Deruxtecan – Amisulpride Antagonist

Trastuzumab Deruxtecan (DS-8201a): The Latest Research and Advances in Breast Cancer

Angeliki Andrikopoulou, Eleni Zografos, Michalis Liontos, Konstantinos Koutsoukos, Meletios-Athanasios Dimopoulos, Flora Zagouri

Keywords: Antibodyedrug conjugate, Breast cancer, DS-8201a, HER2, Trastuzumab deruxtecan

Introduction

Ever since cancer patients were ﬁrst treated with cytotoxic drugs, oncologists have looked for ways to elicit greater antitumor activity without signiﬁcantly affecting overall toxicity. Antibodyedrug conjugates (ADCs) speciﬁcally deliver the cytotoxic payload to the target cancer cell by selectively binding to expressing antigens, reducing systemic toxicity, and widening the therapeutic index. This concept was ﬁnally implemented by the US Food and Drug Administration’s (FDA) approval of 4 ADCs,1 3 of which were developed for hematologic malignancies (gemtuzumab ozogamicin, Mylotarg; inotuzumab ozogamicin, CMC-544; brentuximab vedotin, Besponsa; SGN-35, Adcetris). The ﬁrst ADC to receive full FDA approval for solid tumors was ado-trastuzumab emtansine (T- DM1; Kadcyla) in 2013 on the basis of overall survival data in patients with HER2-positive metastatic breast cancer (BC) previ- ously treated with a taxane and trastuzumab.

T-DM1 is an antiehuman epidermal growth factor receptor 2 (HER2) ADC consisting of a trastuzumab monoclonal antibody conjugated to a tubulin polymerization inhibitor maytansinoid (DM1) cytotoxic agent via a noncleavable maleimidomethyl cyclohexane-1-carboxylate thioether linker. T-DM1 resulted in a tumor-selective delivery of the cytotoxic payload, minimizing systematic toxicity. However, T-DM1 was constructed via conjugation of the payload to lysine residues on the antibody carrier, leading to the release of a positively charged, and thus membrane impermeable, lysine derivative payload after the ADC internalization process. The low membrane permeability of the cytotoxic payload renders T-DM1 unable to exhibit a bystander killing effect through dissemination to adjacent HER2- loweexpressing cells.3 This lack of a bystander killing effect limits T-DM1’s ability to overcome intratumor heterogeneity of HER2 expression.

Acquired resistance to T-DM1,4 drug-emergent concerning toxicities,5,6 and an absence of a therapeutic alternative for HER2-loweexpressing (immunohistochemistry [IHC] 2þ/in-situ hybridization [ISH] negative or IHC 1þ/ISH—) BC7,8 led to the development of a next-generation anti-HER2 ADC based on a novel topoisomerase I (Topo I) inhibitor (fam-trastuzumab der- uxtecan, DS-8201a) with a potential to overcome current treatment limitations. Here we critically synthesize all available data con- cerning the safety and efﬁcacy of DS-8201a in BC patients.

Structure of DS-8201a

Trastuzumab deruxtecan (DS-8201a) is a next-generation HER2-targeting antibodyedrug conjugate (ADC), structurally composed of a humanized monoclonal anti-human HER2 anti- body, an enzymatically cleavable peptide linker, and a Topo I in- hibitor, DX-8951f derivative (Dxd).9 The anti-HER2 antibody component is a human monoclonal immunoglobulin G1 antibody produced based on the same amino acid sequence as trastuzumab. Thus, DS-8201a retains the HER2 binding afﬁnity of trastuzumab. The monoclonal antibody used is humanized in order to avoid the induced immunogenic potential of antibodies inoculated into sys- temic circulation. The cytotoxic payload is a camptothecin (CPT) derivative. CPT is an alkaloid that has exhibited effectiveness against various tumors via affecting human DNA Topo I. CPT binds to Topo I and DNA complexes through hydrogen bonds and stabilizes them, preventing DNA religation and therefore causing DNA damage and apoptosis. Irinotecan hydrochloride (CPT-11) is a semisynthetic derivative of CPT with a widely established antitumor activity, mainly in colorectal cancer. Studies assessing irinotecan in patients with metastatic BC, most commonly pretreated with anthracyclines or taxanes, reported response rates ranging from 5% to 23%, which are indicative of limited efﬁcacy.10 However, when combined with other chemotherapy regimens, response rates were increased to 28% to 64% of patients.10 Irinotecan hydrochloride is a prodrug that is enzymatically converted to its active metabolite, SN-38, in vivo, which is approximately 100-fold more cytotoxic than the parent drug.11 Exatecan methanesulfonate (DX-8951f) is a water-soluble synthetic CPT analog, cyclized at C7 and C9, which exhibited stronger Topo I inhibitory and antitumor activity than the other CPT analogs.12 In addition to this, DX-8951f showed effectiveness against P-glycoproteinemediated resistance, a drug- transporting protein responsible for the resistance to various anti- cancer drugs, including CPT-1111 and T-DM1.13

