Coker, E.A.
Stewart, A.
Ozer, B.
Minchom, A.
Pickard, L.
Ruddle, R.
Carreira, S.
Popat, S.
O'Brien, M.
Raynaud, F.
de Bono, J.
Al-Lazikani, B.
Banerji, U.
(2022). Individualized Prediction of Drug Response and Rational Combination Therapy in NSCLC Using Artificial Intelligence-Enabled Studies of Acute Phosphoproteomic Changes. Mol cancer ther,
Vol.21
(6),
pp. 1020-1029.
show abstract
We hypothesize that the study of acute protein perturbation in signal transduction by targeted anticancer drugs can predict drug sensitivity of these agents used as single agents and rational combination therapy. We assayed dynamic changes in 52 phosphoproteins caused by an acute exposure (1 hour) to clinically relevant concentrations of seven targeted anticancer drugs in 35 non-small cell lung cancer (NSCLC) cell lines and 16 samples of NSCLC cells isolated from pleural effusions. We studied drug sensitivities across 35 cell lines and synergy of combinations of all drugs in six cell lines (252 combinations). We developed orthogonal machine-learning approaches to predict drug response and rational combination therapy. Our methods predicted the most and least sensitive quartiles of drug sensitivity with an AUC of 0.79 and 0.78, respectively, whereas predictions based on mutations in three genes commonly known to predict response to the drug studied, for example, EGFR, PIK3CA, and KRAS, did not predict sensitivity (AUC of 0.5 across all quartiles). The machine-learning predictions of combinations that were compared with experimentally generated data showed a bias to the highest quartile of Bliss synergy scores (P = 0.0243). We confirmed feasibility of running such assays on 16 patient samples of freshly isolated NSCLC cells from pleural effusions. We have provided proof of concept for novel methods of using acute ex vivo exposure of cancer cells to targeted anticancer drugs to predict response as single agents or combinations. These approaches could complement current approaches using gene mutations/amplifications/rearrangements as biomarkers and demonstrate the utility of proteomics data to inform treatment selection in the clinic..
Stapleton, S.E.
Darlington, A.-.
Minchom, A.
Pal, A.
Raynaud, F.
Wiseman, T.
(2022). Assessing cognitive toxicity in early phase trials - What are we missing?. Psychooncology,
Vol.31
(3),
pp. 405-415.
show abstract
OBJECTIVES: Novel therapies, such as, small protein molecule inhibitors and immunotherapies are first tested clinically in Phase I trials. Moving on to later phase trials and ultimately standard practice. A key aim of these early clinical trials is to define a toxicity profile; however, the emphasis is often on safety. The concern is cognitive toxicity is poorly studied in this context and may be under-reported. The aim of this review is to map evidence of cognitive assessment, toxicity, and confounding factors within reports from Phase I trials and consider putative mechanisms of impairment aligned with mechanisms of novel therapies. METHODS: A scoping review methodology was applied to the search of databases, including Embase, MEDLINE, Clinicaltrials.gov. A [keyword search was conducted, results screened for duplication then inclusion/exclusion criteria applied. Articles were further screened for relevance; data organised into categories and charted in a tabular format]. Evidence was collated and summarised into a narrative synthesis. RESULTS: Despite the availability of robust ways to assess cognitive function, these are not routinely included in the conduct of early clinical trials. Reports of cognitive toxicity in early Phase I trials are limited and available evidence on this shows that a proportion of patients experience impaired cognitive function over the course of participating in a Phase I trial. Links are identified between the targeted action of some novel therapies and putative mechanisms of cognitive impairment. CONCLUSION: The review provides rationale for research investigating cognitive function in this context. A study exploring the cognitive function of patients on Phase I trials and the feasibility of formally assessing this within early clinical trials is currently underway at the Royal Marsden..
Minchom, A.
Viteri, S.
Bazhenova, L.
Gadgeel, S.M.
Ou, S.-.
Trigo, J.
Bauml, J.M.
Backenroth, D.
Bhattacharya, A.
Li, T.
Mahadevia, P.
Girard, N.
(2022). Amivantamab compared with real-world therapies in patients with advanced non-small cell lung cancer harboring EGFR exon 20 insertion mutations who progressed after platinum-based chemotherapy. Lung cancer,
Vol.168,
pp. 74-82.
Cui, W.
Milner-Watts, C.
O'Sullivan, H.
Lyons, H.
Minchom, A.
Bhosle, J.
Davidson, M.
Yousaf, N.
Scott, S.
Faull, I.
Kushnir, M.
Nagy, R.
O'Brien, M.
Popat, S.
(2022). Up-front cell-free DNA next generation sequencing improves target identification in UK first line advanced non-small cell lung cancer (NSCLC) patients. European journal of cancer,
Vol.171,
pp. 44-54.
Cui, W.
Milner-Watts, C.
McVeigh, T.P.
Minchom, A.
Bholse, J.
Davidson, M.
Yousaf, N.
MacMahon, S.
Mugalaasi, H.
Gunapala, R.
Lee, R.
George, A.
Popat, S.
O'Brien, M.
(2022). A pilot of Blood-First diagnostic cell free DNA (cfDNA) next generation sequencing (NGS) in patients with suspected advanced lung cancer. Lung cancer (amsterdam, netherlands),
Vol.165,
pp. 34-42.
show abstract
Introduction
The diagnostic pathway for lung cancer can be long. Availability of front-line targeted therapies for NSCLC demands access to good quality tissue for genomic sequencing and rapid reporting of results. Diagnosis of lung cancer and availability of tissue was delayed during the COVID-19 pandemic.
Methods
A pilot study assessing Guardant360™ cfDNA-NGS in patients with radiological-suspected advanced-stage lung cancer was performed at an academic cancer centre during COVID-19. Variants were tiered using AMP/ASCO/CAP guidelines and discussed at a tumour molecular board. The primary endpoint was the proportion of patients who commenced targeted treatment based on cfDNA-NGS results without tissue molecular results, predicted to be ≥ 10%.
Results
Between April 2020-May 2021, 51 patients were enrolled; 49 were evaluable. The median age was 71 years, 43% were never-smokers, 86% had stage IV disease. 80% of evaluable cfDNA-NGS were informative (tumour-derived cfDNA detected). cfDNA-NGS detected 30 (61%) AMP/ASCO/CAP tier 1 variants, including 20 additional tier 1 variants compared to tissue testing. Three patients with non-informative cfDNA-NGS had tier 1 variants identified on tissue testing. Eleven (22%; 95%CI 12%-27%) patients commenced targeted therapy based on cfDNA-NGS results without tissue molecular results, meeting the primary endpoint. Median time to results was shorter for cfDNA-NGS compared to standard-of-care tissue tests (9 versus 25 days, P < 0.0001).
Conclusion
Blood-first cfDNA-NGS in NSCLC patients increased the breadth and rapidity of detection of actionable variants with high tissue concordance and led to timely treatment decisions. A blood-first approach should be considered to improve the speed and accuracy of therapeutic decision-making..
