Disease-Free Survival and the KATHERINE Study

Pharmacists in the breast cancer field discuss the role for disease-free survival as an end point and the implications of the KATHERINE trial.

Jacob Kettle, PharmD, BCOP: What are your thoughts on invasive disease-free survival as an end point and its limitations? It’s unique in this space. This is an impromptu question, but how does that end point compare with more common end points like disease-free survival, just as a standalone progression-free survival, those kinds of end points. What do you make of this?

Allison Butts, PharmD, BCOP: Overall survival, of course, is our gold standard. We need to get some overall survival data both from the neoadjuvant pertuzumab as well as the adjuvant setting here, so that’s certainly the goal. As a second end point, though, I like invasive disease-free survival because cutting out those noninvasive recurrences is very important. Of course, the worst-case scenario, as you mentioned, at the onset, is distant recurrence and metastatic disease. This is very important as well, but invasive disease-free survival is an appropriate outcome to be using for these trials, personally.

Jacob Kettle, PharmD, BCOP: It does seem to get to the heart of what we’re trying to achieve. It just seems like a metric that helps show whether we are achieving that potential for cure. Are we driving down that risk of relapse and meaningful relapse down as low as possible? This continues to be the goal.

You alluded to it earlier, so we’ll go into this molecule, and that’s trastuzumab emtansine [T-DM1]. We saw a few years ago from the KATHERINE trial that, if we incorporate T-DM1 [trastuzumab emtansine] in patients with residual disease after neoadjuvant treatment compared with trastuzumab, we saw that invasive disease-free survival at 3 years dropped from 88.3% to 77%. Mathematically, there is a bigger gap there than what we saw with pertuzumab. Thoughts? It sounds like already know where you’re headed with that, but what are your thoughts on how to incorporate this treatment? Where do you recommend it for breast cancer patients?

Allison Butts, PharmD, BCOP: Of the trials that have come out recently in the neoadjuvant and adjuvant space, the KATHERINE trial is to me the most convincing. As you mentioned, you’ve got about an 11% improvement in your invasive disease-free survival there, which is much better than the 1% to 3% that we just talked about. In our books, here at UK [the University of Kentucky School of Pharmacy] and across the country, this study is undeniably practice changing. It has certainly changed the way we practice in a number of ways. One, in terms of just changing the molecules.

If a patient has residual disease, or more than microscopic anyway, it’s the standard at this point to change the patient’s therapy to ado-trastuzumab if they can tolerate it, rather than trastuzumab on its own. That’s certainly important. The other factor that comes along as we talk a bit more is this: If we’re on the fence about neoadjuvant versus adjuvant therapy and are leaning more toward giving that patient neoadjuvant therapy, we know we have this important therapy that we can switch them to. We need that prognostic information that comes about from their pathologic complete response or lack thereof.

This is a huge trial with huge results. Going forward, it’s going to be interesting to see if we get similar results with some of the other antibody-drug conjugates, namely trastuzumab deruxtecan, to see if this therapy has the same benefit. Is it any better than the trastuzumab emtansine? Where do we go from there? It’s an important piece of literature.

Jacob Kettle, PharmD, BCOP: I want to follow up on adverse events in just a second. What this helps crystallize is that value of having in vivo ability to manage risk or monitor response to treatment and to be able to see in real time if the patient is having that complete response we’re looking for or if we have a little additional ground.

That helps. In addition to having the new treatment option, it helps solidify going after that complete response and that neoadjuvant treatment. Getting those deep responses is valuable, and it’s a key part of early breast cancer management. It’s going to be critical when we start to evaluate new drugs in the space in the future because we know that underlying principle is so critical. You mentioned that this drug is the standard of practice if patients can tolerate it. What are the types of patients for whom this benefit may not be worth the risk?

Allison Butts, PharmD, BCOP: It’s worth trying in the vast majority of cases. As I mentioned, we’ve had a couple of cases where you have microscopic disease left over, so this is probably not for them. But if they have measurable disease, I would certainly be a proponent of trying it across the board. The issues we’ve run into are primarily some unusual, unexpected toxicities. Of course, this is the drug we’ve been using in the metastatic space for quite a long time.

The main dose-limiting toxicity in that group tends to be thrombocytopenia. We’ve not necessarily seen that much in the adjuvant setting. What we’ve seen more is lack of appetite and some worsening of neuropathy. That’s been why we’ve had to discontinue it, and we didn’t expect it because we have patients sail through in the metastatic setting who are heavily pretreated and have seen a number of drugs. For some reason, when we’ve used this adjuvantly, we have had to switch patients back to trastuzumab, unfortunately, a few times because of the adverse effects.