Efficacy of PD-1/PD-L1 therapy: Do proton pump inhibitors affect the outcome?

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 208-208
Author(s):  
Sarbajit Mukherjee ◽  
Bilal Khalid ◽  
Sami Ibrahimi ◽  
Jordan Malie Morton ◽  
Darwin Roman ◽  
...  
Keyword(s):  
Proton Pump Inhibitors ◽  
Proton Pump ◽  
Gut Microbiome ◽  
Progression Free Survival ◽  
Significance Level ◽  
Exact Test ◽  
Common Diagnosis ◽  
Significant Difference ◽  
Grade 3 ◽  
Oklahoma Health

208 Background: Recent studies have shown that manipulating the gut microbiome modulates the efficacy of anti-PD1/PD-L1 directed therapy leading to increase in the activity of CD8+ T-cells. Proton Pump inhibitors (PPIs) affect the gut microbiome. The objective of this study was to investigate the effects of PPIs use on agents that target the PD-1/PD-L1 pathway in patients treated with these agents. Methods: We looked at the outcomes of 158 patients aged 18 years or older, treated at the University of Oklahoma Health Sciences Center between 2014 and 2016. The primary aim of this study was to investigate whether survival of patients treated with agents that target PD-1/PD-L1 pathway was affected by PPI use. The secondary objective was to identify if there is any difference in the immune related side effect profile between PPI users and non-users. The overall survival (OS) and progression free survival (PFS) were compared between PPI users and nonusers using the log-rank tests. Survival curves were generated using the Kaplan-Meyer method. The proportions of Grade 3 or 4 colitis or pneumonitis were compared between PPI users and nonusers using the Fisher’s exact test. SAS 9.4 was used for the statistical analysis and a 0.05 significance level was used. Results: The majority of patients were females (57%). The median age was 63 years. Lung cancer was the most common diagnosis (20%) followed by melanoma (20%) and ovarian cancer (12%). Nivolumab was the most commonly used agent (47%) followed by Pembrolizumab (22%), other investigational agents (22%) and Atezolizumab (7%). The median follow-up time from the date of first PPI dose was 7 months. There was no statistically significant difference in OS or PFS between PPI users and nonusers (p = 0.77). There were no significant differences in proportions of Grade 3 or 4 colitis between PPI users and nonusers (5% vs. 5.26%, p > .99). Similarly, there were no significant differences in proportions of Grade 3 or 4 pneumonitis between PPI users and nonusers (6.25% vs. 1.75%, p = 0.40). Conclusions: Use of PPI does not affect the outcome of patients receiving agents that target PD1/PD-L1 pathway. The incidence of important immune related side effects was similar between PPI users and non-users.

Bevacizumab (BEV) plus capecitabine as maintenance therapy after initial treatment with BEV plus XELOX in previously untreated patients (pts) with metastatic colorectal cancer (mCRC): Mature data from STOP and GO, a phase III, randomized, multicenter study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3565-3565 ◽  
Author(s):  
Suayib Yalcin ◽  
Ruchan Uslu ◽  
Faysal Dane ◽  
Ugur Yilmaz ◽  
Nurullah Zengin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Maintenance Therapy ◽  
Objective Response ◽  
Progression Free Survival ◽  
Drop Out ◽  
Phase Iii ◽  
Significance Level ◽  
First Line Therapy ◽  
Significant Difference ◽  
Grade 3

