Newly Approved and Emerging Agents in HER2-Positive Metastatic Breast Cancer

Breastcancer.org. Breast cancer facts and statistics. 2022. Available at: https://www.breastcancer.org/symptoms/understand_bc/statistics. Accessed October 6, 2022 American Cancer Society. Cancer facts and figures 2022. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2022/2022-cancer-facts-and-figures.pdf. Accessed February 7, 2022 Mariotto, 2017, Estimation of the number of women living with metastatic breast cancer in the United States, Cancer Epidemiol Biomarkers Prev, 26, 809, 10.1158/1055-9965.EPI-16-0889 Harbeck, 2019, Breast cancer, Nat Rev Dis Primers, 5, 66, 10.1038/s41572-019-0111-2 Moasser, 2007, The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis, Oncogene, 26, 6469, 10.1038/sj.onc.1210477 Onitilo, 2009, Breast cancer subtypes based on ER/PR and HER2 expression: comparison of clinicopathologic features and survival, Clin Med Res, 7, 4, 10.3121/cmr.2008.825 Slamon, 1987, Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene, Science, 235, 177, 10.1126/science.3798106 Wolff, 2018, Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline focused update, J Clin Oncol, 36, 2105, 10.1200/JCO.2018.77.8738 Kamangar E, Bishop J. Current challenges for HER2 immunohistochemistry testing in diagnostic pathology. UC Davis Health Lab Best Practice Blog. 2022. Available at: https://health.ucdavis.edu/blog/lab-best-practice/current-challenges-for-her2-immunohistochemistry-testing-in-diagnostic-pathology/2019/05. Accessed July 21, 2022 Tarantino, 2020, HER2-low breast cancer: Pathological and clinical landscape, J Clin Oncol, 38, 1951, 10.1200/JCO.19.02488 National Comprehensive Cancer Network. Breast cancer (version 4.2023). Available at: https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed March 29, 2023 TUKYSA (tucatinib) [package insert]: Bothell, WA: Seattle Genetics, Inc; 2022. MARGENZA (margetuximab-cmkb) [package insert]: Rockville, MD: MacroGenics, Inc; 2020. ENHERTU (fam-trastuzumab deruxtecan-nxki) [package insert]: Basking Ridge, NJ: Daiichi Sankyo, Inc; Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2022. Lam, 2023, Abstract P4-03-34: treatment patterns and associated outcomes among patients with HER2+ metastatic breast cancer in the United States, Cancer Res, 83, P4-03-34, 10.1158/1538-7445.SABCS22-P4-03-34 Santa-Maria, 2016, Management of metastatic HER2-positive breast cancer: where are we and where do we go from here?, Oncol (Williston Park), 30, 148 Varghese, 2023, Abstract P1-11-19: A real-world evidence study of treatment patterns in patients with HER2-positive metastatic breast cancer who have received at least 2-lines of therapy, Cancer Res, 83, P1-11-19, 10.1158/1538-7445.SABCS22-P1-11-19 US Food & Drug Administration. FDA approves neratinib for metastatic HER2-positive breast cancer. 2020. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neratinib-metastatic-her2-positive-breast-cancer. Accessed July 29, 2022 Xuhong, 2019, Mechanism, safety and efficacy of three tyrosine kinase inhibitors lapatinib, neratinib and pyrotinib in HER2-positive breast cancer, Am J Cancer Res, 9, 2103 Jain, 2015, Current ADC linker chemistry, Pharm Res, 32, 3526, 10.1007/s11095-015-1657-7 Ferraro, 2021, Implementing antibody-drug conjugates (ADCs) in HER2-positive breast cancer: state of the art and future directions, Breast Cancer Res, 23, 84, 10.1186/s13058-021-01459-y HERCEPTIN (trastuzumab) [package insert]: South San Francisco, CA: Genentech, Inc; 2021. PERJETA (pertuzumab) [package insert]: South San Francisco, CA: Genentech, Inc; 2021. Vu, 2012, Trastuzumab: updated mechanisms of action and resistance in breast cancer, Front Oncol, 2, 62, 10.3389/fonc.2012.00062 Greenblatt, 2022, Treasure Islang (FL) Nami, 2018, Mechanisms underlying