Expert Opinion on Biological Therapy

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Trastuzumab deruxtecan in HER2-positive metastatic breast cancer and beyond

Jose Perez, Laia Garrigós, Maria Gion, Pasi A. Jänne, Kohei Shitara, Salvatore Siena & Javier Cortés

To cite this article: Jose Perez, Laia Garrigós, Maria Gion, Pasi A. Jänne, Kohei Shitara, Salvatore Siena & Javier Cortés (2021): Trastuzumab deruxtecan in HER2-positive metastatic breast cancer and beyond, Expert Opinion on Biological Therapy, DOI: 10.1080/14712598.2021.1890710 To link to this article: https://doi.org/10.1080/14712598.2021.1890710

© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

Published online: 01 Apr 2021.

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Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=iebt20 EXPERT OPINION ON BIOLOGICAL THERAPY https://doi.org/10.1080/14712598.2021.1890710

DRUG EVALUATION Trastuzumab deruxtecan in HER2-positive metastatic breast cancer and beyond Jose Pereza,b, Laia Garrigósa, Maria Gionc,d, Pasi A. Jännee, Kohei Shitaraf, Salvatore Sienag,h and Javier Cortésa,b,i aInternational Breast Cancer Center, Quiron Group, Barcelona, Spain; bMedical Department, Medica Scientia Innovation Research (MedSIR), Valencia, Spain; cQuironsalud Group, Madrid, Spain; dDepartment of Medical Oncology, Hospital Universitario Ramón Y Cajal, Madrid, Spain; eDepartment of Medical Oncology, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; fDepartment of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan; gDepartment of Oncology and Hematology-Oncology, Università Degli Studi Di Milano, Milan, Italy; hNiguarda Cancer Center Grande Ospedale Metropolitano Niguarda, Milan, Italy; iDepartment of Medical Oncology, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain

ABSTRACT ARTICLE HISTORY Introduction: Despite the substantial improvements made in human epidermal growth factor Received 24 November 2020 receptor 2 (HER2)–targeted therapies since the approval of trastuzumab more than 20 years ago, Accepted 11 February 2021 there is still considerable unmet need in patients with HER2-expressing breast cancer (BC) and other KEYWORDS solid tumors. Trastuzumab deruxtecan (T-DXd) is a newer antibody-drug conjugate approved for the Antibody-drug conjugate; treatment of metastatic breast cancer (BC) and gastric cancer (GC) and is under active investigation breast cancer; colorectal in other solid tumors, including non–small cell lung cancer, colorectal cancer, and HER2-low tumors. cancer; DS8201; gastric Areas covered: The current treatment and investigational landscape of HER2-positive and HER2- cancer; HER2-positive; HER2 low metastatic BC (mBC) and the preclinical and clinical trials investigating T-DXd. To identify targeted; non–small cell relevant literature, a search was performed on English-language publications and congress lung cancer; t-DXd; abstracts. trastuzumab deruxtecan Expert opinion: T-DXd is likely to become the standard of care for second-line treatment of HER2- positive mBC, and it may play a role in the treatment of hormone receptor–positive and triple-negative mBC with HER2-low expression. Because it was recently approved in the United States and Japan to treat HER2-positive metastatic GC, it holds promise for the treatment of other HER2-positive solid tumors, including colorectal cancer, non–small cell lung cancer, and HER2-low BC.

1. Introduction humanized monoclonal antibodies that target different regions of the extracellular domain of HER2 [4]. In the phase 1.1. Human epidermal growth factor receptor 2–positive 3 CLEOPATRA trial, the combination of trastuzumab, pertuzu­ breast cancer mab, and docetaxel resulted in a substantial improvement in In women, breast cancer (BC) is the most commonly diag­ median progression-free survival (mPFS; 18.7 months, 95% CI, nosed cancer type and the leading cause of cancer-related 17–22) compared with trastuzumab, placebo, and docetaxel death worldwide [1]. The presence or absence of human (12.4 months, 10–14; hazard ratio [HR], 0.69; 95% CI, 0.59–0.81) epidermal growth factor receptor 2 (HER2) and hormone and in median overall survival (mOS; 57.1 months vs receptor expression on tumor cells determines treatment 40.8 months; HR, 0.69; 0.58–0.82) in patients with HER2- course and prognosis [2,3]. In HER2-positive tumors, amplifica­ positive metastatic BC (mBC) without prior chemotherapy or tion of the ERBB2 gene leads to overexpression of HER2 [4,5]. biologic therapy [14]. From a biological perspective, about 15–20% of all BCs are Upon disease progression, patients can be treated with HER2-positive and are associated with poorer prognosis and the antibody-drug conjugate (ADC) trastuzumab emtansine are more likely to metastasize [6–8]. (T-DM1), which is the standard-of-care second-line treat­ ment [2,3,9]. T-DM1 comprises 3.0–3.6 molecules of emtan­ sine, a microtubule inhibitor, bound to trastuzumab via 1.2. Current treatment practices for HER2-positive a noncleavable thioether linker [15]. The safety and efficacy advanced breast cancer of T-DM1 has been tested as second-line therapy or later in Although HER2-positive BC is considered an aggressive sub­ two phase 3 clinical trials [16–18]. In the pivotal EMILIA trial, type of cancer with a high rate of recurrence and worse out­ T-DM1 compared with the combination of lapatinib and comes, the development of HER2-targeted therapies has capecitabine significantly improved mPFS (9.6 months vs provided treatment options [2,3,9–13]. Current guidelines 6.4 months; HR, 0.65; 95% CI, 0.55–0.77; P < 0.001) and recommend initial treatment with a combination of two HER2- mOS (30.9 months vs 25.1 months; HR, 0.68; 0.55–0.85; targeted antibodies, trastuzumab and pertuzumab, in combi­ P < 0.001) in patients with HER2-positive locally advanced nation with a taxane [2,3,9]. Trastuzumab and pertuzumab are or mBC who had been treated previously with trastuzumab

CONTACT Javier Cortés [email protected] International Breast Cancer Center, Quiron Group, Barcelona, Spain © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. 2 J. PEREZ ET AL.

