Oncology Conference Triple-Negative Breast Cancer: Fitting New and - PowerPoint PPT Presentation

2020 Spring Oncology Conference

Triple-Negative Breast Cancer: Fitting New and Emerging Strategies Into Patient Care

Learning Objectives • Summarize the mechanisms of action of available and emerging therapies for TNBC within the context of the underlying tumor biology • Identify the role of new and emerging therapies in the treatment of TNBC • Formulate strategies for the identification and management of toxicities of novel therapies in TNBC 3 TNBC = triple-negative breast cancer.

Features of TNBC Common Features Risk Factors Lacks ER, PR, and HER2 Younger age Family history of breast cancer Subtypes include “basal - like” (>75% of TNBC), immunomodulatory, mesenchymal, mesenchymal stem-like, and African American and High BMI luminal androgen receptor Hispanic women More aggressive clinical course in metastatic setting Underlying BRCA1 Low levels of physical Tends to be higher grade vs other types of breast cancer mutation activity More responsive to chemotherapy vs other types of breast Higher parity Low socioeconomic cancer (≥3 children) conditions Rapid progression from onset of metastasis to death Most deaths occur in first 5 years ER = estrogen receptor; HER2 = human epidermal growth factor receptor 2; PR = progesterone receptor. Audeh MW. Pharmgenomics Pers Med. 2014;7:307-316; Brookes L. www.medscape.com/viewarticle/871606. Accessed Mar 23, 2020; Ismail-Khan R, Bui MM. Cancer Control. 2010;17:173-176; Mustacchi G, De Laurentiis M. Drug Des Devel Ther. 2015;9:4303-4318; 4 Phipps AI, et al. Cancer Epidemiol Biomarkers Prev. 2011;20:454-463; Phipps AI, et al. J Natl Cancer Inst. 2011;103:470-477.

Case Study: Carol, 56 Years Old • Carol reported nodules in her right breast to her gynecologist ‒ No family history of breast or ovarian cancer ‒ Core biopsy: 2-cm high-grade infiltrating ductal carcinoma ‒ Immunohistochemistry: ER/PR/HER2-negative tumor • Carol is diagnosed with TNBC 5

BRCA Testing in Breast Cancer • Testing recommendations include: ‒ Individuals from families with a known BRCA1/2 mutation ‒ Patients with a personal history of breast cancer plus one or more of the following: • Diagnosed ≤45 years of age • Diagnosed between 46 and 50 years with: ‒ An unknown or limited family history • Diagnosed ≤60 years of age with TNBC • Diagnosed at any age with: ‒ An additional primary breast cancer ‒ ≥1 close blood relative with breast cancer ‒ ≥1 close blood relative with high -grade prostate cancer ‒ Male relative with breast cancer ‒ Ashkenazi Jewish ancestry • In metastatic breast cancer: ‒ Assess germline BRCA1/2 mutations to identify candidates for PARP inhibitor monotherapy NCCN.org. www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf. Accessed Mar 23, 2020; NCCN Guidelines. Breast cancer. 6 www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed Mar 23, 2020

Case Study (cont’d) • Immunohistochemistry: ER/PR/HER2-negative tumor with BRCA1 mutation • Staging studies: right breast mass with possible lymph node involvement; no other areas of disease • After neoadjuvant dose dense AC-T chemotherapy, Carol underwent a lumpectomy and was found to have residual disease in her breast and one lymph node with malignant cells, RCB-II • She is treated with adjuvant capecitabine for 6 months • Two years later, Carol comes to see you complaining of intermittent right-upper quadrant pain, fatigue, and unexplained weight loss • A scan shows liver metastases; biopsy confirms mTNBC 7 AC-T = doxorubicin and cyclophosphamide followed by paclitaxel; mTNBC = metastatic triple-negative breast cancer; RCB = residual cancer burden.

PD-L1 Biomarker Testing in TNBC • PD-L1 expression: status can currently help identify patients most likely to benefit from atezolizumab plus nab -paclitaxel ‒ PD-L1 expression occurs mainly on tumor-infiltrating immune cells • Can inhibit anticancer immune responses ‒ PD-L1 expression is defined as negative or positive Keytruda [prescribing information]. Merck & Co, Inc; 2020; NCCN Guidelines. Breast cancer. www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed Mar 23, 2020; Schmid P, et al. N Engl J Med . 2018;379:2108-2121; Tecentriq [prescribing information]. Genentech, Inc; 2019; Vennapusa B, 8 et al. Appl Immunohistochem Mol Morphol . 2019;27:92-100.

PD-L1 Biomarker Testing: Available Assays • SP142 assay: only validated test to predict benefit with atezolizumab plus nab -paclitaxel ⎻ PD- L1 expression: <1% or ≥1% • 22C3 assay: used to select patients for therapy with pembrolizumab ⎻ PD-L1 expression: calculated using CPS • Other assays used for different cancers/immunotherapies CPS = combined positive score. Keytruda [prescribing information]. Merck & Co, Inc; 2020; NCCN Guidelines. Breast cancer. www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed Mar 23, 2020; Schmid P, et al. N Engl J Med . 2018;379:2108-2121; Tecentriq [prescribing information]. Genentech, Inc; 2019; Vennapusa B, 9 et al. Appl Immunohistochem Mol Morphol . 2019;27:92-100.

