Development of a Canadian Guidance for Reporting Real-world Evidence for Regulatory and Health-Technology Assessment (HTA) Decision Making.

Real-world evidence (RWE) can complement and fill knowledge gaps from randomized controlled trials to assist in health-technology assessment (HTA) for regulatory decision-making. However, the generation of RWE is an intricate process with many sequential decision points, and different methods and approaches may impact the quality and reliability of evidence. Standardization and transparency in reporting these decisions is imperative to appraise RWE and incorporate it into HTA decision-making. A partnership between Canadian health system stakeholders, namely Health Canada and Canada's Drug Agency (formerly the Canadian Agency for Drugs and Technologies in Health (CADTH)), was established to develop a guidance for standardization of reporting of RWE for regulatory and HTA decision-making in Canada. In this article, we describe the methods to develop the Guidance for Reporting Real-World Evidence document and checklist for reporting RWE for regulatory and HTA decision-making in Canada. This guidance can be adapted for other jurisdictions and will have future extensions to incorporate emerging issues with RWE and HTA decision-making.

Feasibility of structuring electronic health record data to facilitate real-world data research: ICAREdata methods applied to multicenter cancer clinical trials.

BACKGROUND: The use of electronic health record (EHR) data for research is limited by a lack of structure and a standard data model. The objective of the ICAREdata (Integrating Clinical Trials and Real-World Endpoints Data) project was to structure key research data elements in EHRs using a minimal Common Oncology Data Elements (mCODE) data model to extract and transmit data. METHODS: The ICAREdata project captured two EHR data elements essential to clinical trials: cancer disease status and treatment plan change. The project was implemented in clinical sites participating in Alliance for Clinical Trials in Oncology trials. Data were extracted from EHRs and sent by secure Fast Healthcare Interoperability Resource messaging (a standard for exchanging EHRs) to a database. Selected elements were compared with corresponding data from the trial's electronic data capture (EDC) system, Medidata Rave. RESULTS: By December 2023, data were extracted and transmitted from 10 sites for 35 patients, involving 367 clinical encounters across 15 clinical trials. Data through March 2023 demonstrated that concordance for the elements treatment plan change and cancer disease status was 79% and 34%, respectively. When disease evaluation was reported by both EHR and EDC (n = 15), there was 87% agreement on cancer disease status. CONCLUSIONS: Documentation, extraction, and aggregation of structured data elements in EHRs using mCODE and ICAREdata methods is feasible in multi-institutional cancer clinical trials. EDC as a reference data set allowed assessment of the completeness of EHR data capture. Future initiatives will focus on elements with shared definitions in clinical and research environments and efficient workflows. PLAIN LANGUAGE SUMMARY: Clinical trials use electronic case report forms to report data, and data must be manually entered on these forms, which is costly and time consuming. ICAREdata methods use structured, organized data from clinical trials that can be more easily shared instead having to enter free text into electronic health records.

The landscape of use of NCCN-guideline chemotherapy regimens in stage I-IIIA breast cancer in an integrated healthcare delivery system.

PURPOSE: The National Comprehensive Cancer Network (NCCN) guidelines recommend a variety of drug combinations with specific administration schedules for the treatment of early-stage breast cancer, allowing physicians to deliver treatments recognizing individual patient complexities, including comorbidities, and patient-physician preference. While use of guideline regimens has shifted over time, there is little data to describe changes in how treatment for early-stage breast cancer has evolved over time. METHODS: In a cohort of 34,109 women treated for stage I-IIIA breast cancer between 2006-2019 at Kaiser Permanente Northern California and Kaiser Permanente Washington, we present the changes in chemotherapy regimens over time, and explore use of NCCN-guideline regimens (GR), guideline regimens used when said regimens were not included in guidelines, referred to as time-discordant regimens (TDR), and non-guideline regimens (NGR). Results are presented by drug combination and over time. RESULTS: Among 12,506 women receiving chemotherapy, 77.4% (n = 9681) received GRs, 9.1% (n = 1140) received TDRs, and 13.5% (n = 1685) received NGRs. In 2006, AC-T (cyclophosphamide-doxorubicin, paclitaxel) was the most common regimen, with TC (cyclophosphamide-docetaxel) becoming the most prevalent by 2019. NGRs were more common in cyclophosphamide-methotrexate-5-fluorouracil (CMF); cyclophosphamide-doxorubicin-paclitaxel-trastuzumab (ACTH); and paclitaxel-trastuzumab (TH). The use of GR has increased over time (p-trend < 0.001), while use of NGR (both in terms of administration schedule and drug combination) and TDR have decreased, although patterns vary by drug combination. CONCLUSION: Chemotherapy delivery has changed markedly over time, with a move toward more use of GR. These data are important for understanding the landscape of chemotherapy delivery in community healthcare settings.