In order to overcome the systemic toxicity caused by other ADCs, a new linker payload system was developed in an attempt to increase the plasma stability of this ADC. This advanced technology created an ADC designed to be cleaved only after entering the targeted cancer cells and to remain intact in the systemic circulation, limiting plasma drug release and broadening the therapeutic win- dow. The Dxd payload is conjugated to the antibody carrier through an enzymatically cleavable tetrapeptide linker, the mal- eimide glycineephenylalanineeglycine (GGFG) peptide. The linker payload is connected to the antibody through cysteine resi- dues following the reduction of interchain disulﬁde bounds with a reducing agent, Tris(2-carboxyethyl)phosphine hydrochloride (TCEPHCl). These disulﬁde bonds are located between the light and heavy chains of trastuzumab in the distal end of the antigen- binding domain, without affecting the afﬁnity of the antibody to the target antigen.14 The tetrapeptide is designed to be cleaved by lysosomal enzymes such as cathepsins B and L, which are overex- pressed in tumor cells. Moreover, DS-8201a has a self-immolative part between the tetrapeptide linker and the payload part, which is rapidly hydrolyzed inside the tumor cells, resulting in the release of Dxd. First the antibody component is attached to the HER2 antigen of the tumor cells, resulting in the internalization of the ADC in the tumor cells and the selective delivery of the cytotoxic payload to the tumor. This antigen-dependent endocytosis further reduces the exposure of nontumor cells to cytotoxic agents. After the internalization process, the internalized ADC is selectively cleaved to a temporary hydrolysate composed of Dxd by lysosomal enzymes, mainly cathepsins. Finally, an amino methylene, the self-immolative component of the drug, is rapidly hydrolyzed to ammonia and formaldehyde, leading to the intracellular release of the drug.

In addition to this, the average drug-to-antibody ratio (DAR) of DS-8201a is 7 to 8, which is higher than that of most ADCs, including T-DM1. The DAR of current ADCs ranges from 2 to 4, with T-DM1 resulting in a DAR of 3.5.15 The DAR of 8 Dxd molecules per antibody is the maximum payload loading number for conventional interchain cysteine-based conjugation because higher values are linked to increased systemic toxicity.16 This high DAR enables the delivery of greater payload concentrations to cancer cells, providing the rationale for a more potent antitumor activity than other ADCs. High DAR is another result of the self- immolative linker strategy, which is achieved by reducing the hy- drophobicity of the ADC. Moreover, another key characteristic of DS-8201a is its DAR homogeneity. Overall, these physiochemical properties provide DS-8201a with a great therapeutic potential.

