Trastuzumab Deruxtecan: First Approval
Susan J. Keam1

© Springer Nature Switzerland AG 2020

Abstract
Trastuzumab deruxtecan (ENHERTU®), a HER2-directed antibody and DNA topoisomerase I inhibitor conjugate, is being developed for the treatment of HER2-expressing solid tumours, including breast cancer, gastric cancer, colorectal cancer and non-small cell lung cancer by Daiichi Sankyo Company Ltd in collaboration with AstraZeneca. Based primarily on the results of the phase 2 DESTINY-Breast01 trial, trastuzumab deruxtecan was recently approved in the USA under accelerated approval for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. This article summarizes the milestones in the devel- opment of trastuzumab deruxtecan leading to this first approval.

Enhanced material for this AdisInsight Report can be found at https://doi.org/10.6084/m9.figshare.11889147.

This profile has been extracted and modified from the AdisInsight database. AdisInsight tracks drug development worldwide through the entire development process, from discovery, through pre- clinical and clinical studies to market launch and beyond.

 Susan J. Keam [email protected]
1 Springer Nature, Mairangi Bay, Private Bag 65901, Auckland 0754, New Zealand
⦁ Introduction
Trastuzumab deruxtecan (known as fam-trastuzumab derux- tecan-nxki in the USA; T-DXd; ENHERTU®) [1], a HER2- directed antibody-drug conjugate (ADC), is being developed by Daiichi Sankyo Company, Ltd (Daiichi Sankyo) in col- laboration with AstraZeneca for the treatment of numerous HER2-expressing cancers, including HER2-positive meta- static breast cancer, HER2-low metastatic breast cancer, HER2-positive advanced gastric cancer, HER2-expressing advanced colorectal cancer and metastatic nonsquamous HER2-overexpressing or -mutated non-small cell lung can- cer [2, 3]. Trastuzumab deruxtecan consists of a humanized, anti-HER2 IgG1 monoclonal antibody that has the same amino acid sequence as trastuzumab (and which therefore binds to HER2 on tumour cells), covalently linked to a topoisomerase I inhibitor payload (DXd, a derivative of the camptothecin analogue exatecan) via a tetrapeptide-based cleavable linker. Deruxtecan consists of a protease-cleava- ble maleimide tetrapeptide linker and DXd [1]. Delivery of the ADC payload (i.e. DXd) directly to HER2-expressing tumour cells minimizes exposure of the cytotoxic agent to normal cells [1, 4].
Trastuzumab deruxtecan is approved in the USA for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic set- ting [1] and is under regulatory review in Japan for HER2- positive metastatic breast cancer [5]; regulatory submission for this indication in the EU is planned for 2020 [6]. The

Phase I trial (NCT02564900) initiated (Aug)
Fast Track designation in USA (Dec)

Breakthrough Therapy designation in USA (Aug)

NDA submitted in Japan (Sep) BLA accepted in USA (Oct)
Approved in USA (Dec)

2015 2016 2017 2018 2019 2020 2021 2022

Phase II trial Phase III trials
DESTINY-Breast01 (NCT03248492)
DESTINY-Breast02 (NCT03523585) DESTINY-Breast03 (NCT03529110)

Key milestones in the development of trastuzumab deruxtecan for the treatment of HER2-positive unresectable and/or metastatic breast cancer.
BLA biologics license application, NDA new drug application

recommended dosage of trastuzumab deruxtecan in HER2- positive metastatic breast cancer is 5.4 mg/kg administered as an intravenous (IV) infusion once every 3 weeks (i.e., a 21-day cycle) until disease progression or unacceptable tox- icity. The US prescribing information carries boxed warn- ings regarding interstitial lung disease and pneumonitis and embryo-foetal toxicity [1].
⦁ Company Agreements

