Publications by authors named "James Larkin"

332 Publications

Crossover and rechallenge with pembrolizumab in recurrent patients from the EORTC 1325-MG/Keynote-054 phase III trial, pembrolizumab versus placebo after complete resection of high-risk stage III melanoma.

Eur J Cancer 2021 Oct 18;158:156-168. Epub 2021 Oct 18.

Merck & Co., Inc., Kenilworth, NJ, USA.

Background: In the phase III double-blind European Organisation for Research and Treatment of Cancer 1325/KEYNOTE-054 trial, pembrolizumab improved recurrence-free and distant metastasis-free survival in patients with stage III cutaneous melanoma with complete resection of lymph nodes. In the pembrolizumab group, the incidence of grade I-V and of grade III-V immune-related adverse events (irAEs) was 37% and 7%, respectively.

Methods: Patients were randomised to receive intravenous (i.v.) pembrolizumab 200 mg (N = 514) or placebo (N = 505) every 3 weeks, up to 1 year. On recurrence, patients could enter part 2 of the study: pembrolizumab 200 mg i.v. every 3 weeks up to 2 years, for crossover (those who received placebo) or rechallenge (those who had recurrence ≥6 months after completing 1-year adjuvant pembrolizumab therapy). For these patients, we present the safety profile and efficacy outcomes.

Results: At the clinical cut-off (16-Oct-2020), in the placebo group, 298 patients had a disease recurrence, in which 155 (52%) crossed over ('crossover'). In the pembrolizumab group, 297 patients completed the 1-year treatment period; 47 had a recurrence ≥6 months later, in which 20 (43%) entered the rechallenge part 2 ('rechallenge'). In the crossover group, the median progression-free survival (PFS) was 8.5 months (95% confidence interval [CI] 5.7-15.2) and the 3-year PFS rate was 32% (95% CI 25-40%). Among 80 patients with stage IV evaluable disease, 31 (39%) had an objective response: 14 (18%) patients with complete response (CR) and 17 (21%) patients with partial response. The 2-year PFS rate from response was 69% (95% CI 48-83%). In the rechallenge group, the median PFS was 4.1 months (95% CI 2.6-NE). Among 9 patients with stage IV evaluable disease, 1 had an objective response (CR). Among the 175 patients, 51 (29%) had a grade I-IV irAE and 11 (6%) had a grade III-IV irAE.

Conclusions: Pembrolizumab treatment after crossover yielded an overall 3-year PFS rate of 32% and a 39% ORR in evaluable patients, but the efficacy (11% ORR) was lower in those rechallenged.
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http://dx.doi.org/10.1016/j.ejca.2021.09.023DOI Listing
October 2021

Functional antibody and T-cell immunity following SARS-CoV-2 infection, including by variants of concern, in patients with cancer: the CAPTURE study.

Res Sq 2021 Sep 20. Epub 2021 Sep 20.

Patients with cancer have higher COVID-19 morbidity and mortality. Here we present the prospective CAPTURE study (NCT03226886) integrating longitudinal immune profiling with clinical annotation. Of 357 patients with cancer, 118 were SARS-CoV-2-positive, 94 were symptomatic and 2 patients died of COVID-19. In this cohort, 83% patients had S1-reactive antibodies, 82% had neutralizing antibodies against WT, whereas neutralizing antibody titers (NAbT) against the Alpha, Beta, and Delta variants were substantially reduced. Whereas S1-reactive antibody levels decreased in 13% of patients, NAbT remained stable up to 329 days. Patients also had detectable SARS-CoV-2-specific T cells and CD4+ responses correlating with S1-reactive antibody levels, although patients with hematological malignancies had impaired immune responses that were disease and treatment-specific, but presented compensatory cellular responses, further supported by clinical. Overall, these findings advance the understanding of the nature and duration of immune response to SARS-CoV-2 in patients with cancer.
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http://dx.doi.org/10.21203/rs.3.rs-916427/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475970PMC
September 2021

RAMPART: A phase III multi-arm multi-stage trial of adjuvant checkpoint inhibitors in patients with resected primary renal cell carcinoma (RCC) at high or intermediate risk of relapse.

