HSR22-145: Pembrolizumab Plus Chemotherapy for First-Line Treatment of Advanced Triple-Negative Breast Cancer – A Network Meta-Analysis

Background: Pembrolizumab+chemotherapy (paclitaxel, nab-paclitaxel, or gemcitabine/carboplatin) was recently granted FDA and EMA approval for first-line treatment of locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) in patients whose tumors express PD-L1 at the cut-off of combined positive score (CPS) ≥10 based on statistically and clinically meaningful improvements in overall survival (OS) and progression-free survival (PFS) demonstrated in the phase 3 randomized controlled trial (RCT) KEYNOTE-355. Network meta-analysis (NMA) allows the efficacy of pembrolizumab+chemotherapy relative to other treatments used in this population to be estimated without head-to-head RCT evidence. Methods: A systematic literature review was conducted in July 2021, and searches of the EMBASE, MEDLINE, and CENTRAL databases were performed to identify RCTs evaluating first-line therapies for advanced TNBC. Hand-searches were performed for relevant conference proceedings to identify unindexed RCTs eligible for inclusion. Fixed-effects Bayesian NMAs were used to synthesize hazard ratios (HRs) for OS and PFS. Results: Eight trials (total ITT population: 4,466) evaluating 18 treatment arms were identified. Two trials, KEYNOTE-355 and IMpassion130, evaluated a PD-1 and PD-L1 directed therapy respectively. Evidence networks were constructed with the assumption that PD-1/ PD-L1 status is a relative treatment effect modifier only for PD-1/ PD-L1-directed treatment regimens, and data estimating efficacy in patients with CPS ≥ 10 was used for both immuno-oncology trials. The distribution of other relative treatment effect modifiers was similar between trials. The NMA results showed pembrolizumab+nab-paclitaxel was numerically superior to atezolizumab+nab-paclitaxel for both OS (HR: 0.82 95% Crl: 0.46-1.44) and PFS (HR: 0.80; 95% Crl: 0.46-1.40). NMA showed pembrolizumab+nab-paclitaxel was statistically superior to carboplatin and docetaxel for OS and statistically superior to nab-paclitaxel for PFS. Statistical superiority was also reported for pembrolizumab+paclitaxel compared to paclitaxel (for OS and PFS), paclitaxel+ bevacizumab (for OS) and ixabepilone+bevacizumab (for OS). Conclusions: These analyses suggest pembrolizumab+chemotherapy is an effective treatment in terms of OS and PFS relative to most competing interventions, including atezolizumab+nab-paclitaxel, for first-line treatment of locally recurrent inoperable or metastatic TNBC.