Enhertu Gets FDA Accelerated Approval for Unresectable, Metastatic HER2-Positive Solid Tumors

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The FDA has granted accelerated approval to AstraZeneca’s and Daiichi Sankyo's Enhertu (trastuzumab deruxtecan) for adults with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive, immunohistochemistry (IHC) 3+ solid tumors who were previously administered systemic therapy and who have no satisfactory alternative treatment options.¹ The regulatory action for the HER2-directed antibody-drug conjugate (ADC) adds to Enhertu’s approved indications in breast cancer, non-small cell lung cancer (NSCLC), and gastroesophageal junction adenocarcinoma.

“As the first antibody drug conjugate to be granted a tumor-agnostic indication, Enhertu is truly delivering on its potential across metastatic HER2-targetable tumors,” said Dave Fredrickson, executive vice president, Oncology Business Unit, AstraZeneca, in a press release. “This approval also elevates the importance of testing for biomarkers, including HER2, across a broad range of tumors to ensure these patients with advanced cancer who have few options know whether a targeted medicine might be right for them.”¹

Enhertu’s mechanism of action involves the humanized anti-HER2 IgG1 antibody trastuzumab attaching by a cleavable linker to the small molecule DXd. Trastuzumab then attaches to HER2 on tumor cells to halt growth, which causes the antibody to be internalized as lysosomal enzymes cleave off DXd. Subsequently, DXd causes DNA damage as it replicates and apoptotic cell death as a topoisomerase I inhibitor.^2,3

The latest approval was based on findings from the Phase II DESTINY-PanTumor02 (NCT04482309), DESTINY-Lung01 (NCT03505710), and DESTINY-CRC02 (NCT04744831) trials. Across the Phase II trials in the DESTINY program, the primary efficacy endpoint was objective response rate (ORR), with a key secondary endpoint of duration of response (DOR).

In the DESTINY-PanTumor02 trial, investigators evaluated previously treated patients (n=111) with centrally or locally assessed HER2-positive, IHC 3+ solid tumors. The primary analysis of the open-label trial included patients with endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other cancer types with HER2-expressing (IHC 3+/2+ by local or central testing) locally advanced or metastatic tumors following at least one systemic therapy or who lack alternative treatment options. Patients showed an ORR of 51.4% (95% CI, 41.7%-61.0%) and a median DOR of 19.4 months (range, 1.3 to 27.9+).

The DESTINY-Lung01 trial evaluated efficacy from a subgroup of patients (n=17) with centrally confirmed HER2-positive NSCLC classified as IHC 3+. Patients showed an ORR of 52.9% (95% CI: 27.8-77.0) and a median DOR of 6.9 months (range: 4.0, 11.7+).

DESTINY-CRC02 evaluated efficacy in patients (n=64) with centrally confirmed HER2-positive colorectal cancer classified as IHC 3+, who experienced an ORR of 46.9% (95% CI: 34.3-59.8) and a median DOR of 5.5 months (range: 1.3+, 9.7+).

“Until the approval of [Enhertu], patients with metastatic HER2-positive solid tumors have had limited treatment options,” said Funda Meric-Bernstam, MD, chair of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, in a press release. “Based on the clinically meaningful response rates seen across clinical trials, this tumor-agnostic approval means that patients may now be treated with a HER2-directed medicine.”¹

In prior trials, the most common adverse events associated with Enhertu (incidence 20% or greater) were nausea, decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, increased aspartate aminotransferase, fatigue, decreased lymphocyte count, vomiting, decreased platelet count, increased blood alkaline phosphatase, alopecia, constipation, hypokalemia, decreased appetite, and diarrhea.³

“This fifth indication in the US is a significant milestone as eligible patients with previously treated metastatic HER2-positive solid tumors may now be treated with Enhertu,” said Ken Keller, global head of Oncology Business, and president and CEO, Daiichi Sankyo, Inc., in a press release. “The accelerated approval by the FDA for this tumor-agnostic indication is based on the clinically meaningful efficacy seen with Enhertu across numerous types of metastatic cancers.”¹

References

1. ENHERTU Approved in the U.S. as First Tumor Agnostic HER2 Directed Therapy for Previously Treated Patients with Metastatic HER2 Positive Solid Tumors. News Release. Tokyo: Daiichi Sankyo; April 5, 2024. Accessed April 8, 2024. https://daiichisankyo.us/press-releases/-/article/enhertu-approved-in-the-u-s-as-first-tumor-agnostic-her2-directed-therapy-for-previously-treated-patients-with-metastatic-her2-positive-solid-tumors

2. FDA approves new treatment option for patients with HER2-positive breast cancer who have progressed on available therapies. U.S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-option-patients-her2-positive-breast-cancer-who-have-progressed-available. Accessed April 8, 2024.

3. Enhertu. Prescribing information. Daiichi Sankyo, Inc.; 2022. Accessed April 8, 2024.