touchEXPERT OPINIONS

Why novel treatment options are needed for HER2-positive advanced breast cancer Disclaimer • Unapproved products or unapproved uses of approved products may be discussed by the faculty; these situations may reflect the approval status in one or more jurisdictions • The presenting faculty have been advised by touchIME to ensure that they disclose any such references made to unlabelled or unapproved use • No endorsement by touchIME of any unapproved products or unapproved uses is either made or implied by mention of these products or uses in touchIME activities • touchIME accepts no responsibility for errors or omissions Why novel treatment options are needed for HER2-positive advanced breast cancer

Dr Eva Ciruelos

Multidisciplinary Breast Cancer Unit University Hospital 12 de Octubre HM Hospitals Madrid, Spain Treatment HER2-positive advanced breast cancer ESMO clinical practice guidelines

Patient with ER-positive/HER2-positive advanced breast cancer* Continue First line ChT + pertuzumab + trastuzumab or ChT + trastuzumab anti-HER2 treatment Progression through multiple Second line Trastuzumab emtansine (T-DM1) lines of therapy Later lines Trastuzumab in combination with an Trastuzumab + unused ChT agent or ET if appropriate lapatinib + ET, if not previously used

Additional anti-HER2 therapy and Maintenance ET + anti-HER2 therapy ChT or ET

Note: Include in clinical trials when available *Previously treated (neo)adjuvantly with anti-HER2 therapy.

ChT, chemotherapy ET, endocrine therapy; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; T-DM1, trastuzumab emtansine. Cardoso F, et al. Ann Oncol. 2018;29:1634–57. Supplement. Available at: https://www.esmo.org/content/download/181639/3308758/1/Clinical-Practice-Guidelines-Slideset- Advanced-Breast-Cancer.pdf (Accessed. 25 September 2020). Mechanisms of anti-HER2 therapy resistance

Mechanisms of resistance Example factors involved Altered or impaired HER2 binding/signalling Low HER2 levels, p95HER2, MUC4 expression, HER2 mutations Parallel/downstream signalling pathways Splicing variants (p95HER2; Δ16 HER2), NRG, HER2-HER3, PI3KCA mutations, FGFR1 amplifications, PI3K/AKT/mTOR pathway alterations Enhanced lipid metabolism PI3KCA mutations, PTEN loss ER signalling FASN, ER-PgR expression, PI3KCA mutations Cell cycle regulation ER-PgR expression, cyclin D1-CDK4/6 expression Escape from ADCC Poor binding to CD16A, cyclin D1-CDK4/6 expression FGFR1 signalling HER2 mutations T-DM1 internalisation/release SLC46A3, MDR1

• No single mechanism or pathway accounts for HER2 therapy resistance • Defining the best strategies to delay or revert resistance to anti-HER2 therapy is crucial to improve clinical efficacy ADCC, antibody-dependent cellular cytotoxicity; CD16A, Fc receptor FcγRIIIa; CDK4/6, cyclin-dependent kinase 4/6; ER, estrogen receptor; FASN, fatty acid synthase; FGFR1, fibroblast growth factor receptor 1; HER2, human epidermal growth factor receptor 2; HER3, human epidermal growth factor receptor 3; MDR1, multi-drug resistance; MUC4, mucin 4; NRG, neuregulin; PgR, progesterone receptor; PI3K/AKT/mTOR, phosphatidylinositol-3 kinase/protein kinase B/mammalian target of rapamycin signalling pathway; PTEN, phosphate=ase and tensin homolog; SLC46A3, solute carrier family 46 member 3; T-DM1, trastuzumab emtansine Vernieri C, et al. Crit Revs in Onc/Hemat. 2019;139:53–66. Current and emerging HER2-targeted antibody–drug conjugates

Trastuzumab emtansine (T-DM1)1 Trastuzumab-deruxtecan (DS-8201a)2 Trastuzumab-duocarmazine (SYD985)3,4

Immunoconjugate of Immunoconjugate of Immunoconjugate of trastuzumab with a microtubule trastuzumab with a topoisomerase I trastuzumab with DNA alkylating inhibitor agent (DM1, derivative of inhibitor (DXd) payload, an exatecan agent, seco-DUBA maytansine) derivative

