Clinical outcomes of concomitant use of proton pump inhibitors and regorafenib in patients with metastatic colorectal cancer: a multicenter study

To compare survival outcomes, response rates, and adverse events (AEs) in proton pump inhibitor (PPI) user and non-user patients with metastatic colorectal cancer (mCRC) treated with regorafenib. We included 272 patients with mCRC treated with regorafenib in this study. Patients were divided into two categories according to their status of PPI use. The primary endpoint was overall survival (OS). The secondary endpoints were time to treatment failure (TTF), response rates, and safety. To exclude immortal time bias in survival analyses, we compared PPI non-user patients and all patients. There were 141 and 131 patients in the PPI non-user and user groups. Baseline characteristics were similar in each group. Pantoprazole was the most used PPI. At the median 35.2 (95% confidence interval (CI): 32.6–37.9) months follow-up, the median OS was similar in PPI non-user and all patients (6.9 months (95% CI: 5.3–8.5) and 7.7 months (95% CI:6.6–8.8), p = 0.913). TTF was also similar in PPI non-user and all patients (3.3 months (95% CI: 2.7–3.9) and 3.5 months (95% CI: 3.0–4.0), p = 0.661). In multivariable analysis, no statistically significant difference was observed between PPI user and non-user groups in OS and TTF (hazard ratio (HR), 0.99; 95% CI, 0.77–1.28; p = 0.963 for OS; HR, 0.93; 0.77–1.20, p = 0.598 for TTF). The objective response rates (ORR) were similar in the PPI non-user and user groups (19.8% and 16.8%, p = 0.455). The rates of any grade AEs were also similar in each group. This study found no worse outcome in the combined use of PPI and regorafenib among patients with mCRC.


Introduction
Regorafenib is one of the oral multi-target tyrosine kinase inhibitors (TKIs) used in the treatment of metastatic colorectal cancer (mCRC), hepatocellular cancer (HCC), and gastrointestinal stromal tumor (GIST) [1][2][3]. For all TKIs, drug-drug interactions due to their oral route administration are substantial for their effectiveness. In addition, the bioavailability of oral TKIs may change with drugs affecting gastric pH [4]. In this regard, one of the main concerns about the bioavailability of TKIs was the combined use of these agents with acid suppression therapies, such as proton pump inhibitors (PPIs) and anti-acids [5,6]. PPIs are usually prescribed to cancer patients for various reasons, such as treating dyspeptic symptoms, gastric bleeding prophylaxis, and preventing gastric damage from chemotherapy and radiotherapy [7,8]. However, acid suppression with PPIs may affect the solubility and bioavailability of TKIs [9][10][11]. Indeed, the proportion of ionized forms of TKIs changes as per gastric pH. Usually, they need an acid environment for more ionization that can be absorbed easier than the non-ionized form [10,11].
However, there were conflicting results regarding the effect of PPI and TKI combinations on the clinical outcomes. For instance, in a study that assessed the impact of combined use of pazopanib and PPIs on survival outcomes and adverse event (AE) profile, no difference was observed between the PPI user and non-user groups [12]. Conversely, a study including patients with HCC treated with TKIs showed increased mortality in the PPI user group [13]. To date, one study evaluated the effect of esomeprazole on the bioavailability of regorafenib and concluded that the bioavailability of regorafenib was similar in PPI non-user and user groups. However, this study did not compare the survival outcomes between the groups [14]. Unfortunately, there is no data on whether regorafenib combined with PPI affects survival and safety outcomes in patients with mCRC.
This study aimed to assess the effect of PPIs on the survival outcomes, response rates, and AE profile in patients with mCRC treated with regorafenib.

Methods
The local ethical committee approved this study in compliance with the "Declaration of Helsinki" and local guidelines.

Patients' cohort and data extraction
Patients with mCRC treated with regorafenib from eight cancer centers in Turkey between January 2015 and December 2021 were included in this multicenter retrospective cohort study. Patients were divided into groups according to their status of PPI use as PPI non-user and user groups. Demographic and clinical data were extracted from the electronic medical record systems and patients' files. Patients who were prescribed PPI at any time after initiation of regorafenib were categorized in the PPI user group.

Endpoints
The primary endpoint was overall survival (OS), calculated from the initiation of regorafenib to the exitus. The secondary endpoints were time to treatment failure (TTF), calculated from the initiation of regorafenib to discontinuation for any reason, response rates, and safety. Response rates were assessed according to "Response evaluation criteria in solid tumors" (RECIST) 1.1. "Common Terminology Criteria for Adverse Events" (CTCAE version 4.03) was used to evaluate AEs.

Statistical analysis
For descriptive analyses, median with interquartile range (IQR) for non-normally distributed continuous variables, mean ± standard deviation for normally distributed continuous variables, and percentages for categorical variables were used. Mann-Whitney U and independent samples t-tests were used to compare two groups for non-normally and normally distributed continuous variables, respectively. Chisquare or Fisher's exact test was used to compare categorical variables. Kaplan-Meier estimates were used to calculate OS and PFS. To exclude immortal time bias, we compared PPI non-user patients with all patients. A log-rank test was used to compare survival curves. Cox's proportional hazard regression model was constructed by using variables with a p value of less than 0.2 in univariable analysis. A p value of less than 0.05 was considered statistically significant. SPSS 27.0 for Mac (IBM Corp., Armonk, NY) and RStudio were used for all statistical analyses.

