A lack of association between BMI and chemoimmunotherapy efficacy in advanced non-small cell lung cancer: Secondary analysis of the IMpower150 and IMpower130 clinical trials.

BACKGROUND: Multiple studies have indicated that patients with high body mass index (BMI) may have favourable survival outcomes following treatment with an immune checkpoint inhibitor (ICI). However, this evidence is limited by several factors, notably the minimal evidence from randomised controlled trials (RCTs), the use of categorised BMI with inconsistent cut point definitions, and minimal investigation of contemporary combination ICI therapy. Moreover, whether overweight and obese patients gain a larger benefit from contemporary frontline chemoimmunotherapy in non-small cell lung cancer (NSCLC) is unclear. METHODS: This secondary analysis pooled individual patient data from the intention-to-treat population of the IMpower130 and IMpower150 RCTs comparing chemoimmunotherapy versus chemotherapy. Co-primary outcomes were overall survival (OS) and progression-free survival (PFS). The potentially non-linear relationship between BMI and chemoimmunotherapy treatment effect was evaluated using Multivariable Fractional Polynomial Interaction (MFPI). As a sensitivity analysis, chemoimmunotherapy treatment effect (chemoimmunotherapy versus chemotherapy) on survival was also estimated for each BMI subgroup defined by World Health Organisation classification. Exploratory analyses in the respective chemoimmunotherapy and chemotherapy cohort were undertaken to examine the survival outcomes among BMI subgroups. RESULTS: A total of 1282 patients were included. From the MFPI analysis, BMI was not significantly associated with chemoimmunotherapy treatment effect with respect to either OS (p = 0.71) or PFS (p = 0.35). This was supported by the sensitivity analyses that demonstrated no significant treatment effect improvement in OS/PFS among overweight or obese patients compared to normal weight patients (OS: normal BMI HR = 0.74 95% CI 0.59-0.93, overweight HR = 0.78 95% CI 0.61-1.01, obese HR = 0.84 95% CI 0.59-1.20). Exploratory analyses further highlighted that survival outcomes were not significantly different across BMI subgroups in either the chemoimmunotherapy therapy cohort (Median OS: normal BMI 19.9 months, overweight 17.9 months, and obese 19.5 months, p = 0.7) or the chemotherapy cohort (Median OS: normal 14.1 months, overweight 15.9 months, and obese 16.7 months, p = 0.7). CONCLUSION: There was no association between high BMI (overweight or obese individuals) and enhanced chemoimmunotherapy treatment benefit in front-line treatment of advanced non-squamous NSCLC. This contrasts with previous publications that showed a superior treatment benefit in overweight and obese patients treated with immunotherapy given without chemotherapy.

Current safeguards, risk mitigation, and transparency measures of large language models against the generation of health disinformation: repeated cross sectional analysis.