3565 Background: Colorectal cancer is one of the most frequent malignancies, second after breast cancer in women and third after lung cancer and prostate cancer in men. The aim of this study was to evaluate and compare the progression-free survival (PFS) between two arms: Arm A is a combination of BEV + XELOX; Arm B is a combination of BEV + XELOX for 6 cycles followed by maintenance BEV + capecitabine as first-line therapy in mCRC. Methods: BEV (7.5 mg/kg) + XELOX (capecitabine 1000 mg/m2 bid d1–14 + oxaliplatin 130 mg/m2 d1 q3w) were administered until progression (Arm A) or 6 cycles of BEV + XELOX followed by BEV + capecitabine were administered until progression (Arm B). PFS was the primary endpoint; secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. A sample size of 118 pts was required to detect with 80% power an increase of 1.5 months in median PFS between two arms with a standard deviation of 3.9 months and significance level of 0.05 (10% drop-out rate). Results: A total of 123 pts were randomized. Demographic characteristics were balanced between the arms. Median treatment period was 7.5 (range 0.5–13.9) and 8.1 (range 0.1–20.7) months in Arms A and B, respectively. There was a statistically significant difference in median PFS between arms, although there was no significant difference in ORR and OS (see table). Tolerability was acceptable in both arms with the following grade 3/4 adverse events (AEs): Arm A 48.4%; Arm B 34.4% (p=0.116). Grade 3/4 diarrhoea occurred in 9.7% vs. 3.3%, weakness in 8.1% vs. 8.2%, hand-foot syndrome in 3.2% vs. 1.6%, and neuropathy in 4.8% vs. 3.3% of pts in Arms A and B, respectively. Conclusions: These findings suggest that maintenance therapy with BEV + capecitabine following induction with 6 cycles of BEV + XELOX may be superior to continuous BEV + XELOX until progression inpts with previously untreated mCRC. [Table: see text]

What impact do the proton pump inhibitors have on the efficacy of immune check point inhibitors in metastatic malignant melanoma?

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e21040-e21040 ◽  
Author(s):  
Muhammad Zubair Afzal ◽  
Keisuke Shirai
Keyword(s):  
Malignant Melanoma ◽  
Proton Pump Inhibitors ◽  
Proton Pump ◽  
Cox Regression ◽  
Negative Impact ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Progression Free Survival ◽  
Metastatic Malignant Melanoma ◽  
Grade 3

e21040 Background: Acidic microenvironment facilitates the proliferation, progression, and metastasis of the tumors. Mouse models have shown that the proton pump inhibitors (PPI) cause neutralization of the acidic tumor microenvironment (TME) and inhibit the tumor growth. PPI also sensitize the resistant tumors to chemotherapeutic and immunotherapeutic effects. Moreover, PPI’s modify the gut microbiota, that impact the efficacy of immune checkpoint inhibitors (ICI). Clinical studies have shown variable impact of PPI on efficacy of ICI, ranging from no benefit at all to a negative impact. Since, PPI are one of the most commonly used medications, it is important to evaluate its impact on the efficacy of ICI. Methods: We conducted a retrospective analysis on 120 metastatic malignant melanoma patients treated with anti- CTLA-4 (ipilimumab), anti PD-1(pembrolizumab) alone or in combination. Cohort A included patients who were taking PPI at the time of ICI initiation. Cohort B included non-PPI users. Objective response rate (ORR), disease control rate (DCR), overall survival (OS), and progression free survival (PFS) were calculated. ORR and PFS were the primary outcomes. Cox regression univariate and multivariate analyses were performed. The proportions of grade 3 or 4 immune related adverse events (IrAE) were compared between PPI users and nonusers using the Fisher’s exact test. Results: Cohort A included 29 (24.2%) patients, of which 68.7% patients were male. Median age was 65 years. Majority of the patients were taking omeprazole (58.6%). Proportion of the patients taking ipilimumab and pembrolizumab or nivolumab were almost similar (48.3% vs. 44.8%, respectively). Significantly higher proportion of patients achieved ORR and DCR in cohort A [76%, OR = 3.8(1.39 – 10.5), P = 0.009) and 84%, OR = 4.3(1.37 – 13.7), P = 0.013, respectively). The median PFS was significantly higher in cohort A [A = 27.6 vs. B = 4.4 months, HR = 0.3, P = 0.005(0.1 – 0.7)]. Although, median OS was considerably higher in cohort A, the difference was not statistically significant [A = 39.3 vs. B = 28.0 months, HR = 1.01, P = 0.9(0.4-2.0). PPI did not significantly increase the Odds of having grade 3 or 4 IrAE. Conclusions: In this retrospective review, we have observed favorable outcomes in patients receiving PPI when starting on ICI contrary to some of the studies suggesting negative impact of PPI on ICI efficacy. As PPI is one of the commonly used chronic medications, prospective studies are needed to evaluate the real impact of PPI on ICI when taking concomitantly.