Externally Controlled Studies Using Real-World Data in Patients With Hematological Cancers: A Systematic Review.

Importance: The use of real-world data (RWD) external control arms in prospective studies is increasing. The advantages, including the immediate availability of a control population, must be balanced with the requirements of meeting evidentiary standards. Objective: To address the question of whether and to what extent the methods of RWD studies compare to standard methods used in randomized clinical trials. Evidence Review: A systematic search across 4 electronic databases and Google Scholar was conducted from January 1, 2000, to October 23, 2023. Studies were included in the systematic review if they compared an intervention arm in a clinical trial to an RWD control arm in patients with hematological cancers and if they were published between 2000 and 2023. Findings: Thirty-two prospective intervention studies incorporating external control data from RWD sources of patients with hematological cancers were identified. A total of 4306 patients from intervention arms and 10 594 from RWD control arms were included across all studies. Only 2 studies (6%) included prospectively collected RWD. The complete trial inclusion criteria were applied to the RWD cohort in 7 studies (22%). Four studies (13%) published the statistical analysis plan and prespecified use of RWD. A total of 23 studies (72%) applied matching algorithms for trial and RWD cohorts, including matching for demographic, disease, and/or therapy-related characteristics. The end point criteria were the same as the trial in 8 studies (25%). In contrast, 12 studies (38%) used different end points, and 12 (38%) did not provide an end point definition for the RWD. Twelve studies (38%) had a median follow-up difference of less than a year between arms. Eight studies (25%) reported toxic effect data for the trial arm, of which 5 studies reported toxic effect data for the RWD arm. Conclusions and Relevance: In this systematic review, limitations were observed in the application of clinical trial eligibility criteria to RWD, statistical rigor and application of matching methods, the definition of end points, follow-up, and reporting of adverse events, which may challenge the conclusions reported in studies using RWD.

Evaluation of Real-World Tumor Response Derived From Electronic Health Record Data Sources: A Feasibility Analysis in Patients With Metastatic Non-Small Cell Lung Cancer Treated With Chemotherapy.

PURPOSE: Real-world data (RWD) holds promise for ascribing a real-world (rw) outcome to a drug intervention; however, ascertaining rw-response to treatment from RWD can be challenging. Friends of Cancer Research formed a collaboration to assess available data attributes related to rw-response across RWD sources to inform methods for capturing, defining, and evaluating rw-response. MATERIALS AND METHODS: This retrospective noninterventional (observational) study included seven electronic health record data companies (data providers) providing summary-level deidentified data from 200 patients diagnosed with metastatic non-small cell lung cancer (mNSCLC) and treated with first-line platinum doublet chemotherapy following a common protocol. Data providers reviewed the availability and frequency of data components to assess rw-response (ie, images, radiology imaging reports, and clinician response assessments). A common protocol was used to assess and report rw-response end points, including rw-response rate (rwRR), rw-duration of response (rwDOR), and the association of rw-response with rw-overall survival (rwOS), rw-time to treatment discontinuation (rwTTD), and rw-time to next treatment (rwTTNT). RESULTS: The availability and timing of clinician assessments was relatively consistent across data sets in contrast to images and image reports. Real-world response was analyzed using clinician response assessments (median proportion of patients evaluable, 77.5%), which had the highest consistency in the timing of assessments. Relative consistency was observed across data sets for rwRR (median 46.5%), as well as the median and directionality of rwOS, rwTTD, and rwTTNT. There was variability in rwDOR across data sets. CONCLUSION: This collaborative effort demonstrated the feasibility of aligning disparate data sources to evaluate rw-response end points using clinician-documented responses in patients with mNSCLC. Heterogeneity exists in the availability of data components to assess response and related rw-end points, and further work is needed to inform drug effectiveness evaluation within RWD sources.

Patient characteristics associated with delayed time to adjuvant chemotherapy among women treated for stage I-IIIA breast cancer.