Tiu, C.
Shinde, R.
Pal, A.
Biondo, A.
Lee, A.
Tunariu, N.
Jhanji, S.
Grover, V.
Tatham, K.
Gruber, P.
Banerji, U.
De Bono, J.S.
Nicholson, E.
Minchom, A.R.
Lopez, J.S.
(2021). A Wolf in Sheep's Clothing: Systemic Immune Activation Post Immunotherapy. Journal of immunotherapy and precision oncology,
Vol.4
(4),
pp. 189-195.
show abstract
ABSTRACT
Introduction
Immune checkpoint inhibitors (ICIs) are increasingly a standard of care for many cancers; these agents can result in immune-related adverse events (irAEs) including fever, which is common but can rarely be associated with systemic immune activation (SIA or acquired HLH).
Methods
All consecutive patients receiving ICIs in the Drug Development Unit of the Royal Marsden Hospital between May 2014 and November 2019 were retrospectively reviewed. Patients with fever ≥ 38°C or chills/rigors (without fever) ≤ 6 weeks of commencing ICIs were identified for clinical data collection.
Results
Three patients met diagnostic criteria for SIA/HLH with median time to onset of symptoms of 10 days. We describe the clinical evolution, treatment used, and outcomes for these patients. High-dose steroids are used first-line with other treatments, such as tocilizumab, immunoglobulin and therapeutic plasmapheresis can be considered for steroid-refractory SIA/HLH.
Conclusion
SIA/HLH post ICI is a rare but a potentially fatal irAE that presents with fever and a constellation of nonspecific symptoms. Early recognition and timely treatment are key to improving outcomes.
.
Lai-Kwon, J.
Tiu, C.
Pal, A.
Khurana, S.
Minchom, A.
(2021). Moving beyond epidermal growth factor receptor resistance in metastatic non-small cell lung cancer - a drug development perspective. Critical reviews in oncology/hematology,
Vol.159,
pp. 103225-103225.
Joshi, K.
Muhith, A.
Obeid, M.
Milner-Watts, C.
Yousaf, N.
Popat, S.
Davidson, M.
Bhosle, J.
O’Brien, M.
Minchom, A.
(2021). Safety monitoring of two and four-weekly adjuvant durvalumab for patients with stage III NSCLC: implications for the COVID-19 pandemic and beyond. Lung cancer,
Vol.156,
pp. 147-150.
Virtakoivu, R.
Rannikko, J.H.
Viitala, M.
Vaura, F.
Takeda, A.
Lönnberg, T.
Koivunen, J.
Jaakkola, P.
Pasanen, A.
Shetty, S.
de Jonge, M.J.
Robbrecht, D.
Ma, Y.T.
Skyttä, T.
Minchom, A.
Jalkanen, S.
Karvonen, M.K.
Mandelin, J.
Bono, P.
Hollmén, M.
(2021). Systemic Blockade of Clever-1 Elicits Lymphocyte Activation Alongside Checkpoint Molecule Downregulation in Patients with Solid Tumors: Results from a Phase I/II Clinical Trial. Clinical cancer research : an official journal of the american association for cancer research,
Vol.27
(15),
pp. 4205-4220.
show abstract
Purpose
Macrophages are critical in driving an immunosuppressive tumor microenvironment that counteracts the efficacy of T-cell-targeting therapies. Thus, agents able to reprogram macrophages toward a proinflammatory state hold promise as novel immunotherapies for solid cancers. Inhibition of the macrophage scavenger receptor Clever-1 has shown benefit in inducing CD8
+ T-cell-mediated antitumor responses in mouse models of cancer, which supports the clinical development of Clever-1-targeting antibodies for cancer treatment.
Patients and methods
In this study, we analyzed the mode of action of a humanized IgG4 anti-Clever-1 antibody, FP-1305 (bexmarilimab), both
in vitro and in patients with heavily pretreated metastatic cancer (
n = 30) participating in part 1 (dose-finding) of a phase I/II open-label trial (NCT03733990). We studied the Clever-1 interactome in primary human macrophages in antibody pull-down assays and utilized mass cytometry, RNA sequencing, and cytokine profiling to evaluate FP-1305-induced systemic immune activation in patients with cancer.
Results
Our pull-down assays and functional studies indicated that FP-1305 impaired multiprotein vacuolar ATPase-mediated endosomal acidification and improved the ability of macrophages to activate CD8
+ T-cells. In patients with cancer, FP-1305 administration led to suppression of nuclear lipid signaling pathways and a proinflammatory phenotypic switch in blood monocytes. These effects were accompanied by a significant increase and activation of peripheral T-cells with indications of antitumor responses in some patients.
Conclusions
Our results reveal a nonredundant role played by the receptor Clever-1 in suppressing adaptive immune cells in humans. We provide evidence that targeting macrophage scavenging activity can promote an immune switch, potentially leading to intratumoral proinflammatory responses in patients with metastatic cancer..
Manickavasagar, T.
Yuan, W.
Carreira, S.
Gurel, B.
Miranda, S.
Ferreira, A.
Crespo, M.
Riisnaes, R.
Baker, C.
O'Brien, M.
Bhosle, J.
Popat, S.
Banerji, U.
Lopez, J.
de Bono, J.
Minchom, A.
(2021). HER3 expression and MEK activation in non-small-cell lung carcinoma. Lung cancer management,
,
pp. ?-? (12).
Biondo, A.
Pal, A.
Riisnaes, R.
Shinde, R.
Tiu, C.
Lockie, F.
Baker, C.
Bertan, C.
Crespo, M.
Ferreira, A.
Pereira, R.
Figueiredo, I.
Miranda, S.
Gurel, B.
Carreira, S.
Banerji, U.
de Bono, J.
Lopez, J.
Tunariu, N.
Minchom, A.
(2021). Research Related Tumour Biopsies in Early-Phase Trials with Simultaneous Molecular Characterisation - a Single Unit Experience. Cancer treatment and research communications,
Vol.27,
pp. 100309-?.
show abstract
Early-phase cancer clinical trials are becoming increasingly accessible for patients with advanced cancer who have exhausted standard treatment options and later phase trial options. Many of these trials mandate research tissue biopsies. Research biopsies have been perceived as ethically fraught due to the perception of potential coercion of vulnerable human subjects. We performed an audit of two years of practice to assess the safety of ultrasound (US)-guided research biopsies, and to look at the yield of a simultaneous tumour next-generation sequencing (NGS) and immunohistochemistry (IHC) molecular characterisation programme. We show that in our institution, US-guided research biopsies were safe, produced adequate tumour content and in a selected subset who underwent in-house NGS sequencing, showed a high rate of actionable mutations with 30% having a Tier 1 variant. Nevertheless, these research biopsies may only provide direct benefit for a minority of patients and we conclude with a reflection on the importance of obtaining truly informed consent..
