FDA Approval Summary: Fam-Trastuzumab Deruxtecan-Nxki for the Treatment of Unresectable or Metastatic HER2-Positive Breast Cancer

Breast cancer is the most commonly diagnosed cancer and second leading cause of death in women. (1). In the United States, more than 270,00 cases are diagnosed with at least 40,000 deaths annually (2). Cases are rare in men, with approximately 2,600 diagnosed per year (3). Among patients with metastatic breast cancer, 15%–20% are HER2 positive with a 5-year relative survival rate ranging from 37% to 44%, depending on hormone-receptor (HR) status (4). HER2-positive disease is associated with a more aggressive tumor and a younger patient population (5). The standard of care for first-line metastatic HER2-positive breast cancer in the United States is the combination of trastuzumab, pertuzumab, and a taxane, while ado-trastuzumab emtansine (T-DM1) is currently the preferred second-line option based on results from trials in these settings (6, 7). Beyond the second line, treatment options are more limited and could include lapatinib and capecitabine, or trastuzumab combined with a chemotherapeutic agent; however, although patients initially respond to these therapies, they are less durable and ultimately relapse will occur (8, 9). After the accelerated approval of fam-trastuzumab deruxtecan-nxki (T-DXd), there have been two additional approvals in this space. The combination of neratinib and capecitabine was granted regular approval in February 2020 for adult patients with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2–based regimens in the metastatic setting (10). Tucatinib in combination with trastuzumab and capecitabine was granted regular approval in April 2020 for adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2–based regimens in the metastatic setting (11). Although treatment with anti-HER2 therapies has improved disease outcomes in unresectable or metastatic HER2-positive breast cancer, the disease remains incurable in the metastatic setting. Therefore, there remains an unmet need for further effective therapies for metastatic HER2-positive breast cancer, especially in later lines of therapy. This article summarizes the data and FDA's review leading to the accelerated approval of T-DXd (12).

T-DXd is an antibody–drug conjugate (ADC) composed of a humanized anti-HER2 IgG1 mAb (MAAL-9001) with the same amino acid sequence as trastuzumab, covalently linked to a topoisomerase inhibitor (MAAA-1181a, DXd) via a tetrapeptide-based cleavable linker (Fig. 1; ref. 13). The antibody is produced using recombinant DNA technology in Chinese hamster ovary cells, and the topoisomerase inhibitor and linker are produced by chemical synthesis. The target number of drug-linkers coupled to one antibody molecule is 8, resulting in a drug-to-antibody ratio of approximately 8. The drug product is a sterile, white to yellowish white, preservative-free lyophilized powder in single-dose vials for reconstitution and further dilution.

In vitro, MAAL-9001 and T-DXd bound to human recombinant HER2 protein but not to recombinant EGFR, HER3, or HER4 proteins, and showed antibody-dependent cellular cytotoxic activity. DXd, an exatecan derivative, inhibited the activity of topoisomerase 1, in vitro, as shown by inhibition of supercoiled DNA relaxation in a concentration-dependent manner (11). T-DXd showed antitumor activity in HER2-positive or HER2-low–expressing breast cancer mouse tumor models (13).

Good laboratory practice–compliant, repeat-dose general toxicology studies were conducted to evaluate the toxicity of T-DXd in rats and monkeys. The major observed target organs of toxicity following administration of T-DXd once every 3 weeks for up to 6 weeks to rats or 3 months to monkeys included the bone marrow, skin, lung, testis, kidney, and the gastrointestinal system. Except for the findings in the skin and kidneys in monkeys and testes in rats, all other toxicologic findings were reversible by the end of the recovery period. The major findings induced by T-DXd except for those in the lung in monkeys, were observed in both species. Overall, the toxicity findings in animals administered T-DXd were consistent with clinical adverse reactions observed in clinical trials with T-DXd. DXd was clastogenic in both an in vivo rat bone marrow micronucleus assay and an in vitro Chinese hamster lung chromosome aberration assay, but was not mutagenic in an in vitro bacterial reverse mutation assay. On the basis of postmarketing reports of oligohydramnios following use of trastuzumab during pregnancy and data showing that DXd is genotoxic, T-DXd can cause fetal harm when administered to a pregnant woman and a Warning and Precaution for embryo-fetal toxicity is included in the label (14, 15).

