Trastuzumab Deruxtecan Receives FDA Approval for All HER2-Positive Cancers

On 5 April 2024, the United States Food and Drug Administration (FDA) granted accelerated approval to Enhertu (fam-trastuzumab deruxtecan-nxki; Japan's Daiichi Sankyo) for adults with unresectable or metastatic HER2-positive (IHC3+) solid tumors who had received prior systemic treatment and had no satisfactory alternative options.

What Is Tumor-Agnostic Treatment?

Tumor-agnostic approaches target a tumor's genetic features regardless of its tissue or organ of origin. They represent a revolutionary development in oncology. Conventional treatment generally focuses on cancer type and origin, whereas tumor-agnostic therapy targets genetic characteristics rather than location, treating tumors with particular biomarkers wherever they occur.

The first tumor-agnostic approval, in 2017, was for tumors with  high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) , treated with pembrolizumab (Keytruda). Significant progress has been made in this field since then.

Current examples include:

1. MSI-H/dMMR: pembrolizumab (Keytruda) for MSI-H/dMMR. Dostarlimab (Jemperli) for dMMR alone
2. NTRK gene fusions: larotrectinib (Vitrakvi) and entrectinib (Rozlytrek) 
3. High tumor mutational burden (TMB-H): pembrolizumab (Keytruda)
4. BRAF mutations: dabrafenib (Tafinlar) and trametinib (Mekinist)
5. RET fusions: selpercatinib (Retevmo)
6. HER2-positive (IHC3+): fam-trastuzumab deruxtecan (Enhertu)

There are therefore 6 different tumor-agnostic biomarkers  with corresponding FDA-approved treatments.

How Does Trastuzumab Deruxtecan Work?

Enhertu, scientifically known as trastuzumab deruxtecan, is an antibody–drug conjugate (ADC). It combines two important components: an antibody and a chemotherapy drug. The antibody specifically binds to cancer cells expressing high levels of HER2, directing treatment to these cells.

Enhertu's chemotherapy component is a topoisomerase inhibitor. When the antibody carries Enhertu to cells expressing high levels of HER2, the drug is released inside them. It damages DNA, preventing growth and proliferation, and can cause cell death, shrinking the tumor or slowing its growth.

Antibody–drug conjugates and tumor-agnostic treatments have both become important parts of personalized cancer care.

HER2 Alterations and Their Importance in Cancer

The HER (Human Epidermal Growth Factor Receptor) family comprises receptor tyrosine kinases affecting signaling pathways that regulate growth, differentiation and survival. It plays a central role in cancer development and progression. HER2, one of its most studied members, can cause uncontrolled cell division and growth when overexpressed in certain cancers. HER2 is an important target in several cancers, particularly breast and lung cancer.

FDA Approval Based on 3 Trials

Enhertu's effectiveness in previously treated unresectable or metastatic HER2-positive (IHC 3+) solid tumors was assessed in 192 adults.

Patients enrolled in one of three multicenter trials:

• DESTINY-PanTumor02 (all solid tumors),
• DESTINY-Lung01 (lung cancer), and
• DESTINY-CRC02 (colorectal cancer).

These trials excluded patients with interstitial lung disease/pneumonitis requiring steroids or present at screening, and those with clinically significant cardiac disease. Active brain metastases and ECOG performance status >1 were also exclusion criteria.

Treatment continued until progression, death, withdrawal of consent or unacceptable toxicity.

The primary efficacy endpoint in all three trials was confirmed objective response rate (ORR), with duration of response (DOR) as an additional endpoint. Independent central review (ICR) assessed all results according to RECIST v1.1.

• In DESTINY-PanTumor02, objective response was 51.4% (95% CI: 41.7, 61.0), with median response duration of 19.4 months (range 1.3, 27.9+).
• In DESTINY-Lung01, ORR was 52.9% (95% CI: 27.8, 77.0), with median response duration of 6.9 months (range 4.0, 11.7+).
• In DESTINY-CRC02, median response rate was 46.9% (95% CI: 34.3, 59.8), with median response duration of 5.5 months (range 1.3+, 9.7+).

The most common adverse reactions (≥20%), including laboratory abnormalities, were decreased white blood cells, nausea, decreased hemoglobin, decreased neutrophils, fatigue, decreased lymphocytes, decreased platelets, increased aspartate aminotransferase (AST), alanine aminotransferase (ALT) and blood alkaline phosphatase (ALP), vomiting, reduced appetite, alopecia, diarrhea, decreased blood potassium, constipation, decreased sodium (Na), stomatitis and upper respiratory tract infection. Prescribing information contains a Boxed Warning about interstitial lung disease and embryo-fetal toxicity.

For this indication, the recommended fam-trastuzumab deruxtecan-nxki dose is 5.4 mg/kg by intravenous infusion every 3 weeks (a 21-day cycle) until progression or unacceptable toxicity.

This tumor-agnostic indication received accelerated approval based on objective response rate and duration of response. Continued approval may depend on verification and description of clinical benefit in confirmatory trials.

Conclusion

The FDA's accelerated approval of Enhertu, whose full active ingredient name is "fam-trastuzumab deruxtecan-nxki," marks an important milestone. It offers new hope for patients with HER2-positive (IHC3+) solid tumors who have limited options and have not responded adequately to prior systemic treatment. HER2 thus becomes a tumor-agnostic biomarker guiding treatment decisions regardless of cancer type. This is a first for patients identified as positive through local HER2 testing (IHC 3+), rather than genomic test results.