Double-positive results for triple-negative metastatic breast cancer

According to results of the KEYNOTE-355 trial, adding pembrolizumab to first-line chemotherapy led to statistically significant improvement in the dual primary endpoints of progression-free survival (PFS) and overall survival (OS) among patients with PD-L1-positive metastatic triple-negative breast cancer. Patients had 27% reduced risk for death, although this was only true for the subset of patients with clearly PD-L1-positive tumours.

Prof. Hope Rugo (University of California, San Francisco, USA) presented the data from the randomised, placebo-controlled, double-blind, phase 3 KEYNOTE-355 trial (NCT02819518), in which untreated patients with locally recurrent inoperable or metastatic triple-negative breast cancer were randomised 2:1 to pembrolizumab (200 mg every 3 weeks) plus chemotherapy (nab-paclitaxel; paclitaxel; or gemcitabine plus carboplatin, n=566) or placebo plus chemotherapy (n=281) [1]. Median age of patients was 53 years. Randomisation was stratified by type of on-study chemotherapy (taxane or gemcitabine/carboplatin), PD-L1 expression at baseline (combined positive score [CPS] ≥1 or <1), and previous treatment with the same class of chemotherapy in the neoadjuvant or adjuvant setting.

Dual primary efficacy endpoints were PFS and OS assessed in the PD-L1 CPS ≥10, CPS ≥1, and intention-to-treat populations. The definitive assessment of PFS was reported earlier [2]; OS was reported for the first time at ESMO 2021. Secondary endpoints included objective response rate (ORR), duration of response, disease control rate, and safety.

At the final data cut-off on 15 June 2021, the median follow-up was 44 months in both groups. The findings revealed a median OS of 23.0 months in the pembrolizumab group versus 16.1 months in the placebo group (HR 0.73; 95% CI 0.55‒0.95; P=0.0093) among patients with a PD-L1 CPS ≥10. The difference in OS among patients with a CPS ≥1 did not meet the prespecified criteria for statistical significance (17.6 vs 16.1 months; HR 0.86; 95% CI 0.72‒1.04; P=0.056). Median OS in the intention-to-treat population was 17.2 months with pembrolizumab versus 15.5 months with placebo (HR 0.89; 95% CI 0.76‒1.05), which did not warrant statistical testing.

Updated PFS results were similar to previously reported interim data [2], with 65.5% in the pembrolizumab group and 78.6% in the placebo group experiencing a PFS event at data cut-off (HR 0.66; 95% CI 0.50‒0.88).

Those with a CPS ≥10 derived the greatest ORR benefit with pembrolizumab versus chemotherapy (52.7% vs 40.8%), followed by patients with a CPS ≥1 (44.9% vs 38.9%), and the intention-to-treat population (40.8% vs 37%). Patients in all 3 groups also had longer duration of response with the pembrolizumab regimen.

Grade 3 or higher treatment-related adverse events occurred among 68.1% of patients in the pembrolizumab group and 66.9% of patients in the placebo group and included anaemia, neutropenia, and nausea. In the pembrolizumab group, 18.3% of patients discontinued the trial due to treatment-related adverse events, as compared with 11% of patients in the chemotherapy group. In total, 2 patients in the pembrolizumab cohort died due to treatment-related adverse events. The safety profile was deemed consistent with previous reports.

In conclusion, pembrolizumab plus chemotherapy showed a significant and clinically meaningful improvement in PFS and OS versus placebo plus chemotherapy among patients with metastatic triple-negative breast cancer and a CPS ≥10. When asked which chemotherapy agent works best with pembrolizumab, Prof. Rugo replied that nab-paclitaxel and paclitaxel were both good options for patients without resistance to taxanes.

1. Rugo HS, et al. KEYNOTE-355: Final results from a randomized, double-blind phase III study of first-line pembrolizumab + chemotherapy vs placebo + chemotherapy for metastatic TNBC. Abstract LBA16, ESMO Congress 2021, 16–21 September.
2. Cortes J, et al. Lancet. 2020;396(10265):1817-1828.

 

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Posted on 19 November, 202115 February, 2024