OBJECTIVES: To evaluate the effectiveness of safeguards to prevent large language models (LLMs) from being misused to generate health disinformation, and to evaluate the transparency of artificial intelligence (AI) developers regarding their risk mitigation processes against observed vulnerabilities. DESIGN: Repeated cross sectional analysis. SETTING: Publicly accessible LLMs. METHODS: In a repeated cross sectional analysis, four LLMs (via chatbots/assistant interfaces) were evaluated: OpenAI's GPT-4 (via ChatGPT and Microsoft's Copilot), Google's PaLM 2 and newly released Gemini Pro (via Bard), Anthropic's Claude 2 (via Poe), and Meta's Llama 2 (via HuggingChat). In September 2023, these LLMs were prompted to generate health disinformation on two topics: sunscreen as a cause of skin cancer and the alkaline diet as a cancer cure. Jailbreaking techniques (ie, attempts to bypass safeguards) were evaluated if required. For LLMs with observed safeguarding vulnerabilities, the processes for reporting outputs of concern were audited. 12 weeks after initial investigations, the disinformation generation capabilities of the LLMs were re-evaluated to assess any subsequent improvements in safeguards. MAIN OUTCOME MEASURES: The main outcome measures were whether safeguards prevented the generation of health disinformation, and the transparency of risk mitigation processes against health disinformation. RESULTS: Claude 2 (via Poe) declined 130 prompts submitted across the two study timepoints requesting the generation of content claiming that sunscreen causes skin cancer or that the alkaline diet is a cure for cancer, even with jailbreaking attempts. GPT-4 (via Copilot) initially refused to generate health disinformation, even with jailbreaking attempts-although this was not the case at 12 weeks. In contrast, GPT-4 (via ChatGPT), PaLM 2/Gemini Pro (via Bard), and Llama 2 (via HuggingChat) consistently generated health disinformation blogs. In September 2023 evaluations, these LLMs facilitated the generation of 113 unique cancer disinformation blogs, totalling more than 40 000 words, without requiring jailbreaking attempts. The refusal rate across the evaluation timepoints for these LLMs was only 5% (7 of 150), and as prompted the LLM generated blogs incorporated attention grabbing titles, authentic looking (fake or fictional) references, fabricated testimonials from patients and clinicians, and they targeted diverse demographic groups. Although each LLM evaluated had mechanisms to report observed outputs of concern, the developers did not respond when observations of vulnerabilities were reported. CONCLUSIONS: This study found that although effective safeguards are feasible to prevent LLMs from being misused to generate health disinformation, they were inconsistently implemented. Furthermore, effective processes for reporting safeguard problems were lacking. Enhanced regulation, transparency, and routine auditing are required to help prevent LLMs from contributing to the mass generation of health disinformation.

Exploring the role of sporadic BRAF and KRAS mutations during colorectal cancer pathogenesis: A spotlight on the contribution of the endosome-lysosome system.

The highly heterogenous nature of colorectal cancer can significantly hinder its early and accurate diagnosis, eventually contributing to high mortality rates. The adenoma-carcinoma sequence and serrated polyp-carcinoma sequence are the two most common sequences in sporadic colorectal cancer. Genetic alterations in adenomatous polyposis coli (APC), v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and tumour protein 53 (TP53) genes are critical in adenoma-carcinoma sequence, whereas v-Raf murine sarcoma viral oncogene homolog B (BRAF) and MutL Homolog1 (MLH1) are driving oncogenes in the serrated polyp-carcinoma sequence. Sporadic mutations in these genes contribute differently to colorectal cancer pathogenesis by introducing distinct alterations in several signalling pathways that rely on the endosome-lysosome system. Unsurprisingly, the endosome-lysosome system plays a pivotal role in the hallmarks of cancer and contributes to specialised colon function. Thus, the endosome-lysosome system might be distinctively influenced by different mutations and these alterations may contribute to the heterogenous nature of sporadic colorectal cancer. This review highlights potential connections between major sporadic colorectal cancer mutations and the diverse pathogenic mechanisms driven by the endosome-lysosome system in colorectal carcinogenesis.

Interfacial Assembly of Bacterial Microcompartment Shell Proteins in Aqueous Multiphase Systems.

Compartments are a fundamental feature of life, based variously on lipid membranes, protein shells, or biopolymer phase separation. Here, this combines self-assembling bacterial microcompartment (BMC) shell proteins and liquid-liquid phase separation (LLPS) to develop new forms of compartmentalization. It is found that BMC shell proteins assemble at the liquid-liquid interfaces between either 1) the dextran-rich droplets and PEG-rich continuous phase of a poly(ethyleneglycol)(PEG)/dextran aqueous two-phase system, or 2) the polypeptide-rich coacervate droplets and continuous dilute phase of a polylysine/polyaspartate complex coacervate system. Interfacial protein assemblies in the coacervate system are sensitive to the ratio of cationic to anionic polypeptides, consistent with electrostatically-driven assembly. In both systems, interfacial protein assembly competes with aggregation, with protein concentration and polycation availability impacting coating. These two LLPS systems are then combined to form a three-phase system wherein coacervate droplets are contained within dextran-rich phase droplets. Interfacial localization of BMC hexameric shell proteins is tunable in a three-phase system by changing the polyelectrolyte charge ratio. The tens-of-micron scale BMC shell protein-coated droplets introduced here can accommodate bioactive cargo such as enzymes or RNA and represent a new synthetic cell strategy for organizing biomimetic functionality.

