Palbociclib as a Post-Neoadjuvant Treatment in Breast Cancer

, MD

Gunter von Minckwitz

An upcoming study could uncover new uses for palbociclib in the post-neoadjuvant setting for hormone receptor (HR)-positive breast cancer, according to Gunter von Minckwitz, MD.

The trial, dubbed PENELOPE-B, will examine the drug plus endocrine therapy as a post-neoadjuvant treatment for HR-positive patients with residual disease following chemotherapy and surgery, according to von Minckwitz, director of the German Breast Group Research Institute, in an interview with Targeted Oncology.

Additionally, Minckwitz touches on the companion trial to PENELOPE-2, the PALLAS study. The PALLAS study seeks to obtain similar information, though it will be performed later than PENELOPE-2 after toxicities have been identified.

TARGETED ONCOLOGY:Can you discuss the clinical need for the PENELOPE-B trial?von Minckwitz:Palbociclib is an innovative new agent, a CDK4/6 inhibitor which showed very promising results in metastatic disease when combined with an aromatase inhibitor in patients with HR-positive metastatic breast cancer. It got a rapid approval, so we were trying to find a way to get a drug that is in very early development to move into the treatment paradigm of early breast cancer. We were looking for a certain high-risk group where the uncertainties of such a compound are as acceptable as the medical need of the patients is.

The idea finally was to use the neoadjuvant approach as a selection tool, so patients are getting conventional neoadjuvant treatment. If they do not get sufficient pathologic response, they become candidates for the study.

The trial is focused on the action of palbociclib in luminal tumors. The usual pathologic complete response (pCR) is not appropriate, as we know that pCR is a rare occasion in these patients. Independent of their final prognosis, it's not a good prognostic marker, so we had to look for another kind of assessment tool to define an insufficient pathologic response.

We finally came up with the CPSEG score, which is a scoring system where the stage of the disease before and after the neoadjuvant treatment is rated and taken together. If the patient reaches 3 points at least, it's a candidate for PENELOPE, and we enlarged the eligibility criteria a while ago. We are also allowing patients that only have 2 points, but they also need to have positive nodes at surgery.

These patients have a very high relapse rate, so a somewhat small adjuvant study can be designed and we are now investigating 1 year of palbociclib in the usual way of 2 weeks on and 1 week off with a placebo and a backbone treatment of various endocrine options that are being used in the adjuvant treatment of HR-sensitive breast cancer.

The trial is targeting 1,100 patients now. It's a global study running in 13 countries all over the world, including the United States. We hope that within the next 2 years, we will complete accrual and then immediately after that, the first efficacy analysis is planned as these patients have very early events. We expect a sufficient number of events are already present and will be in 2017.

TARGETED ONCOLOGY:What are the next steps in this study?von Minckwitz:There is actually a companion study that has just started, the PALLAS study, which is a traditional adjuvant trial that has more than 4,500 patients where palbociclib is given to patients with HR-positive disease. The trial is exploring a 2-year palbociclib treatment versus placebo.

As PENOLOPE-B is running before the trial, the 2 trials will have each other to be sure that toxicities are acceptable after 1 year, so patients can continue on PALLAS for the second year. Also, we expect taking the 2 trials together will give us some information on how long the palbocilib treatment has to be, and if 1 year is enough or if 2 years are needed. This can be answered with both of these trials combined.

TARGETED ONCOLOGY:Can you highlight the lessons that have been learned from neoadjuvant studies?von Minckwitz:The topic is related mainly to correlative science and correlative markers, and my impression currently is that we have to learn a lot more before we can use this information. We have this situation where we have markers like hormone receptors in HER2-positive disease, which predict a higher efficacy of trastuzumab in HR-negative disease with regard to pCR. If you look at the adjuvant studies, there's no such difference in efficacy of trastuzumab, in that it works similarly in both hormone receptor groups.

Then we have markers that are favorable, predictive markers of pCR, and poor prognostic markers. For example, if p67 is high, it predicts a higher sensitivity to chemotherapy, but patients still have a poor outcome. There are markers where it's just the opposite, like if there are a high number of tumor-infiltrating lymphocytes, it predicts a higher sensitivity to chemotherapy, but these patients also have a more favorable prognosis.

So, finally we have all these various constellations where everything seems to be possible, and it's very difficult to say that we can learn something on a correlative marker from the neoadjuvant setting that can be extrapolated to the adjuvant setting. Currently, it looks very much like we can identify interesting markers in the neoadjuvant setting, but then they have to be confirmed for the adjuvant disease separately.

TARGETED ONCOLOGY:Can you discuss the neoadjuvant platform for drug approvals?von Minckwitz:Both the FDA and the European Agency have approved this new pathway, and of course we are now looking forward to the first drugs going through this way. Pertuzumab was the first successful agent on this pathway, but the situation might be a little different according to what was intended by the agencies, which wanted to have new drugs with new modes of action in earlier phases of development, and pertuzumab already has a huge database of metastatic trials with high efficacies. Also, the adjuvant studies had already fully accrued. So it was quite easy for the agencies to approve pertuzumab by this pathway.

The next compound that I'm aware of is olaparib, where its trial has just completed its accrual. This is a trial that wants to go the one-trial approach, so this is a somewhat larger neoadjuvant study with over 600 patients with 2 primary endpoints; pCR and event-free survival. Of course if pCR is positive, the company will try to get conditional approval. Then they would want to confirm the effects with the same study for event-free survival so that the conditional approval becomes a full approval of the drug.