In March 2019, Daiichi Sankyo and AstraZeneca entered into a global development and commercialization collabo- ration agreement for trastuzumab deruxtecan, a proprietary antibody-drug conjugate (ADC) and potential new targeted medicine for cancer treatment. Under the terms of the agree- ment, both companies would jointly develop and commer- cialize the drug as a monotherapy or as a combination therapy worldwide, except in Japan, where Daiichi Sankyo would maintain exclusive rights to the product. Daiichi San- kyo would be solely responsible for manufacturing and the supply of the drug. Both companies would share equally the development costs, commercialization costs and profits from the drug worldwide, except for Japan [2, 3].
In October 2018, Daiichi Sankyo entered into a clinical trial collaboration agreement with Merck KGaA and Pfizer to investigate the combination of trastuzumab deruxtecan with avelumab and/or an investigational Merck KGaA DNA damage response inhibitor, in patients with HER2-express- ing or -mutated solid tumours, in a three-part phase 1b trial [7].
In December 2017, Daiichi Sankyo and Puma Biotechnol- ogy entered a research collaboration with Memorial Sloan Kettering Cancer Center (MSK) to investigate combination of trastuzumab deruxtecan and neratinib for HER2-mutated or HER2-positive solid tumours. Under the terms of the agreement, MSK will use isogenic models and established
patient-derived xenograft models to assess the susceptibility of HER2-mutated or HER2-positive cancers to trastuzumab deruxtecan, neratinib and other HER2-targeting therapies, elucidate mechanisms of action and resistance of these vari- ous tumour types, and evaluate the potential for synergistic combinations. Daiichi Sankyo and Puma Biotechnology will co-sponsor the research [8].
In August 2017, Bristol-Myers Squibb and Daiichi San- kyo announced a collaborative clinical trial to evaluate the combination of nivolumab and trastuzumab deruxtecan in HER2-expressing metastatic breast and urothelial (bladder) cancers. Under the terms of the agreement, Daiichi Sankyo will be the sponsor conducting the phase 1b trial in the US and Europe [9].

⦁ Scientific Summary
⦁ Pharmacodynamics

After binding to HER2 (ErbB2) on tumour cells, trastu- zumab deruxtecan is internalized and the linker is cleaved within the cell by lysosomal enzymes [1, 4]. Once released, DXd (which is highly membrane permeable [10]) binds to and inhibits topoisomerase I-DNA complexes, leading to inhibition of DNA replication, cell cycle arrest and tumour cell apoptosis [1, 4]. In vitro, the topoisomerase I inhibitory potency of the exatecan derivative DXd was 10-fold higher than that of 7-ethyl-10-hydroxy-camptothecin (SN-38), the active metabolite of the camptothecin analogue irinotecan, and when used as a payload for ADCs, DXd is expected to have sufficient anti-tumour efficacy [4]. Trastuzumab der- uxtecan achieves a higher drug-to-antibody ratio (of ≈ 8) [1, 4] with homogenous conjugation compared with other approved ADCs (including trastuzumab emtansine) [4]. The linker-payload of trastuzumab deruxtecan was shown

Deruxtecan
O
H H
N N
N N
H H
O O

Linker
F n
Topoisomerase I inhibitor Where n ~ 8 deruxtecan
per mAb

Structure of trastuzumab deruxtecan. mAb monoclonal antibody

to be stable in plasma in vitro (after 21 days’ incubation, the release rate of DXd from trastuzumab deruxtecan in human plasma was 2.1%) and in vivo. The short half-life of DXd in the systemic circulation was also demonstrated in vivo. [4]. The antitumour activity of trastuzumab deruxtecan was shown to be dependent on HER2 expression, rather than HER2 amplification, with activity evident in HER2-express- ing colorectal cancer cell lines negative for HER2 amplifi- cation [11]. Trastuzumab deruxtecan also demonstrated a bystander killing effect in vitro (in a coculture study) and in mouse xenograft models. In the presence of neighbouring HER2-expressing cells, adjacent tumour cells negative for HER2 expression were also killed by trastuzumab derux- tecan, but the drug had no effect on non-adjacent HER2-
negative tumour cells [10, 11].
In vitro, trastuzumab deruxtecan induced HER2 expres- sion-dependent, dose-dependent cell growth inhibition across a range of human cancer cell lines and inhibited Akt phosphorylation and induced phosphorylation of Chk1 and Histone H2A.X. The drug also induced tumour regression in a HER2-positive gastric cancer NCI-N87 xenograft model with administration of a single dose of trastuzumab derux- tecan > 1 mg/kg [12].
Trastuzumab deruxtecan showed efficacy in a trastuzumab emtansine-insensitive patient-derived xenograft (PDX) model with high HER2 expression [12] and abrogated resistance to the trastuzumab emtansine, evidenced by anti-tumour effi- cacy against N87-TDMR (a trastuzumab emtansine-resistant gastric cancer cell line) xenograft cells in a mouse model [13]. Trastuzumab deruxtecan exhibited anti-tumour efficacy against several breast cancer PDX models with low HER2 expression, unlike trastuzumab emtansine [12].
There was no large mean effect (i.e., > 20 ms) on the QTc interval or clinically relevant QTc prolongation when patients with HER-expressing metastatic breast cancer (n = 51) were administered multiple doses of trastuzumab
deruxtecan 6.4 mg/kg every 3 weeks (1.2 times the recom- mended dosage in HER2-positive metastatic breast cancer) in a QT/QTc study (NCT03366428). The upper bound of the 95% CI was < 10 ms at all assessments [1, 14].
⦁ Pharmacokinetics

