Faculty Information Laura Bobolts, PharmD, BCOP Danielle Roman, - PowerPoint PPT Presentation

Faculty Information Laura Bobolts, PharmD, BCOP Danielle Roman, PharmD, BCOP Senior Vice President, Clinical Strategy Manager, Clinical Pharmacy Services and Growth Allegheny Health Network Oncology Analytics, Inc Pittsburgh, Pennsylvania Plantation, Florida Andrea Iannucci, PharmD, BCOP Assistant Chief Pharmacist, Oncology and Investigational Drugs Services PGY2 Oncology Pharmacy Residency Program Director, UC Davis Health Clinical Professor, UC Davis School of Medicine UCSF School of Pharmacy Sacramento, California

Educational Objectives After completion of this activity, participants will be able to: • Explain the pathophysiology, prognosis, and challenges of treating metastatic triple-negative breast cancer (TNBC) • Analyze the clinical and safety evidence to support current and emerging therapies and treatment algorithms for TNBC • Explore the economic impact of TNBC and identify strategies to optimize medication therapy for patients with TNBC

Metastatic Triple-Negative Breast Cancer Danielle Roman, PharmD, BCOP Manager, Clinical Pharmacy Services Allegheny Health Network Pittsburgh, Pennsylvania

Triple-Negative Breast Cancer (TNBC) • Lack of expression of ER, PR, and absence of HER2 overexpression TNBC • Most fatal subtype of breast cancer • Generally displays a short time to relapse • 5-year OS for metastatic TNBC = 11% ER, estrogen receptor; PR, progesterone receptor; OS, overall survival Breast cancer facts and figures, 2019-2020 . ACS. Published 2019. Accessed August 14, 2020. Sharma P. The Oncologist. 2016;21:1050-1062; Triple-negative breast cancer. American Cancer Society (ACS). Accessed November 3, 2020. cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/breast-cancer-facts- cancer.org/cancer/breast-cancer/understanding-a-breast-cancer- and-figures/breast-cancer-facts-and-figures-2019-2020.pdf diagnosis/types-of-breast-cancer/triple-negative.html

Clinical Features of TNBC • Aggressive natural history • Worse prognosis compared with hormone receptor (HR)-positive breast cancer • High 5-year recurrence rate for early-stage disease, which peaks 2-3 years after diagnosis • High propensity for brain and lung metastases • Median OS for metastatic TNBC is 12-18 months • More commonly seen in the following women: • Younger • Obese • Premenopausal • African American Lebert JM, et al. Curr Oncol 2018;25:S142-150; Azim HA, et al. Breast J. 2020;26:69-80.

Pathologic and Molecular Features of TNBC • High pathologic grade • Molecular heterogeneity • Strong correlation with BRCA1/2 mutation status • 15%-20% of patients with TNBC demonstrate a germline BRCA mutation • Somatic p53 mutations are common but not clinically actionable • Tumor-infiltrating lymphocyte (TIL) infiltration is more common than other subtypes • Basal-like subtype is the most common intrinsic subtype by gene expression analysis • P13K activation is common Sharma P. The Oncologist. 2016;21:1050-1062; Azim HA, et al. Breast J. 2020;26:69-80; Lebert JM, et al. Curr Oncol. 2018;25:S142-150.

Biomarker Testing in Metastatic TNBC Breast cancer subtype Biomarker Detection FDA-approved agents Any BRCA1/2 mutation Germline sequencing Olaparib Talazoparib Any NTRK fusion FISH, NGS, PCR Larotrectinib (tissue block) Entrectinib Any MSI-H/dMMR IHC, PCR (tissue block) Pembrolizumab Any TMB-H NGS Pembrolizumab Triple negative PD-L1 expression IHC Atezolizumab + albumin- (considered positive if ≥1% on bound paclitaxel tumor-infiltrating immune cells) BRCA, breast cancer gene; dMMR, deficient mismatch repair; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; MSI-H, microsatellite instability-high; NGS, next-generation sequencing; NTRK, neurotrophic tropomyosin receptor kinase; PCR, polymerase chain reaction; TMB-H, tumor mutational burden-high. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Breast Cancer, v6.2020; Keytruda. Prescribing information. Merck & Co, Inc; October 2020.

Treatment Options for Metastatic Breast Cancer Hormonal therapies HER2-targeted agents Chemotherapy PARP inhibitors Immunotherapy (for germline (for PD-L1+) BRCA1/2 mutation) NCCN Clinical Practice Guidelines in Oncology. Breast Cancer, v6.2020.

Treatment Options for Metastatic TNBC Hormonal Therapies HER2-targeted agents Chemotherapy PARP inhibitors Immunotherapy (for germline (for PD-L1+) BRCA1/2 mutation) NCCN Clinical Practice Guidelines in Oncology. Breast Cancer, v6.2020.

Factors Influencing Treatment Decision Patient preferences Tumor Previous burden treatment Performance status Rate of disease progression Lebert JM, et al. Curr Oncol. 2018;25:S142-S150.

Treatment Algorithm Metastatic TNBC Germline BRCA1/2 PD-L1 negative; no NTRK fusion PD-L1 positive MSI-H; mutation germline BRCA1/2 dMMR mutation Larotrectinib Olaparib Atezolizumab + nab- Pembrolizumab Entrectinib Talazoparib paclitaxel Chemotherapy NCCN Clinical Practice Guidelines in Oncology. Breast Cancer, v6.2020.

