Fam-Trastuzumab Deruxtecan-nxki Receives Accelerated Approval for HER2-Positive Solid Tumors

Joseph Kalis, PharmD, BCOP.

The FDA has granted accelerated approval to fam-trastuzumab deruxtecan-nxki (Enhertu®, Daiichi Sankyo, Inc.) for adult patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)–positive (immunohistochemistry [IHC] 3+) solid tumors who have previously received systemic treatment and have no satisfactory alternative therapeutic options. The accelerated approval for this tumor-agnostic indication is based on objective response rate and duration of response; continued approval may be contingent upon confirmatory trial results. 

Why it matters: “The approval of fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors gives clinicians another arrow in the quiver of treatment options for these patients,” commented Joseph Kalis, PharmD, BCOP, Oncology Data Advisor Editorial Board Member and Ambulatory Oncology Clinical Pharmacy Specialist at the University of Colorado Health. “This approval follows the growing trend of tumor-agnostic approvals, where treatments can be used for any tumor type as long as the appropriate target is expressed.”

What they studied: The efficacy of fam-trastuzumab deruxtecan was evaluated in 192 patients enrolled in the multicenter DESTINY-PanTumor02 (NCT04482309), DESTINY-Lung01 (NCT03505710), and DESTINY-CRC02 (NCT04744831) trials. Eligible patients had previously treated unresectable or metastatic HER2-positive (IHC 3+) solid tumors. Patients were excluded who had interstitial lung disease (ILD)/pneumonitis at screening, a history of ILD/pneumonitis that required treatment with steroids, clinically significant cardiac disease, active brain metastases, or Eastern Cooperative Oncology Group (ECOG) performance status of >1.

Treatment with fam-trastuzumab deruxtecan was administered until disease progression, death, withdrawal of consent, or unacceptable toxicity. The primary end point of all three trials was confirmed objective response rate (ORR), with an additional end point of duration of response (DOR), both of which were accessed by independent central review based on RECIST 1.1.

What they found: Response outcomes in the three trials were as follows:

  • In DESTINY-PanTumor02, ORR was 51.4% and median DOR was 19.4 months
  • In DESTINY-Lung01, ORR was 52.9% and median DOR was 6.9 months
  • In DESTINY-CRC02, ORR was 46.9% and DOR was 5.5 months

Adverse events: The most common adverse events (≥20%) experienced by patients receiving fam-trastuzumab deruxtecan, 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 for fam-trastuzumab deruxtecan includes a Boxed Warning for the risk of interstitial lung disease and embryo-fetal toxicity.

Conclusion: “I’m curious to see what we learn about treatment sequencing for the HER2-targeted therapies, as many questions still exist,” concluded Dr. Kalis. “Which agent is best to use first? Or does sequencing matter for these patients? Regardless, clinicians can now customize later-line treatment for HER2-positive solid tumors to each patient’s unique situation.”

Instructions: The recommended dose of fam-trastuzumab deruxtecan-nxki 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.

For More Information

Meric-Bernstam F, Makker V, Oaknin A, et al (2024). Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: primary results from the DESTINY-PanTumor02 phase II trial. J Clin Oncol, 42(1):47-58. DOI:10.1200/JCO.23.02005

Li BT, Smit EF, Goto Y, et al (2022). Trastuzumab deruxtecan in HER2-mutant non–small-cell lung cancer. N Engl J Med, 386(3):241-251. DOI:10.1056/NEJMoa2112431

Raghav KPS, Siena S, Takashima A, et al (2023). Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-overexpressing/amplified (HER2+) metastatic colorectal cancer (mCRC): Primary results from the multicenter, randomized, phase 2 DESTINY-CRC02 study. J Clin Oncol (ASCO Annual Meeting Abstracts), 41(suppl_16). DOI:10.1200/JCO.2023.41.16_suppl.3501

US Food & Drug Administration (2024). FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2

Enhertu® (fam-trastuzumab deruxtecan-nxki) prescribing information (2024). Daiichi Sankyo, Inc. Available at: https://daiichisankyo.us/prescribing-information-portlet/getPIContent?productName=Enhertu&inline=true

Image courtesy of Fvasconcellos (PDB entry 1N8Z). Licensed under public domain. 

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