The histopathological spectrum and molecular changes associated with KRAS G12C mutation in non-small cell lung carcinoma.

KRAS G12C is the most common KRAS mutation in non-small cell lung carcinoma (NSCLC), for which targeted therapy has recently been developed. From the 732 cases of NSCLC that underwent next-generation sequencing at the Department of Anatomical Pathology, Liverpool Hospital, between July 2021 and May 2023, we retrieved 83 (11%) consecutive cases of KRAS G12C mutated NSCLC, and analysed their clinical, pathological, and molecular features. Of the 83 cases of KRAS G12C mutated NSCLC, there were 46 (55%) men and 37 (45%) women, with mean age of 72 years. Of the 49 cases with known clinical information, 94% were current or ex-smokers, and 49% were stage IV at diagnosis with median survival of 12 months. Sixty-three percent were histology cases and the remainder were cytology cases. Eighty-two percent were non-mucinous adenocarcinomas, with conventional histology including lepidic, acinar, solid, single cells and micropapillary patterns, and 62% were poorly differentiated. There were five (6%) cases of mucinous adenocarcinoma, one case of pleomorphic carcinoma and one case of high-grade fetal adenocarcinoma. TTF1 was positive in the majority (89%) of cases. Nineteen (23%) cases had TP53 co-mutation, and these cases had trends towards higher PD-L1 expression, poor differentiation, and presentation as stage IV disease, but the differences were not statistically significant. KRAS G12C mutated NSCLCs almost exclusively occurred in smokers and were mostly non-mucinous adenocarcinomas with conventional histological patterns which ranged from well to poorly differentiated. Around a quarter had TP53 co-mutation, the histological impacts and immune profile of which need to be assessed in a larger study.

A Phase II trial of alternating osimertinib and gefitinib therapy in advanced EGFR-T790M positive non-small cell lung cancer: OSCILLATE.

In this phase II, single arm trial (ACTRN12617000720314), we investigate if alternating osimertinib and gefitinib would delay the development of resistance to osimertinib in advanced, non-small cell lung cancer (NSCLC) with the epidermal growth factor receptor (EGFR) T790M mutation (n = 47) by modulating selective pressure on resistant clones. The primary endpoint is progression free-survival (PFS) rate at 12 months, and secondary endpoints include: feasibility of alternating therapy, overall response rate (ORR), overall survival (OS), and safety. The 12-month PFS rate is 38% (95% CI 27.5-55), not meeting the pre-specified primary endpoint. Serial circulating tumor DNA (ctDNA) analysis reveals decrease and clearance of the original activating EGFR and EGFR-T790M mutations which are prognostic of clinical outcomes. In 73% of participants, loss of T790M ctDNA is observed at progression and no participants have evidence of the EGFR C797S resistance mutation following the alternating regimen. These findings highlight the challenges of treatment strategies designed to modulate clonal evolution and the clinical importance of resistance mechanisms beyond suppression of selected genetic mutations in driving therapeutic escape to highly potent targeted therapies.

Real world efficacy and toxicity of consolidation durvalumab following chemoradiotherapy in older Australian patients with unresectable stage III non-small cell lung cancer.

