Dr. Burns on the Evolving Use of ADCs in HER2-mutant NSCLC

Timothy Burns, MD, PhD, associate professor of medicine, associate program director, Research, associate program director, Hematology/Oncology Fellowship Program, Department of Medicine, Division of Hematology-Oncology, UPMC Hillman Cancer Center, discusses the evolution of antibody-drug conjugates (ADCs) in HER2-mutant non–small cell lung cancer (NSCLC).

Although ADCs have been employed as an effective treatment option in the breast cancer space for several years, these agents have only recently been evaluated and approved for lung cancer, Burns begins.

Fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) received a breakthrough therapy designationfrom the FDA in 2020 for patients with metastatic NSCLC whose tumors express HER2 mutations and who have disease progression on or after platinum-based therapy. This designation was based on the results of the phase 2 DESTINY-Lung01 trial (NCT03505710), which evaluated the efficacy and safety of T-DXd in patients with HER2-overexpressing tumors (2+ or 3+ via immunohistochemistry) and HER2 mutations. In the latter population, the regimen elicited an objective response rate (ORR) of 54.9%, Burns says.

On August 11, 2022, T-DXd became the first ADC to gain FDA approval for this specific patient population, Burns continues. Notably, it is also the first non-TKI targeted therapy to show activity in HER2-mutant NSCLC, which is a smaller subgroup within lung cancer, Burns adds. The regimen’s approval was based on efficacy findings from the phase 2 DESTINY-Lung02 trial (NCT04644237), in which T-DXd elicited a confirmed ORR of 57.7% and a median duration of response of 8.7 months.

There’s also increased interest in expanding the use of ADCs for other HER2-expressing tumors, Burns says. Moreover, ADCs are being investigated for other molecular targets beyond HER2, Burns details. These mutations could function as oncogenic drivers and others may help define select populations within small cell lung cancer or mesothelioma that could benefit from ADCs, he states.

Although these agents are not new, novel methods of linking drugs to antibodies could be explored to improve their efficacy in other disease spaces, Burns explains. For example, ado-trastuzumab emtansine (Kadcyla) showed success in the treatment of HER2-positive breast cancer, but was less effective in HER2-overexpressing lung cancers, he expands. Therefore, it is important to find the optimal drug to utilize in NSCLC, Burns concludes.

Editor’s Note: Dr Burns is on advisory boards for Amgen, AstraZeneca, Blueprint Medicines Corporation, EMD Serono Inc, Janssen, Mirati Therapeutics, and Takeda; is on the data and safety monitoring board for Advarra, Inc; and has received research funding for an investigator-initiated trial from Novartis (Inst.).