Contemp Clin Trials 2021 09 16;108:106482. Epub 2021 Sep 16.

MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, 2nd Floor 90 High Holborn, London WC1V 6LJ, UK.

Background: 20-60% of patients with initially locally advanced Renal Cell Carcinoma (RCC) develop metastatic disease despite optimal surgical excision. Adjuvant strategies have been tested in RCC including cytokines, radiotherapy, hormones and oral tyrosine-kinase inhibitors (TKIs), with limited success. The predominant global standard-of-care after nephrectomy remains active monitoring. Immune checkpoint inhibitors (ICIs) are effective in the treatment of metastatic RCC; RAMPART will investigate these agents in the adjuvant setting.

Methods/design: RAMPART is an international, UK-led trial investigating the addition of ICIs after nephrectomy in patients with resected locally advanced RCC. RAMPART is a multi-arm multi-stage (MAMS) platform trial, upon which additional research questions may be addressed over time. The target population is patients with histologically proven resected locally advanced RCC (clear cell and non-clear cell histological subtypes), with no residual macroscopic disease, who are at high or intermediate risk of relapse (Leibovich score 3-11). Patients with fully resected synchronous ipsilateral adrenal metastases are included. Participants are randomly assigned (3,2:2) to Arm A - active monitoring (no placebo) for one year, Arm B - durvalumab (PD-L1 inhibitor) 4-weekly for one year; or Arm C - combination therapy with durvalumab 4-weekly for one year plus two doses of tremelimumab (CTLA-4 inhibitor) at day 1 of the first two 4-weekly cycles. The co-primary outcomes are disease-free-survival (DFS) and overall survival (OS). Secondary outcomes include safety, metastasis-free survival, RCC specific survival, quality of life, and patient and clinician preferences. Tumour tissue, plasma and urine are collected for molecular analysis (TransRAMPART).

Trial Registration: ISRCTN #: ISRCTN53348826, NCT #: NCT03288532, EUDRACT #: 2017-002329-39, CTA #: 20363/0380/001-0001, MREC #: 17/LO/1875, ClinicalTrials.gov Identifier: NCT03288532, RAMPART grant number: MC_UU_12023/25, TransRAMPART grant number: A28690 Cancer Research UK, RAMPART Protocol version 5.0.
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http://dx.doi.org/10.1016/j.cct.2021.106482DOI Listing
September 2021

RAMPART: A model for a regulatory-ready academic-led phase III trial in the adjuvant renal cell carcinoma setting.

Contemp Clin Trials 2021 09 16;108:106481. Epub 2021 Sep 16.

MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, 2nd Floor 90 High Holborn, London WC1V 6LJ.

The development of therapeutics in oncology is a highly active research area for the pharmaceutical and biotechnology industries, but also has a strong academic base. Many new agents have been developed in recent years, most with specific biological targets. This has mandated the need to look at different ways to streamline the evaluation of new agents. One solution has been the development of adaptive trial designs that allow the evaluation of multiple agents, concentrating on the most promising agents while screening out those which are unlikely to benefit patients. Another way forward has been the growth of partnerships between academia and industry with the shared goal of designing and conducting high quality clinical trials which answer important clinical questions as efficiently as possible. The RAMPART trial (NCT03288532) brings together both of these processes in an attempt to improve outcomes for patients with locally advanced renal cell carcinoma (RCC), where no globally acceptable adjuvant strategy after nephrectomy currently exist. RAMPART is led by the MRC CTU at University College London (UCL), in collaboration with other international academic groups and industry. We aim to facilitate the use of data from RAMPART, (dependent on outcomes), for a future regulatory submission that will extend the license of the agents being investigated. We share our experience in order to lay the foundations for an effective trial design and conduct framework and to guide others who may be considering similar collaborations. Trial Registration: ISRCTN #: ISRCTN53348826, NCT #: NCT03288532, EUDRACT #: 2017-002329-39. CTA #: 20363/0380/001-0001. MREC #: 17/LO/1875. ClinicalTrials.gov Identifier: NCT03288532 RAMPART grant number: MC_UU_12023/25. . RAMPART Protocol version 5.0.
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http://dx.doi.org/10.1016/j.cct.2021.106481DOI Listing
September 2021

Immune checkpoint inhibitors in melanoma.

