EGFR exon 20 (EGFR Ex20) insertion mutations in non-small cell lung cancer (NSCLC) are insensitive to traditional EGFR tyrosine kinase inhibitors (TKIs). Mobocertinib is the only approved TKI specifically designed to target EGFR Ex20. We performed an international, real-world safety and efficacy analysis on patients with EGFR Ex20-positive NSCLC enrolled in a mobocertinib early access program. We explored the mechanisms of resistance by analyzing postprogression biopsies, as well as cross-resistance to amivantamab. Data from 86 patients with a median age of 67 years and a median of two prior lines of treatment were analyzed. Treatment-related adverse events (TRAEs) occurred in 95% of patients. Grade ≥3 TRAEs were reported in 38% of patients and included diarrhea (22%) and rash (8%). In 17% of patients, therapy was permanently discontinued, and two patients died due to TRAEs. Women were seven times more likely to discontinue treatment than men. In the overall cohort, the objective response rate to mobocertinib was 34% (95% CI, 24–45). The response rate in treatment-naïve patients was 27% (95% CI, 8–58). The median progression-free and overall survival was 5 months (95% CI, 3.5–6.5) and 12 months (95% CI, 6.8–17.2), respectively. The intracranial response rate was limited (13%), and one-third of disease progression cases involved the brain. Mobocertinib also showed antitumor activity following EGFR Ex20-specific therapy and vice versa. Potential mechanisms of resistance to mobocertinib included amplifications in MET, PIK3CA, and NRAS. Mobocertinib demonstrated meaningful efficacy in a real-world setting but was associated with considerable gastrointestinal and cutaneous toxicity.

Background: Of all adverse drug reactions, 35-45% are due to medication errors and would therefore be preventable. Thus, it is essential to implement effective strategies to prevent medication errors. However, it remains unclear whether medication reviews provide an additional benefit compared to medication reconciliation regarding medication safety. Aim: The present study aimed to evaluate whether medication reconciliation and medication reviews affect the incidence of preventable adverse drug reactions in elderly patients. Method: Non-elective patients 65 years and above admitted to the hospital, taking at least one high-risk drug, were eligible for participation in a three-armed randomized controlled trial. One group went through the medication reconciliation process, a second group received a comprehensive medication review, including medication reconciliation, and the third group did not receive any pharmaceutical intervention (control group). The incidence of preventable adverse drug reactions during hospitalization was set as the primary endpoint. The severity of the preventable adverse drug reactions and the number and clinical relevance of drug-related problems and discrepancies were defined as secondary endpoints. Results: In 207 patients, 74 preventable adverse drug reactions were detected. Neither medication reconciliation nor medication reviews showed a significant impact on the incidence of preventable adverse drug reactions compared to the control group. However, medication reviews significantly reduced the severity of preventable adverse drug reactions (p=0.017). Conclusion: The current study results suggest that medication reviews may have an impact on a clinically relevant outcome by reducing the severity of preventable adverse drug reactions. A significant impact of medication reconciliation on clinically relevant outcomes could not be demonstrated. Based on the results of this study, when deciding on a pharmaceutical intervention comprehensive medication reviews should be preferred over sole medication reconciliation whenever possible.

ROS1 fusions are well treatable aberrations in NSCLC. Besides solvent-front mutations (SFM) in resistance to targeted therapy, small-scale ROS1 mutations are largely unknown. We exploratively analyzed the clinicopathological characteristics, survival and therapy of small-scale ROS1 mutations in NSCLC patients without activating ROS1 fusions or SFMs. Next-generation sequencing was performed on tissue samples from NSCLC patients within the Network Genomic Medicine. Patients with ROS1 fusions and SFMs were excluded. We analyzed the characteristics of the patients, their survival and their response to systemic therapy. Of 10,396 patients analyzed, 101 (1.0%) patients harbored small-scale ROS1 mutations. Most patients were male (73.3%) and smokers (96.6%). Nearly half of the patients presented with squamous-cell carcinoma (SqCC, 40.4%). Most mutations were transversions (50.5%), and 66% were in the kinase domain. Besides TP53 mutations (65.3%), KRAS (22.8%), EGFR (5.9%), PIK3CA (9.9%) and FGFR1-4 mutations (8.9%) co-occurred. In 10 (9.9%) patients, ROS1 mutation was the only aberration detected. The median overall survival (mOS) of all stage IV patients was 10.5 months and the survival differed significantly in patients with or without KRAS co-mutations (9.7 vs 21.5 months, p=0.02, HR 2.6, 95% CI: 1.1-5.9). Altough not significant, the most common KRAS mutation in this cohort G12V (n=7/17) worsened survival (4.4 versus 9.7 months). Patients significantly benefited from treatment with immune-checkpoint blockade (21.5 vs 4.4 months, p=0.003, HR 0.14, 95% CI: 0.03-0.6). KRAS co-mutant patients treated with ICB only had an mOS of 8 months. In three patients with co-occurring mutations, qualifying for and having received targeted therapy (2x EGFRmut, 1x MET fusion), mOS was 23.5 months (95% CI: NA). The cohort's clinical characteristics contrasted ROS1-fused cohorts. Co-occurrence of KRAS mutations led to shortened survival and patients benefited from ICB. Our data does not support the idea of ROS1 small-scale mutations as strong oncogenic drivers in NSCLC, but rather as relevant bystanders altering the efficacy of treatment approaches.

