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Aims: We aim to evaluate change in the use of prognostic guideline‐directed medical therapies (GDMTs) for heart failure (HF) before and after a cancer diagnosis as well as the matched non‐cancer controls, including renin‐angiotensin‐system inhibitors (RASIs), beta‐blockers, and mineralocorticoid receptor antagonists (MRAs). Methods and results: We conducted a longitudinal study in patients with HF in the UK Clinical Practice Research Datalink between 2005 and 2021. We selected patients with probable HF with reduced ejection fraction (HFrEF) based on diagnostic and prescription records. We described the longitudinal trends in the use and dosing of GDMTs before and after receiving an incident cancer diagnosis. HF patients with cancer were matched with a 1:1 ratio to HF patients without cancer to investigate the association between cancer diagnosis and treatment adherence, persistence, initiation, and dose titration as odds ratios (ORs) with 95% confidence intervals (CIs) using multivariable logistic regression models. Of 8504 eligible HFrEF patients with incident cancer, 4890 were matched to controls without cancer. The mean age was 75.7 (±8.4) years and 73.9% were male. In the 12 months following a cancer diagnosis, patients experienced reductions in the use and dosing of GDMT. Compared with the non‐cancer controls, patients with cancer had higher risks for poor adherence for all three medication classes (RASIs: OR = 1.51, 95% CI = 1.35–1.68; beta‐blockers: OR = 1.22, 95% CI = 1.08–1.37; MRAs: OR = 1.31, 95% CI = 1.08–1.59) and poor persistence (RASIs: OR = 2.04, 95% CI = 1.75–2.37; beta‐blockers: OR = 1.35, 95% CI = 1.12–1.63; MRAs: OR = 1.49, 95% CI = 1.16–1.93), and higher risks for dose down‐titration for RASIs (OR = 1.69, 95% CI = 1.40–2.04) and beta‐blockers (OR = 1.31, 95% CI = 1.05–1.62). Cancer diagnosis was not associated with treatment initiation or dose up‐titration. Event rates for HF hospitalization and mortality were higher in patients with poor adherence or persistence to GDMTs. Conclusions: Following a cancer diagnosis, patients with HFrEF were more likely to have reduced use of GDMTs for HF. [ABSTRACT FROM AUTHOR]

Introduction Chemotherapy forms the cornerstone of systemic treatment for advanced ovarian cancer, extending overall survival; however, drug-related toxicity can lead to treatment delays, potentially diminishing treatment efficacy. This study evaluated the impact of treatment delays on all-cause mortality of patients with ovarian cancer, to better inform decisions on patient management. Methods This retrospective, population-based cohort study included 1517 women with advanced-stage ovarian cancer, receiving first-line adjuvant or neoadjuvant chemotherapy in 2014 and 2015. The frequency of inter-cycle delays >7 days was calculated using drug administration dates. Kaplan-Meier estimates were used to compare 2-year overall survival (OS) between patients who were delayed and those treated to schedule. Cox proportional hazards regression was used to investigate the impact of treatment delay on all-cause mortality. Inverse probability of treatment weighting propensity scores were used to adjust for confounding variables. Results Delays >7 days occurred in 35.3% of patients. Two-year OS probability was 62.7% in patients who experienced treatment delays >7 days (95% CI, 58.7-66.9) compared to 69.1% in those treated to schedule (95% CI, 66.2-72.0). Delays were not significantly associated with all-cause mortality when adjusted for confounders (HR 1.00 95% CI, 0.83-1.20, P  = .9). Conclusions Delays to chemotherapy treatment were not significantly associated with worsened survival in patients with advanced-stage ovarian cancer. These results can inform clinical decision making that prioritize toxicity management and quality of life for those treated with chemotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: The phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B)/mammalian target of the rapamycin (mTOR) signaling pathway is important in regulating cell proliferation, growth, metabolism, and motility in response to environmental and growth signals. Inhibition of the PI3K/Akt/mTOR pathway by specific targeted inhibitors has been shown to lead to regression in human tumors in the preclinical setting. Clinically, several drugs targeting this pathway are in development. However, some of them have been subsequently withdrawn due to dose-related toxicity issues. Bimiralisib is an oral-balanced dual-acting PI3K/mTOR inhibitor. The aim of our study was to assess safety with different schedules of administration of bimiralisib. Results showed a good safety profile for the drug when administered using intermittent schedules, which may extend the drug exposure of patients and potentially increase the chance to see antitumor efficacy. The improved safety profile of the drug when given on an intermittent schedule also supports future potential combination with other targeted therapies. Background: Bimiralisib is a pan-PI3K/mTOR inhibitor demonstrating antitumor efficacy in preclinical models. The objectives of this study were to identify a maximum tolerated dose (MTD), pharmacokinetics (PK), a dosing schedule, and adverse events (AEs) in patients with advanced solid tumors. Patients and Methods: Patients received oral bimiralisib to determine the MTD of one continuous (once daily) and two intermittent schedules (A: Days 1, 2 weekly; B: Days 1, 4 weekly) until progression or unacceptable AEs occurred. Results: The MTD for the continuous schedule was 80 mg, with grade three fatigue as the dose-limiting toxicity (DLT). No MTD was reached with intermittent schedules, with only one DLT in schedule B. PK analysis suggested that 140 mg (schedule A) was within the biologically active dose range and was selected for further exploration. The most frequent treatment-emergent AEs were hyperglycemia (76.2%) in the continuous schedule, and nausea (56–62.5%) in schedules A and B. The most frequent treatment-emergent > grade three AE for all schedules combined was hyperglycemia (28.6%, continuous schedule; 12.0%, schedule A; 12.5%, schedule B). There was one partial response in a head and neck squamous cancer patient with a NOTCH1T1997M mutation. Conclusions: Bimiralisib demonstrated a manageable AE profile consistent with this compound class. Intermittent schedules had fewer > grade three AEs, while also maintaining favorable PK profiles. Intermittent schedule A is proposed for further development in biomarker-selected patient populations. [ABSTRACT FROM AUTHOR]