needed. This expert opinion highlights the newer ADC Article highlights T-DXd, which has been approved in the United States, Japan, and Europe for metastatic HER2-positive BC and in the United ● HER2-positive breast cancer has a high rate of recurrence and poor prognosis, but recent advances in HER2-targeted therapies have States and Japan for HER2-positive unresectable advanced or provided treatment options recurrent GC indications. It is also being evaluated in ● However, there is still an unmet need in patients with HER2- advanced HER2-low BC and GC and in CRC and NSCLC in expressing breast cancer and other solid tumors because of develop­ ment of resistance to HER2-targeted therapies and lack of options in ongoing multinational trials. later lines of therapy ● Trastuzumab deruxtecan (T-DXd) is a newer antibody-drug conjugate with a high drug-to-antibody ratio, stability in systemic circulation, and payload with a short half-life 2. Overview of the market ● T-DXd has shown antitumor activity and a manageable safety profile in HER2-positive metastatic breast cancer and other metastatic solid 2.1. Unmet needs tumors ● Currently, there are numerous ongoing trials to further investigate Unfortunately, many patients with metastatic disease even­ the antitumor activity and safety of T-DXd in different disease set­ tually develop resistance to HER2-targeted therapies such as tings, including HER2-low metastatic breast cancer trastuzumab, and there are no targeted treatment standards This box summarizes key points contained in the article. for patients with HER2-positive BC who have received ≥2 HER2-targeted therapies or for patients with HER2-positive GC after first-line therapy with trastuzumab [2,3,9,20,25–31]. In addition, there are no approved HER2-targeted therapies for advanced NSCLC or CRC [21], highlighting the need for and a taxane [18]. In the TH3RESA trial, in patients with HER2-targeted therapies in HER2-positive metastatic solid progressive HER2-positive advanced BC who had received tumors. ≥2 prior HER2-targeted treatments and previous taxane Brain metastases are common in patients with HER2- therapy and who were treated with T-DM1 as opposed to positive mBC; it is estimated that brain metastases will physician’s choice, mPFS was significantly improved ultimately develop in 25–50% of female patients [32]. (6.2 months vs 3.3 months; HR, 0.528; 95% CI, 0.422–0.661; Even after treatment with whole brain radiotherapy, brain P < 0.0001) as was mOS (22.7 months vs 15.8 months; HR, metastases have a negative impact on patients’ quality of 0.68; 0.54–0.85; P = 0.0007) [16,17]. life and outcome [33], highlighting the need for more effective treatments. Trastuzumab has low central nervous system penetrance and is not effective at treating brain 1.3. Targeting HER2 in other solid tumors metastases compared with HER2-targeted therapies in HER2 is being targeted in other solid tumor types such as development, such as tucatinib [32,34–36]. Long-term fol­ gastric cancer (GC), non–small cell lung cancer (NSCLC), and low-up of patients with HER2-positive CRC treated with colorectal cancer (CRC) in multiple ongoing clinical trials. trastuzumab and lapatinib also showed the central nervous Trastuzumab-based therapy is the first-line standard of care system to be a ‘sanctuary site’ of relapse [37,38]. for patients with HER2-positive GC [19,20], but there are no approved HER2-targeted therapies for NSCLC or CRC [21]. 2.2. Newer therapies to treat HER2-positive breast cancer

1.4. Beyond a binary definition of HER2-positive and Many treatments are in development or approved for patients HER2-negative: HER2-low with HER2-positive mBC, including antibodies, ADCs, and tyr­ osine kinase inhibitors (Table 1) [27,48]. Recently, new treat­ Historically, HER2 status has been defined as HER2 positive ments have been approved to treat HER2-positive mBC and (immunohistochemistry [IHC] 3+ or IHC2+/in situ hybridization positive phase 2 and 3 data have been reported for other (ISH)-positive) or HER2 negative (IHC2+/ISH-negative, IHC1+, compounds (Table 1). IHC0) [22]. Recent trials have defined a new HER2 categoriza­ tion, HER2-low, which includes tumors that express HER2 (IHC2+ or 1+) but lack amplification of the ERBB2 gene (ISH- 3. Introduction to T-DXd negative) [23]. HER2-low BC, which likely includes many 3.1. Chemistry of T-DXd patients formerly classified as hormone receptor-positive /HER2-negative or triple-negative breast cancer (TNBC), may T-DXd is an ADC, a class of cancer therapies that combines antigen account for more than 50% of BC cases [24] and represents specificity and potent cytotoxicity in a single molecule [49,50]. a substantial patient population that could benefit from newer T-DXd is a humanized anti-HER2 immunoglobulin G1 monoclonal HER2-targeted therapies with activity in HER2-low tumors. antibody (with the same amino acid sequence as trastuzumab), which is linked to deruxtecan (a topoisomerase I inhibitor [DXd] and a tetrapeptide-based cleavable linker) (Figure 1) [51,52]. 1.5. Trastuzumab deruxtecan (T-DXd), a newer ADC Compared with other topoisomerase I inhibitors such as SN-38, Due to a growing number of solid tumor types with HER2 as DXd was shown to be almost 10-fold more potent, with an half an actionable target and the risk of resistance to current HER2- maximal inhibitory concentration of 0.31 µmol/L compared with targeted therapies, newer HER2-targeted therapies are 2.78 µmol/L for SN-38 [51]. EXPERT OPINION ON BIOLOGICAL THERAPY 3

Table 1. Summary of compounds under investigation or approved for HER2-positive mBC. Mechanism of action Phase Main published findings Antibodies Margetuximab Anti-HER2 monoclonal 3 ● Margetuximab has shown greater antitumor activity in patients with antibody HER2-positive mBC than trastuzumab in the phase 3 SOPHIA trial (ClinicalTrials.gov, NCT02492711) [39]

● mPFS for 266 patients treated with margetuximab and chemotherapy was higher than that of 270 patients with trastuzumab and che­ motherapy (5.8 vs 4.9 months; HR, 0.76; 95% CI, 0.59–0.98; P = 0.033) ● Safety profiles were similar between 2 treatment groups; 52% and 48% had grade ≥3 AEs and 15% and 17% had serious AEs in the margetux­ imab and trastuzumab treatment groups, respectively [39]

ZW25 Anti-HER2 bispecific 1b/2 ● ZW25 showed antitumor activity in patients with advanced and/or antibody metastatic HER2-positive BC (ClinicalTrials.gov, NCT02892123) [40]

● Of 13 BC patients, 46% had PR ● DCR was 54% ● The most common TEAEs were diarrhea and infusion reactions [40]

MCLA-128 Anti-HER2 and HER3 2 ● In a phase 1 trial, of 8 patients with HER2-positive mBC treated with bispecific antibody 750 mg Q3W, 1 patient had PR, and 7 patients had SD (ClinicalTrials.gov, NCT02912949) [41]