Lancet 2021 Sep;398(10304):1002-1014

Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia; Royal North Shore and Mater Hospitals, North Sydney, Sydney, NSW, Australia. Electronic address:

Immune checkpoint inhibitors target the dysfunctional immune system, to induce cancer-cell killing by CD8-positive T cells. Immune checkpoint inhibitors, specifically anti-CTLA4 and anti-PD-1 antibodies, have revolutionised the management of many cancers, particularly advanced melanoma, for which tumour regression and long-term durable cancer control is possible in nearly 50% of patients, compared with less than 10% historically. Despite the absence of adequately powered trial data, combined anti-CTLA4 and anti-PD-1 checkpoint inhibition has the highest 5-year overall survival rate of all therapies in advanced melanoma, and has high activity in melanoma brain metastases. A phase 3 study has shown the addition of an anti-LAG3 antibody to nivolumab improves progression-free survival, but its effect on overall survival and how this combination compares to combined anti-CTLA4 and anti-PD-1 checkpoint inhibition is unknown. At present, there are no highly sensitive and specific biomarkers of response to immune checkpoint inhibitors, and clinical factors, such as volume and sites of disease, serum lactate dehydrogenase, and BRAF mutation status, are used to select initial therapy for patients with advanced melanoma. Immune checkpoint inhibitors can induce autoimmune toxicities by virtue of their mechanism of action. These toxicities, termed immune-related adverse events, occur most frequently with combined anti-CTLA4 and anti-PD-1 checkpoint inhibition; can have a variety of presentations; can affect any organ system (most often the skin, colon, endocrine system, and liver); and appear to mimic classic autoimmune diseases. Immune-related adverse events require prompt recognition and management, which may be different from the autoimmune disease it mimics. Immune checkpoint inhibitors appear to be safe for use in patients with HIV, viral hepatitis, and patients with mild-to-moderate pre-existing autoimmune diseases. Patients with organ transplants can respond to immune checkpoint inhibitors but have a high chance of transplant loss. PD-1 inhibitors are now an established standard of care as adjuvant therapy in high-risk resected stage III or IV melanoma. Neoadjuvant checkpoint inhibition for resectable stage III melanoma, which is currently limited to clinical trials, is emerging as a highly effective therapy.
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http://dx.doi.org/10.1016/S0140-6736(21)01206-XDOI Listing
September 2021

Cross-sectional analysis of coding, patient characteristics, consultation frequency and pharmacological treatment of adults with severe mental disorders in Irish general practice.

Ir J Med Sci 2021 Sep 8. Epub 2021 Sep 8.

Irish College of General Practitioners, 4-5 Lincoln Place, Dublin, Ireland.

Background: General practitioners are the gatekeepers of Irish healthcare and they offer continuity of care to patients. Irish general practice is therefore considered appropriate for preventing, diagnosing and managing most mental health problems.

Aims: This study sought to establish the coding frequency, consultation frequency, patient characteristics and pharmacological treatment of patients with severe mental disorders (SMDs) in Irish general practice.

Methods: A cross-sectional design was used. A finder tool embedded in the practice software assisted general practitioners (GPs) coding adult patients with SMDs. Eleven practices uploaded anonymous data on 2,203 patients. Variables analysed included disease code, consultations, prescriptions, sex, patient status and age.

Results: Overall, 2.9% (n = 2,337) of patients had ever been coded with a SMD, 2.4% (n = 1,964) coded with depressive disorder ever and 0.26% (n = 209) and 0.3% (n = 233) with bipolar disorder and schizophrenia, respectively. Overall, 68.0% (n = 1,336) of patients with depressive disorder were female, and 74.0% (n = 171) of patients with schizophrenia were public patients. The median consultation rate in the previous 3 years was highest for schizophrenia patients at 24.5 visits.

Conclusions: Coding of SMDs in Irish general practice appears incomplete. Patients with SMDs have high consultation rates. Patients with depressive disorder are more likely to be female and public patients. This research suggests that the improvement of coding in Irish general practice is the first practical step required to detecting prevalence rates.
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http://dx.doi.org/10.1007/s11845-021-02747-4DOI Listing
September 2021

Diagnostic coding of chronic physical conditions in Irish general practice.

