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Expert Opinion on Biological Therapy

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Trastuzumab deruxtecan in HER2-positivemetastatic breast cancer and beyond

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

To cite this article: Jose Perez, Laia Garrigós, Maria Gion, Pasi A. Jänne, Kohei Shitara, SalvatoreSiena & Javier Cortés (2021): Trastuzumab deruxtecan in HER2-positive metastatic breast cancerand 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 InformaUK Limited, trading as Taylor & FrancisGroup.

Published online: 01 Apr 2021.

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DRUG EVALUATION

Trastuzumab deruxtecan in HER2-positive metastatic breast cancer and beyondJose 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

ABSTRACTIntroduction: Despite the substantial improvements made in human epidermal growth factor receptor 2 (HER2)–targeted therapies since the approval of trastuzumab more than 20 years ago, there is still considerable unmet need in patients with HER2-expressing breast cancer (BC) and other solid tumors. Trastuzumab deruxtecan (T-DXd) is a newer antibody-drug conjugate approved for the treatment of metastatic breast cancer (BC) and gastric cancer (GC) and is under active investigation in other solid tumors, including non–small cell lung cancer, colorectal cancer, and HER2-low tumors.Areas covered: The current treatment and investigational landscape of HER2-positive and HER2- low metastatic BC (mBC) and the preclinical and clinical trials investigating T-DXd. To identify relevant literature, a search was performed on English-language publications and congress abstracts.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.

ARTICLE HISTORYReceived 24 November 2020 Accepted 11 February 2021

KEYWORDSAntibody-drug conjugate; breast cancer; colorectal cancer; DS8201; gastric cancer; HER2-positive; HER2 targeted; non–small cell lung cancer; t-DXd; trastuzumab deruxtecan

1. Introduction

1.1. Human epidermal growth factor receptor 2–positive breast cancer

In women, breast cancer (BC) is the most commonly diag-nosed cancer type and the leading cause of cancer-related death worldwide [1]. The presence or absence of human epidermal growth factor receptor 2 (HER2) and hormone receptor expression on tumor cells determines treatment course and prognosis [2,3]. In HER2-positive tumors, amplifica-tion of the ERBB2 gene leads to overexpression of HER2 [4,5]. From a biological perspective, about 15–20% of all BCs are HER2-positive and are associated with poorer prognosis and are more likely to metastasize [6–8].

1.2. Current treatment practices for HER2-positive advanced breast cancer

Although HER2-positive BC is considered an aggressive sub-type of cancer with a high rate of recurrence and worse out-comes, the development of HER2-targeted therapies has provided treatment options [2,3,9–13]. Current guidelines recommend initial treatment with a combination of two HER2- targeted antibodies, trastuzumab and pertuzumab, in combi-nation with a taxane [2,3,9]. Trastuzumab and pertuzumab are

humanized monoclonal antibodies that target different regions of the extracellular domain of HER2 [4]. In the phase 3 CLEOPATRA trial, the combination of trastuzumab, pertuzu-mab, and docetaxel resulted in a substantial improvement in median progression-free survival (mPFS; 18.7 months, 95% CI, 17–22) compared with trastuzumab, placebo, and docetaxel (12.4 months, 10–14; hazard ratio [HR], 0.69; 95% CI, 0.59–0.81) and in median overall survival (mOS; 57.1 months vs 40.8 months; HR, 0.69; 0.58–0.82) in patients with HER2- positive metastatic BC (mBC) without prior chemotherapy or biologic therapy [14].

Upon disease progression, patients can be treated with the antibody-drug conjugate (ADC) trastuzumab emtansine (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 a noncleavable thioether linker [15]. The safety and efficacy of T-DM1 has been tested as second-line therapy or later in two phase 3 clinical trials [16–18]. In the pivotal EMILIA trial, T-DM1 compared with the combination of lapatinib and capecitabine significantly improved mPFS (9.6 months vs 6.4 months; HR, 0.65; 95% CI, 0.55–0.77; P < 0.001) and mOS (30.9 months vs 25.1 months; HR, 0.68; 0.55–0.85; P < 0.001) in patients with HER2-positive locally advanced or mBC who had been treated previously with trastuzumab

CONTACT Javier Cortés jacortes@vhio.net International Breast Cancer Center, Quiron Group, Barcelona, Spain

EXPERT OPINION ON BIOLOGICAL THERAPY https://doi.org/10.1080/14712598.2021.1890710

© 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.

and a taxane [18]. In the TH3RESA trial, in patients with progressive HER2-positive advanced BC who had received ≥2 prior HER2-targeted treatments and previous taxane therapy and who were treated with T-DM1 as opposed to physician’s choice, mPFS was significantly improved (6.2 months vs 3.3 months; HR, 0.528; 95% CI, 0.422–0.661; P < 0.0001) as was mOS (22.7 months vs 15.8 months; HR, 0.68; 0.54–0.85; P = 0.0007) [16,17].

1.3. Targeting HER2 in other solid tumors

HER2 is being targeted in other solid tumor types such as gastric cancer (GC), non–small cell lung cancer (NSCLC), and colorectal cancer (CRC) in multiple ongoing clinical trials. Trastuzumab-based therapy is the first-line standard of care for patients with HER2-positive GC [19,20], but there are no approved HER2-targeted therapies for NSCLC or CRC [21].

1.4. Beyond a binary definition of HER2-positive and HER2-negative: HER2-low

Historically, HER2 status has been defined as HER2 positive (immunohistochemistry [IHC] 3+ or IHC2+/in situ hybridization (ISH)-positive) or HER2 negative (IHC2+/ISH-negative, IHC1+, 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- negative) [23]. HER2-low BC, which likely includes many patients formerly classified as hormone receptor-positive /HER2-negative or triple-negative breast cancer (TNBC), may account for more than 50% of BC cases [24] and represents a substantial patient population that could benefit from newer HER2-targeted therapies with activity in HER2-low tumors.

1.5. Trastuzumab deruxtecan (T-DXd), a newer ADC

Due to a growing number of solid tumor types with HER2 as an actionable target and the risk of resistance to current HER2- targeted therapies, newer HER2-targeted therapies are

needed. This expert opinion highlights the newer ADC T-DXd, which has been approved in the United States, Japan, and Europe for metastatic HER2-positive BC and in the United States and Japan for HER2-positive unresectable advanced or recurrent GC indications. It is also being evaluated in advanced HER2-low BC and GC and in CRC and NSCLC in ongoing multinational trials.

2. Overview of the market

2.1. Unmet needs

Unfortunately, many patients with metastatic disease even-tually develop resistance to HER2-targeted therapies such as trastuzumab, and there are no targeted treatment standards 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 HER2-targeted therapies in HER2-positive metastatic solid tumors.

Brain metastases are common in patients with HER2- positive mBC; it is estimated that brain metastases will ultimately develop in 25–50% of female patients [32]. Even after treatment with whole brain radiotherapy, brain metastases have a negative impact on patients’ quality of 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 metastases compared with HER2-targeted therapies in development, such as tucatinib [32,34–36]. Long-term fol-low-up of patients with HER2-positive CRC treated with trastuzumab and lapatinib also showed the central nervous system to be a ‘sanctuary site’ of relapse [37,38].

2.2. Newer therapies to treat HER2-positive breast cancer

Many treatments are in development or approved for patients with HER2-positive mBC, including antibodies, ADCs, and tyr-osine kinase inhibitors (Table 1) [27,48]. Recently, new treat-ments have been approved to treat HER2-positive mBC and positive phase 2 and 3 data have been reported for other compounds (Table 1).

