FDA Approval Summary: Fam-trastuzumab deruxtecan-nxki for the treatment of unresectable or metastatic HER2-positive breast cancer. (2024)

The publisher's final edited version of this article is available at Clin Cancer Res

Chemistry, Manufacturing, and Control

T-DXd is an antibody-drug conjugate (ADC) composed of a humanized anti-HER2 IgG1 monoclonal antibody (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 (Figure 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 (DAR) 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.

Nonclinical Pharmacology and Toxicology

In vitro, MAAL-9001 and T-DXdbound 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 anti-tumor activity in HER2-positive or HER2-low-expressing breast cancer mouse tumor models (13).

Good laboratory practice (GLP)-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 toxicological 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. Based on 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).

Clinical Pharmacology

Based on 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 (ULN) and any aspartate aminotransferase (AST)] hepatic impairment. Additionally, 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 anti-drug antibodies (ADA) against fam-trastuzumab deruxtecan-nxki 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.

Clinical Trial Design:

Efficacy:

A total of 184 participants with HER2-positive breast cancer were enrolled at the 5.4mg/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 5.4mg/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 2 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 hormone receptor 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% CI: 52.9, 67.4). At data cut-off (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 based on 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.

Safety:

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 1 dose of T-DXd at 5.4mg/kg. The median duration of treatment was 7 months (range: 0.7 to 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 5.4mg/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 to 8.3).

Neutropenia and left ventricular dysfunction were included as Warnings and Precautions in the 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.

Regulatory Insights

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. Based on this assessment, patients received a median of 5 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 3, 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 a adverse reaction that required appropriate communication to the presecriber and patient and was thus included as a boxed warning in the U.S. prescribing information (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 this data is limited as most patients with these underlying conditions were excluded from these trials for safety concerns.

Among HER2-negative disease, HER2-low expression (either immunohistochemistry [IHC] 1+ or IHC 2+ and in situ hybridization [ISH] negative) is estimated to compromise 40–50% including both luminal-type HR-positive and TNBC cancers (20). HER2-low disease is treated similarly to the HER2-negative population including use of endocrine therapies (for hormone receptor 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 based on 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 based on 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 NME application utilized the Assessment Aid (AAid), 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.

Table 5:

FDA Benefit-Risk Assessment of T-DXd (12)

Note: This is a U.S. Government work. There are no restrictions on its use.

Disclosure of Potential Conflicts of Interest: The authors report no financial interests or relationships with the commercial sponsors of any products discussed in this report.

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