Differential influence of antibiotic therapy and other medications on oncological outcomes of patients with non-small cell lung cancer treated with first-line pembrolizumab versus cytotoxic chemotherapy

Abstract

BackgroundSome concomitant medications including antibiotics (ATB) have been reproducibly associated with worse survival following immune checkpoint inhibitors (ICIs) in unselected patients with non-small cell lung cancer (NSCLC) (according to programmed death-ligand 1 (PD-L1) expression and treatment line). Whether such relationship is causative or associative is matter of debate.MethodsWe present the outcomes analysis according to concomitant baseline medications (prior to ICI initiation) with putative immune-modulatory effects in a large cohort of patients with metastatic NSCLC with a PD-L1 expression ≥50%, receiving first-line pembrolizumab monotherapy. We also evaluated a control cohort of patients with metastatic NSCLC treated with first-line chemotherapy. The interaction between key medications and therapeutic modality (pembrolizumab vs chemotherapy) was validated in pooled multivariable analyses.Results950 and 595 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. Corticosteroid and proton pump inhibitor (PPI) therapy but not ATB therapy was associated with poorer performance status at baseline in both the cohorts. No association with clinical outcomes was found according to baseline statin, aspirin, β-blocker and metformin within the pembrolizumab cohort. On the multivariable analysis, ATB emerged as a strong predictor of worse overall survival (OS) (HR=1.42 (95% CI 1.13 to 1.79); p=0.0024), and progression free survival (PFS) (HR=1.29 (95% CI 1.04 to 1.59); p=0.0192) in the pembrolizumab but not in the chemotherapy cohort. Corticosteroids were associated with shorter PFS (HR=1.69 (95% CI 1.42 to 2.03); p<0.0001), and OS (HR=1.93 (95% CI 1.59 to 2.35); p<0.0001) following pembrolizumab, and shorter PFS (HR=1.30 (95% CI 1.08 to 1.56), p=0.0046) and OS (HR=1.58 (95% CI 1.29 to 1.94), p<0.0001), following chemotherapy. PPIs were associated with worse OS (HR=1.49 (95% CI 1.26 to 1.77); p<0.0001) with pembrolizumab and shorter OS (HR=1.12 (95% CI 1.02 to 1.24), p=0.0139), with chemotherapy. At the pooled analysis, there was a statistically significant interaction with treatment (pembrolizumab vs chemotherapy) for corticosteroids (p=0.0020) and PPIs (p=0.0460) with respect to OS, for corticosteroids (p<0.0001), ATB (p=0.0290), and PPIs (p=0.0487) with respect to PFS, and only corticosteroids (p=0.0033) with respect to objective response rate.ConclusionIn this study, we validate the significant negative impact of ATB on pembrolizumab monotherapy but not chemotherapy outcomes in NSCLC, producing further evidence about their underlying immune-modulatory effect. Even though the magnitude of the impact of corticosteroids and PPIs is significantly different across the cohorts, their effects might be driven by adverse disease features.

Baseline co-medications may alter the anti-tumoural effect of checkpoint inhibitors as well as the risk of immune-related adverse events

“…We noticed differences between cancer types, with a negative impact of several co-medications only observed in melanoma patients highly represented in our cohort. Therefore, focusing on one cancer type with a multicentric design or unplanned pooled post hoc analyses of clinical trials are of interest [41,42]. One may also consider that currently ICI are more often prescribed as first-line treatment, notably in lung cancer patients (only 9 of 150 patients in our cohort), and that previous systemic treatments may represent an additional bias in the interpretation of our results.…”

Prognostic Value of the Pretreatment Lung Immune Prognostic Index in Advanced Small Cell Lung Cancer Patients Treated With First-Line PD-1/PD-L1 Inhibitors Plus Chemotherapy

“…Conversely, the difference in OS between the LIPI good group and LIPI intermediate/poor group is more convincing. In addition, although multivariate analysis took many factors into consideration, other factors not included in the analysis, such as PD-L1, TMB and antibiotic therapy (41), may also affect the final results. We further conducted a subgroup analysis by patients' characteristics, and the results indicated that the LIPI good group had better PFS and OS than the LIPI intermediate/ poor group, especially in subgroups of males, smokers, those with ED, those receiving PD-1 inhibitor treatment, and those with liver metastasis, which revealed that the pretreatment LIPI might be prognostic only for specific subgroups of SCLC patients.…”

The effect of concomitant use of statins, NSAIDs, low-dose aspirin, metformin and beta-blockers on outcomes in patients receiving immune checkpoint inhibitors: a systematic review and meta-analysis

“… 3–6 Cortellini et al further demonstrated that negative impact of antibiotics on ICIs monotherapy but not chemotherapy might be as a result of their underlying immune-modulatory effect, while the effects of corticosteroids and PPIs on clinical outcomes might be driven by adverse disease features. 7 …”