Purpose: A recent observational study suggested statins could reduce cancer diagnosis in patients with heart failure (HF). The findings need to be validated using robust epidemiological methods. This study aimed to evaluate the effect of statin treatment on the risk of cancer in patients with HF. Methods: We conducted two target trial emulations using primary care data from IQVIA Medical Research Database‐UK (2000 to 2019) with a clone‐censor‐weight design. The first emulated trial addressed the treatment initiation effect: initiating within 1 year versus not initiating a statin after the HF diagnosis. The second emulated trial addressed the cumulative exposure effect: continuing a statin for ≤3 years, 3–6 years, and >6 years after initiation. The study outcomes were any incident cancer and site‐specific cancer diagnoses. Weighted pooled logistic regression models were used to estimate 10‐year risk ratios (RR). 95% confidence intervals (CIs) were estimated using non‐parametric bootstrapping. Results: The first emulated trial showed that, compared to no statin, statins did not reduce the cancer risk in patients with HF (RR, 1.05; 95% CI, 0.94–1.15). The second emulated trial showed that, compared to treatment ≤3 years, statins with longer durations did not reduce the cancer risk (3–6 years: RR, 0.94; 95% CI, 0.70–1.33. >6 years: RR, 0.97; 95% CI, 0.79–1.26). No significant risk difference was observed on any site‐specific cancer diagnoses. Conclusions: The results from the target trial emulations suggest that statin treatment is not associated with cancer risk in patients with HF. [ABSTRACT FROM AUTHOR]

This article discusses a study that aimed to evaluate the practice patterns and outcomes for patients with recurrent and metastatic sinonasal undifferentiated carcinoma (SNUC). SNUC is a rare and aggressive tumor of the sinonasal cavity and skull base. The study analyzed data from 97 patients with recurrent or metastatic SNUC and found that the management of these cases varied widely, with different treatment regimens involving surgery, chemotherapy, and/or radiation. The study also found that the survival rates for metastatic and recurrent SNUC were relatively low, highlighting the need for further research to improve outcomes. [Extracted from the article]