For patients with breast cancer, delays in chemotherapy initiation have been adversely associated with recurrence and survival. We evaluated patient-level factors associated with delayed chemotherapy initiation, from both diagnosis and surgery, in a community-based cohort of women with early-stage breast cancer. For the Optimal Breast Cancer Chemotherapy Dosing study, we identified a cohort of 34,109 women diagnosed with stage I-IIIA breast cancer at two U.S. integrated healthcare delivery systems between 2004 and 2019. We used logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) to identify patient factors associated with delays in chemotherapy initiation after diagnosis (≥90 days) and surgery (≥60 days). Among 10,968 women receiving adjuvant chemotherapy, 21.1% experienced delays in chemotherapy initiation after diagnosis and 21.3% after surgery. Older age, non-Hispanic Black and Hispanic race and ethnicity, and ER+ and/or PR+ disease were associated with increased likelihood of delays to chemotherapy initiation after diagnosis and surgery. People diagnosed in 2012-2019 (vs. 2005-2011), with a higher grade and larger tumor size were less likely to experience delays. Other factors were associated with a higher likelihood of delays specifically from diagnosis (earlier stage, mastectomy vs. breast-conserving surgery), or surgery (higher comorbidity, increased nodal number). Women diagnosed with breast cancer who were at highest risk of progression and recurrence were less likely to experience delays in chemotherapy initiation after diagnosis and surgery. Understanding reasons for chemotherapy delays beyond patient factors may be potentially important to reduce risk of breast cancer recurrence and progression.

Patient characteristics associated with intended non-guideline chemotherapy in women with stage I-IIIA breast cancer.

BACKGROUND: Guidelines informing chemotherapy regimen selection are based on clinical trials with participants who do not necessarily represent general populations with breast cancer. Understanding who receives non-guideline regimens is important to understanding real-world chemotherapy administration and how it relates to patient outcomes. METHODS: Using data from the Optimal Breast Cancer Chemotherapy Dosing (OBCD) cohort study, based at Kaiser Permanente Northern California (2006-2019) and Kaiser Permanente Washington (2004-2015), we use logistic regression to examine the associations between patient characteristics and receipt of non-NCCN-guideline chemotherapy among 11,293 women with primary stage I-IIIA breast cancer receiving chemotherapy. RESULTS: Use of non-guideline regimens was strongly associated with several factors, including older age (OR≥80 vs 18-39: 5.25, 95%CI: 3.06-9.00)(p-trend=0.002) and human epidermal growth factor-2 status (ORHER2+ vs HER2-: 3.44; 95%CI: 3.06-3.87) and was less likely in women with larger tumor size (OR>5cm vs 0.1-≤0.5cm: 0.56; 95%CI: 0.36-0.87)(p-trend=0.01) and diagnosed in later years (OR2012-2019 vs 2005-2011: 0.80; 95%CI: 0.71-0.90). Factors associated varied by type of non-guideline regimen. For example, women with comorbidity and older age were more likely to receive non-guideline drug combinations in particular, while women with larger tumor size were less likely to receive non-guideline administration schedules. CONCLUSIONS: Non-guideline chemotherapy regimens are more likely in certain patient populations. IMPACT: These associations highlight that vulnerable patient populations may be less likely to receive guideline care and thus real-world studies are essential to understanding how the use of non-guideline regimens impacts patient outcomes in these groups.

Trends in chemotherapy use for early-stage breast cancer from 2006 to 2019.

BACKGROUND: Little is known about how use of chemotherapy has evolved in breast cancer patients. We therefore describe chemotherapy patterns for women with stage I-IIIA breast cancer in the Optimal Breast Cancer Chemotherapy Dosing (OBCD) Study using data from KPNC (Kaiser Permanente Northern California) and KPWA (Kaiser Permanente Washington). FINDINGS: Among 33,670 women, aged 18 + y, diagnosed with primary stage I-IIIA breast cancer at KPNC and KPWA from 2006 to 2019, we explored patterns of intravenous chemotherapy use, defined here as receipt of intravenous cytotoxic drugs and/or anti-HER2 therapies. We evaluated trends in chemotherapy receipt, duration over which chemotherapy was received, and number of associated infusion visits. In secondary analyses, we stratified by receipt of anti-HER2 therapies (trastuzumab and/or pertuzumab), given their longer duration. 38.9% received chemotherapy intravenously, declining from 40.2% in 2006 to 35.6% in 2019 (p-trend < 0.001). Among 13,089 women receiving chemotherapy, neoadjuvant treatment increased (4.1-14.7%; p-trend < 0.001), as did receipt of anti-HER2 therapies (20.8-30.9%) (p-trend < 0.001). The average treatment duration increased (5.3 to 6.0 months; p-trend < 0.001), as did the number of infusion visits (10.8 to 12.5; p-trend < 0.001). For those receiving anti-HER2 therapies, treatment duration and average number of visits decreased; among those not receiving anti-HER2 therapies, number of visits increased, with no change in duration. CONCLUSIONS: While the prevalence of chemotherapy receipt has decreased over time, the use of neoadjuvant chemotherapy has increased, as has use of anti-HER2 therapies; duration and number of administration visits have also increased. Understanding these trends is useful to inform clinical and administrative planning.