3. Introduction to T-DXd

3.1. Chemistry of T-DXd

T-DXd is an ADC, a class of cancer therapies that combines antigen specificity and potent cytotoxicity in a single molecule [49,50]. T-DXd is a humanized anti-HER2 immunoglobulin G1 monoclonal 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]. Compared with other topoisomerase I inhibitors such as SN-38, DXd was shown to be almost 10-fold more potent, with an half maximal inhibitory concentration of 0.31 µmol/L compared with 2.78 µmol/L for SN-38 [51].

Article highlights

● HER2-positive breast cancer has a high rate of recurrence and poor prognosis, but recent advances in HER2-targeted therapies have provided treatment options

● However, there is still an unmet need in patients with HER2- expressing breast cancer and other solid tumors because of develop-ment of resistance to HER2-targeted therapies and lack of options in 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

● T-DXd has shown antitumor activity and a manageable safety profile in HER2-positive metastatic breast cancer and other metastatic solid tumors

● Currently, there are numerous ongoing trials to further investigate the antitumor activity and safety of T-DXd in different disease set-tings, including HER2-low metastatic breast cancer

This box summarizes key points contained in the article.

2 J. PEREZ ET AL.

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 antibody

3 ● Margetuximab has shown greater antitumor activity in patients with 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 antibody

1b/2 ● ZW25 showed antitumor activity in patients with advanced and/or 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 bispecific antibody

2 ● In a phase 1 trial, of 8 patients with HER2-positive mBC treated with 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 conjugatesSYD985 (trastuzumab

duocarmazine)Anti-HER2 antibody

trastuzumab linked to a synthetic duocarmycin analog

3 ● In 48 SYD985-treated patients with HER2-positive mBC, ORR was 33% (95% CI, 20.4–48.4) and mPFS was 7.6 months (4.2–10.9) (ClinicalTrials. gov, NCT02277717) [42]

● 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 hertuzumab conjugated with MMAE

2 ● In a phase 1b study with 30 patients with HER2-posititvemBC, RC48-ADC showed antitumor activity (ClinicalTrial.gov, NCT03052634) [43]

● 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 moleculesNeratinib Irreversible pan-HER

TKIApproved ● The NALA trial, a phase 3 study to compare neratinib and capecitabine

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 TKI

3 (China) 1 (United States)

● In PHOEBE, a phase 3 trial, patients with HER2-positive mBC previously treated with taxanes and trastuzumab were assessed [45]

● 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 TKI

2 ● In NOV120101-203, a phase 2 trial, patients with HER2-positive mBC 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 )

EXPERT OPINION ON BIOLOGICAL THERAPY 3

3.2. Pharmacodynamics, pharmacokinetics, and metabolism

T-DXd has a high drug-to-antibody ratio of ≈8, which is higher than other currently approved ADCs [51,52], allowing T-DXd to deliver more payload molecules to targeted tumor cells. The payload of T-DXd has a short half-life (≈1.37 hours in systemic circulation based on animal data [53]), which can potentially help to minimize off-target toxicity. The linker reduces hydrophobicity and stabilizes the ADC; the release rate of the payload in human plasma for T-DXd is 2.1% after day 21 of incubation compared with 18.4% after day 4 of incubation for T-DM1 [51,52]. In addi-tion, the linker is cleaved by lysosomal enzymes highly expressed in tumor cells (e.g. cathepsins B and L), which ensures stability in systemic circulation and limited systemic toxicity of T-DXd [51]. In a phase 1 dose escalation and expansion study, the serum

concentration of free DXd was low [54], indicating that T-DXd is indeed stable in circulation. The median elimination half-life was approximately 5.7 days [55].

T-DXd may be cytotoxic to not just the targeted tumor cell, but also surrounding tumor cells due to high membrane permeability of DXd [51,52]. Due to this bystander antitumor effect, T-DXd was shown to be effective against both HER2- positive and HER2-low cancer cells that were inoculated together in xenograft mice [55,56], suggesting that T-DXd may be effective in treating heterogeneous tumors, including those that are HER2-low. This was in contrast to T-DM1, which only showed antitumor activity against HER2-positive cells in the same mouse model; in addition, T-DXd was active against T-DM1-resistant tumor cells with both high and low levels of HER2 expression [55,56].

Deruxtecan

Tetrapeptide-based cleavable linker Topoisomerase I inhibitor payload (DXd)

Humanized anti-HER2 IgG1monoclonal antibody

High drug-to-antibody ratio ≈8

Trastuzumab deruxtecan (T-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.

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.

4 J. PEREZ ET AL.

In a phase 1 drug–drug interaction study (DS8201-A-A104), there were no clinically meaningful interactions between T-DXd and ritonavir (a dual OATP1B/CYP3A inhibitor) or itra-conazole (a CYP3A inhibitor), as the concomitant use of rito-navir or itraconazole resulted in minimal increase in exposure of T-DXd [57].

4. Clinical efficacy

There are many completed and ongoing trials evaluating T-DXd in different HER2-expressing solid tumor types (Tables 2, 3, and 4).

4.1. Phase 1 studies

DS8201-A-J101 was an open-label, dose-escalation, and 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 study established 5.4 mg/kg or 6.4 mg/kg as recom-mended doses, no dose-limiting toxicities were observed, and the maximum tolerated dose was not reached [54]. Patients had antitumor activity regardless of their HER2 status, as among the 23 patients (6 of whom had HER2- low tumors), 10 patients achieved objective response (43%; 95% CI, 23.2–65.5) and 21 patients achieved disease con-trol (91%; 72.0–98.9) [54]. The dose-expansion portion of the study in HER2-positive mBC patients showed prelimin-ary antitumor activity, with confirmed objective response rate (ORR) of 59.5% (95% CI, 49.7–68.7) [59].

As part of the dose-expansion portion of the phase 1 trial, 54 patients with extensively pretreated HER2-low mBC were enrolled (median, 7.5 prior therapies) [60]. Confirmed ORR was 37.0% (20/54; 95% CI, 24.3–51.3), with a median duration of response (mDOR) of 10.4 months (8.8–not eva-luable [NE]). Antitumor activity was also seen in other HER2- 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) [21,64].

4.2. Phase 2 studies

DESTINY-Breast01 was a two-part, open-label, single-group, multicenter, phase 2 study that evaluated T-DXd in adult patients with HER2-positive mBC who were heavily pretreated, including with T-DM1 (median of six previous lines of therapy) [61]. The pharmacokinetics portion of the study established 5.4 mg/kg as the recommended dose based on the balance of safety and efficacy [61]. ORR was 61.4% (113/184); the mDOR was 20.8 months (95% CI, 15.0–not evaluable), and mPFS was 19.4 months (14.1–NE) [62]. ORR and mPFS of patients who had brain metastases at baseline were comparable (58.3% [14/ 24] and 18.1 months [95% CI, 6.7–18.1], respectively). Interestingly, brain progression was observed at time of pro-gression in only 8% of patients (4/48) without brain metastatic involvement at time of enrollment [64]. The estimated overall survival (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) [62].

Phase 2 trials have also evaluated T-DXd in CRC, GC, and NSCLC. In the single-arm DESTINY-CRC01 trial, confirmed ORR was 45.3% (95% CI, 31.6–59.6), mPFS was 6.9 months (4.1–NE), and mOS was not reached [65]. In the rando-mized DESTINY-Gastric01 trial, the ORR was 51% (95% CI, 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 8.4 months (6.9–10.7) for chemotherapy-treated patients [61]. In the DESTINY-Lung01 trial, the interim confirmed ORR was 61.9% (95% CI, 45.6–76.4) and interim estimated 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 (2.8–7.0) in patients with HER2-overexpressing NSCLC [66,67].

