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A 72-year-old man presented to his general practitioner with worsening dyspnea and was diagnosed with having recurrent ROS1-positive stage IIIB NSCLC 8 years after initial diagnosis and radical treatment for early stage disease. He was subsequently started on entrectinib but required hospital admissions for recurrent acute kidney injuries on a background of chronic kidney disease. His entrectinib was withheld on day 20 since his first dose of treatment while he was being investigated. Nevertheless, he continued to experience worsening dyspnea and bilateral pedal edema and later developed acute pulmonary edema 31 days after his first dose of entrectinib, despite the drug being withheld for the past 11 days. Results of biochemical tests and cardiac imaging confirmed acute myocarditis. Initially, he was treated with standard heart failure medications without clinical improvement or decline in N-terminal pro B-type natriuretic peptide levels. Nevertheless, he noticed significant improvement after starting a short course of prednisolone, which led to complete resolution of symptoms, improved N-terminal pro B-type natriuretic peptide levels, and recovery of left ventricular ejection fraction. His treatment was subsequently changed to crizotinib, which was well tolerated. This is the third reported case of entrectinib-induced myocarditis and the first reported case which has been successfully managed with steroid therapy. This case was also associated with concurrent acute heart failure after entrectinib treatment which responded promptly to prednisolone (40 mg). Entrectinib-induced cardiotoxicity is an important adverse event to be aware of, particularly as patients may be asymptomatic for an initial period before significant deterioration.

Abstract Background Immune checkpoint inhibitors, including those against programmed cell death protein-1 (PD-1) or its ligand (PD-L1), are routinely used to treat non-small cell lung cancer (NSCLC). PD-L1 is a validated prognostic and predictive immunohistochemical biomarker of anti-PD-1/PD-L1 therapy but displays temporospatial heterogeneity of expression. Non-invasive radiopharmaceutical techniques, including technetium-99m [99mTc]-labelled anti-PD-L1 single-domain antibody (NM-01) SPECT/CT, have the potential to improve the predictive value of PD-L1 assessment. This study aims to determine the inter- and intra-rater agreement of the quantitative measurement of [99mTc]NM-01 SPECT/CT in NSCLC. Methods Participants (n = 14) with untreated advanced NSCLC underwent [99mTc]NM-01 SPECT/CT at baseline (n = 3) or at baseline plus 9-week follow-up (n = 11). [99mTc]NM-01 uptake (of primary lung, lymph node, thoracic and distant metastases, and healthy reference tissues) was measured using SUVmax and malignant lesion-to-blood pool ratios with Siemens xSPECT Broad Quantification software by three independent raters. Intraclass correlation coefficients (ICC) were calculated and Bland–Altman plot analysis performed to determine inter- and intra-rater agreement. Results There was excellent inter-rater agreement of manual freehand SUVmax scores of primary lung tumour (T; n = 25; ICC 1.00; 95% CI 0.99–1.00), individual lymph node metastases (LN; n = 56; ICC 0.97; 95% CI 0.95–0.98), thoracic metastases (ThMet; n = 9; ICC 0.94; 95% CI 0.83–0.99) and distant metastases (DisMet; n = 21; ICC 0.91; 95% CI 0.83–0.96). The inter-rater ICCs of tumour-to-blood pool (T:BP), LN:BP, ThMet:BP and DisMet:BP measures of [99mTc]NM-01 uptake also demonstrated good or excellent agreement. Manual freehand scoring of T, LN, ThMet, DisMet and their ratios using [99mTc]NM-01 SPECT/CT following a 28-day interval was consistent for all raters with good or excellent intra-rater agreement demonstrated (ICCs range 0.86–1.00). Conclusion Quantitative assessment of [99mTc]NM-01 SPECT/CT in NSCLC, using SUVmax of malignant primary or metastatic lesions and their ratios with healthy reference tissues, demonstrated good or excellent inter- and intra-rater agreement in this study. Further validation with ongoing and future larger cohort studies is now warranted. Clinical trial registration ClinicalTrials.gov identifier no. NCT04436406 (registered 18th June 2020; available at https://clinicaltrials.gov/ct2/show/NCT04436406 ) and NCT04992715 (registered 5th August 2021; available at https://clinicaltrials.gov/ct2/show/NCT04992715 ).

Abstract Background Myocardial programmed death-ligand 1 (PD-L1) expression is implicated in immune checkpoint inhibitor (ICI)-associated myocarditis. Measurement of myocardial PD-L1 expression may have potential use as a mechanistic and predictive biomarker. The aim of this study was to determine non-invasive assessment of myocardial PD-L1 expression using [99mTc]-labelled anti-PD-L1 single-domain antibody (NM-01) SPECT/CT. Methods Thoracic [99mTc]NM-01 SPECT/CT was performed in lung cancer patients (n = 10) at baseline and 9-weeks following anti-programmed cell death protein 1 (PD-1) therapy. Baseline and 9-week left ventricular and right ventricular to blood pool ratios (LVmax:BP) and (RVmax:BP) were measured. LVmax was compared to background skeletal muscle (musclemax). Intra-rater reliability was determined by intraclass correlation coefficient (ICC) and Bland–Altman analysis. Results Mean LVmax:BP values were 2.76 ± 0.67 at baseline vs 2.55 ± 0.77 at 9 weeks (p = 0.42). Mean RVmax:BP was 1.82 ± 0.32 at baseline vs 1.76 ± 0.45 at 9 weeks (p = 0.67). Myocardial PD-L1 expression was at least threefold greater than skeletal muscle at baseline for the LV (LVmax to musclemax 3.71 ± 0.77 vs 0.98 ± 0.20 (p