● 2 mBC patients treated with 480 mg Q3W also had SD ● No suspected cardiac AEs occurred. Infusion-related reactions and gas­ trointestinal issues were the most common AEs [41] Antibody-drug conjugates SYD985 (trastuzumab Anti-HER2 antibody 3 ● In 48 SYD985-treated patients with HER2-positive mBC, ORR was 33% duocarmazine) trastuzumab linked (95% CI, 20.4–48.4) and mPFS was 7.6 months (4.2–10.9) (ClinicalTrials. to a synthetic gov, NCT02277717) [42] duocarmycin analog ● The most common AEs were fatigue (33%), conjunctivitis (31%), and dry eye (31%); 35% of patients had grade 3 or 4 TEAEs, and the most common grade 3 or 4 TEAEs were neutropenia (6%), fatigue (4%), and conjunctivitis (3%) [42]

RC48-ADC Anti-HER2 antibody 2 ● In a phase 1b study with 30 patients with HER2-posititvemBC, RC48-ADC hertuzumab showed antitumor activity (ClinicalTrial.gov, NCT03052634) [43] conjugated with MMAE ● DCR was observed in 96.7% of patients, and ORR was 26.7% and 46.7% in the 1.5-mg/kg and 2.0-mg/kg cohorts, respectively ● The common TEAEs reported were AST elevation (50.0%), ALT elevation (43.3%), leukopenia (33.3%), neutropenia (33.3%), and numbness (23.3%); most were grade ≤2 [43] Small molecules Neratinib Irreversible pan-HER Approved ● The NALA trial, a phase 3 study to compare neratinib and capecitabine TKI against lapatinib and capecitabine, assessed patients with HER2-positive mBC previously treated with ≥2 HER2-targeted therapies (ClinicalTrials. gov, NCT01808573) [44]

● Compared with lapatinib/capecitabine (n = 314), neratinib/capecitabine (n = 307) significantly improved PFS (HR, 0.76; 95% CI, 0.63–0.93, P = 0.0059) and mDOR (8.5 vs 5.6 months; HR, 0.50; 0.33–0.74; P = 0.0004) ● Grade 3 diarrhea occurred more frequently in the neratinib/capecitabine group than in the lapatinib/capecitabine group (24.4% vs 12.5%) [44]

Pyrotinib Irreversible pan-HER 3 (China) ● In PHOEBE, a phase 3 trial, patients with HER2-positive mBC previously TKI 1 treated with taxanes and trastuzumab were assessed [45] (United States) ● mPFS was 11.1 months (95% CI, 9.66–16.53) for the pyrotinib + capecitabine arm (n = 185) and 4.1 months (2.79–4.17) for the placebo + capecitabine arm (n = 94) ● mPFS was 5.5 months (95% CI, 4.07–6.90) for pyrotinib monotherapy ● The most frequent (≥5%) grade ≥3 TEAEs were diarrhea (30.8% vs 12.8%) and hand-foot syndrome (15.7% vs 5.3%), both higher in the pyrotinib arm [45]

Poziotinib Irreversible pan-HER 2 ● In NOV120101-203, a phase 2 trial, patients with HER2-positive mBC TKI previously treated with anticancer chemotherapy or ≥2 HER2-targeted regimens, including trastuzumab (ClinicalTrials.gov, NCT02418689) [46]

● ORR was 25.5%, mPFS was 4.04 months (95% CI, 2.96–4.40), and 1-year OS rate was 63% (median not yet reached) among 106 patients ● The most common AEs were diarrhea (96%) and stomatitis (92%). Dermatologic toxicities (e.g. pruritus, rash, and dry skin) were also com­ mon [46]

(Continued) 4 J. PEREZ ET AL.

Table 1. (Continued). Mechanism of action Phase Main published findings Antibodies Tucatinib HER2-selective TKI Approved ● The HER2CLIMB trial was conducted to assess patients with HER2- positive advanced or mBC who were previously treated with trastuzumab, pertuzumab, and T-DM1 (ClinicalTrials.gov, NCT02614794) [47]

● Compared with trastuzumab and capecitabine (placebo group, n = 197), the combination of tucatinib, trastuzumab, and capecitabine (tucatinib group; n = 404) resulted in an improvement in mPFS (7.8 months [95% CI, 7.5–9.6] vs 5.6 months [4.2–7.1]) and estimated OS (44.9% [36.6–52.8] vs 26.6% [15.7–38.7]) ● Risk for brain metastases progression in patients in the tucatinib group was reduced by 68% compared with patients in the placebo group (HR, 0.32; 95% CI, 0.22–0.48; P < 0.0001), and the risk for death was reduced by 42% (HR, 0.58; 0.40–0.85; P = 0.005) [35] ● Compared with the placebo group, diarrhea (12.9% vs 8.6%) and elevated aminotransferase levels (AST: 4.5% vs 0.5%; ALT: 5.4% vs 0.5%) of grade ≥3 were more common in the tucatinib group [47] AEs, adverse events; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; DCR, disease control rate; GC, gastric cancer; HER, human epidermal growth factor receptor; HR, hazard ratio; IHC, immunohistochemistry; ISH, in situ hybridization; mBC, metastatic breast cancer; mDOR, median duration of response; MMAE, monomethyl auristatin E; mPFS, median progression-free survival; ORR, objective response rate; OS, overall survival; PFS, progression- free survival; PR, partial response; Q3W, every 3 weeks; SD, stable disease; T-DM1, trastuzumab emtansine; TEAEs, treatment-emergent adverse events; TKI, tyrosine kinase inhibitor.

3.2. Pharmacodynamics, pharmacokinetics, and concentration of free DXd was low [54], indicating that T-DXd is metabolism indeed stable in circulation. The median elimination half-life was T-DXd has a high drug-to-antibody ratio of ≈8, which is higher approximately 5.7 days [55]. than other currently approved ADCs [51,52], allowing T-DXd to T-DXd may be cytotoxic to not just the targeted tumor cell, deliver more payload molecules to targeted tumor cells. The but also surrounding tumor cells due to high membrane payload of T-DXd has a short half-life (≈1.37 hours in systemic permeability of DXd [51,52]. Due to this bystander antitumor circulation based on animal data [53]), which can potentially help effect, T-DXd was shown to be effective against both HER2- to minimize off-target toxicity. The linker reduces hydrophobicity positive and HER2-low cancer cells that were inoculated and stabilizes the ADC; the release rate of the payload in human together in xenograft mice [55,56], suggesting that T-DXd plasma for T-DXd is 2.1% after day 21 of incubation compared may be effective in treating heterogeneous tumors, including with 18.4% after day 4 of incubation for T-DM1 [51,52]. In addi­ those that are HER2-low. This was in contrast to T-DM1, which tion, the linker is cleaved by lysosomal enzymes highly expressed only showed antitumor activity against HER2-positive cells in in tumor cells (e.g. cathepsins B and L), which ensures stability in the same mouse model; in addition, T-DXd was active against systemic circulation and limited systemic toxicity of T-DXd [51]. In T-DM1-resistant tumor cells with both high and low levels of a phase 1 dose escalation and expansion study, the serum HER2 expression [55,56].

