Helena Linardou, MD, PhD
Helena Linardou, MD, PhD, Director of the 4th Department of Oncology and the Comprehensive Clinical Trials Center, Metropolitan Hospital, Athens, served as discussant of the session on antibody-drug conjugates at the 2023 World Conference on Lung Cancer. Calling antibody-drug conjugates “the next tsunami,” Dr. Linardou noted that three have received either accelerated approval or Breakthrough Therapy designation in advanced non–small cell lung cancer (NSCLC): fam-trastuzumab deruxtecan-nxki for pretreated patients with HER2-mutant disease; patritumab deruxtecan (HER-DXd) for disease with mutations of the epidermal growth factor receptor (EGFR) after a third-generation tyrosine kinase inhibitor and platinum-based chemotherapy; and telisotuzumab vedotin for c-MET–overexpressing NSCLC after failure of platinum-based chemotherapy. In this “rapidly evolving scene,” she added, numerous early-phase trials are assessing other antibody-drug conjugates as monotherapy or in combinations.
Closer Look at HER3-DXd
The first-in-class antibody-drug conjugate HER3-DXd targets HER3, which is a “biologically and clinically important target,” according to Dr. Linardou. HER3 is highly expressed in NSCLC (83%) and upregulated in tyrosine kinase inhibitor–resistant EGFR-mutant disease, a setting with limited treatment options, and is associated with a poor prognosis. HER3 is targeted now by HER3-DXd, which works via topoisomerase inhibition, has a high antibody-to-drug ratio, and elicits a bystander antitumor effect.
HER3-DXd showed activity in small, early-phase studies of NSCLC, in patients both with and without EGFR mutations. Building upon these early findings, the HERTHENA-Lung01 trial was a randomized, open-label phase II study of HER3-DXd given at a fixed dose of 5.6 mg/kg to 225 previously treated patients, half of whom had a history of central nervous system (CNS) metastases. The phase II design, large sample size, and considerable proportion of patients with brain metastases, she said, “are extremely important to note,” as they contribute to the validity of the findings.
“We saw a molecule that showed clinically meaningful efficacy not only in the overall population but also across subgroups,” Dr. Linardou commented. “We saw an objective response rate of approximately 30%—almost one in three patients—regardless of the type of mutation or mechanism of resistance. Also, for the first time with this agent, we saw meaningful intracranial responses: again, one in three patients with CNS disease had an objective response, and nine patients had complete responses.”
Most of the toxicity was “chemo-like” events, while hematologic toxicity largely occurred early and was transient, she noted. However, 64.9% of patients had a grade ≥ 3 treatment-related adverse event, although the therapy discontinuation rate (7%) was low—probably a result of successful management with dose interruption—and the rate of interstitial lung disease was also relatively low (5%), Dr. Linardou observed.
“Overall, this large phase II study of a first-in-class antibody-drug conjugate shows meaningful and durable efficacy in a population with an unmet medical need, including CNS efficacy in patients without prior radiotherapy, and it has an easy dosing schedule. Unfortunately, we don’t have a predictive biomarker of activity, which is a recurring issue with antibody-drug conjugates…. However, I think HER3 is now a clinically actionable therapeutic target that may have broader application to HER3-overexpressing tumors and perhaps to a broader range of drug-resistant tumors.”
DISCLOSURE: Dr. Linardou has served as a consultant for or received honoraria from AstraZeneca, Amgen, Merck, Novartis, Pfizer, Roche, MSD Oncology, Bristol Myers Squibb, and Takeda.
