Adjuvant trastuzumab emtansine vs paclitaxel and trastuzumab for HER2-positive breast cancer
Dr Sara Tolaney - Dana-Farber Cancer Institute, Boston, USA
We know that patients who have stage 1 HER2 positive breast cancers are at more than just a minimal risk of disease recurrence. We have seen data from retrospective series of untreated patients that suggests their rates of recurrence are somewhere between 10-30%. We knew that we had data from a study we had previously conducted called the APT trial in which patients with tumours that were less than 3cm and node negative and HER2 positive had a seven year disease free survival of 93%. Given the low event rate seen in that trial many physicians had adopted using that regimen, the TH regimen, as an option for patients with stage 1 HER2 positive cancers. But we were really hoping to find a potentially less toxic treatment option for this patient population and at the time we knew that T-DM1 was very active amongst patients with metastatic HER2 positive disease. We knew that when T-DM1 was compared to chemotherapy and trastuzumab it was associated with less toxicity so we thought it would be a nice agent to consider looking at in a stage 1 population where hopefully we could achieve very good efficacy but less toxicity than TH.
Could you outline the design of the trial?
The ATEMPT trial was a randomised phase II study that was for patients who had stage 1 HER2 positive disease. They had to be within 90 days of their last breast surgery and they had to have HER2 status that was confirmed upon central testing. They were then randomised in a three to one fashion to a year of T-DM1 or to get the TH regimen and the TH regimen is paclitaxel and trastuzumab given weekly for twelve weeks followed by nine months of trastuzumab.
What were the results?
The ATEMPT trial had co-primary endpoints. One was to look at the three year disease free survival in the T-DM1 arm and then also to compare the incidence of clinically relevant toxicities between the two arms. What we found for the first endpoint, which was the disease free survival, was that in the T-DM1 arm the three year disease free survival was 97.7% so patients did very well and it met our primary endpoint in that the rate was significantly better than we would have predicted. So we were shooting for a 5% event rate or less and this was significantly better than that.
When looking at the clinically relevant toxicity endpoint we found that actually the rates of clinically relevant toxicities were identical in the T-DM1 arm and the TH arm at 46% so really no difference in the rates of toxicities as we measured them. We did see, though, that there were differences in the toxicity profiles. So the TH regimen was associated with more neutropenia, neuropathy and infusion related reactions whereas the T-DM1 arm was associated with more thrombocytopenia and elevated liver enzymes.
So based on these data we really have felt that T-DM1 is a highly efficacious regimen in patients with stage 1 HER2 positive disease but by the toxicity endpoint that we used we really say that it’s very similar in toxicity to the TH regimen when looking at the overall rates of toxicity. But, again, there are distinguishing features of each regimen with different toxicity profiles and so one could consider using T-DM1 in select patients with stage 1 HER2 positive disease, potentially those patients who may be at more risk for the TH related toxicities such as neuropathy.
What are the next steps for this trial?
What we found in the ATEMPT trial was that patients, again, did very well with T-DM1 but we did find that 24% of patients actually weren’t able to complete the full year of T-DM1. Those patients actually went on to complete their year of treatment with trastuzumab. So seeing such a good efficacy even when a quarter of your patients didn’t complete the treatment makes you think that you may see just as good efficacy with a little less therapy and potentially allow us to reduce our rate of toxicities. So we’re hoping to be able to do a trial where we could look at shorter duration T-DM1 and where patients could get somewhere between 3-6 months of T-DM1 and then complete the year of therapy with trastuzumab and see if that’s potentially a less toxic and highly efficacious treatment option for stage 1 patients.
How does the drug fare in relation to financial toxicity?
We know that a year of T-DM1 costs a little more than two times as much as the TH regimen and so certainly it is more expensive to give a year of T-DM1 than to give TH. But it’s important when we look at financial toxicity that we also balance that with the toxicities our patients are experiencing. So while the study did not find that there is a difference in rates of clinically relevant toxicities, there were differences in specific toxicities. So, again for some patients, potentially patients who have underlying neuropathy, it is a much nicer option from a toxicity standpoint to get T-DM1. We’re hoping in the future that we can create a shorter duration of T-DM1 where we can not only reduce financial toxicity but also reduce the toxicity patients are experiencing.