Lai-Kwon, J.
Yin, Z.
Minchom, A.
Yap, C.
(2021). Trends in patient-reported outcome use in early phase dose-finding oncology trials - an analysis of ClinicalTrials gov. Cancer med,
Vol.10
(22),
pp. 7943-7957.
show abstract
BACKGROUND: Patient-reported adverse events (AEs) may be a useful adjunct to clinician-assessed AEs for assessing tolerability in early phase, dose-finding oncology trials (DFOTs). We reviewed DFOTs on ClinicalTrials.gov to describe trends in patient-reported outcome (PRO) use. METHODS: DFOTs commencing 01 January 2007 - 20 January 2020 with 'PROs' or 'quality of life' as an outcome were extracted and inclusion criteria confirmed. Study and PRO characteristics were extracted. Completed trials that reported PRO outcomes and published manuscripts on ClinicalTrials.gov were identified, and PRO reporting details were extracted. RESULTS: 5.3% (548/10 372) DFOTs included PROs as an outcome. 231 (42.2%) were eligible: adult (224, 97%), solid tumour (175, 75.8%), and seamless phase 1/2 (108, 46.8%). PRO endpoints were identified in more trials (2.3 increase/year, 95% CI: 1.6-2.9) from an increasing variety of countries (0.7/year) (95% CI: 0.4-0.9) over time. PROs were typically secondary endpoints (207, 89.6%). 15/77 (19.5%) completed trials reported results on the ClinicalTrials.gov results database, and of those eight included their PRO results. Eighteen trials had published manuscripts available on ClinicalTrials.gov. Three (16.7%) used PROs to confirm the maximum tolerated dose. No trials identified who completed the PROs or how PROs were collected. CONCLUSIONS: PRO use in DFOT has increased but remains limited. Future work should explore the role of PROs in DFOT and determine what guidelines are needed to standardise PRO use..
Bazhenova, L.
Minchom, A.
Viteri, S.
Bauml, J.M.
Ou, S.-.
Gadgeel, S.M.
Trigo, J.M.
Backenroth, D.
Li, T.
Londhe, A.
Mahadevia, P.
Girard, N.
(2021). Comparative clinical outcomes for patients with advanced NSCLC harboring EGFR exon 20 insertion mutations and common EGFR mutations. Lung cancer,
Vol.162,
pp. 154-161.
Minchom, A.
Tan, A.C.
Massarelli, E.
Subbiah, V.
Boni, V.
Robinson, B.
Wirth, L.J.
Hess, L.M.
Jen, M.
Kherani, J.
Olek, E.
McCoach, C.E.
(2021). Patient‐Reported
Outcomes with Selpercatinib Among Patients with
RET
Fusion‐Positive
Non‐small Cell Lung Cancer in the Phase 1/2
LIBRETTO
‐001 Trial. The oncologist,
.
Minchom, A.
Yuan, W.
Crespo, M.
Gurel, B.
Figueiredo, I.
Wotherspoon, A.
Miranda, S.
Riisnaes, R.
Ferreira, A.
Bertan, C.
Pereira, R.
Clarke, M.
Baker, C.
Ang, J.E.
Fotiadis, N.
Tunariu, N.
Carreira, S.
Popat, S.
O'Brien, M.
Banerji, U.
de Bono, J.
Lopez, J.
(2020). Molecular and immunological features of a prolonged exceptional responder with malignant pleural mesothelioma treated initially and rechallenged with pembrolizumab. Journal for immunotherapy of cancer,
Vol.8
(1).
show abstract
Background This case represents an exceptional response to pembrolizumab in a patient with epithelioid mesothelioma with a further response on rechallenge.Case presentation A 77-year-old woman with advanced epithelioid mesothelioma extensively pretreated with chemotherapy demonstrated a prolonged response of 45 months to 52 cycles of pembrolizumab. On rechallenge with pembrolizumab, further disease stability was achieved. Serial biopsies and analysis by immunohistochemistry and immunofluorescence demonstrated marked immune infiltration and documented the emergency of markers of immune exhaustion. Whole exome sequencing demonstrated a reduction in tumor mutational burden consistent with subclone elimination by immune checkpoint inhibitor (CPI) therapy. The relapse biopsy had missense mutation in BTN2A1.Conclusion This case supports rechallenge of programme death receptor 1 inhibitor in cases of previous CPI sensitivity and gives molecular insights..
Page, S.
Milner-Watts, C.
Perna, M.
Janzic, U.
Vidal, N.
Kaudeer, N.
Ahmed, M.
McDonald, F.
Locke, I.
Minchom, A.
Bhosle, J.
Welsh, L.
O'Brien, M.
(2020). Systemic treatment of brain metastases in non-small cell lung cancer. European journal of cancer,
Vol.132,
pp. 187-198.
Tiu, C.
Shinde, R.
Yap, C.
Rao Baikady, B.
Banerji, U.
Minchom, A.R.
de Bono, J.S.
Lopez, J.S.
(2020). A risk-based approach to experimental early phase clinical trials during the COVID-19 pandemic. The lancet. oncology,
Vol.21
(7),
pp. 889-891.
Collins, D.C.
Sundar, R.
Constantidinou, A.
Dolling, D.
Yap, T.A.
Popat, S.
O'Brien, M.E.
Banerji, U.
de Bono, J.S.
Lopez, J.S.
Tunariu, N.
Minchom, A.
(2020). Radiological evaluation of malignant pleural mesothelioma - defining distant metastatic disease. Bmc cancer,
Vol.20
(1),
pp. 1210-?.
show abstract
Background Malignant pleural mesothelioma (MPM) is traditionally characterized by local destructive spread of the pleura and surrounding tissues. Patient outcomes in MPM with distant metastatic dissemination are lacking.Methods In this retrospective study, we reviewed a cohort of 164 MPM patients referred to a Phase I trials unit, aiming to describe identified metastatic sites, and correlate with clinical outcomes.Results 67% of patients were diagnosed with distant metastatic disease with a high incidence of bone (19%), visceral (14%), contralateral lung (35%) and peritoneal metastases (22%). Peritoneal metastases were more likely in epithelioid versus biphasic/ sarcomatoid MPM (p = 0.015). Overall survival was 23.8 months with no statistical difference in survival between those with distant metastases and those without.Conclusions This report highlights the frequency of distant metastases and encourages further radiological investigations in the presence of symptoms. In particular, given the relatively high incidence of bone metastases, bone imaging should be considered in advanced MPM clinical workflow and trial protocols. The presence of distant metastases does not appear to have prognostic implications under existing treatment paradigms. This cohort of MPM patients gives an indication of patterns of metastatic spread that are likely to become prevalent as prognosis improves with emerging treatment paradigms..
Terbuch, A.
Tiu, C.
Candilejo, I.M.
Scaranti, M.
Curcean, A.
Bar, D.
Estevez Timon, M.
Ameratunga, M.