4.3. Phase 3 studies

There are five ongoing phase 3 BC T-DXd trials. DESTINY-Breast02 will compare the efficacy and safety of T-DXd with those of the investigator’s choice of therapy in patients with HER2-positive unresectable and/or mBC pretreated with T-DM1 [68]. DESTINY- Breast03 will compare the efficacy and safety of T-DXd vs T-DM1 in patients with HER2-positive unresectable and/or mBCpreviously treated with trastuzumab and a taxane [69], while DESTINY-Breast05 will compare T-DXd with T-DM1 in patients with HER2-positive primary BC who have residual inva-sive disease in breast or axillary lymph nodes, DESTINY-Breast04 will compare the efficacy and safety of T-DXd and those of investigator’s choice of treatment in HER2-low unresectable and/or mBC [70], and DESTINY-Breast06 will compare T-DXd with capecitabine, paclitaxel, or nab-paclitaxel in HER2-low, hor-mone receptor-positive mBC after ≥2 previous lines of endocrine therapy. The results from these trials are expected to further inform the optimal use of T-DXd in patients with BC.

5. Safety and tolerability

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 3) [59,61,63,65,66]. The most common (≥10%) grade ≥3 TEAEs were decreased neutrophil count, anemia, nausea, decreased white cell count, and decreased platelet count [59,61,62,65,66].

Interstitial lung disease (ILD)/pneumonitis is an important risk for patients treated with T-DXd and must be closely monitored and managed according to recommended guidelines. Early identifica-tion, diagnosis, and intervention are important for optimal man-agement; patients must be counseled to report any pulmonary symptoms as soon as possible. When ILD/pneumonitis is sus-pected, treatment with T-DXd should be interrupted and patients should be evaluated via high-resolution computed tomography, pulmonologist consultation, pulmonary function testing, and oxy-gen saturation; arterial blood gas should be considered if ILD/ pneumonitis is clinically indicated [61]. Corticosteroid treatment should be started promptly at doses based on the severity of ILD/ pneumonitis [61,72]. In the DESTINY-Breast01 study, 15.2% of patients had ILD/pneumonitis, with 82.1% grade ≤4 (23/28) [62].

EXPERT OPINION ON BIOLOGICAL THERAPY 5

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rt (

0.8,

1.6

, 3.2

, and

8.0

mg/

kg)

or 6

pa

tient

s (5

.4 a

nd 6

.4 m

g/kg

)●

Ther

e w

ere

3 pa

tient

s in

eac

h of

the

fol

low

ing

coho

rts

– 0.

8, 1

.6, 3

.2, a

nd 8

.0 m

g/

kg –

and

6 p

atie

nts

in t

he 5

.4 –

and

6.4

-mg/

kg c

ohor

ts●

Ther

e w

ere

no d

ose-

limiti

ng t

oxic

ities

, and

max

imum

tol

erat

ed d

ose

was

not

re

ache

d [5

4]●

The

dose

-exp

ansi

on p

ortio

n of

the

stu

dy in

HER

2-po

sitiv

e BC

pat

ient

s sh

owed

pr

elim

inar

y an

titum

or a

ctiv

ity, w

ith c

onfir

med

ORR

of

59.5

% (

95%

CI,

49.7

–68.

7)

[59]

●In

the

dos

e-ex

pans

ion

port

ion

of t

he s

tudy

in H

ER2-

low

BC

patie

nts,

con

firm

ed O

RR

was

37.

0% (

20/5

4; 9

5% C

I, 24

.3–5

1.3)

, with

a m

DO

R of

10.

4 m

onth

s (8

.8 t

o no

t ev

alua

ble)

[60

]

DS8

201-

A-A1

04N

CT03

3836

921

Adva

nced

sol

id H

ER2-

posi

tive

mal

igna

nt t

umor

with

≥1

prio

r sy

stem

ic c

hem

othe

rapy

re

gim

en

T-D

Xd w

ith r

itona

vir

or T

-DXd

w

ith it

raco

nazo

le●

This

was

a p

hase

1 s

tudy

to

eval

uate

pot

entia

l DD

Is b

etw

een

T-D

Xd a

nd O

ATP1

B/

CYP3

A in

hibi

tor

●Th

ere

wer

e no

clin

ical

ly m

eani

ngfu

l DD

Is b

etw

een

T-D

Xd a

nd r

itona

vir

(a d

ual

OAT

P1B/

CYP3

A in

hibi

tor)

or

itrac

onaz

ole

(a C

YP3A

inhi

bito

r) [

57]

●In

26

patie

nts,

the

con

com

itant

use

of

riton

avir

or it

raco

nazo

le r

esul

ted

in

a m

inim

al in

crea

se in

exp

osur

e of

T-D

Xd

DES

TIN

Y-Br

east

01N

CT03

2484

922

T-D

M1-

resi

stan

t/-r

efra

ctor

y an

d T-

DM

1-ex

plor

ator

y H

ER2-

po

sitiv

e BC

T-D

Xd●

DES

TIN

Y-Br

east

01 w

as a

pha

se 2

stu

dy t

hat

show

ed a

ntitu

mor

act

iviti

es in

T-D

Xd

in a

dult

patie

nts

with

HER

2-po

sitiv

e m

etas

tatic

BC

who

wer

e he

avily

pre

trea

ted

(med

ian

of 6

pre

viou

s lin

es o

f th

erap

y), w

hich

mus

t ha

ve in

clud

ed T

-DM

1 [6

1,62

]

●Th

e ph

arm

acok

inet

ics

port

ion

of t

he s

tudy

est

ablis

hed

5.4

mg/

kg a

s th

e re

com

men

ded

dose

bas

ed o

n th

e ba

lanc

e of

saf

ety

and

effic

acy

●Am

ong

184

patie

nts,

a r

espo

nse

was

rep

orte

d in

113

pat

ient

s (6

1.4%

)●

mD

OR

was

20.

8 m

onth

s (9

5% C

I, 20

.8–N

E), a

nd m

PFS

was

19.

4 m

onth

s (1

4.1–

N

E)●

Estim

ated

OS

was

85%

(95

% C

I, 79

–90)

at

12 m

onth

s an

d 74

% (

67–8

0) a

t 18

mon

ths;

mO

S w

as 2

4.6

mon

ths

(23.

1–N

E)●

The

mos

t co

mm

on g

rade

≥3

AEs

wer

e de

crea

sed

neut

roph

il co

unt

(20.

7%),

anem

ia

(8.7

%),

and

naus

ea (

7.6%

) [6

1]●

ILD

/pne

umon

itis

was

obs

erve

d in

15.

2% o

f pa

tient

s (g

rade

5, 2

.7%

) [6

2]

DES

TIN

Y-CR

C01

NCT

0338

4940

2H

ER2-

posi

tive

(IHC3

+ o

r IH

C2

+/IS

H-p

ositi

ve)

CRC,

HER

2 IH

C2+

/ISH

-neg

ativ

e CR

C, a

nd

HER

2 IH

C1+

CRC

with

≥2

prio

r re

gim

ens

T-D

Xd●

DES

TIN

Y-CR

C01

was

a p

hase

2 s

tudy

sho

win

g th

e an

titum

or a

ctiv

ity o

f T-

DXd

in

adul

t pa

tient

s w

ith m

etas

tatic

CRC

with

var

ying

HER

2 st

atus

who

had

≥2

prio

r re

gim

ens

[63]

●In

HER

2-po

sitiv

e m

CRC

patie

nts

(n =

53)

, con

firm

ed O

RR w

as 4

5.3%

(95

% C

I, 31

.6–5

9.6)

, mPF

S w

as 6

.9 m

onth

s (4

.1 t

o no

t ev

alua

ble)

, and

mO

S w

as n

ot

reac

hed

●N

o re

spon

ses

wer

e ob

serv

ed f

or t

he 2

HER

2-lo

w c

ohor

ts (

n =

7 a

nd n

= 1

8)●

Gra

de 3

TEA

Es w

ere

obse

rved

in 6

1.5%

of

patie

nts,

and

the

mos

t co

mm

on T

EAEs

w

ere

decr

ease

d ne

utro

phil

coun

t (2

1.8%

) an

d an

emia

(14

.1%

) [6

5]●

5 pa

tient

s (6

.4%

) ha

d IL

D/p

neum

oniti

s (g

rade

2, 2

pat

ient

s; g

rade

3, 1

pat

ient

; gr

ade

5, 2

pat

ient

s) [

65]

●Th

e 2

grad

e 5

ILD

/pne

umon

itis

case

s le

d to

the

onl

y tr

eatm

ent-

rela

ted

deat

hs

6 J. PEREZ ET AL.

Tabl

e 2.