Mechanism of Action

DS-8201a selectively inhibited cell growth of HER2þ cell lines, whereas it had no effect against human breast adenocarcinoma HER2— cell line, indicating an antigen-speciﬁc tumor inhibition.17 In vivo, tumor growth inhibition in HER2þ xenograft models was dose dependent and was higher than that of the unconjugated antibody (99% vs. 33% tumor growth inhibition, respectively). Moreover, DS-8201a and anti-HER2 antibody exhibited almost the same afﬁnity rates to HER2 antigen.17 Not only was binding af- ﬁnity to HER2 preserved, but also antibody-dependent cellular cytotoxic activity was unaffected by the conjugation process.17 Regarding payload cytotoxicity, DS-8201a caused the same DNA damage and level of apoptosis as unconjugated Dxd. DS-8201a exhibited a bystander killing effect in vitro and in vivo by affecting both tumor cells and adjacent cells—a result of the high membrane permeability of Dxd.18,19 More speciﬁcally, the degra- dation of DS-8201a by HER2þ targeted cells is followed by the release of the cytotoxic payload Dxd and the subsequent invasion of nontargeted surrounding cells.

In vitro, DS-8201a eliminated both cell populations in a coculture of HER2þ and HER2— cells, whereas T-DM1 selectively affected HER2þ cells.18 DS-8201a reduced the luciferase signal of xenograft mice inoculated with a mixture of HER2þ NCI-N87 cells and HER2— MDA-MB-468- Luc cells by suppressing the MDA-MB-468-Luc cell population and inhibiting tumor growth.18 This in vivo bystander killing effect of DS-8201a was not observed in other ADCs, including T-DM1, suggesting that it may provide a potential beneﬁt in treating HER2 heterogenous tumors unresponsive to T-DM1. Considering that HER2-loweexpressing tumors (IHC 2þ/ISH— or IHC 1þ/ISH—) constitute 50% of BC,20,21 DS-8201a could prove effective in the treatment of this HER2-negative population, which is associated with resistance to conventional anti-HER2 therapies.

Enhancing this theory, DS-8201a inhibited growth of xenograft tumors with different levels of HER2 expression—KPL-4 (3þ), JIMT-1 (2þ), and Capan-1 (1þ) cell lines—whereas T-DM1 showed efﬁcacy against only KPL-4 (3þ) tumors, which are char- acterized by high HER2 expression.11 In vivo, DS-8201a exhibited the same effect in patient-derived HER2-negative (IHC 2þ/ISH— or IHC 1þ/ISH—) BC xenograft models insensitive to T-DM1. Effectiveness of DS-8201a in HER2-loweexpressing tumors could potentially overcome BC resistance to conventional anti-HER2 treatment regimens as a result of loss of HER2 ampliﬁcation and intratumor heterogeneity in HER2 expression, which remain an obstacle to both trastuzumab and T-DM1 use.

Innate drug resistance to trastuzumab and T-DM1 includes expression of truncated HER2-positive receptors such as p95HER2 fragments that lack the trastuzumab binding site, tumor heteroge- neity with regions exhibiting minimal HER2 staining, aberrant activation of PI3K/Akt/mTOR pathway, and DM1-related mech- anisms of resistance, like expression of drug efﬂux pumps including MDR1/PgP and mutations in tubulins.24,25 DS-8201a can also overcome many of the intrinsic mechanisms of resistance to previ- ous HER2 therapies. Dxd is not a substrate of P-glycoproteinein- duced drug efﬂux and is not subject to maytansinoid-related resistance mechanisms. Tumor HER2 expression heterogeneity is encountered by the bystander killing effect of DS-8201a. Finally,DS-8201a showed antitumor efﬁcacy in HER2-ampliﬁed cells (IHC 3þ and/or ISHþ), but also in HER2-expressing tumors that lack HER2 ampliﬁcation.

Pharmacokinetic Proﬁle in Preclinical Studies

Table 1 lists the ongoing studies of DS-8201a in BC. The pharmacokinetic proﬁle of DS-8201a has been demonstrated in cynomolgus monkeys after intravenous administration of 0.1 to 8 mg/kg doses.26 The concentration of Dxd released in plasma was low, while the clearance rate decreased and the half-life was pro- longed according to increasing doses, indicating a dose-dependent pharmacokinetic proﬁle. The biodistribution of the drug was mainly restricted to the systemic circulation, following the bio- distribution of the anti-HER2 antibody. The excretion route observed was mainly into the feces at 336 hours, which is consistent with the excretion in bile shown in rats at 24 hours and the Dxd excretion route, which is 67.3% through feces.26 The application of SN-38 and irinotecan is restricted by UGT1A1 (UDP glucur- onosyltransferase family 1 member A1) gene polymorphism and by drug interactions that inhibit the formation of SN-38 by UGT1A1, like nifedipine and vinorelbine.27-29 Analysis of Dxd concentration in the bile revealed negligible metabolism via glucuronidation, in contrast to the other Topo I inhibitors, which indicates that DS- 8201a is not vulnerable to UGT1A1 metabolism.