Abstract Purpose Checkpoint inhibition therapy using monoclonal antibodies against programmed cell death protein 1 (PD-1) or its ligand (PD-L1) is now standard management of non-small cell lung cancer (NSCLC). PD-L1 expression is a validated and approved prognostic and predictive biomarker for anti-PD-1/PD-L1 therapy. Technetium-99 m [99mTc]-labelled anti-PD-L1 single-domain antibody (NM-01) SPECT/CT quantification correlates with PD-L1 expression in NSCLC, presenting an opportunity for non-invasive assessment. The aim of this study was to determine the inter- and intraobserver agreement of the quantitative assessment of [99mTc]NM-01 SPECT/CT in NSCLC. Methods [99mTc]NM-01 SPECT/CT studies of 21 consecutive NSCLC participants imaged for the evaluation of PD-L1 expression were analysed. Three independent observers measured maximum counts in a tumour region of interest (ROImax) of primary lung, metastatic lesions and normal tissue references of both 1 and 2 h post-injection (n = 42) anonymised studies using a manual technique. Intraclass correlation coefficients (ICC) were calculated, and Bland–Altman plot analysis was performed to determine inter- and intraobserver agreement. Results Intraclass correlation of primary lung tumour-to-blood pool (T:BP; ICC 0.83, 95% CI 0.73–0.90) and lymph node metastasis-to-blood pool (LN:BP; ICC 0.87, 0.81–0.92) measures of [99mTc]NM-01 uptake was good to excellent between observers. Freehand ROImax of T (ICC 0.94), LN (ICC 0.97), liver (ICC 0.97) and BP (ICC 0.90) reference tissues also demonstrated excellent interobserver agreement. ROImax scoring of healthy lung demonstrated moderate to excellent interobserver agreement (ICC 0.84) and improved when measured consistently at the level of the aortic arch (ICC 0.89). Manual ROImax re-scoring of T, LN, T:BP and LN:BP using [99mTc]NM-01 SPECT/CT following a 42-day interval was consistent with excellent intraobserver agreement (ICC range 0.95–0.97). Conclusion Good to excellent inter- and intraobserver agreement of the quantitative assessment of [99mTc]NM-01 SPECT/CT in NSCLC was demonstrated in this study, including T:BP which has been shown to correlate with PD-L1 status. [99mTc]NM-01 SPECT/CT has the potential to reliably and non-invasively assess PD-L1 expression. Clinical trial registration ClinicalTrials.gov identifier no. NCT02978196. Registered 30th November 2016.

Activating epidermal growth factor receptor gene mutations (EGFRm) are relatively common in non-small cell lung cancer (NSCLC) and are predictive of superior outcomes with EGFR tyrosine kinase inhibitors (TKIs). Eventually, acquired genetic or phenotypic resistance overcomes EGFR TKI therapy. Heterogeneity of acquired anti-EGFR resistance mechanisms is increasingly described, presenting a significant challenge in their clinical management. Here, we report a rare case of concurrent acquired EGFRT790M and small cell lung cancer transformation in a patient with EGFR exon 21-L858R mutant lung adenocarcinoma, following treatment with a second-generation EGFR TKI. The case highlights the clinical significance of serial EGFR genotyping with peripheral ctDNA alongside targeted biopsies, for the detection of genetic and phenotypic resistance mechanisms to EGFR TKIs, which can occur concurrently. This case provides further evidence in favour of upfront treatment approaches that target the heterogeneity of acquired anti-EGFR resistance mechanisms, such as experimental combinations of cytotoxic chemotherapy with a third-generation EGFR TKI.

Introduction Over one million people in the UK identify as LGBTQ+ (lesbian, gay, bisexual, transgender, queer or questioning). Research has shown that this population experience differing cancer risk factors compared with non-LGBTQ+ patients and persistent inequalities in cancer care. Literature concerning the knowledge of oncologists of this group’s healthcare needs is limited; our study aimed to evaluate knowledge, attitudes and behaviours of UK oncologists about LGBTQ+ patients.Methods A 53-question survey was delivered via a secure online platform. Questions covered respondent demographics, knowledge, attitudes and behaviours with the majority of responses on a Likert scale. Oncologists were recruited via email from professional bodies and social media promotion. Informed consent was sought and responses fully anonymised. Multifactorial ordinal logistic regression and Fisher’s exact test were used to assess for interactions between demographics and responses with Holm-Bonferroni multiple testing correction.Results 258 fully completed responses were received. Respondents had a median age of 43 years (range 28–69); 65% consultants and 35% registrars; 42% medical, and 54% clinical, oncologists. 84% felt comfortable treating LGBTQ+ patients but only 8% agreed that they were confident in their knowledge of specific LGBTQ+ patient healthcare needs. There were low rates of routine enquiry about sexual orientation (5%), gender identity (3%) and preferred pronouns (2%). 68% of oncologists felt LGBTQ+ healthcare needs should be a mandatory component of postgraduate training.Conclusions This survey showed that UK oncologists feel comfortable treating LGBTQ+ patients but may fail to identify these patients in their clinic, making it more difficult to meet LGBTQ+ healthcare needs. There is self-awareness of deficits in knowledge of LGBTQ+ healthcare and a willingness to address this through postgraduate training. Educational resources collated and developed in accordance with this study would potentially improve the confidence of oncologists in treating LGBTQ+ patients and the cancer care these patients receive.