Targeting KRAS G12C Mutation in Colorectal Cancer, A Review: New Arrows in the Quiver.

Kirsten rat sarcoma virus oncogene homolog (KRAS) is the most frequently mutated oncogene in human cancer. In colorectal cancer (CRC), KRAS mutations are present in more than 50% of cases, and the KRAS glycine-to-cysteine mutation at codon 12 (KRAS G12C) occurs in up to 4% of patients. This mutation is associated with short responses to standard chemotherapy and worse overall survival compared to non-G12C mutations. In recent years, several KRAS G12C inhibitors have demonstrated clinical activity, although all patients eventually progressed. The identification of negative feedback through the EGFR receptor has led to the development of KRAS inhibitors plus an anti-EGFR combination, thus boosting antitumor activity. Currently, several KRAS G12C inhibitors are under development, and results from phase I and phase II clinical trials are promising. Moreover, the phase III CodeBreaK 300 trial demonstrates the superiority of sotorasib-panitumumab over trifluridine/tipiracil, establishing a new standard of care for patients with colorectal cancer harboring KRAS G12C mutations. Other combinations such as adagrasib-cetuximab, divarasib-cetuximab, or FOLFIRI-panitumumab-sotorasib have also shown a meaningful response rate and are currently under evaluation. Nonetheless, most of these patients will eventually relapse. In this setting, liquid biopsy emerges as a critical tool to characterize the mechanisms of resistance, consisting mainly of acquired genomic alterations in the MAPK and PI3K pathways and tyrosine kinase receptor alterations, but gene fusions, histological changes, or conformational changes in the kinase have also been described. In this paper, we review the development of KRAS G12C inhibitors in colorectal cancer as well as the main mechanisms of resistance.

Cetuximab as a Key Partner in Personalized Targeted Therapy for Metastatic Colorectal Cancer.

Cetuximab, a chimeric IgG1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has revolutionized personalized treatment of metastatic colorectal cancer (mCRC) patients. This review highlights the mechanism of action, characteristics, and optimal indications for cetuximab in mCRC. Cetuximab has emerged as a pivotal partner for novel therapies in specific molecular subgroups, including BRAF V600E, KRAS G12C, and HER2-altered mCRC. Combining cetuximab with immunotherapy and other targeted agents further expands the therapeutic landscape, offering renewed hope for mCRC patients who face the development of resistance to conventional therapies. Ongoing clinical trials have continued to uncover innovative cetuximab-based treatment strategies, promising a brighter future for mCRC patients. This review provides a comprehensive overview of cetuximab's role and its evolving importance in personalized targeted therapy of mCRC patients, offering valuable insights into the evolving landscape of colorectal cancer treatment.

Disparities in Preoperative Goals of Care Documentation in Veterans.

Importance: Preoperative goals of care discussion and documentation are important for patients undergoing surgery, a major health care stressor that incurs risk. Objective: To assess the association of race, ethnicity, and other factors, including history of mental health disability, with disparities in preoperative goals of care documentation among veterans. Design, Setting, and Participants: This retrospective cross-sectional study assessed data from the Veterans Healthcare Administration (VHA) of 229 737 veterans who underwent surgical procedures between January 1, 2017, and October 18, 2022. Exposures: Patient-level (ie, race, ethnicity, medical comorbidities, history of mental health comorbidity) and system-level (ie, facility complexity level) factors. Main Outcomes and Measures: Preoperative life-sustaining treatment (LST) note documentation or no LST note documentation within 30 days prior to or on day of surgery. The standardized mean differences were calculated to assess the magnitude of differences between groups. Odds ratios (ORs) and 95% CIs were estimated with logistic regression. Results: In this study, 13 408 patients (5.8%) completed preoperative LST from 229 737 VHA patients (209 123 [91.0%] male; 20 614 [9.0%] female; mean [SD] age, 65.5 [11.9] years) who received surgery. Compared with patients who did complete preoperative LST, patients tended to complete preoperative documentation less often if they were female (19 914 [9.2%] vs 700 [5.2%]), Black individuals (42 571 [19.7%] vs 2416 [18.0%]), Hispanic individuals (11 793 [5.5%] vs 631 [4.7%]), or from rural areas (75 637 [35.0%] vs 4273 [31.9%]); had a history of mental health disability (65 974 [30.5%] vs 4053 [30.2%]); or were seen at lowest-complexity (ie, level 3) facilities (7849 [3.6%] vs 78 [0.6%]). Over time, despite the COVID-19 pandemic, patients undergoing surgical procedures completed preoperative LST increasingly more often. Covariate-adjusted estimates of preoperative LST completion demonstrated that patients of racial or ethnic minority background (Black patients: OR, 0.79; 95% CI, 0.77-0.80; P <.001; patients selecting other race: OR, 0.78; 95% CI, 0.74-0.81; P <.001; Hispanic patients: OR, 0.78; 95% CI, 0.76-0.81; P <.001) and patients from rural regions (OR, 0.91; 95% CI, 0.90-0.93; P <.001) had lower likelihoods of completing LST compared with patients who were White or non-Hispanic and patients from urban areas. Patients with any mental health disability history also had lower likelihood of completing preoperative LST than those without a history (OR, 0.93; 95% CI, 0.92-0.94; P = .001). Conclusions and Relevance: In this cross-sectional study, disparities in documentation rates within a VHA cohort persisted based on race, ethnicity, rurality of patient residence, history of mental health disability, and access to high-volume, high-complexity facilities.