In terms of safety, the highest noneseverely toxic dose for monkeys was considered to be 30 mg/kg.17 This value was subse- quently used for the calculation of the safe starting dose cutoff in humans. The main adverse events (AEs) included gastrointestinal, bone marrow, and pulmonary toxicity, all consistent with in-human ﬁndings. Anemia and leukopenia were induced only at a dose of 78.8 mg/kg; no such AEs occurred at 30 mg/kg. Lung toxicity was developed at doses of 30 mg/kg and higher, while it was absent in rat studies. The effect of DS-8201a in lungs seems to be antigen dependent and may be associated with HER2 expression in epithelial cells of the respiratory tract.30 Pneumonitis has been re- ported as a rare complication of CPT analog and irinotecan treat- ment.31,32 However, CPT11-induced lung toxicity is described in just a few individual case reports.31,32 Incidence of pneumonitis is estimated to be around 0.9% in the CPT11-treated population.33 Pneumonitis, reported infrequently in clinical studies of irinote- can, mostly affects patients with lung metastasis, those with another preexisting pulmonary disease, or those undergoing concurrent chemoradiotherapy, and could not be attributed solely to the study drug.31,34

Phase 1 studies evaluated the pharmacokinetic proﬁle of DS- 8201a in humans. Pharmacokinetic analysis demonstrated a dose- dependent half-life and a median half-life of 5.7 days.35 Plasma concentrations of free Dxd were low in accordance with animal studies.36 Drug exposure area under the receiver operating charac- teristic curve (AUC) and maximum serum concentration (Cmax) increased dose dependently in doses ranging from 3.2 to 8 mg/kg.36 Cmax of DS-8201a and Dxd was 122 mg/mL and 4.4 ng/mL, respectively, while the estimated clearance rate was 0.42 L per day.35 Dxd is mainly metabolized by CYP3A4; however, no clinically signiﬁcant drug interaction was observed in coadministration with CYP3A4 inhibitors.35 On the basis of DS-8201a’s pharmacokinetic and safety proﬁle, a dose of 5.4 mg/kg was recommended for human
administration.37

DS-8201a and Immune Checkpoint Inhibitors

Topo I inhibitors have shown a synergistic activity with immune checkpoint inhibitors, as a nivolumab and anti-CTLA anti- body,38,39 by further triggering T-cell activity and inducing immunogenic cell death. T-DM1 showed beneﬁt in combination with immune checkpoint inhibitors in BC.40,41 Combination therapy with antieprogrammed cell death 1 (PD-1) nivolumab was examined in mouse models and human BC cell lines.42 Cured mice initially treated with DS-8201a were reinoculated with both HER2þ and HER2— cell lines and demonstrated complete and partial rejection of HER2þ and HER2— cells, respectively, unlike naive mice, in which both grew. Inhibition of HER2— cell popu- lation implies an efﬁcient immune memory formation with synchronous recognition of various surface antigens other than HER2 by the immune system after DS-8201a treatment. This is an effect that could potentially overcome acquired resistance due to HER2 downregulation.23 Splenocytes isolated from the cured mice reacted to both cell lines by secreting interferon gamma, further supporting the theory of immune sensitization.42 Athymic mice with impaired immunity did not attenuate the growth of HER2þ cells when treated with DS-8201a, further supporting the contribution of immune system to DS-8201a antitumor efﬁcacy. The study also revealed an involvement of the adaptive immunity (CD8þ) cells to the antitumor effect, an in vivo activation of dendritic cells in immunocompetent mice, and an increase in the expression of major histocompatibility complex I on tumor cells after DS-8201a treat- ment. To examine the combination of DS-8201a and antiePD-1 antibody in vivo, mice inoculated with HER2þ cells were treated with either monotherapy or combination regimens. Mice treated with the combination therapy had better survival and complete response rates than either monotherapy.42 The same pattern was course of DS-8201a at the recommended doses of 5.4 and 6.4 mg/ kg every 3 weeks.44 Of these 115 patients, 49 received doses of 5.4 mg/kg and 66 received doses of 6.4 mg/kg. Overall, 111 (97%) of 115 patients had data evaluable for response assessment. Overall response occurred in 59.5% (66/111 patients), and disease control occurred in 93.7% (104/111 patients). Median (range) progression- free survival (PFS) was 22.1 (0-27.9) months, while the median overall survival has not yet been reached.