Use of quantitative bias analysis to evaluate single-arm trials with real-world data external controls.

PURPOSE: Use of real-world data (RWD) for external controls added to single-arm trials (SAT) is increasingly prevalent in regulatory submissions. Due to inherent differences in the data-generating mechanisms, biases can arise. This paper aims to illustrate how to use quantitative bias analysis (QBA). METHODS: Advanced non-small cell lung cancer (NSCLC) serves as an example, where many small subsets of patients with molecular tumor subtypes exist. First, some sources of bias that may occur in oncology when comparing RWD to SAT are described. Second, using a hypothetical immunotherapy agent, a dataset is simulated based on expert input for survival analysis of advanced NSCLC. Finally, we illustrate the impact of three biases: missing confounder, misclassification of exposure, and outcome evaluation. RESULTS: For each simulated scenario, bias was induced by removing or adding data; hazard ratios (HRs) were estimated applying conventional analyses. Estimating the bias-adjusted treatment effect and uncertainty required carefully selecting the bias model and bias factors. Although the magnitude of each biased and bias-adjusted HR appeared moderate in all three hypothetical scenarios, the direction of bias was variable. CONCLUSION: These findings suggest that QBA can provide an intuitive framework for bias analysis, providing a key means of challenging assumptions about the evidence. However, the accuracy of bias analysis is itself dependent on correct specification of the bias model and bias factors. Ultimately, study design should reduce bias, but QBA allows us to evaluate the impact of unavoidable bias to assess the quality of the evidence.

Methodology for Using Real-World Data From Electronic Health Records to Assess Chemotherapy Administration in Women With Breast Cancer.

PURPOSE: Identification of patients' intended chemotherapy regimens is critical to most research questions conducted in the real-world setting of cancer care. Yet, these data are not routinely available in electronic health records (EHRs) at the specificity required to address these questions. We developed a methodology to identify patients' intended regimens from EHR data in the Optimal Breast Cancer Chemotherapy Dosing (OBCD) study. METHODS: In women older than 18 years, diagnosed with primary stage I-IIIA breast cancer at Kaiser Permanente Northern California (2006-2019), we categorized participants into 24 drug combinations described in National Comprehensive Cancer Network guidelines for breast cancer treatment. Participants were categorized into 50 guideline chemotherapy administration schedules within these combinations using an iterative algorithm process, followed by chart abstraction where necessary. We also identified patients intended to receive nonguideline administration schedules within guideline drug combinations and nonguideline drug combinations. This process was adapted at Kaiser Permanente Washington using abstracted data (2004-2015). RESULTS: In the OBCD cohort, 13,231 women received adjuvant or neoadjuvant chemotherapy, of whom 10,213 (77%) had their intended regimen identified via the algorithm, 2,416 (18%) had their intended regimen identified via abstraction, and 602 (4.5%) could not be identified. Across guideline drug combinations, 111 nonguideline dosing schedules were used, alongside 61 nonguideline drug combinations. A number of factors were associated with requiring abstraction for regimen determination, including: decreasing neighborhood household income, earlier diagnosis year, later stage, nodal status, and human epidermal growth factor receptor 2 (HER2)+ status. CONCLUSION: We describe the challenges and approaches to operationalize complex, real-world data to identify intended chemotherapy regimens in large, observational studies. This methodology can improve efficiency of use of large-scale clinical data in real-world populations, helping answer critical questions to improve care delivery and patient outcomes.

FDA Approval Summary: Alpelisib for PIK3CA-Related Overgrowth Spectrum.