Transition of care in geriatric patients is a complex and high risk process, particularly the continuation of discharge medication in primary care. We aimed to determine how general practitioners' management of geriatric patients' discharge medication is associated with rehospitalizations. A prospective monocentric cohort study was done in an acute geriatric inpatient clinic with six-months follow-up. Acutely hospitalized patients ≥ 70 years old with functional impairment and frailty currently taking medications were followed up after hospital discharge and continuation (n=27) or change (n=44) of discharge medication by the General Practitioner was determined. Outcomes were rehospitalizations, days spent at home and time until recurrent rehospitalizations. 71 patients (mean age 82 years, 46 women [65%]) were followed up for six months after hospital discharge. In a negative binomial regression model, the rehospitalization rate after three months was 3.8 times higher in participants whose discharge medication was changed (p = 0.023). The effect did not persist over six months. Patients who were continued on their discharge medication were rehospitalized significantly later and/or less often during the six months observation period, statistically measured by a recurrent events survival model (HR 0.267, p = 0.003). In conclusion, continuation of discharge medication after an acute hospitalization in a specialized geriatric clinic could prevent early rehospitalizations.

Background: RET fusions are a known tumor driver in 1–2% of patients with advanced non-small cell lung cancer (aNSCLC). The advent of selective RET inhibitors (RETi) significantly improved prognosis, but around 20% of patients show primary resistance. Moreover, secondary resistance inevitably occurs and molecular mechanisms are still incompletely characterized. Methods: This multicentric retrospective study included 24 centres. Eligible patients had a RET-rearranged aNSCLC, received treatment with a RETi and had at least one molecular profile by next-generation sequencing (NGS), performed before and/or after RETi, on tissue and/or plasma samples. Primary resistance under RETi was defined as disease progression (PD) within 6 months of therapy. Results: 95 patients were included with 112 biopsies: 93 performed at baseline, 19 at PD. 17 patients had paired NGS (baseline and PD). Median age was 65 years (range 56–72); 62% were female, 54% were never smokers, 17% presented with brain metastasis (BM) at diagnosis. 55 patients received pralsetinib, 36 selpercatinib, 4 other RETi. Overall, median progression-free survival (PFS) under RETi was 17.1 months (95%CI 12.6–28). Primary resistance to RETi occurred in 22 (23%) patients. Primary resistant did not show statistically significant differences when compared to durable responders to RETi in terms of histology (adenocarcinoma vs other, 9% vs 46%, p = 0.61), smoking history (57% vs 40%, p = 0.21), BM (5% vs 21%, p = 0.1), TP53 co-mutations (37% vs 22%, p = 0.23). KRAS G12 V mutation and SMARCA4 alterations were found only in poor responders (4.5% vs 0%, p = 0.2; and 25% vs 0%, p = 0.04, respectively). Considering biopsies at PD (N = 19, 13 liquid and 6 tissue biopsies), 7/13 (54%) liquid biopsies failed due to insufficient ctDNA. Among 12 evaluable patients, 3 (25%) acquired secondary RET mutations (G810S in two cases, S904F in one case), and 3 (25%) patients had off-target alterations, consisting in 2 MET amplification and 1 MYC amplification. Three patients (25%) developed novel TP53 mutations, while 3 (25%) had no novel identifiable alterations at PD. Conclusions: SMARCA4 and KRAS baseline co-mutations may have a role in primary resistance to RETi. Secondary RET mutations and MET/MYC amplifications were identified after treatment with RETi. Conflict of interest: Ownership: none Advisory Board: Viatris, Takeda, AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche/Genentech, Eli Lilly and Company, Novartis, Merck Sharp & Dohme, Bristol Myers Squibb, AMGEN, GSK, Sanofi Board of Directors: none Corporate-sponsored Research: Merck Sharp & Dome, Abbvie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, IPSEN, Merck KGaA, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma. Other Substantive Relationships: none

We developed a KEAP1/NFE2L2 pathway signature that robustly predicts functional mutations of KEAP1- and NFE2L2-mutated NSCLC. To determine the prognostic value of this signature, we identified a cohort with KEAP1/NFE2L2 mutations and compared it with a control cohort lacking established targetable driver mutations.

