Trastuzumab Deruxtecan First Approval for HER2-Mutant Non–Small Cell Lung Cancer

Non–small cell lung cancer carcinoma.

The FDA has granted accelerated approval to fam-trastuzumab deruxtecan-nxki (T-DXd) (Enhertu®, Daiichi Sankyo Inc.) for treatment of adult patients with unresectable or metastatic non–small cell lung cancer (NSCLC) with human epidermal growth factor receptor 2 (HER2) mutations. This approval is specific to individuals who have undergone previous systemic therapy. Trastuzumab deruxtecan is the first drug to be approved for treatment of HER2-mutant NSCLC.

“HER2 mutations are an established molecular target in NSCLC; however, there are no approved therapies for patients with HER2-mutated NSCLC” wrote Professor Egbert Smit, Professor of Pulmonology at Leiden University, and colleagues, in their report of the DESTINY-Lung02 trial (NCT04644237). “T-DXd is an antibody-drug conjugate consisting of an anti-HER2 antibody, cleavable linker, and topoisomerase I inhibitor payload.”

The safety and efficacy of trastuzumab deruxtecan were evaluated across multiple trials, but accelerated approval was based off the DESTINY-Lung02 trial. This phase 2, multicenter, two-arm trial randomized 152 patients to study optimized dosage by receiving either 5.4 mg/kg of trastuzumab deruxtecan intravenously every three weeks, or 6.4 mg/kg of trastuzumab deruxtecan intravenously every three weeks.

Treatment was favorable in those being treated with 5.4 mg/kg of trastuzumab deruxtecan. The primary end point of objective response rate, evaluated by blinded independent central review, was 58%, with a key secondary end point being duration of response, which saw a median of 8.7 months.

The most common adverse events in ≥20% of patients receiving trastuzumab deruxtecan 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. These adverse events include the laboratory abnormalities. Trastuzumab deruxtecan comes with a Boxed Warning advisory for risk of interstitial lung disease and embryo-fetal toxicity

“The approval of trastuzumab deruxtecan in non–small cell lung cancer is an important milestone for patients and the oncology community,” said Dr. Bob T. Li, MD, PhD, MPH, Medical Oncologist at Memorial Sloan Kettering Center Center and study author of the DESTINY-Lung02 trial, in the Daiichi Sankyo Press Release. “After two decades of research into the role of targeting HER2 in lung cancer, the approval of the first HER2-directed treatment option validates HER2 as an actionable target in lung cancer and marks an important step forward for treating this patient population with unmet medical needs.”

The recommended dose of trastuzumab deruxtecan for treatment of patients with HER2-mutant NSCLC is 5.4 mg/kg every three weeks intravenously until unacceptable toxicity or disease progression.

For More Information

Smit EFF, Li BT, Mazieres J, et al (2021). Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-mutated (HER2M) metastatic non-small cell lung cancer (NSCLC): a phase (ph) II study (DESTINY-Lung02). Ann Oncol, 32(suppl_5):1032-1032. Abstract 1361TiP. DOI:10.1016/j.annonc.2021.08.1962 (2022). Trastuzumab deruxtecan in participants with HER2-mutated metastatic non–small cell lung cancer (NSCLC) (DESTINY-LUNG02). NLM identifier: NCT04644237.

Daiichi-Sankyo (2022). Press release: ENHERTU® approved in the U.S. as the first HER2 directed therapy for patients with previously treated HER2-mutant metastatic non–small cell lung cancer. Available at:

Enhertu® (fam-trastuzumab deruxtecan-nxki) prescribing information (2022). Daiichi Sankyo Inc. Available at:

US Food and Drug Administration (2022). FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for HER2-mutant non-small cell lung cancer. Available at:

Îmage credit: Yale Rosen. Licensed under CC BY-SA 2.0

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