Trastuzumab deruxtecan (T-DXd)

Deruxtecan

Humanized anti-HER2 IgG1 monoclonal antibody

High drug-to-antibody ratio ≈8 Tetrapeptide-based cleavable linker Topoisomerase I inhibitor payload (DXd)

Figure 1. Structure of T-DXd. T-DXd is an ADC with three components. It is a humanized anti-HER2 IgG1 mAb with the same amino acid sequence as trastuzumab, linked to a topoisomerase I inhibitor payload (an exatecan derivative; DXd) via a tetrapeptide-based cleavable linker, which is tumor-selective. The payload has a short systemic half-life and is membrane-permeable, highly potent, and stable. Abbreviations: ADC, antibody-drug conjugate; DXd, deruxtecan; HER2, human epidermal growth factor receptor 2; IgG1, immunoglobulin G1; mAb, monoclonal antibody; T-DXd, trastuzumab deruxtecan. EXPERT OPINION ON BIOLOGICAL THERAPY 5

In a phase 1 drug–drug interaction study (DS8201-A-A104), Phase 2 trials have also evaluated T-DXd in CRC, GC, and there were no clinically meaningful interactions between NSCLC. In the single-arm DESTINY-CRC01 trial, confirmed T-DXd and ritonavir (a dual OATP1B/CYP3A inhibitor) or itra­ ORR was 45.3% (95% CI, 31.6–59.6), mPFS was 6.9 months conazole (a CYP3A inhibitor), as the concomitant use of rito­ (4.1–NE), and mOS was not reached [65]. In the rando­ navir or itraconazole resulted in minimal increase in exposure mized DESTINY-Gastric01 trial, the ORR was 51% (95% CI, of T-DXd [57]. 42–61), mPFS was 5.6 months (4.3–6.9), and mOS was 12.5 months (9.6–14.3) for T-DXd-treated patients com­ pared with 14% (6–26), 3.5 months (2.0–4.3), and 4. Clinical efficacy 8.4 months (6.9–10.7) for chemotherapy-treated patients There are many completed and ongoing trials evaluating T-DXd [61]. In the DESTINY-Lung01 trial, the interim confirmed in different HER2-expressing solid tumor types (Tables 2, 3, ORR was 61.9% (95% CI, 45.6–76.4) and interim estimated and 4). mPFS was 14.0 months (6.4–4.0) in patients with HER2- mutated NSCLC; the interim confirmed ORR was 24.5% (13.3–38.9) and interim estimated mPFS was 5.4 months 4.1. Phase 1 studies (2.8–7.0) in patients with HER2-overexpressing NSCLC DS8201-A-J101 was an open-label, dose-escalation, and [66,67]. dose-expansion phase 1 trial designed to assess safety, tolerability, and activity of T-DXd in HER2-expressing, advanced solid tumors. The dose-escalation portion of the 4.3. Phase 3 studies study established 5.4 mg/kg or 6.4 mg/kg as recom­ There are five ongoing phase 3 BC T-DXd trials. DESTINY-Breast02 mended doses, no dose-limiting toxicities were observed, will compare the efficacy and safety of T-DXd with those of the and the maximum tolerated dose was not reached [54]. investigator’s choice of therapy in patients with HER2-positive Patients had antitumor activity regardless of their HER2 unresectable and/or mBC pretreated with T-DM1 [68]. DESTINY- status, as among the 23 patients (6 of whom had HER2- Breast03 will compare the efficacy and safety of T-DXd vs T-DM1 low tumors), 10 patients achieved objective response (43%; in patients with HER2-positive unresectable and/or 95% CI, 23.2–65.5) and 21 patients achieved disease con­ mBCpreviously treated with trastuzumab and a taxane [69], trol (91%; 72.0–98.9) [54]. The dose-expansion portion of while DESTINY-Breast05 will compare T-DXd with T-DM1 in the study in HER2-positive mBC patients showed prelimin­ patients with HER2-positive primary BC who have residual inva­ ary antitumor activity, with confirmed objective response sive disease in breast or axillary lymph nodes, DESTINY-Breast04 rate (ORR) of 59.5% (95% CI, 49.7–68.7) [59]. will compare the efficacy and safety of T-DXd and those of As part of the dose-expansion portion of the phase 1 investigator’s choice of treatment in HER2-low unresectable trial, 54 patients with extensively pretreated HER2-low mBC and/or mBC [70], and DESTINY-Breast06 will compare T-DXd were enrolled (median, 7.5 prior therapies) [60]. Confirmed with capecitabine, paclitaxel, or nab-paclitaxel in HER2-low, hor­ ORR was 37.0% (20/54; 95% CI, 24.3–51.3), with a median mone receptor-positive mBC after ≥2 previous lines of endocrine duration of response (mDOR) of 10.4 months (8.8–not eva­ therapy. The results from these trials are expected to further luable [NE]). Antitumor activity was also seen in other HER2- inform the optimal use of T-DXd in patients with BC. expressing and/or HER2-mutant solid tumors, including CRC (ORR 5% [1/20]; 95% CI, 0.1–24.9), GC (ORR 43.2% [19/44]; 28.3–59.0), and NSCLC (ORR 55.6% [10/18]; 30.8–78.5) 5. Safety and tolerability [21,64]. In all completed clinical trials, T-DXd had a manageable safety profile with ≤64.3% of the TEAEs reported as grade 1 or 2 (Table 4.2. Phase 2 studies 3) [59,61,63,65,66]. The most common (≥10%) grade ≥3 TEAEs DESTINY-Breast01 was a two-part, open-label, single-group, were decreased neutrophil count, anemia, nausea, decreased multicenter, phase 2 study that evaluated T-DXd in adult white cell count, and decreased platelet count [59,61,62,65,66]. patients with HER2-positive mBC who were heavily pretreated, Interstitial lung disease (ILD)/pneumonitis is an important risk including with T-DM1 (median of six previous lines of therapy) for patients treated with T-DXd and must be closely monitored and [61]. The pharmacokinetics portion of the study established managed according to recommended guidelines. Early identifica­ 5.4 mg/kg as the recommended dose based on the balance of tion, diagnosis, and intervention are important for optimal man­ safety and efficacy [61]. ORR was 61.4% (113/184); the mDOR agement; patients must be counseled to report any pulmonary was 20.8 months (95% CI, 15.0–not evaluable), and mPFS was symptoms as soon as possible. When ILD/pneumonitis is sus­ 19.4 months (14.1–NE) [62]. ORR and mPFS of patients who pected, treatment with T-DXd should be interrupted and patients had brain metastases at baseline were comparable (58.3% [14/ should be evaluated via high-resolution computed tomography, 24] and 18.1 months [95% CI, 6.7–18.1], respectively). pulmonologist consultation, pulmonary function testing, and oxy­ Interestingly, brain progression was observed at time of pro­ gen saturation; arterial blood gas should be considered if ILD/ gression in only 8% of patients (4/48) without brain metastatic pneumonitis is clinically indicated [61]. Corticosteroid treatment involvement at time of enrollment [64]. The estimated overall should be started promptly at doses based on the severity of ILD/ survival (OS) was 85% (95% CI, 79–90) at 12 months and 74% pneumonitis [61,72]. In the DESTINY-Breast01 study, 15.2% of (67–80) at 18 months; mOS was 24.6 months (23.1–NE) [62]. patients had ILD/pneumonitis, with 82.1% grade ≤4 (23/28) [62]. 6 Table 2. Summary of T-DXd clinical trial data. ClinicalTrials.gov