Background: In hospital, falls are frequent adverse events. Certain drugs affect the fall risk, therefore studying prescriptions may reveal perilous combinations and support falls prevention. As neurologic diseases frequently increase fall risk, neurologic patients require special attention concerning fall prevention. Aim: To analyse the performance of the electronic adverse drug reaction check programmes VERIKO® and SCHOLZ Datenbank® in identifying neurologic patients with a high drug-associated fall risk. Method: Falls in the Department of Neurology in 2016 were matched to fall-free control patients of the same age, sex and principal diagnosis. Their estimated fall risk and other risk factors were compared using univariate and a multifactorial conditional logistic regression. Receiver operating characteristic curves visualised the performance of both programmes. R² for a model with and without software was calculated. Results: Eighty-seven matched pairs were analysed. In the univariate analyses, VERIKO risk estimations showed a significant correlation to fall events (OR=1.448, CI=1.061-1.975). Additionally, the number of comorbidities (OR=1.086, CI=1.013-1.164), the Hospital Frailty Risk Score (OR=1.085, CI=1.025-1.149), impaired balance (OR=3.6, CI=1.337-9.696), gait abnormality (OR=4.75, CI=1.616-13.962), presence of delirium (OR=3.4, CI=1.254-9.216) and previous falls (OR=8.0, CI=1.839-34.793) were related to high fall risk. Polypharmacy and the number of potentially inappropriate medications did not correlate with fall events. In the multivariate analysis, the Hospital Frailty Risk Score was associated to fall risk (OR=1.390, 95%-CI=1.049-1.842). Both programmes showed an area under the receiver operating characteristics curves < 0.6 and improved the model performance slightly (ΔR² ≤ 0.0006). Conclusion: VERIKO risk estimations correlated significantly to fall events. Nevertheless, both programmes showed little accuracy in identifying drug-associated fall risk.

ROS1-directed Tyrosine-Kinase-Inhibitors (TKIs) target activating fusions in the ROS1 proto-oncogene efficiently in non-small cell lung cancer (NSCLC) patients. Besides solvent-front mutations (SFMs) in resistance to targeted therapy, ROS1 aberrations other than fusions remain biologically unexplored. Driving on our thus far clinical investigations, we aimed at determining the functional impact and the potential to act as a drug target. Tumor samples from NSCLC patients were screened with two next-generation sequencing (NGS) panels. Patients with activating ROS1 fusions, SFMs and benign Single-Nucleotide Polymorphisms (SNPs) were excluded using the gnomAD database. The Provean and PolyPhen-2 tools predicted the functional impact of the detected aberrations. ChimeraX was used for drug binding analysis. Of 8072 patients analyzed by NGS between 2018 and 2022, 110 (1.4%) patients harbored small-scale ROS1 aberrations. Our cohort consists of 113 aberrations leading to 95 (84.1%) missense, 12 (10.6%) truncating and 1 (0.1%) in-frame aberrations. In 10% of patients ROS1 aberration was mutually exclusive and most ROS1 aberrations were transitions (55%). Polyphen predicts 75.5% of aberrations to be ‘possibly’ (6.4%), respectively ‘probably damaging’ (68.1%, mean score 0.75, median score 0.999). Provean predicts 50% of aberrations to be ‘deleterious’. Polyphen-2 and Provean coherently predict 46.8% of aberrations to be ‘deleterious’ respectively ‘possibly/probably damaging’. Amid the tyrosine kinase domain almost all aberrations are predicted to be ‘probably damaging’ respectively ‘deleterious’ by both tools coherently and feature a higher-than-average score. Besides, no distinct molecular pattern occurs. The M2029T and R2083T missense mutations interfere with single hydrogen-bonds and Van-Der-Waals forces in the ROS1 drug-binding pocket between the respective residues and the TKIs crizotinib and lorlatinib. However, drug binding analysis revealed that the overall binding of the TKIs is not affected. This evidence proves a functional and deleterious impact of specific aberrations and indicates a high potential to be targetable. We warrant further studies to elaborate these findings in vitro and in vivo.

Fusions in the ROS1 proto-oncogene are among the best treatable genetic aberrations in Non-small cell lung cancer (NSCLC). Besides the occurrence of solvent-front mutations (SFM) in acquired resistance to targeted therapy, little is known about small-scale ROS1 aberrations. We comprehensively analyzed clinical and molecular characteristics of ROS1 mutations in NSCLC patients without activating ROS1 fusions or SFMs.