The impact of clinical and translational research on the quality of life during the metastatic colorectal cancer patient journey.

The journey of metastatic colorectal cancer patients is complex and challenging, requiring coordination and collaboration between multiple healthcare providers. Understanding patients' needs, fears, feelings, concerns, and behaviors is essential for providing individualized patient-centered care. In recent years, mCRC patients have experienced improvements in clinical outcomes, from 16 months of overall survival to 32 months, thanks to research. However, there is still room for improvement, and integrating clinical and translational research into routine practice can help patients benefit from treatments and techniques that would not be an option. In the Journey of mCRC patients, living well with cancer and quality of life becomes a priority given the outcomes of the disease. Patient reported outcomes (PRO) and Patient Reported Outcome Measures (PROMs) are becoming therefore new estimands in Oncology. Patient advocates represent important figures in this process by prioritizing issues and research questions; evaluating research designs and the performance of the research; the analysis and interpretation of data; and how results are disseminated. Multidisciplinary Tumor Boards and shared decision-making is essential for designing treatment strategies for individual patients. Quality of Life is often prioritized only when it comes to refractory advanced disease and end-of-life care, but it has to be integrated from the beginning, as the emotional impact of diagnosis leads to a vulnerable situation where patients' needs and preferences can be easily overseen. First-line treatment will be chosen among more treatment options than subsequent lines, with longer progression-free survival and a bigger impact on the outcomes. Practicing patient-centered care and optimizing first-line treatment for colorectal cancer patients requires a comprehensive understanding of patient experience and treatment outcomes, which can guide clinical practice and inform regulatory decisions for the benefit of patients.

Major Adverse Dystrophinopathy Events (MADE) Score as Marker of Cumulative Morbidity and Risk for Mortality in Boys with Duchenne Muscular Dystrophy.

Background: Overlapping symptoms from cardiomyopathy, respiratory insufficiency, and skeletal myopathy confound assessment of heart failure in Duchenne Muscular Dystrophy. We developed an ordinal scale of multiorgan clinical variables that reflect cumulative disease burden-the Major Adverse Dystrophinopathy Event (MADE) Score. We hypothesized that a higher MADE score would be associated with increased mortality in boys with Duchenne Muscular Dystrophy. The Cooperative International Neuromuscular Research Group Duchenne Natural History Study dataset was utilized for validation. Methods: Duchenne Natural History Study variables were selected based on clinical relevance to prespecified domains: Cardiac, Pulmonary, Myopathy, Nutrition. Severity points (0-4) were assigned and summed for study visits. MADE score for cohorts defined by age, ambulatory status, and survival were compared at enrollment and longitudinally.Associations between MADE score and mortality were examined. Results: Duchenne Natural History Study enrolled 440 males, 12.6 ±6.1 years old, with 3,559 visits over 4.6 ±2.8 years, 45 deaths. MADE score increased with age and nonambulatory status. Mean MADE score per visit was 19 ±10 for those who died vs. 9.8 ±9.3 in survivors p=0.03. Baseline MADE score >12 predicted mortality independent of age (78% sensitivity, CPE.70). Rising MADE score trajectory was associated with mortality in models adjusted for enrollment age, follow-up time, and ambulatory status, all p<.001. Conclusion: A multiorgan severity score, MADE, was developed to track cumulative morbidities that impact heart failure in Duchenne muscular dystrophy. MADE score predicted Duchenne Natural History Study mortality. MADE score can be used for serial heart failure assessment in males and may serve as an endpoint for Duchenne muscular dystrophy clinical research.

