Fam-trastuzumab deruxtecan-nxki is a new antibody-drug conjugate currently approved to treat HER2-positive breast cancer and HER2-positive gastroesophageal cancer.

Approval of a new anti-HER2 agent for HER2-positive gastric cancer serves as an important milestone in the treatment of this disease. For more than a decade, trastuzumab has been among standard first-line treatment options for patients with these tumors. However, many subsequent attempts to target the HER2 pathway with novel agents and in different lines of treatments have been unsuccessful.

DESTINY-Gastric01 demonstrated clinically and statistically significant improvement in objective response rate and OS in the experimental group. These updated results continue to demonstrate that fam-trastuzumab deruxtecan-nxki is an active drug against HER2-positive upper gastrointestinal cancer.

Initial results of this study led to FDA approval of fam-trastuzumab deruxtecan-nxki in the U.S. for patients with HER2-positive gastroesophageal cancer in the second-line setting. The approval was a bit surprising because DESTINY-Gastric01 enrolled Asian patients only and was conducted in the third-line setting. In the fall, we saw results of DESTINY-Gastric02, an open-label, multicenter phase 2 study among Western patients who progressed on one line of therapy. The drug demonstrated significant activity in this nonrandomized trial, with an ORR of 38% that compared favorably to standard second-line treatment. Although this study showed the agent has activity in the approved setting, randomized data are still needed.

As studies continue to explore activity of this drug in earlier lines of therapy, we continue to focus on safety and tolerability. The drug has clinically meaningful benefits, but its active component is chemotherapy and thus comes with chemotherapy-associated side effects. This may limit our ability to combine with other cytotoxic agents. Another side effect of concern is pneumonitis, which has been observed in breast cancer studies and upper gastrointestinal studies. Clinicians who prescribe this drug should be aware of this toxicity, which may occur after a few months of treatment.

When this drug is prescribed, it is also important to ensure that patients remain eligible for anti-HER2 treatments after progression on first-line trastuzumab. HER2 expression can be lost by tumors under the pressure of therapy. Therefore, it is important to confirm that patients still have HER2-positive disease prior to treatment initiation. Although DESTINY-Gastric01 did not require confirmation of HER2-positive disease, in practice we should make sure patients still have HER2-positive tumors — repeat tissue biopsy or liquid biopsy can be attempted to obtain this information.

In summary, patients with HER2-positive upper gastrointestinal cancers have a new treatment option, which improves prognosis of this devastating disease. There are several other exciting agents targeting this pathway in development. As more of these treatments become available to our patients, toxicity profiles, in addition to efficacy, will be important in determining how to sequence their use.

Reference:

Van Cutsem E, et al. Abstract LBA55. Presented at: European Society for Medical Oncology Congress (virtual meeting); Sept. 17-21, 2021.