At ESMO this year we presented results from the monarcHER trial. This was a randomised phase II trial that was really trying to investigate the use of CDK4/6 inhibition in ER positive/HER2 positive metastatic breast cancer. We’re all very familiar with CDK4/6 inhibitors and know that they have very robust efficacy in ER positive/HER2 negative disease but there is actually quite a bit of pre-clinical data to suggest that these agents can also work in HER2 positive breast cancer and, in fact, even some early clinical data suggesting activity in the HER2 positive setting. So this trial was really designed to explore if CDK4/6 inhibition with HER2 directed therapy would work better than standard chemotherapy and trastuzumab in pre-treated HER2 positive breast cancer patients.
monarcHER was a randomised phase II study, it had three arms. It took patients who had ER positive/HER2 positive breast cancer who had progressed on at least two prior lines of HER2 directed therapy in the metastatic setting and randomised them in a 1:1:1 fashion to get either a triplet combination, so fulvestrant, abemaciclib and trastuzumab, or to get a doublet of abemaciclib and trastuzumab, or to get chemotherapy and trastuzumab, which was the control arm. So, in essence the study was comparing the abemaciclib containing regimens in a hierarchical design to the control with chemotherapy and trastuzumab, again trying to show that CDK4/6 inhibition can work better than chemotherapy and trastuzumab.
What we found and what had initially been presented at a previous meeting, and actually has been previously published, was a progression free survival data where we had seen that the triplet, so fulvestrant, abemaciclib and trastuzumab, did lead to a statistically significant improvement in progression free survival compared to chemotherapy trastuzumab, with a difference between those arms of 2.6 months. So what I thought was a clinically meaningful difference and statistically significant, again, suggesting that a non-chemotherapy containing regimen could actually do better than the chemotherapy and trastuzumab which was a really interesting finding.
But now at ESMO what we are seeing is data from the overall survival. So everyone has been quite interested to know if this combination is actually going to extend true survival outcomes. What we’re seeing now is that the two abemaciclib containing arms did lead to numerically longer overall survival compared to the chemotherapy trastuzumab. So the overall survival in the abemaciclib containing arms was around 30 months compared to about 20 months in the control arm. This was not technically statistically significant but I do think the 10 month delta between those arms is, in my mind, quite clinically meaningful. So what you’re seeing is that CDK4/6 inhibition with HER2 inhibition and with endocrine therapy can lead to improved progression free survival and, in fact, to get a numerical improvement in overall survival which means that for select patients we could consider a combination of endocrine therapy CDK4/6 inhibition with abemaciclib and trastuzumab as an alternative approach to chemotherapy and trastuzumab.
While this was a randomised phase II, it is not a study that, unfortunately, will lead to regulatory approval of abemaciclib with endocrine therapy and trastuzumab in this pre-treated population. But abemaciclib is a drug that is available so, I will be honest, sometimes periodically I do use it in this situation in very select patients. But there are other trials that are ongoing looking at CDK4/6 inhibition in the HER2 positive setting and, in fact, we’re awaiting data from the PATINA study which was a trial that looked at patients getting first-line HER2 directed therapy. So people, for example, who had completed their induction therapy with a standard taxane trastuzumab pertuzumab and when those patients go on to the maintenance of trastuzumab pertuzumab in PATINA they were given endocrine therapy with or without palbociclib. So the study is really looking to see if adding the CDK4/6 inhibitor palbociclib to endocrine therapy and HP maintenance, if it will improve survival outcomes. So that trial has completed accrual and those data are pending.
There is also another study ongoing, the PATRICIA trial, which is also looking at endocrine therapy, CDK4/6 inhibition and trastuzumab and comparing it to treatment of choice in a pre-treated HER2 positive setting. So we’re all going to await these data to see if there officially will be a regulatory approval for CDK4/6 inhibition in the metastatic HER2 positive setting. But, for now, these agents are available and can selectively be utilised with endocrine therapy and HER2 directed therapy in pre-treated patients.