On April 5, 2022, FDA granted accelerated approval to alpelisib for the treatment of adult and pediatric patients 2 years of age and older with severe manifestations of PIK3CA-related overgrowth spectrum (PROS) who require systemic therapy. Efficacy was evaluated using real-world data (RWD) from EPIK-P1 (NCT04285723), a single-arm clinical study in patients 2 years of age and older with severe or life-threatening PROS who received alpelisib as part of an expanded access program (EAP) for compassionate use. The primary endpoint was confirmed radiologic response rate at week 24 as determined by blinded independent central review (BICR), using volumetric-based criteria given the atypical growth pattern and irregular shape of PROS lesions. Radiologic response was defined as a ≥20% reduction from baseline in the sum of measurable target lesion volume in up to three lesions. Of the 37 patients in the efficacy population, 27% [95% confidence interval (CI), 14-44] had a radiologic response at week 24. Duration of response (DOR) was an additional efficacy outcome measure, and among responders, 60% had a response lasting ≥12 months. Furthermore, supportive clinical documentation suggested early signals of clinical benefit (i.e., improvement in PROS-related signs and symptoms). The most common (≥10%) adverse reactions were diarrhea, stomatitis, and hyperglycemia.

Assessment of breast cancer chemotherapy dose reduction in an integrated healthcare delivery system.

PURPOSE: Most cytotoxic drugs are dosed using body surface area (BSA), yet not all cancer patients receive the full BSA-determined dose. Prior work suggests that breast cancer patients who are obese are more likely to experience dose reduction than normal weight patients. However, the factors driving dose reduction remain unclear. METHODS: In 452 women diagnosed with stage I-IIIA primary breast cancer at Kaiser Permanente Northern California, we evaluated the association between obesity and dose reduction, and further explored other factors in relation to dose reduction, including various sociodemographic characteristics, tumor characteristics, and comorbidities. Study participants were a part of the Pathways Study, diagnosed between 2006 and 2013 and treated with cyclophosphamide + doxorubicin, followed by paclitaxel (ACT). Dose reduction was assessed using first cycle dose proportion (FCDP) and average relative dose intensity (ARDI), a metric of dose intensity over the course of chemotherapy. RESULTS: Overall, 8% of participants received a FCDP < 90% and 21.2% had an ARDI < 90%, with dose reduction increasing with body mass index. In adjusted logistic regression models, obese women had 4.1-fold higher odds of receiving an ARDI < 90% than normal weight women (95% CI: 1.9-8.9; p-trend = 0.0006). Increasing age was positively associated with an ADRI < 90%, as was the presence of comorbidity. Dose reduction was less common in later calendar years. CONCLUSION: Results offer insight on factors associated with chemotherapy dosing for a common breast cancer regimen. Larger studies are required to evaluate relevance to other regimens, and further work will be needed to determine whether dose reductions impact outcomes in obese women.

Trends in new and persistent opioid use in older adults with and without cancer.

BACKGROUND: The impact of ongoing efforts to decrease opioid use on patients with cancer remains undefined. Our objective was to determine trends in new and additional opioid use in patients with and without cancer. METHODS: This retrospective cohort study used data from Surveillance, Epidemiology, and End Results program-Medicare for opioid-naive patients with solid tumor malignancies diagnosed from 2012 through 2017 and a random sample of patients without cancer. We identified 238 470 eligible patients with cancer and further focused on 4 clinical strata: patients without cancer, patients with metastatic cancer, patients with nonmetastatic cancer treated with surgery alone ("surgery alone"), and patients with nonmetastatic cancer treated with surgery plus chemotherapy or radiation therapy ("surgery+"). We identified new, early additional, and long-term additional opioid use and calculated the change in predicted probability of these outcomes from 2012 to 2017. RESULTS: New opioid use was higher in patients with cancer (46.4%) than in those without (6.9%) (P < .001). From 2012 to 2017, the predicted probability of new opioid use was more stable in the cancer strata (relative declines: 0.1% surgery alone; 2.4% surgery+; 8.8% metastatic cancer), than in the noncancer stratum (20.0%) (P < .001 for each cancer to noncancer comparison). Early additional use declined among surgery patients (‒14.9% and ‒17.5% for surgery alone and surgery+, respectively) but was stable among patients with metastatic disease (‒2.8%, P = .50). CONCLUSIONS: Opioid prescribing declined over time at a slower rate in patients with cancer than in patients without cancer. Our study suggests important but tempered effects of the changing opioid climate on patients with cancer.