the action and synergism of trastuzumab and pertuzumab in targeting HER2-positive breast cancer, Cancers (Basel), 10, 342, 10.3390/cancers10100342 TYKERB (lapatinib) [prescribing information]: East Hanover, NJ: Novartis Pharmaceuticals Co.; 2022. Geyer, 2006, Lapatinib plus capecitabine for HER2-positive advanced breast cancer, N Engl J Med, 355, 2733, 10.1056/NEJMoa064320 Verma, 2012, Trastuzumab emtansine for HER2-positive advanced breast cancer, N Engl J Med, 367, 1783, 10.1056/NEJMoa1209124 KADCYLA (ado-trastuzumab emtansine) [package insert]: South San Francisco, CA: Genentech, Inc; 2022. Yver, 2020, The art of innovation: clinical development of trastuzumab deruxtecan and redefining how antibody-drug conjugates target HER2-positive cancers, Ann Oncol, 31, 430, 10.1016/j.annonc.2019.11.019 NERLYNX (neratinib) [package insert]: Los Angeles, CA: Puma Biotechnology, Inc; 2022. Murthy, 2020, Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer, N Engl J Med, 382, 597, 10.1056/NEJMoa1914609 Saura, 2020, Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: findings from the multinational, randomized, phase III NALA trial, J Clin Oncol, 37, 1002 Rugo, 2021, Efficacy of margetuximab vs trastuzumab in patients with pretreated ERBB2-positive advanced breast cancer: a phase 3 randomized clinical trial, JAMA Oncol, 7, 573, 10.1001/jamaoncol.2020.7932 Modi, 2020, Antitumor activity and safety of trastuzumab deruxtecan in patients with HER2-low-expressing advanced breast cancer: results from a phase Ib study, J Clin Oncol, 38, 1887, 10.1200/JCO.19.02318 Baselga, 2012, Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer, N Engl J Med, 366, 109, 10.1056/NEJMoa1113216 Swain, 2015, Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer, N Engl J Med, 372, 724, 10.1056/NEJMoa1413513 Bachelot, 2019, Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy for HER2-positive locally recurrent or metastatic breast cancer (PERUSE), Ann Oncol, 30, 766, 10.1093/annonc/mdz061 Cortés, 2022, Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer, N Engl J Med, 386, 1143, 10.1056/NEJMoa2115022 Diéras, 2017, Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial, Lancet Oncol, 18, 732, 10.1016/S1470-2045(17)30312-1 Bon, 2020, Loss of HER2 and decreased T-DM1 efficacy in HER2 positive advanced breast cancer treated with dual HER2 blockade: the SePHER Study, J Exp Clin Cancer Res, 39, 279, 10.1186/s13046-020-01797-3 Michel, 2020, Progression-free survival and overall survival in patients with advanced HER2-positive breast cancer treated with trastuzumab emtansine (T-DM1) after previous treatment with pertuzumab, Cancers (Basel), 12, 3021, 10.3390/cancers12103021 Vici, 2017, A retrospective multicentric observational study of trastuzumab emtansine in HER2 positive metastatic breast cancer: a real-world experience, Oncotarget, 8, 56921, 10.18632/oncotarget.18176 Hurvitz, 2022, Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial, Lancet, 401, 105, 10.1016/S0140-6736(22)02420-5 Hurvitz, 2022, Abstract GS3-01: Trastuzumab deruxtecan (T-DXd; DS-8201a) vs. trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): subgroup analyses from the randomized phase 3 study DESTINY-Breast03, Cancer Res, 82, GS3 Curigliano, 2022, Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis, Ann Oncol, 33, 321, 10.1016/j.annonc.2021.12.005 Rugo, 2019, SOPHIA primary analysis: a phase 3 (P3) study of margetuximab (M) + chemotherapy (C) versus trastuzumab (T) + C in patients (pts) with HER2+ metastatic (met) breast cancer (MBC) after prior anti-HER2 therapies (Tx), J Clin Oncol, 37, 1000, 10.1200/JCO.2019.37.15_suppl.1000 Rugo, 2022, Abstract PD8-01: Phase 3 SOPHIA study of margetuximab (M) + chemotherapy (CTX) vs trastuzumab (T) + CTX in patients (pts) with HER2+ metastatic breast cancer (MBC) after prior anti-HER2 therapies: Final overall survival (OS) analysis, Cancer Res, 82, PD8 Martínez-Sáez, 2021, Current and future management of HER2-positive metastatic breast cancer, JCO Oncol Pract, 17, 594, 10.1200/OP.21.00172 Koniali, 2020, Risk factors for breast cancer brain metastases: a systematic review, Oncotarget, 11, 650, 10.18632/oncotarget.27453 Zimmer, 2020, HER2-positive breast cancer brain metastasis: a new and exciting landscape, Cancer Rep (Hoboken), 5, e1274, 10.1002/cnr2.1274 Swain, 2014, Incidence of central nervous system metastases in patients with HER2-positive metastatic breast cancer treated with pertuzumab, trastuzumab, and docetaxel: results from the randomized phase III study CLEOPATRA, Ann Oncol, 25, 1116, 10.1093/annonc/mdu133 Haque, 2021, Outcomes following stereotactic radiosurgery or whole brain radiation therapy by molecular subtype of metastatic breast cancer, Rep Pract Oncol Radiother, 26, 341 Lin, 2017, Modernizing clinical trial eligibility criteria: recommendations of the American Society of Clinical Oncology-Friends of Cancer Research Brain Metastases Working Group, J Clin Oncol, 35, 3760, 10.1200/JCO.2017.74.0761 Modi, 2020, Trastuzumab deruxtecan in previously treated HER2-positive breast cancer, N Engl J Med, 382, 610, 10.1056/NEJMoa1914510 Perez-Garcia, 2023, Trastuzumab deruxtecan in patients with central nervous system involvement from HER2-positive breast cancer: The DEBBRAH trial, Neuro Oncol, 25, 157, 10.1093/neuonc/noac144 Bartsch, 2022, 165MO Trastuzumab-deruxtecan (T-DXd) in HER2-positive breast cancer patients (pts) with active brain metastases: primary outcome analysis from the TUXEDO-1 trial, Ann Oncol, 33, S198, 10.1016/j.annonc.2022.03.184 Awada, 2016, Neratinib plus paclitaxel vs trastuzumab plus paclitaxel in previously untreated metastatic ERBB2-positive breast cancer: the NEfERT-T randomized clinical trial, JAMA Oncol, 2, 1557, 10.1001/jamaoncol.2016.0237 von Minckwitz, 2019, Trastuzumab emtansine for residual invasive HER2-positive breast cancer, N Engl J Med, 380, 617, 10.1056/NEJMoa1814017 Williamson, 2019, Ann Oncol, 30, v65, 10.1093/annonc/mdz240.019 Howlader, 2014, US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status, J Natl Cancer Inst, 106, dju055, 10.1093/jnci/dju055 Cronin, 2010, Population-based estimate of the prevalence of HER-2 positive breast cancer tumors for early stage patients in the US, Cancer Invest, 28, 963, 10.3109/07357907.2010.496759 Statler, 2019, Real-world treatment patterns and outcomes in HR+/HER2+ metastatic breast cancer patients: a National Cancer Database analysis, Sci Rep, 9, 18126, 10.1038/s41598-019-54402-9 Hua, 2022, Trastuzumab plus endocrine therapy or chemotherapy as first-line treatment for patients with hormone receptor–positive and HER2-positive metastatic breast cancer (SYSUCC-002), Clin Cancer Res, 28, 637, 10.1158/1078-0432.CCR-21-3435 Yi, 2020, Molecular landscape and efficacy of HER2-targeted therapy in patients with HER2-mutated metastatic breast cancer, NPJ Breast Cancer, 6, 59, 10.1038/s41523-020-00201-9 Jhaveri, 2022, Abstract GS4-10: Neratinib + fulvestrant + trastuzumab for hormone receptor-positive, HER2-mutant metastatic breast cancer and neratinib + trastuzumab for triple-negative disease: Latest updates from the SUMMIT trial, Cancer Res, 82, GS4, 10.1158/1538-7445.SABCS21-GS4-10 Smyth, 2020, Efficacy and determinants of response to HER kinase inhibition in HER2-mutant metastatic breast cancer, Cancer Discov, 10, 198, 10.1158/2159-8290.CD-19-0966 Harbeck, 2018, Impact of PIK3CA mutation status on immune marker response and pCR in the WSG-ADAPT HER2+/HR+ phase II trial, J Clin Oncol, 36, 572, 10.1200/JCO.2018.36.15_suppl.572 Barillet, 2015, Oral antineoplastic agents: how do we care about adherence?, Br J Clin