Ang, J.E.
Ratoff, J.
Minchom, A.R.
Banerji, U.
de Bono, J.S.
Tunariu, N.
Lopez, J.S.
(2020). Radiological Patterns of Drug-induced Interstitial Lung Disease (DILD) in Early-phase Oncology Clinical Trials. Clinical cancer research : an official journal of the american association for cancer research,
Vol.26
(18),
pp. 4805-4813.
show abstract
Purpose Drug-induced interstitial lung disease (DILD) is a rare, but potentially fatal toxicity. Clinical and radiological features of DILD in the early experimental setting are poorly described.Patients and methods A total of 2,499 consecutive patients with advanced cancer on phase I clinical trials were included. DILD was identified by a dedicated radiologist and investigators, categorized per internationally recognized radiological patterns, and graded per Common Terminology Criteria for Adverse Events (CTCAE) and the Royal Marsden Hospital (RMH) DILD score. Clinical and radiological features of DILD were analyzed.Results Sixty patients overall (2.4%) developed DILD. Median time to onset of DILD was 63 days (range, 14-336 days). A total of 45% of patients who developed DILD were clinically asymptomatic. Incidence was highest in patients receiving drug conjugates (7.4%), followed by inhibitors of the PI3K/AKT/mTOR pathway (3.9%). The most common pattern seen was hypersensitivity pneumonitis (33.3%), followed by nonspecific interstitial pneumonia (30%), and cryptogenic organizing pneumonia (26.7%). A higher DILD score [OR, 1.47, 95% confidence interval (CI), 1.19-1.81; P < 0.001] and the pattern of DILD (OR, 5.83 for acute interstitial pneumonia; 95% CI, 0.38-90.26; P = 0.002) were significantly associated with a higher CTCAE grading. The only predictive factor for an improvement in DILD was an interruption of treatment (OR, 0.05; 95% CI, 0.01-0.35; P = 0.01).Conclusions DILD in early-phase clinical trials is a toxicity of variable onset, with diverse clinical and radiological findings. Radiological findings precede clinical symptoms. The extent of the affected lung parenchyma, scored by the RMH DILD score, correlates with clinical presentation. Most events are low grade, and improve with treatment interruption, which should be considered early..
Guo, C.
Chénard-Poirier, M.
Roda, D.
de Miguel, M.
Harris, S.J.
Candilejo, I.M.
Sriskandarajah, P.
Xu, W.
Scaranti, M.
Constantinidou, A.
King, J.
Parmar, M.
Turner, A.J.
Carreira, S.
Riisnaes, R.
Finneran, L.
Hall, E.
Ishikawa, Y.
Nakai, K.
Tunariu, N.
Basu, B.
Kaiser, M.
Lopez, J.S.
Minchom, A.
de Bono, J.S.
Banerji, U.
(2020). Intermittent schedules of the oral RAF-MEK inhibitor CH5126766/VS-6766 in patients with RAS/RAF-mutant solid tumours and multiple myeloma: a single-centre, open-label, phase 1 dose-escalation and basket dose-expansion study. Lancet oncol,
Vol.21
(11),
pp. 1478-1488.
show abstract
BACKGROUND: CH5126766 (also known as VS-6766, and previously named RO5126766), a novel MEK-pan-RAF inhibitor, has shown antitumour activity across various solid tumours; however, its initial development was limited by toxicity. We aimed to investigate the safety and toxicity profile of intermittent dosing schedules of CH5126766, and the antitumour activity of this drug in patients with solid tumours and multiple myeloma harbouring RAS-RAF-MEK pathway mutations. METHODS: We did a single-centre, open-label, phase 1 dose-escalation and basket dose-expansion study at the Royal Marsden National Health Service Foundation Trust (London, UK). Patients were eligible for the study if they were aged 18 years or older, had cancers that were refractory to conventional treatment or for which no conventional therapy existed, and if they had a WHO performance status score of 0 or 1. For the dose-escalation phase, eligible patients had histologically or cytologically confirmed advanced or metastatic solid tumours. For the basket dose-expansion phase, eligible patients had advanced or metastatic solid tumours or multiple myeloma harbouring RAS-RAF-MEK pathway mutations. During the dose-escalation phase, we evaluated three intermittent oral schedules (28-day cycles) in patients with solid tumours: (1) 4·0 mg or 3·2 mg CH5126766 three times per week; (2) 4·0 mg CH5126766 twice per week; and (3) toxicity-guided dose interruption schedule, in which treatment at the recommended phase 2 dose (4·0 mg CH5126766 twice per week) was de-escalated to 3 weeks on followed by 1 week off if patients had prespecified toxic effects (grade 2 or worse diarrhoea, rash, or creatinine phosphokinase elevation). In the basket dose-expansion phase, we evaluated antitumour activity at the recommended phase 2 dose, determined from the dose-escalation phase, in biomarker-selected patients. The primary endpoints were the recommended phase 2 dose at which no more than one out of six patients had a treatment-related dose-limiting toxicity, and the safety and toxicity profile of each dosing schedule. The key secondary endpoint was investigator-assessed response rate in the dose-expansion phase. Patients who received at least one dose of the study drug were evaluable for safety and patients who received one cycle of the study drug and underwent baseline disease assessment were evaluable for response. This trial is registered with ClinicalTrials.gov, NCT02407509. FINDINGS: Between June 5, 2013, and Jan 10, 2019, 58 eligible patients were enrolled to the study: 29 patients with solid tumours were included in the dose-escalation cohort and 29 patients with solid tumours or multiple myeloma were included in the basket dose-expansion cohort (12 non-small-cell lung cancer, five gynaecological malignancy, four colorectal cancer, one melanoma, and seven multiple myeloma). Median follow-up at the time of data cutoff was 2·3 months (IQR 1·6-3·5). Dose-limiting toxicities included grade 3 bilateral retinal pigment epithelial detachment in one patient who received 4·0 mg CH5126766 three times per week, and grade 3 rash (in two patients) and grade 3 creatinine phosphokinase elevation (in one patient) in those who received 3·2 mg CH5126766 three times per week. 4·0 mg CH5126766 twice per week (on Monday and Thursday or Tuesday and Friday) was established as the recommended phase 2 dose. The most common grade 3-4 treatment-related adverse events were rash (11 [19%] patients), creatinine phosphokinase elevation (six [11%]), hypoalbuminaemia (six [11%]), and fatigue (four [7%]). Five (9%) patients had serious treatment-related adverse events. There were no treatment-related deaths. Eight (14%) of 57 patients died during the trial due to disease progression. Seven (27% [95% CI 11·6-47·8]) of 26 response-evaluable patients in the basket expansion achieved objective responses. INTERPRETATION: To our knowledge, this is the first study to show that highly intermittent schedules of a RAF-MEK inhibitor has antitumour activity across various cancers with RAF-RAS-MEK pathway mutations, and that this inhibitor is tolerable. CH5126766 used as a monotherapy and in combination regimens warrants further evaluation. FUNDING: Chugai Pharmaceutical..