Ir J Med Sci 2021 Sep 2. Epub 2021 Sep 2.

Irish College of General Practitioners, 4-5 Lincoln Place, Dublin, Ireland.

Background: Chronic conditions are responsible for significant mortality and morbidity among the population in Ireland. It is estimated that almost one million people are affected by one of the four main categories of chronic disease (cardiovascular disease, chronic obstructive pulmonary disease, asthma, and diabetes). Primary healthcare is an essential cornerstone for individuals, families, and the community and, as such, should play a central role in all aspects of chronic disease management.

Aim: The aim of the project was to examine the extent of chronic disease coding of four chronic physical conditions in the general practice setting.

Methods: The design was a descriptive cross-sectional study with anonymous retrospective data extracted from practices.

Results: Overall, 8.8% of the adult population in the six participating practices were coded with at least one chronic condition. Only 0.7% of adult patients were coded with asthma, 0.3% with COPD, 3% with diabetes, and 3.3% with CVD. Male patients who visited their GP in the last year were more likely to be coded with any of the four chronic diseases in comparison with female patients. A significant relationship between gender and being coded with diabetes and CVD was found.

Conclusions: For a likely multitude of reasons, diagnostic coding in Irish general practice clinics in this study is low and insufficient for an accurate estimation of chronic disease prevalence. Monitoring of information provided through diagnostic coding is important for patients' care and safety, and therefore appropriate training and reimbursement for these services is essential.
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http://dx.doi.org/10.1007/s11845-021-02748-3DOI Listing
September 2021

Prevalence and predictors of medication non-adherence among people living with multimorbidity: a systematic review and meta-analysis.

BMJ Open 2021 09 2;11(9):e044987. Epub 2021 Sep 2.

School of Psychology, National University of Ireland Galway, Galway, Ireland.

Objectives: This systematic review aimed to describe medication non-adherence among people living with multimorbidity according to the current literature, and synthesise predictors of non-adherence in this population.

Methods: A systematic review was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses. PubMed, EMBASE, CINAHL and PsycINFO were searched for relevant articles published in English language between January 2009 and April 2019. Quantitative studies reporting medication non-adherence and/or predictors of non-adherence among people with two or more chronic conditions were included in the review. A meta-analysis was conducted with a subgroup of studies that used an inclusive definition of multimorbidity to recruit participants, rather than seeking people with specific conditions. Remaining studies reporting prevalence and predictors of non-adherence were narratively synthesised.

Results: The database search produced 10 998 records and a further 75 were identified through other sources. Following full-text screening, 178 studies were included in the review. The range of reported non-adherence differed by measurement method, at 76.5% for self-report, 69.4% for pharmacy data, and 44.1% for electronic monitoring. A meta-analysis was conducted with eight studies (=8949) that used an inclusive definition of multimorbidity to recruit participants. The pooled prevalence of non-adherence was 42.6% (95% CI: 34.0 - 51.3%, =8, =97%, <0.01). The overall range of non-adherence was 7.0%-83.5%. Frequently reported correlates of non-adherence included previous non-adherence and treatment-related beliefs.

Conclusions: The review identified a heterogeneous literature in terms of conditions studied, and definitions and measures of non-adherence used. Results suggest that future attempts to improve adherence among people with multimorbidity should determine for which conditions individuals require most support. The variable levels of medication non-adherence highlight the need for more attention to be paid by healthcare providers to the impact of multimorbidity on chronic disease self-management.

Prospero Registration Number: CRD42019133849.
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http://dx.doi.org/10.1136/bmjopen-2020-044987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413882PMC
September 2021

Isolated imbalance due to bilateral vestibular failure following immune checkpoint inhibitor administration: two cases.

Eur J Cancer 2021 Oct 28;156:187-189. Epub 2021 Aug 28.