(Co

ntin

ued)

.

Tria

lCl

inic

alTr

ials

.gov

Id

entif

ier

Phas

eTu

mor

Typ

esCo

mpo

unds

Mai

n Fi

ndin

gs

DES

TIN

Y-G

astr

ic01

NCT

0332

9690

2H

ER2-

over

expr

essi

ng (

IHC3

+ o

r IH

C2+

/ISH

-pos

itive

) adv

ance

d G

C or

GEJ

ade

noca

rcin

oma

with

≥2

prio

r re

gim

ens,

tr

eatm

ent-

naiv

e H

ER2

IHC2

+

/ISH

-pos

itive

adv

ance

d G

C or

GEJ

ade

noca

rcin

oma,

tr

eatm

ent-

naiv

e IH

C1

+ a

dvan

ced

GC

or G

EJ

aden

ocar

cino

ma

T-D

Xd c

ompa

red

with

iri

note

can

or p

aclit

axel

m

onot

hera

py

●D

ESTI

NY-

Gas

tric

01 w

as a

pha

se 2

stu

dy s

how

ing

the

antit

umor

act

ivity

of T

-DXd

in

adul

t pa

tient

s w

ith H

ER2-

posi

tive

adva

nced

GC

or G

EJ a

deno

carc

inom

a w

ith

vary

ing

HER

2 st

atus

pre

viou

sly

trea

ted

usin

g ≥

2 re

gim

ens

[61]

●O

RR w

as 5

1% (

95%

CI,

42–6

1), m

PFS

was

5.6

mon

ths

(4.3

–6.9

), an

d m

OS

was

12

.5 m

onth

s (9

.6–1

4.3)

for

T-D

Xd-t

reat

ed p

atie

nts

●Co

rres

pond

ing

valu

es w

ere

14%

(95

% C

I, 6–

26),

3.5

mon

ths

(2.0

–4.3

), an

d 8.

4 m

onth

s (6

.9–1

0.7)

for

che

mot

hera

py-t

reat

ed p

atie

nts

●Th

e m

ost

com

mon

gra

de ≥

3 AE

s w

ere

decr

ease

d ne

utro

phil

coun

t (5

1% in

T-D

Xd

grou

p an

d 24

% in

che

mot

hera

py g

roup

), an

emia

(38

% a

nd 2

3%)

and

decr

ease

d w

hite

cel

l cou

nt (

21%

and

11%

) [6

1]●

12 p

atie

nts

in th

e T-

DXd

gro

up h

ad IL

D/p

neum

oniti

s (g

rade

1 o

r 2 in

9 p

atie

nts

and

grad

e 3

or 4

in 3

pat

ient

s) [

61]

DES

TIN

Y-Lu

ng01

NCT

0350

5710

2H

ER1-

over

expr

essi

ng (

IHC3

+ o

r IH

C2+

) un

rese

ctab

le a

nd/o

r m

etas

tatic

NSC

LC, H

ER2-

m

utat

ed u

nres

ecta

ble

and/

or

met

asta

tic N

SCLC

tha

t re

laps

ed f

rom

or

is r

efra

ctor

y to

sta

ndar

d tr

eatm

ent

or f

or

whi

ch n

o st

anda

rd t

reat

men

t is

ava

ilabl

e

T-D

Xd●

DES

TIN

Y-Lu

ng01

was

a p

hase

2 s

tudy

sho

win

g th

e an

titum

or a

ctiv

ity o

f T-

DXd

in

adul

t pa

tient

s w

ith H

ER2-

posi

tive

or H

ER2-

mut

ated

met

asta

tic N

SCLC

with

var

ying

H

ER2

stat

us [

65]

●Co

nfirm

ed O

RR f

or p

atie

nts

with

HER

2 m

utat

ions

was

61.

9% (

95%

CI,

45.6

–76.

4)

and

estim

ated

mPF

S w

as 1

4.0

mon

ths

(6.4

–14.

0)●

Out

of

42 p

atie

nts,

64.

3% h

ad g

rade

≥3

AEs,

incl

udin

g de

crea

sed

neut

roph

il co

unt

(26.

2%)

and

anem

ia (

16.7

%)

[65]

●5

patie

nts

had

ILD

/pne

umon

itis

and

all o

ccur

renc

es w

ere

grad

e 2

[65]

AE,

adve

rse

even

t; BC

, br

east

can

cer;

CI,

conf

iden

ce i

nter

val;

CRC,

col

orec

tal

canc

er;

DD

I, dr

ug–d

rug

inte

ract

ion;

GC,

gas

tric

can

cer;

GEJ

, ga

stro

esop

hage

al j

unct

ion;

HER

2, h

uman

epi

derm

al g

row

th f

acto

r re

cept

or 2

; IH

C,

imm

unoh

isto

chem

istr

y; IL

D, i

nter

stiti

al lu

ng d

isea

se; I

SH, i

n si

tu h

ybrid

izat

ion;

mD

OR,

med

ian

dura

tion

of r

espo

nse;

mO

S, m

edia

n ov

eral

l sur

viva

l; m

PFS,

med

ian

prog

ress

ion-

free

sur

viva

l; N

SCLC

, non

–sm

all c

ell l

ung

canc

er;

ORR

, obj

ectiv

e re

spon

se r

ate;

T-D

M1,

tra

stuz

umab

em

tans

ine;

T-D

Xd, t

rast

uzum

ab d

erux

teca

n.

EXPERT OPINION ON BIOLOGICAL THERAPY 7

Tabl

e 3.

Sum

mar

y of

ong

oing

T-D

Xd b

reas

t ca

ncer

clin

ical

tria

ls [

66].

Tria

lPh

ase

Tum

or

type

sPo

pula

tion

N (

estim

ated

)Co

mpo

unds

Stud

y su

mm

ary

Prim

ary

endp

oint

Clin

ical

Tria

ls.

