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The addition of pembrolizumab to chemotherapy resulted in a statistically significant and clinically meaningful improvement in overall survival vs chemotherapy alone in patients with metastatic triple-negative breast cancer whose tumors had a PD-L1 expression of a combined positive score of 10 or higher, meeting the primary end point of the phase 3 KEYNOTE-355 trial.
The addition of pembrolizumab (Keytruda) to chemotherapy resulted in a statistically significant and clinically meaningful improvement in overall survival (OS) vs chemotherapy alone in patients with metastatic triple-negative breast cancer (TNBC) whose tumors had a PD-L1 expression of a combined positive score of 10 or higher, meeting the primary end point of the phase 3 KEYNOTE-355 trial (NCT02819518).1
No new safety signals were reported with the regimen.
Merck shared plans to present the OS data at an upcoming medical meeting and to submit to regulatory authorities.
“In the fight against TNBC, the subtype with the worst survival prognosis, new options that can extend the lives of patients are urgently needed,” Vicki Goodman, MD, vice president of clinical research at Merck Research Laboratories, stated in a press release. “These new OS results confirm that [pembrolizumab] in combination with chemotherapy represents an important treatment option for certain patients with metastatic TNBC. We thank the patients and investigators who have allowed us to evaluate innovative treatment approaches, anchored by [pembrolizumab], across multiple settings and stages of TNBC.”
The two-part KEYNOTE-355 trial examined pembrolizumab in combination with investigator's choice of either nab-paclitaxel (Abraxane), paclitaxel, or gemcitabine/carboplatin vs placebo plus 1 of the 3 chemotherapy agents in patients with previously untreated locally recurrent inoperable or metastatic TNBC.2
To be eligible for enrollment, patients must have been at least 18 years, have had central determination of TNBC and PD-L1 expression, had completed treatment with curative intent at least 6 months before their first disease recurrence, had an ECOG performance status of 0 or 1, a life expectancy of 12 weeks or longer from randomization, and acceptable organ function. They could not have received systemic steroids, had central nervous system metastases, or active immune disease.
In the first part of the study, investigators assessed the safety and tolerability of pembrolizumab in combination with 1 of the chemotherapy regimens in 30 patients.
In part 2, a total of 847 patients were randomized 2:1 to receive either placebo (n = 281) or pembrolizumab (n = 566) at an intravenous (IV) dose of 200 mg day 1 of each 21-day treatment cycle plus either nab-paclitaxel at 100 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle; paclitaxel at 90 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle; or 1000 mg/m2 of gemcitabine and area under the curve (AUC) 2 of carboplatin on days 1 and 8 of each 21-day cycle. The trial was not designed to compare the efficacy of the chemotherapy regimens, and treatment was continued until progressive disease or cessation of study therapy.
Stratification factors included the chemotherapy given on study, PD-L1 tumor expression (CPS of 1 or higher vs CPS of less than 1), and prior treatment with the same class of neoadjuvant/adjuvant chemotherapy (yes vs no).
The coprimary end points of the trial were progression-free survival (PFS) and OS in patients with PD-L1–positive tumors and in the intent-to-treat (ITT) population. Key secondary end points included objective response rate (ORR), duration of response, disease control rate, and safety.
Baseline characteristics were noted to be well balanced between the 2 treatment arms. The median age of study participants was 53 years, and approximately 39.7% had an ECOG performance status of 1. Moreover, 75.1% of patients had a PD-L1 CPS of 1 or greater, and 37.8% had a CPS of 10 or greater.
Approximately 45% of patients received a taxane as their chemotherapy, and about 54% of patients received gemcitabine/carboplatin. Twenty-two percent of patients received the same chemotherapy previously in the neoadjuvant/adjuvant setting. Moreover, 29.7% of patients had de novo metastasis, 20.1% had a disease-free interval (DFI) of less than 12 months, and 50% of patients had a DFI of 12 months or longer.
Earlier data from KEYNOTE-355 were presented during the 2020 ASCO Virtual Scientific Program and demonstrated that pembrolizumab in combination with various chemotherapy partners resulted in a statistically significant and clinically meaningful improvement in PFS vs chemotherapy alone in the frontline treatment of this patient population.
At a median follow-up of 26.1 months, the combination resulted in a median PFS of 9.7 months vs 5.6 months with chemotherapy alone in this subgroup; this translated to a 35% reduction in the risk of disease progression or death (HR, 0.65; 95% CI, 0.49-0.86; one-sided P = .0012).
In those with a PD-L1 CPS of 1 or higher, the regimen resulted in a median PFS of 7.6 months vs 5.6 months with chemotherapy alone (HR, 0.74; 95% CI, 0.61-0.90; P = .0014), although this was not determined to be of statistical significance.
In the ITT population, the median PFS in the investigative and control arms was 7.5 months vs 5.6 months, respectively; this translated to a 18% reduction in the risk of disease progression or death (HR, 0.82; 95% CI, 0.69-0.97). Statistical significance was not evaluated in this subset.
Additional data indicated that among patients with a PD-L1 CPS or 10 or higher, the PFS rates at 1 year in the investigative and control arms were 39.1% and 23.0%, respectively. At 6 months, these rates were 65.0% and 46.9%, respectively, in this patient subset. The PFS benefit in patients whose tumors had a PD-L1 CPS of 10 or higher was observed across the majority of subgroups evaluated, with the exception of those who had a DFI of 12 months or longer (HR, 1.00; 95% CI, 0.51-1.95).
Among the patients with PD-L1 CPS of 1 or higher, the PFS rate at 1 year with pembrolizumab plus chemotherapy was 31.7% vs 19.4% with chemotherapy alone. The 6-month PFS rates in the investigative and control arms were 56.4% and 46.6%, respectively.
In the ITT population, the PFS rate at 1 year with pembrolizumab plus chemotherapy was 29.8% vs 20.9% with chemotherapy alone. The 6-month PFS rates in the investigative and control arms were 55.4% and 47.8%, respectively. The PFS benefit achieved with the immunotherapy was noted across subgroups in the ITT subset and in those with a PD-L1 CPS of 1 or higher.
Patients with a PD-L1 CPS of 20 or higher also derived benefit from pembrolizumab plus chemotherapy. In this subset, the median PFS was 9.5 months (HR, 0.61; 95% CI, 0.43-0.87).
All-grade adverse effects (AEs) were comparable between the 2 treatment arms. Just under 70% (68.1%) of patients on the investigative arm experienced grade 3 to 5 AEs vs 66.9% of those on the control arm. Two treatment-related AEs (TRAEs) resulted in death with the pembrolizumab combination vs none with chemotherapy alone. A slightly higher treatment discontinuation rate was noted in the investigative arm vs the control arm, at 18.1% and 11.0%, respectively.
All-grade TRAEs reported in 20% or more of patients in the investigative and control arms included anemia (48.9% vs 45.9%, respectively), neutropenia (41.1% vs 38.1%), nausea (39.3% vs 40.9%), alopecia (33.1% vs 33.5%), fatigue (28.5% vs 29.5%), reduced neutrophil count (22.2% vs 26.3%), and increased alanine aminotransferase levels (20.5% vs 16.4%).