FDA Approves Pertuzumab for Neoadjuvant Breast Cancer On Sept. 30, 2013 the FDA granted accelerated approval to pertuzumab in combination with trastuzumab & docetaxel for the neoadjuvant treatment of patients with HER2+, locally advanced, inflammatory, or early stage BC as part of a complete treatment regimen for early breast cancer Is this setting a new precedent? http://www.asco.org/advocacy/fda-approves-pertuzumab-neoadjuvant-breast-cancer. Accessed 10/01/13

Neoadjuvant Pertuzumab Should be administered every 3 weeks for 3 to 6 cycles as part of one of the following treatment regimens for early breast cancer: Four preoperative cycles of pertuzumab in combination with trastuzumab and docetaxel followed by 3 postoperative cycles of FEC Three preoperative cycles of FEC alone followed by 3 preoperative cycles of pertuzumab in combination with docetaxel and trastuzumab Six preoperative cycles of pertuzumab in combination with docetaxel, carboplatin and trastuzumab (TCH) Following surgery, patients should continue to receive trastuzumab to complete 1 year of treatment Insufficient evidence to recommend: continued use of pertuzumab for greater than 6 cycles for early breast cancer concomitant administration of an anthracycline with pertuzumab, and there are no safety data to support sequential use of doxorubicin with pertuzumab

Ado-Trastuzumab Emtansine IV (Kadcyla, Genentech) First antibody-drug conjugate (ADC) for the treatment of HER2+ tumors HER2-targeted antitumor properties of trastuzumab Cytotoxic activity of the microtubule-inhibitory agent DM1 Single agent for HER2+, metastatic BC who have received trastuzumab and a taxane (separate or in combo) Received prior therapy for metastatic disease Developed recurrence during or within six months of completing adjuvant therapy Kadcyla IV injection [package insert]. South San Francisco, CA: Genentech Inc.; Feb 2013

http://www.kadcyla.com/hcp/about. Accessed 9/12/13

Ado-Trastuzumab Emtansine Dose: 3.6 mg/kg diluted it in 250 ml NS IV every 3 weeks DO NOT administer at doses greater than 3.6 mg/kg. Do not substitute for or with trastuzumab Infuse first dose over 90 minutes, subsequent doses over 30 min Administer with a 0.22 micron in-line non-protein adsorptive polyethersulfone (PES) filter Monitor for at least 30 minutes after infusion Monitoring similar to taxanes and trastuzumab Kadcyla IV injection [package insert]. South San Francisco, CA: Genentech Inc.; Feb 2013

Randomized 991 patients with HER2+ advanced BC, previously treated with trastuzumab & a taxane, to T-DM1 or lapatinib plus capecitabine Primary end points: PFS (independent review), OS, & safety Secondary end points: PFS (investigator-assessed), objective response rate, & time to symptom progression

EMILIA: Progression-Free Survival Verma S, et al. NEJM. 2012; 367: 1783-91

EMILIA: Overall Survival Verma S, et al. NEJM. 2012; 367: 1783-91

Toxicity Most common (> 25%): fatigue, nausea, musculoskeletal pain, thrombocytopenia, headache, increased transaminases, and constipation Most common (> 2%) Grade 3-4: thrombocytopenia*, increased transaminases*, anemia, hypokalemia, peripheral neuropathy and fatigue Serious hepatobiliary disorders have been reported Other significant adverse reactions include left ventricular dysfunction, interstitial lung disease, & infusion-associated reactions *most common leading to withdrawal from study Kadcyla IV injection [package insert]. South San Francisco, CA: Genentech Inc.; Feb 2013 Verma S, et al. NEJM. 2012; 367: 1783-91

Toxicity Severity Recommendation Thrombocytopenia Grade 3 (Platelets [PLT] 25K to < 50K) Do not administer until PLT count recovers to Grade 1 (>75K), then treat at same dose level Grade 4 (PLT < 25K) Do not administer until PLT count recovers to Grade 1, then reduce one dose level Increased AST/ALT Grade 2 (>2.5 to 5 x Upper Limit Normal) Treat at same dose level Grade 3 (> 5 to 20 x ULN) Grade 4 (>20 x ULN) Do not administer until AST/ALT recovers to Grade 2, then reduce one dose level Permanently discontinue Hyperbilirubinemia Grade 2 (>1.5 to 3 x ULN) Do not administer until total bilirubin recovers to Grade 1, then treat at same dose level Grade 3 (>3 to 10 x ULN) Grade 4 (> 10 x ULN) Do not administer until total bilirubin recovers to Grade 1, then reduce one dose level Permanently discontinue Left Ventricular Dysfunction (Left ventricular ejection fraction [LVEF]) LVEF > 45% LVEF 40% to 45% and decrease is < 10% points from baseline LVEF 40% to 45% and decrease is 10% points from baseline LVEF < 40% Symptomatic CHF Continue treatment Continue treatment & repeat LVEF assessment within 3 weeks Do not administer. Repeat within 3 weeks & if LVEF has not recovered to within 10% points from baseline, Discontinue Do not administer. Repeat within 3 weeks & if LVEF < 40% is confirmed, Discontinue Discontinue