DS-8201a was further analyzed in different BC populations. In pertuzumab-pretreated patients, overall response and disease control rates were higher than that of the general BC population (62.5% and 93.8%, respectively), and median PFS was 16.4 months. More importantly, 59.5% (47/79) of patients with hormone receptor (HR)-positive, HER2-positive disease experienced an objective response, and 92.4% (73/79) experienced disease control. In HR- negative patients, 19 (61.3%) of 31 experienced an objective response, and 30 (96.8%) of 31 experienced disease control. In terms of safety, all patients had one or more treatment-emergent AE of any grade, whereas half of them had a grade 3 or higher AE. The most common grade 3/4 events were mainly hematologic toxicities, including anemia (19/115, 17%), neutropenia (16/115, 14%), thrombocytopenia (9/115, 8%), and leukopenia (10/115, 9%).44 Moreover, 20 cases (20/115, 17%) of interstitial lung disease (ILD), pneumonia, or pneumonitis were reported, 2 of which resulted in treatment-related deaths and 7 others of which resulted in treatment interruption. All in all, DS-8201a exhibited a signiﬁ- cant therapeutic beneﬁt in T-DM1epretreated patients, with some concerns remaining regarding ILD and pneumonitis.

Assessing the HER2-loweexpressing population from the 2c cohort, data from 54 HER2-loweexpressing BC subjects were collected at the cutoff date of February 2019,45-48 with the disease of most heavily pretreated with 5 or more lines of therapy. The majority of patients had HR-positive disease (87%), and one third had previously been treated with a CDK4/6 inhibitor. The conﬁrmed overall response rate was 37% (20/54), with all patients experiencing a partial response, while 87% (47/54) of patients experienced disease control. These data were reported by indepen- dent central reviewers. The median (range) duration of response was 10.4 (8.8 to not evaluated) months, and the median PFS was 11.1 months (95% conﬁdence interval, 7.6 to not evaluated). A further subgroup analysis of 47 HR-positive patients demonstrated an overall response rate of 40% (19/47 patients) with a median PFS of 7.9 months (95% conﬁdence interval, 4.4-13.7), indicating that DS-8201a could be applied in HR-positive disease as well. Inter- estingly, the disease of 44% (7/16) of patients previously treated with a CDK4/6 inhibitor responded to DS-8201a, indicating that CDK4/6 treatment did not affect the efﬁcacy of DS-8201a treat- ment. Assessing the relationship between different levels of HER2 expression and response to treatment, overall response rates were similar in both HER2-loweexpressing subgroups (HER2 IHC 1þ and 2þ), exhibiting a mild superiority in the latter one (35.7% vs. 38.5%). As far as drug toxicity was concerned, most patients (53/ 54) experienced a treatment-related AE, with 63% (34/54) being grade 3 or higher. Gastrointestinal disorders and bone marrow toxicity accounted for the majority of treatment-related AEs— ﬁndings consistent with previously reported AEs. The primary reasons for treatment discontinuation in 11 patients (20%) were pneumonitis and ILD. Three deaths were reported as treatment related, all of which were attributed to pneumonitis and ILD.

