Dr Cortés Discusses Final KEYNOTE-522 Results in Early-Stage TNBC

The final analysis of the phase 3 KEYNOTE-522 trial (NCT03036488), presented with a median follow-up of 7.8 years, confirmed that neoadjuvant pembrolizumab (Keytruda) plus chemotherapy followed by adjuvant pembrolizumab continues to provide a clinically meaningful survival benefit over chemotherapy alone in patients with high-risk, early-stage triple-negative breast cancer (TNBC). The 7-year event-free survival (EFS) rate was 78.3% with pembrolizumab vs 69.8% with placebo (HR, 0.68; 95% CI, 0.54-0.86), and the 7-year overall survival (OS) rate was 85.1% vs 77.2%, respectively (HR, 0.64; 95% CI, 0.49-0.85). Rates of grade 3 or higher treatment-related adverse events (AEs) were 77.1% in the pembrolizumab group and 73.3% in the placebo group, and rates of any-grade immune-mediated AEs were 35.0% vs 13.1%, respectively.

The significance of these results lies in their durability. With many cancer therapies, the magnitude of benefit seen in early follow-up tends to narrow over time; in KEYNOTE-522, the benefit associated with pembrolizumab has instead held steady, and by 7 years is numerically larger than it appeared at earlier analyses. For clinicians, this final analysis reinforces neoadjuvant pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab, as the standard of care for high-risk, early-stage TNBC, with a consistent benefit across most prespecified subgroups, including those defined by PD-L1 expression, nodal status, and disease stage. For patients, it translates into a higher likelihood of achieving a pathologic complete response, a lower likelihood of distant recurrence, and, ultimately, a greater chance of long-term cure, without an accompanying increase in the more common chemotherapy-related toxicities.

In an interview with Targeted Oncology^TM, Javier Cortes, MD, PhD, of the International Breast Cancer Center (IBCC), Pangaea Oncol, Quironsalud Group, and Medica Scientia Innovation Research (MEDSIR), Barcelona, Spain, and the Faculty of Biomedical and Health Sciences, Department of Medicine, Universidad Europea de Madrid, Madrid, Spain, discusses the design of KEYNOTE-522, the durability of the survival benefit at this extended follow-up, the safety profile with longer-term monitoring, and what these findings mean for patients and the clinicians who manage their care. He also looks ahead to how treatment for this subtype may evolve, including the potential roles of antibody-drug conjugates and chemotherapy de-escalation.

Targeted Oncology: Could you give an overview of the key design and the most significant findings from the trial?

Javier Cortes, MD, PhD: KEYNOTE-522 established, a few years ago, the standard of care for patients with the more aggressive subtype of breast cancer, triple-negative breast cancer. When we designed the study, we established the optimal chemotherapy backbone—carboplatin, paclitaxel, and an anthracycline—and we added either placebo or pembrolizumab. We first demonstrated the pathologic complete response [pCR] benefit years ago, and Peter Schmid, [MD, PhD] subsequently presented the event-free survival results at an interim analysis, and later we also demonstrated the overall survival benefit.

Why is this new data so important? Sometimes when you continue following patients, the impressive results you see early on start to diminish—the benefit is substantial at 4 or 5 years, but by 7 or 8 years it's much smaller. The good news here is that the benefit is not only holding up, but also even numerically better. We've now seen clearly and consistently that adding pembrolizumab improves pathologic response, improves event-free survival, distant disease-free survival or metastasis-free survival, and improves overall survival.

Did you see any new or late-onset adverse events associated with this regimen?

This trial was conducted in both the neoadjuvant and adjuvant settings, and the total duration of treatment was 1 year. We presented a very complete picture of the safety profile a couple of years ago, so it was not expected that we would now see adverse events we hadn't seen before, and that's exactly what we found. Nothing new, nothing unexpected. The adverse event profile of pembrolizumab plus chemotherapy is well characterized, and nothing has changed.

For the patient, what do these long-term data mean for someone newly diagnosed with high-risk, early-stage TNBC, in terms of long-term survival outlook and peace of mind?

For patients with stage II or III disease—tumors 11 mm or larger, node-positive disease, or T2 to T4 tumors—we can now tell them that yesterday's standard of care was chemotherapy alone, and today's standard of care is chemotherapy plus pembrolizumab, for 3 reasons. First, we may increase the pCR, meaning that after surgery they will not need additional chemotherapy. Second, we can decrease the likelihood of developing metastatic disease. Third, we can tell them that beyond reducing recurrence, they have a greater opportunity to be cured, which is, in the end, the best outcome we can offer. The best prognosis for metastasis is the metastasis that never develops.

Are there proactive strategies you'd recommend to manage toxicities and minimize treatment delays?

We need to differentiate the chemotherapy-related adverse events, which are well known, from the immune-related ones. With chemotherapy, we typically manage neutropenia, gastrointestinal adverse events such as nausea and vomiting, and neurotoxicity associated with carboplatin and paclitaxel. These are not increased by the addition of pembrolizumab; the overall adverse event rates are similar between the 2 treatment arms. What does increase is immune-related adverse events.

My advice: always test thyroid function, because hypothyroidism or hyperthyroidism is relatively common but easily managed. Other immune-related adverse events are much less frequent—skin reactions occur in roughly 5% to 6% of patients, for example—and aside from thyroid dysfunction, everything else typically occurs in fewer than 5% of patients. Grade 4 or grade 5 events are very infrequent. So, the priority is prompt diagnosis and appropriate management, but severe events remain rare.

Where do you see this field heading?

I think we need to work on 2 fronts. First, treatment escalation for patients who do not achieve a pCR—this is where antibody-drug conjugates plus pembrolizumab may play an important role in the coming years, potentially even replacing anthracyclines in the neoadjuvant setting. Can we integrate antibody-drug conjugates into our treatment armamentarium? My answer is yes, but we still need to learn how and where to use them.

Second, can we de-escalate treatment in certain patients? Specifically, can we reduce the amount of chemotherapy they receive? Trials are underway trying to demonstrate this. In my own clinical practice, if a patient achieves a complete clinical response, I have started to decrease anthracycline administration. So, I think the next step is learning which patients can safely receive fewer chemotherapy cycles.

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: Final analysis results from the phase 3 KEYNOTE-522 study. J Clin Oncol. 44, 507-507(2026). doi:10.1200/JCO.2026.44.16_suppl.507