Trial Identifier Phase Tumor Types Compounds Main Findings J.

DS8201-A-J101 NCT02564900 T-DM1-treated HER2 T-DXd ● This was an open-label, 2-part, multiple study to assess safety and tolerability of PEREZ 1 overexpressing BC, T-DXd [54]

trastuzumab-treated GC or ● The dose-escalation portion of the study established 5.4 mg/kg and 6.4 mg/kg as ET GEJ adenocarcinoma, HER2- recommended doses [54] AL. low BC, and other HER2- expressing advanced solid ● There were either 3 patients in each cohort (0.8, 1.6, 3.2, and 8.0 mg/kg) or 6 malignant tumor types patients (5.4 and 6.4 mg/kg) ● There were 3 patients in each of the following cohorts – 0.8, 1.6, 3.2, and 8.0 mg/ kg – and 6 patients in the 5.4 – and 6.4-mg/kg cohorts ● There were no dose-limiting toxicities, and maximum tolerated dose was not reached [54] ● The dose-expansion portion of the study in HER2-positive BC patients showed preliminary antitumor activity, with confirmed ORR of 59.5% (95% CI, 49.7–68.7) [59] ● In the dose-expansion portion of the study in HER2-low BC patients, confirmed ORR was 37.0% (20/54; 95% CI, 24.3–51.3), with a mDOR of 10.4 months (8.8 to not evaluable) [60]

DS8201-A-A104 NCT03383692 Advanced solid HER2-positive T-DXd with ritonavir or T-DXd ● This was a phase 1 study to evaluate potential DDIs between T-DXd and OATP1B/ 1 malignant tumor with ≥1 with itraconazole CYP3A inhibitor prior systemic chemotherapy ● There were no clinically meaningful DDIs between T-DXd and ritonavir (a dual regimen OATP1B/CYP3A inhibitor) or itraconazole (a CYP3A inhibitor) [57]

● In 26 patients, the concomitant use of ritonavir or itraconazole resulted in a minimal increase in exposure of T-DXd

DESTINY-Breast01 NCT03248492 T-DM1-resistant/-refractory and T-DXd ● DESTINY-Breast01 was a phase 2 study that showed antitumor activities in T-DXd 2 T-DM1-exploratory HER2- in adult patients with HER2-positive metastatic BC who were heavily pretreated positive BC (median of 6 previous lines of therapy), which must have included T-DM1 [61,62]

● The pharmacokinetics portion of the study established 5.4 mg/kg as the recommended dose based on the balance of safety and efficacy ● Among 184 patients, a response was reported in 113 patients (61.4%) ● mDOR was 20.8 months (95% CI, 20.8–NE), and mPFS was 19.4 months (14.1– NE) ● Estimated OS was 85% (95% CI, 79–90) at 12 months and 74% (67–80) at 18 months; mOS was 24.6 months (23.1–NE) ● The most common grade ≥3 AEs were decreased neutrophil count (20.7%), anemia (8.7%), and nausea (7.6%) [61] ● ILD/pneumonitis was observed in 15.2% of patients (grade 5, 2.7%) [62]

DESTINY-CRC01 NCT03384940 HER2-positive (IHC3+ or IHC2 T-DXd ● DESTINY-CRC01 was a phase 2 study showing the antitumor activity of T-DXd in 2 +/ISH-positive) CRC, HER2 adult patients with metastatic CRC with varying HER2 status who had ≥2 prior IHC2+/ISH-negative CRC, and regimens [63] HER2 IHC1+ CRC with ≥2 prior regimens ● In HER2-positive mCRC patients (n = 53), confirmed ORR was 45.3% (95% CI, 31.6–59.6), mPFS was 6.9 months (4.1 to not evaluable), and mOS was not reached ● No responses were observed for the 2 HER2-low cohorts (n = 7 and n = 18) ● Grade 3 TEAEs were observed in 61.5% of patients, and the most common TEAEs were decreased neutrophil count (21.8%) and anemia (14.1%) [65] ● 5 patients (6.4%) had ILD/pneumonitis (grade 2, 2 patients; grade 3, 1 patient; grade 5, 2 patients) [65]

● The 2 grade 5 ILD/pneumonitis cases led to the only treatment-related deaths Table 2. (Continued). ClinicalTrials.gov Trial Identifier Phase Tumor Types Compounds Main Findings DESTINY-Gastric01 NCT03329690 HER2-overexpressing (IHC3+ or T-DXd compared with ● DESTINY-Gastric01 was a phase 2 study showing the antitumor activity of T-DXd in 2 IHC2+/ISH-positive) advanced irinotecan or paclitaxel adult patients with HER2-positive advanced GC or GEJ adenocarcinoma with GC or GEJ adenocarcinoma monotherapy varying HER2 status previously treated using ≥2 regimens [61] with ≥2 prior regimens, treatment-naive HER2 IHC2 ● ORR was 51% (95% CI, 42–61), mPFS was 5.6 months (4.3–6.9), and mOS was +/ISH-positive advanced GC 12.5 months (9.6–14.3) for T-DXd-treated patients or GEJ adenocarcinoma, ● Corresponding values were 14% (95% CI, 6–26), 3.5 months (2.0–4.3), and treatment-naive IHC1 8.4 months (6.9–10.7) for chemotherapy-treated patients + advanced GC or GEJ ● The most common grade ≥3 AEs were decreased neutrophil count (51% in T-DXd adenocarcinoma group and 24% in chemotherapy group), anemia (38% and 23%) and decreased white cell count (21% and 11%) [61] ● 12 patients in the T-DXd group had ILD/pneumonitis (grade 1 or 2 in 9 patients and grade 3 or 4 in 3 patients) [61]

