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Neoadjuvant pembrolizumab (Keytruda) plus chemotherapy, continued as a single agent after surgery, significantly improved event-free survival in patients with high-risk, early-stage triple-negative breast cancer (TNBC) in the KEYNOTE-522 trial.

The pembrolizumab regimen reduced the risk of progression, recurrence, second primary cancers, or death by 37% compared with neoadjuvant chemotherapy alone over a median follow-up of 39 months, reported Peter Schmid, MD, PhD, of Barts Cancer Institute at Queen Mary University of London, during a .

"These data support that pembrolizumab plus platinum-containing neoadjuvant chemotherapy, followed by adjuvant pembrolizumab after surgery, should be a new standard of treatment for patients with high-risk early stage triple-negative breast cancer," Schmid said during his presentation.

In discussing the results of KEYNOTE-522, Giuseppe Curigliano, MD, PhD, of the University of Milan, Italy, called them "practice changing" and added that the best chemotherapy backbone for the pembrolizumab regimen still needs to be determined.

"But we know very well that the combination used in the KEYNOTE-522 trial really increased event-free survival," Curigliano said.

KEYNOTE-522 was a phase III, randomized, double-blind trial that enrolled 1,174 patients who were randomized 2:1 to either pembrolizumab or placebo.

Pembrolizumab was administered every 3 weeks, with paclitaxel weekly and carboplatin (weekly or every 3 weeks) for four cycles, followed by pembrolizumab plus cyclophosphamide every 3 weeks and either doxorubicin or epirubicin for four cycles as neoadjuvant therapy prior to surgery. This was followed by up to 27 weeks of pembrolizumab post-surgery.

Patients in the placebo arm received matching placebo and the same regimen of chemotherapy.

The study had two primary endpoints: pathological complete response (pCR) and event-free survival (EFS), which was the time from randomization to the first occurrence of either disease progression that precluded definitive surgery, a local or distance recurrence, a second primary cancer, or death from any cause.

In an analysis reported at the ESMO annual congress in 2019, Schmid said that pCR was observed in 64.8% of patients treated with pembrolizumab plus chemotherapy -- an absolute increase of 13.6% compared with the 51.2% rate among patients treated with neoadjuvant chemotherapy plus placebo.

Here, Schmid reported that neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab showed a "statistically significant and clinically meaningful improvement" in EFS (HR 0.63, 95% CI 0.48-0.82). Events occurred in 23.8% of patients in the placebo arm compared with 15.7% of patients in the pembrolizumab arm.

The 3-year EFS rate was 84.5% in the pembrolizumab arm compared with 76.8% in the placebo arm – a difference of 7.7% "that for this patient population is quite important," Curigliano observed.

Schmid pointed out that the majority of events observed were distant recurrence, with rates of 7.7% among patients treated with the pembrolizumab regimen compared to 13.1% of patients in the placebo arm.

When the researchers looked at EFS by pCR, they observed that patients with residual disease at the time of surgery had a substantially higher rate of EFS when treated with pembrolizumab compared to the placebo arm (67.4% to 56.8%), suggesting "the type and quality of pCR seems to be altered by the addition of pembrolizumab to chemotherapy," Schmid said.

He noted that subanalysis was not a randomized comparison. "Obviously, substantially more patients achieved pCR when treated with pembrolizumab," he said. "But, if you focus on the groups in each arm that had a pCR there is a 2.1% difference in favor of the pembrolizumab arm."

Schmid made particular note of the fact that, in terms of distant progression or distant recurrence-free survival, "we see a clear benefit for patients treated with pembrolizumab," with a hazard ratio of 0.61 (95% CI 0.46-0.82). He and his colleagues observed that 20.3% of patients in the placebo arm experienced distant recurrences compared with just 12.8% of patients in the pembrolizumab arm.

As of data cutoff, 14.1% of patients in the placebo arm had died compared to 10.2% in the pembrolizumab arm. This represented a nonsignificant 28% relative reduction in the risk of death with the pembrolizumab regimen, although the overall survival data is still immature, Schmid reported.

Schmid said there was relatively little difference between the two groups in the neoadjuvant phase of the trial regarding safety. Adverse events were "dominated" by chemotherapy, with nausea, alopecia, and anemia the most common side effects.

"In the adjuvant phase, after the completion of chemotherapy, we see the incidence of side effects is dramatically lower and comparable between the two groups," he said.

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