KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer.

Abstract

1000 Background: Pembrolizumab (pembro) monotherapy showed promising antitumor activity and manageable safety in patients (pts) with metastatic TNBC in KEYNOTE-012, -086 and -119. KEYNOTE-355 (ClinicalTrials.gov, NCT02819518) compared pembro + chemotherapy (chemo) vs placebo (pbo) + chemo for previously untreated locally recurrent inoperable or metastatic TNBC. Methods: Pts with ≥6 mo DFI were randomized 2:1 to pembro + chemo (nab-paclitaxel; paclitaxel; or gemcitabine/carboplatin) or pbo + chemo for up to 35 administrations of pembro/pbo or until progression/intolerable toxicity. Pts were stratified by chemo type (taxane vs gemcitabine/carboplatin), PD-L1 status (CPS ≥1 vs <1), and prior (neo)adjuvant treatment with same-class chemo (yes vs no). Dual primary endpoints are PFS (RECIST v1.1, blinded independent central review) and OS by tumor PD-L1 expression (CPS ≥10 and ≥1) and in all pts. PFS was estimated using the Kaplan-Meier method. Stratified log-rank tests were used to assess treatment group differences. HR and 95% CIs were based on a stratified Cox regression model. AEs were monitored throughout the study and graded per NCI CTCAE v4.0. Results: As of Dec 11 2019, median follow-up was 17.5 mo for pembro + chemo (n=566) and 15.5 mo for chemo (n=281). Pembro + chemo significantly improved PFS vs chemo alone in pts with CPS ≥10 tumors (Table), meeting one of the protocol-defined primary objectives. Although the boundary for a statistically significant benefit of pembro + chemo in pts with CPS ≥1 tumors was not met and formal testing in ITT was not performed, the pembro treatment effect increased with PD-L1 enrichment (Table). OS follow-up is ongoing. Grade 3-5 treatment-related AE rates were 68.1% with pembro + chemo (2 deaths) vs 66.9% with chemo (0 deaths); rates of grade 3-4 immune-mediated AEs and infusion reactions were 5.5% vs 0%. Clinical trial information: NCT02819518 . Conclusion: Pembro combined with several chemo partners showed a statistically significant and clinically meaningful improvement in PFS vs chemo alone in pts with previously untreated locally recurrent inoperable or metastatic TNBC whose tumors expressed PD-L1 (CPS ≥10). Pembro + chemo was generally well tolerated, with no new safety concerns. [Table: see text]

Breast Cancer Heterogeneity and Response to Novel Therapeutics

“…Patients with metastatic or locally advanced TNBC with PD-L1 expression on immune cells occupying ≥1% of tumor area have demonstrated survival benefit with combined therapy of Atezolizumab and Nab-Paclitaxel [46]. Similar results were obtained recently with Pembrolizumab, confirming that patients expressing PD-L1 obtain better outcomes [47]. Moreover, it has been shown that PD-L1 expression remains largely unaltered after neoadjuvant chemotherapy [48,49], raising the possibility that adjuvant immune checkpoint inhibitor therapy could improve survival in this patient population.…”

Triple‑negative breast cancer therapy: Current and future perspectives (Review)

“…nab-paclitaxel, paclitaxel or gemcitabine/carboplatin), compared to placebo plus chemotherapy (KEYNOTE-355 Phase III trial, NCT02819518). A significant PFS benefit with the pembrolizumab-chemo combination in patients whose tumors expressed PD-L1 (CPS ≥10) was reported (9.7 vs. 5.6 months for chemotherapy alone) (34). The study is currently in progress to evaluate OS, the other primary endpoint of the trial.…”

Update Breast Cancer 2020 Part 4 – Advanced Breast Cancer

“…Since atezolizumab in combination with nab-paclitaxel is already licensed in the first treatment line for patients with metastatic breast cancer, the results of the KEYNOTE-355 study, which tests the PD-1 antibody pembrolizumab also in the first treatment line, have also been published 45 .…”

“…Die KEYNOTE-355-Studie hat Patienten mit fortgeschrittenen TNBC eingeschlossen, die im metastasierten Stadium noch keine Vorbehandlung hatten. Verglichen wurde eine Kombination aus Chemotherapie und Pembrolizumab mit einer alleinigen Chemotherapie 45 . Als Chemotherapie konnte eingesetzt werden: nab-Paclitaxel, Paclitaxel oder Gemcitabin/Carboplatin.…”

“…ZNS: zentrales Nervensystem; ECOG: Eastern Cooperative Oncology Group; PD-L1: Programmed Death Ligand 1; R: randomisiert; TNBC: triple-negativer Brustkrebs. Modifiziert nach: 45 .…”