Effects of concomitant proton pump inhibitor use on immune checkpoint inhibitor efficacy among patients with advanced cancer

Figures & data

Figure 1. Flowchart showing article identification as well as inclusion and exclusion criteria

Table 1. Summary of Studies Included in the Meta-analysis

Author	Year	Country	Histological type	ICIs type	Drug	Treatment line	Total No. of Patients	No. of patients with PPI (%)	Study Endpoint	PPI window respective to ICIs start
Iglesias‑Santamaría. A^Citation22	2020	Spain	Pan-cancer (NSCLC, RCC, bladder cancer, melanoma, and head and neck cancer)	PD-1/L1 inhibitor CTLA-4 inhibitor	Ipilimumab, Nivolumab, Pembrolizumab, Atezolizumab	First, Second or beyond	102	76 (74.5%)	PFS/OS	Within 4 weeks before or after ICIs initiation or any time later
Buti S, et al.^Citation17	2020	Italy	Pan-cancer (NSCLC, melanoma, and RCC)	PD-1/L1 inhibitor CTLA-4 inhibitor	NS	First, Second or beyond	217	104 (47.9%)	OS	Within 30 days before ICIs initiation
Cortellini A, et al.^Citation19	2020	Italy	Pan-cancer (NSCLC, melanoma, and RCC)	PD-1/L1 inhibitor	Pembrolizumab, Nivolumab, Atezolizumab	First, Second or beyond	1012	491 (44.2%)	PFS/OS	Within the 30 days before ICIs initiation
Hopkins AM, et al.^Citation21	2020	Worldwide (IMvigor210, IMvigor211)	Urothelial carcinoma	PD-L1 inhibitor	Atezolizumab	First, second	1360	471 (35.0%)	PFS/OS	Within a period of 30 days prior and 30 days after ICIs initiation
Chalabi M, et al.^Citation18	2020	Worldwide (OAK/POPLAR)	NSCLC	PD-L1 inhibitor	Atezolizumab	Second or beyond	757	234 (30.9%)	PFS/OS	Within a period of 30 days prior and 30 days after ICIs initiation
Hakozaki T, et al.^Citation20	2019	Japan	NSCLC	PD-1 inhibitor	Nivolumab	Second or beyond	90	47 (52.2%)	OS	Within 2 months before and 1 month after ICIs initiation
Zhao, et al.^Citation25	2019	China	NSCLC	PD-1 inhibitor/PD-1 inhibitor plus chemo or apatinib	Pembrolizumab, Nivolumab, Camrelizumab	First, Second or beyond	109	40 (36.7%)	PFS/OS	Within 1 month before and 1 month after ICIs initiation

PFS: progression-free survival; OS: overall survival; RCC: renal cell carcinoma; NSCLC: non-small cell lung cancer; PD-1/L1: programmed death-1/ligand-1; PPI: proton pump inhibitor; NS: not stated.

Figure 2. HRs of PFS(a) and OS(b) in patients receiving ICIs with concomitant PPIs use or not. HRs: Hazard Ratios; PFS: Progression-Free Survival; OS: Overall Survival

Figure 3. Sensitivity analysis for HRs of PFS (a) and OS (b)

Figure 4. Publication bias. (a) Begg’s funnel plot of HR ratios of PFS; (b) Begg’s funnel plot of HR ratio of OS

Iglesias-Santamaria A. Impact of antibiotic use and other concomitant medications on the efficacy of immune checkpoint inhibitors in patients with advanced cancer. Clin Transl Oncol. 2020;22(9):1481–1490. doi:10.1007/s12094-019-02282-w.

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Cortellini A, Tucci M, Adamo V, Stucci LS, Russo A, Tanda ET, Spagnolo F, Rastelli F, Bisonni R, Santini D, et al. Ficorella C and Ascierto PA. Integrated analysis of concomitant medications and oncological outcomes from PD-1/PD-L1 checkpoint inhibitors in clinical practice. J Immunother Cancer. 2020;8:e001361.

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Hopkins AM, Kichenadasse G, Karapetis CS, Rowland A, Sorich MJ. Rowland A and Sorich MJ. concomitant proton pump inhibitor use and survival in urothelial carcinoma treated with atezolizumab. Clin Cancer Res. 2020;26(20):5487–5493. doi:10.1158/1078-0432.CCR-20-1876.

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Chalabi M, Cardona A, Nagarkar DR, Dhawahir Scala A, Gandara DR, Rittmeyer A, Albert ML, Powles T, Kok M, Fg H, et al. Efficacy of chemotherapy and atezolizumab in patients with non-small-cell lung cancer receiving antibiotics and proton pump inhibitors: pooled post hoc analyses of the OAK and POPLAR trials. Ann Oncol. 2020;31(4):525–531. doi:10.1016/j.annonc.2020.01.006.

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Hakozaki T, Okuma Y, Omori M, Hosomi Y. Omori M and Hosomi Y. Impact of prior antibiotic use on the efficacy of nivolumab for non-small cell lung cancer. Oncol Lett. 2019;17(3):2946–2952. doi:10.3892/ol.2019.9899.

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Zhao S, Gao G, Li W, Li X, Zhao C, Jiang T, Jia Y, He Y, Li A, Su C, et al. Chen X and Zhou C. Antibiotics are associated with attenuated efficacy of anti-PD-1/PD-L1 therapies in Chinese patients with advanced non-small cell lung cancer. Lung Cancer. 2019;130:10–17. doi:10.1016/j.lungcan.2019.01.017.

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