Identifying subgroups deriving the most benefit from PD-1 checkpoint inhibition plus chemotherapy in advanced metastatic triple-negative breast cancer: a systematic review and meta-analysis.

Background: The combination of immunotherapy and chemotherapy has demonstrated an enhancement in progression-free survival (PFS) for individuals with advanced and metastatic triple-negative breast cancer (TNBC) when compared to the use of chemotherapy alone. Nevertheless, the extent to which different subgroups of metastatic TNBC patients experience this benefit remains uncertain.

Objectives: Our objective was to conduct subgroup analyses to more precisely identify the factors influencing these outcomes.

Materials and methods: The PubMed database was searched until Dec 2023 for studies that compared PD-1 checkpoint inhibitors plus chemotherapy (ICT) with chemotherapy (CT) alone. The primary outcome of interest was progression-free survival (PFS). Review Manager (RevMan) version 5.4. was used for the data analysis.

Results: Four randomized controlled trials (RCTs) comprising 2468 advanced and metastatic TNBC were included in this systematic review and meta-analysis. PFS surge with combined therapy was observed in White (HR 0.80 [0.70, 0.91], p = 0.0007) and Asian ethnicities (HR 0.73 [0.58, 0.93], p = 0.01) but not in Blacks (HR 0.72 [0.42, 1.24], p = 0.24). Overall, patients with distant metastasis demonstrated to derive the PFS benefit from additional immunotherapy (HR 0.87 [0.77, 0.99], p = 0.03); however, metastasis to individual distant site was associated with failure to achieve any treatment difference (Bone: HR 0.79 [0.41, 1.52], p = 0.49; Lung: HR 0.85 [0.70, 1.04], p = 0.11; Liver: HR 0.80 [0.64, 1.01], p = 0.06). While number of metastases > 3 also showed to impact the PFS advantage (HR 0.89 [0.69, 1.16], p = 0.39). While patients, regardless of prior chemotherapy, experienced a notable enhancement in PFS with ICT (Overall: HR 0.79 [0.71, 0.88], p < 0.0001; Yes: HR 0.87 [0.76, 1.00], p = 0.05; No: HR 0.67 [0.56, 0.80], p < 0.00001), those previously exposed to chemotherapy exhibited a significantly smaller PFS advantage compared to those without prior chemotherapy, as evidenced by a significant subgroup difference (Test for subgroup difference: P = 0.02, I2 = 82.2%). Patients lacking PD-L1 expression also failed to achieve any additional benefit from immunotherapy (PD-L1-: HR 0.95 [0.81, 1.12]; p = 0.54; PD-L1+: HR 0.73 [0.64, 0.85], p < 0.0001). Age, ECOG status, and presentation with de novo metastasis/recurrent shown no impact on IT-associated PFS advantage.

Conclusions: Patient- and treatment- related factors such as ethnicity, distant metastases, number of metastases (> 3), previous exposure to chemotherapy and PD-L1 expression, seem to influence or restrict the advantage in progression-free survival associated with the addition of immunotherapy to chemotherapy, as opposed to chemotherapy alone, in patients with advanced and metastatic TNBC. Larger studies are warranted to validate these outcomes.