A New Tumor-Agnostic Cancer Drug Is Making a Difference: Trastuzumab Deruxtecan

What Does Tumor-Agnostic Mean?

Regardless of the organ where cancer originates, drugs targeting genetic alterations specific to cancer cells are called tumor-agnostic . The number of cancer drugs approved in this way is growing.

Which Cancer Drugs Have Tumor-Agnostic Approvals?

The first FDA (US Food and Drug Administration) approval for this purpose concerned patients with MSI-H or dMMR tumors in 2017 , when the immunotherapy pembrolizumab (Keytruda) was approved. This approval established MSI-H and dMMR status as the first tumor-agnostic biomarkers.

Then, in 2018, for tumors with NTRK gene fusions, larotrectinib (Vitrakvi) became the second tumor-agnostic drug to receive FDA approval. The number increased each year. Entrectinib (Rozlytrek) followed in 2019, also targeting NTRK alterations. In June 2020, pembrolizumab received FDA approval for patients with any solid/organ tumor with high tumor mutational burden (TMB-H). In June 2022, trametinib (Mekinist) plus dabrafenib (Tafinlar) was approved for BRAF-mutated tumors. In September 2022, selpercatinib (Retevmo) joined the list for RET fusion-positive tumors.

Oncology therefore gained 5 tumor-agnostic biomarkers (MSI-H/dMMR, NTRK, TMB-H, BRAF and RET) and 5 different treatment regimens. Another candidate is now emerging: the antibody-drug conjugate trastuzumab deruxtecan (Enhertu) for all solid tumors with low or high HER2 positivity.

Developed by Japanese biotechnology company Daiichi Sankyo, Enhertu has so far received approvals for:

• Advanced HER2-positive breast cancer previously treated with at least 2 lines of anti-HER2 therapy, in 2019;
• Previously treated advanced HER2-positive gastric cancer, in 2021;
• Advanced HER2-positive breast cancer previously treated with one line of anti-HER2 therapy, in May 2022;
• HER2-low-positive breast cancer, on August 6, 2022. This introduced the concept of HER2-low positivity. Enhertu became the first drug approved for HER2-low cancers.
• On August 12, 2022, it received FDA approval for previously treated advanced HER2-positive non-small cell lung cancer. This was the first HER2-targeted drug approval in lung cancer.

How Does Enhertu Work?

Trastuzumab deruxtecan combines a monoclonal antibody designed to bind the HER2 receptor with a chemotherapy drug attached to that antibody. It is a new-generation cancer drug in the antibody-drug conjugate class.

HER2 is a receptor expressed at high or low levels on breast cancer cells. It provides information about the disease course and is a target for targeted drugs. Since 2000, breast cancers have been classified according to HER2 positivity.

A Small but Important Study in Gastric Cancer

A study published in the leading oncology journal Journal of Clinical Oncology on November 15, 2022 suggested that approval of trastuzumab deruxtecan for HER2-low-positive gastric cancer could be close.

Trastuzumab deruxtecan (abbreviated T-DXd) had, as noted above, received FDA approval for previously treated HER2-positive gastric cancer. However, its efficacy in HER2-low patients was unclear.

Study Details

To investigate the efficacy and safety of trastuzumab deruxtecan in HER2-low gastric or gastroesophageal junction (GEJ) adenocarcinoma, the phase II clinical trial DESTINY-Gastric01 was conducted.

Patients with locally advanced or metastatic disease previously treated with at least two regimens, including fluoropyrimidine and platinum, but no anti-HER2 therapy, received intravenous T-DXd at 6.4 mg/kg every 3 weeks. The primary endpoint, confirmed by independent central review, was the objective response rate.

Results

• Between February 2018 and February 2019, 21 patients were enrolled in group 1 (HER2 IHC 2+/FISH–) and 24 in group 2 (IHC 1+) at 27 cancer centers in Japan and South Korea.
• The confirmed objective response rate was 26.3% in group 1, with five partial responses (95% CI, 9.1 to 51.2), and 9.5% in group 2, with two partial responses (95% CI, 1.2 to 30.4).
• Tumor size decreased in thirteen patients in group 1 (68.4%) and 12 in group 2 (60.0%).
• Median overall survival was 7.8 months in group 1 (95% CI, 4.7 to not evaluable) and 8.5 months in group 2 (95% CI, 4.3 to 10.9).
• Median progression-free survival was 4.4 months (95% CI, 2.7 to 7.1) and 2.8 months (95% CI, 1.5 to 4.3), respectively.
• The most common serious (grade ≥ 3) treatment-emergent adverse events in groups 1 and 2 were anemia (30.0% and 29.2%), decreased neutrophil count (25.0% and 29.2%), and decreased appetite (20.0% and 20.8%). Drug-related interstitial lung disease/pneumonitis occurred in one patient per group (grade 1 or 2). There were no treatment-related deaths.

In conclusion, this study provides preliminary evidence of clinical activity for T-DXd in heavily pretreated patients with HER2-low gastric or gastroesophageal junction adenocarcinoma. Approval for treating these patients may therefore be possible in the future.