Chemotherapy Options: Preferred Regimens First or Subsequent Lines Anthracyclines Microtubule inhibitors • Doxorubicin • Vinorelbine • Liposomal doxorubicin • Eribulin Chemotherapy + immunotherapy (PD-L1+) Taxanes • Atezolizumab + albumin-bound paclitaxel • Paclitaxel Platinum (for germline BRCA1/2 mutation) Antimetabolites • Carboplatin • Capecitabine • Cisplatin • Gemcitabine NCCN Clinical Practice Guidelines in Oncology. Breast Cancer, v6.2020.

Use of Taxanes in mTNBC Agent Every 3 weeks Weekly Adverse effects (AEs) 35 mg/m 2 IV • 60-100 mg/m 2 IV Docetaxel Edema (↓ with steroid 6 weeks on/2 weeks off prophylaxis), myelosuppression (neutropenia); GI AEs — stomatitis, N/V/D • Should not be used with liver dysfunction • 175 mg/m 2 IV 80 mg/m 2 IV Paclitaxel Neuropathy and myalgias, infusion- related reactions • May be used with mild-moderate liver dysfunction 100-125 mg/m 2 IV • 260 mg/m 2 IV Albumin bound/ Shorter infusion time/less risk of nab-paclitaxel 3 weeks on/1 week off reactions; does not require steroid premedication GI, gastrointestinal; IV, intravenous; N/V/D, nausea/vomiting/diarrhea. Mauri D, et al. Cancer Treat Rev . 2010;36(1):69-74.

TNT Trial: Carboplatin vs Docetaxel in Advanced TNBC or BRCA1/2 + Breast Cancer Median PFS Carboplatin Docetaxel P value All patients 3.1 months 4.4 months 0.4 BRCA1/2 6.8 months 4.4 months 0.002 patients • PFS favored carboplatin in the BRCA1/2 group • No OS benefit found; carboplatin = 12.8 months and docetaxel = 12 months • More grade 3/4 AEs in the docetaxel group Conclusion: Data from this trial confirm that carboplatin is active in BRCA1/2 -mutated advanced breast cancer. Carboplatin is a viable option for treatment of patients with breast cancer with BRCA1/2 mutation. • Significantly improved response to carboplatin in BRCA1/2 patients ORR, objective response rate; PFS, progression-free survival. • ORR 68% vs 33% Tutt A, et al. Nat Med . 2018;(24)5:628-637.

EMBRACE: Eribulin 2:1 n = 508 Eribulin 1.4 mg/m 2 IV R Days 1, 8 every 21 days A Study design: phase 3, N open-label D N = 762 O • Locally recurrent or M metastatic disease I • n = 254 2-5 previous Z Treatment of physician’s chemotherapy regimen E choice (TPC) D Included 19% patients with TNBC. • Primary end point: OS improved with eribulin vs TPC (13.1 mo vs 10.6 mo; HR, 0.81; P = 0.041) • FDA approved for patients with metastatic breast cancer who have received ≥ 2 prior therapies for metastatic disease (including anthracycline and taxane) Cortes J, et al. Lancet. 2011;377:914-923.

Other Chemotherapy Options First or Subsequent Lines Recommended regimens: Useful in certain circumstances: • • Cyclophosphamide AC (doxorubicin/cyclophosphamide) • • Docetaxel EC (epirubicin/cyclophosphamide) • • Albumin-bound paclitaxel CMF (cyclophosphamide/methotrexate/fluorouracil) • • Epirubicin Docetaxel/capecitabine • • Ixabepilone GT (gemcitabine/paclitaxel) • • Sacituzumab govitecan-hziy* Gemcitabine/carboplatin • Paclitaxel/bevacizumab • Carboplatin + paclitaxel or albumin-bound paclitaxel *Recommended for patients who have received ≥ 2 prior therapies for metastatic disease. NCCN Clinical Practice Guidelines in Oncology. Breast Cancer, v6.2020.

ASCENT: Sacituzumab Govetecan-hziy N = 108 patients • Study design: open- mTNBC Sacituzumab govetecan-hziy • label, basket design, Received ≥2 previous 10 mg/kg IV days 1, 8 every 21 days phase 1/2 anticancer therapies for metastatic disease • ORR (primary end point) = 33.3% (3 complete response; 33 partial response) • Median DOR = 7.7 months • Clinical benefit rate = 45.4% FDA approved for treatment of • PFS = 5.5 months patients with metastatic TNBC who have received ≥ 2 prior • OS = 13 months therapies for metastatic disease. DOR, duration of response. Bardia A, et al. N Eng J Med. 2019;380:741-751.

Key Points: Role of Chemotherapy • Generally chemotherapy-sensitive • Single-agent versus combination chemotherapy • Patients who require rapid response may benefit from combination therapy despite added toxicity • Continue until disease progression or unacceptable toxicity • Most patients will receive multiple lines of systemic therapy as palliation Azim HA, et al. Breast J. 2020;26:69-80; NCCN Clinical Practice Guidelines in Oncology. Breast Cancer, v6.2020.