DESTINY-Lung01 NCT03505710 HER1-overexpressing (IHC3+ or T-DXd ● DESTINY-Lung01 was a phase 2 study showing the antitumor activity of T-DXd in 2 IHC2+) unresectable and/or adult patients with HER2-positive or HER2-mutated metastatic NSCLC with varying metastatic NSCLC, HER2- HER2 status [65] mutated unresectable and/or metastatic NSCLC that ● Confirmed ORR for patients with HER2 mutations was 61.9% (95% CI, 45.6–76.4) relapsed from or is refractory and estimated mPFS was 14.0 months (6.4–14.0) ● to standard treatment or for Out of 42 patients, 64.3% had grade ≥3 AEs, including decreased neutrophil count EXPERT which no standard treatment (26.2%) and anemia (16.7%) [65] is available ● 5 patients had ILD/pneumonitis and all occurrences were grade 2 [65] AE, adverse event; BC, breast cancer; CI, confidence interval; CRC, colorectal cancer; DDI, drug–drug interaction; GC, gastric cancer; GEJ, gastroesophageal junction; HER2, human epidermal growth factor receptor 2; IHC, OPINION immunohistochemistry; ILD, interstitial lung disease; ISH, in situ hybridization; mDOR, median duration of response; mOS, median overall survival; mPFS, median progression-free survival; NSCLC, non–small cell lung cancer; ORR, objective response rate; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan. ON BIOLOGICAL THERAPY 7 8 Table 3. Summary of ongoing T-DXd breast cancer clinical trials [66]. Tumor Primary ClinicalTrials. Trial Phase types Population N (estimated) Compounds Study summary endpoint gov identifier J. PEREZ DESTINY-Breast08 1 BC HER2-low advanced or metastatic BC 185 T-DXd in combination Investigate safety, tolerability, PK and Occurrence NCT04556773 with durvalumab/ preliminary antitumor activity of T-DXd in of AEs paclitaxel, combination with other therapies in HER- and ET

capivasertib, 2-low advanced or metastatic BC serious AL. anastrozole, AEs fulvestrant, or capecitabine BEGONIA 1/2 BC Metastatic TNBC 170 Durvalumab in Determine safety and efficacy of durvalumab Incidence laboratory combination with in combination with novel targeted of AEs, findings capivasertib, therapies with or without paclitaxel and oleclumab, or T-DXd durvalumab+paclitaxel for first-line with or without metastatic TNBC paclitaxel NCT03742102 DESTINY-Breast07 1/2 BC HER2-positive metastatic BC 350 T-DXd in combination Investigate safety, tolerability, and antitumor Occurrence NCT04538742 with durvalumab, activity of T-DXd in combination with other of AEs paclitaxel, therapies in HER2-positive metastatic BC and durvalumab/ serious paclitaxel, or AEs pertuzumab DEBBRAH 2 BC Pretreated, unresectable locally advanced or 39 T-DXd Study of T-DXd in HER2-positive advanced BC Cohort 1: NCT04420598 metastatic HER2-positive or HER2-low with brain metastases and/or PFS; expressing BC with untreated or treated brain leptomeningeal carcinomatosis cohorts metastases or leptomeningeal carcinomatosis 2–4: CNS ORR; cohort 5: OS HER2CLIMB-04 2 BC HER2-positive unresectable or metastatic BC 70 Combination therapy of Study of efficacy and safety of tucatinib in ORR NCT04539938 T-DXd and tucatinib combination with T-DXd in HER2-positive metastatic or unresectable BC Trastuzumab Deruxtecan Alone or 2 BC HER2-low, hormone receptor–positive BC 88 T-DXd monotherapy or Investigate the efficacy of T-DXd Pathologic NCT04553770 Combination With Anastrozole in combination with monotherapy or in combination with complete for the Treatment of Early anastrozole anastrozole in the treatment of patients response Stage HER2-Low, Hormone with HER2-low, hormone receptor-positive rate Receptor Positive Breast Cancer BC DESTINY-Breast02 3 BC HER2-positive unresectable and/or metastatic BC 600 T-DXd compared with Compare T-DXd to standard of care PFS NCT03523585 previously treated with standard-of-care HER2 trastuzumab/ chemotherapy in unresectable and/or therapies (eg, T-DM1) capecitabine or metastatic BC previously treated with lapatinib/ T-DM1 capecitabine DESTINY-Breast03 3 BC HER2-positive unresectable and/or metastatic BC 500 T-DXd compared with Compare safety, efficacy, and antitumor PFS NCT03529110 previously treated with trastuzumab and taxane T-DM1 activity of T-DXd to T-DM1 in HER2-positive unresectable and/or metastatic BC previously treated with trastuzumab and taxane DESTINY-Breast04 3 BC HER2-low, unresectable, and/or metastatic BC 557 T-DXd compared with Compare safety and efficacy of T-DXd to PFS NCT03734029 previously treated with chemotherapy capecitabine, physician’s choice standard chemotherapy eribulin, in HER2-low unresectable and/or gemcitabine, metastatic BC paclitaxel, or nab- paclitaxel (Continued) EXPERT OPINION ON BIOLOGICAL THERAPY 9

Similarly, in other completed trials, ILD/pneumonitis was reported in ≈10% of patients, and most cases were either grade 1 or grade 2,

identifier except for DESTINY-CRC01, in which ILD/pneumonitis was grade 2

trastuzumab in 2 patients, grade 3 in 1 patient, and grade 5 in 2 patients ClinicalTrials. gov NCT04622319 NCT04494425 [59,61,65,66]. T-DXd can be restarted after recovery for patients T-DXd, with grade 1 ILD/pneumonitis and should be permanently discon­ tinued for any patient diagnosed with symptomatic (grade ≥2) disease- free survival Primary endpoint

Invasive PFS ILD/pneumonitis [54]. emtansine; of with therapy

residual 6. Regulatory affairs patients T-DXd trastuzumab BC hormone with

tolerability T-DXd was approved on 20 December 2019 in the United of choice endocrine States for the treatment of unresectable or metastatic HER2- and on neoadjuvant T-DM1, positive BC after ≥2 prior anti-HER2–targeted therapies, on patients summary efficacy HER2-low, metastatic 25 September 2020 in Japan for HER2-positive unresectable safety, in and

