On April 5, 2024, 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 (IHC3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options. It is one of seven anticancer agents with a tumor-agnostic FDA approval.

FDA update

Efficacy was evaluated in 192 adult patients with previously treated unresectable or metastatic IHC 3+ solid tumors who were enrolled in one of three multicenter trials: DESTINY-PanTumor02 (NCT04482309), DESTINY-Lung01 (NCT03505710), and DESTINY-CRC02 (NCT04744831). All three trials excluded patients with a screening diagnosis or history of interstitial lung disease or pneumonitis requiring treatment with steroids or clinically significant cardiac disease. Patients were also excluded for active brain metastases or ECOG performance status higher than 1. Patients received treatment until they withdrew consent or experienced disease progression, unacceptable toxicity, or death.

The major efficacy outcome measure in all three trials was confirmed objective response rate (ORR), and an additional efficacy outcome was duration of response (DOR). All outcomes were assessed by independent central review based on RECIST v1.1. In DESTINY-PanTumor02, ORR was 51.4% (95% CI = 41.7, 61.0) and median DOR was 19.4 months (range = 1.3, 27.9+). In DESTINY-Lung01, ORR was 52.9% (95% CI = 27.8, 77.0) and median DOR was 6.9 months (range = 4.0, 11.7+). In DESTINY-CRC02, ORR was 46.9% (95% CI = 34.3, 59.8) and DOR was 5.5 months (range - 1.3+, 9.7+).

The most common adverse reactions reported in at least 20% of patients during the drug’s clinical trials, 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 about the risk for interstitial lung disease and embryo-fetal toxicity.

The recommended fam-trastuzumab deruxtecan-nxki dosage for this indication is 5.4 mg/kg given as an IV infusion once every 3 weeks (21-day cycle) until patients experience disease progression or unacceptable toxicity.

View the prescribing information for fam-trastuzumab deruxtecan-niki.

FDA approved the tumor-agnostic indication under accelerated approval based on objective response rate and duration of response. Continued approval for the indication may be contingent on verification and description of clinical benefit in confirmatory trial(s).

The review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence (OCE). Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. FDA collaborated with the Australian Therapeutic Goods Administration, Brazilian Health Regulatory Agency, Health Canada, and Singapore Health Sciences Authority for its review. The application reviews are ongoing at the other regulatory agencies.

The applicant used the Assessment Aid, a voluntary submission, to facilitate FDA’s assessment. FDA approved the application almost two months ahead of its goal date.

The application was granted Priority Review and Breakthrough Therapy Designation. FDA-expedited programs are described in the Guidance for Industry: Expedited Programs for Serious Conditions—Drugs and Biologics.

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.

For assistance with single-patient applications for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email OncProjectFacilitate@fda.hhs.gov.