On the basis of the totality of data (drug–drug interaction results, activity, and safety), no dose adjustment was recommended in patients with moderate hepatic impairment, but close safety monitoring is recommended due to potentially increased exposure of DXd, the topoisomerase inhibitor. No data were available in patients with severe (total bilirubin >3 to 10 times upper limits of normal and any aspartate aminotransferase) hepatic impairment. In addition, no adjustments are recommended in patients with mild or moderate renal impairment.

Across all doses evaluated in clinical studies, only 0.6% (4/640) of evaluable patients developed antidrug antibodies against T-DXd following treatment. Therefore, no conclusions can be drawn concerning a potential effect of immunogenicity on efficacy or safety due to the limited number of patients who tested positive. The neutralizing activity of anti-T-DXd antibodies has also not been assessed.

This was a phase II, multicenter, open-label, single-arm, two-part study designed to justify the recommended dose of T-DXd and investigate the safety and efficacy in trial participants with unresectable and/or metastatic HER2-positive breast cancer previously treated with T-DM1. T-DXd was administered intravenously once every 3 weeks at various doses.

Part 1 of the study was randomized and consisted of two stages, a pharmacokinetic stage and a dose-finding stage. In the pharmacokinetic stage, trial participants were randomized in a 1:1:1 ratio to three doses (5.4, 6.4, and 7.4 mg/kg), and in the dose-finding stage participants were randomized in a 1:1 ratio to two doses that were selected for further evaluation (5.4 and 6.4 mg/kg). In Part 2 of the study, all patients received T-DXd at 5.4 mg/kg every 3 weeks, which was determined to be the optimal dose from Part 1. Part 2 was divided into two cohorts consisting of Part 2a in participants with unresectable and/or metastatic HER2-positive breast cancer previously treated with T-DM1 and Part 2b in participants who discontinued T-DM1 for reasons other than progressive disease. HER2 expression was confirmed from the most recent adequate tumor sample by central laboratory according to American Society of Clinical Oncology College of American Pathologists (ASCO/CAP) 2013 guidelines.

Treatment continued until unacceptable toxicity or progressive disease. The primary efficacy endpoint was overall response rate (ORR) based on confirmed responses by blinded independent central review (ICR) using RECIST 1.1 in all participants who were assigned to receive the recommended dose of 5.4 mg/kg. Secondary endpoints included duration of response (DoR). Tumor imaging was obtained every 6 weeks and CT/MRI of the brain was mandatory for patients with brain metastases at baseline. All responses had to be confirmed at the subsequent scan.

This was a phase I, two-part dose escalation and dose expansion, nonrandomized, open-label first-in-human study of T-DXd in various solid tumors that were either HER2 positive or with HER2-low expression. Part 1 (dose escalation) evaluated doses ranging from 0.8 to 8.0 mg/kg and was intended to identify the MTD or the recommended dose of T-DXd. Part 2 (dose expansion) was intended to further assess the safety and efficacy of T-DXd at the MTD/recommended doses of 5.4 and 6.4 mg/kg. The dose expansion was conducted in five cohorts of subjects with various tumor types [breast cancer, gastric or gastroesophageal junction (GEJ) adenocarcinoma, and others] and levels of HER2 expression.

The tumor HER2 status was determined locally either on archival tissue samples or on fresh tissue samples obtained after the last HER2-targeting treatment for metastatic disease, which differed from study DS8201-A-U201 in which HER2 status was confirmed centrally. Similar to DESTINY-Breast01, the primary efficacy endpoint was ORR based on confirmed responses by ICR and treatment continued until unacceptable toxicity or progressive disease.