Exposures (Cmax and AUC) of trastuzumab deruxtecan and released DXd increased proportionally over the dose range 3.2–8 mg/kg after IV administration of a single dose in patients with cancer. According to a population phar- macokinetic analysis, at the recommended dosage of tras- tuzumab deruxtecan for HER2-positive metastatic breast cancer (5.4 mg/kg once every 3 weeks), the geometric mean Cmax values of trastuzumab deruxtecan and DXd were 122 μg/mL and 4.4 ng/mL and the respective AUC values were 735 μg day/mL and 28 ng day/mL. Steady state accumulation (at cycle 3) of trastuzumab deruxtecan was
≈ 35%. The estimated volume of distribution of the central compartment of trastuzumab deruxtecan was 2.77 L. DXd is highly (≈ 97%) plasma protein bound; in vitro, the blood: plasma ratio is ≈ 0.6 [1]
Trastuzumab is expected to be degraded into small pep- tides and amino acids through catabolic pathways in the same way that endogenous IgG is metabolized; in vitro studies indicate that DXd is metabolized by CYP3A4. The median t1/2 of trastuzumab deruxtecan was ≈ 5.7 days and the median apparent t1/2 of DXd was ≈ 5.8 days. The esti- mated CL of trastuzumab deruxtecan was 0.42 L/day, and the estimated apparent CL of DXd was 19.2 L/h [1].
DXd is a substrate for CYP3A enzymes and OATP1B [15]; however, the small increase in trastuzumab deruxte- can and DXd AUC17d when trastuzumab deruxtecan was coadministered with concomitant ritonavir (OATP1B/ CYP3A inhibitor) or itraconazole (strong CYP3A strong inhibitor) was not considered clinically meaningful [1].

Features and properties of trastuzumab deruxtecan

Alternative names DS-8201; DS-8201a; ENHERTU®; fam-trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki; T-DXd Class Antineoplastics; Camptothecins; Drug conjugates; Immunoconjugates; Monoclonal antibodies
Target DNA topoisomerase I; HER2 receptor
Mechanism of action HER2-directed antibody and DNA topoisomerase I inhibitor conjugate Route of administration IV infusion
Pharmacodynamics Multiple-dose administration of trastuzumab deruxtecan 6.4 mg/kg every 3 weeks (1.2 × the recommended dosage in HER2-positive metastatic breast cancer) had no clinically relevant effect on the QTc interval in patients with HER2-expressing metastatic breast cancer

Pharmacokinetics at the recom- mended dosage in HER2- positive metastatic breast cancer (5.4 mg/kg once every 3 weeks)
Adverse events
Trastuzumab deruxtecan Cmax 122 μg/mL, AUC 735 μg day/mL. t1/2 ≈ 5.7 days, CL 0.42 L/day Released topoisomerase inhibitor Cmax 4.4 ng/mL, AUC 28 ng day/mL, t1/2 ≈ 5.8 days, CL 19.2 L/h

Most frequent (≥ 20%) Nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anaemia, neutropenia, diarrhoea, leukopenia, cough, thrombocytopenia
Occasional Infusion-related reactions, febrile neutropenia

Serious adverse reactions (>1%) Interstitial lung disease, pneumonia, vomiting, nausea, cellulitis, hypokalaemia, intestinal obstruction ATC codes
WHO ATC code L01X-X (other antineoplastic agents)
EphMRA ATC code L1X9 (all other antineoplastics)

Dosage adjustment is not required in patients with mild or moderate renal or hepatic impairment; however, in those with moderate hepatic impairment there is the potential for increased exposure to trastuzumab deruxtecan and DXd and close monitoring for increased toxicities associated with DXd is required. Data are not available in patients with severe renal or hepatic impairment [1]
⦁ Therapeutic Trials