INTRODUCTION: Consolidation durvalumab following platinum-based chemoradiotherapy (CRT) significantly improved overall survival for patients with unresectable stage III non-small cell lung cancer (NSCLC) in the PACIFIC trial. However, older patients were underrepresented in PACIFIC, and subsequent analyses suggested trends toward poorer survival and increased toxicity in patients aged ≥70 years old. We assessed the effectiveness and safety of consolidation durvalumab following CRT in older Australian patients with unresectable stage III NSCLC. MATERIALS AND METHODS: This retrospective observational study was conducted across seven sites in Sydney, Australia between January 2018 and September 2021. All adult patients with unresectable stage III NSCLC who received platinum-based chemoradiotherapy followed by at least one cycle of consolidation durvalumab were included. Older patients were defined as being ≥70 years old. RESULTS: Of 152 patients included in the analysis, 42.8% (n = 67) patients were 70 years or older. Median follow-up was 26.1 months. The two-year overall survival and median PFS was similar between older and younger patients. At two years, 74.8% (95% confidence interval [CI]: 65.4-84.2%) of patients <70 years old and 65.2% (95% CI: 53.4-77.0%) of older patients were alive (p = 0.07; hazard ratio [HR] 1.64, 95% CI: 0.95-2.81). Median progression-free survival (PFS) in patients <70 years was 30.3 months (95% CI: 22.2-38.4 months) compared with 26.7 months (95% CI: 12.8-40.6 months) in older patients (p = 0.22; HR 1.46, 95% CI: 0.80-2.65). Toxicity was also similar, with 11.5% of patients <70 years old and 18.5% of older patients experiencing grade 3-4 adverse events (AEs; p = 0.23); 16.1% and 24.6% of the patients, respectively, discontinued treatment due to toxicity (p = 0.19). Grade 3-4 AEs and treatment discontinuation were associated with Charlson Comorbidity Index >5 (p = 0.011) and chronic obstructive pulmonary disease diagnosis at presentation (p = 0.002), respectively. DISCUSSION: Older Australian patients receiving consolidation durvalumab following CRT experienced comparable outcomes to their younger peers. Comorbidity burden may be more important determinants of treatment tolerance than chronological age.

Variations in patterns of prescribing durvalumab in stage III lung cancer: a survey of Australian Medical Oncologists.

BACKGROUND: Local Australian guidelines for the optimal management of stage III unresectable NSCLC are lacking. The American Society of Clinical Oncology (ASCO) guidelines recommend consolidation durvalumab for all patients with unresectable stage III NSCLC irrespective of their PD-L1 expression or driver mutation status. The European Society of Medical Oncology (ESMO) differs, with consolidation durvalumab only recommended in those patients whose tumours express PD-L1. METHODS: Due to differing global guidelines we conducted an Australia and New Zealand wide survey of medical oncologists specialising in thoracic cancer to determine the variations in patterns of prescribing durvalumab in stage III unresectable NSCLC. This survey was done electronically and sponsored by the Thoracic Oncology Group of Australia (TOGA). RESULTS: Thirty-two medical oncologists completed the survey. In patients with EGFR¬-mutated stage III unresectable NSCLC, 6% of respondents stated that they prescribed durvalumab for all patients, whilst an additional 6% strongly recommended treatment. Fourty-four percent suggested little benefit of consolidation durvalumab in this cohort, with an additional 19% advocating for observation only. In patients with PD-L1 negative (0%) stage III unresectable NSCLC, 13% of respondents prescribed durvalumab for all patients, whilst an additional 56% strongly recommended treatment. Interestingly, 18%, 10% and 10% of prescribers discussed self-funded oral tyrosine kinase inhibitor (TKI) therapy in patients with EGFR, ALK or ROS-1 mutated NSCLC respectively as a substitute for consolidation durvalumab. CONCLUSION: Overall, the clinical practice of Australian and New Zealand Medical Oncologists is variable, but remains consistent with either the ASCO or ESMO guidelines. Local practice guidelines are required to ensure consistency in prescribing patterns across Australia, as well as providing evidence for self-funded treatments outside standard of care.

Utility of multigene panel next-generation sequencing in routine clinical practice for identifying genomic alterations in newly diagnosed metastatic nonsmall cell lung cancer.

