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Pembrolizumab in combination with chemotherapy led to a statistically significant improvement in pathological complete response rates compared with placebo plus chemotherapy in the neoadjuvant phase of a neoadjuvant/adjuvant treatment regimen in patients with triple-negative breast cancer, meeting one of the dual primary endpoints of the phase III KEYNOTE-522 trial.
Roger M. Perlmutter, MD, PhD
Pembrolizumab (Keytruda) in combination with chemotherapy led to a statistically significant improvement in pathological complete response (pCR) rates compared with placebo plus chemotherapy in the neoadjuvant phase of a neoadjuvant/adjuvant treatment regimen in patients with triple-negative breast cancer (TNBC), meeting one of the dual primary endpoints of the phase III KEYNOTE-522 trial.1
Results of the interim analysis showed that the improvement in pCR was observed in patients regardless of PD-L1 status. Based on a recommendation by an Independent Data Monitoring Committee, the study will continue without changes to evaluate event-free survival (EFS), which is the other dual primary endpoint as per the trial design.
The safety data were consistent with prior data of pembrolizumab and no new safety signals were identified, Merck, the developer of the PD-1 inhibitor, stated in a press release. Full findings will be presented at an upcoming medical meeting.
“These findings from this innovatively designed trial with Keytruda mark 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,” Roger M. Perlmutter, MD, president, Merck Research Laboratories, stated in the press release. “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.”
In the double-blind, phase III KEYNOTE-522 trial (NCT03036488), researchers evaluated the combination of pembrolizumab and chemotherapy compared with placebo plus chemotherapy as neoadjuvant therapy, followed by pembrolizumab/placebo as adjuvant therapy in 1174 patients with TNBC.
Patients were randomized 2:1 to receive pembrolizumab or placebo every 3 weeks plus carboplatin weekly or every 3 weeks plus weekly paclitaxel for 4 cycles, followed by pembrolizumab plus cyclophosphamide and either doxorubicin or epirubicin every 3 weeks for 4 cycles as neoadjuvant treatment, followed by 9 cycles of single-agent pembrolizumab or placebo every 3 weeks as adjuvant therapy.
To be eligible for enrollment, patients had to have newly diagnosed, locally advanced, centrally confirmed TNBC; had previously untreated locally advanced nonmetastatic TNBC; an ECOG performance status of 0 or 1 performed within 10 days of treatment initiation; and demonstrate adequate organ function. Those who received prior chemotherapy, targeted therapy, radiation therapy in the past 1 year, or received a PD-1/PD-L1 inhibitor were excluded.
The dual-primary endpoints are pCR and EFS, and secondary endpoints include pCR rate using alternative definitions—such as no invasive or noninvasive residual cancer in breast or nodes—at the time of definitive surgery, EFS in PD-L1—tumors, overall survival, safety and patient-reported outcomes.
Prior phase Ib findings of the KEYNOTE-173 trial showed that the combination of pembrolizumab and platinum/taxane chemotherapy in the neoadjuvant setting induced high rates of pCR in patients with locally advanced TNBC.2
In this study, 60 patients were randomized to 1 of 6 cohorts with varying doses of a taxane-based chemotherapy alone or in combination with platinum chemotherapy for four 3-week cycles, followed by 60 mg/m2 of doxorubicin and 600 mg/m2 of cyclophosphamide for another 4 3-week cycles. The cohorts were the following:
Pembrolizumab was given at a single dose of 200 mg on day 1 of cycle 1 and on the first day of each 3-week cycle thereafter in all cohorts. All patients then underwent definitive surgery within 3 to 6 weeks of receiving 9 cycles of neoadjuvant therapy.
At the time of data cut-off in May 2018, results showed that 78.3% of patients (n = 47) completed neoadjuvant therapy. Of the 13 patients who discontinued neoadjuvant treatment, 9 stopped treatment due to adverse events, 2 to withdrawal, 1 to physician’s choice, and 1 to progressive disease. Fifty-eight patients had surgery, after which 90% (n = 54) remained on the study. The median follow-up across cohorts was 19.6 months (range, 4.0-27.4).
At the time of surgery, 60% of patients had achieved a pCR, defined as ypT0/Tis ypN0 (no invasive residual disease in breast or nodes) versus 57% of those who achieved a pCR defined as ypT0 ypN0 (no invasive or noninvasive residual disease in breast or nodes). The highest rates of pCR were achieved by patients who received nab-paclitaxel and carboplatin in cohorts B, C, and D.
Results also showed that the overall response rate was higher in the cohorts of patients who received carboplatin (B-F; 90% [90% CI, 80%-96%]), versus that in cohort A (80% [90% CI, 49%-96%]). There were 2 cases of disease progression were identified prior to surgery, both of which were from cohort A.
Patients who achieved a pCR were more likely to have higher 12- and 24-month EFS rates than those who did not. In responders, the 12- and 24-months EFS rates were 100% and 88% compared with 97% and 66%, respectively, in non-responders. Also, patients who received platinum-based therapy had a higher likelihood of achieving a 12-month EFS.
Pembrolizumab is also being evaluated in TNBC in the KEYNOTE-355 and KEYNOTE-242 studies.