Pembrolizumab plus chemotherapy confirmed as a standard first-line treatment for metastatic TNBC with a PD-L1 CPS ≥10
The final analysis of the pivotal KEYNOTE-355 trial confirms that combining pembrolizumab with chemotherapy results in a statistically significant improvement in the progression-free and overall survival compared to chemotherapy alone in the first-line treatment of metastatic TNBC patients with sufficient PD-L1 expression. An analysis of the trial results, in function of different PD-L1 CPS cut-offs, confirms that a CPS ≥10 is a reasonable cut-off to define the population of patients with metastatic TNBC expected to derive a benefit of the addition of pembrolizumab.
In KEYNOTE-355 the combination of pembrolizumab plus chemotherapy was assessed as first-line treatment for patients with metastatic triple negative breast cancer (TNBC). Previous reports of this study showed that this combination results in a statistically significant and clinically relevant improvement in progression-free (PFS) and overall survival (OS) compared to chemotherapy alone in the subgroup of patients with a PD-L1 combined positive score (CPS) of >10. In contrast, no significant benefit in PFS or OS was observed in patients with a CPS ≥1. As a result of the hierarchical testing strategy that was applied in this trial, the PFS and OS were not formally tested in the intention-to-treat population. During SABCS 2021, the final analysis of this trial was presented.
In KEYNOTE-355, 847 patients with previously untreated, locally recurrent, inoperable or metastatic TNBC were randomized (2:1) to pembrolizumab plus chemotherapy or placebo plus chemotherapy. To be eligible for the study, patients were required to have de novo metastatic disease or disease recurrence within 6 months after the completion of their treatment with curative intent. The primary endpoints of the study were PFS and OS in the PD-L1 CPS ≥10, CPS ≥1 and ITT populations, with secondary objectives including objective response rate (ORR), duration of response (DoR), disease control rate (DCR) and safety in all treated patients. In the analysis presented at SABCS 2021, outcomes were assessed in subgroups of patients by additional CPS cut-offs (CPS <1, CPS 1-9, CPS 10-19 and CPS≥20).
The median age of patients in the study was 53 years, about three quarters had a PD-L1 CPS ≥1 and 30% had de novo metastatic disease. In 45% of patients in the trial, the on-study chemotherapy was taxane-based, while 55% received gemcitabine/carboplatin. In just over three quarters of patients the chemotherapy class used in the study was different from the class used in the prior treatment line.
In the final analysis, the median OS with pembrolizumab + chemotherapy in the PD-L1 CPS ≥10 population was 23.0 months, which is significantly longer than the 16.1 months seen with chemotherapy alone (HR [95%CI]: 0.73 [0.55-0.95]; p=0.0093). At 18 months this translated into an OS rate of 58.3% and 44.7% for pembrolizumab + chemotherapy and chemotherapy plus placebo, respectively. In line with what was reported earlier, no significant OS benefit was seen in PD-L1 CPS ≥1 patients (median OS: 17.6 versus 16.0 months; HR [95%CI]: 0.86 [0.72-1.04]; p=0.056) or in the ITT population (median OS: 17.2 versus 15.5 months; HR [95%CI]: 0.89 [0.76-1.05]; p not formally tested).
A further analysis of the data with different CPS cut-offs showed a comparable OS for pembrolizumab + chemotherapy compared to chemotherapy alone for patients with a PD-L1 CPS >1 (HR [95%CI]: 0.97 [0.72-1.32]) and PD-L1 CPS 1-9 (HR [95%CI]: 1.09 [0.85-1.40]). For CPS 10-19 and ≥20 an OS benefit of pembrolizumab + chemotherapy was observed with a HR for OS of 0.71 and 0.72, respectively. The results for PFS were very much in line with what has been described for OS, with a statistically significant benefit of the addition of pembrolizumab to chemotherapy in patients with a PD-L1 CPS 10-19 and ≥20 and no PFS benefit in the CPS <1 and CPS 1-9 subgroups.
With respect to safety, the incidence of grade ≥3 adverse events was similar in both treatment groups at 68.1% with pembrolizumab + chemotherapy and 66.9% with chemotherapy alone. Serious adverse events were reported by 17.8% of patients in the pembrolizumab arm compared to 12.1% in the control arm. Adverse events led to treatment discontinuation in 18.3% of patients in the pembrolizumab + chemotherapy arm while this was the case for 11.0% of patients in the placebo + chemotherapy arm. Grade ≥3 immune related adverse events were reported by 5.3% of patients treated with pembrolizumab + chemotherapy (versus 0% in the control arm.
Combining pembrolizumab with chemotherapy in the first-line treatment of metastatic TNBC patients with a PD-L1 CPS ≥10 resulted in a statistically significant and clinically meaningful improvement in PFS and OS compared to chemotherapy alone The presented analysis with additional CPS cut-offs showed that a PD-L1 CPS ≥10 is a reasonable cut-off to define the population of patients with metastatic TNBC expected to derive a benefit of the addition of pembrolizumab to chemotherapy. As such, these results provide further support for the use of pembrolizumab plus chemotherapy as a new standard of care regimen for patients with PD-L1 expressing, locally recurrent or metastatic TNBC.
Cortés J, et al. Final results of KEYNOTE-355: Randomized, double-blind, phase 3 study of pembrolizumab + chemotherapy vs placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. Presented at SABCS 2021; abstract GS1-02.