⦁ Breast Cancer

Trastuzumab deruxtecan showed durable antitumour activ- ity in the phase 2 DESTINY-Breast01 trial in patients with HER2-positive metastatic breast cancer who had been pre- viously treated with ≥ 2 anti-HER2 therapies, including trastuzumab emtansine (NCT03248492) [16]. In this trial, patients were randomized to receive trastuzumab deruxtecan 5.4 mg/kg (n = 50), 6.4 mg/kg (n = 48) or 7.4 mg/kg (n = 21) as an intravenous infusion once every 3 weeks in part 1 (pharmacokinetics and dose-finding) of the trial; based on efficacy and tolerability outcomes, the recommended dos- age for part 2 was 5.4 mg/kg every 3 weeks [n = 184 (50 patients from part 1 and 134 patients recruited in part 2)] and this was administered until unacceptable toxicity or disease progression.
The confirmed overall response rate (ORR) on independ- ent central review in patients (n = 184) who received tras- tuzumab deruxtecan 5.4 mg/kg (the recommended dosage
in HER2-positive metastatic breast cancer) was 60.9% (complete response 6.0%; partial response 54.9%), the con- firmed disease-control rate (DCR) was 97.3% and the clini- cal benefit rate was 76.1% [16]. The median time to response was 1.6 months and the median duration of response was
14.8 months; median progression-free survival (PFS) was
16.4 months and median overall survival duration (OS) has not been reached (estimated overall survival was 93.9% at 6 months and 86.2% at 12 months). The median treat- ment duration was 10.0 months and median follow-up was
11.1 months; data cutoff was 1 August 2019 [16].
Treatment with trastuzumab deruxtecan 5.4 or 6.4 mg/kg once every 3 weeks achieved a confirmed ORR (as assessed by the investigators) of 59.5% (66 of 111 evaluable patients) and a confirmed DCR of 93.7% in patients with advanced HER2-positive metastatic breast cancer previously treated with trastuzumab emtansine in a two-part phase 1 trial (NCT02564900; data cut-off 10 August 2018) [17]. The median time to response was 1.6 months and the median duration of response was 20.7 months; median PFS was 22.1 months and median OS has not been reached. Patients from the dose escalation and dose expansion parts who received either of these dosage regimens were included in this anal- ysis; the median treatment duration was 8.3 months and median follow-up was 9.9 months [17].
A confirmed ORR of 44.2% (19 of 43 evaluable patients) and a confirmed DCR of 79.1% (34 of 43) were seen in patients with heavily pretreated advanced HER2-low meta- static breast cancer who received trastuzumab deruxtecan

in a dose-expansion phase 1 trial (NCT02564900; data cut-off 12 October 2018). The median time to response was 2.8 months and the median duration of response was
9.4 months; median PFS was 7.6 months [18].
⦁ Gastric Cancer

Preliminary results from the phase 2 DESTINY-Gastric01 trial (NCT03329690) indicate that treatment with trastu- zumab deruxtecan 6.4 mg/kg once every three weeks sig- nificantly improved ORR (as assessed by an independent review committee) and OS compared with investigator’s choice of chemotherapy (irinotecan or paclitaxel mono- therapy) in patients with HER2-positive unresectable or metastatic gastric or gastroesophageal junction cancer that had progressed after two or more prior treatment regimens including trastuzumab and chemotherapy [19].
Treatment with trastuzumab deruxtecan 5.4 or 6.4 mg/kg once every 3 weeks achieved a confirmed ORR (as assessed by the investigators) of 43.2% (19 of 44 evaluable patients) and a DCR of 79.5% in patients with advanced HER2- positive gastric or gastroesophageal junction cancer in a two-part phase 1 trial in patients with heavily pretreated, advanced HER2-expressing tumours (NCT02564900; data cutoff 10 August 2018) [20]. The median time to response was 1.4 months, the median duration of response was
7.0 months, the median PFS was 5.6 months and the median OS was 12.8 months. Patients from the dose escalation and dose expansion parts who received either dosage regimen were included in this analysis; the median treatment duration was 4.4 months and median follow-up was 5.5 months [20].
⦁ Other Cancers

In the subgroup of patients with HER2-expressing and/ or -mutated NSCLC in the phase 1 trial in heavily pre- treated patients with advanced HER2-expressing tumours (NCT02564900), the confirmed ORR was 58.8% and DCR was 88.2% (n = 17 evaluable; data cutoff 10 August 2018); [21, 22]. In the subgroup of patients with HER2-expressing advanced colorectal cancer, the ORR was 15.8% (3 of 19 evaluable patients) and DCR was 84.2% (data cutoff 10 August 2018) [23, 24].