Air Medical Transport for Acute Ischemic Stroke Patients: A Retrospective Cohort Study of National Trends Over an 8-Year Period.

OBJECTIVE: Optimal management of ischemic stroke is time dependent. An understanding of patterns of air medical transport may identify disparities that could affect patient care. METHODS: In this 8-year (2007-2014) observational, retrospective, cohort study, we abstracted a 20% national sample of Medicare data from patients ≥ 66 years of age hospitalized with a primary diagnosis of acute ischemic stroke who presented to the emergency department by ambulance (air or ground). RESULTS: Among 149,751 hospitalized stroke patients who arrived by ambulance, the mean age was 81.6 years (standard deviation = 8.0 years), 62.1% were female (n = 93,007), and 86.3% were White (n = 129,268). Of these, 5,534 patients (3.7%) used any form of air ambulance. Air ambulance use (2007: 2.5%, 2014: 4.9%; P < .001) and arrival at certified stroke centers (2007: 40.3%, 2014: 63.2%; P < .001) increased over time. Air ambulance use was less likely among older patients (76-85 years and >85 years vs. 66-75 years; odds ratio [OR] = 0.68; 95% confidence interval [CI], 0.64-0.72 and OR = 0.34; 95% CI, 0.32-0.37, respectively) and all racial minorities except American Natives (OR = 2.07; 95% CI, 1.57-2.73) and more likely among sicker patients (Charlson Comorbidity Index ≥ 2 vs. 1, OR = 1.23; 95% CI, 1.09-1.38) and rural residents (OR = 1.34; 95% CI, 1.09-1.64). After adjustment for covariates, air ambulance use was associated with higher odds of thrombolysis (adjusted OR = 2.57; 95% CI, 2.38-2.79). CONCLUSION: Air ambulance use is independently associated with increased thrombolysis use for stroke, but disparities exist in both air ambulance and thrombolysis use. Further research into underlying causes for these disparities would be beneficial for systems and public health-based interventions for improving outcomes for ischemic stroke.

The evolving role of data & safety monitoring boards for real-world clinical trials.

Introduction: Clinical trials provide the "gold standard" evidence for advancing the practice of medicine, even as they evolve to integrate real-world data sources. Modern clinical trials are increasingly incorporating real-world data sources - data not intended for research and often collected in free-living contexts. We refer to trials that incorporate real-world data sources as real-world trials. Such trials may have the potential to enhance the generalizability of findings, facilitate pragmatic study designs, and evaluate real-world effectiveness. However, key differences in the design, conduct, and implementation of real-world vs traditional trials have ramifications in data management that can threaten their desired rigor. Methods: Three examples of real-world trials that leverage different types of data sources - wearables, medical devices, and electronic health records are described. Key insights applicable to all three trials in their relationship to Data and Safety Monitoring Boards (DSMBs) are derived. Results: Insight and recommendations are given on four topic areas: A. Charge of the DSMB; B. Composition of the DSMB; C. Pre-launch Activities; and D. Post-launch Activities. We recommend stronger and additional focus on data integrity. Conclusions: Clinical trials can benefit from incorporating real-world data sources, potentially increasing the generalizability of findings and overall trial scale and efficiency. The data, however, present a level of informatic complexity that relies heavily on a robust data science infrastructure. The nature of monitoring the data and safety must evolve to adapt to new trial scenarios to protect the rigor of clinical trials.

Unravelling the Complexity of Colorectal Cancer: Heterogeneity, Clonal Evolution, and Clinical Implications.