Introduction: Targeted therapy in non-small cell lung cancer (NSCLC) patients with mesenchymal epithelial transition (MET) exon 14 skipping mutations (METex14) and MET amplifications has improved patients' outcomes. The development of more potent MET kinase inhibitors could further benefit these patients. The aim of this trial is to determine the safety and recommended phase 2 dose (RP2D) of OMO-1 (an oral dual MET kinase/OCT-2 inhibitor) and to assess preliminary clinical efficacy in METex14-positive NSCLC and other MET-positive solid tumors. Materials and Methods: This was a first-in-patient, open-label, multicenter study of OMO-1 in patients with locally advanced or metastatic solid malignancies. A standard 3 + 3 dose escalation design was utilized starting at a dose level of 100 mg BID continuously. Preliminary efficacy was investigated in patients with METex14-positive NSCLC, and MET amplified NSCLC and other solid tumors (MET basket). Results: In the dose-escalation part, 24 patients were included in 5 dose levels ranging from 100 mg twice daily (BID) to 400 mg BID. Most common adverse events (≥ 20%) were nausea, fatigue, vomiting, increased blood creatinine, and headache. The RP2D was determined at 250 mg BID. In the expansion cohorts, 15 patients were included (10 in METex14-positive NSCLC cohort and 5 in MET basket cohort) and received either 200 or 250 mg BID. Eight out of the 10 patients with METex14 positive NSCLC had stable disease as the best response. Conclusion: OMO-1 was tolerated at the dose of 250 mg BID and shows initial signs of MET inhibition and anti-tumor activity in METex14 mutated NSCLC patients. Targeted therapy for non-small cell lung cancer (NSCLC) with mesenchymal epithelial transition (MET) exon 14 skipping mutations and MET amplifications have improved outcomes. This study aimed to determine the safety and recommended phase II dose of OMO-1 to assess preliminary clinical efficacy in METex14-positive NSCLC and other MET-positive solid tumors. [ABSTRACT FROM AUTHOR]

Background: In those receiving chemotherapy, renal and hepatic dysfunction can increase the risk of toxicity and should therefore be monitored. We aimed to develop a machine learning model to identify those patients that need closer monitoring, enabling a safer and more efficient service. Methods: We used retrospective data from a large academic hospital, for patients treated with chemotherapy for breast cancer, colorectal cancer and diffuse‐large B‐cell lymphoma, to train and validate a Multi‐Layer Perceptrons (MLP) model to predict the outcomes of unacceptable rises in bilirubin or creatinine. To assess the performance of the model, validation was performed using patient data from a separate, independent hospital using the same variables. Using this dataset, we evaluated the sensitivity and specificity of the model. Results: 1214 patients in total were identified. The training set had almost perfect sensitivity and specificity of >0.95; the area under the curve (AUC) was 0.99 (95% CI 0.98–1.00) for creatinine and 0.97 (95% CI: 0.95–0.99) for bilirubin. The validation set had good sensitivity (creatinine: 0.60, 95% CI: 0.55–0.64, bilirubin: 0.54, 95% CI: 0.52–0.56), and specificity (creatinine 0.98, 95% CI: 0.96–0.99, bilirubin 0.90, 95% CI: 0.87–0.94) and area under the curve (creatinine: 0.76, 95% CI: 0.70, 0.82, bilirubin 0.72, 95% CI: 0.68–0.76). Conclusions: We have demonstrated that a MLP model can be used to reduce the number of blood tests required for some patients at low risk of organ dysfunction, whilst improving safety for others at high risk. [ABSTRACT FROM AUTHOR]

Background: Re‐designing services and processes to meet growing demands in chemotherapy services is necessary with increasing treatments. There is little evidence guiding the timing and thresholds to be attained of pre‐chemotherapy blood assessments, namely neutrophils. Methods: A survey was developed and distributed to health professionals in the United Kingdom (UK) to examine current practice in timing and threshold values of neutrophils and platelets before treatment administration. This was followed by a retrospective cohort study, using data from electronic patient record systems; including patients initiating treatment between January 2013 and December 2018, to determine a safe timeframe for blood assessments; comparing neutrophil, platelet, creatinine and bilirubin levels at different time points. Results: The survey captured 25% of hospitals in the UK and variations were apparent in both the timing of assessments and thresholds needed, particularly for neutrophils. 616 (6.5%) of 4007 patients included had neutrophil levels measured twice within 7 days of treatment (with the first level taken beyond 3 days and the second test being within 3 days of treatment‐ the UK standard). Of the patients that attained an acceptable neutrophil level at their first test, five of the 616 (0.8%) became ineligible for administration from the test 2 level. 23% of patients improved their grade and became eligible for treatment. Little difference was observed for platelets. Conclusions: We have demonstrated that extending the timeframe for blood tests can be safe, however, this practice may cause unnecessary delays for patients if only an early test is relied on for eligibility. [ABSTRACT FROM AUTHOR]