gov

iden

tifie

r

DES

TIN

Y-Br

east

081

BCH

ER2-

low

adv

ance

d or

met

asta

tic B

C18

5T-

DXd

in c

ombi

natio

n w

ith d

urva

lum

ab/

pacl

itaxe

l, ca

piva

sert

ib,

anas

troz

ole,

fu

lves

tran

t, or

ca

peci

tabi

ne

Inve

stig

ate

safe

ty, t

oler

abili

ty, P

K an

d pr

elim

inar

y an

titum

or a

ctiv

ity o

f T-

DXd

in

com

bina

tion

with

oth

er t

hera

pies

in H

ER-

2-lo

w a

dvan

ced

or m

etas

tatic

BC

Occ

urre

nce

of A

Es

and

serio

us

AEs

NCT

0455

6773

BEG

ON

IA1/

2BC

Met

asta

tic T

NBC

170

Dur

valu

mab

in

com

bina

tion

with

ca

piva

sert

ib,

olec

lum

ab, o

r T-

DXd

w

ith o

r w

ithou

t pa

clita

xel

Det

erm

ine

safe

ty a

nd e

ffica

cy o

f du

rval

umab

in

com

bina

tion

with

nov

el t

arge

ted

ther

apie

s w

ith o

r w

ithou

t pa

clita

xel a

nd

durv

alum

ab+

pacl

itaxe

l for

firs

t-lin

e m

etas

tatic

TN

BC

Inci

denc

e of

AEs

, la

bora

tory

fin

ding

s

NCT

0374

2102

DES

TIN

Y-Br

east

071/

2BC

HER

2-po

sitiv

e m

etas

tatic

BC

350

T-D

Xd in

com

bina

tion

with

dur

valu

mab

, pa

clita

xel,

durv

alum

ab/

pacl

itaxe

l, or

pe

rtuz

umab

Inve

stig

ate

safe

ty, t

oler

abili

ty, a

nd a

ntitu

mor

ac

tivity

of T

-DXd

in c

ombi

natio

n w

ith o

ther

th

erap

ies

in H

ER2-

posi

tive

met

asta

tic B

C

Occ

urre

nce

of A

Es

and

serio

us

AEs

NCT

0453

8742

DEB

BRAH

2BC

Pret

reat

ed, u

nres

ecta

ble

loca

lly a

dvan

ced

or

met

asta

tic H

ER2-

posi

tive

or H

ER2-

low

ex

pres

sing

BC

with

unt

reat

ed o

r tr

eate

d br

ain

met

asta

ses

or le

ptom

enin

geal

car

cino

mat

osis

39T-

DXd

Stud

y of

T-D

Xd in

HER

2-po

sitiv

e ad

vanc

ed B

C w

ith b

rain

met

asta

ses

and/

or

lept

omen

inge

al c

arci

nom

atos

is

Coho

rt 1

: PF

S;

coho

rts

2–4:

CN

S O

RR;

coho

rt 5

: O

S

NCT

0442

0598

HER

2CLI

MB-

042

BCH

ER2-

posi

tive

unre

sect

able

or

met

asta

tic B

C70

Com

bina

tion

ther

apy

of

T-D

Xd a

nd t

ucat

inib

Stud

y of

effi

cacy

and

saf

ety

of t

ucat

inib

in

com

bina

tion

with

T-D

Xd in

HER

2-po

sitiv

e m

etas

tatic

or

unre

sect

able

BC

ORR

NCT

0453

9938

Tras

tuzu

mab

Der

uxte

can

Alon

e or

Co

mbi

natio

n W

ith A

nast

rozo

le

for

the

Trea

tmen

t of

Ear

ly

Stag

e H

ER2-

Low

, Hor

mon

e Re

cept

or P

ositi

ve B

reas

t Can

cer

2BC

HER

2-lo

w, h

orm

one

rece

ptor

–pos

itive

BC

88T-

DXd

mon

othe

rapy

or

in c

ombi

natio

n w

ith

anas

troz

ole

Inve

stig

ate

the

effic

acy

of T

-DXd

m

onot

hera

py o

r in

com

bina

tion

with

an

astr

ozol

e in

the

tre

atm

ent

of p

atie

nts

with

HER

2-lo

w, h

orm

one

rece

ptor

-pos

itive

BC

Path

olog

ic

com

plet

e re

spon

se

rate

NCT

0455

3770

DES

TIN

Y-Br

east

023

BCH

ER2-

posi

tive

unre

sect

able

and

/or

met

asta

tic B

C pr

evio

usly

tre

ated

with

sta

ndar

d-of

-car

e H

ER2

ther

apie

s (e

g, T

-DM

1)

600

T-D

Xd c

ompa

red

with

tr

astu

zum

ab/

cape

cita

bine

or

lapa

tinib

/ ca

peci

tabi

ne

Com

pare

T-D

Xd t

o st

anda

rd o

f ca

re

chem

othe

rapy

in u

nres

ecta

ble

and/

or

met

asta

tic B

C pr

evio

usly

tre

ated

with

T-

DM

1

PFS

NCT

0352

3585

DES

TIN

Y-Br

east

033

BCH

ER2-

posi

tive

unre

sect

able

and

/or

met

asta

tic B

C pr

evio

usly

tre

ated

with

tra

stuz

umab

and

tax

ane

500

T-D

Xd c

ompa

red

with

T-

DM

1Co

mpa

re s

afet

y, e

ffica

cy, a

nd a

ntitu

mor

ac

tivity

of T

-DXd

to T

-DM

1 in

HER

2-po

sitiv

e un

rese

ctab

le a

nd/o

r m

etas

tatic

BC

prev

ious

ly t

reat

ed w

ith t

rast

uzum

ab a

nd

taxa

ne

PFS

NCT

0352

9110

DES

TIN

Y-Br

east

043

BCH

ER2-

low

, unr

esec

tabl

e, a

nd/o

r m

etas

tatic

BC

prev

ious

ly t

reat

ed w

ith c

hem

othe

rapy

557

T-D

Xd c

ompa

red

with

ca

peci

tabi

ne,

erib

ulin

, ge

mci

tabi

ne,

pacl

itaxe

l, or

nab

- pa

clita

xel

Com

pare

saf

ety

and

effic

acy

of T

-DXd

to

phys

icia

n’s

choi

ce s

tand

ard

chem

othe

rapy

in

HER

2-lo

w u

nres

ecta

ble

and/

or

met

asta

tic B

C

PFS

NCT

0373

4029

(Con

tinue

d)

8 J. PEREZ ET AL.

Similarly, in other completed trials, ILD/pneumonitis was reported in ≈10% of patients, and most cases were either grade 1 or grade 2, except for DESTINY-CRC01, in which ILD/pneumonitis was grade 2 in 2 patients, grade 3 in 1 patient, and grade 5 in 2 patients [59,61,65,66]. T-DXd can be restarted after recovery for patients with grade 1 ILD/pneumonitis and should be permanently discon-tinued for any patient diagnosed with symptomatic (grade ≥2) ILD/pneumonitis [54].

6. Regulatory affairs

T-DXd was approved on 20 December 2019 in the United States for the treatment of unresectable or metastatic HER2- positive BC after ≥2 prior anti-HER2–targeted therapies, on 25 September 2020 in Japan for HER2-positive unresectable or mBC, and on 20 January 2021 in Europe for treatment of unresectable or metastatic HER2-positive BC after ≥2 prior anti-HER2–targeted therapies (Box 1).

Box 1. Drug Summary Box

Tabl

e 3.

(Co

ntin

ued)

.

Tria

lPh

ase

Tum

or

type

sPo

pula

tion

N (

estim

ated

)Co

mpo

unds

Stud

y su

mm

ary

Prim

ary

endp

oint

Clin

ical

Tria

ls.