Paediatric patients are more vulnerable to be harmed by medication errors compared to adults due to pharmacokinetic and pharmacodynamic changes in their development, individual dosing calculations, and manipulation of ready to-use products intended for adult patients. According to the Institute of Safe Medication Practices, there are some "drugs that bear a heightened risk of causing significant patient harm when they are used in error"; these drugs are called high-alert medications (HAM). The two-step survey among paediatric clinical expert pharmacists presented here aimed to compile a nation-wide HAM list. To provide detailed guidance, this survey followed a drugbased approach, resulting in specific potential drug related problems (DRPs) and associated recommendations for prevention. In contrast to this approach, in the first round of the survey two drug classes were included that both were rated as HAM (i.e.chemotherapy and parenteral nutrition). Twenty single drugs were identified as HAM, 65% of which were cardiovascular or neurological drugs. The paediatric expert pharmacists mentioned in total 216 potential DRPs; in particular, they identified potential administration-related problems (28% of all DRPs), dosing-related problems (26%), and drug-choice-related problems (18%, e.g.drug confusion and drug monitoring). Moreover, they suggested 275 potential interventions to address these DRPs. Two thirds of all interventions dealt with the preparation by the hospital pharmacy, standardisation of processes (e.g.labelling), and education or training. In conclusion, this survey provided a German paediatric high-alert medication list from a paediatric pharmacist point of view. Moreover, the experts mentioned for the first time specific potential DRPs and associated interventions to guide a local multidisciplinary approach for preventing medication-related harm in children.

Background: At the end of March 2020, the state government in NRW created the Virtual Hospital COVID-19 as part of its pandemic strategy, a unique healthcare structure in Germany to provide all intensive care beds in the state with the expertise of a maximum care provider. Objective: Evaluation of feasibility and patient benefit of the digital care network VKH COVID-19. Methods: The innovative digital health-care network offers nationwide 24 / 7 / 365 expert teleconsultations via audio and video connection for COVID-19 patients requiring intensive care medicine. The expert teleconsultation request is made over a web-based platform, and the standardised expert teleconsultations follows promptly. Data protection-compliant exchange takes place with the aid of an electronic case file. Results: Between 30 Mar. and 9 Nov. 2020, 93 hospitals joined the VKH digital healthcare network. A total of 112 critically ill COVID-19 patients requiring intensive care were treated with 790 tele-intensive care expert consultations (mean 7 per patient (SD +/- 9.6)) by the expert site University Hospital RWTH Aachen. Lung protective ventilation (68.1 %, in 538/790 consults), negative fluid balance (63.9 %, in 505 / 790 consults) and positioning therapy (46.4 % in 52 / 112 patients) were among the most common treatment recommendations. The transfer rate to the maximum care provider was 8 %. The lethality rate of critically ill COVID-19 patients with expert teleconsultations was 22.3 %. In the collective of ventilated patients, the lethality rate was 34,2 %. Conclusions: The challenges of the COVID-19 pandemic were competently met by establishing the innovative digital healthcare network VKH COVID-19. Since the beginning of the pandemic in NRW, access to a maximum care pro-vider has been ensured through expert teleconsultations for critically ill COVID-19 patients, independent of time and location.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are beneficial in surgical settings, they may however lead to adverse drug reactions including decreased renal function, a risk, which is exacerbated by combination with other nephrotoxics, and particularly when NSAIDs are given as part of a so-called 'Triple Whammy' (TW) with diuretics and renin-angiotensin system blockers. The objective of this study was to identify the prevalence of TW-prescriptions in a surgical inpatient setting and to document the changes in renal function after pharmacist recommendations. A prospective, observational single centre pilot study was performed using a series of eleven weekly Point-Prevalence Analyses (PPA). Adult surgical inpatients were screened for a TW-prescription by a clinical pharmacist, who made one of two recommendations on identification of a TW: for patients with eGFR > 60 ml/min/1.73m² close monitoring of renal function; for patients with eGFR ≤ 60 ml/min/1.73m² discontinuation of NSAID. A TW was identified in 18 of 317 patients (prevalence 5.7%; mean age 75 years). NSAID discontinuation was recommended for 7/18 patients (39%) and implemented for six (33%). In cases where the NSAID was de-prescribed, an improvement in renal function until the time of discharge was observed, whilst in patients with eGFR > 60 ml/min/1.73m² for whom monitoring was recommended eGFR remained stable. TW-prescriptions were found to be a potential problem in the studied group of older surgical inpatients. Clinical pharmacists are well placed to identify patients who are prescribed a TW, and to advise on the management of these patients.