Classical MoA Bystander killing effect MoA Classical and bystander killing effect • ADC binds HER2 receptor • ADC binds HER2 receptor MoA • Internalized by endocytosis • Payload released before • ADC binds HER2 receptor • Linker cleavage by lysosomal internalization • DNA alkylation and high enzymes and payload release • High drug–membrane drug–-membrane permeability • Cytotoxicity permeability and cytotoxicity • Cytotoxicity

• Anti-HER2 function of • Anti-HER2 function of • Anti-HER2 function of trastuzumab trastuzumab (including in HER2- trastuzumab (including in HER2- • DM1-induced cytotoxicity low models) low models) • DAR: 3.5:1 • DXd-induced cytotoxicity with • Duocarmycin-mediated DNA high cell membrane permeability damage and bystander killing • DAR: 7–8:1 with high cell membrane permeability (DAR: 2.8:1)

ADC, antibody–drug conjugate; DAR, drug to antibody ratio; HER2, human epidermal growth factor receptor 2; MoA, mechanism of action; seco-DUBA, seco-duocarmycin- hydroxybenzamide-azaindole. 1. Barok M et al. Breast Cancer Res. 2014;16:209. 2. Ogitani Y, et al. Cancer Sci. 2016;107:1039–46. 3. Elgersma RC, et al. Mol Pharm. 2015;12:1813–35. 4. Nadal-Serrano M, et al. Cancers (Basel). 2020;12(3):670. Novel HER2-targeted tyrosine kinase inhibitors

Neratinib1,2 Tucatinib3,4

• Irreversible, pan-HER TKI1 • Reversible TKI, selective for HER2 relative to EGFR3

• Inhibits EGFR (HER1), HER2 and HER4 • Inhibits HER2 and HER3 phosphorylation at phosphorylation at intercellular binding intercellular binding domains3 domains1 • Prevents activation of proliferative • Prevents activation of proliferative pathways pathways MAPK/Erk1/2 and PI3K/Akt3 MAPK/Erk1/2 and PI3K/Akt1

• Capacity to be used in combination with • Capacity to be used in combination with trastuzumab and vinorelbine2 trastuzumab and capecitabine3,4 • More potent and consistent inhibitory effect in • Indicated in patients with feasible resistance pathways vs lapatinib1 brain metastases3

Akt, protein kinase B; EGFR, epidermal growth factor receptor; Erk1, extracellular signal-regulated kinase 1; HER2, human epidermal growth factor receptor 2; MAPK, mitogen-activated protein kinase; PI3K, phosphoinositide 3-kinase; TKI, tyrosine kinase inhibitor. 1. Collins DM, et al. Cancers. 2019;11:737. 2. Awada A, et al. Anal Oncol. 2013;24:109–116. 3. Kulukan A, et al. Mol Cancer Ther. 2020;19:976–987. 4. Murthy RK, et al. N Engl J Med. 2020;382:597–609. Leveraging ADCC to enhance anti-HER2 therapy

Margetuximab1,2

• Derived from trastuzumab • Chimeric anti-HER2 monoclonal antibody with specificity and affinity similar to trastuzumab1 • Fc domain engineered for increased binding to both alleles of human CD16A1

• Glycosylated Fc increases binding affinity for CD16A with high affinity for both 158V (high binding) and 158F (low binding) alleles1 • Enhances clonality of the T-cell repertoire and induction of HER2-specific T- and B-cell responses2

• The optimized Fc domain confers enhanced ADCC against all HER2-positive tumour cells tested, including cells resistant to trastuzumab's anti-proliferative activity or expressing low HER2 levels3

• TrasGex, a second-generation anti-HER2 monoclonal antibody with specificity and affinity similar to trastuzumab, is also under development (phase I) for HER2-positive breast cancer4

ADCC, antibody-dependent cellular cytotoxicity; BC, breast cancer; HER2, human epidermal growth factor receptor 2. 1. Bang YJ, et al. Anal Oncol. 2017;28:855–61. 2. Rugo HS, et al. Cancer Res. 2020. Abstract GS1–02. 3. Nordstrom et al. Breast Cancer Research. 2011;13:R123. 4. Fieldler W, et al. ESMO Open. 2018;3:e000381.