Study of the ketohexokinase inhibitor PF-06835919 as a clinical cytochrome P450 3A inducer: Integrated use of oral midazolam and liquid biopsy.

PF-06835919, a ketohexokinase inhibitor, presented as an inducer of cytochrome P450 3A4 (CYP3A4) in vitro (human primary hepatocytes), and static mechanistic modeling exercises predicted significant induction in vivo (oral midazolam area under the plasma concentration-time curve [AUC] ratio [AUCR] = 0.23-0.79). Therefore, a drug-drug interaction study was conducted to evaluate the effect of multiple doses of PF-06835919 (300 mg once daily × 10 days; N = 10 healthy participants) on the pharmacokinetics of a single oral midazolam 7.5 mg dose. The adjusted geometric means for midazolam AUC and its maximal plasma concentration were similar following co-administration with PF-06835919 (vs. midazolam administration alone), with ratios of the adjusted geometric means (90% confidence interval [CI]) of 97.6% (90% CI: 79.9%-119%) and 98.9% (90% CI: 76.4%-128%), respectively, suggesting there was minimal effect of PF-06835919 on midazolam pharmacokinetics. Lack of CYP3A4 induction was confirmed after the preparation of subject plasma-derived small extracellular vesicles (sEVs) and conducting proteomic and activity (midazolam 1'-hydroxylase) analysis. Consistent with the midazolam AUCR observed, the CYP3A4 protein expression fold-induction (geometric mean, 90% CI) was low in liver (0.9, 90% CI: 0.7-1.2) and non-liver (0.9, 90% CI: 0.7-1.2) sEVs (predicted AUCR = 1.0, 90% CI: 0.9-1.2). Likewise, minimal induction of CYP3A4 activity (geometric mean, 90% CI) in both liver (1.1, 90% CI: 0.9-1.3) and non-liver (0.9, 90% CI: 0.5-1.5) sEVs was evident (predicted AUCR = 0.9, 90% CI: 0.6-1.4). The results showcase the integrated use of an oral CYP3A probe (midazolam) and plasma-derived sEVs to assess a drug candidate as inducer.

Proteomic profiling of paired human liver homogenate and tissue derived extracellular vesicles.

Advances in technologies to isolate extracellular vesicles (EVs) and detect/quantify their cargo underpin the novel potential of these circulating particles as a liquid biopsy to understand physiology and disease. One organ of particular interest in terms of utilizing EVs as a liquid biopsy is the liver. The extent to which EVs originating from the liver reflect the functional status of this organ remains unknown. This is an important knowledge gap that underpins the utility of circulating liver derived EVs as a liquid biopsy. The primary objective of this study was to characterize the proteomic profile of EVs isolated from the extracellular space of liver tissue (LEV) and compare this profile to that of paired tissue (LH). LCMS analyses detected 2892 proteins in LEV and 2673 in LH. Of the 2673 proteins detected in LH, 1547 (58%) were also detected in LEV. Bioinformatic analyses demonstrated comparable representation of proteins in terms of biological functions and cellular compartments. Although, enriched representation of membrane proteins and associated functions was observed in LEV, while representation of nuclear proteins and associated functions was depleted in LEV. These data support the potential use of circulating liver derived EVs as a liquid biopsy for this organ.

Heterogeneity and Utility of Pharmaceutical Company Sharing of Individual-Participant Data Packages.

