On August 11, 2022, the U.S. Food and Drug Administration (FDA) granted accelerated approval to fam-trastuzumab deruxtecan-nxki (Enhertu®) for adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating human epidermal growth factor receptor 2 (HER2) variants, as detected by an FDA-approved test, and who have received a prior systemic therapy. This is the first drug approved for HER2-variant NSCLC.
FDA also approved Guardant Health, Inc.’s Guardant360® CDx (plasma) and Life Technologies Corporation’s Oncomine™ Dx Target Test (tissue) as companion diagnostics for fam-trastuzumab deruxtecan-nxki. Providers should obtain a tumor tissue test if plasma testing does not identify a variant.
Fam-trastuzumab deruxtecan-nxki was evaluated at a 6.4 mg/kg dose (N = 152) across multiple trials and at a 5.4 mg/kg dose (N = 102) in a randomized dose-finding trial. Response rates were consistent for both dose levels, but researchers observed increased rates of interstitial lung disease and pneumonitis in patients receiving the higher dose.
Efficacy for accelerated approval at a 5.4 mg/kg dose was based on DESTINY-Lung02, a multicenter, multicohort, randomized, blinded, dose-optimization trial. Eligible patients were required to have unresectable or metastatic, HER2-variant, nonsquamous NSCLC with disease progression after prior systemic therapy. Patients were selected for treatment with fam-trastuzumab deruxtecan-nxki based on the presence of activating HER2 variants in a tumor specimen. Patients received fam-trastuzumab deruxtecan-nxki 5.4 mg/kg by IV infusion, every three weeks until patients experience unacceptable toxicity or disease progression.
Of the 52 patients in the clinical trial’s primary efficacy population, the median age was 58 years (range = 30–78); 69% were female; and 79% were Asian, 12% were White, and 10% were of other races. The major efficacy outcome measures were confirmed objective response rate (ORR) as assessed by blinded independent central review using RECIST v1.1 and duration of response (DOR). The confirmed ORR was 58% (95% CI = 43, 71) and the median DOR was 8.7 months (95% CI = 7.1, not estimable).
The most common adverse reactions reported in at least 20% of patients, 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 of interstitial lung disease and embryo-fetal toxicity.
The application used advice from FDA Oncology Center of Excellence (OCE) Project Optimus to conduct a dose randomization study, which led to a lower dose being approved. For more information regarding the OCE’s efforts to modernize dose selection for oncology products, refer to Project Optimus.
The review used the Assessment Aid, a voluntary submission from the applicant to facilitate FDA’s assessment.
The application was granted priority review and breakthrough designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics. The application also was granted orphan drug designation.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 800-FDA-1088.