Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation.

BACKGROUNDPhase 1 study of ATRinhibition alone or with radiation therapy (PATRIOT) was a first-in-human phase I study of the oral ATR (ataxia telangiectasia and Rad3-related) inhibitor ceralasertib (AZD6738) in advanced solid tumors.METHODSThe primary objective was safety. Secondary objectives included assessment of antitumor responses and pharmacokinetic (PK) and pharmacodynamic (PD) studies. Sixty-seven patients received 20-240 mg ceralasertib BD continuously or intermittently (14 of a 28-day cycle).RESULTSIntermittent dosing was better tolerated than continuous, which was associated with dose-limiting hematological toxicity. The recommended phase 2 dose of ceralasertib was 160 mg twice daily for 2 weeks in a 4-weekly cycle. Modulation of target and increased DNA damage were identified in tumor and surrogate PD. There were 5 (8%) confirmed partial responses (PRs) (40-240 mg BD), 34 (52%) stable disease (SD), including 1 unconfirmed PR, and 27 (41%) progressive disease. Durable responses were seen in tumors with loss of AT-rich interactive domain-containing protein 1A (ARID1A) and DNA damage-response defects. Treatment-modulated tumor and systemic immune markers and responding tumors were more immune inflamed than nonresponding.CONCLUSIONCeralasertib monotherapy was tolerated at 160 mg BD intermittently and associated with antitumor activity.TRIAL REGISTRATIONClinicaltrials.gov: NCT02223923, EudraCT: 2013-003994-84.FUNDINGCancer Research UK, AstraZeneca, UK Department of Health (National Institute for Health Research), Rosetrees Trust, Experimental Cancer Medicine Centre.

Patient experience of imaging reports: A systematic literature review.

Introduction: Written reports are often the sole form of communication from diagnostic imaging. Reports are increasingly being accessed by patients through electronic records. Experiencing medical terminology can be confusing and lead to miscommunication, a decrease in involvement and increased anxiety for patients. Methods: This systematic review was designed to include predefined study selection criteria and was registered prospectively on PROSPERO (CRD42020221734). MEDLINE, CINAHL, Academic Search Complete (EBSCOhost), EMBASE, Scopus and EThOS were searched to identify articles meeting the inclusion criteria. Studies were assessed against the Mixed-Methods Appraisal Tool version 2018 for quality. A segregated approach was used to synthesise data. A thematic synthesis of the qualitative data and a narrative review of the quantitative data were performed, and findings of both syntheses were then integrated. Findings: Twelve articles reporting 13 studies were included. This review found that patients' experiences of imaging reports included positive and negative aspects. The study identified two main themes encompassing both qualitative and quantitative findings. Patients reported their experiences regarding their understanding of reports and self-management. Discussion: Patient understanding of imaging reports is multi factorial including medical terminology, communication aids and errors. Self-management through direct access is important to patients. While receiving bad news is a concern, responsibility for accessing this is accepted. Conclusion: A patient-centred approach to writing imaging reports may help to improve the quality of service, patient experience and wider health outcomes.

Epitope Lability of Phosphorylated Biomarkers of the DNA Damage Response Pathway Results in Increased Vulnerability to Effects of Delayed or Incomplete Formalin Fixation.

Phosphorylated biomarkers are crucial for our understanding of drug mechanism of action and dose selection during clinical trials, particularly for drugs that target protein kinases, such as DNA-damage-response (DDR) inhibitors. However, tissue fixation conditions needed to preserve DDR-specific phospho-biomarkers have not been previously investigated. Using xenograft tissues and tightly controlled formalin fixation conditions, we assessed how preanalytical factors affect phosphorylated DDR biomarkers pRAD50(Ser635), ɣH2AX(Ser139), pKAP1(Ser824), and non-phosphorylated biomarkers cMYC and ATM. Cold ischemia times ranged from 15 min to 6 hr, and the fixation duration ranged from 24 hr to 4 weeks. Epitopes pRAD50 and pKAP1 appeared the most labile assessed with staining loss after just 15 min of cold ischemia time, while ATM was more robust showing consistent expression up to 1 hr of cold ischemia. Notably, ɣH2AX expression was lost with formalin fixation over 48 hr. The use of core needle biopsies where possible and novel fixation methods such as the 2-step temperature-controlled formalin approach may improve phosphorylated biomarker preservation; however, practical challenges may affect wider clinical application. The most essential tissue-processing step when downstream analysis includes DDR phosphorylated biomarkers is immediate tissue submersion in formalin, without delay, upon excision from the patient, followed by room temperature fixation for 24 hr.