Proton pump inhibitors and response to immune check-point inhibitors: Single center study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14092-e14092 ◽  
Author(s):  
Asaad Trabolsi ◽  
Megan Winter ◽  
Estelamari Rodriguez
Keyword(s):  
Lung Cancer ◽  
Retrospective Study ◽  
Proton Pump Inhibitors ◽  
Proton Pump ◽  
Gut Microbiome ◽  
Checkpoint Inhibitors ◽  
Small Cell ◽  
Single Center ◽  
Small Cell Lung ◽  
Significant Difference

e14092 Background: Checkpoint inhibitors (blocking antibodies to PD-1, PD-L1, CTLA-4) have proven effective against several tumor types. While the response is impressive in some patients, we still don’t understand all the patient factors that determine resistance to this class of medication. Studies of host factors have identified composition of the gut microbiome at baseline as a positive predictor of ICI response. Proton pump inhibitors have been reported to interfere with gut microbiome composition. In this single center, retrospective study, we studied the effect of concomitant treatment of proton pump inhibitors on response to ICIs in patients with locally advanced and metastatic cancer. Methods: A retrospective cohort of Non-small cell lung cancer, renal cell carcinoma and Melanoma patients that were treated from January 2016 to May 2018 at the Mount Sinai Medical Center were included in this study. Demographics, prior systemic treatment, performance status, ICI agent, and use of PPI (with in 30 days prior to 30 days after the first dose of ICI administration) were collected. Primary objective of the study was progression free survival (PFS) by utilization of PPIs. PFS was calculated using the log-rank test and survival curve was generated using the Kaplan-Meier method. Information was collected from electronic medical records. Results: Of the 97 patients that met the study criteria, 63 patients had complete data and included in the analysis. 46 patients had Non-small cell lung cancer, 13 had melanoma and 4 renal cancer. Checkpoint inhibitors most commonly prescribed included: Pembrolizumab (29 patients : 46%), Nivolumab (22 patients:35%), Nivolumab + Ipilimumab (9:14 %). 25 patients were taking PPI upon initiation of ICI treatment. In addition, 26 patients received steroids with in 30 days of treatment initiation. There was no statistically significant difference in PFS between patients on PPIs and not on PPIs. The median PFS was 672 days (95% CI: 32, 1311) for PPI users and 341 days (95% CI: 123, 558) for non PPI users. P = 0.244. Conclusions: In this, single-center, retrospective study, we did not detect a significant difference in PFS between patients who used PPI at baseline and patients who did not. Limitations of this study mainly included retrospective analysis, a small sample size, single center population and heterogeneity in disease pathology. We did not collect information on other tumor and treatment related factors like PDL 1 expression, tumor mutation burden, use of antibiotics, and immunotherapy related adverse reactions.

Clinical Impact of Co-medication of Levetiracetam and Clobazam with Proton Pump Inhibitors: A Drug Interaction Study

2020 ◽  
Vol 21 (2) ◽  
pp. 126-131
Author(s):  
Bhuvanachandra Pasupuleti ◽  
Vamshikrishna Gone ◽  
Ravali Baddam ◽  
Raj Kumar Venisetty ◽  
Om Prakash Prasad
Keyword(s):  
Plasma Concentration ◽  
Proton Pump Inhibitors ◽  
Proton Pump ◽  
Plasma Concentrations ◽  
Control Group ◽  
Drug Concentrations ◽  
Significant Difference ◽  
Post Hoc ◽  
Hydrolysis Of ◽  
Cytochrome P 450

