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BARCELONA -- Neoadjuvant therapy with pembrolizumab (Keytruda) and chemotherapy significantly improved pathologic complete response (pCR) in early triple-negative breast cancer (TNBC), initial data from a randomized trial showed.

The proportion of patients with no residual disease in the breast or lymph nodes (ypT0/Tis ypN0) was 64.8% with pembrolizumab and chemotherapy, followed by adjuvant pembrolizumab, as compared with 51.2% for neoadjuvant chemotherapy and placebo, followed by adjuvant placebo. Patients with and without PD-L1-positive tumors benefited from the anti-PD-1 regimen.

"It's well established that in chemotherapy before surgery in early breast cancer, those patients where the cancer disappears -- a pathological complete response -- have a long-term benefit," Peter Schmid, MD, PhD, of Barts Cancer Institute and Queen Mary University in London, said here at the . "A large data analysis shows that people who don't have tumor left in the breast at the time we do surgery, after chemotherapy, have progressively longer recurrence-free survival."

Neoadjuvant chemotherapy with a taxane and an anthracycline achieves a pCR in about 40% of patients, increasing to 50-55% with the addition of a platinum agent. The FDA and European Medicines Agency have supported pCR as an endpoint for accelerated approval of neoadjuvant regimens in early TNBC, Schmid continued. But that must be supported by evidence of long-term benefit in the form of improved event-free-survival (EFS), he added.

At the 2018 ESMO conference, investigators reported the first evidence of a survival benefit with immunotherapy for metastatic TNBC. Schmid said the KEYNOTE-522 trial was designed with the goal of demonstrating similar durable benefits with immunotherapy in early TNBC.

Eligible patients had newly diagnosed TNBC, good performance status, and tissue available for assessment of PD-L1 expression status. The investigators randomized 1,174 patients 2:1 to a standard neoadjuvant chemotherapy regimen with pembrolizumab or placebo, followed by surgery, and then adjuvant pembrolizumab or placebo for as long as 27 weeks. The trial had dual primary endpoints of pCR and EFS, and 603 patients were evaluable for pCR.

The 13.6% absolute difference in pCR easily achieved statistical significance (P=0.00055), Schmid reported. Analysis of pCR by PD-L1 expression showed that patients with PD-L1-positive tumors (combined positive score of 1 or greater, 498 patients) had a pCR rate of 68.9% with pembrolizumab and 54.9% with placebo. In the PD-L1-negative subgroup of 97 patients, pCR rates were 45.3% with pembrolizumab and 30.3% with placebo.

After a median follow-up of about 15 months, the researchers performed an interim analysis of EFS. The data suggested an estimated 18-month EFS rate of 91.3% with pembrolizumab and 85.3% with placebo. Follow-up for EFS and survival will continue, said Schmid.

Treatment-related adverse events occurred in a similar proportion of patients in the two randomized groups, as did grade 3-5 events and fatal adverse events (0.3% in each group). Adverse events led to a higher rate of discontinuation (any drug in the regimen) in the pembrolizumab arm (24.5% vs 13.1%). Schmid said the types of adverse events were consistent with the known toxicities associated with the drugs.

Because pCR is a surrogate for improved survival, the trial provided reason for optimism that pembrolizumab-containing neoadjuvant therapy might improve progression-free survival and overall survival in patients with newly diagnosed TNBC, said Giuseppe Curigliano, MD, of the European Institute of Oncology and the University of Milan, who was not affiliated with the study.

"This is really a breakthrough result, because you can increase the pCR and potentially you can increase overall survival or disease-free survival," he said. "This is an important trial that will provide a lot of data. The baseline biopsies can help us better identify those patients who will be more likely to respond to immunotherapy. If we can characterize those patients who had a pCR, we can find those patients who would maximize the benefits of immunotherapy. For those who had no response, we can use the residual tumor to help us better understand the mechanisms of resistance to immune checkpoint inhibitors."

In the discussion that followed his presentation, Schmid said the results could not answer the question of whether the benefits observed with pembrolizumab were owed to the neoadjuvant or adjuvant use or to both.

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