PracticeUpdate: What are some of the most important studies pertaining to the adjuvant treatment of breast cancer being presented at this year's ESMO?
Dr. Tolaney: I think we saw some very exciting data emerge from ESMO in the adjuvant setting, specifically in the hormone receptor-positive setting, where we saw two very large Phase 3 trials that explored the benefits of adding a CDK4/6 inhibitor to endocrine therapy for our hormone receptor-positive patients. The first of these was the PALLAS trial. This trial took patients who had stage II and III breast cancer, and randomized them to receive endocrine therapy, with or without palbociclib, with the palbociclib being given for two years of therapy. The study did not demonstrate any benefit to the addition of palbociclib to the endocrine agent, with really no difference in disease-free survival, with the median follow-up time of just under two years.
I think this was very surprising to many of us in the breast cancer community, given the very large benefits that have been seen in the metastatic setting. I think most of us were assuming we would continue to see benefit in the early disease then. However, I think what was also very confusing is we saw the result of a second randomized Phase 3 study in the adjuvant setting, the MonarchE trial, which looked at adding adjuvant abemaciclib to endocrine therapy and this trial was slightly different than the PALLAS trial, in that it focused on very high-risk hormone receptor-positive patients. So patients who had more than four positive lymph nodes or had to have one to three positive nodes, then have another high-risk feature.
Either a tumor over five centimeters, a high-grade tumor or a high Ki-67, defined as being over 20% by central testing. And so these patients were randomized to get their endocrine agent alone or to get the endocrine agent with abemaciclib for two years and the study had a median follow-up time of about 15 months and at that early time point has already demonstrated a statistically significant difference between the two arms, with an absolute difference of about 3.5%, consistent with the 25% reduction in risk of occurrence.
This was a very big finding, really suggesting that we could give two years of adjuvant abemaciclib to help prevent recurrence in our high-risk hormone receptor-positive patients. I think the challenge is, why are the two trial results so different? And why is PALLAS a negative study with adjuvant palbociclib and why is MonarchE a positive study with adjuvant abemaciclib. We had not seen any significant difference in efficacy, when looking across the three different CDK4/6 inhibitors in the metastatic setting and yet, here we're seeing really differences in efficacy in the adjuvant setting.
I think one has to remember the trial populations were very different, with the PALLAS trial including some stage IIA patients, whereas the monarchE trial, again, very restricted to high-risk, hormone receptor-positive patients, so all patients had nodal involvement. I think the other thing is, could it be a difference in the efficacy of CDK4/6 inhibitors? Is abemaciclib, for example, a more potent CDK4/6 inhibitor than palbociclib? It has more CDK4 inhibition relative to CDK6. It's dosed continuously. So it may be differences in the agents.
And then I think, lastly, the other factor to keep in mind is there was a very high rate of discontinuation in the PALLAS trial, with 42% of patients not completing their two years of palbociclib, with the majority of these patients discontinuing early, due to toxicity, mostly due to neutropenia. Whereas in the MonarchE study, at this early time point we've only seen a 16% rate of discontinuation. And I think the challenge is a lot of patients in PALLAS weren't actually getting palbociclib for very long and certainly this could have influenced the outcomes.
I think it was very exciting data coming out suggesting that abemaciclib may become a new standard of care for our high-risk hormone receptor-positive patients in the adjuvant setting.
PracticeUpdate: Was there any subset analysis in the palbociclib study for either the discontinuation patients or the high-risk patients that might give you some signal to say that what you saw in the metastatic setting remains true in the adjuvant setting?
Dr. Tolaney: So it definitely is a big interest to look at the subsets in PALLAS because one of the concerns is that maybe the low-risk patients don't need any more than endocrine therapy alone because their outcomes are so good, but maybe it's the high-risk patients in PALLAS that are going to derive benefit. And so they actually did separate the PALLAS population in to a high-risk population defined similarly to the MonarchE trial and that was a little under 60% of patients in PALLAS. And when they looked at the subgroups by low risk versus high risk, they actually did not see any significant difference in efficacy.
It's very important to remember, these are early data from both of these trials. And it's very hard to know how these data will evolve with longer follow-up. We certainly do know that hormone receptor-positive patients do tend to recur later and, again, this is follow-up under 2 years for both trials.
But on the flip side, high-risk patients due tend to recur early and these were event-driven analyses. I think, right now, no difference in subgroups from PALLAS but that may evolve over time.