Department of Neuro-otology, Royal National ENT and Eastman Dental Hospitals UCLH, London, UK; Department of Clinical and Movement Neurosciences, Centre for Vestibular and Behavioural Neuroscience, Institute of Neurology, University College London, London, UK. Electronic address:

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http://dx.doi.org/10.1016/j.ejca.2021.07.024DOI Listing
October 2021

Adjuvant nivolumab for stage III/IV melanoma: evaluation of safety outcomes and association with recurrence-free survival.

J Immunother Cancer 2021 Aug;9(8)

Perlmutter Cancer Center, NYU Langone Health, New York, New York, USA

Background: Several therapeutic options are now available in the adjuvant melanoma setting, mandating an understanding of their benefit‒risk profiles in order to make informed treatment decisions. Herein we characterize adjuvant nivolumab select (immune-related) treatment-related adverse events (TRAEs) and evaluate possible associations between safety and recurrence-free survival (RFS) in the phase III CheckMate 238 trial.

Methods: Patients with resected stage IIIB-C or IV melanoma received nivolumab 3 mg/kg every 2 weeks (n=452) or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks (n=453) for up to 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. First-occurrence and all-occurrence select TRAEs were analyzed within discrete time intervals: from 0 to 3 months of treatment, from >3-12 months of treatment, and from the last dose (regardless of early or per-protocol treatment discontinuation) to 100 days after the last dose. Possible associations between select TRAEs and RFS were investigated post randomization in 3-month landmark analyses and in Cox model analyses (including a time-varying covariate of select TRAE), within and between treatment groups.

Results: From the first nivolumab dose to 100 days after the last dose, first-occurrence select TRAEs were reported in 67.7% (306/452) of patients. First-occurrence select TRAEs were reported most frequently from 0 to 3 months (48.0%), during which the most common were pruritus (15.5%) and diarrhea (15.3%). Most select TRAEs resolved within 6 months. There was no clear association between the occurrence (or not) of select TRAEs and RFS by landmark analysis or by Cox model analysis within treatment arms or comparing nivolumab to the ipilimumab comparator arm.

Conclusion: Results of this safety analysis of nivolumab in adjuvant melanoma were consistent with its established safety profile. In the discrete time intervals evaluated, most first-occurrence TRAEs occurred early during treatment and resolved. No association between RFS and select TRAEs was evident.

Trial Registration Number: NCT02388906.
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http://dx.doi.org/10.1136/jitc-2021-003188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404438PMC
August 2021

Payments reported by the pharmaceutical industry in Ireland from 2015 to 2019: An observational study.

Health Policy 2021 Oct 3;125(10):1297-1304. Epub 2021 Aug 3.

Department of General Practice, RCSI University of Medicine and Health Sciences, Dublin, Ireland.

Background: The pharmaceutical industry makes large numbers of payments to healthcare organisations (HCOs) and healthcare professionals (HCPs). Ireland has a large pharmaceutical industry presence and national debate on legislating for greater industry payment transparency. This study characterises payments in Ireland to HCPs and HCOs during 2015-2019, and the content, consistency and methodology of the data source.

Methods: An observational study of TransfersOfValue.ie, the disclosure website for the Irish Pharmaceutical Health Association pharmaceutical companies. We conducted a quantitative analysis, summarising payments to HCOs, HCPs and for research and development (R&D). We quantified disclosure rates of names for HCP and HCO payment recipients. We also conducted a content analysis of the methodology notes and website content.

Results: Payments totalling €163 million were reported by 47 companies during 2015-2019, €84.6 million for R&D, with non-R&D payments of €45.1 million to HCOs and €33.6 million to HCPs. HCOs were named for 91.2% of payments, and HCPs for 55.1-62.8% across study years. For 2019, ten companies disclosed >€1 million in payments, and three disclosed >€1 million in HCO and HCP payments. Content analysis of 132 data reports and 46 methodology notes indicated substantial variation in methodologies for reporting between companies.

Conclusions: There are substantial payments in Ireland, often the recipient is undisclosed, and companies differ in their reporting. A mandatory disclosure system could enhance transparency.
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http://dx.doi.org/10.1016/j.healthpol.2021.07.016DOI Listing
October 2021

TMB and Inflammatory Gene Expression Associated with Clinical Outcomes following Immunotherapy in Advanced Melanoma.

Cancer Immunol Res 2021 Oct 13;9(10):1202-1213. Epub 2021 Aug 13.

