The Rise of Organ-Independent Cancer Treatments – Enhertu for All HER2-Positive Tumors

Tumor-agnostic approaches are treatments targeting a tumor's genetic characteristics regardless of the tissue or organ where it originated. They are considered a revolutionary development in oncology. Traditional cancer treatments generally focus on cancer type and origin, whereas tumor-agnostic therapies target genetic characteristics rather than location. This strategy aims to treat tumors with certain biomarkers regardless of where they are in the body.

The first tumor-agnostic approval came in 2017 for tumors with high microsatellite instability (MSI-H) or deficient mismatch repair (dMMR), using pembrolizumab (Keytruda). Important advances have been made in this field since then.

Currently,

1. MSI-H/dMMR,
2. NTRK gene fusions,
3. High tumor mutational burden (TMB-H),
4. BRAF mutations and
5. RET fusions are among the biomarkers addressed by treatments approved by the FDA (Food and Drug Administration in the United States), with 5 distinct tumor-agnostic treatment approaches available.

Enhertu, containing trastuzumab deruxtecan, is a candidate to become the 6th tumor-agnostic treatment, for HER2-positive tumors.

How Does Trastuzumab Deruxtecan Work?

Enhertu, scientifically known as trastuzumab deruxtecan, is an antibody-drug conjugate (ADC). Its mechanism combines two important components: an antibody and a chemotherapy drug. The antibody is specific to cancer cells highly expressing the HER2 protein and binds to them in a targeted manner. This binding directs the drug straight to cancer cells.

Enhertu's chemotherapy component is a topoisomerase inhibitor. When the antibody carries Enhertu to cancer cells highly expressing HER2, the chemotherapy drug is released inside them. It damages cancer-cell DNA, preventing their growth and proliferation. It may also cause cell death, leading to tumor shrinkage or slower growth.

These treatments have become an important part of personalized approaches to cancer treatment.

FDA Grants Priority Review to Enhertu for Metastatic HER2+ Solid Tumors

The FDA accepted a supplemental biologics license application for priority review in adults who have previously received treatment or have no satisfactory alternative treatment options and have unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+) solid tumors, for the use of trastuzumab deruxtecan.

Trastuzumab deruxtecan is a HER2-directed antibody and topoisomerase inhibitor conjugate used to treat breast cancer, non-small cell lung cancer, and gastric or gastroesophageal junction adenocarcinoma. It is currently marketed as Enhertu.

The DESTINY-PanTumor02 Trial

This new FDA application for trastuzumab deruxtecan is supported by data from the ongoing phase 2 DESTINY-PanTumor02 trial, designed to evaluate its effectiveness in selected HER2-positive tumors.

The primary analysis included 267 patients with urothelial, biliary tract, cervical, endometrial, ovarian, pancreatic, and other cancers.

The study's primary endpoint was confirmed objective response rate.

• At a median follow-up of 12.75 months, the objective response rate was 37.1%, and median response duration was 11.3 months.
• Median progression-free survival (PFS) was 6.9 months, and
• Median overall survival was 13.4 months.
• Among 75 patients with strongly positive HER2 expression (3+),
  • the objective response rate was 61.3%,
  • median response duration was 22.1 months,
  • median PFS was 11.9 months, and
  • median overall survival was 21.1 months.

Dr. Ken Takeshita, global head of research and development at Enhertu's manufacturer, Japan's Daiichi Sankyo, said, “The ongoing data from DESTINY-PanTumor02 and Enhertu's clinical development program continue to demonstrate its potential beyond its approved indications. If approved, Enhertu could become the first HER2-targeted therapy and antibody-drug conjugate with a tumor-agnostic indication, potentially providing patients with a new treatment option,” and stated that the target for FDA approval was the second quarter of 2024.