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PD-L1 Subgroup Benefits Most From Neoadjuvant Immunotherapy in Early Breast Cancer

— Lajos Pusztai reviews the two "potentially paradigm-shifting trials"

MedpageToday

Promising findings from two clinical trials at the San Antonio Breast Cancer Symposium (SABCS) suggest that adding immunotherapy to chemotherapy in the neoadjuvant setting may lead to better pathologic complete response (pCR) rates in high-risk early-stage estrogen receptor (ER)-positive/HER2-negative breast cancer.

In this exclusive ľֱ video, Lajos Pusztai, MD, DPhil, of the Yale School of Medicine in New Haven, Connecticut, discusses the potential impact of the CheckMate 7FL and KEYNOTE-756 trials.

The following is a transcript of his remarks:

There were a couple of really potentially paradigm-shifting important clinical trials announced at the morning session at the San Antonio Breast Cancer meeting. These were randomized trials for estrogen receptor-positive, high-risk early-stage patients. So mostly stage II and stage III ER-positive, HER2-negative grade II, grade III breast cancers.

So two of these trials tested neoadjuvant, that is preoperative chemotherapy, alone or the same chemotherapy with an immune checkpoint inhibitor. And one of these trials, the used nivolumab [Opdivo] as the immunotherapy agent. And the other trial, the trial used pembrolizumab [Keytruda]. So both of these trials showed essentially identical results. The pathologic complete response rates improved. So this is important because in the past we really considered ER-positive disease as not a particularly immunotherapy-sensitive disease. There was in triple-negative disease, immunotherapy added to chemotherapy improved survival, reduced the risk of recurrence. So what these trials are suggesting that the same strategy could also work in a select group of ER-positive patients.

The other really important finding from both of these studies was that it was not the entire study population who seemed to derive benefit from inclusion of the immune checkpoint inhibitor with the chemotherapy, but the PD-ligand 1-positive subset. So the PD-ligand 1 is the actual target of these agents and the higher the PD-ligand expression was, and the more immune cells were in the tumor microenvironment, the more the immunotherapy drugs synergized and improved the pathologic complete response rate.

So both of these studies leave a very important question open, and that's the question that needs to be answered before we really adopt this new strategy as an improved treatment for ER-positive disease. And the question is how the improvement in pathologic CR, or complete response rate, translates into improvement in recurrence-free survival. In other words, how many recurrences we avoid by adding an immunotherapy agent.

So of course, the challenge is that these drugs bring in additional side effects, immunotherapy-related side effects that we are all familiar with because of the widespread use of these drugs in other settings, metastatic settings, early-stage, triple-negative setting, and of course the costs that they involve. But the promising thing is that we have a biomarker. So for the ER-positive patients, it's the PD-ligand 1-positive subset that seems to be benefiting. And we are just waiting for the major results from these trials, particularly the KEYNOTE-756 trial to hopefully show improvement in event-free survival or recurrence with survival.

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    Greg Laub is the Senior Director of Video and currently leads the video and podcast production teams.