Defining Trop-2 and Antibody-Drug Conjugates in NSCLC

Rebecca Suk Heist, MD, MPH: What is TROP-2 [trophoblast cell surface antigen 2]? TROP-2 is a transmembrane glycoprotein. It’s overexpressed on many cancers. It has been associated with increased tumor growth and sometimes increased metastasis. It has been associated with a worse prognosis in some cancers. TROP-2 is overexpressed in the majority of epithelial cancers. Cancers like lung cancer and many of the epithelial cancers will have expression or a high-level overexpression of TROP-2.

What are antibody-drug conjugates? These are a class of drugs where we have a monoclonal antibody that’s targeted to an antigen or a receptor on a cell and that is linked via a cleavable linker to a cytotoxic payload. This is a really interesting class of drugs. Essentially what ADCs [antibody-drug conjugates] help us do is target the cancer cells so that the antibody can attach to something that’s preferentially expressed in a cancer cell, for example, and then deliver the cytotoxic payload directly to the cancer cell. That lets us get a chemotherapy drug right to where we want it and hopefully minimizes systemic exposure, and hopefully because of that minimizes toxicity.

Solange Peters, MD, PhD: In terms of targeting TROP-2, it is a good biomarker for many peculiar tumors coming from breast cancer to urothelial cancer, lung cancer. This is a good target, and it is being targeted by more than 1 compound trying to use this new technology, a second life of what you call antibody-drug conjugates. I need to quote 2 of these drugs, which are quite advanced in the development, but there are others coming. It’s important to say that it is not exhaustive. One is sacituzumab govitecan [Trodelvy], which has been developed mainly in triple-negative breast cancer. But also, across some epithelial, other cancer and urinary cancers. There is little data in lung cancer, but most of the data in lung cancer have been using another antibody-drug conjugates targeting the same TROP-2—datopotamab deruxtecan, Dato-DXd, which is one of these new antibody-drug conjugates. As I mentioned it’s a second burst or a second life of this antibody-drug conjugate. We have been using them in breast cancer, T-DM1. We’ve been trying them across diseases but it’s a bit like pharmacological developments or I would say then industrial developments in oncology. We have been improving a lot on how this antibody-drug conjugate is designed and how they work. First, we have a better affinity for the targets. Then we have a better payload, meaning, the molecules of chemotherapy which are carried by this antibody-drug conjugate are more potent chemotherapy. Very often topoisomerase is 1 inhibitor but a very potent one. These are the ones that you can potentially deliver locally because it would be too toxic to give them systemically. They are highly potent. Very often you can optimize the drug to antibody ratio. Now having only 1 molecule of chemotherapy but more than 1. The 2 drugs I mentioned before, are a ratio of 4 molecules of chemotherapy for 1 antibody. They can have a short half-life, toxicity is limited. You can have a linker which is binding the antibody to the chemotherapy, which gives rise to a cleavable linker where the release of the chemotherapy component happens at the binding of the antibody. Why is it important? To be on the site of the tumor, but more than that, to create what we have been calling a bystander effect. Meaning that even the cancer cells around, which wouldn’t be binding the antibody-drug conjugate, or it would be negative for the biomarker, will also be affected by the chemotherapy. All of these new mechanisms make the drugs of today, the antibody-drug conjugates of today are not the same as the antibody-drug conjugates of yesterday. That’s why, and we’ll maybe discuss it later on, the results are better and more promising.

This transcript has been edited for clarity.