Background: Clobazam (CLBZ) metabolized primarily by Cytochrome P-450 isoenzyme CYP3A4 than with CYP2C19, Whereas Levetiracetam (LEV) is metabolized by hydrolysis of the acetamide group. Few CYP enzymes are inhibited by Proton Pump Inhibitors (PPIs) Pantoprazole, Esomeprazole, and Rabeprazole in different extents that could affect drug concentrations in blood. The aim of the present study was to evaluate the effect of these PPIs on the plasma concentrations of LEV and CLBZ. Methods: Blood samples from 542 patients were included out of which 343 were male and 199 were female patients and were categorized as control and test. Plasma samples analyzed using an HPLC-UV method. Plasma concentrations were measured and compared to those treated and those not treated with PPIs. One way ANOVA and games Howell post hoc test used by SPSS 20 software. Results: CLBZ concentrations were significantly 10 folds higher in patients treated with Pantoprazole (P=0.000) and 07 folds higher in patients treated with Esmoprazole and Rabeprazole (P=0.00). Whereas plasma concentration of LEV control group has no statistical and significant difference when compared to pantoprazole (P=0.546) and with rabeprazole and esomeprazole was P=0.999. Conclusion: The effect of comedication with PPIs on the plasma concentration of clobazam is more pronounced for pantoprazole to a greater extent when compared to esomeprazole and rabeprazole. When pantoprazole is used in combination with clobazam, dose reduction of clobazam should be considered, or significance of PPIs is seen to avoid adverse effects.

scholarly journals Evaluation of efficacy and toxicity of nivolumab combined with or without docetaxel in patients with advanced NSCLC

2021 ◽  
Author(s):  
Yang Wang ◽  
Jun Nie ◽  
Ling Dai ◽  
Weiheng Hu ◽  
Jie Zhang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Advanced Nsclc ◽  
Objective Response ◽  
Progression Free Survival ◽  
Meaningful Improvement ◽  
Free Survival ◽  
Significant Difference ◽  
Grade 3 ◽  
Doublet Chemotherapy ◽  
Platinum Doublet

Abstract Background The combination of PD-1/PD-L1 inhibitor and chemotherapy has been clinically confirmed to be beneficial as the first-line treatment of patients with advanced NSCLC. This study aimed to assess the effect of nivolumab + docetaxel versus nivolumab monotherapy in patients with NSCLC after the failure of platinum doublet chemotherapy. Materials and methods The efficacy and toxicity of nivolumab + docetaxel combination therapy versus nivolumab monotherapy were compared in this retrospective study. Primary endpoint of the study was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), overall survival (OS), and toxicity. Results Between November 2017 and December 2019, 77 patients were included in this study, with 58 patients in the nivolumab group and 19 in the nivolumab + docetaxel group. The median follow-up was 18 months, and the PFS was 8 months for patients receiving nivolumab + docetaxel and 2 months for those receiving nivolumab alone (p = 0.001), respectively. Nivolumab + docetaxel showed superior OS compared with nivolumab, with the median OS unreached versus 7 months (p = 0.011). Among patients without EGFR/ALK variation, compared to nivolumab monotherapy, nivolumab + docetaxel showed better PFS (p = 0.04) and OS (p  = 0.05). There was no significant difference in grade 3–4 adverse events (AEs) between the two groups (p = 0.253). Conclusions The combination of nivolumab and docetaxel demonstrated a meaningful improvement in progression-free survival and overall survival compared to nivolumab monotherapy, in patients with NSCLC after the failure of platinum doublet chemotherapy, irrespective of EGFR/ALK variation status.

