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Proton Pump Inhibitors Affect Atezolizumab Efficacy in Advanced NSCLC

The use of immune checkpoint inhibitors (ICIs) has improved the survival of patients with advanced non-small cell lung cancer (NSCLC) markedly, although the survival benefit among patients is quite heterogeneous. Identifying factors associated with ICI resistance is a hot research topic. One hypothesis is that commonly used non-cancer medications, such as antibiotics and proton pump inhibitors (PPIs) which disrupt the gut flora and cause gut dysbiosis, may lead to reduced ICI efficacy. However, results from studies, including three post-hoc analyses of randomized controlled studies evaluating the association between the use of antibiotics or PPIs and efficacy of ICIs are not conclusive. A recent pooled post-hoc analysis of individual patient data from 5 randomized clinical trials of atezolizumab in advanced NSCLC (IMpower 130, IMpower131, IMpower140, OAK, and POPLAR) aimed to determine whether antibiotic or PPI use modified ICI efficacy.

The pooled cohort included 4458 patients, 2723 that were randomized to atezolizumab-based treatment and 1735 to treatment without atezolizumab. Among patients who received atezolizumab, 194 (7%) received an antibiotic within 30 days prior initiation of atezolizumab and 762 (28%) were taking a PPI on the day of starting ICI. Among patients who received treatment without atezolizumab, 91 (5%) received an antibiotic within 30 days prior treatment and 463 (27%) were taking a PPI on the day they started treatment. Within the pooled cohort, the median follow-up was 19 months. Primary outcomes were progression-free survival (PFS) and overall survival (OS). In addition, an exploratory analysis evaluated the association between antibiotic and PPI use with pretreatment peripheral blood immunophenotype.

The results from the pooled analysis showed that PPI use was associated with decreased atezolizumab efficacy, resulting in inferior OS and PFS compared with patients who were not taking PPIs. In contrast, recent antibiotic use did not impact atezolizumab efficacy. In patients who received atezolizumab, PPI use was associated with worse OS based on a univariable analysis (Hazard Ratio [HR] = 1.30, P < 0.001) and also on an adjusted analysis according to patient, tumor characteristics and PD-L1 expression (HR = 1.23, P < 0.001). This finding was consistent across all randomized trials in first-line chemoimmunotherapy and later-line ICI monotherapy cohorts. Similarly, PPI use was associated with worse PFS on univariable (HR = 1.18, P < 0.001) and adjusted (HR = 1.15, P = 0.01) analyses. Among patients who were randomized to treatment without atezolizumab, the authors observed no association between PPI use and OS (HR = 1.01, P = 0.87) or PFS (HR = 0.95, P = 0.55). Exploratory analysis evaluating peripheral blood immunophenotypes indicated that PPI use was associated with 9%, 18%, and 9% lower pretreatment counts of lymphocytes, CD19+, and CD16+CD56+ immune cells in peripheral blood, respectively (P < 0.01). No significant difference in immune cell counts were observed among patients who received antibiotics before starting atezolizumab, although antibiotic use was associated with 7% higher neutrophil count.

Based on this research, the authors concluded that PPI use is a clinical marker that identifies reduced atezolizumab efficacy. Since approximately 30% of patients with cancer are taking PPIs, there is an urgent need to investigate how they affect the activity of other ICIs, and to develop guidelines for the use of PPI in patients who are being considered for treatment with ICIs. The authors also called for investigations into the impact of H2-receptor antagonists and antacids use on survival outcomes in patients treated with ICIs.

Reference:
Hopkins AM, et al. J Thorac Oncol. 2022 Feb 17. [Online ahead of print].