Aditya Bardia, MD, MPH, FASCO, on the Current and Future Landscape of Antibody-Drug Conjugates

I'll review the current and future landscape of antibody drug conjugates with a focus on practical elements. Antibody drug conjugates essentially are drugs which have antibody connected to a payload, usually toxic chemotherapy, with a linker. At this time there are three antibody drug conjugates that are FDA approved. The first one was T-DM1, which is currently approved for patients with metastatic HER2-positive breast cancer as well as early HER2-positive breast cancer patients who have residual disease after neoadjuvant anti-HER2 therapy. The second antibody drug conjugate that was FDA approved was trastuzumab deruxtecan, which is the same antibody as T-DM1, but the payload is different, the number of payload molecules attached to T-DXd are much higher, and it has shown very impressive efficacy in metastatic HER2-positive breast cancer. In the second line setting, it was compared head to head to T-DM1, and it's the recommended second line treatment regimen for patient with metastatic HER2-positive breast cancer. But the drug also has a bystander effect, and it can even work in tumors that have lower expression of HER2 called HER2 low breast cancer. So that's HER2 IHC 1+ or HER2 IHC 2+, traditionally considered HER2-negative. But this drug has shown activity in this setting. It's FDA approved for HER2 low breast cancer in patients who've received at least one prior line of chemotherapy, both for hormone receptive-positive breast cancer as well as hormone receptor-negative breast cancer. This might change in the future based on DESTINY-Breast06 where the drug was evaluated against capecitabine and taxanes and was found to be superior in patients who had not received prior chemotherapy, patients with metastatic hormone receptor-positive breast cancer. This trial included HER2 low, but also included HER2 ultra low, which is some expression of HER2, not enough to be called IHC 1+, but a bit more than IHC 0, the so-called 0+. So we'll see the approval, but if it's approved, that'll broaden the use of T-DXd. In terms of practical components besides line of therapy, the common side effects with T-DXd include nausea/ usually we recommend a three-drug antiemetic regimen. Olanzapine is a good breakthrough medication for nausea with T-DXd. It can cause pneumonitis, which can be fatal as seen in the DESTINY Breast series. The key is early recognition management. When patients are getting scans, you're not just looking for response, you're also looking for evidence of pneumonitis when a patient is on T-DXd. The third important thing to remember, particularly for hormone receptive-positive metastatic breast cancer, where sometimes we don't get routine echos is that because this is an anti-HER2 agent, it can impact the heart, so getting regular echocardiograms is important when using T-DXd. The third FDA-approved therapy is sacituzumab govitecan. It targets Trop-2. It has a payload which is a topoisomerase inhibitor. It's approved for patients with metastatic TNBC as well as metastatic hormone receptive-positive breast cancer. As per the FDA label require two prior lines of therapy in hormone receptor-positive breast cancer. Also in metastatic, one prior line of therapy is needed, so it's usually used in the second line setting. In terms of side effects to watch out for with SG, the payload is S-38, the active metabolite of irinotecan. So the side effect profile is similar to irinotecan, myelosuppression, neutropenia being a common side effect, nausea, again, recommended three-drug antiemetic regimen, diarrhea, usually patients should have a prescription of antidiarrheals when prescribing the drug, and alopecia. Now, besides this, in terms of the future, there are other exciting antibody drug conjugates. Datopotamab deruxtecan is one, which is also a Trop-2-directed ADC, has shown positive results in metastatic hormone receptive-positive breast cancer, is being evaluated in other settings as well. There are newer HER2-directed ADCs, interest in combining ADCs with immunotherapy. So the landscape might change in the future, and more and more antibody drug conjugates are replacing chemotherapy. So the key would be to understand the antibody drug conjugates, particularly the side effect profile as these drugs are used in clinic.