On August 11, 2022, the FDA accelerated the approval of the antibody–drug conjugate fam-trastuzumab deruxtecan-nxki (Enhertu; Daiichi Sankyo) for the treatment of adult patients with unresectable or metastatic non–small-cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as determined by an FDA-approved test, and who have received a previous systemic therapy. The FDA granted trastuzumab deruxtecan a priority review and breakthrough designation for this indication.
Concurrently, the FDA approved Life Technologies Corporation’s Oncomine Dx Target tissue test and Guardant Health’s Guardant30 CDx plasma test as companion diagnostics for determining HER2 mutations in this patient population.
Trastuzumab deruxtecan was previously approved for the treatment of patients with unresectable or metastatic HER2-positive breast cancer who have received ≥2 previous anti–HER2-based regimens in the metastatic setting and in patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a previous trastuzumab-based regimen.
This new indication was based on an interim efficacy analysis in a prespecified patient cohort of patients in the DESTINY-Lung02 study, a multicenter, multicohort, randomized, blinded, dose-optimization clinical trial. Patients with previously treated unresectable or metastatic nonsquamous HER2 mutation–positive NSCLC received intravenous (IV) trastuzumab deruxtecan 5.4 mg/kg every 3 weeks until unacceptable toxicity or disease progression.
The primary efficacy measures were confirmed objective response rate (ORR) as assessed by blinded independent central review using RECIST version 1.1 and duration of response. An interim efficacy analysis in a prespecified patient cohort showed a confirmed ORR of 57.7% (N = 52; 95% confidence interval [CI], 43.2-71.3). Complete responses were observed in 1.9% of patients and partial responses in 55.8% of patients, with a median duration of response of 8.7 months (95% CI, 7.1-not evaluable).
The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea, decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, decreased lymphocyte count, decreased platelet count, decreased albumin, increased aspartate aminotransferase, increased alanine aminotransferase, fatigue, constipation, decreased appetite, vomiting, increased alkaline phosphatase, and alopecia.
The prescribing information includes a boxed warning advising health professionals of the risk for interstitial lung disease and embryo-fetal toxicity.
On August 5, 2022, the FDA approved trastuzumab deruxtecan for the treatment of adult patients with unresectable or metastatic HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization [ISH]-negative) breast cancer who have received previous chemotherapy in the metastatic setting or had disease recurrence during or within 6 months of completing adjuvant chemotherapy. The FDA granted trastuzumab deruxtecan a priority review and breakthrough designation for this indication.
This new indication was based on efficacy data from the DESTINY-Breast04 study, a randomized, multicenter, open-label clinical trial of 557 patients with unresectable or metastatic HER2-low breast cancer. The trial included 2 cohorts: 494 patients with hormone receptor (HR)-positive disease and 63 patients with HR-negative disease. HER2-low expression was defined as IHC 1+ or IHC 2+/ISH-negative, determined at a central laboratory.
The patients were randomized in a 2:1 ratio to receive trastuzumab deruxtecan 5.4 mg/kg IV (N = 373) every 3 weeks or physician’s chemotherapy choice (N = 184).
The primary efficacy measure was progression-free survival (PFS) in patients with HR-positive breast cancer, assessed by blinded independent central review using RECIST version 1.1. Secondary efficacy measures included PFS in the overall population (all randomized patients with HR-positive and HR-negative disease), overall survival (OS) in patients with HR-positive disease, and OS in the overall population.
Median PFS in the HR-positive cohort was 10.1 months in the trastuzumab deruxtecan arm and 5.4 months in the chemotherapy arm. Median PFS in the overall population was 9.9 months for patients receiving trastuzumab deruxtecan and 5.1 months for those receiving chemotherapy.
In the HR-positive cohort, the median OS was 23.9 months and 17.5 months in the trastuzumab deruxtecan and chemotherapy arms, respectively. In the overall population, median OS was 23.4 months in the trastuzumab deruxtecan arm versus 16.8 months in the chemotherapy arm.
The most common (≥20%) adverse reactions reported with trastuzumab deruxtecan were nausea, fatigue, alopecia, vomiting, anemia, constipation, decreased appetite, diarrhea, and musculoskeletal pain.