⦁ Adverse Events

The most common adverse reactions (frequency ≥ 20%; any grade) reported in patients (n = 234; pooled data) with unre- sectable or metastatic HER2-positive breast cancer who received at least one dose of trastuzumab deruxtecan 5.4 mg/ kg in the phase 2 DESTINY-Breast01 trial (NCT03248492) or a phase 1 trial in advanced HER2-expressing solid tumours
(NCT02564900) (discussed in Sect. 2.3.1) were nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anaemia, neutropenia, diarrhoea, leukopenia, cough and thrombocyto- penia [1]. The most common (frequency ≥ 5%) grade 3 or 4 adverse reactions in these patients were neutropenia (16%), anaemia (7%), nausea (7%), fatigue (6%) and leukopenia (6%). Infusion-related reactions occurred in 2.6% of patients, febrile neutropenia in 1.7% and asymptomatic left ventricular ejection fraction decrease in 0.9% (two patients) [1].
Serious adverse reactions occurred in 20% of patients with unresectable or metastatic HER2-positive breast cancer receiving trastuzumab deruxtecan; those occurring in >1% of patients included interstitial lung disease, pneumonia, vomit- ing, nausea, cellulitis, hypokalemia and intestinal obstruc- tion. Adverse reactions causing death occurred in 4.3% of patients [1]. Interstitial lung disease (Sect. 2.4.1) was the most frequent; death due to acute hepatic failure/acute kid- ney injury, general physical health deterioration, pneumonia and haemorrhagic shock occurred in one patient (0.4%) each. Treatment with trastuzumab deruxtecan was permanently dis- continued in 9% of patients with unresectable or metastatic HER2-positive breast cancer, mostly because of interstitial lung disease (6% of patients). Dose interruptions because of adverse reactions occurred in 33% of patients and dose reduc- tions because of adverse reactions were required in 18% of patients. The median treatment duration was 7 months [1].
In patients with gastric cancer (see Sect. 2.3.2), the adverse events profile of trastuzumab deruxtecan in DESTINY-Gastric01 (NCT03329690) was consistent with that seen in the phase 1 trial in gastric cancer (NCT NCT02564900), where the most common adverse events (frequency ≥ 30%; any grade) were decreased neutrophil count, anaemia, nausea and decreased appetite [19, 20].
⦁ Interstitial Lung Disease

Interstitial lung disease (all grades) occurred in 9% of patients with unresectable or metastatic HER2-positive breast cancer receiving trastuzumab deruxtecan in the DESTINY-Breast01 (NCT03248492) and phase 1 trial (NCT02564900) (n = 234; pooled data), with a median time to first onset of 4.1 months. Death due to interstitial lung disease and/or pneumonitis occurred in 2.6% of patients receiving trastuzumab deruxtecan in these trials [1].
While treatment-related interstitial lung disease and pneu- monitis was reported in trastuzumab deruxtecan recipients with gastric cancer in DESTINY-Gastric01 (NCT03329690) and the phase 1 trial (NCT NCT02564900), most cases were grade 1 or 2 in severity (two were grade 3 and one was grade 4) and no deaths related to interstitial lung disease occurred [19].
In the cohort of patients with NSCLC (n = 17) in the phase 1 trial of trastuzumab deruxtecan in advanced

Key clinical trials of trastuzumab deruxtecan

Drug(s) Indication Phase Status Sponsor (Collaborator) Location(s) Identifier
Trastuzumab deruxtecan, Advanced HER2-low breast III Recruiting Daiichi Sankyo (Astra- Global NCT03734029; DES-

capecitabine, eribulin, gemcitabine, paclitaxel, nab-paclitaxel
Trastuzumab deruxtecan, trastuzumab emtansine
Trastuzumab deruxtecan, trastuzumab, capecit- abine, lapatinib,
cancer