Baseline characteristics
A total of 272 patients were included in this study. There were 141 and 131 patients in the PPI non-user and user groups, respectively. The median age at starting regorafenib was 61 (IQR:52-67) and 57 (IQR:48-65) in the PPI non-user and user groups. Most patients had an Eastern Cooperative Oncology Group (ECOG) 0 or 1 performance status and had left-sided colon or rectum tumors in each group. A full dose of regorafenib was started in approximately half of the patients, and dose reduction was required in about one out of four patients in the PPI non-user and user groups. Most patients received regorafenib in the third line in each group. All baseline characteristics were similar in the PPI non-user and user groups ( Table 1). The objective response rates (ORR) were similar in the PPI non-user and user groups (19. 8% and 16.8%, p=0.455). The best responses with regorafenib in each group are shown in Table 2.

Safety
The rates of any AEs were similar in PPI non-user and user groups (37.6% vs. 38.9%, p=0.820 for grades 1-2, 21.3% vs. 22.1%, p=0.863). All subtypes of AEs were also similar in each group. All AEs are shown in Table 3.

Discussion
To the best of our knowledge, this was the first study that assessed the effect of PPI use on survival and safety outcomes in patients with mCRC treated with regorafenib. This study revealed no worse impact of PPIs in those patients.
In a study assessing the bioavailability of regorafenib combined with omeprazole, de Man et al. showed no impact of esomeprazole on the bioavailability of regorafenib. This study also established that neither concomitant use nor 3-h interval time between esomeprazole and regorafenib did not affect the bioavailability of regorafenib [14]. However, it should be noticed that the study of de Man et al. did not evaluate the survival outcomes. Drug-drug interactions (DDIs) due to cytochrome P450 (CYP) may also affect the outcomes in patients with cancer treated with anti-cancer therapy [15]. Regorafenib is an inhibitor of various CYP isoenzymes, such as CYP2C8, CYP2C9, and CYP2B6. Generally, PPIs are metabolized by CYP2C19 and CYP3A4 isoenzymes. A clinical probe substrate study showed no drug-drug interactions (DDIs) between regorafenib and omeprazole, a substrate of CYP2C19 [16][17][18]. Our findings were consistent with pharmacokinetic studies assessing the combined use of regorafenib and PPIs. P-glycoprotein is an adenosine triphosphate (ATP) dependent-efflux transporter, which plays a role in multidrug resistance. PPIs decrease the activity of P-glycoprotein by inhibiting ATPase activity. Combined use of PPIs and substrates of P-glycoprotein may result in increased activity of P-glycoprotein substrates [18,19]. A pre-clinical study demonstrated the effect of inhibitors and inducers of P-glycoprotein in the active metabolites of regorafenib. However, the clinical importance of this effect is not clear [16,20]. At that point, our study is important because it evaluated the clinical outcomes of the combined use of PPIs and regorafenib.
Abdominal symptoms and dyspepsia are common in advanced cancer patients, and the rate of PPI use in those patients is high [21]. In addition to symptom control, PPIs protect gastric damage from steroids, radiation, and  [8]. However, the results for interaction between the PPIs and TKIs are usually extrapolated from the studies, including patients with non-CRC treated with regorafenib. In this regard, a study by Wu et al. compared the PPI non-user and user groups in patients with HCC treated with TKIs, such as sorafenib, regorafenib, lenvatinib, and cabozantinib. This study showed that the mortality rate was higher in the PPI user group than in the PPI non-user group [22]. Of note, this study was critical as it demonstrated the effect of TKIs and PPIs interaction on the survival outcomes. However, we did not show the impact of PPIs on the survival outcomes of regorafenib. Patients receiving various TKIs and PPIs were included in the study of Wu et al. It might explain the difference between the results [22].
PPIs may also have an impact on anti-cancer therapies based on the changes in the gut microbiome. The gut microbiome has an essential role in the immune system. Decreasing bacterial diversity may negatively affect immunity, thus response to anti-cancer therapies. However, this interaction is usually observed in patients with cancer treated with immune checkpoint inhibitors [23].
It is well known that PPIs may cause diarrhea [24]. Several mechanisms, such as microscopic colitis and Clostridium difficile infection, may play a role in PPI-related diarrhea [25,26]. However, the rate of patients who reported diarrhea among PPI non-user and PPI user groups were similar in our study. Furthermore, the rates of all AEs were similar in PPI non-user and user groups.
A study by Xie et al. concluded that chronic PPI use increases mortality in the general population [27]. However, our results did not confirm this data. Indeed, our patients did not receive PPIs for the time required to see the chronic effects of those drugs.
Our study has several limitations, mainly based on its retrospective nature. We did not have data regarding antiacids received without a prescription. Furthermore, we did not know the PPI indications of included patients. We did not assess the duration of PPI use and patients' daily receiving time. It should be noted that the interval time of regorafenib and PPI receiving may affect the bioavailability of regorafenib. Despite the retrospective and observational nature of our study, we had more than one endpoint.  In conclusion, this study found no worse outcome in the combined use of PPI and regorafenib among patients with mCRC. Although it is hard to suggest that PPIs are entirely safe in those patients with the results of this retrospective study, they can be used in special conditions where they must be used.
Data availability All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.