An investigation of barriers and enablers to community eye care for children in England: A qualitative descriptive study.

PURPOSE: Research suggests that there are challenges in the accessibility of eye care for children in England. This study explores the barriers and enablers to eye examinations for children under 5 years of age from the perspective of community optometrists in England. METHODS: Optometrists working in community settings were invited to participate in virtual focus group discussions using an online platform based on a topic guide. The discussions were audio-recorded, transcribed and thematically analysed. Themes were derived from the focus group data based on the study aim and research question. RESULTS: Thirty optometrists participated in the focus group discussions. The overarching themes identified as barriers to eye examinations for young children in a community setting were as follows: 'Time and Money', 'Knowledge, Skills and Confidence', 'Awareness and Communication', 'Range of Attitudes' and 'Clinical Setting'. The key themes for enabling eye examinations for young children were as follows: 'Improving behaviour', 'Enhancing training and education', 'Enhancing eye care services', 'Raising awareness', 'Changes in professional bodies' and 'Balancing commercial pressures and health care'. CONCLUSION: Time, money, training and equipment are perceived by optometrists as key factors in providing an eye examination for a young child. This study identified a need for improved training and robust governance related to eye examinations for young children. There is a need for change within eye care service delivery such that all children, regardless of age and ability, are examined regularly, and by conducting these examinations, optometrists remain confident.

Retrospective analysis of Schlafen11 (SLFN11) to predict the outcomes to therapies affecting the DNA damage response.

BACKGROUND: The absence of the putative DNA/RNA helicase Schlafen11 (SLFN11) is thought to cause resistance to DNA-damaging agents (DDAs) and PARP inhibitors. METHODS: We developed and validated a clinically applicable SLFN11 immunohistochemistry assay and retrospectively correlated SLFN11 tumour levels to patient outcome to the standard of care therapies and olaparib maintenance. RESULTS: High SLFN11 associated with improved prognosis to the first-line treatment with DDAs platinum-plus-etoposide in SCLC patients, but was not strongly linked to paclitaxel-platinum response in ovarian cancer patients. Multivariate analysis of patients with relapsed platinum-sensitive ovarian cancer from the randomised, placebo-controlled Phase II olaparib maintenance Study19 showed SLFN11 tumour levels associated with sensitivity to olaparib. Study19 patients with high SLFN11 had a lower progression-free survival (PFS) hazard ratio compared to patients with low SLFN11, although both groups had the benefit of olaparib over placebo. Whilst caveated by small sample size, this trend was maintained for PFS, but not overall survival, when adjusting for BRCA status across the olaparib and placebo treatment groups, a key driver of PARP inhibitor sensitivity. CONCLUSION: We provide clinical evidence supporting the role of SLFN11 as a DDA therapy selection biomarker in SCLC and highlight the need for further clinical investigation into SLFN11 as a PARP inhibitor predictive biomarker.

Specific targeting of the KRAS mutational landscape in myeloma as a tool to unveil the elicited antitumor activity.