gov

iden

tifie

r

DES

TIN

Y-Br

east

053

BCH

ER2-

posi

tive

prim

ary

BC w

ith r

esid

ual i

nvas

ive

dise

ase

in b

reas

t or

axi

llary

lym

ph n

odes

with

hi

gher

ris

k of

rec

urre

nce,

incl

udin

g on

es t

hat

wer

e in

oper

able

at

dise

ase

pres

enta

tion

or h

ad

path

olog

ical

nod

e-po

sitiv

e st

atus

aft

er

neoa

djuv

ant

ther

apy

1600

T-D

Xd c

ompa

red

with

T-

DM

1Co

mpa

re s

afet

y an

d ef

ficac

y of

T-D

Xd w

ith

T-D

M1

in h

igh-

risk

patie

nts

with

res

idua

l in

vasi

ve B

C fo

llow

ing

neoa

djuv

ant

ther

apy

Inva

sive

di

seas

e-

free

su

rviv

al

NCT

0462

2319

DES

TIN

Y-Br

east

063

BCH

ER2-

low

, hor

mon

e re

cept

or–p

ositi

ve a

dvan

ced

or

met

asta

tic B

C tr

eate

d w

ith ≥

2 pr

evio

us li

nes

of

endo

crin

e th

erap

y

850

T-D

Xd c

ompa

red

with

ca

peci

tabi

ne,

pacl

itaxe

l, or

nab

- pa

clita

xel

Com

pare

effi

cacy

, saf

ety,

and

tol

erab

ility

of

T-D

Xd w

ith in

vest

igat

or’s

choi

ce

chem

othe

rapy

in H

ER2-

low

, hor

mon

e re

cept

or-p

ositi

ve m

etas

tatic

BC

patie

nts

who

hav

e pr

ogre

ssed

on

endo

crin

e th

erap

y

PFS

NCT

0449

4425

AE, a

dver

se e

vent

; BC,

bre

ast

canc

er; H

ER2,

hum

an e

pide

rmal

gro

wth

fac

tor

rece

ptor

2; O

RR, o

bjec

tive

resp

onse

rat

e; O

S, o

vera

ll su

rviv

al; P

FS, p

rogr

essi

on-f

ree

surv

ival

; T-D

M1,

tra

stuz

umab

em

tans

ine;

T-D

Xd, t

rast

uzum

ab

deru

xtec

an; T

NBC

, trip

le-n

egat

ive

brea

st c

ance

r.

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

Phase Breast cancer (BC): 3 Gastric cancer (GC): 2 Colorectal cancer (CRC): 2 Non–small cell lung cancer (NSCLC): 2

Indication In the United States, T-DXd is indicated to treat adult patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive BC who have previously received ≥2 anti-HER2-based therapies for metastases and advanced or metastatic HER2- positive gastric or gastroesophageal adenocarcinoma who have received a prior trastuzumab-based regimen.

In Japan, T-DXd is indicated to treat adult patients with HER2-positive unresectable or metastatic BC and HER2-positive unresectable advanced or recurrent GC that has progressed after chemotherapy

In the European Union, T-DXd is indicated to treat unresectable or metastatic HER2-positive BC who have previously received ≥2 HER2- based regimens

Pharmacology description/ mechanism of action

T-DXd is a HER2-targeted antibody-drug conjugate. The antibody is a humanized anti- HER2 immunoglobulin G1, and the payload is a topoisomerase I inhibitor. T-DXd binds to HER2 on tumor cells, is internalized, and is cleaved by lysosomal enzymes. The membrane-permeable payload causes DNA damage and apoptosis, killing the tumor cells

Route of administration Intravenous infusion once every 3 weeks (21-day cycle) at a dose of 5.4 mg/kg body weight (for BC) or 6.4 mg/kg (for GC, CRC, and NSCLC)

Pivotal trials BC: Results from DESTINY-Breast01 led to approval in both the United States and Japan for patients with unresectable or metastatic HER2-positive BC who had received ≥2 prior anti-HER2-based therapies for metastases GC: Results from DESTINY-Gastric01 led to approval in Japan for patients with HER2- positive unresectable advanced or recurrent GC that progressed after chemotherapy

EXPERT OPINION ON BIOLOGICAL THERAPY 9

Tabl

e 4.

Sum

mar

y of

ong

oing

T-D

Xd c

linic

al t

rials

for

oth

er s

olid

tum

or in

dica

tions

[58

].

Tria

lPh

ase

Tum

or t

ypes

Popu

latio

nCo

mpo

unds

Clin

ical

Trai

ls.

gov

iden

tifie

r

DS8

201-

A-U

106

1BC

, NSC

LCPa

rt 1

(do

se e

scal

atio

n): H

ER2-

posi

tive

BC, H

ER2-

low

BC,

HER

2-

expr

essi

ng N

SCLC

, HER

2-m

utan

t N

SCLC

Pa

rt 2

(do

se e

xpan

sion

): T-

DM

1-tr

eate

d H

ER2-

posi

tive

BC, H

ER2-

lo

w B

C w

ith f

aile

d pr

ior

stan

dard

tre

atm

ents

, HER

2-ex

pres

sing

N

SCLC

with

no

prio

r an

ti–PD

-1, a

nti–

PD-L

1, o

r H

ER2

agen

ts, a

nd

HER

2-m

utan

t N

SCLC

with

no

prio

r an

ti–PD

-1, a

nti–

PD-L

1, o

r H

ER2

agen

ts

T-D

Xd w

ith p

embr

oliz

umab

NCT

0404

2701

Test

ing

the

Biol

ogic

al E

ffect

s of

DS-

82

01a

on P

atie

nts

With

Adv

ance

d Ca

ncer

1So

lid t

umor

sH

ER2-

posi

tive

met

asta

tic, r

efra

ctor

y, a

nd/o

r un

rese

ctab

le s

olid

tum

orT-

DXd

NCT

0429

4628

Test

ing

the

Com

bina

tion

of D

S-82

01a

and

Ola

parib

in H

ER2-

Expr

essi

ng

Canc

ers

With

Exp

ansi

on in

Pat

ient

s W

ith E

ndom

etria

l Can

cer

1En

dom

etria

l Se

rous

Ad

enoc

arci

nom

aH

ER2-

posi

tive

endo

met

rial s

erio

us a

deno

carc

inom

aT-

DXd

in

com

bina

tion

with

ola

parib

NCT

0458

5958

Tras

tuzu

mab

Der

uxte

can

With

Niv

olum

ab in

Adv

ance

d Br

east

and

U

roth

elia

l Can

cer

1

BC, u

roth

elia

l can

cer

HER

2-

expr

essi

ng B

C an

d ur

othe

lial

canc

er in

pa

tient

s w

ho

expe

rienc

ed

dise

ase

prog

ress

ion

durin

g or

af

ter

prio

r th

erap

y, d

id

not

resp

ond

to s

tand

ard

ther

apy,

or

for

who

m n

o st

anda

rd

ther

apy

is

avai

labl

e

T-D

Xd in

com

bina

tion

with

niv

olum

abN

CT03

5235

72

DES

TIN

Y-G

astr

ic02

2G

C/G

EJH

ER2-

posi

tive

adva

nced

, unr

esec

tabl

e, o

r m

etas

tatic

GC

or G

EJ

canc

er t

hat

wor

sene

d du

ring

or a

fter

tre

atm

ent

that

incl

uded

tr

astu

zum

ab

T-D

XdN

CT04

0140

75

DES

TIN

Y-G

astr

ic03

2G

C/G

EJH

ER2-

posi

tive

adva

nced

/met

asta

tic G

C or

GEJ

ade

noca

rcin

oma

T-D

Xd m

onot

hera

py o

r in

com

bina

tion

with

5-F

U, o

xalip

latin

, tr

astu

zum

ab, c

ispl

atin

, or

durv

alum

ab;

T-D

Xd a

nd 5

-FU

or

cape

cita

bine

and

oxa

lipla

tin; T

-DXd

, du

rval

umab

and

5-F

U o

r ca

peci

tabi

ne; t

rast

uzum

ab, 5

-FU

/ ca

peci

tabi

ne, a

nd c

ispl

atin

/oxa

lipla

tin; T

-DXd

, 5-F

U o

r ca

peci

tabi

ne, a

nd o

xalip

latin

; T-D

Xd, 5

-FU

or

cape

cita

bine

, and

du

rval

umab

NCT

0437

9596

DES

TIN

Y-Pa

nTum

or02

2H

ER2-

expr

essi

ng

tum

ors

HER

2-ex

pres

sing

tum

ors

(uro

thel

ial b

ladd

er c

ance

r, bi

liary

tra

ct

canc

er, c

ervi

cal c

ance

r, en

dom

etria

l can

cer,

ovar

ian

canc

er,

panc

reat

ic c

ance

r, an

d ra

re t

umor

s)

