The final overall survival (OS) results of the phase III KEYNOTE-355 trial demonstrated that first-line treatment with pembrolizumab–chemotherapy resulted in significantly longer overall survival than chemotherapy alone among patients with advanced triple-negative breast cancer whose tumours expressed PD-L1 with a combined positive score (CPS) of 10 or more.
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that lacks expression of oestrogen and progesterone receptors and amplification or overexpression of human epidermal growth factor receptor 2(HER2). The absence of these receptors renders endocrine and HER2-targeted therapies ineffective, leaving cytotoxic chemotherapy as the standard treatment option. However, chemotherapy results in suboptimal antitumour response rates and short overall survival (OS) and response durations. New therapeutic strategies to improve outcomes are needed. The phase III KEYNOTE-355 trial examined whether the addition of pembrolizumab would enhance the antitumour activity of chemotherapy, including taxanes and a non-taxane platinum-based regimen, in patients with previously untreated locally recurrent inoperable or metastatic TNBC. Data from a prespecified interim analysis showed that pembrolizumab plus chemotherapy resulted in significantly longer progression-free survival (PFS) than placebo plus chemotherapy among patients with a PD-L1 combined positive score (CPS) of 10 or more. Recently, the results of the protocol-specified final analysis of KEYNOTE-355 were published.
KEYNOTE-355 randomly assigned patients with previously untreated locally recurrent inoperable or metastatic TNBC in a 2:1 ratio to receive pembrolizumab (200 mg) every 3 weeks plus the investigator’s choice of chemotherapy (nanoparticle albumin-bound paclitaxel, paclitaxel, or gemcitabine–carboplatin) or placebo plus chemotherapy. The primary endpoints were PFS (reported previously) and OS among patients whose tumours expressed PD-L1 with a CPS of 10 or more (the CPS-10 subgroup), among patients whose tumours expressed PD-L1 with a CPS of 1 or more (the CPS-1 subgroup), and in the intention-to-treat population. Safety was also assessed.
From January 2017 through June 2018, 847 patients underwent randomisation. Of them, 566 patients were assigned to the pembrolizumab-chemotherapy group and 281 to the placebo-chemotherapy group. The median follow-up was 44.1 months. In the CPS-10 subgroup, the median OS in the pembrolizumab arm was 23.0 months, as compared to 16.1 months in the placebo arm (HR[95%CI]: 0.73[0.55-0.95], p= 0.0185). The estimated OS at 18 months was 58.3% in the pembrolizumab-chemotherapy group and 44.7% in the placebo-chemotherapy group. In the CPS-1 subgroup, the median overall survival was 17.6 and 16.0 months in the two groups, respectively (HR[95%CI]: 0.86[0.72-1.04], p= 0.1125 [not significant]). The estimated 18-months OS was 48.4% and 41.4%, respectively. Finally, in the intention-to-treat (ITT) population, the median OS was 17.2 and 15.5 months, respectively (HR[95%CI]: 0.89[0.76-1.05]). Significance was not tested because of the prespecified multiplicity strategy. The treatment effect of pembrolizumab on OS increased with higher PD-L1 expression, with similar treatment effects observed among patients whose tumours expressed PD-L1 with a CPS of 10 or more and among those whose tumours expressed PD-L1 with a CPS of 20 or more.
The median PFS in the CPS-10 subgroup was 9.7 months in the pembrolizumab–chemotherapy group and 5.6 months in the placebo–chemotherapy group (HR[95%CI]: 0.66[0.50-0.88]). In the CPS-1 subgroup, the median PFS was 7.6 months in the pembrolizumab-arm and 5.6 months in the placebo–arm (HR[95%CI]: 0.75[0.62-0.91]). In the ITT population, the median PFS in the two groups was 7.5 and 5.6 months, respectively (HR[95%CI]: 0.82[0.70-0.98]). In the CPS-10 subgroup, a confirmed objective response occurred in 52.7% of patients treated in the pembrolizumab group and in 40.8% of patients in the placebo group. Corresponding values for the CPS-1 subgroup and the ITT population were 44.9% vs. 38.9% and 40.8% vs. 37.0%, respectively. In the CPS-10 subgroup, the median duration of response was 12.8 months in the pembrolizumab–chemotherapy group and 7.3 months in the placebo–chemotherapy group.
Adverse events of grade 3-5 that were related to the trial regimen occurred in 68.1% of the patients in the pembrolizumab–chemotherapy group and in 66.9% in the placebo–chemotherapy group, including death in 0.4% of the patients in the pembrolizumab–chemotherapy group and in no patients in the placebo–chemotherapy group. Anaemia, neutropenia and nausea were the most common adverse events.
Among patients with advanced TNBC whose tumours expressed PD-L1 with a CPS of 10 or more, the addition of pembrolizumab to chemotherapy resulted in significantly longer overall survival than chemotherapy alone.