ADC Treatment Options and Breast Cancer Clinical Evidence

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Kevin Kalinsky, MD, MS: Komal, talk to us through ADCs [antibody-drug conjugates] that are available. I mentioned metastatic disease, but we also have approval for TDM-1 [trastuzumab emtansine] in the adjuvant setting. Tell us about some of these agents and their indications.

Komal Jhaveri, MD, FACP: They have helped us transform the care for our patients, both in the metastatic setting and, as you mentioned, in the early condition. The first excitement for our patients and approval for our patients was for HER2 [human epidermal growth factor receptor]–Metastatic positive cancer with the prototype antibody-drug conjugate — a first-generation antibody-drug conjugate — TDM-1, or ado-trastuzumab emtansine. It had a maytansinoid payload, and approval was initially based on the Phase 3 EMILIA trial, which compared adotrastuzumab emtansine to lapatinib and capecitabine, which was the standard of care when we were looking at MDD- 1 [trastuzumab emtansine] for HER2+ metastatic breast cancer. This led to a significant improvement in progression-free survival and overall survival and the approval of TDM-1 [trastuzumab emtansine].

It also showed activity for patients who had not received TDM-1 [trastuzumab emtansine] second-line according to the TH3RESA trial, when TDM-1 [trastuzumab emtansine] was compared to the chemotherapy chosen by the doctor. This is something that we have become familiar with. It is very well tolerated. There is no hair loss. We see a certain fatigue. The largest dose-limiting toxicity that we observed or observed was thrombocytopenia, which we are also seeing. We are seeing elevations in liver function tests and some patients have neuropathy.

In the metastatic setting, we now have approval for the next generation of antibody-drug conjugates in development. The 1 that has really succeeded and is already being implemented in our standard of care is trastuzumab deruxtecan. Deruxtecan is a TOP1 inhibitor payload. When we think about the drug-to-antibody ratio (how many chemotherapy molecules do we deliver to a cancer cell when this conjugate binds to the target protein), trastuzumab deruxtecan delivers about 8, compared to TDM-1 [trastuzumab emtansine], which provides about 3.5. There are differences in the binding technology, as Allison pointed out, which is really important, but there are also differences in the payloads within these next generation ADCs and differences in the drug / antibody ratios. .

We have data to support trastuzumab deruxtecan in the third-line setting and beyond the DESTINY-Breast01 trial, but we also have the first randomized data comparing T-DXd, or trastuzumab deruxtecan, with MDD -1 [trastuzumab emtansine] based on DESTINY-Breast03 trial data presented to ESMO [European Society for Medical Oncology]. There was an unprecedented improvement: the hazard ratio was 0.28 with P value of 10-22. This is something we haven’t really seen in breast cancer, let alone HER2+ breast cancer. So it’s exciting.

True, the toxicity is slightly different. We see more nausea and fatigue. Significant AEs [adverse effects] of interest were interstitial lung disease and pneumonia. We saw much more in the DESTINY-Breast01 trial in heavily pretreated patients. Fortunately, there were no Grade 4 or 5 events among those in the DESTINY-Breast03 trial, but it is something that we have continued to see with this agent, to which we must be vigilant.

As you pointed out, we also have data from the KATHERINE trial, which supports the use of TDM-1, trastuzumab emtansine, at an early stage. HER2+ disease. Patients who have received neoadjuvant chemotherapy and who still have residual disease at the time of surgery may warrant receiving TDM-1 [trastuzumab emtansine] instead of continuing their anti-HER2 treatment, given the 11% benefit on invasive disease survival at 3 years. It went from 77% in the control arm with a treatment regimen containing trastuzumab to 88% in the TDM-1 group [trastuzumab emtansine] arm. This is our standard of care. We have clinical trials comparing T-DXd [trastuzumab deruxtecan] with TDM-1 [trastuzumab emtansine] to see if that might transform our standard of care, but that’s what we’re using right now.

To address what we have approved for triple negative metastatic breast cancer, we have an antibody-drug conjugate directed by TROP2, sacituzumab govitecan. It is already approved for patients with metastatic disease who have had up to 2 lines of treatment, at least 1 with taxane in the metastatic setting. These patients may be given sacituzumab govitecan, which is given on days 1 and 8 of a 3-week cycle. We see a bit of neutropenia, diarrhea and fatigue as side effects. It is very exciting that we have the approval and efficacy of these agents for both breast cancer subtypes.

Kevin Kalinsky, MD, MS: We’ll get into some of the granular details about the responses and some of the toxicity that we’re seeing. As you mentioned, with sacituzumab govitecan seeing the response rates we are seeing has certainly changed and added to our armament of agents. Before moving on to a case, Kandra, from your clinical point of view, explain to us the use and development of ADCs and their impact on the treatment of breast cancer.

Kandra Horne, DNP, MSN, WHNP-BC: It has been incredible. The development of these anti-HER2 and ADC agents has been one of the most significant advances in the management of metastatic breast cancer. It was amazing to see a significant improvement in survival outcomes for our patients.

Kevin Kalinsky, MD, MS: Absoutely. You can completely change the way the landscape evolves, especially against this backdrop of residual disease, which we’ll focus on in our next case.

Transcription edited for clarity.

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