BACKGROUND: The standard of care in newly diagnosed metastatic non-small cell lung cancer (NSCLC) is to test for aberrations in three genes for driver mutations - ALK, ROS1 and epidermal growth factor receptor (EGFR) - and also for immunohistochemistry to be performed for programmed death-ligand 1 expression level. Next-generation sequencing (NGS), with or without RNA fusion testing, is increasingly used in standard clinical practice to identify patients with potentially actionable mutations. Stratification of NGS mutation tiers is currently based on the European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT) Tiers I-V and X. AIM: Our aim was to analyse NSCLC tumour samples for the prevalence of Tiers I-V mutations to establish guidance for current and novel treatments in patients with metastatic disease. METHODS: NGS was performed employing the Oncomine Precision Assay (without RNA fusion testing) that interrogates DNA hotspot variants across 45 genes to screen 210 NSCLC tissue samples obtained across six Sydney hospitals between June 2021 and March 2022. RESULTS: In our cohort, 161 of 210 (77%) had at least one gene mutation identified, with 41 of 210 (20%) having two or more concurrent mutations. Tier I mutations included 42 of 210 (20%) EGFR mutations (EIA) and five of 210 (3%) MET exon 14 skipping mutations (EIB). Non-Tier I variants included 22 of 210 (11%) KRAS G12C hotspot mutations (EIIB), with a further 47 of 210 (22%) having non-G12C KRAS (EX) mutations. NGS testing revealed an additional 15% of cases with Tier II ESCAT mutations in NSCLC. Forty-six percent of patients also demonstrated potential Tier III and IV mutations that are currently under investigation in early-phase clinical trials. CONCLUSIONS: In addition to identifying patients with genomic alterations suitable for clinically proven standard-of-care therapeutic options, the 45-gene NGS panel has significant potential in identifying potentially actionable non-Tier 1 mutations that may become future standard clinical practice in NSCLC.

Influence of EGFR mutation status and PD-L1 expression in stage III unresectable non-small cell lung cancer treated with chemoradiation and consolidation durvalumab.

BACKGROUND: Consolidation durvalumab after concurrent chemoradiation is the standard of care for unresectable stage III non-small cell lung cancer (NSCLC) based on the PACIFIC trial. However, there have been reports in the literature suggesting the efficacy of the treatment differs in patients whose tumors harbor epidermal growth factor receptor (EGFR) mutations and in those with low programed death ligand-1 (PD-L1) expression. This study describes the survival outcomes for patients with unresectable stage III NSCLC treated with chemoradiation followed by durvalumab with a specific focus on EGFR mutation status and PD-L1 expression. METHODS: This retrospective observational study was conducted across six sites in Greater Sydney, Australia. It included all patients diagnosed with unresectable stage III NSCLC treated with chemoradiation and who received at least one cycle of durvalumab between January 2018 and September 2021. Patients were stratified according to EGFR mutation status and PD-L1 tumor proportion score (TPS) of 1%. RESULTS: Of the 145 patients included in the analysis, 15/145 (10%) patients harbored an EGFR mutation and 61/145 (42%) patients had PD-L1 TPS of <1%. At a median follow-up of 15.1 months from the start of durvalumab, median progression-free survival (PFS) in EGFR mutant versus wild-type patients was 7.5 and 33.9 months, respectively (hazard ratio [HR]: 2.7; 95% confidence intervals [95% CI] 1.2-5.7; p = .01). Overall survival (OS) was not different between EGFR mutant and wild-type patients. There was no statistically significant difference in PFS (HR .7, 95% CI .4-1.7, p = .43) or OS (HR .5, 95% CI .4-4.7, p = .16) between patients with PD-L1 TPS of <1% versus PD-L1 TPS of ≥1%. CONCLUSIONS: Our data adds to the growing evidence that suggests consolidation durvalumab after definitive chemoradiation may not be as efficacious in patients with EGFR-mutant tumors compared with EGFR wild-type NSCLC.

Central airway squamous metaplasia following radiation therapy mimicking local tumour recurrence.

Radiation therapy can result in injury to the lung parenchyma and central airways; the latter is less well documented in the literature. Here, we describe a 65-year-old Caucasian male, who developed focal endobronchial nodules and right main bronchial stenosis suggesting tumour recurrence, 32 months following curative intent concurrent chemoradiation therapy for Stage 3B squamous cell carcinoma of the lung. Computed tomography and positron emission tomography results are detailed. Flexible bronchoscopy with bronchial biopsies revealed squamous metaplasia rather than malignant tumour recurrence, with ongoing observation planned.