Advanced HER2-positive breast cancer
Advanced HER2-positive breast cancer
Zeneca)

III Recruiting Daiichi Sankyo (Astra-
Zeneca)
III Recruiting Daiichi Sankyo (Astra-
Zeneca)
TINY-Breast04

Global NCT03529110; DES-
TINY-Breast03
Global NCT03523585; DES-
TINY-Breast02

Trastuzumab deruxtecan Advanced HER2-positive
breast cancer
II Ongoing Daiichi Sankyo (Astra-
Zeneca)
Global NCT03248492; DES-
TINY-Breast01

Trastuzumab deruxtecan, Nivolumab
Advanced HER2-expressing breast or urothelial cancer
I/II Recruiting Daiichi Sankyo, (Bris-
tol-Myers Squibb, AstraZeneca)
Global NCT03523572

Trastuzumab deruxtecan Advanced HER2-expressing
breast cancer (QT/QTc study)
⦁ Ongoing Daiichi Sankyo (Astra-
Zeneca)
Japan NCT03366428

Trastuzumab deruxtecan, pembrolizumab
Advanced HER2-positive breast cancer or NSCLC
⦁ Pending Daiichi Sankyo (Astra-
Zeneca, Merck Sharp & Dohme)
Europe, USA NCT04042701

Trastuzumab deruxtecan Advanced HER2-positive
gastric or gastroesophageal junction cancer
⦁ Recruiting Daiichi Sankyo (Astra-
Zeneca)
Global NCT04014075

Trastuzumab deruxtecan, irinotecan, paclitaxel
Advanced HER2-expressing gastric or oesophageal cancer
⦁ Ongoing Daiichi Sankyo (Astra-
Zeneca)
Japan, South Korea
NCT03329690; DES-
TINY-Gastric01

Trastuzumab deruxtecan Advanced HER2-positive
biliary tract cancer
II Recruiting Daiichi Sankyo Japan JMA-IIA00423; HERB

Trastuzumab deruxtecan Advanced HER2-expressing
colorectal cancer
Trastuzumab deruxtecan Advanced HER2-overexpress-
ing or -mutated NSCLC
II Recruiting Daiichi Sankyo (Astra-
Zeneca)
II Recruiting Daiichi Sankyo (Astra-
Zeneca)
Global NCT03384940

Global NCT03505710

Trastuzumab deruxtecan, cediranib, ceralasertib, danvatirsen, dur- valumab, olaparib, oleclumab, vistusertib
Advanced NSCLC II Recruiting AstraZeneca Global NCT03334617; HUDSON

Trastuzumab deruxtecan Advanced HER2-positive
uterine cancer
II Recruiting Daiichi Sankyo Japan UMIN000029506;
STATICE

Trastuzumab deruxtecan Advanced HER2-expressing
solid tumours
I Ongoing Daiichi Sankyo (Astra-
Zeneca)
Japan, USA NCT02564900; Japi-
cCTI-152978

Trastuzumab deruxtecan, ritonavir, itraconazole
Advanced HER2-expressing solid tumours
I Ongoing Daiichi Sankyo (Astra-
Zeneca)
Japan, Taiwan, South Korea
NCT03383692

Trastuzumab deruxtecan Advanced HER2-positive solid
tumours
I Ongoing Daiichi Sankyo (Astra-
Zeneca)
Taiwan NCT03368196

Investigator-initiated trials
Trastuzumab deruxtecan Advanced breast cancer II Recruiting UNICANCER (Daiichi
Sankyo)

France NCT04132960; DAISY

Trastuzumab deruxtecan Advanced HER2-positive
breast cancer
II Recruiting SOLTI (Daiichi San-
kyo)
Spain EudraCT2019-002991-15; SOLTI-1804; HER2- PREDICT

HER2-expressing solid tumours (NCT02564900) (see Sect. 2.3.3), one case of grade 5 pneumonitis was reported. However, the independent adjudication committee
evaluating reported cases of interstitial lung disease/pneu- monitis in the trastuzumab deruxtecan trials considered this death to be unrelated to treatment with the ADC [21, 22].