Cojocaru, E.
Scaranti, M.
Minchom, A.
(2019). Tackling Immunotherapy Resistance: Developing Rational Combinations of Immunotherapy and Targeted Drugs. Journal of immunotherapy and precision oncology,
Vol.2
(2),
pp. 23-35.
show abstract
Abstract
Mechanisms of resistance to immunotherapies are multiple and complex with components intrinsic to the tumor cell and within the immune microenvironment. We review evidence of the interaction of tumor cell signaling pathways with immune pathways and the role this plays in de novo and acquired resistance. The mitogen-activated protein kinase (MAPK) pathway activation and effects on T-cell function are discussed. Phosphoinositide 3-kinase (PI3K) pathway activation (including PTEN loss of function) correlates with T-cell inhibition and immunotherapy resistance. Wnt signaling has been implicated in T-cell function suppression. Key evidence from preclinical models exists for the role of these signaling pathways and is described. Clinical evidence is less advanced though correlation of mutations in key nodes with immune resistance provides a limited clinical correlation. Serial biomarker analysis in patients receiving targeted drugs has been attempted with notable examples including BRAF inhibition in melanoma patients resulting in dynamic changes in programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes. Drug combinations aim to overcome mechanisms of resistance, and recent years have seen numerous combinations of targeted therapies and immune checkpoint inhibitors proposed. However, clear biological rationale and thoughtful trial designs with a translational focus are required to allow such combinations to achieve their full potential..
Moss, C.A.
Cojocaru, E.
Hanwell, J.
Ward, S.
Xu, W.
van Zyl, M.
O'Leary, L.
de Bono, J.S.
Banerji, U.
Kaye, S.B.
Minchom, A.
George, A.J.
Lopez, J.
McVeigh, T.P.
(2019). Multidisciplinary interventions in a specialist Drug Development Unit to improve family history documentation and onward referral of patients with advanced cancer to cancer genetics services. European journal of cancer (oxford, england : 1990),
Vol.114,
pp. 97-106.
show abstract
Background Molecular aberrations in cancer may represent therapeutic targets, and, if arising from the germline, may impact further cancer risk management in patients and their blood relatives. Annually, 600-700 patients are referred for consideration of experimental drug trials in the Drug Development Unit (DDU) in our institution. A proportion of patients may merit germline genetic testing because of suspicious personal/family history or findings of tumour-based testing. We aimed to assess the impact of different multidisciplinary interventions on family history taking and referral rates from DDU to Cancer Genetics Unit (CGU).Methods Over 42 months, three interventions were undertaken at different intervals: (1) embedding a genetics provider in the DDU review clinic, (2) 'traffic light' system flagging cancers with a heritable component and (3) virtual multidisciplinary meeting (MDM). Comparative analyses between intervals were undertaken, including referral rates to CGU, investigations and patient outcomes. Family history taking in a sample of 20 patients managed in each interval was assessed by a retrospective chart review.Results Frequency of family history taking and referral to CGU, increased with each intervention, particularly, the virtual MDM (40% vs 85%). Referral rates increased over the study period, from 0.1 referral/week (5/year, 0.36% total referrals) to 1.2/week (projected 63/year, 3.81%). Forty-four (52%) patients referred required germline testing; in three of whom, variants were identified. Non-attendance rates were low (6, 7%).Conclusion Patients in the DDU are unique, with long cancer histories and often short estimated life expectancy. Multidisciplinary working between CGU and DDU facilitates germline testing of those patients who may otherwise miss the opportunity..
Georgiou, A.
Minchom, A.
O'Brien, M.
(2019). Comment on ‘Randomised phase 2 study of pembrolizumab plus CC-486 versus pembrolizumab plus placebo in patients with previously treated advanced non-small cell lung cancer’—No support for de-escalation of immunotherapy. European journal of cancer,
Vol.115,
pp. 24-26.
Stewart, A.
Coker, E.A.
Pölsterl, S.
Georgiou, A.
Minchom, A.R.
Carreira, S.
Cunningham, D.
O'Brien, M.E.
Raynaud, F.I.
de Bono, J.S.
Al-Lazikani, B.
Banerji, U.
(2019). Differences in Signaling Patterns on PI3K Inhibition Reveal Context Specificity in KRAS-Mutant Cancers. Molecular cancer therapeutics,
Vol.18
(8),
pp. 1396-1404.
show abstract
It is increasingly appreciated that drug response to different cancers driven by the same oncogene is different and may relate to differences in rewiring of signal transduction. We aimed to study differences in dynamic signaling changes within mutant KRAS ( KRAS MT ), non-small cell lung cancer (NSCLC), colorectal cancer, and pancreatic ductal adenocarcinoma (PDAC) cells. We used an antibody-based phosphoproteomic platform to study changes in 50 phosphoproteins caused by seven targeted anticancer drugs in a panel of 30 KRAS MT cell lines and cancer cells isolated from 10 patients with KRAS MT cancers. We report for the first time significant differences in dynamic signaling between colorectal cancer and NSCLC cell lines exposed to clinically relevant equimolar concentrations of the pan-PI3K inhibitor pictilisib including a lack of reduction of p-AKTser473 in colorectal cancer cell lines ( P = 0.037) and lack of compensatory increase in p-MEK in NSCLC cell lines ( P = 0.036). Differences in rewiring of signal transduction between tumor types driven by KRAS MT cancers exist and influence response to combination therapy using targeted agents..
Mak, D.W.
Li, S.
Minchom, A.
(2019). Challenging the recalcitrant disease—developing molecularly driven treatments for small cell lung cancer. European journal of cancer,
Vol.119,
pp. 132-150.
Georgiou, A.
Khakoo, S.
Edwards, P.
Minchom, A.
Kouvelakis, K.
Kalaitzaki, E.
Nobar, N.
Calamai, V.
Ifijen, M.
Husson, O.
Watkins, D.
Rao, S.
Chau, I.
Cunningham, D.
Starling, N.
(2019). Outcomes of Patients with Early Onset Colorectal Cancer Treated in a UK Specialist Cancer Center. Cancers (basel),
Vol.11
(10).
show abstract
The incidence of early onset colorectal cancer (EOCRC) is rapidly increasing, but there remains paucity of outcome data for young CRC patients. We reviewed the characteristics and outcomes of 241 adults, age <50, who were diagnosed with EOCRC between January 2009 and December 2014. Median age was 42, 56% were male, and 7% had hereditary etiology. Seventy percent had left-sided primaries. At diagnosis, 11%, 50%, and 39% had stage II, III, and IV CRC. Of the patients with stage II and III CRC who underwent curative surgery, 60% and 88% had adjuvant chemotherapy, with 5-year relapse free survival of 82% and 74% respectively. Of the 123 patients with metastatic (m) EOCRC, 93%, 63%, 33%, and 12% had 1st, 2nd, 3rd, and 4th line systemic anticancer therapy (SACT) respectively. For first line SACT, 99% had doublet chemotherapy, with bevacizumab or an anti-EGFR antibody in 57%. Median overall survival (mOS) of mEOCRC patients was 20.1 months (95% C.I: 15.9-23.2). Younger age and signet cells were associated with shorter mOS, whereas more lines of SACT and curative metastasectomy with longer mOS. Metastatic EOCRC patients had poorer outcomes than expected, despite optimal multimodality treatment. This suggests an aggressive disease biology that warrants further research and therapy development..
