KATHERINE was a phase III clinical trial that was designed to address an unmet medical need in that we have known for some time that our HER2 targeted therapies combined with chemotherapies have greatly improved outcomes for women with HER2 positive breast cancer. However, patients who receive those therapies initially, have surgery but have residual disease we’ve known have a higher risk of developing recurrence and ultimately dying from their disease. So there has been a need to identify something else to administer there.
We know that TDM1 is effective in patients with metastatic breast cancer who have had the types of therapies already that we use as neoadjuvant therapy. So it was logical to evaluate if substituting TDM1 for just continuing completion of the HER2 targeted therapy might improve outcomes for those women and it clearly does do that.
What did you find?
Our primary endpoint for KATHERINE was invasive disease free survival. We had powered the study, established a sample size for the study to basically try to detect a hazard rate between 0.7-0.75. But we included an interim analysis which is normal to see if there might be a larger effect and indeed there was. The reduction in events for patients receiving TDM1 was a full 50% relative to those receiving standard trastuzumab which is really a very large benefit.
The other thing that was striking about it is when we looked at the activity across different subsets of patients the efficacy was strikingly consistent again. So it was that double message there that we had across all groups this great benefit; when you went into the subsets same thing, very consistent. Typically we will see in studies you might have different benefits in the hormone receptor positives from the hormone receptor negatives, these are quick, clinical questions that come up but the answer here is no, it works pretty much the same for everybody so it’s a nice result.
Were there any side effects?
We know that TDM1 is associated with more side effects than trastuzumab, it’s basically trastuzumab with a chemotherapy drug linked to it, so we were expecting to see a greater number of adverse events in the study. But the important thing is that the more severe adverse events, the grade 3 and higher adverse events were really infrequent in both arms. Those that did occur were largely laboratory abnormalities that are asymptomatic for a patient but these are things that we monitor to make adjustments in our therapy and so forth and so on. So the toxicity was really what we expect; we use TDM1 in metastatic disease so we have experience with that and I think it will be an easy transition.
There was fatigue and there was nausea, these will be things that we’ll have to manage but I think they will be manageable. We also do have quality of life data that is being analysed that we’ll be able to present soon, we just haven’t had time to get all of the analyses done that we’re going to be doing.
What are the next steps?
Right now we’re working to prepare the data for filing with the FDA and EMA and other global regulatory authorities. The quality of life analysis is part of that. Additionally, there are further subset analyses, hypothesis generating analyses, that we’ll want to do. Now that we know we have a very positive study we will also begin the process of looking at biomarkers and doing the translational work on the specimens because in spite of the improvement that we see, there are still patients receiving TDM1 who still recur. So we will need to understand the failures; we have a great success but we continue to not be all the way with it so these are things that we’ll be working on as well. Of course, ultimately what we hope to see and what we think is likely to see is that we will have an impact on overall survival when we’re able to analyse that in a few years. That endpoint just takes a while, of course, to be able to analyse it. But this kind of a benefit on the IDFS makes it likely that we’re going to see, we won’t know until we get the data, but it’s likely enough and the data is compelling enough that I’m hopeful that we’ll see regulatory authorities give approval in this indication.
What are the implications of the trial?
The KATHERINE results will actually be transformative in the way we take care of HER2 positive early breast cancer. We have used neoadjuvant therapy selectively – patients with larger tumours, patients with positive nodes where you might want to downstage to limit surgery – but there really has not been a reason to do it to determine subsequent therapy. Now that that exists we’re going to see that transformation in the approach to the disease where that will really become pretty much the standard with the exception of women who have their cancer discovered on screening that is a very small early lesion where we know that outcomes with the APT regimen from Tolaney and colleagues is quite good. So with the exception of that small subset I think this will quickly become a standard where TDM1 is available. It will have to be available in order to change the practice but once that happens we’ll see it.
