The FDA has granted an accelerated approval to fam-trastuzumab deruxtecan-nxki (Enhertu) for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received ≥2 prior anti–HER2-based regimens in the metastatic setting.
The FDA has granted an accelerated approval to fam-trastuzumab deruxtecan-nxki (Enhertu; DS-8201) for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received ≥2 prior anti—HER2-based regimens in the metastatic setting.1
The approval is based on findings from the phase II DESTINY-Breast01 trial, updated data of which were presented at the 2019 San Antonio Breast Cancer Symposium.2 In the study, trastuzumab deruxtecan induced a confirmed objective response rate (ORR) of 60.3% per independent central review (ICR; 95% CI, 52.9-67.4), including a 4.3% complete response (CR) rate, and a 56% partial response (PR) rate. Sixty-seven patients had stable disease (SD; 36.4%), and 3 with progressive disease (PD; 1.6%). Two patients were not evaluable. ORRs were consistent across subgroups, including those with prior treatment with pertuzumab (Perjeta; 64%) and those with ≥ 3 prior regimens (59%).
"There have been many advances in the development of drugs for HER2-positive breast cancer since the introduction of Herceptin (trastuzumab) in 1998. The approval of Enhertu represents the newest treatment option for patients who have progressed on available HER2-directed therapies," Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, stated in a press release. “Drug development in the area of targeted therapies builds on our scientific understanding of malignant diseases not only in breast cancer, but in multiple other diseases.”
In the open-label, international, multicenter phase II registration study, investigators enrolled 184 patients with HER2-positive breast cancer who were heavily pretreated, including with T-DM1 (Kadcyla) and other HER2-targeted treatments. The trial consisted of part 1 to evaluate pharmacokinetics (n= 65) and to determine recommended dose (RP2D; n = 54) for part 2 (n = 134): 5.4 mg/kg fam-trastuzumab deruxtecan-nxki. Data from this study were published simultaneously in the New England Journal of Medicine.3
ORR per ICR served as the primary endpoint. Secondary endpoints included DCR, DOR, and PFS.
Inclusion criteria included ≥18 years of age, unresectable and/or metastatic breast cancer, HER2-positive (centrally confirmed on archival tissue), prior T-DM1 therapy. Patients with a history of significant interstitial lung disease (ILD) were excluded. Those with stable, treated brain metastases were allowed.
All patients were female, the majority were white (55%), and 38% were Asian. Median age was 56 years (range, 28-96 years). Fifty-three percent were hormone receptor (HR)-positive and 45% were HR-negative. At baseline, the median number of prior treatment regimens was 6 (range, 2-27), including trastuzumab (Herceptin; 100%), T-DM1 (100%), pertuzumab (65.8%), and other HER2-targeted regimens (54.3%). The reported best response to T-DM1 before enrollment on the study were a CR and PR rate of 22%, 21% of patients with SD, and 36% with PD. Twenty-one percent were not evaluable.
As of the data cutoff (August 1, 2019), 79 patients (42.9%) are still on treatment, while 105 patients (57.1%) discontinued treatment, primarily for progressive disease (28.8%). In total, 184 patients enrolled on the study have received 5.4 mg/kg T-DXd for a median treatment duration of 6.9 months (range, 0.7-16 months).
Moreover, the investigational HER2-targeted antibody-drug conjugate yielded a median duration of response (DOR) of 14.8 months (95% CI, 13.8-16.9), and a disease control rate (DCR) of 97.3% (95% CI, 93.8-99.1). Clinical benefit ratio at 6 months was 76.1% (95% CI, 69.3%-82.1%), and median time to response was 1.6 months (95% CI, 1.4-2.6 months). Activity of fam-trastuzumab deruxtecan-nxki across all major subgroups appeared consistent.
After a median follow-up of 11.1 months (range, 0.7-19.9 months), median progression-free survival (PFS) of 16.4 months (95% CI, 12.7-NE). Median PFS in the 24 patients with brain metastases was 18.1 months (95% CI, 6.7-18.1 months). Median overall survival was not reached (95% CI, NE-NE).
For the approval, the FDA evaluated the safety of fam-trastuzumab deruxtecan-nxki in a pooled analysis of 234 patients in the DESTINY-Breast01 and Study DS8201-A-J101 trials.
Specifically in DESTINY-Breast01, treatment-emergent adverse events (TEAE) occurred in 99% of patients, 51% being grade ≥ 3. The most common any-grade TEAEs were nausea (77%), alopecia (48%), fatigue (48%), vomiting (45%), constipation (34%), decreased neutrophil count (31%), decreased appetite (29%), diarrhea (27%), and anemia (26%). The most common grade ≥ 3 AEs were decreased neutrophil count (in 31% of the patients), nausea (7.6%), and anemia (in 26%).
Of note, 25 patients (13.6%) experienced ILD related to fam-trastuzumab deruxtecan-nxki by an independent adjudication committee. However, ILD was primarily grade 1 (2.7%) or 2 (8.2%). Median time to investigator-reported onset of ILD was 193 days (range, 42-535 days), and 13 of the 20 patients with grade ≥2 ILD received corticosteroids. Overall, 7 patients recovered, 2 were recovering at data cutoff, 12 were either outcome unknown or not followed until resolution, and 4 died. Of the 4 fatal cases, onset was from 63 to 148 days, of which 3 received steroids as part of their treatment, and death occurred 9 to 60 days after ILD diagnosis.
Fam-trastuzumab deruxtecan-nxki is a novel antibody drug conjugate that is comprised of 3 components: a humanized anti-HER2 IgG1 monoclonal antibody with the same amino acid sequence as trastuzumab; a topoisomerase I inhibitor payload, an exatecan derivative; and a tetrapeptide-based cleavable linker.
Phase I data, previously published in Lancet Oncology, showed that T-DXd demonstrated an ORR of 59.5% (95% CI, 49.7-68.7) in patients with advanced HER-2 positive breast cancer previously treated with T-DM1.4