The DESTINY-Breast01 phase 2 multicenter trial (NCT03248492) evaluated DS-8201a in previously treated HER2- positive BC.49,50 The ﬁrst part of the study consisted of 2 cohorts: pharmacokinetics, where patients received 5.4, 6.4, and 7.4 mg/kg doses of DS-8201a in a 1:1:1 ratio, and a dose-ﬁnding part, where patients would receive 5.4 or 6.4 mg/kg in a 1:1 ratio. Balancing safety and efﬁcacy, a dose of 5.4 mg/kg was ﬁnally recommended. The second part of the study evaluated the safety and efﬁcacy of DS-8201a at the recommended dose of 5.4 mg/kg in patients who had pro- gressive disease while or after receiving T-DM1 (part 2a) and in pa- tients who discontinued T-DM1 for other reasons (part 2b). Overall, 253 patients were enrolled onto the study, of whom 184 received the recommended dose of 5.4 mg/kg. One hundred ﬁfty-four patients (83.7%) had HER2 IHC 3þ disease, while 28 (15.2%) had IHC 1þ or 2þ, ISH-positive disease. At the data cutoff of August 1, 2019, overall response rate was 60.9% (112/184), including complete response and partial response rates of 6.0% and 54.9%, respectively. Disease control resulted in 97.3% of patients. Median duration of response was 14.8 months, and median PFS was 16.4 months. The median overall survival was not reached at the time of this report. Estimated overall survival was 93.9% at 6 months and 86.2% at 12 months. Among the 180 patients who had progressive disease during or after T-DM1 treatment, the disease of 61% responded to DS- 8201a. Further subgroup analysis showed an objective response of 64% (78/121) in patients who had previously received pertuzumab and a 58% objective response in HR-positive, HER2-positive patients (56/97). Moreover, objective response occurred in 63% (97/154) of HER2 IHC 3þ patients and 46% (13/28) in patients with IHC 1þ or 2þ, ISH-positive disease. In terms of safety, almost all patients (99.5%) who received the 5.4 mg/kg dose of DS-8201a had at least one AE; 57% had an AE of grade 3 or higher. The most common grade 3/4 AEs were neutropenia (20.7%), leukopenia (6.5%) and lymphopenia (6.5%), anemia (8.7%), nausea (7.6%), and fatigue (6.0%). The drug was associated with ILD in 13.6% of patients (grade 1 or 2, 10.9%; grade 3 or 4, 0.5%; grade 5, 2.2%). Four of the re- ported deaths (2.2%) were caused by ILD. To sum up, clinical data prove that DS-8201a retains efﬁcacy in disease previously treated with T-DM1.

A subgroup analysis of patients with central nervous system (CNS) metastases enrolled onto the DESTINY-Breast01 trial was recently presented at the European Society of Medical Oncology Breast 2020 conference.51,52 Twenty-four of 184 patients who received the recommended dose had CNS metastases before study enrollment. This heavily pretreated population was characterized by a good performance status (Eastern Cooperative Oncology Group performance status of 0; 62.5%) and a high rate of HR-negative disease (58.3%). Objective response occurred in 58.3% of these patients, including complete response in 4.2% and partial response in 54.2% of patients.51 Of note, a reduction by 55% of a brain metastasis was reported in a woman with HER2-positive disease and receipt of 17 previous lines of treatment. Disease control occurred in 91.7% of patients with CNS metastases.52 Median PFS was 18.1 months (95% conﬁdence interval, 6.7-18.1), versus 16.4 months in the overall population. Progressive disease was reported in 8 (33%) of 24 of CNS subgroup patients until data cutoff. These ﬁndings were consistent with the results obtained from the overall popula- tion despite the initial high disease burden. The Debbrah phase 2 study was recently initiated to treat HER2-positive or HER2- loweexpressing BC patients with brain metastases or lep- tomeningeal carcinomatosis (NCT04420598).

