Optimizing Anti-HER2 Therapy in Advanced Breast Cancer: Integrating New Data and Agents Into Practice

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1 Optimizing Anti-HER2 Therapy in Advanced Breast Cancer: Integrating New Data and Agents Into Practice Learning Objectives Discuss recent clinical trials showing survival advantages in the treatment of HER2-positive advanced breast cancer Describe evidence-based management plans for patients with metastatic HER2-positive breast cancer, including issues related to the combination and sequencing of anti-her2 treatment Manage toxicities associated with treatment for breast cancer, including providing appropriate patient education 2 HER2 = human epidermal growth factor receptor 2. Advanced HER2-Positive MBC Anti-HER2 therapy has significantly improved outcomes Meta-analysis of adding anti-her2 therapy to standard treatment 1 22% reduction in the hazard of death 67% increase in RR Trastuzumab is historically the front-line anti-her2 treatment with chemotherapy Also effective with HT in HR-positive disease 15%-25% of patients are HER2 positive 2 About half of these are also HR positive Brain metastases eventually occur in up to half of patients 3 HR = hormone receptor; HT = hormone therapy; MBC = metastatic breast cancer; RR = response rate. 1. Harris C, et al. Ann Oncol. 2011;22: ; 2. Mohd Sharial MS, et al. Ann Oncol. 2012;23:

2 Trastuzumab Has Changed the Natural History of HER2-Positive MBC Patients with HER2-positive MBC now have comparable outcomes to patients with HER2-negative MBC Probability of Survival, % HER2 positive, trastuzumab (n = 191) HER2 negative (n = 1782) HER2 positive, no trastuzumab (n = 118) Months From Diagnosis 4 Dawood S, et al. J Clin Oncol. 2010;28: Anti-HER2 Therapy: Mechanisms of Action 5 AKT = protein kinase B; mtor = mammalian target of rapamycin; PI3K = phosphatidylinositol 3-kinase. Gajria D, et al. Expert Rev Anticancer Ther. 2011;11: First-Line Single-Agent Anti-HER2 Therapy Trastuzumab (n = 111 assessable patients) with MBC ORR = 26% RR: 7% in FISH negative (n = 29); 34% in FISH positive (n = 79) RR: 30% in ER negative (n = 54); 23% in ER positive (n = 52) Lapatinib (n = 138) with locally advanced or MBC All FISH positive ORR = 24% Approximately one-third of patients were HR positive 6 ER = estrogen receptor; FISH = fluorescence in situ hybridization; ORR = overall response rate. Vogel C, et al. J Clin Oncol. 2002;20: ; 2. Gomez HL, et al. J Clin Oncol. 2008;26:

3 First-Line Treatment of HER2-Positive/HR-Positive MBC: Trastuzumab/Anastrozole HER2-positive/ HR-positive MBC without prior therapy for advanced disease (n = 207) R 1:1 Anastrozole 1 mg daily (n = 104) Anastrozole 1 mg daily + trastuzumab (4 mg/kg day 1, then 2 mg/kg weekly) (n = 103) 7 Anastrozole Anastrozole + Trastuzumab P Value CBR (%) Median PFS (months) Median OS (months) Not significant Grade 3/4 AEs higher with combination arm (28%) vs control (16%) All-grade cardiac AEs higher with combination (14 patients vs 2 patients) Grade 3/4 cardiac AEs: 2 patients in each arm AEs = adverse events; CBR = clinical benefit rate (response or stable 6 months); R = randomized. Kaufman B, et al. J Clin Oncol. 2009;27: First-Line Treatment in HER2-Positive/HR-Positive MBC: Letrozole/Lapatinib 1286 patients with HER2-positive/HR-positive MBC were randomized to first-line letrozole + lapatinib (n = 642) or letrozole alone (n = 644) 219 patients were also HER2 positive Significantly improved ORR and CBR with combination Significantly improved PFS (8.2 vs 3.0 months) with combination (P =.019) Patients (%) P = % P = % 29% 23% 20% 14% 15% 11% 4% 5% CR PR SD 6 mo ORR CBR Letrozole 2.5 mg + placebo Letrozole 2.5 mg + lapatinib 1500 mg 8 CR = complete response; PR = partial response; SD = stable disease. Johnston S, et al. J Clin Oncol. 2009;27: Letrozole/Lapatinib Combination: Safety Toxicities With Significant Differences Between Treatment Arms Letrozole + Placebo (n = 624) Letrozole + Lapatinib (n = 654) AE Grade 1 or 2 (%) Grade 3 or 4 (%) Grade 1 or 2 (%) Grade 3 or 4 (%) Diarrhea 19 < Rash Nausea Pruritus Alopecia Treatment-related decline in LV dysfunction was infrequent 5 patients in the combination treatment arm compared with 2 patients in the letrozole monotherapy arm LV = left ventricular. 9 Johnston S, et al. J Clin Oncol. 2009;27:

4 registher: Real-World Evidence registher is a prospective, observational cohort of patients with HER2-positive MBC (N = 1023) In the HER2-positive/HR-positive subgroup (n = 530) First-line trastuzumab + HT conferred significantly longer PFS times than HT alone (13.8 vs 4.8 months) 1.0 Proportion Event-Free 0.8 Trastuzumab + HT (n = 52) 0.6 HT only (n = 54) Unadjusted hazard ratio (95% Cl) = (0.320, 0.756) 0.4 Log-rank test P < PFS (months) 10 Tripathy D, et al. Oncologist. 2013;18: registher: Real-World Evidence (cont d) First-line trastuzumab + chemotherapy and HT conferred significantly longer PFS than trastuzumab + chemotherapy alone (20.4 vs 9.5 months) Sequential use of chemotherapy and HT improved OS times when compared with concurrent use Proportion Event-Free Sequential chemo + HT (n = 107) Concurrent chemo + HT (n = 49) Unadjusted hazard ratio (95% Cl) = (0.554, 1.198) Log-rank test P =.297 Trastuzumab + chemo + HT (n = 156) Trastuzumab + chemo (n = 209) Unadjusted hazard ratio (95% Cl) = (0.407, 0.649) Log-rank test P < PFS (months) 11 Tripathy D, et al. Oncologist. 2013;18: Patient Selection for Anti-HER2/HT Combinations Optimal patient selection for either HT with anti-her2 or chemotherapy and anti-her2 is unknown No studies have directly compared chemotherapy vs HT with anti-her2 agent Potential candidates Bone-only disease Asymptomatic or minimally symptomatic Low tumor burden Pre-existing cardiac dysfunction 12 Giordano S, et al. J Clin Oncol. 2014;32:

5 Case: Nancy Nancy is a 55-year-old woman with a history of stage III, HER2- positive, HR-negative breast cancer treated with adjuvant doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab 5 years ago She presents with persistent cough CT scan shows: 2 right middle/lower lobe nodules (largest is 3.5 cm) 3 smaller lung nodules on left CT-guided biopsy sample of a lung nodule confirms recurrent breast cancer; HR negative, HER2 3+ on immunohistochemistry Brain MRI negative, normal LV function 13 CT = computed tomography; MRI = magnetic resonance imaging. What is the preferred first-line therapy for Nancy??DECISION POINT 1. Capecitabine + lapatinib 2. Trastuzumab alone 3. Trastuzumab + chemotherapy 4. Trastuzumab + pertuzumab + taxane Use your keypad to vote now! 14 First-Line Therapy Options for HER2-Positive, HR-Negative MBC Trastuzumab with chemotherapy Trastuzumab is effective with multiple chemotherapeutic agents (paclitaxel, vinorelbine, docetaxel, or capecitabine) Cross-trial comparisons suggest that all combinations are comparably efficacious and the addition of trastuzumab to chemotherapy improves outcomes Dual HER2 blockade Trastuzumab/pertuzumab/docetaxel: recommended first line in NCCN and ASCO guidelines 1,2 15 ASCO = American Society of Clinical Oncology; NCCN = National Comprehensive Cancer Network. 1. National Comprehensive Cancer Network. breast.pdf. Accessed June 5, 2015; 2. Giordano S, et al. J Clin Oncol. 2014;32:

6 Lapatinib or Trastuzumab With a Taxane as First-Line Therapy HER2- positive MBC without prior therapy for advanced disease (n = 652) R 1:1 Trastuzumab administered weekly or every 3 weeks, depending on taxane choice + taxane Lapatinib orally 1250 mg daily + taxane for 24 weeks, followed by lapatinib alone 1500 mg daily 16 Gelmon K, et al. J Clin Oncol. 2015;33: Lapatinib or Trastuzumab With a Taxane as First-Line Therapy Median PFS (months) ITT population (n = 652) Median PFS (months) centrally confirmed HER2-positive (n = 537) Taxane + Lapatinib Taxane + Trastuzumab Hazard Ratio P Value <.001 Taxane was either paclitaxel 80 mg/m 2 on days 1, 8, and 15 of 28-day cycle, or docetaxel 75 mg/m 2 every 3 weeks OS not significantly different in ITT population; inferior in lapatinib arm in patients with centrally confirmed HER2-positive disease More grade 3 diarrhea and rash with lapatinib 17 ITT = intent to treat. Gelmon K, et al. J Clin Oncol. 2015;33: Dual HER2 Blockade Has Superior Antitumor Activity Tumor Volume (mm 3 ) a a b,c d Days Post Injection b b Control Trastuzumab Lapatinib Trastuzumab + lapatinib Lapatinib + trastuzumab resulted in complete tumor remission in mice 1 Effect was durable: no tumor relapse observed 8 months post completion of treatment Lapatinib induced accumulation of inactive HER2 at plasma membrane Trastuzumab-mediated cytotoxicity was higher with the addition of lapatinib in MCF7/HER2 cells 1 In vivo activity was consistent with in vitro data, demonstrating the combination of lapatinib and trastuzumab as synergistic 2,3 18 a P <.05; b P <.01 vs control; c P <.05 vs trastuzumab; d P <.01 vs both lapatinib and trastuzumab. 1. Scaltriti M, et al. Oncogene. 2009;28: ; 2. Konecny GE, et al. Cancer Res. 2006;66: ; 3. Xia W, et al. Oncogene. 2004;23:

7 CLEOPATRA: First-Line Dual HER2 Blockade HER2-positive MBC without prior therapy for advanced disease (n = 808) R 1:1 Docetaxel (75 mg/m 2 ) + trastuzumab (8 mg/kg cycle 1, then 6 mg/kg) every 3 weeks Control regimen + pertuzumab (840 mg cycle 1, then 420 mg) every 3 weeks Docetaxel + Trastuzumab Docetaxel + Trastuzumab + Pertuzumab P Value Median PFS (months) <.001 Median OS (months) <.001 Results were not adjusted for crossover Pertuzumab extended duration of response by 7.7 months 19 CLEOPATRA = Clinical Evaluation of Pertuzumab and Trastuzumab. Swain SM, et al. Lancet Oncol. 2013;14: ; Swain SM, et al. N Engl J Med. 2015;372: CLEOPATRA: Survival Curves Pertuzumab, 168 events Control, 221 events Months Pertuzumab, 284 events Control, 320 events Months 80 Swain SM, et al. N Engl J Med. 2015;372: Massachusetts Medical Society. OS (%) PFS (%) 40.8 months for placebo vs 56.5 months for pertuzumab 12.4 months for placebo vs 18.7 months for pertuzumab CLEOPATRA: Grade 3 and 4 AEs AE Trastuzumab + Docetaxel + Placebo (n = 397) No. (%) Trastuzumab + Docetaxel + Pertuzumab (n = 407) No. (%) Neutropenia 182 (45.8) 199 (48.9) Febrile 30 (7.6) 56 (13.8) neutropenia Diarrhea 20 (5) 32 (7.9) LV dysfunction 11 (2.8) 5 (1.2) Peripheral 7 (1.8) 11 (2.7) neuropathy Anemia 14 (3.5) 10 (2.5) Dyspnea 8 (2) 4 (1) 21 Baselga J, et al. N Engl J Med. 2012;366:

8 Case (cont d) Nancy is treated with trastuzumab, pertuzumab, and docetaxel After 6 cycles, lung nodules have significantly regressed Right: both nodules are almost 1 cm Left: resolved Major AE: grade 3 peripheral neuropathy LV function: stable 22 What would be your next step in treating Nancy??DECISION POINT 1. Continue treatment with trastuzumab, pertuzumab, and docetaxel 2. Discontinue docetaxel, but continue trastuzumab and pertuzumab 3. Discontinue trastuzumab only 4. Discontinue all treatment Use your keypad to vote now! 23 Duration of Treatment Patients receiving anti-her2 therapy with chemotherapy and no progression: Continue chemotherapy approximately 4-6 months and/or to the time of maximal response, depending on toxicity Continue HER2-targeted therapy; no further change in the regimen is needed until progression or unacceptable toxicities This recommendation is based on the approach used in most of the relevant clinical trials, but it has not been formally studied 24 Giordano S, et al. J Clin Oncol. 2014;32:

9 Case (cont d) Docetaxel is stopped and trastuzumab and pertuzumab are continued Disease remains stable for 9 months, at which time a CT scan shows growth of lung nodules as well as several new liver nodules Nancy feels relatively well Peripheral neuropathy decreased to grade 1 Mild-moderate fatigue LV function remains stable No headaches, and neurological examination is normal 25 What is the preferred second-line therapy for Nancy??DECISION POINT 1. Capecitabine + lapatinib 2. Trastuzumab alone 3. T-DM1 4. Trastuzumab with chemotherapy Use your keypad to vote now! 26 Second-Line Therapy T-DM1 In NCCN and ASCO guidelines, T-DM1 is the preferred therapy for trastuzumab-exposed patients 1,2 Antibody-drug conjugate 3 Trastuzumab is linked to DM1, an antimicrotubule agent Retains mechanism of trastuzumab, delivers cytotoxic agent directly to tumor Shown to be superior to lapatinib + capecitabine, a regimen that had shown increased PFS over capecitabine alone in patients progressing on trastuzumab National Comprehensive Cancer Network. breast.pdf. Accessed June 5, 2015; 2. Giordano S, et al. J Clin Oncol. 2014;32: ; 3. Junttila TT, et al. Breast Cancer Res Treat. 2011;128: ; 4. Cameron D, et al. Oncologist. 2010;15:

10 EMILIA: Phase 3 Trial of T-DM1 vs Lapatinib + Capecitabine in Previously Treated HER2-Positive Breast Cancer HER2-positive MBC previously treated with trastuzumab and a taxane Study arm: T-DM1 at 3.6 mg/kg IV every 3 weeks Control arm: lapatinib 1250 mg daily + capecitabine 1000 mg/m 2 every 12 hours for 14 days of 21-day cycle End Point T-DM1 Lapatinib/Capecitabine P Value n = 495 n = 496 Median PFS (months) <.001 Median OS (months) <.001 n = 397 n = 389 PR or CR (%) < IV = intravenous. Verma S, et al. N Engl J Med. 2012;367: EMILIA: Safety Analysis Rates of grade 3 or 4 AEs were higher in the lapatinib/capecitabine arm (57.0%) than in the T-DM1 arm (40.8%) Most common grade 3 or 4 AEs Lapatinib/capecitabine: hand-foot syndrome (21%) and diarrhea (16%) T-DM1: thrombocytopenia (13%) and elevated LFT results (7%) Bleeding events Any grade Lapatinib/capecitabine: 16% T-DM1: 30% Grade 3 or 4: <2% in both treatment arms LV dysfunction Lapatinib/capecitabine: none T-DM1: 1 patient (grade 3) 29 LFT = liver function test. Verma S, et al. N Engl J Med. 2012;367: TH3RESA: Confirmatory Phase 3 T-DM1 Trial HER2-positive MBC progressing after 2 or more anti-her2 therapies (n = 602) R 2:1 T-DM1 3.6 mg/kg IV every 3 weeks (n = 404) Physicians choice (n = 198) 69%: chemotherapy + trastuzumab 17%: lapatinib + trastuzumab 10%: lapatinib + chemotherapy 2%: HT + trastuzumab Median PFS for T-DM1 was significantly higher than that with physicians choice (6.2 vs 3.3 months; hazard ratio 0.53; P <.0001) Interim OS favored T-DM1, but stopping boundary not crossed (hazard ratio = 0.55; P <.0034) Lower incidence of grade 3 or worse adverse events with T-DM1 (32% vs 43%) 30 Krop I, et al. Lancet Oncol. 2014;15:

11 EGF10499: Lapatinib With Trastuzumab in Patients With Previously Treated HER2-Positive Disease Patients with HER2- positive MBC who progressed during prior trastuzumab regimens (n = 291) R 1:1 Lapatinib 1500 mg daily Lapatinib 1000 mg daily + trastuzumab 2 mg/kg weekly after 4 mg/kg loading dose Lapatinib Lapatinib + Hazard Trastuzumab Ratio P Value Median PFS (weeks) Median OS (months) In both arms, patients had a median of 3 prior trastuzumab regimens Overall AE rates similar in both groups Serious AEs were higher in combination arm (26% vs 16%) 11 patients in combination arm and 3 in lapatinib arm had a cardiac event 31 Blackwell KL, et al. J Clin Oncol. 2012;30: Case (cont d) Nancy is given T-DM1 and her disease is stable for 8 months Grade 2 thrombocytopenia and mildly elevated LFT results occur but do not cause therapy delays After 8 months, her cough returns, and her lung lesions have progressed 32 What would be an appropriate third-line therapy for Nancy? (Select all that apply and then press the send key)?decision POINT 1. Lapatinib + capecitabine 2. Trastuzumab + capecitabine 3. Trastuzumab + lapatinib 4. Trastuzumab + vinorelbine Use your keypad to vote now! 33 11