Central airway squamous metaplasia following radiation therapy mimicking local tumour recurrence.

Radiation therapy can result in injury to the lung parenchyma and central airways; the latter is less well documented in the literature. Here, we describe a 65-year-old Caucasian male, who developed focal endobronchial nodules and right main bronchial stenosis suggesting tumour recurrence, 32 months following curative intent concurrent chemoradiation therapy for Stage 3B squamous cell carcinoma of the lung. Computed tomography and positron emission tomography results are detailed. Flexible bronchoscopy with bronchial biopsies revealed squamous metaplasia rather than malignant tumour recurrence, with ongoing observation planned.

Phase II, double blind, placebo controlled, multi-site study to evaluate the safety, feasibility and desirability of conducting a phase III study of anamorelin for anorexia in people with small cell lung cancer: A study protocol (LUANA trial).

Anorexia is experienced by most people with lung cancer during the course of their disease and treatment. Anorexia reduces response to chemotherapy and the ability of patients to cope with, and complete their treatment leading to greater morbidity, poorer prognosis and outcomes. Despite the significant importance of cancer-related anorexia, current therapies are limited, have marginal benefits and unwarranted side effects. In this multi-site, randomised, double blind, placebo controlled, phase II trial, participants will be randomly assigned (1:1) to receive once-daily oral dosing of 100mg of anamorelin HCl or matched placebo for 12 weeks. Participants can then opt into an extension phase to receive blinded intervention for another 12 weeks (weeks 13-24) at the same dose and frequency. Adults (≥18 years) with small cell lung cancer (SCLC); newly diagnosed with planned systemic therapy OR with first recurrence of disease following a documented disease-free interval ≥6 months, AND with anorexia (i.e., ≤ 37 points on the 12-item Functional Assessment of Anorexia Cachexia Treatment (FAACT A/CS) scale) will be invited to participate. Primary outcomes are safety, desirability and feasibility outcomes related to participant recruitment, adherence to interventions, and completion of study tools to inform the design of a robust Phase III effectiveness trial. Secondary outcomes are the effects of study interventions on body weight and composition, functional status, nutritional intake, biochemistry, fatigue, harms, survival and quality of life. Primary and secondary efficacy analysis will be conducted at 12 weeks. Additional exploratory efficacy and safety analyses will also be conducted at 24 weeks to collect data over longer treatment duration. The feasibility of economic evaluations in Phase III trial will be assessed, including the indicative costs and benefits of anamorelin for SCLC to the healthcare system and society, the choice of methods for data collection and the future evaluation design. Trial registration. The trial has been registered with the Australian New Zealand Clinical Trials Registry [ACTRN12622000129785] and approved by the South Western Sydney Local Health District Human Research Ethics Committee [2021/ETH11339]. https://clin.larvol.com/trial-detail/ACTRN12622000129785.

Elevated neutrophil-to-lymphocyte ratio (NLR) is associated with poorer progression-free survival in unresectable stage III NSCLC treated with consolidation durvalumab.

Sustained elevation in neutrophil-to-lymphocyte ratio (NLR) after initial chemoradiotherapy (CRT) has been shown to correlate with worse prognosis in a number of solid organ malignancies. Here, we conducted a retrospective observational cohort study involving six sites across Sydney, Australia, including all patients with unresectable stage III NSCLC treated with CRT and consolidation durvalumab between January 2018 and September 2021. Patients had NLR collected prior to CRT and prior to cycle one of durvalumab. We used an NLR value of 3 to stratify patients into high and low groups. Patients with sustained NLR were defined as those with values ≥3 at both timepoints. A total of 145 patients were included in the study. The median age of patients was 66 years with median follow-up of 15.1 months. The median PFS was 17.6 months in the pre-CRT NLR high cohort and not reached (NR) in the pre-CRT NLR low cohort (HR 1.99; p = 0.01). The median OS was 35.5 months in the high pre-CRT NLR cohort compared with 42.0 months in the low pre-CRT NLR cohort (HR 2.62; 95% CI: 1.23-5.56, p < 0.01). Median PFS for sustained NLR elevation was 17.1 months versus NR (HR 1.5; p < 0.01). Pre-CRT NLR and sustained NLR remained independently prognostic for PFS on multivariate analysis (p = 0.04, p = 0.01) respectively. Pre-CRT NLR and sustained NLR is associated with worse PFS outcomes in unresectable stage III NSCLC treated with CRT and durvalumab. Pre-CRT NLR is also associated with worse OS.

