Merck’s Keytruda Hits Another Endpoint, This Time in Triple-Negative Breast Cancer

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Merck’s checkpoint inhibitor Keytruda (pembrolizumab) keeps racking up approvals for new cancer indications. The therapy, which is an anti-PD-1 checkpoint inhibitor, hit the primary endpoint in the company’s Phase III KEYNOTE-522 in triple-negative breast cancer (TNBC). Keytruda was used in combination with chemotherapy.

Based on interim analysis by the independent Data Monitoring Committee (DMC), Keytruda with chemotherapy showed a statistically significant improvement in pathological complete response (pCR) compared to chemotherapy alone, regardless of PD-L1 status. pCR is defined as lack of all signs of cancer in tissue samples analyzed after finishing neoadjuvant therapy and definitive surgery.

The DMC recommended the trial continue without changes in order to determine other dual-primary endpoints, such as event-free survival (EFS).

“These findings from this innovatively designed trial with Keytruda marks the first time an anti-PD-1 therapy plus chemotherapy has demonstrated a statistically significant improvement in pathological complete response rate as a neoadjuvant, or pre-surgical, segment of treatment for triple-negative breast cancer,” stated Roger M. Perlmutter, president, Merck Research Laboratories. “TNBC is an aggressive malignancy with a high rate of recurrence within the first five years of diagnosis. We are encouraged by these results and plan to discuss these data with health authorities and to present these findings at an upcoming medical congress.”

TNBC is marked by high recurrence rate within the first five years after being diagnosed. The triple-negative refers to the cancer testing negative for estrogen receptor (ER), progesterone receptor (PR) or human epidermal growth factor receptor 2 (HER2). Because of the triple-negative component, TNBC doesn’t respond to therapies that target those three markers, which makes it difficult to treat. About 15 to 20% of breast cancer patients are TNBC.

The KEYNOTE-522 trial has 1,174 patients in it. It is a Phase III, ranbdomized, double-blind trial studying Keytruda with chemotherapy compared to placebo plus chemotherapy as neoadjuvant therapy. The dual-primary endpoints are pCR and EFS. Secondary endpoints are pCR rate, EFS in patients expressing PD-L1, overall survival, safety and patient-reported outcomes.

Patients were randomized 2:1 to receive either Keytruda every three weeks plus weekly paclitaxel and carboplatin (weekly or every three weeks) for four cycles, followed by Keytruda and cyclophosphamide and either doxorubicin or epirubicin for four cycles as neoadjuvant therapy before surgery, followed by nine cycles of Keytruda every three weeks as adjuvant therapy after surgery; or, placebo every three weeks plus weekly paclitaxel and carboplatin (weekly or every three weeks) for four cycles, followed by placebo plus cyclophosphamide and either doxorubicin or epirubicin every three weeks for four cycles, followed by nine cycles of placebo every three weeks as adjuvant therapy post-surgery.

One particularly interesting aspect of this announcement is that it is the first time a checkpoint inhibitor has been successful as neoadjuvant treatment in breast cancer. Checkpoint inhibitors have revolutionized many types of cancer treatments, but been less effective in breast cancer, partly because of the complexity of breast cancer, but also because of the availability of other treatments.

In March, the U.S. Food and Drug Administration (FDA) approved Roche’s Tecentriq (atezolizumab) in combination with paclitaxel for adults with unresectable locally advanced or metastatic TNBC whose tumors express PD-L1. The PD-L1 intensity is determined by an FDA-approved test, the Ventana PD-L1 (SP142) Assay.