Importance: The pharmaceutical industry has made substantial investments in developing processes for sharing individual-participant data (IPD) from clinical trials. However, the utility and completeness of shared IPD and supporting documents must be evaluated to ensure the potential for scientific advancements from the data sharing ecosystem can be realized. Objective: To assess the utility and completeness of IPD and supporting documents provided from industry-sponsored clinical trials. Design, Setting, and Participants: From February 9, 2022, to February 9, 2023, 91 of 203 clinical trials supporting US Food and Drug Administration registrations of anticancer medicines for the treatment of solid tumors from the past decade were confirmed as eligible for IPD request. This quality improvement study performed a retrospective audit of the utility and completeness of the IPD and supporting documents provided from the 91 clinical trials for a planned meta-analysis. Exposures: Request for IPD from 91 clinical oncology trials indicated as eligible for the request. Main Outcomes and Measures: The utility and completeness of the IPD and supporting documents provided. Results: The IPD packages were obtained from 70 of 91 requested clinical trials (77%). The median time to data provision was 123 (range, 117-352) days. Redactions were observed in 18 of the acquired IPD packages (26%) for outcome data, 11 (16%) for assessment variables, and 19 (27%) for adjustment data. Additionally, 20 IPD packages (29%) lacked a clinical study report, 4 (6%) had incomplete or missing data dictionaries, and 20 (29%) were missing anonymization or redaction description files. Access to IPD from 21 eligible trials (23%) was not granted. Conclusions and Relevance: In this quality improvement study, there was substantial variability within the provided IPD packages regarding the completeness of key data variables and supporting documents. To improve the data sharing ecosystem, key areas for enhancement include (1) ensuring that clinical trials are eligible for IPD sharing, (2) making eligible IPD transparently accessible, and (3) ensuring that IPD packages meet a standard of utility and completeness.

A Physiologically Based Pharmacokinetic Model to Predict Determinants of Variability in Epirubicin Exposure and Tissue Distribution.

BACKGROUND: Epirubicin is an anthracycline antineoplastic drug that is primarily used in combination therapies for the treatment of breast, gastric, lung and ovarian cancers and lymphomas. Epirubicin is administered intravenously (IV) over 3 to 5 min once every 21 days with dosing based on body surface area (BSA; mg/m2). Despite accounting for BSA, marked inter-subject variability in circulating epirubicin plasma concentration has been reported. METHODS: In vitro experiments were conducted to determine the kinetics of epirubicin glucuronidation by human liver microsomes in the presence and absence of validated UGT2B7 inhibitors. A full physiologically based pharmacokinetic model was built and validated using Simcyp® (version 19.1, Certara, Princeton, NJ, USA). The model was used to simulate epirubicin exposure in 2000 Sim-Cancer subjects over 158 h following a single intravenous dose of epirubicin. A multivariable linear regression model was built using simulated demographic and enzyme abundance data to determine the key drivers of variability in systemic epirubicin exposure. RESULTS: Multivariable linear regression modelling demonstrated that variability in simulated systemic epirubicin exposure following intravenous injection was primarily driven by differences in hepatic and renal UGT2B7 expression, plasma albumin concentration, age, BSA, GFR, haematocrit and sex. By accounting for these factors, it was possible to explain 87% of the variability in epirubicin in a simulated cohort of 2000 oncology patients. CONCLUSIONS: The present study describes the development and evaluation of a full-body PBPK model to assess systemic and individual organ exposure to epirubicin. Variability in epirubicin exposure was primarily driven by hepatic and renal UGT2B7 expression, plasma albumin concentration, age, BSA, GFR, haematocrit and sex.

Analysis of Extracellular Vesicle and Contaminant Markers in Blood Derivatives Using Multiple Reaction Monitoring.