Pharmacol, 80, 1289, 10.1111/bcp.12734 Greer, 2016, A systematic review of adherence to oral antineoplastic therapies, Oncologist, 21, 354, 10.1634/theoncologist.2015-0405 Hackshaw, 2020, Incidence of pneumonitis/interstitial lung disease induced by HER2-targeting therapy for HER2-positive metastatic breast cancer, Breast Cancer Res Treat, 183, 23, 10.1007/s10549-020-05754-8 Hurvitz SA, Gradishar WJ, Tolaney SM. Case 2: addressing ILD associated with HER2-targeted therapy in mBC. MJH Life Sciences and Targeted Oncology, 2022. Available at: https://www.targetedonc.com/view/case-2-addressing-ild-associated-with-her2-targeted-therapy-in-mbc. Accessed August 16, 2022 Conte, 2022, Drug-induced interstitial lung disease during cancer therapies: expert opinion on diagnosis and treatment, ESMO open, 7, 100404, 10.1016/j.esmoop.2022.100404 Tarantino, 2021, Interstitial lung disease induced by anti-ERBB2 antibody-drug conjugates: a review, JAMA Oncol, 7, 1873, 10.1001/jamaoncol.2021.3595 Cobert, 2020, Risk of hepatotoxicity with trastuzumab emtansine in breast cancer patients: a systematic review and meta-analysis, Ther Adv Drug Saf, 11, 1, 10.1177/2042098620915058 Stenger M. Tucatinib in previously treated HER2-positive metastatic breast cancer. The ASCO Post. 2020. Available at: https://ascopost.com/issues/may-25-2020/tucatinib-in-previously-treated-her2-positive-metastatic-breast-cancer. Accessed July 29, 2022 Sharp, 2015, Dose-reduced trastuzumab emtansine: active and safe in acute hepatic dysfunction, Case Rep Oncol, 8, 113, 10.1159/000371720 Jerusalem, 2019, HER2+ breast cancer treatment and cardiotoxicity: monitoring and management, Breast Cancer Res Treat, 177, 237, 10.1007/s10549-019-05303-y Long, 2016, Risk of congestive heart failure in early breast cancer patients undergoing adjuvant treatment with trastuzumab: a meta-analysis, Oncologist, 21, 547, 10.1634/theoncologist.2015-0424 Curigliano, 2016, Cardiotoxicity of anticancer treatments: epidemiology, detection, and management, CA Cancer J Clin, 66, 309, 10.3322/caac.21341 Collier, 2021, Cardiac surveillance for anti-HER2 chemotherapy, Cleve Clin J Med, 88, 110, 10.3949/ccjm.88a.19150 Curigliano, 2021, Updated results of tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB), J Clin Oncol, 39, 1043, 10.1200/JCO.2021.39.15_suppl.1043 Yu X. Comparative study of scalp cooling system and chemical cold cap on prevention of chemotherapy-induced alopecia in women with breast cancer, NCT03711877. 2021. Available at: https://www.clinicaltrials.gov/ct2/show/NCT03711877?term=cold+caps+and+breast+cancer&draw=2&rank=2. Accessed April 6, 2023 Trastuzumab deruxtecan (T-DXd) with or without pertuzumab versus taxane, trastuzumab and pertuzumab in HER2-positive metastatic breast cancer (DESTINY-Breast09). ClinicalTrials.gov identifier: NCT04784715. 2022. Available at: https://clinicaltrials.gov/ct2/show/NCT04784715. Accessed January 17, 2022 A dose-escalation study evaluating the combination of trastuzumab emtansine (T-DM1) with neratinib in women with metastatic HER2-positive breast cancer. ClinicalTrials.gov identifier: NCT02236000. 2020. Available at: https://clinicaltrials.gov/ct2/show/NCT02236000. Accessed January 12, 2022 DZD1516 in combination with trastuzumab and capecitabine, or in combination with T-DM1, in patients with metastatic HER2 positive breast cancer. ClinicalTrials.gov identifier: NCT04509596. 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT04509596. Accessed January 12, 2022 A study of tucatinib vs. placebo in combination with ado-trastuzumab emtansine (T-DM1) for patients with advanced or metastatic HER2+ breast cancer. ClinicalTrials.gov identifier: NCT03975647. 