The combination of the ant-PD-1 inhibitor, pembrolizumab plus chemotherapy before surgery continued by pembrolizumab as a single agent led to statistically significant event-free survival result versus neoadjuvant chemotherapy alone in patients with high-risk early-stage triple-negative breast cancer.
The combination of the ant-PD-1 inhibitor, pembrolizumab (Keytruda) plus chemotherapy before surgery continued by pembrolizumab as a single agent led to statistically significant event-free survival (EFS) result versus neoadjuvant chemotherapy alone in patients with high-risk early-stage triple-negative breast cancer (TNBC), according to an update from the phase 3 KEYNOTE-522 reported in a press release by Merck.
“Given the high rates of recurrence within the first 5 years of diagnosis, patients with high-risk early-stage TNBC need new treatment options,” said Peter Schmid, FRCP, MD, PhD
lead, Centre for Experimental Cancer Medicine, Barts Cancer Institute in London, England, ina statement. “KEYNOTE-522 was designed to study whether the combined neoadjuvant and adjuvant regimen with Keytruda could help treat the cancer earlier. Now, with more than three years of follow-up, we see the potential of this approach. These event-free survival data are very encouraging for patients and show that this combination of Keytruda plus chemotherapy as neoadjuvant therapy, followed by single-agent Keytruda as adjuvant therapy, may offer women with high-risk early-stage TNBC a new treatment option for this aggressive disease.”
The phase 3 KEYNOTE-522 study (NCT03036488) enrolled 1174 patients. The study is randomized, placebo-controlled, and utilizes a quadruple masking method. The primary end points of the study are pathological complete response (pCR), and EFS. Secondary end points include overall survival, percentage of participants who experience adverse events (AEs), the percentage of participants who discontinue study treatment due to an AE, and quality of life as assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of life Questionnaire (QoL) and the EROTC Breast Cancer-Specific QoL Questionnaire score.
Patients in the study were randomized 2:1. In arm 1, patients received pembrolizumab every 3 weeks plus weekly paclitaxel and carboplatin for 4 cycles. This was followed by pembrolizumab once every 3 weeks plus doxorubicin or epirubicin plus cyclophosphamide once every 3 weeks for 4 cycles as neoadjuvant therapy prior to surgery. This was then followed by 9 cycles of pembrolizumab every 3 weeks as adjuvant therapy post-surgery. All cycles lasted for 21 days. Arm 2 followed the same schedule with the exception that pembrolizumab was replaced by a placebo.
At the median follow-up of 39 months, the pembrolizumab-containing regimen reduced the risk of EFS events by 37% compared to the placebo (HR, 0.63; 95% CI, 0.48-0.82; P =.00031). Additionally, there was a 28% reduction in the risk of death with the pembrolizumab-containing regimen.
Additionally, the study met its dual primary endpoint of pCR at the first interim analysis. Over half, 64.8% of patients treated with pembrolizumab had pCR compared to the 51.2% of those treated with the placebo. Furthermore, at 3 years, 84.5% of patients treated with pembrolizumab were alive and did not experience EFS compared to the 76.85 in the placebo group.
In patients who were PD-L1 positive, pembrolizumab reduced the risk of EFS events by 33% over placebo (HR, 0.67; 95% CI, 0.49-0.92).
At the time of data-cutoff, no patients were receiving the protocol regimen. Any grade TEAEs occurred in 43.6% of patients receiving pembrolizumab and in 21.9% of patients receiving the placebo. The most common were infusion reactions (18%), hypothyroidism (15.1%).
In order to participate in the study of the pembrolizumab combination, patients must be 18 years of age or older, have newly diagnosed or previously untreated, locally advanced, centrally confirmed TNBC, an ECOG score of 0 or 1 within 10 days prior to treatment initiation, have adequate organ function, and must be willing to use contraceptive. Patients who received prior chemotherapy, targeted therapy, or radiation therapy within the past 12 months prior to treatment, have prior therapy with a PD-1 inhibitor, has received a live vaccine within 30 days of trial initiation, have a known history of HIV, has known active hepatitis B or C, have an active infection requiring systemic therapy, or has significant cardiovascular disease were not eligible to participate.
Analyses in KEYNOTE-522 are and ongoing and the estimated study completion date is September 20, 2025.
“These highly-anticipated event-free survival results in this TNBC population build upon earlier findings from the KEYNOTE-522 trial and further support the potential use of Keytruda in these patients,” said Vicki Goodman, MD, vice president, clinical research, Merck Research Laboratories, in a press release. “KEYNOTE-522 is the first large randomized phase 3 study to report a statistically significant and clinically meaningful EFS result among patients with stage II and stage III TNBC. We have submitted these data to the FDA and are working closely with the agency on its review of our application.”