Study or mBC, and on 20 January 2021 in Europe for treatment of survival; following investigator’s progressed high-risk

BC unresectable or metastatic HER2-positive BC after ≥2 prior in safety efficacy, with

have anti-HER2–targeted therapies (Box 1). T-DM1 invasive T-DXd chemotherapy receptor-positive who therapy Compare Compare

progression-free Box 1. Drug Summary Box PFS, with with nab-

or Drug name (generic) Trastuzumab deruxtecan (T-DXd)

survival; Phase Breast cancer (BC): 3 compared compared

Compounds Gastric cancer (GC): 2 Colorectal cancer (CRC): 2 T-DM1 capecitabine, paclitaxel, paclitaxel overall

T-DXd T-DXd Non–small cell lung cancer (NSCLC): 2

OS, Indication In the United States, T-DXd is indicated to treat adult patients with unresectable or metastatic rate; human epidermal growth factor receptor 2 850

1600 (HER2)-positive BC who have previously (estimated) received ≥2 anti-HER2-based therapies for N

response metastases and advanced or metastatic HER2- or of positive gastric or gastroesophageal had with

that adenocarcinoma who have received a prior or lines trastuzumab-based regimen. objective invasive ones advanced nodes after

ORR, In Japan, T-DXd is indicated to treat adult previous

2; patients with HER2-positive unresectable or residual lymph presentation ≥2

status metastatic BC and HER2-positive unresectable including advanced or recurrent GC that has progressed with

with after chemotherapy receptor axillary BC disease receptor–positive or Population at In the European Union, T-DXd is indicated to factor treated recurrence, therapy

node-positive treat unresectable or metastatic HER2-positive primary of BC breast therapy BC who have previously received ≥2 HER2- hormone in based regimens risk growth inoperable Pharmacology description/ T-DXd is a HER2-targeted antibody-drug mechanism of action conjugate. The antibody is a humanized anti- disease higher were pathological neoadjuvant metastatic endocrine HER2 immunoglobulin G1, and the payload is HER2-positive HER2-low,

epidermal a topoisomerase I inhibitor. T-DXd binds to HER2 on tumor cells, is internalized, and is cleaved by lysosomal enzymes. The types Tumor BC BC human

cancer. membrane-permeable payload causes DNA

3 3 damage and apoptosis, killing the tumor cells HER2,

Phase Route of administration Intravenous infusion once every 3 weeks breast (21-day cycle) at a dose of 5.4 mg/kg body weight (for BC) or 6.4 mg/kg (for GC, CRC, cancer; and NSCLC) Pivotal trials BC: Results from DESTINY-Breast01 led to breast approval in both the United States and Japan triple-negative

BC, for patients with unresectable or metastatic HER2-positive BC who had received ≥2 prior TNBC, anti-HER2-based therapies for metastases event; GC: Results from DESTINY-Gastric01 led to (Continued). approval in Japan for patients with HER2- 3. positive unresectable advanced or recurrent GC adverse

deruxtecan; that progressed after chemotherapy Trial DESTINY-Breast05 DESTINY-Breast06 Table AE, 10

Table 4. Summary of ongoing T-DXd clinical trials for other solid tumor indications [58].

ClinicalTrails. J.

Trial Phase Tumor types Population Compounds gov identifier PEREZ DS8201-A-U106 1 BC, NSCLC Part 1 (dose escalation): HER2-positive BC, HER2-low BC, HER2- T-DXd with pembrolizumab NCT04042701

expressing NSCLC, HER2-mutant NSCLC ET Part 2 (dose expansion): T-DM1-treated HER2-positive BC, HER2- AL. low BC with failed prior standard treatments, HER2-expressing NSCLC with no prior anti–PD-1, anti–PD-L1, or HER2 agents, and HER2-mutant NSCLC with no prior anti–PD-1, anti–PD-L1, or HER2 agents Testing the Biological Effects of DS- 1 Solid tumors HER2-positive metastatic, refractory, and/or unresectable solid tumor T-DXd NCT04294628 8201a on Patients With Advanced Cancer Testing the Combination of DS-8201a 1 Endometrial Adenocarcinoma HER2-positive endometrial serious adenocarcinoma T-DXd in and Olaparib in HER2-Expressing Serous Cancers With Expansion in Patients With Endometrial Cancer combination with olaparib NCT04585958 Trastuzumab Deruxtecan With Nivolumab in Advanced Breast and 1 Urothelial Cancer BC, urothelial cancer HER2- expressing BC T-DXd in combination with nivolumab NCT03523572 and urothelial cancer in patients who experienced disease progression during or after prior therapy, did not respond to standard therapy, or for whom no standard therapy is available DESTINY-Gastric02 2 GC/GEJ HER2-positive advanced, unresectable, or metastatic GC or GEJ T-DXd NCT04014075 cancer that worsened during or after treatment that included trastuzumab DESTINY-Gastric03 2 GC/GEJ HER2-positive advanced/metastatic GC or GEJ adenocarcinoma T-DXd monotherapy or in combination with 5-FU, oxaliplatin, NCT04379596 trastuzumab, cisplatin, or durvalumab; T-DXd and 5-FU or capecitabine and oxaliplatin; T-DXd, durvalumab and 5-FU or capecitabine; trastuzumab, 5-FU/ capecitabine, and cisplatin/oxaliplatin; T-DXd, 5-FU or capecitabine, and oxaliplatin; T-DXd, 5-FU or capecitabine, and durvalumab DESTINY-PanTumor02 2 HER2-expressing HER2-expressing tumors (urothelial bladder cancer, biliary tract T-DXd NCT04482309 tumors cancer, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, and rare tumors) HUDSON 2 NSCLC Metastatic NSCLC progressed with anti–PD-1–containing/anti–PD- Durvalumab in combination with AZD9150, AZD6738, vistusertib, NCT03334617 L1–containing therapy olaparib, oleclumab, T-DXd, or cediranib; AZD6738 monotherapy 5-FU, 5-fluorouracil; anti-PD-1, anti–programmed cell death 1; anti-PD-L1, anti–programmed cell death ligand 1; BC, breast cancer; GC, gastric cancer; GEJ, gastroesophageal junction; HER2, human epidermal growth factor receptor 2; NSCLC, non–small cell lung cancer; T-DM1, trastuzumab emtansine; T-DXd, trastuzumab deruxtecan. EXPERT OPINION ON BIOLOGICAL THERAPY 11

