On April 5, the U.S. Food and Drug Administration (FDA) granted accelerated approval to fam-trastuzumab deruxtecan-nxki (Enhertu) for adult patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.
Confirmatory Trials
Efficacy was evaluated in 192 adult patients with previously treated unresectable or metastatic HER2-positive (IHC 3+) solid tumors who were enrolled in one of three multicenter trials: DESTINY-PanTumor02 (ClinicalTrials.gov identifier NCT04482309), DESTINY-Lung01 (NCT03505710), and DESTINY-CRC02 (NCT04744831). All three trials excluded patients with a history of interstitial lung disease (ILD)/pneumonitis requiring treatment with steroids or ILD/pneumonitis at screening and clinically significant cardiac disease. Patients were also excluded for active brain metastases or Eastern Cooperative Oncology Group performance status > 1. Treatment was administered until disease progression, death, withdrawal of consent, or unacceptable toxicity.
The major efficacy outcome measure in all three trials was confirmed objective response rate, and an additional efficacy outcome was duration of response. All outcomes were assessed by independent central review based on Response Evaluation Criteria in Solid Tumors version 1.1. In DESTINY-PanTumor02, objective response rate was 51.4% (95% confidence interval [CI] = 41.7%–61.0%) and median duration of response was 19.4 months (range = 1.3–27.9 months). In DESTINY-Lung01, objective response rate was 52.9% (95% CI = 27.8%–77.0%) and median duration of response was 6.9 months (range = 4.0–11.7 months). In DESTINY-CRC02, objective response rate was 46.9% (95% CI = 34.3%–59.8%) and duration of response was 5.5 months (range = 1.3–9.7 months).
The most common adverse reactions (occurring in ≥ 20% of patients), including laboratory abnormalities, were decreased white blood cell count, nausea, decreased hemoglobin, decreased neutrophil count, fatigue, decreased lymphocyte count, decreased platelet count, increased aspartate aminotransferase, increased alanine aminotransferase, increased blood alkaline phosphatase, vomiting, decreased appetite, alopecia, diarrhea, decreased blood potassium, constipation, decreased sodium, stomatitis, and upper respiratory tract infection. The prescribing information includes a Boxed Warning advising health professionals of the risk of ILD and embryofetal toxicity.
Dosing and Regulatory Information
The recommended fam-trastuzumab deruxtecan-nxki dosage for this indication is 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.
This tumor-agnostic indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in at least one confirmatory trial.
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, the FDA collaborated with the Australian Therapeutic Goods Administration, the Brazilian Health Regulatory Agency, Health Canada, and Singapore’s Health Sciences Authority. The application reviews are ongoing at the other regulatory agencies.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The FDA approved this application almost 2 months ahead of the FDA goal date. This application was granted Priority Review and Breakthrough Therapy designation.