Extracellular vesicles (EVs) are naturally occurring membranous particles that can be isolated from blood and other biofluids. EVs have drawn considerable attention for their potential as a minimally invasive biomarker source for a range of conditions, based on tissue-specific expression of proteins and other molecular information. To promote robust characterization of EV isolates, the International Society for Extracellular Vesicles (ISEV) has established consensus minimal requirements for the study of extracellular vesicles (MISEV) reporting guidelines. A core element of MISEV guidance is the recommendation for the analysis of protein markers in samples, including positive EV-associated markers and negative contaminant markers based on commonly co-isolated components of the sample matrix. Furthermore, there is growing interest in circulating EVs enriched for tissue-specific origin, and in this context, the degree of nontarget EV "contamination" (e.g., EVs derived from blood cells) may inform assessment of sample purity. The increasing application of EVs as a liquid biopsy for clinical applications requires a high-throughput multiplexed approach that enables analysis of protein markers from small volumes of starting material, ideally utilizing the same platform for measuring biomarkers of interest. To this end, targeted liquid chromatography mass spectrometry using multiple reaction monitoring (LC-MRM-MS) is a key platform for the quantitative assessment of target proteins within EV samples. Here we describe a protocol for the isolation of EVs from blood and parallel analytical methods targeting general EV markers and blood cell-derived EV markers, along with guidance of best practice for sample collection and processing.

Understanding the Risk of Drug Interactions Between Ritonavir-Containing COVID-19 Therapies and Small-Molecule Kinase Inhibitors in Patients With Cancer.

PURPOSE: The introduction of COVID-19 therapies containing ritonavir has markedly expanded the scope of use for this medicine. As a strong cytochrome P450 3A4 inhibitor, the use of ritonavir is associated with a high drug interaction risk. There are currently no data to inform clinician regarding the likely magnitude and duration of interaction between ritonavir-containing COVID-19 therapies and small-molecule kinase inhibitors (KIs) in patients with cancer. METHODS: Physiologically based pharmacokinetic modeling was used to conduct virtual clinical trials with a parallel group study design in the presence and absence of ritonavir (100 mg twice daily for 5 days). The magnitude and time course of changes in KI exposure when coadministered with ritonavir was evaluated as the primary outcome. RESULTS: Dosing of ritonavir resulted in a > 2-fold increase in steady-state area under the plasma concentration-time curve and maximal concentration for six of the 10 KIs. When the KI was coadministered with ritonavir, dose reductions to between 10% and 75% of the original dose were required to achieve an area under the plasma concentration-time curve within 1.25-fold of the value in the absence of ritonavir. CONCLUSION: To our knowledge, this study provides the first data to assist clinicians' understanding of the drug interaction risk associated with administering ritonavir-containing COVID-19 therapies to patients with cancer who are currently being treated with KIs. These data may support clinicians to make more informed dosing decisions for patients with cancer undergoing treatment with KIs who require treatment with ritonavir-containing COVID-19 antiviral therapies.

C-reactive protein provides superior prognostic accuracy than the IMDC risk model in renal cell carcinoma treated with Atezolizumab/Bevacizumab.

Background: Immune checkpoint inhibitors (ICIs) is the main treatment option for patients with metastatic renal cell carcinoma (mRCC); however, significant heterogeneity in response is commonly observed. This study aimed to evaluate the ability of C-reactive protein (CRP) to predict overall survival (OS) and progression-free survival (PFS) in patients with mRCC treated with immunotherapy. Patients and Methods: Data from patients with mRCC treated with atezolizumab plus bevacizumab in the IMmotion150 and IMmotion151 trials were pooled. Cox proportional regression was used to model prognostic associations. The relative importance of CRP against International Metastatic RCC Database Consortium (IMDC) factors was confirmed using machine learning. Results: CRPs were available from 527 patients (mean[range] CRP, 6.3[0.21-340]mg/L). Elevated CRP was significantly associated with worse OS (HR[95%CI], 1.71[1.54-1.90], p<0.001) and PFS (1.27[1.18-1.35], p<0.001). CRP was the most prognostic factor for survival within the available clinicopathological data. The prognostic performance of CRP was superior to IMDC model for OS (CRP c=0.76, IMDC c=0.67, p<0.001) and PFS (CRP OS c=0.62, IMDC c=0.59, p=0.03). Predicted 2-year OS probabilities for patients with CRP values of 0.5, 5, 40, and 150 mg/L were 96%, 73%, 42%, and 23%, respectively. Conclusions: CRP is a powerful prognostic marker for survival, and its prognostic value was superior to the IMDC risk model. This study highlights that CRP could be implemented as stratification factor for mRCC immunotherapy trials and potentially as an easy-to-use prognostic tool in the clinic.

