PD-L1 expression as biomarker of efficacy of PD-1/PD-L1 checkpoint inhibitors in metastatic triple negative breast cancer: A systematic review and meta-analysis

Abstract

BackgroundInhibitors of programmed cell death 1 (PD-1)/programmed cell death ligand 1(PD-L1) checkpoint have been approved for metastatic triple negative breast cancer (mTNBC) in patients positive for PD-L1 expression. Negative results from the recent phase III trials (IMPassion131 and IMPassion132) have raises questions on the efficacy of PD-1/PD-L1 checkpoint inhibitors and the predictive value of PD-L1 expression. Here we attempt to systematically analyze the biomarker value of PD-L1 expression for predicting the response of PD-1/PD-L1 checkpoint inhibitors in mTNBC.Materials and methodsPubMed database was searched until Dec 2021 for studies evaluating PD-1/PD-L1 checkpoint inhibitors plus/minus chemotherapy in mTNBC. Outcome of interest included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Review Manager (RevMan) version 5.4. was used for data-analysis.ResultsIn total, 20 clinical trials comprising 3962 mTNBC patients (ICT: 2665 (67%); CT: 1297 (33%) were included in this study. Overall ORR was 22% (95%CI, 14-30%) and significant improvement was observed for PD-L1+ patients (ORR 1.78 [95%CI, 1.45-2.19], p<0.00001) as compared to PD-L1- cohort. Pooled outcome also indicated a significant 1-year PFS and 2-year OS advantage for patients with PD-L1 expression (1-year PFS: ORR 1.39 [95%CI, 1.04-1.85], p=0.02; I2 = 0%; 2-year OS: (ORR 2.47 [95%CI, 1.30-4.69], p=0.006; I2 = 63%). Subgroup analysis indicated that PD-L1 expression can successfully predict tumor response and 2-year OS benefit in mTNBC patients regardless of the type of investigating agent, line of treatment administration, and to some extent the type of treatment. Biomarker ability of PD-L1 expression to predict 1-year PFS was slightly better with pembrolizumab (p=0.09) than atezolizumab (p=0.18), and significantly better when treatment was administered in the first-line setting (OR 1.38 [95%CI, 1.02-1.87], p=0.04) and chemotherapy was added (OR 1.38 [95%CI, 1.02-1.86], p=0.03). Immune-related toxicity of any grade and grade≥3 was 39% (95%CI, 26%-52%) and 10% (95%CI, 8%-13%), respectively.ConclusionsPD-L1 expression can predict objective response rate and 2-year OS in mTNBC patients receiving PD-1/PD-L1 checkpoint inhibitors. One-year PFS is also predicted in selected patients. PD-L1 expression can be a useful biomarker of efficacy of PD-1/PD-L1 checkpoint inhibitors in mTNBC.

The predictive value of PD-L1 expression in response to anti-PD-1/PD-L1 therapy for biliary tract cancer: a systematic review and meta-analysis

“…Interestingly, the predictive value of PD-L1 expression significantly decreased in patients receiving anti-PD-L1 agents compared to those receiving anti-PD-1 agents. This trend has also been observed in carcinomas other than BTC (17,56,57). Further studies are warranted to verify whether the predictive value of PD-L1 expression differs depending on the target of ICIs (PD-1 vs. PD-L1) in cancer immunotherapy.…”

“…In immunotherapy-naïve patients with BTC, PD-L1 expression has been associated with tumor aggressiveness and poor prognosis ( 52 – 54 ). However, with the emergence of cancer immunotherapy, PD-L1 expression has been reported to be a potential predictive biomarker in various types of malignancies ( 16 , 55 , 56 ). Our findings similarly suggest that PD-L1 (+) expression was associated with prolonged PFS and OS, indicating its promise as a predictive biomarker in BTC.…”

Circadian lifestyle determinants of immune checkpoint inhibitor efficacy

“…Although extensive research is aiming at identifying tumour-associated or host-related factors predicting for ICI efficacy or tolerability, most of them are immutable and intrinsic to the patient and the disease, thus potentially impossible to be manipulated (e.g., PD-L1 expression levels) or very hard to be meaningfully modified in a relatively short timeframe (e.g., body mass index) ( 129 ). Similarly, the use of some drugs (e.g., antibiotics, proton-pump inhibitors and obviously steroids) has been shown to impair ICI efficacy in retrospective studies ( 130 ).…”

Triple-negative breast cancer: from none to multiple therapeutic targets in two decades

“…Immunotherapy in TNBC is based on ICIs targeting PD-1 or PD-L1, which facilitate the reactivation of cytotoxic T cells to kill tumor cells. Atezolizumab, pembrolizumab, durvalumab, avelumab, and nivolumab, are examples of monoclonal antibodies designed to bind to PD-L1 or PD-1, inhibiting the axis and enabling the reactivation of T cells (110). The expression of PDL1 is a biomarker for these drugs, particularly in metastatic/advanced disease (65,70).…”