PRACTICE AID HER2, HER3, and TROP2 as Therapeutic Targets in Different Cancers

HER2 Aberrations: Clinical Role and Frequency Across Tumor Types1,2

• HER2 is an established therapeutic target in breast and gastric cancer • HER2 alterations, including overexpression, amplifications, and other mutations, are found in a variety of other solid tumors as well • A number of novel HER2-targeted therapies are being evaluated in breast, gastrointestinal, lung, and other cancers, indicating that the role and impact of these therapies will continue to expand, along with the need for broader HER2 testing

ERBB2 amplifications/mutations and HER2 overexpression have been identified in a range of malignancies

Tumor types HER2 HER2 HER2 amplification (%) overexpression (%) mutation (%)

alivary gland 12–52 17–44 1 ung 2–3 2.5 1–3 reast 20 15–20 2 iliary tract 5–15 20 2 tomach Pancreas 11–16 20 3 2 26 <1 Ovary Colorectum 7 27 1 5.8 5 2

terus ladder 4–69 18–80 2 8.6 12.4 9

Cervix Prostate 0.5~14 21 3 5.8–6 10 <1

Access the activity, “Moving in Leaps and Bounds Toward Expanded Precision Treatment of HER2- or HER3-Driven Breast, Gastrointestinal, Lung, and Other Cancers: Current Challenges, Opportunities for Improvement, and Practical Considerations,” at PeerView.com/VJP40 PRACTICE AID HER2, HER3, and TROP2 as Therapeutic Targets in Different Cancers

Mechanism of Action of Agents Targeting HER21

a. Single-Epitope mAbs b. ADCs c. Bispeci c Antibodies

Inhibition of receptor dimerization Pertuzumab Dual targeting of Promotion of the trastuzumab I II I II Targeted I II receptor Dimerization delivery of and pertuzumab internalization III domain III highly III binding sites and/or Trastuzumab cytotoxic degradation Margetuximab agents IV IV IV Z25 Engagement Trastuzumab emtansine Cell of ADCC Trastuzumab deruxtecan membrane

Direct inhibition of Tyrosine-kinase the downstream domain tyrosine-kinase domain d. Small-Molecule Lapatinib Inhibitors eratinib Tucatinib

Inhibition of PI3-kinase signalling promoting cell-cycle arrest

a. Single-epitope monoclonal antibodies bind HER2 at a single extracellular domain, inhibiting downstream signaling, engaging antibody-dependent cytotoxicity, or inhibiting receptor dimerization b. ADCs also have antitumor effects through these pathways, but they additionally exhibit cytotoxicity by releasing a cytotoxic agent close to HER2-positive tumor cells c. Bispecific antibodies target more than one extracellular region of HER2 d. Small-molecule inhibitors bind the intracellular tyrosine-kinase domain

HER3 and TROP2 as Emerging Therapeutic Targets

HER33 pseudokinase activity, pan-HER approaches, • Crucial heterodimeric partner for other EGFR HER3 ADCs, and HER3 nanobiologic therapeutic family members approaches; select examples: U3-1402 (HER3- • Potential to regulate EGFR/HER2-mediated targeting ADC) and MCLA-128 (HER2–HER3 resistance bispecific antibody) • Enhanced expression associated with several cancers, including lung, breast, ovarian, prostate, TROP24,5 gastric, bladder, melanoma, colorectal, and • Transmembrane glycoprotein overexpressed in squamous cell carcinoma many different tumors, including lung, breast, • Implicated in contributing to treatment failure pancreatic, cervical, ovarian, colorectal, and through activation of PI3K/AKT, MAPK/ERK, and gastric cancers JAK/STAT pathways • Membrane bound with an extracellular domain • HER3-targeting investigational therapies: • Effectively internalized with binding antibody mono and bispecific antibodies targeting • High expression correlates with poor prognosis HER3 at multiple subdomains; miscellaneous • Rational therapeutic target; TROP2-targeting HER3-targeting therapies, including antisense investigational therapies: DS-1062, sacituzumab oligonucleotides, HER3-specific peptide govitecan (IMMU-132), and PF-06664178 vaccines, ligand traps, molecules targeting HER3

ADC: antibody–drug conjugate; ADCC: antibody-dependent cellular cytotoxicity; EGFR: epidermal growth factor receptor; ERBB2: erb-B2 receptor tyrosine kinase 2; ERK: extracellular signal–regulated kinase; HER2: human epidermal growth factor receptor 2; HER3: human epidermal growth factor receptor 3; JAK: Janus kinase; mAb: monoclonal antibody; MAPK: mitogen-activated protein kinase; PI3K: phosphoinositide 3-kinase; STAT: signal transducer and activator of transcription; TROP2: trophoblast cell-surface antigen 2. 1. Oh DY, Bang YJ. Nat Rev Clin Oncol. 2020;17:33-48. 2. Hechtman JF, Ross DS. Cancer Cytopathol. 2019;127:428-431. 3. Mishra R et al. Oncol Rev. 2018;12:355. 4. Guerra E et al. Oncogene. 2013;32:1594-1600. 5. Zeng P et al. Sci Rep. 2016;6:33658. Access the activity, “Moving in Leaps and Bounds Toward Expanded Precision Treatment of HER2- or HER3-Driven Breast, Gastrointestinal, Lung, and Other Cancers: Current Challenges, Opportunities for Improvement, and Practical Considerations,” at PeerView.com/VJP40 PRACTICE AID Timeline of Approvals of HER2-Targeted Therapies in Breast Cancer Focus on Newest Options for Pretreated HER2+ Metastatic Disease

1980s 2006 2008 2013 2019 1998 2007 2012 2017 2020

Neratinib Trastuzumab Lapatinib adjuvant post 1L 2L trastuzumab Pertuzumab MBC MBC 1L Pertuzumab MBC Trastuzumab adjuvant adjuvant Pertuzumab NP T-DM1 Discovery of Trastuzumab neoadjuvant adjuvant HER2 as adjuvant residual oncogenic high-risk T-DM1 driver NN 2L MBC

December 20, 2019 Trastuzumab deruxtecan for patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2–based regimens in the metastatic setting1

February 25, 2020 Neratinib in combination with capecitabine for adult patients with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2–based regimens in the metastatic setting2

April 17, 2020 Tucatinib in combination with trastuzumab and capecitabine for adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received ≥1 prior anti-HER2–based regimens in the metastatic setting3

1L: first line; 2L: second line; HER2: human epidermal growth factor receptor 2; MBC: metastatic breast cancer; NN: node negative; NP: node positive; T-DM1: trastuzumab emtansine. 1. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2-positive-breast-cancer. 2. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neratinib- metastatic-her2-positive-breast-cancer. 3. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tucatinib-patients-her2-positive-metastatic-breast-cancer. Access the activity, “Moving in Leaps and Bounds Toward Expanded Precision Treatment of HER2- or HER3-Driven Breast, Gastrointestinal, Lung, and Other Cancers: Current Challenges, Opportunities for Improvement, and Practical Considerations,” at PeerView.com/VJP40