Minchom, A.
Aversa, C.
Lopez, J.
(2018). Dancing with the DNA damage response: next-generation anti-cancer therapeutic strategies. Therapeutic advances in medical oncology,
Vol.10,
pp. 1758835918786658-?.
show abstract
Maintenance of genomic stability is a critical determinant of cell survival and relies on the coordinated action of the DNA damage response (DDR), which orchestrates a network of cellular processes, including DNA replication, DNA repair and cell-cycle progression. In cancer, the critical balance between the loss of genomic stability in malignant cells and the DDR provides exciting therapeutic opportunities. Drugs targeting DDR pathways taking advantage of clinical synthetic lethality have already shown therapeutic benefit - for example, the PARP inhibitor olaparib has shown benefit in BRCA -mutant ovarian and breast cancer. Olaparib has also shown benefit in metastatic prostate cancer in DDR-defective patients, expanding the potential biomarker of response beyond BRCA. Other agents and combinations aiming to block the DDR while pushing damaged DNA through the cell cycle, including PARP, ATR, ATM, CHK and DNA-PK inhibitors, are in development. Emerging work is also uncovering how the DDR interacts intimately with the host immune response, including by activating the innate immune response, further suggesting that clinical applications together with immunotherapy may be beneficial. Here, we review recent considerations related to the DDR from a clinical standpoint, providing a framework to address future directions and clinical opportunities..
Minchom, A.
Thavasu, P.
Ahmad, Z.
Stewart, A.
Georgiou, A.
O'Brien, M.E.
Popat, S.
Bhosle, J.
Yap, T.A.
de Bono, J.
Banerji, U.
(2017). A study of PD-L1 expression in KRAS mutant non-small cell lung cancer cell lines exposed to relevant targeted treatments. Plos one,
Vol.12
(10),
p. e0186106.
show abstract
We investigated PD-L1 changes in response to MEK and AKT inhibitors in KRAS mutant lung adenocarcinoma (adeno-NSCLC). PD-L1 expression was quantified using immunofluorescence and co-culture with a jurkat cell-line transfected with NFAT-luciferase was used to study if changes in PD-L1 expression in cancer cell lines were functionally relevant. Five KRAS mutant cell lines with high PD-L1 expression (H441, H2291, H23, H2030 and A549) were exposed to GI50 inhibitor concentrations of a MEK inhibitor (trametinib) and an AKT inhibitor (AZD5363) for 3 weeks. Only 3/5 (H23, H2030 and A549) and 2/5 cell lines (H441 and H23) showed functionally significant increases in PD-L1 expression when exposed to trametinib or AZD5363 respectively. PD-L1 overexpression is not consistent and is unlikely to be an early mechanism of resistance to KRAS mutant adeno-NSCLC treated with MEK or AKT inhibitors..
Puglisi, M.
Stewart, A.
Thavasu, P.
Frow, M.
Carreira, S.
Minchom, A.
Punwani, R.
Bhosle, J.
Popat, S.
Ratoff, J.
de Bono, J.
Yap, T.A.
O''Brien, M.
Banerji, U.
(2016). Characterisation of the Phosphatidylinositol 3-Kinase Pathway in Non-Small Cell Lung Cancer Cells Isolated from Pleural Effusions. Oncology,
Vol.90
(5),
pp. 280-288.
show abstract
Objectives We hypothesised that it was possible to quantify phosphorylation of important nodes in the phosphatidylinositol 3-kinase (PI3K) pathway in cancer cells isolated from pleural effusions of patients with non-small cell lung cancer (NSCLC) and study their correlation to somatic mutations and clinical outcomes.Materials and methods Cells were immunomagnetically separated from samples of pleural effusion in patients with NSCLC. p-AKT, p-S6K and p-GSK3β levels were quantified by ELISA; targeted next-generation sequencing was used to characterise mutations in 26 genes.Results It was possible to quantify phosphoproteins in cells isolated from 38/43 pleural effusions. There was a significant correlation between p-AKT and p-S6K levels [r = 0.85 (95% confidence interval 0.73-0.92), p < 0.0001], but not p-AKT and p-GSK3β levels [r = 0.19 (95% confidence interval -0.16 to 0.5), p = 0.3]. A wide range of mutations was described and p-S6K was higher in samples that harboured at least one mutation compared to those that did not (p = 0.03). On multivariate analysis, p-S6K levels were significantly associated with poor survival (p < 0.01).Conclusion Our study has shown a correlation between p-AKT levels and p-S6K, but not GSK3β, suggesting differences in regulation of the distal PI3K pathway by AKT. Higher p-S6K levels were associated with adverse survival, making it a critically important target in NSCLC..
Kumar, R.
Lu, S.K.
Minchom, A.
Sharp, A.
Davidson, M.
Gunapala, R.
Yap, T.A.
Bhosle, J.
Popat, S.
O’Brien, M.E.
(2016). A phase 1b trial of the combination of an all-oral regimen of capecitabine and erlotinib in advanced non-small cell lung cancer in Caucasian patients. Cancer chemotherapy and pharmacology,
Vol.77
(2),
pp. 375-383.
Minchom, A.
Punwani, R.
Filshie, J.
Bhosle, J.
Nimako, K.
Myerson, J.
Gunapala, R.
Popat, S.
O'Brien, M.E.
(2016). A randomised study comparing the effectiveness of acupuncture or morphine versus the combination for the relief of dyspnoea in patients with advanced non-small cell lung cancer and mesothelioma. European journal of cancer,
Vol.61,
pp. 102-110.
Minchom, A.
Yu, K.C.
Bhosle, J.
O'Brien, M.
(2014). The diagnosis and treatment of brain metastases in EGFR mutant lung cancer. Cns oncology,
Vol.3
(3),
pp. 209-217.
show abstract
SUMMARY The epidemiology of non-small-cell lung cancer (NSCLC) has changed with a new pattern of disease emerging – a form of adenocarcinoma in mostly younger female patients, who are never or light smokers and more frequently in East Asian populations. Description of EGF receptor (EGFR) mutations has allowed new management strategies to evolve. Oral targeted therapies have broadened the treatment options in the advanced setting with the potential for periods of long term response. The brain is a common site of metastases with EGFR mutated lung cancer typically displaying asymptomatic, small volume, multiple lesions that respond to treatment. We explore the role of local and system therapies for brain metastases in this disease including the role of EGFR inhibitors. .