FDA Approval Summary: Ribociclib Indicated for Male Patients with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer.

On December 10, 2021, the FDA expanded the indications for ribociclib to include male patients for the treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer. Ribociclib is now indicated in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy in adult patients, or with fulvestrant as initial endocrine-based therapy or following disease progression on endocrine therapy (ET), in postmenopausal women or in men. The efficacy of ribociclib + AI for male patients was primarily based on previous favorable benefit-risk assessments of ribociclib from MONALEESA-2 and MONALEESA-7 trials, and supported by COMPLEEMENT-1, an open-label, single-arm, multicenter clinical trial, in which 39 male patients (n = 3,246 total patients) received ribociclib + letrozole + goserelin/leuprolide. The overall response rate (ORR) based on confirmed responses in male patients with measurable disease at baseline was 46.9% [95% confidence interval (CI), 29.1-65.3], consistent with an ORR of 43.6% (95% CI, 41.5-45.8) in the overall population. Overall, adverse reactions occurring in male patients were similar to those occurring in female patients treated with ribociclib + ET. The efficacy of ribociclib + fulvestrant for male patients was primarily based on the previous findings of a favorable benefit-risk assessment from the MONALEESA-3 trial, supported by FDA review of clinical data of a limited number of male patients treated in clinical practice receiving ribociclib + fulvestrant. The known mechanism of action, biologic rationale, and clinical information available adequately demonstrate that the efficacy and safety of ribociclib + AI/fulvestrant are similar in male and female patients. This article summarizes the FDA's decision-making and data supporting the approval of ribociclib in male patients with breast cancer, and discusses regulatory insights.

A Descriptive Cohort Study of Drug Utilization Patterns Among Patients Hospitalized With Coronavirus Disease 2019 in the United States, January 2021-February 2022.

Background: There is a dearth of drug utilization studies for coronavirus disease 2019 (COVID-19) treatments in 2021 and beyond after the introduction of vaccines and updated guidelines; such studies are needed to contextualize ongoing COVID-19 treatment effectiveness studies during these time periods. This study describes utilization patterns for corticosteroids, interleukin-6 (IL-6) inhibitors, Janus kinase inhibitors, and remdesivir among hospitalized adults with COVID-19, over the entire hospitalization, and within hospitalization periods categorized by respiratory support requirements. Methods: This descriptive cohort study included United States adults hospitalized with COVID-19 admitted from 1 January 2021 through 1 February 2022; data included HealthVerity claims and hospital chargemaster. The number and distribution of patients were reported for the first 3 drug regimen lines initiated. Results: The cohort included 51 066 patients; the most common initial drug regimens were corticosteroids (23.4%), corticosteroids plus remdesivir (25.1%), and remdesivir (4.4%). IL-6 inhibitors and Janus kinase inhibitors were included in later drug regimens and were more commonly administered with both corticosteroids and remdesivir than with corticosteroids alone. IL-6 inhibitors were more commonly administered than Janus kinase inhibitors when patients received high-flow oxygen or ventilation. Conclusions: These findings provide important context for comparative studies of COVID-19 treatments with study periods extending into 2021 and later. While prescribing generally aligned with National Institutes of Health COVID-19 treatment guidelines during this period, these findings suggest that prescribing preference, potential confounding by indication, and confounding by prior/concomitant use of other therapeutics should be considered in the design and interpretation of comparative studies.

Association between antibiotics and adverse oncological outcomes in patients receiving targeted or immune-based therapy for hepatocellular carcinoma.