Stepping into the real world: a mixed-methods evaluation of the implementation of electronic patient reported outcomes in routine lung cancer care.

BACKGROUND: To realize the broader benefits of electronic patient-reported outcome measures (ePROMs) in routine care, we used the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework to inform the translation of a clinically effective ePROM system (hereafter referred to as the PRM system) into practice. The study aimed to evaluate the processes and success of implementing the PRM system in the routine care of patients diagnosed with lung cancer. METHOD: A controlled before-and-after mixed-methods study was undertaken. Data sources included a self-report questionnaire and interviews with healthcare providers, electronic health record data for PRMs patients and historical controls, and field notes. Descriptive statistics, logistic regression modelling, negative binomial models, generalized estimating equations and repeated measures ANOVA were used to analyze quantitative data. Qualitative data was thematically analyzed. RESULTS: A total of 48/79 eligible people diagnosed with lung cancer completed 90 assessments during the 5-month implementation period (RE-AIM reach). Every assessment breached the pre-defined threshold and care coordinators reviewed and actioned 95.6% of breaches, resulting in 146 referrals to allied health services, most frequently for social work (25.3%), dietetics (18.5%), physiotherapy (18.5%) and occupational therapy (17.1%). PRMs patients had significantly fewer visits to the cancer assessment unit for problematic symptoms (M = 0.23 vs. M = 0.43; p = 0.035), and were significantly more likely to be offered referrals (71% vs. 29%, p < 0.0001) than historical controls (RE-AIM effect). The levels of 'organizational readiness for implementing change' (ORIC) did not show much differences between baseline and follow-up, though this was already high at baseline; but significantly more staff reported improved confidence when asking patients to complete assessments (64.7% at baseline vs. 88.2% at follow-up, p = 0.0046), and when describing the assessment tool to patients (64.7% at baseline vs. 76.47% at follow-up, p = 0.0018) (RE-AIM adoption). A total of 78 staff received PRM system training, and 95.6% of the PRM system alerts were actioned (RE-AIM implementation); and all lung cancer care coordinators were engaged with the PRM system beyond the end of the study period (RE-AIM maintenance). CONCLUSION: This study demonstrates the potential of the PRM system in enhancing the routine care of lung cancer patients, through leveraging the capabilities of automated web-based care options. Research has shown the clear benefits of using electronically collected patient-reported outcome measures (ePROMs) for cancer patients and health services. However, we need to better understand how to implement ePROMs as part of routine care. This study evaluated the processes and outcomes of implementing an ePROMs system in the routine care of patients diagnosed with lung cancer. Key findings included: (a) a majority of eligible patients completed the scheduled assessments; (b) patient concerns were identified in every assessment, and care coordinators reviewed and actioned almost all of these, including making significantly more referrals to allied health services; (c) patients completing assessments regularly were less likely to present to the cancer assessment unit with problematic symptoms, suggesting that ePROMs identified patient concerns early and this led to a timely response to concerns; (d) staff training and engagement was high, and staff reporting increased confidence when asking patients to complete assessments and when describing the assessment tool to patients at the end of the implementation period. This study shows that implementing ePROMs in routine care is feasible and can lead to improvements in patient care.

Adapting an integrated care pathway for implementing electronic patient reported outcomes assessment in routine oncology care: Lessons learned from a case study.

