Pembrolizumab Plus Chemotherapy Enhances Outcomes in Early-Stage TNBC

Peter Schmid, MD, PhD

Updated results from the phase 3 KEYNOTE-522 trial (NCT03036488) demonstrated that neoadjuvant pembrolizumab (Keytruda) combined with chemotherapy, followed by adjuvant pembrolizumab, led to a statistically significant improvement in overall survival (OS) vs neoadjuvant chemotherapy plus placebo, followed by adjuvant placebo in patients with early-stage triple-negative breast cancer (TNBC).¹

This randomized, double-blind study focused on patients aged 18 years and older with early-stage TNBC. Pembrolizumab was administered both before and after surgery, while the control group received standard chemotherapy and placebo before surgery, followed by a placebo postoperatively.

KEYNOTE-522 builds on previous findings that combining immunotherapy with chemotherapy in the neoadjuvant setting can improve pathologic complete response (pCR) rates in TNBC. The updated data now confirm that the improved responses translate into a longer-term survival benefit.

In an interview with Targeted Oncology^TM, Peter Schmid, MD, PhD, of Barts Cancer Institute at Queen Mary University in London, United Kingdom, discussed the results from the phase 3 KEYNOTE-522 trial.

3D rendered medically accurate illustration of breast cancer: © SciePro - stock.adobe.com

Targeted Oncology: Can you discuss the background of the KEYNOTE-522 trial?

Schmid: The KEYNOTE-522 trial was designed to look into the benefit of pembrolizumab on top of chemotherapy in patients with stage II and stage III triple-negative breast cancer. Patients were randomized 2:1 to 6 months of preoperative chemotherapy, either with pembrolizumab or with placebo, followed by surgery followed by 6 months of pembrolizumab or placebo. The chemotherapy regimen chosen in this trial was what I would describe as the most effective chemotherapy regimen we have at the moment. That is really important, because the benefit of pembrolizumab, shown on top of that, is even more relevant.

We used 12 weeks of weekly paclitaxel and carboplatin, followed by 12 weeks of [doxorubicin or epirubicin and cyclophosphamide]. The trial has 2 coprimary end points. The short-term end point [is] pathological complete response [pCR], which means the complete disappearance of all invasive cancer at the time of surgery, and then the long-term end point is event-free survival, which means the reduction in recurrences, which is obviously the long-term benefit of the treatment.

Can you discuss the findings from the trial?

In 2019, at [the European Society for Medical Oncology (ESMO) Congress] in Barcelona, we presented that the addition of pembrolizumab to preoperative chemotherapy improved pCR rates by 13.6%, reaching nearly 65%. After about 3 years of follow-up, we demonstrated for the first time that this improved response led to a significant 37% reduction in recurrence or EFS.

Now, with 75 months, just over 6 years, of follow-up, which is critical for triple-negative breast cancer, we see these EFS curves flattening, almost plateauing. Most TNBC recurrences happen within the first 5 years, and few additional recurrences have occurred since year 3. The hazard ratio for EFS has remained stable at 0.65, reflecting a 35% reduction in recurrences. At 5 years, EFS rates were 81% with chemotherapy and immunotherapy compared with 72% with chemotherapy alone, a meaningful difference. As a result, this combination has been approved in many countries and is part of all relevant guidelines.

Importantly, we now have overall survival [OS] data, a key secondary end point of the KEYNOTE-522 trial. I was pleased to share at the recent meeting that pembrolizumab added to preoperative chemotherapy significantly improves OS, reducing the risk of death by 34% [HR, 0.66]. This benefit was consistent across all subgroups, regardless of PD-L1 status, tumor size, nodal status, or disease stage, making pembrolizumab a valid option for all [patients with] stage II/III TNBC.

An interesting preplanned analysis examined outcomes based on response to therapy. Historically, patients achieving a pCR have a favorable prognosis, while those with residual disease face higher recurrence risks. With pembrolizumab added to chemotherapy, patients achieving pCR had a 4% lower recurrence risk compared with chemotherapy alone, suggesting a better quality pCR with the combination.

For patients with residual disease, pembrolizumab still provided a substantial benefit, with a 10% improvement in EFS and a 6% improvement in OS compared with chemotherapy alone. This suggests that pembrolizumab alters cancer biology, impacting outcomes beyond response to therapy.

What were the safety findings identified in the study?

The safety profile remains consistent with previous analyses, with no new long-term safety concerns emerging after 6 years of follow-up. The most common [adverse] effects are still chemotherapy related, but immune therapy adds well-known [adverse] effects typical of such agents, with no new safety signals identified.

For a community oncologist, what are your key takeaways from this study?

My key takeaway from the KEYNOTE-522 trial is that this has already changed practice, but also, [and] actually more importantly, this is changing patients' lives. We already see fewer recurrences every day, and this is incredibly humbling to observe. The rate of metastatic triple-negative breast cancer has gone down now, not just by the incorporation initially of platinum, but by the incorporation of pembrolizumab.

We have been able to demonstrate that patients respond better, that the recurrences are reduced, and now finally at ESMO 2024, we could also demonstrate that this reduces the risk of death associated with triple-negative breast cancer by 34%. This is, for me, practice-changing, and therefore, really important for all [of the] clinicians out there.

REFERENCE:

Schmid P, Cortes J, Dent R, 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: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract LBA4.