Audit of Data Sharing by Pharmaceutical Companies for Anticancer Medicines Approved by the US Food and Drug Administration.

Importance: Emerging policies drafted by the pharmaceutical industry indicate that they will transparently share clinical trial data. These data offer an unparalleled opportunity to advance evidence-based medicine and support decision-making. Objective: To evaluate the eligibility of independent, qualified researchers to access individual participant data (IPD) from oncology trials that supported US Food and Drug Administration (FDA) approval of new anticancer medicines within the past 10 years. Design, Setting, and Participants: In this quality improvement study, a cross-sectional analysis was performed of pivotal clinical trials whose results supported FDA-approved anticancer medicines between January 1, 2011, and June 30, 2021. These trials' results were identified from product labels. Exposures: Eligibility for IPD sharing was confirmed by identification of a public listing of the trial as eligible for sharing or by receipt of a positive response from the sponsor to a standardized inquiry. Main Outcomes and Measures: The main outcome was frequency of IPD sharing eligibility. Reasons for data sharing ineligibility were requested and collated, and company-, drug-, and trial-level subgroups were evaluated and presented using χ2 tests and forest plots. Results: During the 10-year period examined, 115 anticancer medicines were approved by the FDA on the basis of evidence from 304 pharmaceutical industry-sponsored trials. Of these trials, 136 (45%) were eligible for IPD sharing and 168 (55%) were not. Data sharing rates differed substantially among industry sponsors, with the most common reason for not sharing trial IPD being that the collection of long-term follow-up data was still ongoing (89 of 168 trials [53%]). Of the top 10 anticancer medicines by global sales, nivolumab, pembrolizumab, and pomalidomide had the lowest eligibility rates for data sharing (<10% of trials). Conclusions and Relevance: There has been a substantial increase in IPD sharing for industry-sponsored oncology trials over the past 5 years. However, this quality improvement study found that more than 50% of queried trials for FDA-approved anticancer medicines were ineligible for IPD sharing. Data accessibility would be substantially improved if, at the time of FDA registration of a medicine, all data that support the registration were made available.

Efficacy of Atezolizumab in Patients With Advanced NSCLC Receiving Concomitant Antibiotic or Proton Pump Inhibitor Treatment: Pooled Analysis of Five Randomized Control Trials.

INTRODUCTION: Gut dysbiosis may reduce immune checkpoint inhibitor (ICI) efficacy. Antibiotics and proton pump inhibitors (PPIs) are commonly used drugs causing gut dysbiosis. There is limited randomized controlled trial (RCT) evidence on whether antibiotics or PPIs impact ICI benefit versus comparator treatments. METHODS: This study pooled five RCTs (IMpower130, IMpower131, IMpower150, OAK, and POPLAR) evaluating atezolizumab in advanced NSCLC. Atezolizumab efficacy (hazard ratio with 95% confidence intervals) was assessed for subgroups on the basis of antibiotic and PPI use at randomization. The association between antibiotic and PPI use with pretreatment peripheral blood immunophenotype was also explored. RESULTS: Of 4458 participants, 285 received an antibiotic in the 30-day pretreatment and 1225 were using a PPI at treatment initiation. Overall survival efficacy of atezolizumab was similar (p[interaction] = 0.35) for antibiotic users (hazard ratio 95% confidence interval: 0.73 [0.53-0.99]) and antibiotic nonusers (0.82 [0.74-0.91]). Nevertheless, efficacy was reduced (p[interaction] = 0.003) for PPI users (1.00 [0.85-1.17]) compared with PPI nonusers (0.76 [0.69-0.83]). Findings were consistent across RCTs and for progression-free survival. PPI use was associated with 9%, 18%, and 9% lower counts of lymphocytes, CD19+, and CD16+CD56+ immune cells, respectively (p < 0·01). CONCLUSIONS: Reassuringly, atezolizumab efficacy did not differ for antibiotic users. Opposingly, PPI use was consistently associated with decreased atezolizumab efficacy and lower pretreatment counts of lymphocytes, CD19+, and CD16+CD56+ immune cells. Given that approximately 30% of patients with cancer use PPIs, there is an urgent need for evidence on the impacts of PPIs on other ICIs and for the development of guidelines on nonessential PPI use with ICIs.