A total of 184 participants with HER2-positive breast cancer were enrolled at the 5.4 mg/kg dose of T-DXd from Parts 1, 2a, and 2b in the DESTINY-Breast01 study, which formed the primary basis of the efficacy analysis. Patient demographics for both studies and the pooled population are presented in Table 1. All 184 patients in DESTINY-Breast01 that supported the target indication at a dose of 5.4 mg/kg were female. The majority (76%) of these participants were <65 years of age, 55% White, and 55% ECOG 0. Twenty-nine percent of participants were enrolled at U.S. sites. Baseline disease characteristics for both studies and the pooled population for the targeted population are presented in Table 2. All patients in DESTINY-Breast-01 had received at least two lines of HER2-directed therapy in the metastatic setting. Ninety-two percent of participants had visceral disease, 29% had bone metastases, 13% had brain metastases, and 53% percent were HR positive. The sum of diameters of target lesions were < 5 cm in 42%, and ≥ 5 cm in 50% (not evaluable by central review in 8% of patients). The median number of prior cancer regimens in the locally advanced/metastatic setting was 5 (range: 2–17). All patients received prior trastuzumab, T-DM1, and 66% had prior pertuzumab.

The confirmed ORR based on ICR in these 184 patients was 60.3% [95% confidence interval (CI): 52.9–67.4]. At data cutoff (DCO) of March 21, 2019, the median DoR for confirmed responses for the primary 5.4 mg/kg dose cohort was not estimable. An efficacy update for DoR occurred on the basis of a DCO of August 1, 2019. The DCO for the efficacy update was 10.3 months after the last patient with HER2-positive breast cancer assigned to the 5.4 mg/kg dose group. The median duration of treatment was 9.97 months. The median DoR of the 111 responders was 14.8 months (95% CI: 13.8–16.9), as shown in Table 3.

The safety evaluation for T-DXd was based on a pooled total of 234 patients with HER2-positive breast cancer in studies DESTINY-Breast01 (184 participants) and DS8201-A-J101 (50 participants) that were treated with at least one dose of T-DXd at 5.4 mg/kg. The median duration of treatment was 7 months (range: 0.7–31). Although 51 participants with HER2-positive breast cancer were enrolled in study DS8201-J101, one was not dosed; therefore, 50 patients were included in the safety analysis from this study.

Severe, life threatening, or fatal interstitial lung disease (ILD), including pneumonitis, have been noted in patients treated with T-DXd. Of the 234 participants with HER2-positive breast cancer who received 5.4 mg/kg, ILD occurred in 9.4% that was adjudicated by the independent ILD committee as related to the drug. Fatal outcomes due to ILD and/or pneumonitis occurred in 6 (2.6%) patients treated with T-DXd. All fatal cases of ILD were adjudicated as drug related. Median time to first onset was 4.1 months (range: 1.2–8.3).

Neutropenia and left ventricular dysfunction were included as Warnings and Precautions in the U.S. prescribing information (USPI). In the 234 patients with unresectable or metastatic HER2-positive breast cancer who received 5.4 mg/kg T-DXd, two cases (0.9%) of asymptomatic left ventricular ejection fraction (LVEF) decrease were reported as of the first clinical cut-off dates. Treatment with T-DXd has not been studied in patients with a history of clinically significant cardiac disease or LVEF less than 50% prior to initiation of treatment. However, as LVEF is a known class effect of HER2-directed therapies, it was justified to be included as a warning. Other important common adverse reactions (≥20%) were nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, diarrhea, leukopenia, cough, and thrombocytopenia.

T-DXd demonstrated adequate efficacy and safety in study DESTINY-Breast01 with supportive safety evidence from study DS8201-A-J101 to support an accelerated approval for the treatment of patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2–based regimens in the metastatic setting (16–18). Prior to the accelerated approval, Fast Track Designation was granted by the FDA in November 2016 and Breakthrough Therapy Designation in August 2017 based on promising preclinical and early clinical data (18). At the time of filing, Priority Review was also granted to this application.

At the time of accelerated approval for T-DXd, treatment options for HER2-positive patients after two lines of therapy in the metastatic setting were limited, and this is an area of unmet need that continues to require further effective therapies. Prior lines of therapy from patient data were retrospectively reviewed to not include dose reductions or interruptions as a new line of therapy, and to only consider a regimen as a line of therapy if a new agent was added or removed. On the basis of this assessment, patients received a median of five therapies with a range from 2 to 17 lines as included in the label. At the time of accelerated approval of T-DXd, response rates for available therapies in third-line metastatic HER2-positive breast cancer ranged from approximately 14% for trastuzumab alone, to 24% for lapatinib plus capecitabine (9, 19). Therefore, T-DXd demonstrated a clear improvement of ORR and DoR over available therapies with an ORR of 60.3% (95% CI: 52.9–67.4) and a DoR of 14.8 months (95% CI: 13.8–16.9) in a heavily pretreated population. Phase III, randomized trials with T-DXd are ongoing for HER2-positive breast cancer and these results may be used to confirm clinical benefit and support a regular approval in the future (Table 4).