Alterations in KRAS have been identified as the most recurring somatic variants in the multiple myeloma (MM) mutational landscape. Combining DNA and RNA sequencing, we studied 756 patients and observed KRAS as the most frequently mutated gene in patients at diagnosis; in addition, we demonstrated the persistence or de novo occurrence of the KRAS aberration at disease relapse. Small-molecule inhibitors targeting KRAS have been developed; however, they are selective for tumors carrying the KRASG12C mutation. Therefore, there is still a need to develop novel therapeutic approaches to target the KRAS mutational events found in other tumor types, including MM. We used AZD4785, a potent and selective antisense oligonucleotide that selectively targets and downregulates all KRAS isoforms, as a tool to dissect the functional sequelae secondary to KRAS silencing in MM within the context of the bone marrow niche and demonstrated its ability to significantly silence KRAS, leading to inhibition of MM tumor growth, both in vitro and in vivo, and confirming KRAS as a driver and therapeutic target in MM.

Phase I Study of Ceralasertib (AZD6738), a Novel DNA Damage Repair Agent, in Combination with Weekly Paclitaxel in Refractory Cancer.

PURPOSE: Ceralasertib is a potent and selective oral inhibitor of the serine/threonine protein kinase ataxia telangiectasia and Rad3-related (ATR) protein. PATIENTS AND METHODS: Eligible patients with solid tumors, enriched for melanoma, received ceralasertib in combination with a fixed dose of paclitaxel (80 mg/m2 on D1, D8, D15) in 28-day cycles. The dose of ceralasertib was escalated to reach an MTD in a rolling 6 design. The starting dose of ceralasertib was 40 mg QD. Fifty-seven patients (33 patients with melanoma who failed prior PD1/L1 treatment) were enrolled in 7 dose cohorts ranging from 40 mg QD to 240 mg BD plus weekly paclitaxel. RESULTS: The RP2D was established as ceralasertib 240 mg BD days 1-14 plus paclitaxel 80 mg/m2 on D1, D8, D15 every 28 days. The most common toxicities were neutropenia (n = 39, 68%), anemia (n = 25, 44%), and thrombocytopenia (n = 21, 37%). In the full analysis set of 57 patients, the overall response rate (ORR) was 22.6% (95% CI, 12.5-35.3). In 33 patients with melanoma, resistant to prior anti-PD1 therapy, the ORR was 33.3% (95% CI, 18.0-51.8). In the melanoma subset, the mPFS was 3.6 months (95% CI, 2.0-5.8), the median duration of response was 9.9 months (95% CI, 3.7-23.2), and the mOS was 7.4 months (95% CI, 5.7-11.9). CONCLUSIONS: Ceralasertib in combination with paclitaxel was well tolerated in patients with advanced malignancies and showed evidence of antitumor activity. Durable responses were observed in patients with advanced cutaneous, acral, and mucosal melanoma resistant to anti-PD1/L1 treatment.See related commentary by Ashworth, p. 4667.

AZD0364 Is a Potent and Selective ERK1/2 Inhibitor That Enhances Antitumor Activity in KRAS-Mutant Tumor Models when Combined with the MEK Inhibitor, Selumetinib.

The RAS-regulated RAF-MEK1/2-ERK1/2 (RAS/MAPK) signaling pathway is a major driver in oncogenesis and is frequently dysregulated in human cancers, primarily by mutations in BRAF or RAS genes. The clinical benefit of inhibitors of this pathway as single agents has only been realized in BRAF-mutant melanoma, with limited effect of single-agent pathway inhibitors in KRAS-mutant tumors. Combined inhibition of multiple nodes within this pathway, such as MEK1/2 and ERK1/2, may be necessary to effectively suppress pathway signaling in KRAS-mutant tumors and achieve meaningful clinical benefit. Here, we report the discovery and characterization of AZD0364, a novel, reversible, ATP-competitive ERK1/2 inhibitor with high potency and kinase selectivity. In vitro, AZD0364 treatment resulted in inhibition of proximal and distal biomarkers and reduced proliferation in sensitive BRAF-mutant and KRAS-mutant cell lines. In multiple in vivo xenograft models, AZD0364 showed dose- and time-dependent modulation of ERK1/2-dependent signaling biomarkers resulting in tumor regression in sensitive BRAF- and KRAS-mutant xenografts. We demonstrate that AZD0364 in combination with the MEK1/2 inhibitor, selumetinib (AZD6244 and ARRY142886), enhances efficacy in KRAS-mutant preclinical models that are moderately sensitive or resistant to MEK1/2 inhibition. This combination results in deeper and more durable suppression of the RAS/MAPK signaling pathway that is not achievable with single-agent treatment. The AZD0364 and selumetinib combination also results in significant tumor regressions in multiple KRAS-mutant xenograft models. The combination of ERK1/2 and MEK1/2 inhibition thereby represents a viable clinical approach to target KRAS-mutant tumors.

AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity.

DNA-dependent protein kinase (DNA-PK) is a critical player in the DNA damage response (DDR) and instrumental in the non-homologous end-joining pathway (NHEJ) used to detect and repair DNA double-strand breaks (DSBs). We demonstrate that the potent and highly selective DNA-PK inhibitor, AZD7648, is an efficient sensitizer of radiation- and doxorubicin-induced DNA damage, with combinations in xenograft and patient-derived xenograft (PDX) models inducing sustained regressions. Using ATM-deficient cells, we demonstrate that AZD7648, in combination with the PARP inhibitor olaparib, increases genomic instability, resulting in cell growth inhibition and apoptosis. AZD7648 enhanced olaparib efficacy across a range of doses and schedules in xenograft and PDX models, enabling sustained tumour regression and providing a clear rationale for its clinical investigation. Through its differentiated mechanism of action as an NHEJ inhibitor, AZD7648 complements the current armamentarium of DDR-targeted agents and has potential in combination with these agents to achieve deeper responses to current therapies.

Therapeutic Error Calls Among Older Adults Reported to a Regional Poison Control Center in Alabama.

OBJECTIVES: Although Americans aged 65 years and older account for only 13.0% of the population, they consume one-third of all prescription medications each year. Increased life expectancy, age-related deterioration in health, and polypharmacy lead to a significant risk of potential medication errors. National Poison Data System studies have evaluated the older adult population and their interaction with poison centers; however, descriptive studies using regional poison center data to evaluate older adult-related medication errors, specifically in Alabama, have not been conducted. Our study assessed therapeutic errors in patients aged 65 years and older to evaluate the need for potential interventions by pharmacists and preventive education to reduce errors reported to the Regional Poison Control Center (RPCC) at Children's of Alabama. METHODS: A four-year retrospective analysis was conducted by gathering call-specific data from the RPCC toxiCALL database. Calls were included if they were made to the RPCC between January 1, 2010 and December 31, 2013, involved patients aged 65 years and older, and were coded as unintentional therapeutic errors. Analysis of call data was conducted using the Centers for Disease Control and Prevention's EpiInfo version 7.0.9.7. RESULTS: A total of 1699 calls were evaluated for patient demographics (sex, age), call data (month, year, shift, caller site), reason for therapeutic error, clinical effects, medical outcome, management site, and reported substance details. Nearly 40.0% of the therapeutic errors were caused by patients taking or being given the same medication twice. Five of the 15 reasons for therapeutic errors accounted for nearly 82.0% of all calls reported. The reasons included taking or being given the same medication twice (37.3%), taking or being given the wrong medication (14.6%), using an incorrect dosing route (13.1%), other incorrect dosing errors (9.9%), and taking doses too close together (7.5%). The top individual substance involved in a therapeutic error was reported verbatim by callers as Spiriva inhalation capsules (10.5%). CONCLUSIONS: Therapeutic error calls represent a significant and increasing proportion of calls made by older adults to the RPCC. The frequent interactions between healthcare providers and patients create opportunities to prospectively prevent medication problems in older adult patients. Healthcare providers, specifically pharmacists, should encourage clients to always read the label on medications and should counsel patients carefully when dispensing a product that is not an oral preparation. In addition, although national drug take-back days are conducted biennially, patients should be encouraged to dispose of old medications and expired over-the-counter medications. The RPCC toll-free telephone number (800-222-1222) may be displayed to educate patients on its 24-hour/day availability. Current data will be used to implement programs for pharmacist interventions and to create appropriate educational material.