Positive KEYNOTE-522 Overall Survival Results in TNBC

The first overall survival analysis of the KEYNOTE-522 trial showed positive outcomes with neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab monotherapy vs neoadjuvant chemotherapy alone in high-risk early-stage triple-negative breast cancer (TNBC).

Primary investigator Peter Schmid, MD, PhD, FRCP, lead at the Centre of Experimental Cancer Medicine and director of the Barts Breast Cancer Institute in London, discussed the findings during a presidential symposium on practice-changing medicine at the European Society for Medical Oncology (ESMO) Congress 2024.

Transcript

Can you explain the rationale for the KEYNOTE-522 treatment regimen and how it addresses the mechanisms of TNBC?

Triple-negative breast cancer is and remains a more aggressive subtype of breast cancer, and there has always been an urgent need to find more effective therapies. Prior to KEYNOTE-522 becoming the new standard of care, the standard treatment for triple-negative breast cancer was preoperative chemotherapy followed by surgery, and that allowed us to see how well patients responded, and then we adjust their treatment after surgery, and some patients required additional chemotherapy after surgery. Now we have seen for many tumor types, including advanced triple-negative breast cancer, the addition of immune therapy to chemotherapy can improve the efficacy of this treatment. So, the rationale of combining immune therapy with chemotherapy in this setting was the attempt to improve the outcomes for patients with early triple-negative breast cancer.

The design of the trial was to randomize patients between 6 months of preoperative chemotherapy and immune therapy or 6 months of preoperative chemotherapy and placebo. Then patients had surgery and they continued either with immune therapy, pembrolizumab, or with placebo for another 6 months. We wanted to see whether with the addition of immune therapy, we could improve outcomes. We measured this in 2 ways. Initially, the 2 main trial primary end points were a short-term effect to see whether the addition of immune therapy can increase the percentage of women who achieve what we call a complete pathological response—a pathCR, as we call it, is the complete disappearance of all invasive cancer at the time of surgery—and then the long-term end point, event-free survival, to see whether we can also prevent recurrences by adding immune therapy to preoperative chemotherapy.

What were the main findings of the overall survival analysis presented at ESMO 2024?

The trial has been positive for its dual primary end points. We already showed a few years ago that the addition of pembrolizumab to chemotherapy increased the pathCR rates by about 30.6% to nearly 65%, and that was a significant and meaningful increase. We then subsequently, with about 3 years of follow-up, showed for the first time that the addition of pembrolizumab also improved event-free survival, so reduced recurrences at that time by about 37%, and that was a highly significant and meaningful result.

We have since had further follow up, so we presented 5-year data; now have a follow up of 75 months or just over 6 years. That's a really important time point in triple-negative breast cancer, because most of the recurrence events unfortunately occur relatively early. So we see about 70% of recurrences in the first 2 to 3 years; [and] we see about 90% of the first 5 years. What we've seen in the updated event-free survival data was that the curves are starting to almost flatten out and plateau—we see relatively few additional recurrences, fortunately, and the hazard ratio—so the relative benefit—has stabilized. We reduced the risk of recurrences by about 35%, so those were the 2 primary end points of the trial.

At ESMO 2024, we also presented the long-waited first overall survival data, which is obviously the ultimate end point of what we want to achieve. This is a key secondary end point of the trial that was α controlled, which means there were preplanned statistics around this.

We were really humbled to be able to demonstrate that the addition of immune therapy improves overall survival significantly in a meaningful way. The hazard ratio for overall survival is 0.66. This means the addition of immune therapy reduced the risk of death by 34%. And that benefit was seen across all subgroups, whether it's patients with PD-L1–positive or PD-L1–negative tumors, patients with larger or smaller tumors, node negative or node positive, or stage II and stage III. We also have an interesting preplanned analysis looking into the outcome of patients who have an optimal response to chemotherapy and immunotherapy—which is a pathCR—and patients who have residual disease at the time of surgery, which obviously is being removed during the operation.

We had previously showed for event-free survival that the quality of the pathCR seems to be better when achieved with chemotherapy and immunotherapy. There was about a 4% lower risk of recurrences if patients had a pathCR with immune therapy compared to chemotherapy plus placebo. But, even more importantly, we showed that in patients who have a suboptimal response—who have residual cancer at the time of surgery—that the risk of recurrence is substantially lower if patients were treated with chemotherapy and immune therapy. Now, we've repeated this analysis with overall survival as the end point and see a very similar pattern. We see for patients who have residual disease, the overall survival is much better if patients had residual disease after chemotherapy and immune therapy compared to patients who have residual disease after chemotherapy alone. That really suggests to me that the addition of immune therapy changes the biology of the cancer, has long-term benefits that go beyond just the tumor response.

Reference

Schmid P, Cortes J, Dent RA, et al. Neoadjuvant pembrolizumab or placebo plus chemotherapy followed by adjuvant pembrolizumab or placebo for high-risk early-stage TNBC: Overall survival results from the phase III KEYNOTE-522 study. Presented at: European Society of Medical Oncology Congress 2024; September 13-17, 2024; Barcelona, Spain. Abstract LBA4.