Trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo and AstraZeneca; previously known as DS-8201a) is an effective treatment option for patients diagnosed with difficult-to-treat HER2-expressing solid tumors.

This conclusion is based on the findings of an international study which was study was sponsored and designed by Astra Zeneca in collaboration with Daiichi Sankyo. The results of the study are presented at the annual meeting of the American Society of Clinical Oncology (ASCO), being held June 2 – 6, 2023 in Chicago, Illinois.

Trastuzumab deruxtecan is an antibody-drug conjugate or ADC designed to target HER2 and is approved in HER2-expressing breast and gastric cancers. However, HER2 expression is also prevalent in other solid tumors and the efficacy of currently available treatments in these populations, including studies with HER2-directed treatments, is relatively modest, and reveals a significant unmet medical need.

Study design
Patients with HER2-expressing biliary tract, bladder, cervical, endometrial, ovarian, pancreatic, or other tumors (excluding breast, gastric, colorectal and non-small cell lung cancers) were enrolled in the study. There were 267 patients, including 75 patients with IHC 3+ expression and 125 with IHC 2+ expression. IHC is the amount of HER2 receptor protein present in cells.

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Although HER2 is expressed across a variety of tumor types, there are currently no approved HER2-targeted therapies for many types of cancer, especially those that are hard to treat. Trastuzumab deruxtecan is an antibody drug conjugate targeting HER2 that is currently approved by the U.S. Food and Drug Administration for HER2-expressing breast cancer, HER2+ gastric cancer, and lung cancers with HER2-mutations. This study is the first global study of tumor-agnostic applications for trastuzumab deruxtecan across a broad range of HER2-expressing solid tumors.

Study results
In the phase II open-label DESTINY-PanTumor02 study, patients with HER2-expressing (immunohistochemistry [IHC] 3+ or IHC 2+) locally advanced or metastatic disease that had worsened after at least one systemic treatment or that had no treatment options were treated with at least one dose of trastuzumab deruxtecan. At the median follow-up of 9.7 months, the treatment resulted in an ORR of 37.1% (ORR is a measure of the number of partial and complete responses to a treatment). The amount of time that tumors continued to respond to treatment—measured by the mDOR—was 11.8 months. In patients with higher levels of HER2 expression (i.e., IHC 3+), trastuzumab deruxtecan was even more effective, resulting in an ORR of 61.3% and an mDOR of 22.1 months. Across different disease sites, trastuzumab deruxtecan resulted in the following ORRs:

  • Endometrial cancer: 57.5% for all patients, 84.6% for IHC 3+, and 47.1% for IHC 2+
  • Cervical cancer: 50% for all patients, 75% for IHC 3+, 40% for IHC 2+
  • Ovarian cancer: 45% for all patients, 63.6% for IHC 3+, 36.8% for IHC 2+
  • Urothelial cancer: 39% for all patients, 56.3% for IHC 3+, 35% for IHC 2+
  • Biliary tract cancer: 22% for all patients, 56.3% for IHC 3+, 0% for IHC 2+
  • Pancreatic cancer: 4% for all patients, 0% for IHC 3+, 5.3% for IHC 2+

The study participants were mostly able to tolerate treatment with trastuzumab deruxtecan, however, 11.6% of participants stopped treatment due to adverse events. The most common treatment-related side effects were nausea, fatigue, and low levels of blood cells (cytopenia).

“HER2 is present in many cancer types, such as breast, gastric, lung, gynecologic, and urothelial cancers, and patients with HER2-expressing, hard-to-treat cancers need new treatment options,” said Funda Meric-Bernstam, MD, chair of the Department of Investigational Cancer Therapeutics at the University of Texas MD Anderson Cancer Center and lead author of the study.

“These results advance our clinical understanding of HER2 expression, reaffirm HER2 as an actionable biomarker across a broad range of tumor types, and show that trastuzumab deruxtecan could potentially provide a new treatment option for patients with advanced disease across these tumors, especially in patients with HER2 IHC 3+ or 2+ expression,” Meric-Bernstam added.

Next Steps
The researchers are currently collecting additional survival outcomes in the DESTINY-PanTumor02 study ( identifier: NCT04482309).

Clinical trials
Study of DS-8201a in Subjects With Advanced Solid Malignant Tumors – NCT02564900
A Phase 2 Study of T-DXd in Patients With Selected HER2 Expressing Tumors (DPT02) – NCT04482309

Highlights of prescribing Information
Trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo and AstraZeneca)[Prescribing Information]

[1] Meric-Bernstam F, Makker V, Oaknin A, Oh DY, Banerjee SN, Gonzalez Martin A, Jung KH, Lugowska IA, et al. LBA3000: Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing solid tumors: DESTINY-PanTumor02 (DP-02) interim results.

Featured Image: Annual Meeting, ASCO, Chicago, IL – McCormick Place – Photo courtesy:  © 2023 ASCO/Scott Morgan. Used with permission.

This article was first published in Onco’Zine.

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