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The FDA granted full approval to the PD-1 inhibitor pembrolizumab (Keytruda) plus chemotherapy for neoadjuvant treatment of high-risk triple-negative breast cancer (TNBC), followed by adjuvant pembrolizumab, Merck .

The expanded indication represents the first approval of an immunotherapy-containing regimen for early-stage TNBC. Both pembrolizumab and atezolizumab (Tecentriq) have FDA-approved indications for unresectable/metastatic TNBC.

Earlier this year, the FDA Oncologic Drugs Advisory Committee unanimously recommended the FDA defer an approval decision on the pembrolizumab regimen until more data became available from the phase III KEYNOTE-522 trial. As was recently reported, an updated analysis of KEYNOTE-522 showed the regimen significantly improved event-free survival (EFS) as compared with chemotherapy alone.

"Even when TNBC is diagnosed early, 30-40% of patients will suffer cancer recurrence after standard neoadjuvant chemotherapy and surgery," said Joyce O'Shaughnessy, MD, of Baylor University Medical Center in Dallas, in a statement from Merck. "Therefore, there is a high unmet need for new treatment options. Today's approval is very welcome news and has the potential to change the treatment paradigm by now including an immunotherapy as part of the regimen for patients with high-risk early TNBC."

The FDA also converted an accelerated approval to full approval for pembrolizumab plus chemotherapy for unresectable/metastatic TNBC associated with PD-L1 expression ≥10%. Primary support for the indication came from the phase III KEYNOTE-355 trial, which showed that adding pembrolizumab to chemotherapy significantly improved progression-free survival versus chemotherapy alone.

KEYNOTE-522 included 1,174 patients with untreated high-risk TNBC. Patients were randomized 2:1 to chemotherapy plus pembrolizumab or placebo before surgery and additional pembrolizumab or placebo afterward. The primary endpoints were pathologic complete response (pCR) and EFS.

The final pCR analysis showed rates of 63.0% with pembrolizumab and 55.6% with chemotherapy and placebo. Patients who received the pembrolizumab regimen had a 37% reduction in the EFS hazard as compared with placebo (P=0.00031). Follow-up continues for overall survival, a secondary endpoint.

The most common adverse events (AEs) associated with pembrolizumab were fatigue (70%), nausea (67%), alopecia (61%), rash (52%), constipation (42%), diarrhea and peripheral neuropathy (41% each), stomatitis (34%), vomiting (31%), headache (30%), arthralgia (29%), pyrexia (28%), cough (26%), abdominal pain (24%), decreased appetite (23%), insomnia (21%), and myalgia (20%). Serious AEs associated with pembrolizumab included febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%).

The FDA action increases the number of approved indications for pembrolizumab to 30.

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