CDK4/6 Inhibitors in Early Breast Cancer: Different Trial Results Means Good Science

Kathy D. Miller, MD


October 07, 2020

This transcript has been edited for clarity.

Hi. It's Dr Kathy Miller from Indiana University. I just finished a phenomenal science weekend at the European Society for Medical Oncology (ESMO) virtual congress, and I want to share some of the breast cancer data with you.

I remember being taught early in my career that a hallmark of good science, whether it's conducted in a laboratory or in the clinic, is that it forces you to ask more questions than it answers. And if that is the case, we saw some really good science this weekend. I want to review two sets of studies with you that have seemingly similar study designs but came to dramatically different conclusions.

First, let's think about the cyclin-dependent kinase (CDK) inhibitors in the adjuvant setting.

We saw the results of the PALLAS trial that studied over 4000 largely stage II and III patients (about 1000 had stage IIA disease, so lymph node–negative patients were allowed to enroll) who were randomized to 2 years of palbociclib or not. It was stopped for futility at the second interim analysis. To be clear, the study was not stopped, but the data monitoring committee suggested that all patients still on palbociclib should stop therapy and enter follow-up. Those patients, along with those who had already finished the 2 years of therapy, will be followed for at least the next 10-15 years. But there was no suggestion of benefit in the overall trial results and no suggestion of any clinical subset that might benefit, including a high-risk subset — about 59% of patients — who would have met the high-risk definition in the monarchE trial.

Now, let's contrast that with the monarchE results. It was a very similar study design, with over 5000 high-risk patients (stage IIA, lymph node–negative patients were not eligible) randomized to 2 years of abemaciclib or not. There was earlier follow-up of only about 15 months, but it was a positive trial nonetheless, with about a 3%-3.5% improvement in invasive disease-free survival and distant recurrence-free survival.

How could these two drugs that look so similar in the metastatic setting have given such different results in the adjuvant setting? There are quite a number of potential reasons:

  • It could be pure chance. Any study, no matter how many zeros in the P value, could be simply the play of chance. And that is true for negative and positive studies.

  • It could be that the study design was wrong. Remember, these are agents that we think of as reversing endocrine resistance and extending the benefit of hormone therapy. And yet we looked at very early results. These are early recurrences, the sort of recurrences we typically think of as being affected by chemotherapy and less affected by hormone therapy. Perhaps the study design was just wrong for palbociclib.

  • Even though these drugs were designed to inhibit CDK4/6, their relative potency for those two CDK inhibitors, as well as the other activity of those drugs, clearly differ. In a metastatic setting, that did not seem to affect effectiveness, but it clearly affected the toxicity profile. Perhaps in the adjuvant setting, those differences really do drive differences in efficacy.

  • Perhaps this is an issue of drug exposure. About 40% of patients in the PALLAS trial with palbociclib stopped therapy before completing the full 2 years of treatment, largely driven by protocol-defined toxicity, but not entirely. That compares with only about 16% of patients in the abemaciclib trial.

  • We also need to think more carefully about the regions of the world where these trials were done. The PALLAS trial was almost entirely done in high-resourced, well-developed countries with well-established medical systems. The monarchE trial had a little bit greater diversity of countries. It included some low-resource countries, so perhaps this represents a difference in the number of patients with very high-risk multiple node–positive disease who underwent extensive staging. And though some of the patients in the monarchE trial had clinically occult but present metastatic disease, this represents simply treatment of early metastasis.

I have no answers for why these two trials are different. It's going to take a lot more data and a lot more time to understand this. But it sure does make you think, and that is clearly a hallmark of good work. Congratulations to the authors of both of these studies. I look forward to your thoughts.

Kathy D. Miller, MD, is associate director of clinical research and co-director of the breast cancer program at the Melvin and Bren Simon Cancer Center at Indiana University. Her career has combined both laboratory and clinical research in breast cancer.

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