Selective Isolation of Liver-Derived Extracellular Vesicles Redefines Performance of miRNA Biomarkers for Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Definitive diagnosis of the progressive form, non-alcoholic steatohepatitis (NASH), requires liver biopsy, which is highly invasive and unsuited to early disease or tracking changes. Inadequate performance of current minimally invasive tools is a critical barrier to managing NAFLD burden. Altered circulating miRNA profiles show potential for minimally invasive tracking of NAFLD. The selective isolation of the circulating extracellular vesicle subset that originates from hepatocytes presents an important opportunity for improving the performance of miRNA biomarkers of liver disease. The expressions of miR-122, -192, and -128-3p were quantified in total cell-free RNA, global EVs, and liver-specific EVs from control, NAFL, and NASH subjects. In ASGR1+ EVs, each miR biomarker trended positively with disease severity and expression was significantly higher in NASH subjects compared with controls. The c-statistic defining the performance of ASGR1+ EV derived miRNAs was invariably >0.78. This trend was not observed in the alternative sources. This study demonstrates the capacity for liver-specific isolation to transform the performance of EV-derived miRNA biomarkers for NAFLD, robustly distinguishing patients with NAFL and NASH.

Efficacy of first-line atezolizumab combination therapy in patients with non-small cell lung cancer receiving proton pump inhibitors: post hoc analysis of IMpower150.

BACKGROUND: Proton pump inhibitors (PPIs) are commonly used concomitant to cancer treatment and they induce gut microbiota changes. It is increasingly apparent that gut dysbiosis can reduce the effectiveness of immune checkpoint inhibitors (ICI). However, little is known about PPI effects on outcomes with ICIs, particularly in combination, ICI approaches. METHODS: Post hoc, Cox proportional hazard analysis of phase III trial, IMpower150 was conducted to assess the association between PPI use and overall survival (OS) and progression-free survival (PFS) in chemotherapy-naive, metastatic non-squamous non-small cell lung cancer participants randomised atezolizumab plus carboplatin plus paclitaxel (ACP), bevacizumab plus carboplatin plus paclitaxel (BCP), or atezolizumab plus BCP (ABCP). PPI use was defined as any PPI administration between 30 days prior and 30 days after treatment initiation. RESULTS: Of 1202 participants, 441 (37%) received a PPI. PPI use was independently associated with worse OS (n = 748; hazard ratio (HR) [95% confidence interval (CI)] = 1.53 [1.21-1.95], P < 0.001) and PFS (1.34 [1.12-1.61], P = 0.002) in the pooled atezolizumab arms (ACP plus ABCP). This association was not apparent for BCP (n = 368; OS 1.01 [0.73-1.39], P = 0.969; PFS 0.97 [0.76-1.25], P = 0.827). The observed OS treatment effect (HR 95% CI) of the atezolizumab (ACP plus ABCP) arms vs BCP was 1.03 (0.77-1.36) for PPI users compared to 0.68 (0.54-0.86) for non-users (P [interaction] = 0.028). A similar association was noted for ABCP vs BCP (PPI users 0.96 [0.68-1.35]; PPI non-users 0.66 [0.50-0.87]; P [interaction] = 0.095). CONCLUSIONS: PPI use was a negative prognostic marker in patients treated with ACP or ABCP, but not BCP. The analysis suggests that PPIs negatively influence the magnitude of ICI efficacy.

