Pembrolizumab plus chemotherapy may be an effective neoadjuvant treatment for triple-negative breast cancer. In the phase III KEYNOTE-522 trial, patients treated with the PD-1 inhibitor in combination with chemotherapy prior to surgery were more likely to have a pathologic complete response than patients who received chemotherapy alone, regardless of PD-L1 levels.

Triple-negative breast cancer (TNBC) is an aggressive disease with a high recurrence rate, and a poor prognosis once it becomes metastatic, creating a need for better treatment options. Neoadjuvant pembrolizumab (Keytruda) plus chemotherapy may be one such option, according to topline results recently announced by Merck. In the phase III KEYNOTE-522 trial, patients treated with the combination prior to surgery were more likely to have a pathologic complete response (pCR) than patients who received chemotherapy alone.

Often, patients with TNBC are initially treated with neoadjuvant chemotherapy followed by surgery and, occasionally, adjuvant chemotherapy, with more chemotherapy if their disease recurs and becomes metastatic. However, in March 2019, the FDA approved the PD-L1 inhibitor atezolizumab (Tecentriq; Genentech) plus nab-paclitaxel (Abraxane; Celgene) in inoperable PD-L1–positive advanced or metastatic TNBC, which led Heather McArthur, MD, MPH, of Cedars-Sinai Medical Center in Los Angeles, CA, and her team to test the PD-1 inhibitor pembrolizumab plus chemotherapy as a neoadjuvant therapy in KEYNOTE-522. “Whenever we see an improvement in the metastatic setting, we typically apply those same strategies in the curative-intent setting to see if we can ultimately improve cure rates,” McArthur explains.

In the earlier phase Ib KEYNOTE-173 trial, 60 patients with early-stage TNBC treated with neoadjuvant pembrolizumab plus chemotherapy had manageable side effects and a pCR rate of 60%. In KEYNOTE-522, patients treated with the combination before surgery had a significantly higher pCR rate than those who received chemotherapy alone regardless of PD-L1 expression, meeting one of the trial's primary endpoints. The trial will continue gathering data on the other primary endpoint, event-free survival, as well as secondary endpoints, such as overall survival.

“Historically, pathologic complete response in triple-negative breast cancer has translated into improved long-term outcomes, so that's an incredibly promising signal that this strategy might improve cure rates,” McArthur says. Clinicians need longer follow-up, she adds, but if the combination does lead to better outcomes, it is likely to become a standard-of-care.

Harold Burstein, MD, PhD, of Dana-Farber/Harvard Cancer Center in Boston, MA, who is not involved in the trial, agrees that the results will be exciting if they are borne out. “We're looking forward to the overall survival data—that's the next big clinical piece,” he says. In 2014, the FDA released a guidance on pCR as an endpoint for accelerated approval of neoadjuvant treatment in TNBC and similar breast cancers, “so there will be a lot of interest in seeing what the FDA makes of these data,” he adds, “and whether it is willing to grant an accelerated approval.”

Burstein is also intrigued by the possibility that unlike atezolizumab in metastatic TNBC, neoadjuvant pembrolizumab may benefit patients regardless of PD-L1 levels, which would make the therapy more broadly applicable. He hopes that the results will compel researchers to investigate key questions such as: “Is there really a difference between pembrolizumab and atezolizumab in terms of what tumors are likely to respond? Is the biomarker really as robust as we think it is? Do we need the biomarker at all?” –Catherine Caruso

©2019 American Association for Cancer Research.
2019
American Association for Cancer Research.