Overview: Chemotherapy Options for mTNBC • Stage I-III: HER2-Negative Neoadjuvant or Preferred regimens adjuvant Anthracyclines PARP inhibitors (for HER2-negative tumors Platinum (for triple-negative tumors • Doxorubicin, liposomal doxorubicin and germline BRCA1/2 mutation) and germline BRCA1/2 mutation) chemotherapy + • • Taxanes Olaparib Carboplatin • • • surgery Paclitaxel Talazoparib Cisplatin Antimetabolites Atezolizumab + albumin-bound • Stage IV: • Capecitabine, gemcitabine paclitaxel (for PD-L1-positive Microtubule inhibitors TNBC) chemotherapy • Vinorelbine, eribulin alone Other recommended regimens • Choice and order Cyclophosphamide Albumin-bound paclitaxel Epirubicin Docetaxel Ixabepilone of chemotherapy Useful in certain circumstances depends on Doxorubicin/cyclophosphamide Docetaxel/capecitabine Gemcitabine/carboplatin multiple factors Epirubicin/cyclophosphamide Gemcitabine/paclitaxel Paclitaxel/bevacizumab Cyclophosphamide/methotrexate/ Carboplatin/albumin-bound fluorouracil paclitaxel Carboplatin/paclitaxel Ehab M, Elbaz M. Breast Cancer (Dove Med Press). 2016;8:83-91; NCCN Guidelines. Breast cancer. www.nccn.org/ 10 professionals/physician_gls/pdf/breast.pdf. Accessed Mar 23, 2020; Schwartz KL, et al. Cancer. 2018;124:2104-2114.

Paclitaxel vs Nab -Paclitaxel: Taxane Derivatives • Taxane therapy indicated in the adjuvant and metastatic setting • Paclitaxel is a poorly water soluble, potent microtubule inhibitor that is a taxane derivative • Nab -paclitaxel: nanoparticle, albumin-bound injectable version of paclitaxel ‒ Eliminates use of polyoxyethylated castor oil (Cremophor EL), a cause of toxicity in patients receiving taxane therapy ‒ Shorter infusion time ‒ Does not require premedication with corticosteroids for hypersensivity reactions ‒ Uses albumin transport mechanisms to form concentrations within the tumor Abraxane [prescribing information]. Celgene Corporation; 2018; Al-Hajeili M, et al. Oncol Targets Ther . 2014;7:187-192; Taxol [prescribing information]. Bristol-Myers Squibb Company; 2011; Waks AG. www.lbbc.org/learn/treatments-and-research/chemotherapy/types-chemotherapy/nab- 11 paclitaxel. Accessed Mar 23, 2020.

Immune Checkpoint Inhibitors: Mechanism of Action • Compared with other subtypes, TNBC is associated with higher prevalence of tumor infiltrating lymphocytes and higher rates of PD-L1 positivity • Checkpoint pathways regulate the immune system and help prevent autoimmune responses ‒ Cancers may evade destruction by the immune system by co-opting the CTLA-4 and PD-1 immune checkpoint pathways • Immune checkpoint inhibitors: ‒ Target CTLA-4, PD-1, PD-L1 ‒ Block cancer cells from using the checkpoint pathway ‒ Allow re-establishment of the immune response Brahmer JR, et al. J Clin Oncol. 2018;36:1714-1768; Buchbinder EI, Desai A. Am J Clin Oncol. 2016;39:98-106; Dine J, et al . Asia Pac J Oncol 12 Nurs . 2017;4:127-135; Katz H, Alsharedi M. Med Oncol . 2017;35:13; Shimelis H, et al. J Natl Cancer Inst. 2018;110:855-862.

IMpassion130: Atezolizumab + Nab -Paclitaxel in PD-L1 + mTNBC 100 Median OS, mo Population HR (95% CI) 90 A + nab -P P + nab -P 80 PD-L1 IC+ 25.0 18.0 0.71 (0.54, 0.94) 70 PD- L1 IC− 19.6 19.6 0.99 (0.80, 1.23) 60 OS (%) 50 40 30 • Improved OS in A + nab -P (PD-L1+ n = 185) P + nab -P (PD-L1+ n = 184) 20 PD-L1 – positive A + nab -P (PD- L1− n = 266) P + nab -P (PD- L1− n = 267) 10 patients 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Time (months) Clinical cutoff date: January 2, 2019. A = Atezolizumab; CI = confidence interval; IC = immune cell; HR = hazard ratio; ITT = intent to treat; nab -P = nab- paclitaxel; OS = overall survival; P = placebo. 13 Schmid P, et al. Lancet Oncol. 2020;21:44-59.

IMpassion130: Progression-free Survival in PD-L1 + mTNBC 100 Median OS, mo A + nab -P (PD-L1+ n = 185) Population HR (95% CI) P + nab -P (PD-L1+ n = 184) A + nab -P (PD- L1− n = 266) A + nab -P P + nab -P 90 P + nab -P (PD- L1− n = 267) PD-L1+ (41%) 7.5 mo 5.3 mo 0.63 (0.50, 0.80) 80 PD-L1- (59%) 5.6 mo 5.6 mo 0.93 (0.77, 1.11) 70 60 PFS (%) 50 40 30 20 10 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Months PFS = progression-free survival. 14 Schmid P, et al. Lancet Oncol. 2020;21:44-59.