Colorectal cancer (CRC) is a global health concern and a leading cause of death worldwide. The disease's course and response to treatment are significantly influenced by its heterogeneity, both within a single lesion and between primary and metastatic sites. Biomarkers, such as mutations in KRAS, NRAS, and BRAF, provide valuable guidance for treatment decisions in patients with metastatic CRC. While high concordance exists between mutational status in primary and metastatic lesions, some heterogeneity may be present. Circulating tumor DNA (ctDNA) analysis has proven invaluable in identifying genetic heterogeneity and predicting prognosis in RAS-mutated metastatic CRC patients. Tumor heterogeneity can arise from genetic and non-genetic factors, affecting tumor development and response to therapy. To comprehend and address clonal evolution and intratumoral heterogeneity, comprehensive genomic studies employing techniques such as next-generation sequencing and computational analysis are essential. Liquid biopsy, notably through analysis of ctDNA, enables real-time clonal evolution and treatment response monitoring. However, challenges remain in standardizing procedures and accurately characterizing tumor subpopulations. Various models elucidate the origin of CRC heterogeneity, highlighting the intricate molecular pathways involved. This review focuses on intrapatient cancer heterogeneity and genetic clonal evolution in metastatic CRC, with an emphasis on clinical applications.

Principles for Good Practice in the Conduct of Non-interventional Studies: The View of Industry Researchers.

This reflection paper presents a consolidated view of EFPIA on the need for principles for good practice in the generation and use of non-interventional studies (NIS), including overarching principles such as the registration of hypothesis evaluating treatment effect (HETE) studies. We first define NIS and the important adjacencies to clinical trials and relationship with real-world evidence (RWE). We then outline the principles for good practice with respect to appropriate research design, study protocol, fit-for-purpose variables and data quality, analytical methods, bias reduction, transparency in conduct and use, privacy management and ethics review. We conclude with recommendations for action for the research community to promote trust and credibility in the use of NIS.

Impact of the COVID-19 pandemic in the early-onset colorectal cancer.

The COVID19 pandemic has affected the spectrum of cancer care worldwide. Early onset colorectal cancer (EOCRC) is defined as diagnosis below the age of 50. Patients with EOCRC faced multiple challenges during the COVID19 pandemic and in some institutions it jeopardized cancer diagnosis and care delivery. Our study aims to identify the clinicopathological features and outcomes of patients with EOCRC in our Centre during the first wave of the pandemic in comparison with the same period in 2019 and 2021. Patients with EOCRC visited for the first time at Vall d'Hebron University Hospital in Spain from the 1st March to 31st August of 2019, 2020 and 2021 were included in the analysis. 177 patients with EOCRC were visited for the first time between 2019 and 2021, of which 90 patients met the inclusion criteria (2019: 30 patients, 2020: 29 patients, 2021: 31 patients). Neither differences in frequency nor in stage at diagnosis or at first visit during the given periods were observed. Of note, indication of systemic therapy in the adjuvant or metastatic setting was not altered. Days to treatment initiation and enrollment in clinical trials in this subpopulation was not affected due to the COVID-19 outbreak.

Economic Evaluation of Nivolumab Versus Docetaxel for the Treatment of Advanced Squamous and Non-squamous Non-small Cell Lung Cancer After Prior Chemotherapy in China.

OBJECTIVE: To evaluate the economic value of nivolumab versus docetaxel for advanced non-small cell lung cancer (aNSCLC) treatment after platinum-based chemotherapy in adults without epidermal growth factor receptor/anaplastic lymphoma kinase aberrations in China. METHODS: Partitioned survival models evaluated lifetime costs and benefits of nivolumab versus docetaxel by squamous and non-squamous histologies from a Chinese healthcare payer perspective. Progression-free disease, progressed disease, and death health states were considered over a 20-year time horizon. Clinical data were derived from the CheckMate pivotal Phase III trials (ClinicalTrials.gov identifiers: NCT01642004, NCT01673867, NCT02613507); patient-level survival data were extrapolated using parametric functions. China-specific health state utilities, healthcare resource utilisation, and unit costs were applied. Sensitivity analyses explored uncertainty. RESULTS: Nivolumab resulted in extended survival (1.489 and 1.228 life-years [1.226 and 0.995 discounted]) and quality-adjusted survival benefits (1.034 and 0.833 quality-adjusted life-years) at additional costs of ¥214,353 (US$31,829) and ¥158,993 (US$23,608) versus docetaxel in squamous and non-squamous aNSCLC, respectively. Nivolumab was associated with higher acquisition costs, lower subsequent treatment costs, and lower adverse event management costs than docetaxel in both histologies. Drug acquisition costs, discount rate for outcomes, and average body weight were key model drivers. Stochastic results aligned with the deterministic results. CONCLUSIONS: Nivolumab yielded survival and quality-adjusted survival benefits at incremental cost versus docetaxel in aNSCLC. As a traditional healthcare payer perspective was applied, the true economic benefit of nivolumab may be underestimated as not all treatment benefits and costs of relevance to society were considered.