Aim: This Phase I study investigated safety of navitoclax and docetaxel in patients (n = 41) with advanced solid tumors. Patients & methods: Two navitoclax plus docetaxel dosing schedules (21 and 28 days) were evaluated. Maximum tolerated dose, dose-limiting toxicities and preliminary antitumor activity were assessed. Results: Ten (24%) patients experienced dose-limiting toxicities; dose-escalation cohorts: n = 7 (21-day schedule: n = 5; 28-day schedule: n = 2) and 21-day expanded safety cohort: n = 3. Navitoclax 150-mg days 1-5 every 21 days with docetaxel 75 mg/m2 day 1 was the maximum tolerated dose and optimal schedule. Adverse events included thrombocytopenia (63%), fatigue (61%), nausea (59%) and neutropenia (51%). Four confirmed partial responses occurred. Conclusion: Navitoclax 150-mg orally once/day was safely administered with docetaxel. Myelosuppression limited dose escalation; antitumor activity was observed. Clinical trial registration: NCT00888108 (ClinicalTrials.gov). [ABSTRACT FROM AUTHOR]

PURPOSE The growth in understanding of molecular biology and genomics has augmented the development of targeted cancer treatments; however, challenges exist in access to molecular testing, an essential precursor to treatment decision-making. We used data from a cross-sectional survey to evaluate the differences in uptake of molecular testing, METHODS Using the aggregated results of a questionnaire developed and distributed to clinicians by IQVIA, including treatment details and investigations undertaken for patients, we compared proportions of patients receiving molecular testing and targeted treatment by cancer type for the United Kingdom, France, Italy, Germany, Spain, South Korea, Japan, and China. We used multivariable logistic regression methods to understand the effect of country on the odds of receiving a molecular test. RESULTS There was a total of 61,491 cases. Across countries and cancer types, uptake rates for molecular testing ranged between 2% and 98%, with the greatest differences seen in gastric cancers (range, 23% to 70%), and significant variations were observed for both European and Asian countries. China consistently demonstrated a significantly reduced uptake for all molecular tests assessed; however; uptake of drug treatment in gastric cancers after testing positive for the human epidermal growth factor receptor 2 gene was higher than in some European countries (China, 85%; European range, 8% to 66%). The uptake of epidermal growth factor receptor gene testing was greater in some Asian countries relative to the United Kingdom, where incidence of lung cancer is higher (Japan: odds ratio, 3.1 [95% CI, 2.6 to 3.8]; South Korea: odds ratio, 2.7 [95% CI, 2 to 3.4]). CONCLUSION We have highlighted inequity in access to molecular testing and subsequent treatments across countries, which warrants improvements. [ABSTRACT FROM AUTHOR]

Background: Neutropenia is associated with an increased risk of mortality and hospitalisation. Strategies, including the prescribing of colony-stimulating growth factors (CSFs), are adopted when a high risk (> 20%) of neutropenic complications are seen in the clinical trial setting. With a diverse treatment population that may differ from the patient groups recruited to studies, appropriate prescribing decisions by clinicians are essential. At present, results are conflicting from studies evaluating the risks of certain patient attributes on neutropenic events; we aimed to aggregate these associations to guide future management.Design: A systematic review with a meta-analysis was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Studies were identified through a literature search using MEDLINE, EMBASE and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases from inception to December 1, 2017. Studies were included into a meta-analysis if they adjusted for confounders; analyses were conducted in STATA v 15.1 SE.Results: A total of 4415 articles were retrieved by the search with 37 meeting the inclusion criteria and 12 eligible for meta-analysis. Meta-analysis was conducted for increasing age and yielded a pooled odds ratio of 1.39 (1.11, 1.76, I2 = 24.1%), in our subgroup analysis of 4814 patients. Odds ratios for studies were pooled that reported associations for one co-morbidity compared to none and resulted in an overall odds of 1.54 (CI 1.09-2.09, I2 = 13.1%), including 9189 patients in total.Conclusions: Results can enhance current guidance in prescribing primary prophylaxis for treatments that either fall marginally under the internationally recognised 20% neutropenia risk. [ABSTRACT FROM AUTHOR]