Background & Aims: Immune checkpoint inhibitors (ICIs) alone or in combination with other ICIs or vascular endothelial growth factor pathway inhibitors are therapeutic options in unresectable/metastatic hepatocellular carcinoma (HCC). Whether antibiotic (ATB) exposure affects outcome remains unclear. Methods: This study retrospectively analysed an FDA database including 4,098 patients receiving ICI (n = 842) either as monotherapy (n = 258) or in combination (n = 584), tyrosine kinase inhibitor (TKI) (n = 1,968), vascular endothelial growth factor pathway inhibitors (n = 480), or placebo (n = 808) as part of nine international clinical trials. Exposure to ATB within 30 days before or after treatment initiation was correlated with overall survival (OS) and progression-free survival (PFS) across therapeutic modality before and after inverse probability of treatment weighting (IPTW). Results: Of 4,098 patients with unresectable/metastatic HCC, of which 39% were of hepatitis B aetiology and 21% were of hepatitis C aetiology, 83% were males with a median age of 64 years (range 18-88), a European Collaborative Oncology Group performance status of 0 (60%), and Child-Pugh A class (98%). Overall, ATB exposure (n = 620, 15%) was associated with shorter median PFS (3.6 months in ATB-exposed vs. 4.2 months; hazard ratio [HR] 1.29; 95% CI 1.22, 1.36) and OS (8.7 months in ATB-exposed vs. 10.6 months; HR 1.36; 95% CI 1.29, 1.43). In IPTW analyses, ATB was associated with shorter PFS in patients treated with ICI (HR 1.52; 95% CI 1.34, 1.73), TKI (HR 1.29; 95% CI 1.19, 1.39), and placebo (HR 1.23; 95% CI 1.11, 1.37). Similar results were observed in IPTW analyses of OS in patients treated with ICI (HR 1.22; 95% CI 1.08, 1.38), TKI (HR 1.40; 95% CI 1.30, 1.52), and placebo (HR 1.40; 95% CI 1.25, 1.57). Conclusions: Unlike other malignancies where the detrimental effect of ATB may be more prominent in ICI recipients, ATB is associated with worse outcomes in this study across different therapies for HCC including placebo. Whether ATB is causally linked to worse outcomes through disruption of the gut-liver axis remains to be demonstrated in translational studies. Impact and Implications: A growing body of evidence suggests the host microbiome, frequently altered by antibiotic treatment, as an important outcome predictor in the context of immune checkpoint inhibitor therapy. In this study, we analysed the effects of early antibiotic exposure on outcomes in almost 4,100 patients with hepatocellular carcinoma treated within nine multicentre clinical trials. Interestingly, early exposure to antibiotic treatment was associated with worse outcomes not only in patients treated with immune checkpoint inhibitors but also in those treated with tyrosine kinase inhibitors and placebo. This is in contrast to data published in other malignancies, where the detrimental effect of antibiotic treatment may be more prominent in immune checkpoint inhibitor recipients, highlighting the uniqueness of hepatocellular carcinoma given the complex interplay between cirrhosis, cancer, risk of infection, and the pleiotropic effect of molecular therapies for this disease.

Evaluating Pneumonitis Incidence in Patients with Non-small Cell Lung Cancer Treated with Immunotherapy and/or Chemotherapy Using Real-world and Clinical Trial Data.

Pneumonitis is a potentially life-threatening complication of anticancer therapy, and future treatment decisions may be informed by characterizing patients receiving therapies in the real-world setting. In this study, the incidence of treatment-associated pneumonitis (TAP) was compared among patients with advanced non-small cell lung cancer receiving immune checkpoint inhibitors (ICI) or chemotherapies in either of two settings: randomized clinical trials (RCT) or real world data (RWD)-based clinical practice. Pneumonitis cases were identified using International Classification of Diseases codes (for RWD), or the Medical Dictionary for Regulatory Activities preferred terms (for RCTs). TAP was defined as pneumonitis diagnosed during treatment or within 30 days of the last treatment administration. Overall TAP rates in the RWD cohort were lower [ICI: 1.9%; 95% confidence interval (CI), 1.2-3.2; chemotherapy: 0.8%; 95% CI, 0.4-1.6] than overall rates in the RCT cohort (ICI: 5.6%; 95% CI, 5.0-6.2; chemotherapy: 1.2%; 95% CI, 0.9-1.5). Overall RWD TAP rates were similar to grade 3+ RCT TAP rates (ICI: 2.0%; 95% CI, 1.6-2.3; chemotherapy: 0.6%; 95% CI, 0.4-0.9). In both cohorts, higher TAP incidence was observed among patients with a past medical history of pneumonitis than those without, regardless of treatment group. On the basis of this sizable study leveraging RWD, TAP incidence was low in the RWD cohort, likely in part due to methodology used for RWD focusing on clinically significant cases. Past medical history of pneumonitis was associated with TAP in both cohorts. Significance: Pneumonitis is a potentially life-threatening complication of anticancer treatment. As treatment options expand, management decisions become increasingly complex, and there is a greater need to understand the safety profiles of the treatment options in the real-world setting. Real-world data serve as an additional source of valuable information to complement clinical trial data and inform understanding of toxicity in patients with non-small cell lung cancer receiving ICIs or chemotherapies.