Alastair Greystoke

Purpose: Preclinical data suggest that ceralasertib, a potent ATR inhibitor, might reverse resistance to anti–PD-(L)1 in KRAS-mutant lung adenocarcinoma (LUAD). Activity of ceralasertib/durvalumab was, therefore, assessed in 2 prospective, parallel immune checkpoint blockade–resistant cohorts, 1 harboring KRAS mutations (J1) and the other without (NAJ), within the National Lung Matrix Trial. Patients and Methods: Oral ceralasertib was administered (240 mg twice daily on days 15–28) with durvalumab (1,500 mg i.v., on day 1 of every 28-day cycle) until disease progression. Coprimary outcomes were objective response (OR) and 24-week durable clinical benefit (DCB). Biological impacts of ceralasertib were assessed in a human BJ-hTERT KRASV12ER-TAM model. Immunologic impact of KRAS mutation was assessed using gene-level processed LUAD The Cancer Genome Atlas PanCancer data. Results: Between July 2, 2020, and October 31, 2021, 43 patients were registered, 19 and 18 of whom were evaluable for outcome analysis in cohorts J1 and NAJ, respectively. Cohort target recruitment (30 participants each) was not reached due to trial closure at the preplanned end of funding. Bayesian estimates of DCB rates (95% credible intervals) were 37.7% (19.1–59.2) for J1 and 29.3% (12.6–51.2) for NAJ. Two participants demonstrated OR, both KRAS mutant, 1 of whom had KEAP1/STK11 co-mutation. KRAS mutation significantly increased the proportion of cells harboring ceralasertib-induced micronuclei. Ceralasertib blunted KRAS-mediated STAT1 downregulation. Conclusions: Although outcome measures on ceralasertib/durvalumab in anti–PD-(L)1–resistant patients with LUAD are modestly higher in KRAS-mutant participants, these differences are not significant, a result likely related to the modest impact of KRAS mutation alone on the immunobiology of LUAD.

Modern cancer diagnostics is heavily reliant on molecular data. Next-generation sequencing using liquid biopsy (LB) is primarily focused on identifying predictive and prognostic biomarkers to guide systemic therapy decision making. However, additional findings including genomic variants of possible or probable germline origin are detected in a significant minority of patients (3%-18%), with significant implications for patients and their families. Pretest information provision regarding both the purpose and potential benefits of the test and additional findings on LB varies in clinical practice, with little guidance for clinicians regarding the degree of detail required regarding possible additional findings. LB requires explicit disclosure of these aspects. Implementing a standardized, context-dependent approach to this discussion, with nationally standardized information provision tools, should be prioritized to enable patient-centered decision making regarding LB, without prioritizing the incidentalome over the primary purpose of the test—refining and optimizing treatment options.

Background/Objectives: Simple frailty assessments, such as the clinical frailty scale (CFS), are prognostic for worse outcomes in older adults with cancer and could support treatment decision-making. This interview study aims to explore clinicians’ experiences of using simple frailty assessments in oncology, including the impacts on patient care and barriers and facilitators to successful implementation. Methods: Semi-structured individual interviews were conducted with clinicians at three UK sites that had implemented CFS screening in lung cancer clinics as part of a national pilot, to explore how frailty assessments are applied and are impacting care. Purposive sampling targeted a range of professionals involved in assessing frailty and making treatment decisions. Recordings were transcribed verbatim and analysed thematically. Results: Ten clinicians participated, and four main themes were identified. ‘Assessing fitness and frailty’ explores the central role of performance status (PS), as well as its limitations, and what frailty assessments add. ‘Scoring and interpreting CFS’ describes the ease and relative yield of CFS use, particularly for patients with ‘borderline’ PS scores (e.g., PS 1–2 or 2–3), and the importance of contextual interpretation. ‘Role of frailty and impacts of assessment’ highlights how frailty assessments can enhance patient-centered care and support, and clinical and shared decision-making, with potential for streamlined care and system-level benefits. ‘Barriers and facilitators to implementation’ are described, including time, culture, guidance, and training, with recommendations provided. Conclusions: Assessing frailty has wide-ranging potential benefits for patients, oncology teams, and the wider system, but barriers must be overcome. Specific recommendations are provided to support the routine implementation of frailty assessments, which is a key step towards the benefits of frailty-informed care being realised at scale.

Supplementary data: Methods, tables, figure.

Background: The Experimental Cancer Medicine Centre (ECMC) Network supports UK-wide access to experimental cancer therapies, many of which require specific genomic alterations. This study aimed to develop expert consensus on essential genes for a pan-cancer sequencing panel, involving subject matter experts (SMEs) from the ECMC Network and the pharmaceutical industry. Methods: A pilot with 8 SMEs graded 526 genes, refining the list to 210. A three-round Delphi process was then used, with SMEs iteratively evaluating each gene. In the final round, SMEs also assessed the inclusion of tumour mutational burden (TMB), microsatellite instability (MSI), and mutation types (structural variations, copy number variations, and/or fusions). Results: Consensus was reached on a final panel of 99 genes applicable across multiple cancers. High agreement was also achieved for including TMB, MSI, and screening for structural variations, copy number variants, and fusions. The panel is intended for both adult and paediatric tumour types. Conclusions: This consensus-based gene panel offers a standardised approach to pan-cancer genomic screening. It supports harmonised diagnostics and could improve patient access to personalised therapies and research trials across clinical and NHS settings.