12 Third-Line Therapy All of these regimens are appropriate for third-line therapy Lapatinib + capecitabine Trastuzumab + capecitabine Trastuzumab + lapatinib Trastuzumab + vinorelbine Clinical trials Reversal of anti-her2 resistance by targeting PI3K/AKT/mTOR pathway 34 PI3K/AKT/mTOR Pathway Involves HR and HER2 ER E PTEN Growth Factors IRS ER PI3K E AKT Overcoming resistance: target pathways known to be upregulated, such as PI3K/AKT/mTOR S6K1 S6 Raptor mtor ER E Translation Nucleus 4E BP1 elf 4E 35 E = estrogen; eif-4e = eukaryotic initiation factor-4e; 4E-BP1 = 4E-binding protein 1; IRS = insulin receptor substrate; PTEN = phosphatase and tensin homolog deleted on chromosome 10; S6 = 40S ribosomal protein; S6K1 = S6 kinase 1. Rugo HS, et al. J Clin Oncol. 2012;30: Targeting mtor Pathway and HER2 Pooled analysis of a phase 1 and phase 2 trial of patients (N = 47) with HER2-positive MBC that had progressed on trastuzumab-based therapy Patients received combination therapy with everolimus and trastuzumab PR rate: 15% Rate of SD 6 months: 19% CBR: 34% Main (nonhematologic) toxicities: fatigue, infection, and mucositis 36 Morrow PK, et al. J Clin Oncol. 2011;29:

13 Targeting mtor Pathway and HER2 (cont d) BOLERO-3: randomized, placebo-controlled, phase 3 trial Patients with HER2-positive breast cancer previously treated with trastuzumab and taxane therapy Patients received combination therapy with weekly trastuzumab (2 mg/kg) and vinorelbine (25 mg/m 2 ) with or without everolimus (5 mg daily) 37 Andre F, et al. Lancet Oncol. 2014;15: BOLERO 3: Targeting mtor and HER2 End Point Trastuzumab + Vinorelbine + Everolimus (n = 284) Trastuzumab + Vinorelbine + Placebo (n = 285) P Value RR (%) PFS (months) OS data not yet mature No unexpected AEs Serious AEs in 42% of patients in everolimus arm, 20% in placebo arm No difference in quality of life between treatment arms Exploratory biomarker analysis: patients with activated PI3K pathways may derive greater benefit from everolimus 38 Andre F, et al. Lancet Oncol. 2014;15: ; Slamon D, et al. J Clin Oncol. 2015;33(suppl): abstract 512. Brain Metastasis in HER2-Positive Breast Cancer Becoming more common with improved systemic therapy Local therapy involves surgery, stereotactic and whole brain radiation At the time of diagnosis of brain metastasis: If systemic disease is not progressive, systemic therapy should not be switched If systemic disease is progressive, administer HER2- targeted therapy according to the algorithms for treatment of HER2-positive MBC Routine surveillance with brain MRI should not be performed However, have a low threshold to test 39 Ramakrishna N, et al. J Clin Oncol. 2014;32:

14 Select Emerging Targeted Therapies for Breast Cancer CDK 4/6 inhibitors LEE011 LY Palbociclib EGFR/HER2 inhibitors Afatinib Neratinib HDAC inhibitors Entinostat Vorinostat Hsp90 inhibitors Retaspimycin Tanespimycin IGF-1R targeted Cixutumumab MEDI-573 PARP inhibitors BMN 673 Iniparib Niraparib Olaparib Rucaparib Veliparib Multitargeted TKIs Axitinib Pazopanib Sorafenib Sunitinib Vandetanib VEGF targeted Aflibercept Ramucirumab CDK 4/6 = cyclin-dependent kinase 4 and 6; EGFR = epidermal growth factor receptor; HDAC = histone deacetylase; Hsp90 = heat shock protein 90; IGF-1R = insulin-like growth factor 1 receptor; PARP = poly (ADP-ribose) polymerase; TKIs = tyrosine kinase inhibitors; VEGF = vascular endothelial growth factor. 40 Perez E, et al. Cancer. 2012;118: ; Finn R, et al. Presented at: San Antonio Breast Cancer Symposium; December 15, 2012; San Antonio, TX. Abstract S1-6. PCE Takeaways Anti-HER2 therapy has improved outcomes in patients with HER2-positive breast cancer Outcomes are improved by dual HER2 targeting and T-DM1 in HER2-positive breast cancer Optimal combinations and sequencing are evolving Targeting mtor pathway may also help overcome anti-her2 therapy resistance Research is ongoing for new effective targeted therapies for breast cancer 41 PCE ACTION PLAN 14

15 PCE Action Plan Individualize therapy based on treatment guidelines and patient factors Recommend dual HER2 blockade with trastuzumab and pertuzumab as first-line therapy in patients with HER2-positive/ HR-negative MBC Consider T-DM1 in patients with HER2-positive MBC previously treated with trastuzumab PCE Promotes Practice Change 43 15