ILD is an AE reported in both studies and a major safety concern. Therefore, an analysis was conducted to identify the risk and clinical course of ILD and the recommended treatment.53 A total of 665 subjects who received one or more doses of DS-8201a from 7 studies were included in the analysis (289 patients from the phase 1 NCT02564900 study, and the remaining 376 from 6 other studies). As of October 15, 2018, a total of 66 (9.9%) of 665 cases of ILD were reported by investigators across all 7 studies, with 13 (2.0%) being grade 3 or higher. The ILD adjudication committee assessed 38 of 66 investigator-reported cases; 30 were considered drug-related ILD, 4 were ILD but not drug related, and 4 were found not to be ILD. Of the reported potential ILD cases from all studies, most were mild to moderate in severity. Among 269 sub- jects with BC who received 5.4 mg/kg of DS-8201a, there were 15 cases of ILD, 5 of which were considered drug-related ILD, including 1 case with fatal outcome. In general, higher doses were related to a higher relative risk of developing ILD. Life-threatening events were uncommon (0.4%) at the recommended dose of 5.4 mg/kg for BC. Pulmonary consultation as well as withdrawal of study medication and management with steroids for moderate to severe cases are recommended. Patients should be carefully moni- tored for respiratory symptoms, including dyspnea, as well as cough, chest tightness, or fever; in addition, radiographic imaging is necessary whenever lung toxicity is suspected. In case of asymp- tomatic ILD or pneumonitis (grade 1), treatment should be with- hold until toxicity is resolved, and corticosteroid treatment with prednisolone of ≥ 0.5 mg/kg or an equivalent regimen should be considered.35 If asymptomatic ILD/pneumonitis requires more than 1 month to resolve, dose should be reduced by one dose level (5.4 mg/kg to 4.4 mg/kg). In case of symptomatic ILD/pneumonitis (grade 2 or higher), treatment should be permanently discontinued, and corticosteroid treatment with prednisolone of ≥ 1 mg/kg or equivalent should be immediately initiated.35

A phase 1 evaluating the effect of DS-8201a on the QT/QTc interval and pharmacokinetics in HER2-expressing BC is currently ongoing at 7 study sites in Japan (NCT03366428). Patients receive 6.4 mg/kg of DS-8201a intravenously once every 3 weeks. At the study cutoff of December 5, 2018, a total of 51 subjects were enrolled and received DS-8201a.54 The dose of 6.4 mg/kg was not associated with a clinically meaningful QTcF prolongation (change of > 10 ms). The pharmacokinetic proﬁle of the unconjugated anti- HER2 antibody was similar to that of DS-8201a, and the payload release was low. Mean accumulation ratio for AUCtau during the ﬁrst 3 cycles of therapy was consistent with the observed half-life of DS-8201a. All subjects had treatment-emergent AEs (67% grade 3 or higher), most of which were gastrointestinal disorders or hema- tologic abnormalities. Overall, DS-8201a at a 6.4 mg/kg dose did not induce signiﬁcant QTcF prolongation and showed a favorable pharmacokinetic proﬁle.

In December 2019, the FDA provided accelerated approval of DS-8201a (Enhertu; Daiichi Sankyo) for patients with unresectable
or advanced HER2-positive BC heavily pretreated with two or more HER2-targeting therapy lines.55 The recommended dose for wide use is 5.4 mg/kg, which is based on the safety and efﬁcacy proﬁle of the analysis of phase 1 (NCT02564900) and phase 2 (NCT03248492) studies.37

Future Perspectives

There are 3 ongoing phase 3 trials (NCT03523585, NCT03529110, NCT03734029). The ﬁrst one (DESTINY- Breast02) aims to compare DS-8201a to treatment of choice (either combination of trastuzumab and capecitabine or lapatinib and capecitabine) in patients with unresectable and/or metastatic BC pretreated with T-DM1 (NCT03523585).56 Another phase 3 trial (DESTINY-Breast03) is designed to evaluate DS-8201a versus T-DM1 in advanced HER2-positive BC patients previously treated with trastuzumab and a taxane (NCT03529110). The DESTINY- Breast04 phase 3 trial is focusing on the HER2-loweexpressing (IHC 2þ/ISH— or IHC 1þ/ISH—) BC subgroup. More specif- ically, DS-8201a is compared to treatment of the investigator’s choice (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel) in patients with unresectable and/or metastatic BC (NCT03734029).57 The phase 2 DAISY trial is evaluating the antitumor activity of DS-8201a in 3 cohorts of advanced BC pa- tients: those with HER2-positive, HER2-negative/low-expressing (IHC 1þ or IHC 2þ/ISH—), and HER2-negative/nonexpressing (IHC 0þ) tumors (NCT04132960).

