CDK4/6 inhibitors as adjuvant therapy in early breast cancer? Uncertain benefits, guaranteed harms

This is the title of our new paper out in the European Journal of Cancer!

CDK4/6 inhibitors are used in the metastatic setting of advanced breast cancer. Now two studies, MonarchE and NATALEE, have reported iDFS (invasive disease-free survival) gains with 2 years of abemaciclib and 3 years of riboclicib, respectively.

In our new work published in the European Journal of Cancer, we are making at least 4 points to reach the following conclusion:

We argue “against their routine use as adjuvant therapy in ER+ /HER2- early breast cancer”.

First: the iDFS gain are fragile, with questionable reliability

We noted an imbalance in early drop-out, with more patients dropping out in the control arm in both studies. When this occurs, the censoring can become “informative” if the patients dropping out are different from those remaining in the study.

Other researchers, Meirson et al., already concluded the MonarchE study results could have been driven by informative censoring. Here, we reconstructed the Kaplan-Meier curves and made a very conservative assumption. We took only patients censored over the first time-interval, and we took only 10% of them. We simulated a different fate for those patients based on reasonable assumptions. Below are the results… the iDFS is no longer significant!

The analysis is available here for reproducibility.

Second: the proportion of “survival” events in the iDFS is minimal

iDFS - invasive disease-free survival - is very precisely defined, and many scenarios can count as an event. But as you can see below, some events are curable, while others may even be deaths.

The first reports of MonarchE and NATALEE provided the breakdown of iDFS events. In other words, we know the proportion of deaths composing the iDFS events, and it was 6.0% of events in MonarchE and 4.7% in NATALEE.

“Among all participants in the study, this is just 0,9 % in MonarchE and 0.4 % in NATALEE. In other words, iDFS gains were mostly driven by non-death events.”

Third: concerns with toxicity

These drugs are toxic, with 50% to 63% grade ≥3 events with abemaciclib and ribociclib, respectively. We also questioned the reasons for why an increase in COVID-related deaths was seen in patients receiving CDK4/6 inhibitors. Was this due to an increase in neutropenia? This signal should be closely monitored. Below is an excerpt from our table summarizing key data from both trials.

Fourth: unprecedented financial toxicity

In previous work, we calculated the cost to avert one event for adjuvant therapy. This number is calculated by multiplying the number of patients needed to be treated (NNT) to avoid one event (here an iDFS event) multiplied by the estimated cost of therapy for one patient. Our original findings are represented below, on the left, with prices ranging from $820,000 to $2,640,000.

This was already staggering… but look now: CDK4/6 inhibitors as adjuvant therapy have unprecedented costs with $5,700,000 for MonarchE and up to $11,200,000 for the NATALEE trial!

Check our full analysis here. See also our Youtube analysis of NATALEE here.

The stakes are high: the NATALEE strategy could affect up to 35% of newly diagnosed breast cancer, which was diagnosed in approximately 2,300,000 people in 2022! If you like this content, become a free or paid subscriber.