trastuzumab deruxtecan in her2-positive metastatic breast
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Expert Opinion on Biological Therapy
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/iebt20
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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ere
wer
e ei
ther
3 p
atie
nts
in e
ach
coho
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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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– small cell lung cancer
T-DM1 trastuzumab emtansineTEAE treatment-emergent adverse event
T-DXd trastuzumab deruxtecanTNBC triple-negative breast cancer.
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• Phase 1 dose-expansion study of T-DXd in patients with HER2- positive BC previously treated with T-DM1.
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• Phase 1b trial demonstrating the efficacy of T-DXd–expressing advanced BC.
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•• Pivotal phase 2 trial demonstrating efficacy of T-DXd in HER2- positive BC.
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•• Pivotal phase 2 trial demonstrating efficacy of T-DXd in HER2- positive GC.
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