The combination of DS-8201a and immunotherapy is also under evaluation. DS-8201a is being tested in combination with nivolu- mab in HER2-positive and HER2-negative metastatic BC (NCT03523572).58 A phase 1 study was initiated in August 2019 to explore DS-8201a and pembrolizumab combination treatment in patients with HER2-positive and HER2-loweexpressing advanced or metastatic BC and patients with HER2-expressing/mutated nonesmall-cell lung cancer (NCT04042701). Enrollment began in February 2020, and approximately 115 patients will be assigned. The BEGONIA phase 1/2 multicenter trial was designed to compare durvalumab in combination with novel regimens, including DS-8201a with or without paclitaxel versus the combi- nation of durvalumab and paclitaxel in triple-negative advanced or metastatic BC (NCT03742102). Patients with HER2- loweexpressing triple-negative (IHC 2þ or IHC 1þ/ISH—) BC will be eligible for enrollment onto the durvalumab and DS-8201a combination arm. The study is still recruiting; its primary completion date is estimated to be December 2020. This combi- nation treatment is also under investigation in nonesmall-cell lung cancer patients (NCT03334617). These studies are going to determine if the synergistic activity of DS-8201a and immune checkpoint inhibitors exhibited in preclinical studies could enhance the current role of immunotherapy in advanced BC.

Conclusion

Overall, ADC development has paved the way for a more efﬁ- cient treatment of advanced BC. T-DM1 introduced a great ther- apeutic potential in HER2-positive advanced BC compared to either traditional chemotherapy with capecitabine plus lapatinib (EMILIA study)59 or the investigator’s treatment of choice (TH3RESA study).60 DS-8201a combines a payload of higher potency, greater homogeneity, and higher DAR ratio with a highly promising bystander killing effect—properties associated with a higher efﬁcacy status. Outcomes of the phase 2 DESTINY-01 study conﬁrmed the data of preclinical studies, further establishing DS-8201a in the treatment of HER2-positive metastatic BC.

Despite promising results in clinical trials, lung toxicity remains a drug-related AE that could potentially limit its clinical application. Pneumonitis is a rare complication of trastuzumab, affecting about 0.5% of patients receiving treatment, but it may still evolve into a life-threatening condition.61 Trastuzumab-related pneumonitis was mostly observed when administered in combination with taxane or after prior treatment with a taxane regimen.62,63 Incidence of pneumonitis in patients receiving T-DM1 is estimated to be rather low (0.8%), but it is still more commonly reported than in treat- ment with trastuzumab.64,65 However, a common AE reported in T-DM1 treatment is thrombocytopenia.59,60 The phase 2 DESTINY-Breast01 study of DS-8201a found a pneumonitis incidence of 13.6%, with 2.2% being lethal. This complication should be taken into account during drug administration, and an effective therapeutic plan in case of occurrence should be developed. The ﬁndings of these studies, as well as the promising efﬁcacy of DS-8201a in HER2-negative disease, remain to be conﬁrmed by ongoing phase 2/3 trials.

Disclosure

M.L. has received honoraria from Roche, AstraZeneca, Astellas, MSD, Janssen, Bristol Myers Squibb, and IPSEN. K.K. has received honoraria from Roche, BMS, MSD, and Ipsen. M.A.D. has received honoraria from participation in advisory boards from Amgen, Bristol Myers Squibb, Celgene, Janssen, and Takeda. F.Z. has received honoraria for lectures and has served in an advisory role for AstraZeneca, Eli Lilly, Merck, Novartis, Pﬁzer, and Roche. The other authors have stated that they have no conﬂict of interest.

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