⦁ Ongoing Clinical Trials

In addition to DESTINY-Breast01 (NCT03248492) and DESTINY-Gastric01 (NCT03329690), three phase 3 tri- als of trastuzumab deruxtecan in advanced breast cancer [DESTINY-Breast02 (NCT03523585), DESTINY-Breast03 (NCT03529110) and DESTINY-Breast04 (NCT03734029)]
are underway.
Phase 2 trials of trastuzumab deruxtecan that are recruiting include studies in HER2-positive gastric or gastroesophageal junction cancer (NCT04014075), HER2- overexpressing or -mutated NSCLC (NCT03505710), HER2-positive uter ine cancer (S TATICE; UMIN000029506), HER2-positive biliary tract cancer (HERB; JMA-IIA00423) and HER2-expressing colorectal cancer (NCT03384940).
Four phase 1 trials in advanced HER2-expressing solid tumours or breast cancer (NCT02564900, NCT03383692, NCT03368196, NCT03366428) are ongoing. A phase 1/2 trial of trastuzumab deruxtecan in combination with nivolumab in advanced HER2-expressing breast or urothe- lial cancer (NCT03523572) is recruiting and a phase 1 trial of trastuzumab deruxtecan in combination with pembroli- zumab (NCT04042701) in advanced HER2-expressing breast cancer or NSCLC is pending.

⦁ Current Status
Trastuzumab deruxtecan was granted accelerated approval in the USA on 20 December 2019 for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti- HER2-based regimens in the metastatic setting [25]. Daiichi Sankyo and Roche are collaborating in the development of a HER2-low companion diagnostic test that will use the VEN- TANA HER2 (4B5) assay to identify patients with cancers that express low levels of HER2 [26].
Compliance with Ethical Standards
Funding The preparation of this review was not supported by any external funding.

Conflict of interest During the peer review process the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes resulting from any comments received were made by the authors on the basis of scientific completeness and accuracy. Susan Keam is a salaried employee of Adis International Ltd/Springer Nature, is responsible for the article content and declares no relevant conflicts of interest.
References
⦁ Daiichi Sankyo Inc. Enhertu (fam-trastuzumab deruxtecan-nxki): US prescribing information. 2019. ⦁ https://www.accessdata.fda. ⦁ gov/drugsatfda_docs/label/2019/761139s000lbl.pdf. Accessed 2020.
⦁ Daiichi Sankyo Company Ltd, AstraZeneca. Daiichi Sankyo and AstraZeneca announce global development and commercializa- tion collaboration for Daiichi Sankyo’s HER2 targeting antibody drug conjugate [fam-] trastuzumab deruxtecan (DS-8201) [media release]. 29 Mar 2019. ⦁ http://www.daiichisankyo.com.
⦁ AstraZeneca. AstraZeneca and Daiichi Sankyo enter collabora- tion for novel HER2-targeting antibody-drug conjugate [media release]. 28 Mar 2019. https://www.astrazeneca.com/.
⦁ 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 (Tokyo). 2019;67(3):173–85.
⦁ Daiichi Sankyo Company Ltd. Daiichi Sankyo advances [fam-] trastuzumab deruxtecan (DS-8201) in Japan with regulatory submission in HER2 positive metastatic breast cancer [media release]. 9 Sep 2019. ⦁ http://www.daiichisankyo.com.
⦁ Daiichi Sankyo Company Ltd. 5-year business plan overview and progress. 2019. ⦁ https://www.daiichisankyo.com/media_investors/ ⦁ investor_relations/annual_reports/pdf/2019/11.pdf. Accessed 20 Jan 2020.
⦁ Daiichi Sankyo Company Ltd. Daiichi Sankyo announces clinical research collaboration with Merck KGaA, Darmstadt, Germany and Pfizer to evaluate [fam-] trastuzumab deruxtecan (DS-8201) with avelumab and a DNA damage response inhibitor in patients with HER2 expressing and mutate [media release]. 25 Oct 2018. ⦁ http://ww⦁ w.daiichisankyo.com.
⦁ Daiichi Sankyo Company Ltd, Puma Biotechnology Inc. Daiichi Sankyo and Puma Biotechnology announce research collabora- tion with major cancer center in HER2-mutated cancer [media release]. 12 Dec 2017. https://www.daiichisankyo.com/.
⦁ Bristol-Myers Squibb, Daiichi Sankyo Company Ltd. Bristol- Myers Squibb and Daiichi Sankyo announce research collabora- tion to evaluate Opdivo® (nivolumab) and DS-8201 in HER2- expressing breast and bladder cancers [media release]. 28 Aug 2017. ⦁ http://www.bms.com.
⦁ Ogitani Y, Hagihara K, Oitate M, et al. Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity. Cancer Sci. 2016;107(7):1039–46.
⦁ Takegawa N, Tsurutani J, Kawakami H, et al. fam- Trastuzumab deruxtecan, antitumor activity is dependent on HER2 expres- sion level rather than on HER2 amplification. Int J Cancer. 2019;145(12):3414–24.
⦁ Ogitani Y, Aida T, Hagihara K, et al. DS-8201a, a novel HER2- targeting ADC with a novel DNA topoisomerase I Inhibitor, dem- onstrates a promising antitumor efficacy with differentiation from T-DM1. Clin Cancer Res. 2016;22(20):5097–108.
⦁ Takegawa N, Nonagase Y, Yonesaka K, et al. DS-8201a, a new HER2-targeting antibody-drug conjugate incorporating a novel DNA topoisomerase I inhibitor, overcomes HER2-positive gastric cancer T-DM1 resistance. Int J Cancer. 2017;141(8):1682–9.
⦁ Yamashita T, Shimomura A, Takano O, et al. A phase 1, multi- center, open-label study to assess the effect of [fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) on QTc and pharmacokinetics in subjects with HER2-expressing metastatic and/or unresectable breast cancer [abstract no. P1-18-12]. In: San Antonio Breast Can- cer Symposium. 2019.