Patient Characteristics Associated With Occurrence of Preoperative Goals-of-Care Conversations.

Importance: Communication about patients' goals and planned and potential treatment is central to advance care planning. Undertaking or confirming advance care plans is also essential to preoperative preparation, particularly among patients who are frail or will undergo high-risk surgery. Objective: To evaluate the association between patient risk of hospitalization or death and goals-of-care conversations documented with a completed Life-Sustaining Treatment (LST) Decisions Initiative note among veterans undergoing surgery. Design, Setting, and Participants: This retrospective cross-sectional study included 190 040 veterans who underwent operations between January 1, 2017, and February 28, 2020. Statistical analysis took place from November 1, 2021, to November 17, 2022. Exposure: Patient risk of hospitalization or death, evaluated with a Care Assessment Need (CAN) score (range, 0-99, with a higher score representing a greater risk of hospitalization or death), dichotomized as less than 80 or 80 or more. Main Outcomes and Measures: Preoperative LST note completion (30 days before or on the day of surgery) or no LST note completion within the 30-day preoperative period prior to or on the day of the index operation. Results: Of 190 040 veterans (90.8% men; mean [SD] age, 65.2 [11.9] years), 3.8% completed an LST note before surgery, and 96.2% did not complete an LST note. In the groups with and without LST note completion before surgery, most were aged between 65 and 84 years (62.1% vs 56.7%), male (94.3% vs 90.7%), and White (82.2% vs 78.3%). Compared with patients who completed an LST note before surgery, patients who did not complete an LST note before surgery tended to be female (9.3% vs 5.7%), Black (19.2% vs 15.7%), married (50.2% vs 46.5%), and in better health (Charlson Comorbidity Index score of 0, 25.9% vs 15.2%); to have a lower risk of hospitalization or death (CAN score <80, 98.3% vs 96.9%); or to undergo neurosurgical (9.8% vs 6.2%) or urologic surgical procedures (5.9% vs 2.0%). Over the 3-year interval, unadjusted rates of LST note completion before surgery increased from 0.1% to 9.6%. Covariate-adjusted estimates of LST note completion indicated that veterans at a relatively elevated risk of hospitalization or death (CAN score ≥80) had higher odds of completing an LST note before surgery (odds ratio [OR], 1.29; 95% CI, 1.09-1.53) compared with those with CAN scores less than 80. High-risk surgery was not associated with increased LST note completion before surgery (OR, 0.93; 95% CI, 0.86-1.01). Veterans who underwent cardiothoracic surgery had the highest likelihood of LST note completion before surgery (OR, 1.35; 95% CI, 1.24-1.47). Conclusions and Relevance: Despite increasing LST note implementation, a minority of veterans completed an LST note preoperatively. Although doing so was more common among veterans with an elevated risk compared with those at lower risk, improving proactive communication and documentation of goals, particularly among higher-risk veterans, is needed. Doing so may promote goal-concordant surgical care and outcomes.

Treatment patterns and outcomes among patients with small-cell lung cancer (SCLC) in Europe: a retrospective cohort study.

