Key CDK 4/6 clinical trial results with Dr. Steven Isakoff and Dr. Hope Rugo
New data and research is constantly emerging in breast cancer care. Following this past year’s major scientific conferences in breast cancer, we spoke with breast oncologist Dr. Hope Rugo and medical oncologist Dr. Steven Isakoff about the latest treatment options for patients diagnosed with hormone-positive, HER2-negative metastatic breast cancer. Uncover highlights from key clinical trials examining CDK 4/6 inhibitors including the post-MONARCH, PACE, and PADMA studies transcribed from our discussions.
For an overview of how CDK 4/6 inhibitors work and the potential side effects they may have, check out our Q&A with Dr. Pooja Advani.
The following questions and responses have been lightly edited for grammatical purposes.
1) For a recent de novo, hormone-positive, HER2-negative metastatic breast cancer diagnosis, would starting with palbociclib and endocrine therapy be a better option than chemotherapy? How are these decisions made?
Dr. Steven Isakoff: This is a great question. This brings up the topic of what’s the preferred first-line treatment for the majority of patients with metastatic hormone receptor-positive breast cancer.
The PADMA study was a late-breaking abstract [at the 2024 San Antonio Breast Cancer Symposium] and a relatively small phase III study with 120 patients previously untreated, so not just de novo but patients might have had a recurrence after early-stage treatment, and most patients had at least two organ systems involved. This wasn’t a low burden of disease. They were randomized to receive endocrine therapy, plus the CDK 4/6 inhibitor palbociclib or chemotherapy of the physician’s choice. The majority of those patients who received chemotherapy got oral capecitabine and about a little less than a third of the patients got paclitaxel instead.
The results showed a significant improvement in the time to treatment failure with the endocrine approach compared to chemotherapy. People who got the endocrine therapy plus palbociclib had a 17-month median time to treatment failure and it was only six months in the chemotherapy arm. The progression-free survival, which is a similar kind of endpoint, was about eight versus 18 months.
This was very encouraging. Number one, it confirms that starting with anti-estrogen therapy is not only safe, but likely in combination with the CDK 4/6 inhibitor, is more effective. This supports the guidance we have from multiple international guideline committees that endocrine therapy with the CDK 4/6 is the preferred first-line treatment.
The question specifically mentions palbociclib and that brings up the second question: Which CDK 4/6 inhibitor is preferred? In this study, palbociclib was used and was clearly more effective than chemotherapy. However, we know that in many other studies looking at endocrine therapy alone versus endocrine therapy plus these CDK 4/6 inhibitors, an overall survival benefit was seen with ribociclib and abemaciclib, but palbociclib in these studies was not able to show a statistically significant improvement in overall survival.
That being said, the progression-free survival of all three of the CDK 4/6 inhibitors we use are all fairly similar. I think the take-home message is, number one, the use of endocrine therapy with the CDK 4/6 inhibitor is generally preferred over chemotherapy in the first-line treatment. Number two, ribociclib and abemaciclib has a demonstrated overall survival benefit, but all three CDK 4/ 6 inhibitors all have slightly different side-effect profiles and it’s reasonable to consider palbociclib in the setting if the side-effect profile for a given individual is preferred.
In this case, I think endocrine plus palbociclib would be preferred over chemotherapy, but whether palbociclib is preferred over ribociclib and abemaciclib is unclear.
2) What are the implications of the postMONARCH study results about continuing on a CDK 4/6 inhibitor therapy after progression on a CDK 4/6 inhibitor? Does it matter which one you started on to see the benefit?
Dr. Hope Rugo: To talk about postMONARCH, these are patients who have metastatic hormone receptor-positive, HER2-negative breast cancer and have received their first treatment in the metastatic setting with an aromatase inhibitor and a CKD 4/6 inhibitor.
There are three that are proven in that setting: palbociclib, ribociclib, and abemaciclib. Palbo was the first approved so it tends to dominate in the first-line setting, but recent data showed big survival advantages with ribociclib. Although cross-trial comparisons are difficult and we have patients who’ve been on palbociclib as first line treatment for almost 10 years, it’s clearly a very effective agent.
The postMONARCH study was looking at patients who got a CDK 4/6 inhibitor and aromatase inhibitor, then had tumor growth and were randomized to get fulvestrant alone or fulvestrant with abemaciclib.
This trial randomized a little over 300 patients and they showed an interim analysis which showed a benefit. In their final analysis, the hazard ratio, or the statistical calculation of relative benefit, was similar but the numeric median was small. If you looked at the median difference of the benefit between patients who got fulvestrant versus fulvestrant and abemaciclib, it was really small, but still statistically significant and a good hazard ratio.
Why is that? There are a number of reasons. One, there was a big falloff in the beginning and that messes up the median differences. What does that mean? The first scan that people got in the study showed growth of tumor for a number of patients. The reason why that happens is because some of the patients enrolled in the trial already had disease that’s resistant to hormone therapy, so fulvestrant is not going to work very well.
The second reason is endocrine therapy can take a while to kick in. Some patients, even when you start the treatment, the bone disease might look a little bit more active at the first scan so they would come off the study even though they might have had stable disease over time. That falloff also affects the median.
The second thing that happened was they looked at patients who had cancer in visceral organs like lung, liver, etc. They found that patients who had visceral disease seemed to not benefit from the addition of abemaciclib, although those with liver metastases did, which doesn’t really make any sense. We’re going to have to see more details on that.
So what do we take from the data? If you got abemaciclib as a first-line treatment, this is not an approach that we have any data to support. So far, using the same CDK 4/ 6 inhibitor in the second-line setting with palbo didn’t benefit patients in the PACE trial.
If you had ribo or palbo with some progression of disease in bone or soft tissue only, then I think it’s reasonable to consider abemaciclib. It’s about balancing side effects for patients and the pace of their disease growth. If you have disease that’s growing in the liver or lung, then it’s a tougher choice. It depends on whether or not your tumor has an ESR1 mutation, if you’re eligible for a clinical trial, which I would always support first, or a PIK3CA mutation, or the pace of the disease is faster.
I think this is incredibly important data and it does suggest for a subset of patients, this could be a very effective and tolerable treatment and avoiding other options that might have more side effects.
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