Background: Adequate organ function and good performance status (PS) are common eligibility criteria for phase I trials. As inflammation is pathogenic and prognostic in cancer we investigated the prognostic performance of inflammation-based indices including the neutrophil (NLR) and platelet to lymphocyte ratio (PLR). Methods: We studied inflammatory scores in 118 unselected referrals. NLR normalization was recalculated at disease reassessment. Each variable was assessed for progression-free (PFS) and overall survival (OS) on uni- and multivariate analyses and tested for 90 days survival (90DS) prediction using receiving operator curves (ROC). Results: We included 118 patients with median OS 4.4 months, 23% PS>1. LDH≥450 and NLR≥5 were multivariate predictors of OS (p<0.001). NLR normalization predicted for longer OS (p<0.001) and PFS (p<0.05). PS and NLR ranked as most accurate predictors of both 90DS with area under ROC values of 0.66 and 0.64, and OS with c-score of 0.69 and 0.60. The combination of NLR+PS increased prognostic accuracy to 0.72. The NLR was externally validated in a cohort of 126 subjects. Conclusions: We identified the NLR as a validated and objective index to improve patient selection for experimental therapies, with its normalization following treatment predicting for a survival benefit of 7 months. Prospective validation of the NLR is warranted. [ABSTRACT FROM AUTHOR]

BACKGROUND Divarasib (GDC-6036) is a covalent KRAS G12C inhibitor that was designed to have high potency and selectivity. METHODS In a phase 1 study, we evaluated divarasib administered orally once daily (at doses ranging from 50 to 400 mg) in patients who had advanced or metastatic solid tumors that harbor a KRAS G12C mutation. The primary objective was an assessment of safety; pharmacokinetics, investigator-evaluated antitumor activity, and biomarkers of response and resistance were also assessed. RESULTS A total of 137 patients (60 with non-small-cell lung cancer [NSCLC], 55 with colorectal cancer, and 22 with other solid tumors) received divarasib. No dose-limiting toxic effects or treatment-related deaths were reported. Treatment-related adverse events occurred in 127 patients (93%); grade 3 events occurred in 15 patients (11%) and a grade 4 event in 1 patient (1%). Treatment-related adverse events resulted in a dose reduction in 19 patients (14%) and discontinuation of treatment in 4 patients (3%). Among patients with NSCLC, a confirmed response was observed in 53.4% of patients (95% confidence interval [CI], 39.9 to 66.7), and the median progression-free survival was 13.1 months (95% CI, 8.8 to could not be estimated). Among patients with colorectal cancer, a confirmed response was observed in 29.1% of patients (95% CI, 17.6 to 42.9), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.2). Responses were also observed in patients with other solid tumors. Serial assessment of circulating tumor DNA showed declines in KRAS G12C variant allele frequency associated with response and identified genomic alterations that may confer resistance to divarasib. CONCLUSIONS Treatment with divarasib resulted in durable clinical responses across KRAS G12C-positive tumors, with mostly low-grade adverse events. (Funded by Genentech; ClinicalTrials.gov number, NCT04449874.) [ABSTRACT FROM AUTHOR]

• There are an increasing number of rare but actionable fusions in NSCLC. • Targeting fusion panel testing in those negative by DNA-NGS led to an enriched positivity rate of 24% • Failure rate and tissue inadequacy was higher in sequential RNA-NGS than initial DNA-NGS. • Collaborating with industry to develop pathways can expand access to identify actionable events. There is an increasing number of driver fusions in NSCLC which are amenable to targeted therapy. Panel testing for fusions is increasingly appropriate but can be costly and requires adequate good quality biopsy material. In light of the typical mutual exclusivity of driver events in NSCLC, the objective of this study was to trial a novel testing pathway, supported by industrial collaboration, in which only patients negative for driver mutations on DNA-NGS were submitted for fusion panel analysis. Over 18 months, all patients from a single centre with non-squamous NSCLC were submitted for DNA-NGS, plus ALK and ROS1 immunohistochemistry +/− FISH. Those which were negative for a driver mutation were then recalled for RNA panel testing. 307 samples were referred for DNA-NGS mutation analysis, of which, 10% of cases were unsuitable for or failed DNA-NGS analysis. Driver mutations were detected in 61% (167/275) of all those successfully tested. Of those without a driver mutation and with some remaining tissue available, 28% had insufficient tissue/extracted RNA or failed RNA-NGS. Of those successfully tested, 24% (17/72) had a fusion gene detected involving either ALK, ROS, MET, RET, FGFR or EGFR. Overall, 66% (184/277) of patients had a driver event detected through the combination of DNA and RNA panels. Sequential DNA and RNA based molecular profiling increased the efficacy of detecting fusion driven NSCLCs. Continued optimisation of tissue procurement, handling and the diagnostic pathways for gene fusion analysis is necessary to reduce analysis failure rates and improve detection rate for treatment with the next generation of small molecule inhibitors. [ABSTRACT FROM AUTHOR]