OBJECTIVE: Describe characteristics, treatment patterns and clinical outcomes of patients with small-cell lung cancer (SCLC). DESIGN: Retrospective chart review study defining several cohorts: (1) limited-stage disease (LD) SCLC initiating 1L therapy (1 L LD-SCLC), (2) extensive-stage disease (ED) SCLC initiating 1L therapy (1L ED-SCLC) and (3) patients initiating 2L therapy. SETTING: 39 physicians (medical oncologists, thoracic oncologists and/or pulmonologists) from France, Italy and the UK. PARTICIPANTS: Patients >18 years of age with a confirmed diagnosis of LD-SCLC or ED-SCLC and a full oncology medical history. Patients included initiated a 1L (2013-2015) or 2L (2013-2016) treatment (chemotherapy and/or radiotherapy-RT). PRIMARY AND SECONDARY OUTCOME MEASURES: Overall survival (OS) and progression-free survival (PFS). RESULTS: 231 patients in 1L LD-SCLC, 308 in 1L ED-SCLC and 225 with relapse/refractory SCLC initiating 2L treatment were included. The proportion of men was higher across all groups (56.8% to 68.5%) and mean age at time of diagnosis was 66.0 and 65.4 years in 1L LD-SCLC and 2L ED-SCLC cohorts. The majority of patients in LD-SCLC 1L group received chemotherapy with RT (76.2%). Patients initiating 2L therapy predominantly received chemotherapy alone (79.6%).Median OS in 1 L patients was 17.3 months in LD-SCLC and 8.8 months in ED-SCLC. Median PFS was 11.6 months in LD-SCLC and 6.1 months in ED-SCLC patients. Median OS in patients initiating 2L treatment was 6.6 months. OS from start of 2L treatment was lower in patients initially diagnosed with ED (5.1 months) than in patients initially diagnosed with LD (9.3 months) (p<0.0001). OS and PFS were assessed from the start of 1L or 2L therapy, depending on the cohort. CONCLUSIONS: Despite the availability of a high number of treatments and combinations, the prognosis of SCLC is still unsatisfactory, especially for those patients diagnosed with ED-SCLC, indicating high unmet need in this patient population.

RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer.

Anti-BRAF/EGFR therapy was recently approved for the treatment of metastatic BRAFV600E colorectal cancer (mCRCBRAF-V600E). However, a large fraction of patients do not respond, underscoring the need to identify molecular determinants of treatment response. Using whole-exome sequencing in a discovery cohort of patients with mCRCBRAF-V600E treated with anti-BRAF/EGFR therapy, we found that inactivating mutations in RNF43, a negative regulator of WNT, predict improved response rates and survival outcomes in patients with microsatellite-stable (MSS) tumors. Analysis of an independent validation cohort confirmed the relevance of RNF43 mutations to predicting clinical benefit (72.7% versus 30.8%; P = 0.03), as well as longer progression-free survival (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.12-0.75; P = 0.01) and overall survival (HR, 0.26; 95% CI, 0.10-0.71; P = 0.008), in patients with MSS-RNF43mutated versus MSS-RNF43wild-type tumors. Microsatellite-instable tumors invariably carried a wild-type-like RNF43 genotype encoding p.G659fs and presented an intermediate response profile. We found no association of RNF43 mutations with patient outcomes in a control cohort of patients with MSS-mCRCBRAF-V600E tumors not exposed to anti-BRAF targeted therapies. Overall, our findings suggest a cross-talk between the MAPK and WNT pathways that may modulate the antitumor activity of anti-BRAF/EGFR therapy and uncover predictive biomarkers to optimize the clinical management of these patients.

COVIDNearTerm: A simple method to forecast COVID-19 hospitalizations.

Introduction: COVID-19 has caused tremendous death and suffering since it first emerged in 2019. Soon after its emergence, models were developed to help predict the course of various disease metrics, and these models have been relied upon to help guide public health policy. Methods: Here we present a method called COVIDNearTerm to "forecast" hospitalizations in the short term, two to four weeks from the time of prediction. COVIDNearTerm is based on an autoregressive model and utilizes a parametric bootstrap approach to make predictions. It is easy to use as it requires only previous hospitalization data, and there is an open-source R package that implements the algorithm. We evaluated COVIDNearTerm on San Francisco Bay Area hospitalizations and compared it to models from the California COVID Assessment Tool (CalCAT). Results: We found that COVIDNearTerm predictions were more accurate than the CalCAT ensemble predictions for all comparisons and any CalCAT component for a majority of comparisons. For instance, at the county level our 14-day hospitalization median absolute percentage errors ranged from 16 to 36%. For those same comparisons, the CalCAT ensemble errors were between 30 and 59%. Conclusion: COVIDNearTerm is a simple and useful tool for predicting near-term COVID-19 hospitalizations.

Lessons learned in the Apple Heart Study and implications for the data management of future digital clinical trials.