⦁ 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-express- ing advanced solid tumours [abstract no. 330P]. Ann Oncol. 2019;30(Suppl 5):v116–7.
⦁ Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2019. https://doi.org/10.1056/NEJMoa1914510.
⦁ Tamura K, Tsurutani J, Takahashi S, et al. Trastuzumab deruxte- can (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):816–26.
⦁ Modi S, Tsurutani J, Tamura K, et al. Trastuzumab deruxtecan (DS-8201a) in subjects with HER2-low expressing breast cancer: updated results of a large phase 1 study [abstract no. P6-17-02 plus poster]. Cancer Res. 2018;79(4 Suppl):6–17.
⦁ Daiichi Sankyo Company Ltd. Phase 2 DESTINY-Gastric01 trial of DS-8201 versus chemotherapy met primary endpoint [media release]. 27 Jan 2020. ⦁ https://www.daiichisankyo.com.
⦁ Shitara K, Iwata H, Takahashi S, et al. Trastuzumab deruxte- can (DS-8201a)in patients with advanced HER2-positive gas- tric cancer: a dose-expansion, phase 1 study. Lancet Oncol. 2019;20(6):827–36.
⦁ Tsurutani J, Park H, Doi T, et al. Updated results of phase 1 study of DS-8201a in HER2-expressing or -mutated advanced non- small-cell lung cancer [abstract no. OA02.07]. J Thorac Oncol. 2018;13(10 Suppl):S324.
⦁ Daiichi Sankyo Company Ltd. Daiichi Sankyo presents updated results for [fam-] trastuzumab deruxtecan (DS-8201) in patients with HER2 mutated or HER2 expressing non-small cell lung can- cer at IASLC 19th World Conference on Lung Cancer [media release]. 24 Sep 2018. ⦁ http://www.daiichisankyo.com.
⦁ Yoshino T, Iwata H, Tamura K, et al. Updated results of phase I study of trastuzumab deruxtecan (DS-8201a) in HER2-express- ing advanced colorectal cancer [abstract no. 563P]. Ann Oncol. 2018;29(Suppl 8):viii188.
⦁ Daiichi Sankyo Company Ltd. Daiichi Sankyo presents updated results of [fam-] trastuzumab deruxtecan (DS-8201) in patients with HER2 expressing advanced colorectal cancer at 2018 Euro- pean Society for Medical Oncology (ESMO) congress [media release]. 22 Oct 2018. ⦁ http://www.daiichisankyo.com.
⦁ US Food and Drug Administration. FDA approves new treatment option for patients with HER2-positive breast cancer who have progressed on available therapies [media release]. 7 Jan 2019. ⦁ https://ww⦁ w.fda.gov/.
⦁ Daiichi Sankyo Company Ltd. Daiichi Sankyo and Roche to col- laborate on new HER2 low companion diagnostic test [media release]. 27 Nov 2018. ⦁ http://www.daiichisankyo.com.