Pembrolizumab + chemo improves PFS in previously untreated, advanced TNBC

Pembrolizumab in combination with chemotherapy significantly improves progression-free survival (PFS) vs chemotherapy alone in patients with previously untreated, locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC), results of the KEYNOTE-355 study have shown.

The study included 847 patients (median age, 53 years) who had completed treatment with curative intent ≥6 months prior to first disease recurrence. The patients were randomized (2:1) to receive pembrolizumab or placebo, for up to 35 administrations or until disease progression or intolerable toxicity, along with investigator-choice chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin). The primary endpoints were PFS and overall survival (OS) in patients with PD-L1–positive tumours and in the intent-to-treat (ITT) population. [Cortes J, et al, ASCO 2020, abstract 1000]

“About 75 percent of patients had a PD-L1 combined positive score [CPS] of ≥1, while 36.7–38.9 percent had a PD-L1 CPS of ≥10,” said investigator Dr Javier Cortes of IOB Institute of Oncology, Quiron Group & Vall d´Hebron Institute of Oncology, Madrid & Barcelona, Spain. “About 45 percent of patients in each arm received a taxane in the study, while about 55 percent received gemcitabine/carboplatin. About 22 percent of patients in each arm had previously received chemotherapy in the same class.”

In patients with PD-L1 CPS ≥10, median PFS was 9.7 months in the pembrolizumab arm vs 5.6 months in the placebo arm (hazard ratio [HR], 0.65; 95 percent confidence interval [CI], 0.49 to 0.86; p=0.0012). “At 12 months, PFS rate in patients was 39.1 percent vs 23 percent,” reported Cortes.

“In patients with PD-L1 CPS ≥1, however, the PFS improvement with pembrolizumab did not meet statistical significance according to the prespecified criteria [ie, p value boundary of 0.00111],” he noted. “In these patients, median PFS was 7.6 months in the pembrolizumab arm vs 5.6 months in the placebo arm [HR, 0.74; 95 percent CI, 0.61 to 0.90; p=0.0014], while 12-month PFS rate was 31.7 percent vs 19.4 percent.”

In the ITT population, median PFS was 7.5 months vs 5.6 months in the pembrolizumab vs placebo arm (HR, 0.82; 95 percent CI, 0.69 to 0.97). “Statistical significance in the ITT population was not tested because the prespecified hierarchy of PFS superiority in patients with PD-L1 CPS ≥1 was not met,” said Cortes.       

“The PFS benefit of pembrolizumab was generally consistent across prespecified subgroups of patients with PD-L1 CPS of ≥10, except for those with a disease-free interval of <12 months [HR, 1.00; 95 percent CI, 0.51 to 1.95]. However, the sample size was very small, and the study was not designed to look at this specific subgroup of patients,” he continued.

Grade 3–5 treatment-related adverse events (TRAEs) were reported in 68.1 percent vs 66.9 percent of patients in the pembrolizumab vs placebo arm, with TRAEs leading to death in 0.4 percent vs 0 percent of patients. The most common TRAEs of all grades were anaemia (48.9 percent vs 45.9 percent), neutropenia (41.1 percent vs 38.1 percent), and nausea (39.3 percent vs 40.9 percent).

Grade 3–5 immune-mediated AEs (AEs) occurred in 5.2 percent vs 0 percent of patients, with none of the events leading to death. The most common immune-mediated AEs of all grades were hypothyroidism (15.5 percent vs 3.2 percent) and hyperthyroidism (4.8 percent vs 1.1 percent).

“Pembrolizumab in combination with chemotherapy was granted a Breakthrough Therapy Designation by the US FDA for neoadjuvant treatment of patients with high-risk, early-stage TNBC. Findings of the KEYNOTE-355 study suggest a role for the addition of pembrolizumab to standard chemotherapy for first-line treatment of metastatic TNBC,” concluded Cortes.