2022. Available at: https://clinicaltrials.gov/ct2/show/NCT03975647. Accessed January 12, 2022 A study of tucatinib (ONT-380) combined with ado-trastuzumab emtansine (T-DM1) in patients with HER2+ breast cancer. ClinicalTrials.gov identifier: NCT01983501. 2020. Available at: https://clinicaltrials.gov/ct2/show/NCT01983501. Accessed January 12, 2022 Borges, 2018, Tucatinib combined with ado-trastuzumab emtansine in advanced ERBB2/HER2-positive metastatic breast cancer: a phase 1b clinical trial, JAMA Oncol, 4, 1214, 10.1001/jamaoncol.2018.1812 A study of tucatinib or placebo with trastuzumab and pertuzumab for metastatic HER2+ breast cancer (HER2CLIMB-05). ClinicalTrials.gov identifier: NCT05132582. 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT05132582. Accessed August 9, 2022 Krop, 2021, HER2CLIMB-04: phase 2 open label trial of tucatinib plus trastuzumab deruxtecan in patients with HER2+ unresectable locally advanced or metastatic breast cancer with and without brain metastases (trial in progress), J Clin Oncol, 39, TPS1097, 10.1200/JCO.2021.39.15_suppl.TPS1097 Andre, 2021, Trastuzumab deruxtecan (T-DXd) combinations in patients with HER2-positive advanced or metastatic breast cancer: a phase 1b/2, open-label, multicenter, dose-finding and dose-expansion study (DESTINY-Breast07), J Clin Oncol, 39, TPS1096, 10.1200/JCO.2021.39.15_suppl.TPS1096 A study of LY3484356 in participants with advanced or metastatic breast cancer or endometrial cancer (EMBER). ClinicalTrials.gov identifier: NCT04188548. 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT04188548. Accessed August 9, 2022 A study to evaluate the efficacy and safety of trastuzumab emtansine in combination with atezolizumab or atezolizumab-placebo in participants with human epidermal growth factor-2 (HER2) positive locally advanced or metastatic breast cancer (BC) who received prior trastuzumab and taxane based therapy (KATE2). ClinicalTrials.gov identifier: NCT02924883. 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT02924883. Accessed January 12, 2022 Emens, 2020, Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive advanced breast cancer (KATE2): a phase 2, multicentre, randomised, double-blind trial, Lancet Oncol, 21, 1283, 10.1016/S1470-2045(20)30465-4 A study of trastuzumab emtansine in combination with atezolizumab or placebo as a treatment for participants with human epidermal growth factor 2 (HER2)-positive and programmed death-ligand 1 (PD-L1)-positive locally advanced (LABC) or metastatic breast cancer (MBC) (KATE3). ClinicalTrials.gov identifier: NCT04740918. 2022. Available at: https://clinicaltrials.gov/ct2/show/NCT04740918. Accessed January 12, 2022 Palbociclib in estrogen receptor positive (ER+) human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer. ClinicalTrials.gov identifier: NCT03709082. 2020. Available at: https://clinicaltrials.gov/ct2/show/NCT03709082. Accessed January 12, 2022 T-DM1 and palbociclib for metastatic HER2 breast cancer (T-DM1). ClinicalTrials.gov identifier: NCT03530696. 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT03530696. Accessed January 12, 2022 Metzger, 2019, Cancer Res, 79, OT3-02-07, 10.1158/1538-7445.SABCS18-OT3-02-07 A study of RC48-ADC administered intravenously to patients with HER2-positive metastatic breast cancer with or without liver metastases. ClinicalTrials.gov identifier: NCT03500380. 