T-D

XdN

CT04

4823

09

HU

DSO

N2

NSC

LCM

etas

tatic

NSC

LC p

rogr

esse

d w

ith a

nti–

PD-1

–con

tain

ing/

anti–

PD-

L1–c

onta

inin

g th

erap

yD

urva

lum

ab in

com

bina

tion

with

AZD

9150

, AZD

6738

, vis

tuse

rtib

, ol

apar

ib, o

lecl

umab

, T-D

Xd, o

r ce

dira

nib;

AZD

6738

mon

othe

rapy

NCT

0333

4617

5-FU

, 5-f

luor

oura

cil;

anti-

PD-1

, ant

i–pr

ogra

mm

ed c

ell d

eath

1; a

nti-P

D-L

1, a

nti–

prog

ram

med

cel

l dea

th li

gand

1; B

C, b

reas

t ca

ncer

; GC,

gas

tric

can

cer;

GEJ

, gas

troe

soph

agea

l jun

ctio

n; H

ER2,

hum

an e

pide

rmal

gro

wth

fac

tor

rece

ptor

2; N

SCLC

, non

–sm

all c

ell l

ung

canc

er; T

-DM

1, t

rast

uzum

ab e

mta

nsin

e; T

-DXd

, tra

stuz

umab

der

uxte

can.

10 J. PEREZ ET AL.

T-DXd was approved for previously treated HER2-positive unre-sectable advanced or recurrent GC in Japan on 25 September 2020 and previously treated advanced or metastatic HER2-positive gas-tric or gastroesophageal adenocarcinoma in the United States on 15 January 2021. For HER2-positive NSCLC, T-DXd received Breakthrough Therapy Designation in the United States on 18 May 2020.

7. Conclusion

T-DXd showed unprecedented activity in heavily pretreated patients with advanced HER2-positive BC in the phase 2 DESTINY-Breast01 clinical trial [61]. Based on clinical trial results, T-DXd was approved in the United States, Japan, and Europe for the treatment of advanced HER2-positive BC. Ongoing phase 3 trials to compare T-DXd to physician’s choice in patients previously treated with T-DM1 and to compare T-DXd to T-DM1 will provide a clearer idea of how and where T-DXd should be used to treat HER2-positive mBC.

Since T-DXd showed antitumor activity in HER2-low mBC patients [60,73], it is being evaluated in 2 phase 3 trials in this patient population. Activity in HER2-low mBC would define 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 patients with HER2-low TNBC. T-DXd was also recently approved in Japan and the United States for the treatment of advanced HER2-positive GC based on the results of the DESTINY-Gastric01 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].

Although the types of adverse events were consistent across T-DXd trials and were generally manageable, ILD/pneumonitis is a notable risk and necessitates thorough patient monitoring and prompt intervention and management [54,59,60,61,63–65,74]. Based on recent clinical trial data, T-DXd represents a valuable addition to the toolkit for treatment of HER2-expressing meta-static solid tumors.

8. Expert opinion

Although there have been many improvements in the treat-ment of HER2-positive mBC in the last 2 decades since the approval of trastuzumab, there is still substantial unmet need. Ultimately, resistance develops, and better treatments are needed, especially as third-line therapy or later. T-DXd is cur-rently approved in the United States and Europe for patients with HER2-positive mBC who had ≥2 prior HER2-targeted therapies, which suggests T-DXd can be a potential treatment option after first-line combination therapy comprising taxanes, trastuzumab, and pertuzumab, and second-line T-DM1, similar to the combination of capecitabine, trastuzumab, and tucati-nib. However, T-DXd is likely to become the new standard of care as second-line therapy for HER2-positive mBC as it is anticipated to outperform T-DM1 in an ongoing trial. T-DXd treatment could also be advantageous for patients with hormone receptor-positive and HER2-low mBC who are che-motherapy-naïve, had prior chemotherapy, or who failed

endocrine-therapy and for patients with HER2-low TNBC with prior therapy. The ongoing studies in patients with brain metastases will help define the role of T-DXd in this patient population. Several trials are ongoing for T-DXd in several solid tumor types (HER2-positive and HER2-low), which will inform how T-DXd can be used optimally.

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- positive GC in the United States and Japan, and is recom-mended in guidelines for HER2-mutant NSCLC and HER2- positive CRC [75–77].

ILD/pneumonitis is a notable risk associated with T-DXd that necessitates vigilance and prompt treatment and management. A history of lung disease should not auto-matically exclude patients from T-DXd treatment; each patient should be evaluated individually. Additional studies are necessary to determine the predisposing factors for ILD/pneumonitis and best management practices for redu-cing toxicity (e.g. inhaled corticosteroids). T-DXd is an important addition to available therapies for managing HER2-positive cancer.

Acknowledgments

Under the guidance of the authors, assistance in medical writing and editorial support was provided by Irene Park, PhD, and Alya Raphael, PhD, of ApotheCom, and was funded by Daiichi Sankyo.

Declaration of interestJ Perez has received consulting fees from Roche and Eli Lilly and travel expenses from Roche. P Jänne has received consulting fees from AstraZeneca, Boehringer Ingelheim, Pfizer, Roche/Genentech, Takeda Oncology, ACEA Biosciences, Eli Lilly, Araxes Pharma, Ignyta, Mirati Therapeutics, Novartis, LOXO Oncology, Daiichi Sankyo, Sanofi Oncology, Voronoi, SFJ Pharmaceuticals, Takeda Oncology, Silicon Therapeutics, Transcenta, and Biocartis; receives postmarketing royalties from DFCI- 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 Pharmaceuticals; and owns stock in LOXO Oncology and Gatekeeper Pharmaceuticals. K Shitara reports nonfinancial support from Daiichi Sankyo, during the drafting of this article; grants and personal fees from Astellas Pharma, Eli Lilly, Ono, Taiho, and Merck; personal fees from Bristol Myers Squibb, Takeda, Pfizer, Novartis, AbbVie, Yakult, and GlaxoSmithKline; and grants from Dainippon Sumitomo Pharma, Daiichi Sankyo, Chugai, and Medi Science, outside the submitted work. S Siena is an advisory board member for AstraZeneca, Daiichi Sankyo, and Seattle Genetics, outside the submitted work. J Cortés is an advisor for Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Eli Lilly, Servier, Merck Sharp & Dohme, GlaxoSmithKline, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, and Kyowa Kirin; has received honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Eli Lilly, Merck Sharp & Dohme, and Daiichi Sankyo; has received research funding to the institution from Roche, Ariad, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer, Eisai, F. Hoffman-La Roche, Guardant Health, Merck Sharp & Dohme, Pfizer, Piqur Therapeutics, Puma, and Queen Mary University of London; owns stock, patents, and intellectual property in MedSIR; and has received travel, accommodations, or expenses from Roche, Novartis, Eisai, Pfizer, and Daiichi Sankyo. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial

EXPERT OPINION ON BIOLOGICAL THERAPY 11

interest in or financial conflict with the subject matter or materials dis-cussed in the manuscript apart from those disclosed.

Author contributionsAll authors participated in the drafting and revising of the paper and gave final approval for the version to be published. All authors agree to be accountable for all aspects of the work.

List of Abbrevition

Funding

This paper is funded by Daiichi Sankyo.

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23. Tarantino P, Hamilton E, Tolaney SM, et al. HER2-low breast cancer: pathological and clinical landscape. J Clin Oncol. 2020;38(17):1951- 1962.

•• Highlighted the idea of HER2-low breast cancer as a targetable patient population.