T-DXd was approved for previously treated HER2-positive unre­ endocrine-therapy and for patients with HER2-low TNBC with sectable advanced or recurrent GC in Japan on 25 September 2020 prior therapy. The ongoing studies in patients with brain and previously treated advanced or metastatic HER2-positive gas­ metastases will help define the role of T-DXd in this patient tric or gastroesophageal adenocarcinoma in the United States population. Several trials are ongoing for T-DXd in several on 15 January 2021. For HER2-positive NSCLC, T-DXd received solid tumor types (HER2-positive and HER2-low), which will Breakthrough Therapy Designation in the United States on inform how T-DXd can be used optimally. 18 May 2020. T-DXd may potentially also become the standard of care for other HER2-positive metastatic solid tumors in later lines, as it was recently approved for use in advanced HER2- 7. Conclusion positive GC in the United States and Japan, and is recom­ T-DXd showed unprecedented activity in heavily pretreated mended in guidelines for HER2-mutant NSCLC and HER2- patients with advanced HER2-positive BC in the phase 2 positive CRC [75–77]. DESTINY-Breast01 clinical trial [61]. Based on clinical trial ILD/pneumonitis is a notable risk associated with T-DXd results, T-DXd was approved in the United States, Japan, and that necessitates vigilance and prompt treatment and Europe for the treatment of advanced HER2-positive BC. management. A history of lung disease should not auto­ Ongoing phase 3 trials to compare T-DXd to physician’s choice matically exclude patients from T-DXd treatment; each in patients previously treated with T-DM1 and to compare patient should be evaluated individually. Additional studies T-DXd to T-DM1 will provide a clearer idea of how and are necessary to determine the predisposing factors for where T-DXd should be used to treat HER2-positive mBC. ILD/pneumonitis and best management practices for redu­ Since T-DXd showed antitumor activity in HER2-low mBC cing toxicity (e.g. inhaled corticosteroids). T-DXd is an patients [60,73], it is being evaluated in 2 phase 3 trials in this important addition to available therapies for managing patient population. Activity in HER2-low mBC would define HER2-positive cancer. a newly targetable patient population, and T-DXd may be a potential treatment option for patients with hormone recep­ tor-positive and HER2-low mBC who are chemotherapy-naive, had prior chemotherapy, or who failed endocrine-therapy and Acknowledgments patients with HER2-low TNBC. T-DXd was also recently approved Under the guidance of the authors, assistance in medical writing and in Japan and the United States for the treatment of advanced editorial support was provided by Irene Park, PhD, and Alya Raphael, HER2-positive GC based on the results of the DESTINY-Gastric01 PhD, of ApotheCom, and was funded by Daiichi Sankyo. phase 2 trial [61]. Promising activity has also been seen in phase 2 trials in metastatic HER2-positive CRC [65] and HER2-mutated and HER2-overexpressing NSCLC [65]. Declaration of interest Although the types of adverse events were consistent across J Perez has received consulting fees from Roche and Eli Lilly and travel T-DXd trials and were generally manageable, ILD/pneumonitis is expenses from Roche. P Jänne has received consulting fees from a notable risk and necessitates thorough patient monitoring and AstraZeneca, Boehringer Ingelheim, Pfizer, Roche/Genentech, Takeda prompt intervention and management [54,59,60,61,63–65,74]. Oncology, ACEA Biosciences, Eli Lilly, Araxes Pharma, Ignyta, Mirati Therapeutics, Novartis, LOXO Oncology, Daiichi Sankyo, Sanofi Oncology, Based on recent clinical trial data, T-DXd represents a valuable Voronoi, SFJ Pharmaceuticals, Takeda Oncology, Silicon Therapeutics, addition to the toolkit for treatment of HER2-expressing meta­ Transcenta, and Biocartis; receives postmarketing royalties from DFCI- static solid tumors. owned intellectual property on EGFR mutations licensed to Lab Corp; has sponsored research agreements with AstraZeneca, Daiichi-Sankyo, PUMA, Boehringer Ingelheim, Eli Lilly, Revolution Medicines, and Astellas 8. Expert opinion Pharmaceuticals; and owns stock in LOXO Oncology and Gatekeeper Pharmaceuticals. K Shitara reports nonfinancial support from Daiichi Although there have been many improvements in the treat­ Sankyo, during the drafting of this article; grants and personal fees from ment of HER2-positive mBC in the last 2 decades since the Astellas Pharma, Eli Lilly, Ono, Taiho, and Merck; personal fees from Bristol approval of trastuzumab, there is still substantial unmet need. Myers Squibb, Takeda, Pfizer, Novartis, AbbVie, Yakult, and Ultimately, resistance develops, and better treatments are GlaxoSmithKline; and grants from Dainippon Sumitomo Pharma, Daiichi Sankyo, Chugai, and Medi Science, outside the submitted work. S Siena is needed, especially as third-line therapy or later. T-DXd is cur­ an advisory board member for AstraZeneca, Daiichi Sankyo, and Seattle rently approved in the United States and Europe for patients Genetics, outside the submitted work. J Cortés is an advisor for Roche, with HER2-positive mBC who had ≥2 prior HER2-targeted Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle therapies, which suggests T-DXd can be a potential treatment Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Eli Lilly, Servier, option after first-line combination therapy comprising taxanes, Merck Sharp & Dohme, GlaxoSmithKline, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, and Kyowa Kirin; has received honoraria from trastuzumab, and pertuzumab, and second-line T-DM1, similar Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Eli Lilly, Merck to the combination of capecitabine, trastuzumab, and tucati­ Sharp & Dohme, and Daiichi Sankyo; has received research funding to the nib. However, T-DXd is likely to become the new standard of institution from Roche, Ariad, AstraZeneca, Baxalta GMBH/Servier Affaires, care as second-line therapy for HER2-positive mBC as it is Bayer, Eisai, F. Hoffman-La Roche, Guardant Health, Merck Sharp & Dohme, anticipated to outperform T-DM1 in an ongoing trial. T-DXd Pfizer, Piqur Therapeutics, Puma, and Queen Mary University of London; owns stock, patents, and intellectual property in MedSIR; and has received treatment could also be advantageous for patients with travel, accommodations, or expenses from Roche, Novartis, Eisai, Pfizer, hormone receptor-positive and HER2-low mBC who are che­ and Daiichi Sankyo. The authors have no other relevant affiliations or motherapy-naïve, had prior chemotherapy, or who failed financial involvement with any organization or entity with a financial 12 J. PEREZ ET AL. interest in or financial conflict with the subject matter or materials dis­ registry: use in clinical routine for therapeutic decisions and its cussed in the manuscript apart from those disclosed. effect on survival. Breast Cancer Res Treat. 2015;153(3):647–658. 9. Aihara T, Toyama T, Takahashi M, et al. 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