Impact of antibiotics and proton pump inhibitors on clinical outcomes of immune check point blockers in advanced non-small cell lung cancers and metastatic renal cell cancer.

Abstract

e20520 Background: Studies have suggested that antibiotics can negatively influence efficacy of immune check-point blockers (ICB) but the results are inconsistent. The impact of concomitant proton pump inhibitors (PPI) is not known. We evaluated whether antibiotic and PPI use in patients with advanced non-small-cell lung cancer (NSCLC) and metastatic renal cell cancer (RCC) affects ICB efficacy. Methods: We identified advanced NSCLC and RCC patients treated with anti-PD1/PD-L1 at our institution between 5/2015 to 1/2019. Data regarding systemic antibiotics and PPI use < 1 month or during ICB treatment were collected. The primary outcome was progression free survival (PFS) per response evaluation criteria in solid tumors (RECIST 1.1). Secondary outcomes were overall survival (OS) and objective response rate (ORR). Logistic regression and cox proportional hazards model were used for statistical analysis. Results: 87/148 (58%) and 40/55 (72%) patients received antibiotics and 57/148 (39%) and 17/55 (31%) received PPI < 1 month or during ICI therapy in NSCLC and RCC respectively. In RCC, antibiotic use was associated with inferior PFS (2.9 v 5.0 months, HR = 2.3 95%CI 1.0-5.0; p = 0.04) but OS and ORR were not affected. In NSCLC, antibiotic exposure was associated with superior PFS (5.0 v 2.5 months, HR = 0.5, 95% CI 0.3-0.7; p < 0.01), OS (13.0 v 8.0 months, HR = 0.5, 95% CI 0.3-0.8; p < 0.01) and ORR (33% v 11%, OR = 4.6, p < 0.01). On univariate analysis, there was trend towards inferior OS in NSCLC (9.0 v 13.0 months, p = 0.05) with PPI use. PPI use was not associated with other primary or secondary outcomes in both the cohorts. The antibiotic effect remained significant for PFS in NSCLC and RCC in multivariate analysis. Conclusions: Antibiotic use significantly affected PFS in both NSCLC and RCC. PPI use did not affect outcomes. In contrast to previous studies, this is the first study to show that antibiotic use was associated with favorable outcomes in NSCLC. More studies are needed to explain this association. Future clinical trials with ICB should consider stratification of patients based on antibiotic exposure.

The effect of proton pump inhibitor uses on outcomes for cancer patients treated with immune checkpoint inhibitors: a meta-analysis

“…Recent studies have shown a variable influence of PPIs on the efficacy of ICIs, ranging from no difference to a negative impact (8)(9)(10)(11)(12)(13)(14). Currently, the role of concomitant PPI use on ICIs' therapeutic efficacy remains controversial, thus a meta-analysis may provide a better understanding of this issue.…”

Use of antibiotics is associated with worse clinical outcomes in patients with cancer treated with immune checkpoint inhibitors: A systematic review and meta-analysis

“…The majority of studies included in this systematic review and meta-analysis estimated the impact of antibiotics on OS and PFS. With few exceptions (Bagley et al, 2019;Derosa et al, 2018;Hakozaki et al, 2019;Hogue et al, 2019;Huemer et al, 2019;Iglesias-Santamaria, 2020;Kulkarni et al, 2019;Masini et al, 2019;Svaton et al, 2020), most studies indicated that the use of antibiotics may have a negative impact on OS. Likewise, most studies demonstrated a negative association with PFS; the exceptions were Ahmed et al ( 2018 Hogue et al (2019), Huemer et al (2019, Iglesias-Santamaria (2020), Kulkarni et al (2019), Ouaknine Krief et al (2019), Schett et al (2020), Sen et al (2018) and Svaton et al (2020).…”

“…Seven studies were excluded from the meta-analysis because they provided insufficient information (only median survival in months and not HR, or only qualitative information) to extract data on any of the four outcomes (Dennehy et al, 2018;Greally et al, 2018;Hemadri et al, 2019;Jun et al, 2020;Metges et al, 2018;Resteghini et al, 2019;Riudavets et al, 2019). Forty-one studies were included in the meta-analysis (Abu-Sbeih et al, 2019;Agarwal et al, 2019;Ahmed et al, 2018;Bagley et al, 2019;Barron et al, 2019;Chalabi et al, 2020;Derosa et al, 2018;Do et al, 2018;Elkrief et al, 2019;Facchinetti et al, 2020;Forde et al, 2020;Galli et al, 2019;Guo et al, 2019;Hakozaki et al, 2019;Hogue et al, 2019;Huemer et al, 2019;Iglesias-Santamaria, 2020;Kaderbhai et al, 2017;Kapoor et al, 2020;Kapoor et al, 2019;Khan et al, 2019;Kim et al, 2019;Kulkarni et al, 2019;Lalani et al, 2020;Masini et al, 2019;Mielgo Rubio et al, 2019;Mohiuddin et al, 2021;Ouaknine Krief et al, 2019;Pinato et al, 2019;Rounis et al, 2019;Routy et al, 2018;Schett et al, 2020;…”

“…These observations may be attributed to microbiome dysbiosis and the resultant suppression of the host immune response against neoplastic cells (Routy et al, 2018). However, some studies did not confirm these findings (Iglesias-Santamaria, 2020; Kulkarni et al, 2019), which could be confounded by the lower threshold to initiate and continue antibiotics in sicker patients compared with those who may have a better prognosis.…”

Concomitant of Proton Pump Inhibitors is Associated with Poor Clinical Outcomes in Patients Treated with Immune Checkpoint Inhibitors ：An Up-to-date Systematic Review and Meta-analysis

“…Nguyen et al (12) in a retrospective study including 95 patients with mixed histological tumors (melanoma 47%, head and neck 24%, stomach 18%) showed that PPI was used concomitantly during the course of nivolumab single-agent immunotherapy although there is a difference in tumor response rate compared with the non-PP group, progression-free survival (PFS) and overall survival (OS) do not show statistical differences, but it should still be recommended Reduce unnecessary PPI prescriptions during immunotherapy. Recently a series of relevant clinical studies have shown the efficacy of PPI for ICI is an uncertain factor, which range from no difference to the negative effects (13)(14)(15)(16)(17)(18) . Given the available evidence is mostly retrospective study, unable to infer the use of PPI reliable suggestions.…”