Antibody-Drug Conjugates Take Center Stage in NSCLC

Antibody-drug conjugates (ADCs) targeting TROP2, HER2, and, most recently, B7H3 have taken the field of non–small cell lung cancer (NSCLC) by storm, said Melissa Johnson, MD. She added that the TROP2-directed ADC, datopotamab deruxtecan, has the potential to cause a paradigm shift for patients with genomic alterations.

“The TROPION-Lung05 trial [NCT04484142] is looking at datopotamab deruxtecan for patients with actionable genomic alterations, such as EGFR mutations, ALK rearrangements, and ROS1 rearrangements,” said Johnson. “That’s a really exciting trial because it’s [investigating] a very different mechanism than we’ve come to think about for the care of our patients with oncogene drivers; [TROP2] is [such a broad target] that we didn’t know was therapeutically relevant until a couple of years ago. It is an exciting breakthrough.”

In an interview with OncLive®, Johnson, program director of Lung Cancer Research at Sarah Cannon Research Institute, discussed highlights from the 2021 ESMO Congress.

OncLive®: What session from the 2021 ESMO Congress did you find most valuable?

Johnson: The highlight for me from the 2021 ESMO Congress was the W40 career development for women in oncology seminar that was held the last day. I wasn’t expecting to get as much out of it as I did. I played it with interest, because I’m a woman in oncology, but the name of the session was titled: Gender Equity: A Broader Perspective, and the 2 speakers were excellent. Michelle Bachelet [MD], who’s the United Nations High Commissioner for Human Rights, a past president of Chile, and a physician; and Ophira Ginsburg, MD, who’s the senior visiting scientist at IARC [The International Agency for Research on Cancer], spoke about the challenges of pushing gender equity into the 21st century.

They talked a lot about how the issues of gender equity that women face in [an industrialized] country are so different from those problems that women face in a [developing] country. We can only begin by addressing the problems that women have. At the very least: Can we affect change throughout our society? There are women who don’t seek care for their breast cancers, because they’re afraid that their husband will leave them. There are women who are not able to leave their children to get the care that they need. These are things that in the United States we take for granted. It really struck me how women patients with cancer need advocacy among their doctors, more than I had thought about before.

Turning to some of the clinical data that were presented, what are your thoughts on the preliminary data from the TROPION-PanTumor01 trial (NCT03401385) with datopotamab deruxtecan?

This late breaking abstract in NSCLC was particularly interesting, because it looked at patients with actionable genomic alterations. These patients have quite nice responses with the TROP2-directed ADC, in addition to patients that are EGFR wild type.

Do you see TROP2 as a potential target for all-comers given the increasing subtyping that we’re seeing in lung cancer?

It is interesting, because until the [TROPION-PanTumor01 trial] started, I wasn’t really aware that TROP2 was a target. A lot of people have learned about TROP2 in the past few years. TROP2 seems to be quite pervasive, not just in lung cancer, but in breast cancer, in small cell lung cancer, in head and neck cancers, and GEJ [gastroesophageal junction] and gastric cancers. Maybe [datopotamab deruxtecan] is going to be another one of these therapies that has potential across tumor types, like pembrolizumab [Keytruda] has been for patients with any amount of tumor mutation burden above 10.

Based on these findings, what are your expectations for the TROPION-Lung01 trial (NCT04656652)?

TROPION-Lung01 is another trial that’s ongoing; it’s a large phase 3 trial vs docetaxel. I fully expect that it will be a positive trial, and we will see a change in the standard of care because of this trial. It’s an interesting time. ADCs seem to have taken lung cancer by storm in the past year or 2.

Another ADC that has generated substantial excitement is fam-trastuzumab deruxtecan-nxki (Enhertu). Could this agent be as effective in lung cancer as it has been in breast cancer?

I’ve heard from my breast cancer colleagues for a long time that trastuzumab deruxtecan is a great drug; that it’s well tolerated and very effective. It is nice to see that data starting to emerge in the treatment of patients with HER2-mutated lung cancer, as well as HER2-overexpressing lung cancer. We’ve been looking for a HER2-directed strategy that is effective and tolerable for the treatment of patients with lung cancer. [Lung cancer is] obviously different than breast cancer, but many of the drugs in that field, such as ado-trastuzumab emtansine [TDM-1; Kadcyla], tucatinib [Tukysa], and trastuzumab [Herceptin] don’t seem to be as effective for lung cancer as they have been for breast cancer in the past. This drug seems to be an exception to that, with some very exciting results, with response rates in the 60% range. We’ll expect an approval here, soon, I would think.

What other novel agents stood out to you from the meeting?

I presented a study with an ADC directed against B7H3. This ADC goes after another novel target that I didn’t know much about before, but 1 that is highly expressed in many tumor types––among them squamous cancers, lung cancer, head and neck cancer, esophageal cancer, and prostate cancer. I reported the results of the phase 1 experience with close to 90 patients who had been treated at a variety of dose levels. We saw responses in several dose levels and several tumor types, including prostate cancer, squamous cancers, and small cell lung cancer. This is another exciting target. B7H3 is an immune checkpoint, but the mechanism of action is an exetecan payload ADC, which sort of combines the knowledge that we’ve been acquiring over the past few years in both arenas. I am hopeful that this agent will continue in development.

This activity is funded in part by Daiichi Sankyo. Content independently produced by OncLive.