RATIONALE, AIMS AND OBJECTIVE: Details of the development and implementation of integrated care pathways (ICPs) in the context of electronic collection of patient reported outcomes (ePROs) for cancer patients are largely lacking in the literature. This study describes what, why and how decisions were made to adapt and implement an ePROs ICP for patients with lung cancer. METHODS: A consensus process was utilized, with the implementation advisory group including multidisciplinary representation from three participating hospitals, to identify local champions and adapt and incorporate the ePRO ICP into the local contexts. Engagement meetings were documented via meeting transcripts, and detailed notes from October 2019 to November 2020 were content-analysed to identify decision-making themes based on the Consolidated Framework for Implementation Research; workflows and process maps were reviewed and modified to integrate ePROs. RESULTS: In total, 55 engagement activities were held (24 meetings, 20 workshops 11 educational sessions), with n = 96 staff from multiple disciplines participating in the ePROs implementation through advisory meetings, process mapping, change management and staff education. Decisions were made regarding eligible patient cohorts to include, the process for onboarding patients onto the ePRO system, and follow-up and referral pathways. Rationales for decisions included alignment with existing workflows, utilizing available staff, minimizing staff and patient burden and maximizing patient engagement. CONCLUSION: Existing resources, staff input and technical and logistical reasons often guided the ICP decisions, highlighting the need for in-depth engagement across all stakeholders for optimal implementation of ePRO ICPs. The ePRO implementation required substantial dialogue and systematic resolution to reach agreement on the final processes. Adapting the local ICP through rigorous engagement facilitated the successful implementation of ePROs as business-as-usual at all three cancer centres. Involving all relevant stakeholders is critical to the successful adaptation of ICPs before their introduction into routine care.

Screening for cognitive symptoms among cancer patients during chemotherapy: Sensitivity and specificity of a single item self-report cognitive change score.

OBJECTIVES: Cognitive symptoms are commonly reported among cancer patients and survivors, yet guidance on when self-reported cognitive symptoms warrant follow-up is lacking. We sought to establish cut-off scores for identifying patients with perceived low cognitive functioning on widely used self-report measures of cognition and a novel single item Cognitive Change Score. METHODS: Adult patients diagnosed with invasive cancer who had completed at least one cycle of chemotherapy completed a questionnaire containing the EORTC-Cognitive Function (CF) subscale, Functional Assessment of Cancer Therapy-Cognitive Function (FACT-COG) Perceived Cognitive Impairment (PCI) and our Cognitive Change Score (CCS). We used receiver operating characteristic analyses to establish the discriminative ability of these measures against the Patient's Assessment of Own Functioning Inventory (PAOFI) as our reference standard. We chose cut-off scores on each measure that maximised both sensitivity and specificity for identifying patients with self-reported low CF. RESULTS: We recruited 294 participants (55.8% women, mean age 56.6 years) with mixed cancer diagnoses (25.5 months since diagnosis). On the CCS, 77.6% reported some cognitive change since starting chemotherapy. On the PAOFI 36% had low CF. The following cut-off scores identified cases of low CF: ≥28.5 on the CCS (75.5% sensitivity, 67.6% specificity); ≤75.0 on the European Organisation for Research and Treatment of Cancer, QLQ-C30 Cognitive Functioning scale (90.9% sensitivity, 57.1% specificity); ≤55.1 on the FACT-COG PCI-18 (84.8% sensitivity, 76.2% specificity), and ≤59.5 on the FACT-COG PCI-20 (78.8% sensitivity, 84.1% specificity). CONCLUSIONS: We found a single item question asking about cognitive change has acceptable discrimination between patients with self-reported normal and low CF when compared to other more comprehensive self-report measures of cognitive symptoms. Further validation work is required.

Plasma pre-treatment T790M relative allelic frequency in patients with advanced EGFR-mutated non-small cell lung cancer predicts treatment response to subsequent-line osimertinib.