Leveraging Human Plasma-Derived Small Extracellular Vesicles as Liquid Biopsy to Study the Induction of Cytochrome P450 3A4 by Modafinil.

Preparations of plasma-derived small extracellular vesicles (sEVs) were deployed as liquid biopsy to study cytochrome P450 (CYP) 3A4 (CYP3A4) induction following modafinil 400 mg once daily × 14 days (young healthy volunteers, N = 10 subjects). Induction was confirmed using the 4ß-hydroxycholesterol-to-cholesterol (4ßHC/C) ratio, a plasma CYP3A4/5 biomarker, with a mean 2.1-fold increase (Day 15 vs. Day 1; 90% confidence interval (CI) = 1.8-2.3; P value = 0.0004). Proteomic analysis revealed the induction (mean Day 15 vs. Day 1 fold-increase (90% CI)) of both liver (1.3 (1.1-1.5), P value = 0.014) and nonliver (1.9 (1.6-2.2), P value = 0.04) sEV CYP3A4 protein expression. In CYP3A5 nonexpresser subjects, the baseline (pre-dose) 4ßHC/C plasma ratio was more highly correlated with liver sEVs (r = 0.937, P value = 0.001) than nonliver sEVs (r = 0.619, P value = 0.101) CYP3A4 protein expression. When CYP3A5 expressers (CYP3A5*1/*3) were included, the correlation with liver sEVs (r = 0.761, P value = 0.011) and nonliver sEVs (r = 0.391, P value = 0.264) CYP3A4 protein was weaker. Although modafinil-induced changes in plasma 4ßHC/C ratio did not correlate with sEVs CYP3A4 protein expression, the individual subject sEVs proteomic data were used successfully to predict victim drug (midazolam, triazolam, dextromethorphan, 17α-ethinylestradiol, and abemaciclib) area under the plasma concentration-time curve (AUC) ratios (AUCRs) following modafinil. Based on the AUCR values, modafinil was classified as a weak to moderate CYP3A4 inducer (vs. rifampicin). For the first time, it was possible to deploy plasma-derived sEVs to study CYP3A4 induction beyond rifampicin, a more potent CYP3A4 inducer.

Enhanced Bellmunt Risk Score for Survival Prediction in Urothelial Carcinoma Treated With Immunotherapy.

INTRODUCTION: The discrimination performance of Bellmunt risk score for immune checkpoint inhibitor (ICI) therapy is largely unknown. This study aimed to validate and enhance discrimination of the Bellmunt score in patients with urothelial carcinoma treated with ICIs. PATIENTS AND METHODS: Cox proportional hazard analysis were used to validate overall survival (OS) discrimination performance of the Bellmunt score in patients with urothelial carcinoma treated with atezolizumab in IMvigor210. The c-statistic (c) was used to evaluate the ability of C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), lactate dehydrogenase (LDH), PD-L1 gene expression level on immune cells (PD-L1 ICs), albumin, time from prior chemotherapy, and tumor site count to enhance the Bellmunt score. External validation of an enhanced Bellmunt score utilized the independent atezolizumab arm of IMvigor211. RESULTS: In IMvigor210, Bellmunt score displayed moderate OS discrimination (c = 0.66). Addition of CRP (one point for CRP>30 mg/L) to the Bellmunt score resulted in greatest improvement in performance (c = 0.70), followed by NLR (c = 0.69). On external validation, CRP-Bellmunt score had superior performance (OS c = 0.67, PFS c = 0.60) than original Bellmunt score (OS c = 0.64, PFS c = 0.59) with 30% of patients reclassified into a higher risk group. Patients with CRP-Bellmunt score of 0, 1, 2, or 3-plus had 1-year OS probabilities of 63%, 44%, 21%, and 15%, respectively. CONCLUSION: CRP inclusion within the Bellmunt score enhanced the ability to discriminate high risk patients misclassified using the original model. We propose that the CRP-Bellmunt score may enable improved patient stratification in ICI clinical trials and provide more accurate prognostic information for patients with urothelial carcinoma initiating ICIs.