Unit of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy.

Outcomes for patients with melanoma have improved over the past decade as a result of the development and FDA approval of immunotherapies targeting cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and programmed death ligand 1 (PD-L1). However, these therapies do not benefit all patients, and an area of intensive research investigation is identifying biomarkers that can predict which patients are most likely to benefit from them. Here, we report exploratory analyses of the associations of tumor mutational burden (TMB), a 4-gene inflammatory gene expression signature, and mutation status with tumor response, progression-free survival, and overall survival in patients with advanced melanoma treated as part of the CheckMate 066 and 067 phase III clinical trials evaluating immuno-oncology therapies. In patients enrolled in CheckMate 067 receiving the anti-PD-1 inhibitor nivolumab (NIVO) alone or in combination with the anti-CTLA-4 inhibitor ipilimumab (IPI) or IPI alone, longer survival appeared to associate with high (>median) versus low (≤median) TMB and with high versus low inflammatory signature scores. For NIVO-treated patients, the results regarding TMB association were confirmed in CheckMate 066. In addition, improved survival was observed with high TMB and absence of mutation. Weak correlations were observed between PD-L1, TMB, and the inflammatory signature. Combined assessment of TMB, inflammatory gene expression signature, and mutation status may be predictive for response to immune checkpoint blockade in advanced melanoma.
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http://dx.doi.org/10.1158/2326-6066.CIR-20-0983DOI Listing
October 2021

GPs' perceptions of their relationship with the pharmaceutical industry: a qualitative study.

BJGP Open 2021 Sep 28. Epub 2021 Sep 28.

School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland.

Background: The pharmaceutical industry invests heavily in promoting medications to physicians. This promotion may influence physicians' prescribing behaviour and lead to inappropriately increased prescribing rates.

Aim: To understand GPs' experience of interacting with the pharmaceutical industry, and explore their views and perceptions of the impact of this interaction in general practice in Ireland.

Design & Setting: A qualitative design was used, and GPs practicing in Ireland were eligible.

Method: A combination of purposive and snowball sampling techniques was applied and semi-structured interviews were conducted. Thematic analysis was used to develop themes from the data.

Results: Twenty-one GPs and one GP trainee participated. Five themes were developed: 1) GP and pharmaceutical industry interface; 2) the industry's methods of influence; 3) the uncomfortable relationship between GPs and industry; 4) GPs' perceptions of being unconsciously influenced; and 5) GPs' lack of knowledge of relevant regulations.Participants interacted with pharmaceutical representatives in their surgery and through continuing professional development (CPD). Reported methods of influence included biased information and the offer of gifts. Most participants felt their prescribing was unconsciously influenced. A minority felt that they were only influenced in a way that improved their prescribing.

Conclusion: The study shows that there can be a lack of clarity among GPs about relevant regulations and about the potential impact on prescribing of interactions with the pharmaceutical industry. Education of trainees and GPs has the potential to address this. Restrictions on interactions with the pharmaceutical industry may also play a role, although alternative CPD funding sources would need to be established.
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http://dx.doi.org/10.3399/BJGPO.2021.0057DOI Listing
September 2021

Selective blood-brain barrier permeabilisation of brain metastases by a type-1 receptor selective tumour necrosis factor mutein.

Neuro Oncol 2021 Jul 23. Epub 2021 Jul 23.

Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK.

Background: Metastasis to the brain is a major challenge with poor prognosis. The blood-brain barrier (BBB) is a significant impediment to effective treatment, being intact during the early stages of tumour development and heterogeneously permeable at later stages. Intravenous injection of tumour necrosis factor (TNF) selectively induces BBB permeabilisation at sites of brain micrometastasis, in a TNF type-1 receptor (TNFR1) dependent manner. Here, to enable clinical translation, we have developed a TNFR1-selective agonist variant of human TNF that induces BBB permeabilisation, whilst minimising potential toxicity.

Methods: A library of human TNF muteins (mutTNF) were generated and assessed for binding specificity to mouse and human TNFR1/2, endothelial permeabilising activity in vitro, potential immunogenicity and circulatory half-life. The permeabilising ability of the most promising variant was assessed in vivo in a model of brain metastasis.