BACKGROUND: Approximately half of all patients with advanced EGFR-mutant NSCLC will develop acquired resistance to first or second-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) with a T790M mutation. In the AURA3 trial, patients with a T790M mutation had a response rate of 71% to osimertinib, a third-generation EGFR-TKI. The response to osimertinib may vary according to plasma T790M mutation frequency. Our aim was to determine the effect of plasma T790M mutation load on treatment response to osimertinib in an Australian multi-institutional cohort. METHODS: We performed a retrospective study on patients treated with osimertinib in the second-line setting and beyond between 2016-2018 from ten centres in Australia, who had T790M mutations detected in tumour or plasma. The primary objective was to investigate if there was a difference in disease control rate (DCR) between patients with high vs. low T790M relative allelic frequency (RAF) as detected in plasma, using a 0.3 RAF cut-off, as determined by ddPCR or BEAMing PCR. Secondary objective was to determine the survival outcomes according to high versus low plasma T790M RAF. Additional analyses were performed to investigate the survival outcome for patients with plasma versus tissue T790M positivity. RESULTS: A total of 139 patients were included in this study. Patients with higher RAF demonstrated higher DCR (74% vs. 36%, P=0.02), however there was no statistically significant difference in survival outcomes in the two groups. Exploratory analysis showed that patients with tissue T790M+ had improved DCR compared with those with plasma T790M+ (89% vs. 68%, P=0.01) and longer progression free survival (median 15.4 vs. 9.7 months; HR 0.51, 95% CI: 0.34 to 0.77, P=0.003) and overall survival (median not reached, HR 0.51, 95% CI: 0.30 to 0.86, P=0.02). Patients who were tissue T790M+ demonstrated superior survival compared to plasma T790M+ after correcting for confounding variables in a multivariate model. CONCLUSIONS: DCR was superior in patients with higher plasma T790M mutation load versus lower plasma T790M mutational load, without significant survival benefit. Plasma T790M RAF is a potential predictive biomarker which should be investigated and validated in larger prospective studies.

Treatment burden experienced by patients with lung cancer.

INTRODUCTION: Patients' burden from lung cancer treatment is not well researched, but this understanding can facilitate a patient-centred treatment approach. Current models of treatment burden suggest it is influenced by a patient's perception of their disease and treatment and their capacity to do the work required to treat their disease. METHODS: Sixteen patients and 1 carer who were undergoing or had completed conventional or stereotactic ablative radiotherapy, chemotherapy or immunotherapy for lung cancer in the last 6 months participated in a semi-structured interview. A treatment burden framework was used with three main themes: a) treatment work, b) consequences of treatment and c) psychosocial factors affecting treatment burden. RESULTS: The majority of patients did not feel unduly burdened by treatment tasks, despite having a large treatment-associated workload. Many saw treatment as a priority, causing them to restructure their life to accommodate for it. Patients wished that they would have been better informed about the lifestyle changes that they would have to make before treatment for lung cancer commenced and that the health service would provide services to assist them with this task. DISCUSSION: While there was a large burden associated with lung cancer treatment, patients felt motivated and equipped to manage the workload because the disease was considered severe and life-threatening, and the treatment was seen as beneficial. Before initiating treatment for lung cancer, patients should be informed about lifestyle changes they likely have to make and should be offered assistance.

The Multiple Potential Biomarkers for Predicting Immunotherapy Response-Finding the Needle in the Haystack.

Immune checkpoint inhibitors (ICIs) are being increasingly utilised in a variety of advanced malignancies. Despite promising outcomes in certain patients, the majority will not derive benefit and are at risk of potentially serious immune-related adverse events (irAEs). The development of predictive biomarkers is therefore critical to personalise treatments and improve outcomes. A number of biomarkers have shown promising results, including from tumour (programmed cell death ligand 1 (PD-L1), tumour mutational burden (TMB), stimulator of interferon genes (STING) and apoptosis-associated speck-like protein containing a CARD (ASC)), from blood (peripheral blood mononuclear cells (PBMCs), circulating tumour DNA (ctDNA), exosomes, cytokines and metal chelators) and finally the microbiome.