Proton pump inhibitors and mandibular bone quality: A preliminary study

2021 ◽  
pp. 20200505
Author(s):  
Aykağan Coşgunarslan ◽  
Emin Murat Canger ◽  
Damla Soydan Çabuk
Keyword(s):  
Proton Pump Inhibitors ◽  
Proton Pump ◽  
Fractal Analysis ◽  
Bone Structure ◽  
Study Groups ◽  
Mental Foramen ◽  
Control Group ◽  
Panoramic Radiographs ◽  
Significant Difference ◽  
Bone Changes

Objectives: Proton pump inhibitors (PPI) provide a long-lasting anti-acidic effect by inhibiting the proton pump, and they are one of the most commonly prescribed drugs worldwide. PPIs adversely affect the bone structure via deficiency of vitamins and minerals. The aim of this study was to investigate the possible PPI-induced bone changes in the mandible on panoramic radiographs with the methods of fractal analysis and panoramic morphometric indices. Methods: Panoramic radiographs of 402 patients were used (201 PPI users, 201 control group). Fractal analysis was performed on 4 regions of interests (ROI): 1- upper part of the ramus, 2- angulus, 3- anterior of the mental foramen, 4- distal of the middle ramus. Also, the panoramic mandibular index (PMI), mandibular cortical width (MCW), and Klemetti index (KI) were performed on radiographs. Results: There were significant differences in terms of ROI3, MCW, and KI between the control and study groups (p < 0.05) while there was no significant difference for ROI1, ROI2, ROI4, and PMI (p > 0.05). Males were severely affected than females. Conclusions: Osteoporotic changes were detected in the trabecular and cortical bone in the mental foramen region in PPI users with fractal analysis and morphometric indices, while there were no differences for mandibular ramus and angulus regions according to fractal analysis.

scholarly journals Efficacy and safety of combined androgen blockade with antiandrogen for advanced prostate cancer

2019 ◽  
Vol 26 (1) ◽  
Author(s):  
Y. Yang ◽  
R. Chen ◽  
T. Sun ◽  
L. Zhao ◽  
F. Liu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Efficacy And Safety ◽  
First Line ◽  
Combined Androgen Blockade ◽  
Hazard Ratios ◽  
Significant Difference ◽  
Grade 3 ◽  
Androgen Blockade

Background Combined androgen blockade (cab) is a promising treatment modality for prostate cancer (pca). In the present meta-analysis, we compared the efficacy and safety of first-line cab using an antiandrogen (aa) with castration monotherapy in patients with advanced pca.Methods PubMed, embase, Cochrane, and Google Scholar were searched for randomized controlled trials (rcts) published through 12 December 2016. Hazard ratios (hrs) with 95% confidence intervals (cis) were determined for primary outcomes: overall survival (os) and progression-free survival (pfs). Subgroup analyses were performed for Western compared with Eastern patients and use of a nonsteroidal aa (nsaa) compared with a steroidal aa (saa).Results Compared with castration monotherapy, cab using an aa was associated with significantly improved os (n = 14; hr: 0.90; 95% ci: 0.84 to 0.97; p = 0.003) and pfs (n = 13; hr: 0.89; 95% ci: 0.80 to 1.00; p = 0.04). No significant difference in os (p = 0.71) and pfs (p = 0.49) was observed between the Western and Eastern patients. Compared with castration monotherapy, cab using a nsaa was associated with significantly improved os (hr: 0.88; 95% ci: 0.82 to 0.95; p = 0.0009) and pfs (hr: 0.85; 95% ci: 0.73 to 0.98; p = 0.007)—a result that was not achieved with cab using a saa. The safety profiles of cab and monotherapy were similar in terms of adverse events, including hot flushes, impotence, and grade 3 or 4 events, with the exception of risk of diarrhea and liver dysfunction or elevation in liver enzymes, which were statistically greater with cab using an aa.Conclusions Compared with castration monotherapy, first-line cab therapy with an aa, especially a nsaa, resulted in significantly improved os and pfs, and had an acceptable safety profile in patients with advanced pca.

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