The digital clinical trial is fast emerging as a pragmatic trial that can improve a trial's design including recruitment and retention, data collection and analytics. To that end, digital platforms such as electronic health records or wearable technologies that enable passive data collection can be leveraged, alleviating burden from the participant and study coordinator. However, there are challenges. For example, many of these data sources not originally intended for research may be noisier than traditionally obtained measures. Further, the secure flow of passively collected data and their integration for analysis is non-trivial. The Apple Heart Study was a prospective, single-arm, site-less digital trial designed to evaluate the ability of an app to detect atrial fibrillation. The study was designed with pragmatic features, such as an app for enrollment, a wearable device (the Apple Watch) for data collection, and electronic surveys for participant-reported outcomes that enabled a high volume of patient enrollment and accompanying data. These elements led to challenges including identifying the number of unique participants, maintaining participant-level linkage of multiple complex data streams, and participant adherence and engagement. Novel solutions were derived that inform future designs with an emphasis on data management. We build upon the excellent framework of the Clinical Trials Transformation Initiative to provide a comprehensive set of guidelines for data management of the digital clinical trial that include an increased role of collaborative data scientists in the design and conduct of the modern digital trial.

Real-world effectiveness of immunotherapies in pre-treated, advanced non-small cell lung cancer Patients: A systematic literature review.

BACKGROUND: Clinical trials have shown immunotherapy (IO) to be more effective than chemotherapy in pre-treated, advanced non-small cell lung cancer (NSCLC). However, there is a lack of understanding of its effectiveness in clinical practice, and among patient groups that are often underrepresented in trials. We aimed to summarize the existing real-world evidence (RWE) on the survival outcomes of IO in second- or higher line in advanced NSCLC. METHODS: We conducted a systematic review of real-world observational studies that reported overall survival (OS) estimates with IO, primarily nivolumab, pembrolizumab or atezolizumab, in adult, previously treated advanced or recurrent NSCLC patients. Meta-analysis was conducted using random-effect models to pool 1- and 2-year OS rates across studies. Additional subgroups were examined among patients treated with IO, including the elderly, those with poor performance status (PS) and those exhibiting metastasis. RESULTS: In total, 66 studies were included, of which 46 (70%) included a nivolumab-specific study arm. Pooled 1-year and 2-year OS rates with nivolumab monotherapy were 45.6% (95% CI; 43.4-47.8) and 28.0% (95% CI; 24.8-31.4), respectively, compared to 43.9% (95% CI; 39.1-48.8) and 20.4% (95% CI; 14.7-27.6) in the mixed immune checkpoint inhibitors (ICI) group. OS rates with nivolumab were slightly lower in elderly compared to non-elderly populations. Poor PS was associated with worse survival rates, with a pooled one-year OS estimate of 27.1% in PS ≥ 2 vs 51.6% in PS < 2. The pooled 2-year OS rate with nivolumab in patients with and without brain metastases was 22.1% and 26.1% respectively, and this difference was significant in 36% of individual studies. CONCLUSIONS: While the OS benefits of IO seen in real-world studies among pre-treated, advanced NSCLC patients are consistent with pivotal clinical trials, these tend to vary for the more vulnerable patient groups, such as patients with poor PS, which are often excluded from trials. Further research is needed to investigate findings in patients with brain and liver metastases.

Three-year follow-up and patient-reported outcomes from CheckMate 078: Nivolumab versus docetaxel in a predominantly Chinese patient population with previously treated advanced non-small cell lung cancer.

OBJECTIVES: In the phase 3 CheckMate 078 study, nivolumab prolonged overall survival (OS) and showed a favorable safety profile versus docetaxel in a predominantly Chinese patient population with previously treated advanced non-small cell lung cancer (aNSCLC). However, long-term efficacy, safety, and health-related quality of life findings with second-line nivolumab are very limited in Asian patients with previously treated aNSCLC. Here, we report updated clinical data and patient-reported outcomes (PROs) from the phase 3 CheckMate 078 trial with a 3-year minimum follow-up. MATERIALS AND METHODS: Patients with aNSCLC and disease progression after platinum-doublet chemotherapy were randomized 2:1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks) until progression or unacceptable toxicity. The primary endpoint was OS; secondary endpoints included objective response rate, progression-free survival, safety, and disease-related symptom deterioration assessed using the Lung Cancer Symptom Scale (LCSS) by Week 12. Additional PRO assessments were exploratory endpoints. RESULTS: At ≥ 37.3 months follow-up, 3-year OS rates were 19% with nivolumab and 12% with docetaxel; 30% and 0% of responders remained in response for ≥ 3 years, respectively. Incidence of treatment-related adverse events occurring after 2 years was lower than during the first 2 years. No new treatment-related deaths were reported. By Week 12 of treatment, rates of disease-related symptom deterioration were 32% with nivolumab and 47% with docetaxel. Completion rates for PRO questionnaires were ≥ 80% in both arms. Clinically meaningful and sustained improvements in LCSS Average Symptom Burden Index scores and delayed time to first symptom deterioration were observed with nivolumab against docetaxel. CONCLUSIONS: At 3 years, nivolumab continued to demonstrate survival benefit versus docetaxel, exhibiting improvements in disease-related symptoms and overall health status in a predominantly Chinese patient population with previously treated aNSCLC. No new safety signals were observed. These findings are similar to the global population.