PURPOSE: This early-phase study evaluated safety/tolerability, pharmacokinetics, and preliminary efficacy of dendrimer-nanoparticle delivery platform (DEP)-SN38, a polylysine-based nanoparticle conjugate of the irinotecan active metabolite, SN38. METHODS: Adults with advanced solid tumors received DEP-SN38 intravenously once every 3 weeks (Q3W) or once every 2 weeks (Q2W) monotherapy, or Q2W combined with fluorouracil/leucovorin (FU/LV) to identify a recommended dose for each regimen. Primary end points were safety/tolerability. Secondary end points included efficacy (RECIST-v1.1) and pharmacokinetics. RESULTS: Heavily pretreated patients (N = 114; median 4 previous therapies) received DEP-SN38 (8-15-mg/m ² SN38), with 12.5 mg/m ² recommended for all regimens. Most DEP-SN38–attributed treatment-related adverse events (TRAEs) were mild/moderate (89.7%), with neutropenia the key dose-limiting toxicity and the most common grade 3/4 TRAE (48% of grade 3/4 events). Severe GI TRAEs were rare (grade 3 diarrhea and vomiting [0.9% of patients each]; nausea [1.8%]). Cholinergic symptoms were not observed. Efficacy signals were observed across several tumor types, particularly Q2W regimens and in patients with platinum-resistant ovarian cancer (PROC) and colorectal cancer (CRC). Among evaluable patients, objective response rates for Q3W or Q2W monotherapy and Q2W DEP-SN38/FU/LV were 1.8%, 21.4% (PROC 42.9%), and 12.5% (CRC 14.3%), respectively; disease control rates were 56.4%, 71.4%, and 81.3%, respectively. Median progression-free survival (PFS, all treated) was 2.1, 6.0, and 4.2 months for Q3W, Q2W, and Q2W DEP-SN38/FU/LV, respectively. Patients achieving PFS for at least 6 months included seven PROC (Q2W monotherapy, n = 5; > 12 months, n = 3), 12 CRC (DEP-SN38/FU/LV, n = 6, including four patients for >12 months), one pancreatic (10.2 months), one non-small cell lung (8.4 months), and two with breast cancer (16.6 months, 6 months). CONCLUSION: DEP-SN38 was clinically well tolerated with minimal severe GI TRAEs. Preliminary antitumor activity in heavily pretreated patients with cancer demonstrates the potential clinical utility of DEP-SN38 monotherapy and combination regimens.

Use of signal transduction inhibitors as single agents to treat cancer leads to resistance because of the plasticity of intracellular signaling, and combination therapy can overcome this. We describe the first-in-human trial of avutometinib (RAF–MEK clamp) and defactinib (focal adhesion kinase inhibitor) in patients with solid tumors. The trial met its primary endpoint and recommended a phase 2 dose and schedule. The recommended phase 2 dose and schedule for a 28-day cycle was determined to be avutometinib 3.2 mg once a day, twice weekly (Monday and Thursday or Tuesday and Friday), and defactinib 200 mg twice a day, seven days a week. Both drugs were administered orally on a 3 weeks ‘on’ and 1 week ‘off’ basis. The pharmacokinetics and pharmacodynamics were consistent with previous reports of avutometinib and defactinib used as single agents. Key findings include an objective response rate of 42.3% (11 of 26; 95% confidence interval 23.4–63.1) and a median progression-free survival of 20.1 months (95% confidence interval 11.2–43.9) in patients with low-grade serous ovarian cancer. This study demonstrates the importance of intermittent dosing schedules in combined targeting of the mitogen-activated protein kinase and focal adhesion kinase pathways to improve tolerability, and has acquired proof of concept of anti-tumor activity against low-grade serous ovarian cancer, a tumor relatively resistant to chemotherapy. ClinicalTrials.gov identifier NCT03875820.

Objectives: Survival from lung cancer is worse in the UK than in some other countries, with late stage at diagnosis implicated in poor prognosis. The route and referral urgency by which patients obtain a diagnosis influence outcomes. This study investigated whether socio-demographic factors are associated with lung cancer routes to diagnosis in England. Materials and Methods: A total of 181,763 primary invasive lung cancers (ICD-10 C34.0-C34.9) diagnosed from 1 January 2012 to 31 December 2016 were abstracted from the English National Cancer Registration Database. Multivariable logistic regression was used to examine associations between patients’ socio-demographic characteristics and likelihood (adjusted odds ratios) of (i) emergency presentation versus all primary care-initiated routes and (ii) urgent (“two-week wait”/2WW) versus standard primary care-initiated referral. Models included the following factors: deprivation quintile of area of residence at diagnosis (IMD income domain); sex; age; ethnic group; rural/urban residence; and (in the emergency model) region. Results: Socio-demographic variations in diagnosis routes were observed. Patients presenting as emergencies (35.2%) were more likely to be 80 years of age or older, female, of non-White ethnicity, and resident in areas of greater deprivation or the London region. In contrast, 2WW patients (28.3%) were more likely to be aged between 50 and 69 years old, of White ethnicity, and resident in an area of greater deprivation or resident outside of an urban centre; diagnosis through 2WW did not vary by sex. Conclusions: Routes to diagnosis are subject to distinct socio-demographic patterning. Action is needed to ensure that new referral guidelines and lung cancer screening roll-out do not widen socio-demographic inequalities in diagnosis.