Concurrent Paraneoplastic Dermatomyositis and Acquired C1 Esterase Inhibitor Deficiency in Primary Laryngeal Small Cell Carcinoma.

Small cell carcinoma is associated with a number of paraneoplastic syndromes. We report a case of a 42-year-old female who presented with primary laryngeal small cell carcinoma associated with concurrent paraneoplastic dermatomyositis and paraneoplastic angioedema secondary to acquired C1 esterase inhibitor deficiency. The patient required extensive treatment for her dermatomyositis including high-dose corticosteroid therapy and intravenous immunoglobulin followed by steroid-sparing disease-modifying immunosuppression. Her angioedema also required multiple lines of therapy including bradykinin inhibitors and human recombinant C1 esterase. We believe this is the first reported case of either of these paraneoplastic syndromes arising from an extrapulmonary small cell carcinoma and highlights the difficulty of its initial diagnosis as well as concurrent management.

Myasthenia gravis and concurrent myositis following PD-L1 checkpoint inhibitor for non-small cell lung cancer.

BACKGROUND: There are increasing reports of myasthenia gravis (MG) following oncological treatment with immune checkpoint inhibitors (ICIs). METHODS AND RESULTS: A 66-year-old man with stage 3A lung adenocarcinoma was treated with second weekly infusions of durvalumab, a programmed cell death ligand-1 inhibitor, at a dose of 10 mg/kg. After the fourth infusion, he developed diplopia, dyspnoea and constitutional symptoms including headache, weakness and anorexia. 1 month later, he developed dysphagia and dysphonia. Examination showed proximal limb weakness with fatigability. An ice pack test was positive. Blood tests revealed a raised creatine kinase and positive PM-Scl75 antibody. Antititin antibody was strongly positive in the serum and cerebrospinal fluid. Antibodies for acetylcholinesterase receptor and antimuscle-specific kinase were negative. Electromyography showed myopathic changes. The patient was treated with steroids, pyridostigmine, mycophenolate mofetil and intravenous immunoglobulin. Eight weeks after treatment initiation ptosis, eye movements and limb strength were markedly improved and repeat creatine kinase was normal. CONCLUSION: Clinicians using ICIs should have a high index of suspicion for ICI-induced MG and concurrent myositis as disease can be severe and is associated with high mortality rates.

Pembrolizumab for anaplastic thyroid cancer: a case study.

Blockade of the PD-1/PD-L1 pathway with targeted monoclonal antibodies has demonstrated encouraging anti-tumour activity in multiple cancer types. We present the case of a patient with BRAF-negative stage IVC anaplastic thyroid cancer (ATC) treated with the anti-PD-1 monoclonal antibody, pembrolizumab, following radiographic progression on chemoradiation. Blood samples were collected prior to and at four time points during treatment with pembrolizumab. Mass cytometry was used to determine expression of relevant biomarkers by peripheral blood mononuclear cells. Faecal samples were collected at baseline and 4 weeks following treatment initiation; taxonomic profiling using 16S ribosomal RNA (rRNA) gene sequencing was performed. Following treatment, a marked expansion in CD20+ B cell, CD16+ CD56lo NK cell and CD45RO+ CCR7+ central memory CD4+ T-cell populations was observed in the peripheral blood. Proportions of cells expressing the co-receptors TIGIT, OX40 and CD86 also increased during treatment. A high abundance of bacteria of the order Bacteroidales, specifically from the Bacteroidaceae and Rikenellaceae families, was identified in the faecal microbiota. Moreover, the patient's microbiome was enriched in Clostridiales order members Ruminococcaceae, Veillonellaceae and Lachnospiraceae. Alpha diversity of the gut microbiome was significantly higher following initiation of checkpoint therapy as assessed by the Shannon and Simpson index. Our results suggest that treatment with pembrolizumab promotes expansion of T-, B- and NK cell populations in the peripheral blood at the time of tumour regression and have the potential to be implemented as predictive biomarkers in the context of checkpoint blockade therapy. Larger studies to confirm these findings are warranted.