Wuerstein Discusses the Implications of the KAMILLA Trial and T-DM1 in HER2+ Metastatic Breast Cancer

The exploratory analysis of trastuzumab emtansine (T-DM1) in the KAMILLA trial (NCT01702571) showed that patients with HER2-positive (HER2+) locally or advanced metastatic breast cancer who have brain metastases had promising activity and tolerability on the therapy. Moreover, this study confirmed the safety and efficacy of T-DM1 and demonstrated no new safety signals, according to Rachel Wuerstein, MD.¹

Wuerstein, of the Universität München and lead investigator of the trial, discussed in an interview with Targeted OncologyTM the implications of the KAMILLA trial and the benefit of T-DM1. Wuerstein also discussed the data that show TDM1’s potential use for patients with HER2+ metastatic breast cancer beyond the standard-of-care second-line setting.

Targeted OncologyTM: Please describe the background of the study and its rationale.

KAMILLA was the safety and efficacy trial for a global and Asian cohort. It was of high importance because there was actually a need to get more safety data for T-DM1 (for patients with) metastatic breast cancer at the time. KAMILLA focused on a global cohort with large patient numbers, but also—and that’s of special interest—on an Asian cohort. Included in the KAMILLA trial is the highest number of patients entering a trial for T-DM1…more than 2000 patients in the global cohort and 182 patients in the Asian cohort. Ultimately, the reason for this trial at the time was need for more safety data of this new track, which, in the meantime, got standard of care for second-line treatment and second- or first-line treatment in HER2+ metastatic breast cancer.

Were there any key differences between the global cohort and Asian cohort?

Interestingly, what we did know from the previous trials, there are some differences in safety of some of the tracks so far in T-DM1 between the global cohort and Asian cohort. What we did find in KAMILLA, and therefore we also entered in the Asian cohort, is a higher rate of thrombocytopenia. Thrombocytopenia was 1 chosen end point in the KAMILLA trial. So what we did see in numbers is a difference in thrombocytopenia general adverse events of 8.7% in the global cohort, 27% in the Asian cohort, and for grade 3 thrombocytopenia, it was 3.7% in the global cohort and 36% in the Asian cohort again. Importantly, all these cases could be resolved by dose reduction and patients could remain on the track.

We had a low rate of trial (discontinuation) for those patients or dropouts, but equivalently, a difference in dose reductions of global 22% and in the Asian cohort 60%. What we did not see, fortunately, was a higher rate of bleeding complications due to thrombocytopenia. So yes, there is an effect and relevant difference in the adverse effect event of thrombocytopenia, and we think the rationale for this might be different genetic polymorphisms between global populations and Asian populations by itself. As I already said, there was no relevant new safety signal, just the difference in the population [sizes], but no difference in maintenance of the trial. And that’s also seen in the efficacy results of KAMILLA, and we do show results for progression-free survival as well as overall survival.

Overall survival even was a little higher for the aging population after our follow-up time. So I think that’s important information, and KAMILLA in both cohorts did also, again, prove the earlier line we use T-DM1 in HER2+ metastatic breast cancer, the more effective it is…. There is also important data coming from KAMILLA (with a) tweaked patient number with regard to brain metastases, and it’s also been shown that T-DM1 is highly effective and safe to use for brain metastases. Therefore, it also broadens our range of treatment options in not only metastatic, but also brain metastases in metastatic to positive breast cancer. We concluded for our poster that we added relevant information, but no new signals with regard to safety in comparison to previous publications of T-DM1, which is important, as I already told them now and is the worldwide standard of care from the second line and further in HER2+ metastatic breast cancer. And there is coming more and more interesting data with regard to these differences, not only in efficacy, but also safety. Now I also already pointed out those genetic reasons for that, and I think that’s something which is becoming very interesting for our worldwide oncology, in treating our patients, but also in our supportive treatments and modes of action.

What are the implications of this research?

As for implications of KAMILLA at ASCO this year, it’s major information, these data we got from previous trials and small numbers, and use of T-DM1 in metastatic breast cancer has been confirmed. One main result is that we didn’t find any new safety signals because if you look for secondary end points of KAMILLA, there has been a variety of adverse event events of special interest. Let’s say pneumonitis, for example, and we didn’t find any new signal. So just confirmation of what we didn’t know before, but this also plays an important role because in the meantime, T-DM1 is not only used in metastatic breast cancer, but it’s been moving to the post-neoadjuvant treatment in early breast cancer as well. We think for this situation, the large population of KAMILLA is relevant information. The confirmation of the efficacy data is important because it fits into the puzzle of new information we get about treatment options, but also sequencing of treatment in metastatic HER2+ breast cancer.

After this study, what is next for the use of T-DM1?

It’s an interesting question to think about what’s going to happen now with T-DM1. There is a well-described track in metastatic breast cancer in second line or further. But as we already know, also in the past-neoadjuvant treatment. We have been working on this question [and I believe] it’s time to move it to the neoadjuvant setting. We have to define the patient population. There have been some interesting presentations at this year’s ASCO, and I think safety populations like this are the backbone to start use of these tracks in the earliest setting. And I think it’s now been moving from metastatic to first line and we’ll have it also in the neoadjuvant setting.

What are your thoughts on the future landscape of treatment for patients with metastatic breast cancer?

As we all have seen in the last month, there is a variety of new tracks coming in trials, but also in an off-label setting in HER2+ metastatic breast cancer. We think T-DM1 plays a major role in this setting and is one of the main factors to prolong survival of our patients with metastatic disease. What’s going to be interesting in the near future is to see how will track combinations be working, and I already pointed out this fact: How are we going to sequence our therapies in this continuously changing field of treatment of early but also metastatic breast cancer? I’m looking forward to seeing these data in individualized sequencing of the new tracks in the field of HER2+ metastatic breast cancer. But again, (until that time), globallyT-DM1 is the second-line standard of care in HER2-positive metastatic breast cancer.

_Reference

_{Montemurro F, Delaloge S, Barrios CH, et al. Trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer and brain metastases: exploratory final analysis of cohort 1 from KAMILLA, a single-arm phase IIIb clinical trial. Ann Oncol. 2020;31(10):1350-1358. doi:10.1016/j.annonc.2020.06.020}