Helena Linardou, MD, PhD

Helena Linardou, MD, PhD, Director of the 4th Department of Oncology and the Comprehensive Clinical Trials Center, Metropolitan Hospital, Athens, was invited as the discussant of the studies on antibody-drug conjugates at the 2023 World Conference on Lung Cancer.

Preliminary Data

Dr. Linardou first emphasized the rapid evolution of the field of antibody-drug conjugates, noting the multiple agents being developed for lung cancer that target different factors involved in this malignancy—including trophoblastic cell-surface antigen, or TROP-2. She discussed the studies of two TROP-2–targeting agents that have been combined with immune checkpoint inhibitors in the advanced non–small cell lung cancer first-line setting: datopotamab deruxtecan (Dato-DXd) plus durvalumab with or without carboplatin in the TROPION-Lung04 trial and sacituzumab govitecan-hziy plus pembrolizumab in the EVOKE-02 trial.

“TROP-2 is a very interesting therapeutic target. It is an epithelial adhesion molecule that regulates stem cell marker–associated cell regeneration and is overexpressed in solid tumors, including triple-negative breast cancer and non–small cell lung cancer. We already have very promising phase I data for these two agents,” Dr. Linardou said.

Reflecting on the activity of sacituzumab govitecan plus pembrolizumab, and Dato-DXd plus durvalumab, vis a vis the activity observed with checkpoint inhibitors plus chemotherapy, she noted that in EVOKE-02, the response rate was 69% in high expressors of PD-L1 (≥ 50%) and 44% among low expressors (< 50%). In the smaller subsets of TROPION-Lung04, 50% of patients responded overall to Dato-DXd plus durvalumab, and 77% responded to this doublet plus chemotherapy. For reference, in KEYNOTE-189,¹ which combined pembrolizumab with chemotherapy and is reflective of what is achieved in clinical practice today, the response rates were 62% in high PD-L1 expressors and 50% in low expressors, she noted.

“Of course, these data are preliminary, but these numbers [from TROPION-Lung04 and EVOKE-2] match nicely with what we see with immunotherapy-plus-chemotherapy combinations. If these findings are confirmed in larger studies, I think they clearly show that these agents could replace chemotherapy in first-line combinations.”

Words of Caution on Toxicity

Dr. Linardou cautioned that these two antibody-drug conjugates cannot “be considered equal, as they are not the same” in terms of side effects. “The toxicity profiles should be taken into account when we use these drugs in combinations,” she said.

The two drugs share a number of toxicities, such as alopecia, fatigue, and nausea, but there are some other “common and notable” drug-specific toxicities, she noted, and they can be severe. With Dato-DXd, these adverse events include dry eye, stomatitis, and interstitial lung disease. With sacituzumab govitecan, they are neutropenia and diarrhea, along with a higher incidence of nausea, vomiting, and constipation than seen with Dato-DXd.

Although interstitial lung disease has been a concern with antibody-drug conjugates containing the deruxtecan component, Dr. Linardou noted the rate of interstitial lung disease was low with Dato-DXd, and most of the events were grade 1 or 2 in TROPION-Lung04. 

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.

REFERENCE

1. Gadgeel S, Rodríguez-Abreu D, Speranza G, et al: Updated analysis from KEYNOTE-189: Pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non-small-cell lung cancer. J Clin Oncol 38:1505-1517, 2020.