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT03500380. Accessed January 12, 2022 Rinnerthaler, 2019, HER2 directed antibody-drug-conjugates beyond T-DM1 in breast cancer, Int J Mol Sci, 20, 1115, 10.3390/ijms20051115 Xu, 2018, An open-label, multicenter, phase Ib study to evaluate RC48-ADC in patients with HER2-positive metastatic breast cancer, J Clin Oncol, 36, 1028, 10.1200/JCO.2018.36.15_suppl.1028 Saura Manich, 2021, LBA15 Primary outcome of the phase III SYD985.002/TULIP trial comparing [vic-]trastuzumab duocarmazine to physician's choice treatment in patients with pre-treated HER2-positive locally advanced or metastatic breast cancer, Ann Oncol, 32, S1288, 10.1016/j.annonc.2021.08.2088 Reiss, 2022, A phase 1, first-in-human (FIH) study of the anti-HER2 CAR macrophage CT-0508 in subjects with HER2 overexpressing solid tumors, J Clin Oncol, 40, 2533, 10.1200/JCO.2022.40.16_suppl.2533 Klichinsky, 2020, Human chimeric antigen receptor macrophages for cancer immunotherapy, Nat Biotechnol, 38, 947, 10.1038/s41587-020-0462-y Geuijen, 2018, Unbiased combinatorial screening identifies a bispecific IgG1 that potently inhibits HER3 signaling via HER2-guided ligand blockade, Cancer Cell, 33, 922, 10.1016/j.ccell.2018.04.003 Bedard, 2022, Abstract P2-13-07: Zanidatamab (ZW25), a HER2-targeted bispecific antibody, in combination with chemotherapy (chemo) for HER2-positive breast cancer (BC): Results from a phase 1 study, Cancer Res, 82, P2-13-07, 10.1158/1538-7445.SABCS21-P2-13-07 Gu, 2022, Bispecific antibody simultaneously targeting PD1 and HER2 inhibits tumor growth via direct tumor cell killing in combination with PD1/PDL1 blockade and HER2 inhibition, Acta Pharmacologica Sinica, 43, 672, 10.1038/s41401-021-00683-8 Mohammadi, 2020, A novel anti-HER2 bispecific antibody with potent tumor inhibitory effects in vitro and in vivo, Front Immunol, 11, 1 Study of DF1001 in patients with advanced solid tumors. ClinicalTrials.gov identifier: NCT04143711. 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT04143711. Accessed February 23, 2022 A study of T-DXd in participants with or without brain metastasis who have previously treated advanced or metastatic HER2 positive breast cancer (DESTINY-B12). ClinicalTrials.gov identifier: NCT04739761. 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT04739761. Accessed January 21, 2022 Hamilton, 2022, Abstract OT1-13-01: HER2CLIMB-04: phase 2 trial of tucatinib+ trastuzumab deruxtecan in patients with HER2+ locally advanced or metastatic breast cancer with and without brain metastases (trial in progress), Cancer Res, 82, OT1-13-01, 10.1158/1538-7445.SABCS21-OT1-13-01 Hamilton, 2023, Abstract OT2-16-03: Phase 3 study of tucatinib or placebo in combination with trastuzumab and pertuzumab as maintenance therapy for HER2+ metastatic breast cancer (HER2CLIMB-05, trial in progress), Cancer Res, 83, OT2-16-03, 10.1158/1538-7445.SABCS22-OT2-16-03 Hamilton, 2022, 162O Primary analysis from DS8201-A-U105: A 2-part, open label, phase Ib trial assessing trastuzumab deruxtecan (T-DXd) with nivolumab (nivo) in patients (pts) with HER2-expressing advanced breast cancer, Ann Oncol, 33, S196, 10.1016/j.annonc.2022.03.181 Trastuzumab deruxtecan with nivolumab in advanced breast and urothelial cancer. ClinicalTrials.gov identifier: NCT03523572. 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT03523572. Accessed November 14, 2022 DS8201a and pembrolizumab in participants with locally advanced/metastatic breast or non-small cell lung cancer. ClinicalTrials.gov identifier: NCT04042701. 2022. Available at: https://clinicaltrials.gov/ct2/show/NCT04042701. Accessed Novemver 10, 2022 A study of pembrolizumab in combination with trastuzumab-DM1. ClinicalTrials.gov identifier: NCT03032107. 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT03032107. Accessed January 12, 2022 4-1BB agonist monoclonal antibody PF-05082566 with trastuzumab emtansine or trastuzumab in treating patients with advanced HER2-positive breast cancer. ClinicalTrials.gov identifier: NCT03364348. 2021. Available at: https://clinicaltrials.gov/ct2/show/NCT03364348. Accessed January 12, 2022 Lo Nigro, 2019, NK-mediated antibody-dependent cell-mediated cytotoxicity in solid tumors: biological evidence and clinical perspectives, Ann Transl Med, 7, 105, 10.21037/atm.2019.01.42