HER2+ Breast Cancer: Evolution of Antibody-Drug Conjugates


Sarah A. Hurvitz, MD: Around a decade ago, we began to see data emerging supporting the efficacy of a class of molecules called antibody-drug conjugates [ADCs] in breast cancer. And the first of these was trastuzumab emtansine, or T-DM1. The idea is that there is a HER2-targeted antibody that is stably linked to a cytotoxic chemotherapy. The antibody then acts like a guided missile that goes to the tumor cell that’s overexpressing HER2 and delivers the chemotherapy like a smart bomb directly to the tumor.

This is a great way of looking at it, and I think it’s exciting because 1 of the benefits might be that we could avoid the toxicity of chemotherapy and spare normal cells that don’t have that antigen normally expressed. Indeed, the early data of T-DM1 [trastuzumab emtansine] demonstrated that women didn’t lose their hair and generally felt well on it, and it looked a lot better in terms of patient-reported outcomes and quality of life compared with chemotherapy with trastuzumab. These data led to a phase III clinical trial of T-DM1 versus lapatinib and capecitabine in patients whose disease had progressed after trastuzumab and taxane-based therapy in the metastatic setting. Indeed, T-DM1 demonstrated an improved PFS [progression-free survival] as well as overall survival, leading to the FDA approval of this drug about 7 years ago.

This has changed the standard way we manage second-line breast cancer. T-DM1 was looked at in the first-line setting compared with standard trastuzumab and taxane-based therapy and did not demonstrate an improved outcome. It looked fairly similar but didn’t demonstrate an improved outcome, and it didn’t replace the paclitaxel, trastuzumab, and pertuzumab [THP] regimen that had become standard since that trial was run. Our gold standard for frontline is THP and for second line is the antibody-drug conjugate T-DM1. We haven’t seen other ADCs come out in those 7 years since the approval of T-DM1 that are as exciting.

Until recently, with trastuzumab deruxtecan, we began to see data regarding this agent. This, too, is a HER2-targeted monoclonal antibody, very similar to trastuzumab, stably linked to a very different cytotoxic payload. Instead of the payload hitting the microtubules, which is what T-DM1 does, this payload is actually targeting topoisomerase I. It’s a payload that we don’t often use as a standard-of-care chemotherapy for breast cancer. The unique feature of this drug is the antibody-drug conjugate comprises a lot more of the cytotoxic payload than T-DM1 was. There are about 8 of these cytotoxic DXd [exatecan derivative] payload per antibody with trastuzumab deruxtecan compared with 3 to 4 with T-DM1.

A phase Ib clinical trial was done looking at this drug, and in very, very heavily pretreated metastatic breast cancer, the objective response rate was well over 50%. That led to a ton of excitement and, of course, development of larger clinical trial to confirm these data.

Transcript Edited for Clarity

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