Minchom, A.R.
Saksornchai, K.
Bhosle, J.
Gunapala, R.
Puglisi, M.
Lu, S.K.
Nimako, K.
Coward, J.
Yu, K.C.
Bordi, P.
Popat, S.
O'Brien, M.E.
(2014). An unblinded, randomised phase II study of platinum-based chemotherapy with vitamin B12and folic acid supplementation in the treatment of lung cancer with plasma homocysteine blood levels as a biomarker of severe neutropenic toxicity. Bmj open respiratory research,
Vol.1
(1),
pp. e000061-e000061.
Young, K.
Minchom, A.
Larkin, J.
(2012). BRIM-1, -2 and -3 trials: improved survival with vemurafenib in metastatic melanoma patients with a BRAFV600E mutation. Future oncology,
Vol.8
(5),
pp. 499-507.
show abstract
Following Phase I and II studies revealing vemurafenib to be a safe potent inhibitor of mutated BRAF in patients with metastatic melanoma, a multicenter randomized Phase III trial was carried out to compare vemurafenib with dacarbazine in treatment-naive patients. The interim analysis results from this trial, BRIM-3, were sufficient for an independent data and safety monitoring board to recommend crossover from dacarbazine to vemurafenib, vemurafenib being associated with a relative risk reduction of 63% in the risk of death and 74% in the risk of death or disease progression compared with dacarbazine (p < 0.001 for both comparisons) with an acceptable toxicity profile. Such striking results have prompted analysis of our approach to the classification and treatment of metastatic melanoma in an age of molecular markers and targeted therapy. .
Minchom, A.
Young, K.
Larkin, J.
(2011). Ipilimumab: showing survival benefit in metastatic melanoma. Future oncology,
Vol.7
(11),
pp. 1255-1264.
show abstract
Ipilimumab is a fully humanized monoclonal antibody to cytotoxic T-lymphocyte-associated antigen 4. Data from preclinical and clinical studies have shown that ipilimumab can cause tumor regression in patients with metastatic melanoma with response rates of 5.8–22%. Phase III trials have demonstrated a benefit in median overall survival in the first-line setting in combination with dacarbazine versus dacarbazine alone (11.2 vs 9.1 months) and in the second-line setting in combination with gp100 versus gp100 alone (10.1 vs 6.4 months). The main toxicities of ipilimumab are immune related, most commonly skin and gastrointestinal. Bowel perforation and treatment-related deaths have occurred, although prompt use of steroids and other immunosuppressive agents can minimize this risk..
Minchom, A.
Chan, S.
Melia, W.
Shah, R.
(2010). An Unusual Case of Pancreatic Cancer with Leptomeningeal Infiltration. Journal of gastrointestinal cancer,
Vol.41
(2),
pp. 107-109.
Minchom, A.
Jones, R.L.
Fisher, C.
Al-Muderis, O.
Ashley, S.
Scurr, M.
Karavasilis, V.
Judson, I.R.
(2010). Clinical Benefit of Second-Line Palliative Chemotherapy in Advanced Soft-Tissue Sarcoma. Sarcoma,
Vol.2010,
pp. 1-8.
show abstract
Background. This paper aimed to assess the utility of second-line chemotherapy in patients with advanced soft-tissue sarcoma.Materials and Methods. A retrospective search of a prospectively maintained database identified patients treated between 1991 and 2005. Patients with gastrointestinal stromal tumours, small round cell tumours, and Ewing's sarcoma were excluded. Response was assessed using WHO and RECIST. Patients who achieved stable disease for 6 months or more were classified as having disease control.Results. Three hundred and seventy-nine patients received second-line chemotherapy. Eighty-six (22.7%) achieved disease control. Median duration of response was 11 months (95% CI: 9–13). On multivariate analysis, pathological subtype, absence of lung metastases, and the use of combination chemotherapy were independent predictors of disease control. Twenty-eight (16.1%) patients who failed to respond to first-line therapy achieved disease control. Eight (2.1%) patients had sufficient downstaging to enable complete surgical resection. Progression-free survival was 23% at 6 months. Median overall survival was 8 months (95% CI: 7–10 months). On multivariate analysis, synovial histology and absence of lung metastases were associated with improved survival.Conclusion. Second-line chemotherapy can provide clinical benefit in over 20% of soft-tissue sarcoma patients..
Bowcock, S.J.
Minchom, A.
Yates, L.R.
Ryali, M.M.
(2008). Ultra low dose thalidomide in elderly patients with myeloma. British journal of haematology,
Vol.141
(1),
pp. 120-122.
Minchom, A.
Mak, D.
Gunapala, R.
Walder, D.
Kumar, R.
Yousaf, N.
Hodgkiss, A.
Bhosle, J.
Popat, S.
O'Brien, M.E.
A prospective observational study of on-treatment plasma homocysteine levels as a biomarker of toxicity, depression and vitamin supplementation lead-in time pre pemetrexed, in patients with non-small cell lung cancer and malignant mesothelioma. Plos one,
Vol.14
(11),
pp. e0225509-?.
show abstract
Objectives Vitamin supplementation reduces pemetrexed toxicity. Raised plasma homocysteine reflects deficiency in vitamin B12 and folate, and is suppressed by supplementation. This observational study of 112 patients receiving pemetrexed-based chemotherapy assessed homocysteine levels after 3 weeks of vitamin supplementation, hypothesising high levels would correlate with ongoing deficiency, thus increased toxicity.Material and methods Primary endpoint was the composite of proportion of patients with treatment delay/ dose reduction/ drug change or hospitalisation during the first six weeks of chemotherapy, comparing those with normal plasma homocysteine (successfully supplemented, SS) and those with high homocysteine (unsuccessfully supplemented, USS). Secondary endpoints included toxicity and analyses for depression. Post-hoc analysis examined correlation between interval of vitamin and folate supplementation and pemetrexed on primary endpoint and grade 3-4 toxicities.Results Eighty-four patients (84%) were successfully supplemented (SS group). The proportion of patients undergoing a treatment delay/ dose reduction/ drug change or hospitalisation in SS group was 44.0% (95% confidence interval [CI] 33.2%-55.3%) and in USS group was 18.8% (95% CI 4.0%-45.6%) (p = 0.09). Twelve percent of patients gave a past history of depression however 66% of patients had an on study Hospital Anxiety and Depression (HAD) score of >7. Supplementation status was not associated with depression. The median overall survival (OS) was 11.8 months (95% CI 8.6-16.5) in the SS group and 8.8 months (95% CI 6.6-16.2) in the US group (p = 0.5). The number of days (<7 or ≥ 7 days) between vitamin B12 and folate initiation and pemetrexed administration, had no effect on the primary endpoint and grade 3-4 toxicities.Conclusion On-treatment homocysteine levels were not a biomarker of toxicity or depression. Standard vitamin supplementation is adequate in the majority of patients receiving pemetrexed. High HAD score were noted in this population giving an opportunity for mental health intervention. The lead-in time for vitamin supplementation can be short..