A Comprehensive Biomarker Analysis of Microsatellite Unstable/Mismatch Repair Deficient Colorectal Cancer Cohort Treated with Immunotherapy.

The search for immunotherapy biomarkers in Microsatellite Instability High/Deficient Mismatch Repair system (MSI-H/dMMR) metastatic colorectal cancer (mCRC) is an unmet need. Sixteen patients with mCRC and MSI-H/dMMR (determined by either immunohistochemistry or polymerase chain reaction) treated with PD-1/PD-L1 inhibitors at our institution were included. According to whether the progression-free survival with PD-1/PD-L1 inhibitors was longer than 6 months or shorter, patients were clustered into the IT-responder group (n: 9 patients) or IT-resistant group (n: 7 patients), respectively. In order to evaluate determinants of benefit with PD-1/PD-L1 inhibitors, we performed multimodal analysis including genomics (through NGS panel tumour-only with 431 genes) and the immune microenvironment (using CD3, CD8, FOXP3 and PD-L1 antibodies). The following mutations were more frequent in IT-resistant compared with IT-responder groups: B2M (4/7 versus 2/9), CTNNB1 (2/7 versus 0/9), and biallelic PTEN (3/7 versus 1/9). Biallelic ARID1A mutations were found exclusively in the IT-responder group (4/9 patients). Tumour mutational burden did not correlate with immunotherapy benefit, neither the rate of indels in homopolymeric regions. Of note, biallelic ARID1A mutated tumours had the highest immune infiltration and PD-L1 scores, contrary to tumours with CTNNB1 mutation. Immune microenvironment analysis showed higher densities of different T cell subpopulations and PD-L1 expression in IT-responders. Misdiagnosis of MSI-H/dMMR inferred by discordances between immunohistochemistry and polymerase chain reaction was only found in the IT-resistant population (3/7 patients). Biallelic ARID1A mutations and Wnt signalling activation through CTNNB1 mutation were associated with high and low T cell immune infiltrates, respectively, and deserve special attention as determinants of response to PD-1/PD-L1 inhibitors. The non-MSI-H phenotype in dMMR is associated with poor benefit to immunotherapy. Our results suggest that mechanisms of resistance to immunotherapy are multi-factorial.

The development of a mobile app-focused deduplication strategy for the Apple Heart Study that informs recommendations for future digital trials.

An app-based clinical trial enrolment process can contribute to duplicated records, carrying data management implications. Our objective was to identify duplicated records in real time in the Apple Heart Study (AHS). We leveraged personal identifiable information (PII) to develop a dissimilarity score (DS) using the Damerau-Levenshtein distance. For computational efficiency, we focused on four types of records at the highest risk of duplication. We used the receiver operating curve (ROC) and resampling methods to derive and validate a decision rule to classify duplicated records. We identified 16,398 (4%) duplicated participants, resulting in 419,297 unique participants out of a total of 438,435 possible. Our decision rule yielded a high positive predictive value (96%) with negligible impact on the trial's original findings. Our findings provide principled solutions for future digital trials. When establishing deduplication procedures for digital trials, we recommend collecting device identifiers in addition to participant identifiers; collecting and ensuring secure access to PII; conducting a pilot study to identify reasons for duplicated records; establishing an initial deduplication algorithm that can be refined; creating a data quality plan that informs refinement; and embedding the initial deduplication algorithm in the enrolment platform to ensure unique enrolment and linkage to previous records.