Results: The primary mutTNF variant showed similar affinity for human TNFR1 than wild-type human TNF, similar affinity for mouse TNFR1 as wild-type mouse TNF, undetectable binding to human/mouse TNFR2, low potential immunogenicity and permeabilisation of an endothelial monolayer. Circulatory half-life was similar to mouse/human TNF and BBB permeabilisation was induced selectively at sites of micrometastases in vivo, with a time window of ≥24h and enabling delivery of agents within a therapeutically-relevant range (0.5-150kDa), including the clinically approved therapy, trastuzumab.

Conclusions: We have developed a clinically-translatable mutTNF that selectively opens the BBB at micrometastatic sites, whilst leaving the rest of the cerebrovasculature intact. This approach will open a window for brain metastasis treatment that currently does not exist.
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http://dx.doi.org/10.1093/neuonc/noab177DOI Listing
July 2021

A protocol for the evaluation of the process and impact of embedding formal and experiential Public and Patient Involvement training in a structured PhD programme.

J Comorb 2021 Jan-Dec;11:26335565211024793. Epub 2021 Jun 28.

PPI Ignite Network, National University of Ireland Galway, Galway, Ireland.

Background: Incorporating Public and Patient Involvement (PPI) into doctoral research is valued by PhD scholars. The importance of providing early career researchers with appropriate education and training to develop skills to conduct meaningful involvement has been articulated. The Collaborative Doctoral Award in MultiMorbidity (CDA-MM) PhD programme embedded formal PPI training as a postgraduate education component. Four PhD scholars taking part in the CDA-MM established a PPI panel comprising people, and carers of people, living with multimorbidity (≥2 chronic conditions), presenting an opportuning for experiential PPI training. The proposed study aims to evaluate the process and impact of formal and experiential PPI training during a PhD programme.

Design: Embedding PPI training in a PhD programme is a novel approach. This evaluation will include a process evaluation to provide an understanding of the workings of the PPI panel and explore the experiences of key stakeholders involved, and an impact evaluation to assess the impact of embedding PPI training in a PhD programme. This study is a longitudinal mixed-methods evaluation, conducted over 24 months. Participants include PhD scholars, PPI contributors and PhD supervisors. An independent researcher not aligned with the CDA-MM will lead the evaluation. Data collection methods include focus groups, individual interviews, an impact log and group reflections. Qualitative data will be analysed using thematic and content analysis and quantitative data will be analysed using descriptive statistics.

Discussion: This evaluation will report the learnings from embedding formal and experiential PPI training and education across a PhD programme.
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http://dx.doi.org/10.1177/26335565211024793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243087PMC
June 2021

Clinical outcomes of patients with corticosteroid refractory immune checkpoint inhibitor-induced enterocolitis treated with infliximab.

J Immunother Cancer 2021 07;9(7)

Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK

Introduction: Immune checkpoint inhibitors (CPIs) have changed the treatment landscape for many cancers, but also cause severe inflammatory side effects including enterocolitis. CPI-induced enterocolitis is treated empirically with corticosteroids, and infliximab (IFX) is used in corticosteroid-refractory cases. However, robust outcome data for these patients are scarce.

Methods: We conducted a multicenter (six cancer centers), cohort study of outcomes in patients treated with IFX for corticosteroid-refractory CPI-induced enterocolitis between 2007 and 2020. The primary outcome was corticosteroid-free clinical remission (CFCR) with Common Terminology Criteria for Adverse Events (CTCAE) grade 0 for diarrhea at 12 weeks after IFX initiation. We also assessed cancer outcomes at 1 year using RECIST V1.1 criteria.

Results: 127 patients (73 male; median age 59 years) were treated with IFX for corticosteroid-refractory CPI-induced enterocolitis. Ninety-six (75.6%) patients had diarrhea CTCAE grade >2 and 115 (90.6%) required hospitalization for colitis. CFCR was 41.2% at 12 weeks and 50.9% at 26 weeks. In multivariable logistic regression, IFX-resistant enterocolitis was associated with rectal bleeding (OR 0.19; 95% CI 0.04 to 0.80; p=0.03) and absence of colonic crypt abscesses (OR 2.16; 95% CI 1.13 to 8.05; p=0.03). Cancer non-progression was significantly more common in patients with IFX-resistant enterocolitis (64.4%) as compared with patients with IFX-responsive enterocolitis (37.5%; p=0.013).