Pal, A.
Stapleton, S.
Yap, C.
Lai-Kwon, J.
Daly, R.
Magkos, D.
Baikady, B.R.
Minchom, A.
Banerji, U.
De Bono, J.
Karikios, D.
Boyle, F.
Lopez, J.
Study protocol for a randomised controlled trial of enhanced informed consent compared to standard informed consent to improve patient understanding of early phase oncology clinical trials (CONSENT). Bmj open,
Vol.11
(9),
pp. e049217-e049217.
show abstract
Introduction Early phase cancer clinical trials have become increasingly complicated in terms of patient selection and trial procedures—this is reflected in the increasing length of participant information sheets (PIS). Informed consent for early phase clinical trials has been contentious due to the potential ethical issues associated with performing experimental research on a terminally ill population which has exhausted standard treatment options. Empirical studies have demonstrated significant gaps in patient understanding regarding the nature and intent of these trials. This study aims to test whether enhanced informed consent for patient education can improve patient scores on a validated questionnaire testing clinical trial comprehension. Methods and analysis This is a randomised controlled trial that will allocate patients who are eligible to participate in one of four investigator-initiated clinical trials at the Royal Marsden Drug Development Unit to either a standard arm or an experimental arm, stratified by age and educational level. The standard arm will involve the full length trial PIS, followed by electronic or paper administration of the Quality of Informed Consent Questionnaire Parts A and B (QuIC-A and QuIC-B). The experimental arm will involve the full length trial PIS, exposure to a two-page study aid and 10 online educational videos, followed by administration of the QuIC-A and QuIC-B. The primary endpoint will be the difference (using a one-sided two-sample t-test) in the QuIC-A score, which measures objective understanding, between the standard and experimental arm. Accrual target is at least 17 patients per arm to detect an 8 point difference (80% power, alpha 0.05). Ethics and dissemination Ethics approval was granted by the National Health Service Health Research Authority on 15 June 2020—IRAS Project ID 277065, Protocol Number CCR5165, REC Reference 20/EE/0155. Results will be disseminated via publication in a relevant journal. Trial registration number NCT04407676; Pre-results..
Hindocha, S.
Campbell, D.
Ahmed, M.
Giorgakoudi, K.
Sharma, B.
Yousaf, N.
Molyneaux, P.
Hunter, B.
Kalsi, H.
Cui, W.
Davidson, M.
Bhosle, J.
Minchom, A.
Locke, I.
McDonald, F.
O'Brien, M.
Popat, S.
Lee, R.W.
Immune Checkpoint Inhibitor and Radiotherapy-Related Pneumonitis: An Informatics Approach to Determine Real-World Incidence, Severity, Management, and Resource Implications. Frontiers in medicine,
Vol.8,
pp. 764563-?.
show abstract
Pneumonitis is a well-described, potentially life-threatening adverse effect of immune checkpoint inhibitors (ICI) and thoracic radiotherapy. It can require additional investigations, treatment, and interruption of cancer therapy. It is important for clinicians to have an awareness of its incidence and severity, however real-world data are lacking and do not always correlate with findings from clinical trials. Similarly, there is a dearth of information on cost impact of symptomatic pneumonitis. Informatics approaches are increasingly being applied to healthcare data for their ability to identify specific patient cohorts efficiently, at scale. We developed a Structured Query Language (SQL)-based informatics algorithm which we applied to CT report text to identify cases of ICI and radiotherapy pneumonitis between 1/1/2015 and 31/12/2020. Further data on severity, investigations, medical management were also acquired from the electronic health record. We identified 248 cases of pneumonitis attributable to ICI and/or radiotherapy, of which 139 were symptomatic with CTCAE severity grade 2 or more. The grade ≥2 ICI pneumonitis incidence in our cohort is 5.43%, greater than the all-grade 1.3-2.7% incidence reported in the literature. Time to onset of ICI pneumonitis was also longer in our cohort (mean 4.5 months, range 4 days-21 months), compared to the median 2.7 months (range 9 days-19.2 months) described in the literature. The estimated average healthcare cost of symptomatic pneumonitis is £3932.33 per patient. In this study we use an informatics approach to present new real-world data on the incidence, severity, management, and resource burden of ICI and radiotherapy pneumonitis. To our knowledge, this is the first study to look at real-world incidence and healthcare resource utilisation at the per-patient level in a UK cancer hospital. Improved management of pneumonitis may facilitate prompt continuation of cancer therapy, and improved outcomes for this not insubstantial cohort of patients..
Curcean, S.
Cheng, L.
Picchia, S.
Tunariu, N.
Collins, D.
Blackledge, M.
Popat, S.
O'Brien, M.
Minchom, A.
Leach, M.O.
Koh, D.-.
Early Response to Chemotherapy in Malignant Pleural Mesothelioma Evaluated Using Diffusion-Weighted Magnetic Resonance Imaging: Initial Observations. Jto clinical and research reports,
Vol.2
(12),
pp. 100253-?.
show abstract
Introduction We compared the magnetic resonance imaging total tumor volume (TTV) and median apparent diffusion coefficient (ADC) of malignant pleural mesothelioma (MPM) before and at 4 weeks after chemotherapy, to evaluate whether these are potential early markers of treatment response. Methods Diffusion-weighted magnetic resonance imaging was performed in 23 patients with MPM before and after 4 weeks of chemotherapy. The TTV was measured by semiautomatic segmentation (GrowCut) and transferred onto ADC maps to record the median ADC. Test-retest repeatability of TTV and ADC was evaluated in eight patients. TTV and median ADC changes were compared between responders and nonresponders, defined using modified Response Evaluation Criteria In Solid Tumors on computed tomography (CT) at 12 weeks after treatment. TTV and median ADC were also correlated with CT size measurement and disease survival. Results The test-retest 95% limits of agreement for TTV were -13.9% to 16.2% and for median ADC -1.2% to 3.3%. A significant increase in median ADC in responders was observed at 4 weeks after treatment ( p = 0.02). Correlation was found between CT tumor size change at 12 weeks and median ADC changes at 4 weeks post-treatment ( r = -0.560, p = 0.006). An increase in median ADC greater than 5.1% at 4 weeks has 100% sensitivity and 90% specificity for responders (area under the curve = 0.933, p < 0.001). There was also moderate correlation between median tumor ADC at baseline and overall survival ( r = 0.45, p = 0.03). Conclusions Diffusion-weighted magnetic resonance imaging measurements of TTV and median ADC in MPM have good measurement repeatability. Increase in ADC at 4 weeks post-treatment has the potential to be an early response biomarker..
Yap, C.
A Phase 1, Dose Escalation Study of Guadecitabine (SGI-110) in Combination with Pembrolizumab in Patients with Solid Tumours. Journal for immunotherapy of cancer,
.