Novel Antibody Drug Conjugates for Triple-Negative Breast Cancer

Sacituzumab Govitecan, Datopotamab Deruxtecan, and Trastuzumab Deruxtecan

Komal Jhaveri, MD, Memorial Sloan Kettering Cancer Center, New York City, New York provides insights and information regarding new and emerging antibody drug conjugates for patients with triple-negative breast cancer, a topic she presented at the 2022 Great Debates & Updates in Women’s Oncology virtual meeting.

In her presentation, Dr Jhaveri discussed the latest breakthroughs and current research in antibody drug conjugates, with specific attention given to sacituzumab govitecan (saci), datopotamab deruxtecan (dato-DXD), and trastuzumab deruxtecan (HER-3DXD).

Transcript:

Hello, my name is Komal Jhaveri, and I'm a breast medical oncologist at Memorial Sloan Kettering Cancer Center. I serve as the Section Head for our Endocrine Therapy Research Program within the Breast Medicine Service, and I also serve as the Clinical Director for our Early Drug Development Service. I did give a talk on novel antibody conjugates in triple-negative breast cancer at the Great Debates & Updates Women's Oncology meeting in September.

At this meeting, we summarized the mechanisms, and safety and efficacy data for the new and emerging agents that are currently already approved for patients with triple-negative breast cancer, specifically focusing on antibody drug conjugates. How do we think about managing those adverse events from these antibody drug conjugates?

We know that a currently-approved antibody drug conjugate for metastatic triple-negative breast cancer is a Trop-2-directed antibody drug conjugate, sacituzumab govitecan. The approval is for patients with metastatic disease who have received at least 1 line in the metastatic setting, but patients with 2 or more lines of therapies in the metastatic setting were enrolled in the phase 3 registrational ASCENT study where patients were randomized to receive sacituzumab govitecan versus physician’s choice of chemotherapy. And there was a statistically significant improvement seen in both progression-free survival and overall survival with this agent, which has changed the standard of care for our patients with metastatic disease.

Where are we going next with this? I think in terms of biomarkers, we'll try to look if the activity deferred by Trop-2 expression. When we looked at Trop-2 expression by 8 scores, we saw that activity was seen with sacituzumab regardless of the Trop-2 expression being high, moderate, or low. The magnitude of benefit for sacituzumab in those low Trop-2 expressors was rather modest, however the numbers were small, and no definitive conclusions can be made about that right now. As of today, in the clinic, we do not select patients based on Trop-2 expression. We just assume that these patients have tumors with high Trop-2 expression and therefore will benefit from sacituzumab, as was seen in the ASCENT trial.

We also looked at germline BRCA mutations, and a benefit was seen regardless of the presence or absence of mutations. The next step forward with this agent is to see if we can further improve activity by combining it with either PARP inhibitors, combining it with checkpoint inhibition, and evaluating its role even in early-stage disease. In fact, the SASCIA trial is evaluating the role of sacituzumab govitecan in those patients who have residual disease after neoadjuvant therapy.

There are other novel Trop-2 antibody drug conjugates also being evaluated in clinic, and one example is datopotamab deruxtecan. This is the same payload as trastuzumab deruxtecan, but here the antibodies are directed against Trop-2. We saw some preliminary activity reported from a phase 1 study in a metastatic cohort of triple-negative breast cancer, where we did see an overall response rate of 34% with this agent. A randomized phase 3 trial is currently on-going to further evaluate its role.

There are other antibody drug conjugates against various targets including LIV-1 and Nectin-4 that are also in development. What was also reported at ASCO this year were results from the Destiny-04 trial evaluating the role of trastuzumab deruxtecan in patients with HER2-low metastatic breast cancer. While the primary endpoint was focused on HR-positive, HER2-low patients or all patients, there was an exploratory analysis that was specifically performed for patients with HR-negative, HER2-low breast cancer.

In that exploratory subgroup of 58 patients, there was an impressive, statistically significant improvement in both progression-free survival and overall survival seen. As such, the current US FDA approval for this agent is for HER2-low regardless of HR status, or hormone receptor status. So that potentially could also be an option for our metastatic triple-negative breast cancer, specifically if they are HER2-low, which is IC-1+ or 2+ that is H-negative. However, we have the Level I evidence, the largest randomized data from sacituzumab, so currently my practice has been to utilize sacituzumab.

I think that brings a very important point about how we think about optimally sequencing all these antibody drug conjugates that are either approved or currently in development. That's an area of research that is currently ongoing.

To summarize, we have an approved Trop-2 directed antibody drug conjugate with another, datopotamab, that looks active in metastatic triple-negative breast cancer. We have trastuzumab deruxtecan for those patients who have HER2-low, HR-negative disease, however many questions remain including can one antibody drug conjugate work after another, if they have non-cross resistant payloads? Will one work after another if they have the same target and distinct payloads? And how can we think about optimal combination partners to further improve outcomes? Looking forward to that.

Thank you.

Source:

Jhaveri K. Novel ADCs – Saci, Dato-DXD, HER-3DXD, LIV-1 & Others. Presented at: Great Debates & Updates in Women’s Oncology; September 21-23, 2022; Virtual.