Assisting Community-Based Oncologists and Surgeons in Making Neoadjuvant Treatment Decisions for Patients with Early Breast CancerOverview of T-DM1
3:44 minutes.
TRANSCRIPTION:
DR BLACKWELL: So T-DM1 is an antibody drug conjugate. It is our old friend trastuzumab, with a stable disulfide linker and chemotherapy, in this case derivative of a maytansine. This derivative of maytansine is just subtype 1 – there’s nothing fancy about the 1 — it’s a microtubule inhibitor. It binds to the end of microtubules and so, in essence, puts a stop in microtubule expansion and remodeling. DR LOVE: It’s chemo, though? DR BLACKWELL: It’s chemo. And it has the same mechanism of action as vinorelbine or eribulin, drugs that we commonly would combine with trastuzumab. The therapeutic index for T-DM1 in my mind is quite high, because it doesn’t have some of the traditional chemotherapy side effects. Patients do not lose their hair on this drug, which is a major quality-of-life advantage for it. There is really no nausea or vomiting. It doesn’t require any premeds, like standard taxanes or even standard chemotherapy. DR LOVE: So the chemo is actually being delivered into the tumor cell? DR BLACKWELL: Yes, but it’s the magic bullet that we’ve all been waiting for in terms of drugs that only kill cancer cells and don’t kill normal cells. It does have 2 side effects. It can cause a mild transaminitis, which requires a dose adjustment. And it has this very unique side effect of thrombocytopenia that occurs in about 10% to 15% of patients, which actually has some relevance if this drug ever moved into the neoadjuvant setting. Our surgeons don’t really like us causing thrombocytopenia in the preop setting. In this trial, it’s being studied in the postop setting. The mechanism of thrombocytopenia has actually been worked out and was just published in Clinical Cancer Research in the fall of 2014. It’s pretty elegant biology, but it’s basically that the trastuzumab antibody has the ability to bind to a low-affinity IgG binding site on the megakaryocyte. And it probably is ethnically distributed, as it’s only a certain subtype of the Ig receptor on the megakaryocyte. So we didn’t see thrombocytopenia when trastuzumab was given alone, because binding of trastuzumab doesn’t kill megakaryocytes. But so specific is T-DM1 that, because it has this chemotherapy component and, on certain people’s megakaryocytes there’s this low-affinity IgG, it’s delivering chemo to a subpopulation of megakaryocytes, leading to thrombocytopenia. DR LOVE: The bottom line, though, Terry, you’ve seen patients now who’ve gotten T-DM1. Normally, the other arm, trastuzumab, you wouldn’t expect any side effects quality-of-life-wise. What are you seeing in patients getting T-DM1? DR MAMOUNAS: I mean, I think these are part of the trial and we’re looking at toxicity. There’s nothing that stands out as something that we cannot be acceptable in the adjuvant setting, so the trial is continuing as planned. DR LOVE: But in terms of quality of life, what do you see in your patients? DR MAMOUNAS: Oh. Very, very good. Very good quality of life. I mean, you don’t lose your hair. Obviously, you have lost it in the adjuvant setting, but certainly they regrow. Very well-tolerated regimen. DR LOVE: What about efficacy of T-DM1? DR BLACKWELL: So we know a bunch of things. We’re awaiting the results of T-DM1 versus taxane/trastuzumab in the first-line setting. We know that T-DM1 in the second- and third-line setting is superior to both lapatinib, which is an oral HER2 inhibitor, in combination with capecitabine. It’s also superior in the third-line setting to chemo/tras combination. So at least in the metastatic setting, it’s conveyed a survival benefit over what we would have been giving anyway in the second- and third-line setting. Other than that, we don’t really have a lot of data regarding T-DM1 in the curable setting. |