24. Schalper KA, Kumar S, Hui P, et al. A retrospective population-based comparison of HER2 immunohistochemistry and fluorescence in situ hybridization in breast carcinomas: impact of 2007 American Society of Clinical Oncology/College of American Pathologists criteria. Arch Pathol Lab Med. 2014;138(2):213–219.

25. Hecht JR, Bang YJ, Qin SK, et al. Lapatinib in combination with capecitabine plus oxaliplatin in human epidermal growth factor receptor 2-positive advanced or metastatic gastric, esophageal,

ADC antibody-Qdrug conjugate

BC breast cancerCI confidence intervalCRC colorectal cancer

GC gastric cancerHER2 human epidermal growth factor receptor 2

HR hazard ratioIHC immunohistochemistry

ILD interstitial lung diseaseISH in situ hybridization

mBC metastatic breast cancermOS median overall survivalmPFS median progression-free survival

NE not evaluableNSCLC non&#x2013 small cell lung cancer

T-DM1 trastuzumab emtansineTEAE treatment-emergent adverse event

T-DXd trastuzumab deruxtecanTNBC triple-negative breast cancer.

12 J. PEREZ ET AL.

or gastroesophageal adenocarcinoma: TRIO-013/LOGiC–a ran-domized phase III trial. J Clin Oncol. 2016;34(5):443–451.

26. Makiyama A, Sukawa Y, Kashiwada T, et al. Randomized, phase II study of trastuzumab beyond progression in patients with HER2-positive advanced gastric or gastroesophageal junction cancer: WJOG7112G (T-ACT study). J Clin Oncol. 2020;38(17):1919–1927.

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28. Satoh T, Xu RH, Chung HC, et al. Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: tyTAN–a rando-mized, phase III study. J Clin Oncol. 2014;32(19):2039–2049.

29. Tabernero J, Hoff PM, Shen L, et al. Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): final analysis of a double-blind, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2018;19(10):1372–1384.

30. Thuss-Patience PC, Shah MA, Ohtsu A, et al., Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction ade-nocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol. 2017;18(5):640–653.

• Phase 2/3 clinical trial in which T-DM1 was not superior to taxane in patients with previously treated, HER2-positive advanced gastric cancer.

31. Wang D-S, Liu Z-X, Lu Y-X, et al. Liquid biopsies to track trastuzu-mab resistance in metastatic HER2-positive gastric cancer. Gut. 2019;68(7):1152.

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35. Lin NU, Borges V, Anders C, et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. J Clin Oncol. 2020;38(23):2610–2619.

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37. Sartore-Bianchi A, Lonardi S, Aglietta M, et al. Central nervous system as possible site of relapse in ERBB2-positive metastatic colorectal cancer: long-term results of treatment with trastuzumab and lapatinib. JAMA Oncol. 2020;6(6):927–929.

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39. Rugo HS, Im S-A, Wright GLS, et al. 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. 2019;37(15_suppl):1000.

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41. Alsina M, Boni V, Schellens JHM, et al. First-in-human phase 1/2 study of MCLA-128, a full length IgG1 bispecific antibody target-ing HER2 and HER3: final phase 1 data and preliminary activity in HER2+ metastatic breast cancer (MBC). J Clin Oncol. 2017;35 (15_suppl):2522.

42. Banerji U, CML VH, Saura C, et al. Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and

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43. Xu B, Wang J, Zhang Q, et al. An open-label, multicenter, phase Ib study to evaluate RC48-ADC in patients with HER2-positive meta-static breast cancer. J Clin Oncol. 2018;36(15_suppl):1028.

44. Saura C, Oliveira M, Feng YH, et al. Neratinib plus capecitabine versus lapatinib plus capecitabine in HER2-positive metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: phase III NALA trial. J Clin Oncol. 2020;38(27):3138–3149.

45. Jiang Z, Yan M, Hu X, et al. Pyrotinib combined with capecitabine in women with HER2+ metastatic breast cancer previously treated with trastuzumab and taxanes: a randomized phase III study. J Clin Oncol. 2019;37(15_suppl):1001.

46. Park YH, Lee KH, Sohn JH, et al. A phase II trial of the pan-HER inhibitor poziotinib, in patients with HER2-positive metastatic breast cancer who had received at least two prior HER2-directed regimens: results of the NOV120101-203 trial. Int J Cancer. 2018;143(12):3240–3247.

47. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382(7):597–609.

48. Lv Q, Meng Z, Yu Y, et al. Molecular mechanisms and translational therapies for human epidermal receptor 2 positive breast cancer. Int J Mol Sci. 2016;17(12):2095.

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50. Trail PA, Dubowchik GM, Lowinger TB. Antibody drug conjugates for treatment of breast cancer: novel targets and diverse approaches in ADC design. Pharmacol Ther. 2018;181:126–142.

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52. Nakada T, Sugihara K, Jikoh T, et al. The latest research and development into the antibody-drug conjugate, [fam-] trastuzumab deruxtecan (DS-8201a), for HER2 cancer therapy. Chem Pharm Bull. 2019;67 (3):173–185.

53. Nagai Y, Oitate M, Shiozawa H, et al. Comprehensive preclinical pharmacokinetic evaluations of trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate, in cyno-molgus monkeys. Xenobiotica. 2019;49(9):1086–1096.

54. Doi T, Shitara K, Naito Y, et al. Safety, pharmacokinetics, and anti-tumour activity of trastuzumab deruxtecan (DS-8201), a HER2- targeting antibody–drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose- escalation study. Lancet Oncol. 2017;18(11):1512–1522.

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• Preclinical study demonstrating the bystander killing effect of T-DXd.

57. Rahmati M, Nikmanesh Y, Abshorshori N. et al. Investigating the cytotoxic and anti-proliferative effects of trastuzumab on MDA-MB- 453 and MDA-MB-468 breast cell lines with different levels of HER2 expression. J Appl Biotechnology Rep. 2020;7(2):87–92.

58. Bang YJ, Karayama M, Takahashi M, et al. Pharmacokinetics (PK), safety, and efficacy of [fam-] trastuzumab deruxtecan with OATP1B/CYP3A inhibitors in subjects with HER2-expressing advanced solid tumours. Ann Oncol. 2019;30:v116–v117.

59. Tamura K, Tsurutani J, Takahashi S, et al., Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study. Lancet Oncol. 2019;20(6): 816–826.

• Phase 1 dose-expansion study of T-DXd in patients with HER2- positive BC previously treated with T-DM1.

EXPERT OPINION ON BIOLOGICAL THERAPY 13

60. Modi S, Park H, Murthy RK, et al., 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. 2020;38(17): 1887–1896.

• Phase 1b trial demonstrating the efficacy of T-DXd–expressing advanced BC.

61. Modi S, Saura C, Yamashita T, et al., Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382(7): 610–621.

•• Pivotal phase 2 trial demonstrating efficacy of T-DXd in HER2- positive BC.

62. Modi S, Saura C, Yamashita T, et al. Updated results from DESTINY-breast01, a phase 2 trial of trastuzumab deruxtecan (T-DXd) in HER2 positive metastatic breast cancer. Abstract presented at: San Antonio Breast Cancer Virtual Symposium; December 8–11, 2020.

63. Siena S, Di Bartolomeo M, Raghav KPS, et al. A phase II, multicenter, open-label study of trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): DESTINY-CRC01. J Clin Oncol. 2020;38(15):4000.

64. Shitara K, Bang YJ, Iwasa S, et al., Trastuzumab deruxtecan in previously treated HER2-Positive gastric cancer. N Engl J Med. 2020;382(25): 2419–2430.

•• Pivotal phase 2 trial demonstrating efficacy of T-DXd in HER2- positive GC.

65. Smit EF, Nakagawa K, Nagasaka M, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): interim results of DESTINY-Lung01. J Clin Oncol. 2020;38(15_suppl):9504.

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