While the safety of T-DXd was acceptable for the intended population, ILD was recognized as an adverse reaction that required appropriate communication to the presecriber and patient and was thus included as a boxed warning in the USPI. The specific biologic mechanisms that may contribute to the development of ILD in those being treated with T-DXd is currently under investigation and may be clarified with results of ongoing studies. Management recommendations include corticiosteroid treatment with potential discontinuation of T-DXd depending on grade of the reaction. Those with a history of pneumonitis or interstitial disease or other chronic lung conditions may be more suseptitble to drug-induced ILD; however, these data are limited as most patients with these underlying conditions were excluded from these trials for safety concerns.

Among HER2-negative disease, HER2-low expression (either IHC 1+ or IHC 2+ and ISH negative) is estimated to compromise 40%–50% including both luminal-type HR-positive and triple-negative breast cancers (20). HER2-low disease is treated similarly to the HER2-negative population including use of endocrine therapies (for HR-positive cancers), chemotherapy, and targeted therapies as there are no specific approved treatments for this population. Therefore, there is an opportunity for drug development in the HER2-low space and various therapies are currently being investigated (21). Similarly, there are no specific therapies approved for HER2-activating mutations as not all tumors with these mutations are also considered HER2 positive. T-DXd is also being investigated in patients with HER2-low–expressing tumors and those with HER2-activating mutations with enrollment into study DS8201-A-J101 (20). Table 4 summarizes the trials currently accruing with T-DXd (22). Some of these trials are evaluating the safety and efficacy of T-DXd across HER2-positive, HER2-low tumors as well as those with HER2-activating mutations regardless of tissue histology.

In DESTINY-Breast01, HER2 expression was determined on the basis of archival tissue tested at a central laboratory prior to enrollment. All subjects enrolled in this study were required to have documented HER2-expressing tumors based on a validated testing method prior to study entry and were screened for HER2 amplification for previous HER2-directed therapies. Therefore, no companion diagnostic device was submitted for concurrent evaluation with this drug. As all participants in both studies received at least two prior therapies in the advanced or metastatic setting, the indication was restricted to the use in the third line or later. However, in this refractory population, prior HER2-based regimens were not specified to allow flexibility in the use of T-DXd as the landscape of therapies in the HER2-positive space continues to evolve.

The indication for T-DXd is inclusive of all adults with HER2-positive breast cancer to ensure flexibility in the use of this therapy across various patient populations. Historically, men have been excluded from breast cancer trials due to the low incidence of the disease in males and their management in clinical practice is extrapolated from data in women. The FDA has encouraged the inclusion of male patients in breast cancer trials and has released a guidance on this topic, which in part details that even when male enrollment is limited, it may be possible to extrapolate findings in cases when no difference between males and females is anticipated on the basis of the mechanism of action of the drug (23). Although only one male participant with breast cancer was enrolled in study DS8201-A-J101, it is not anticipated that T-DXd would have differing efficacy to exclude males from the indication.

The review of this new molecular entity (NME) application utilized the Assessment Aid, a multidisciplinary review template that is a voluntary submission from the applicant with the goal to focus and streamline the FDA's written review on critical thinking and analysis (24). This in part enabled the accelerated approval of T-DXd on December 20, 2019, approximately 4 months ahead of the FDA goal date.

T-DXd represents a new treatment option for patients with heavily pretreated HER2-positive advanced or metastatic breast cancer. Results from DESTINY-Breast01 supported by data from study DS8201-A-J101 demonstrate a favorable benefit-risk profile (Table 5). This indication is approved under accelerated approval based on tumor response rate and DoR. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

No disclosures were reported.

The Editor handling the peer review and decision-making process for this article has no relevant employment associations to disclose.