Conclusion: This is the largest study to date reporting outcomes of IFX therapy in patients with corticosteroid-refractory CPI-induced enterocolitis. Using predefined robust endpoints, we have demonstrated that fewer than half of patients achieved CFCR. Our data also indicate that cancer outcomes may be better in patients developing prolonged and severe inflammatory side effects of CPI therapy.
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http://dx.doi.org/10.1136/jitc-2021-002742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264884PMC
July 2021

Severe progressive scarring pembrolizumab-induced lichen planopilaris in a patient with metastatic melanoma.

Australas J Dermatol 2021 Aug 3;62(3):403-406. Epub 2021 Jul 3.

Chelsea & Westminster Hospital, London, UK.

Lichenoid reactions are one of the many cutaneous immune-related adverse events seen with the use of immune checkpoint inhibitors, particularly anti-PD1 inhibitors. We present a rare care of severe lichen planopilaris secondary to pembrolizumab, with progression even after cessation of immunotherapy. It is important to recognise the significant long-term impact of these cutaneous adverse effects on patient's quality of life.
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http://dx.doi.org/10.1111/ajd.13660DOI Listing
August 2021

Re-induction ipilimumab following acquired resistance to combination ipilimumab and anti-PD-1 therapy.

Eur J Cancer 2021 Aug 29;153:213-222. Epub 2021 Jun 29.

Melanoma Institute Australia, The University of Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Royal North Shore and Mater Hospitals, NSW, Australia. Electronic address:

Purpose: Combination immunotherapy with nivolumab and ipilimumab has a high initial response rate in advanced melanoma; however, up to 55% of patients later progress. The efficacy and safety of ipilimumab re-induction in the setting of acquired resistance (AR) to combination immunotherapy is unknown.

Methods: Patients with advanced melanoma who initially achieved a complete response, partial response or sustained stable disease to induction combination immunotherapy then progressed and were reinduced with ipilimumab (alone or in combination with anti-PD-1) and were analysed retrospectively. Demographics, disease characteristics, efficacy and toxicity were examined.

Results: Forty-seven patients were identified from 12 centres. The response rate to reinduction therapy was 12/47 (26%), and disease control rate was 21/47 (45%). Responses appeared more frequent in patients who developed AR after ceasing induction immunotherapy (30% vs. 18%, P = 0.655). Time to AR was 11 months (95% confidence interval [CI], 8-15 months). After a median follow-up of 16 months (95% CI, 10-25 months), responders to reinduction had a median progression-free survival of 14 months (95% CI, 13, NR months), and in the whole cohort, the median overall survival from reinduction was 17 months (95% CI, 12-NR months). Twenty-seven (58%) immune-related adverse events (irAEs) were reported; 18 (38%) were grade 3/4, and in 11 of 27 (40%), the same irAE observed during induction therapy recurred.

Conclusions: Reinduction with ipilimumab ± anti-PD-1 has modest clinical activity. Clinicians should be attentive to the risk of irAEs, including recurrence of irAEs that occurred during induction therapy. Future studies are necessary to determine best management after resistance to combination immunotherapy.
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http://dx.doi.org/10.1016/j.ejca.2021.04.021DOI Listing
August 2021

Endocrinopathies induced by immune checkpoint inhibitors: the need for clear endocrine diagnosis.

Lancet Oncol 2021 07;22(7):905-907

Skin Unit, Royal Marsden Hospital, London, UK; Department of Endocrinology, Chelsea and Westminster Hospital, London SW10 9NH, UK. Electronic address:

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http://dx.doi.org/10.1016/S1470-2045(21)00305-3DOI Listing
July 2021

Hyperacute toxicity with combination ipilimumab and anti-PD1 immunotherapy.

Eur J Cancer 2021 Aug 25;153:168-178. Epub 2021 Jun 25.

Melanoma Institute Australia, The University of Sydney, Sydney, Australia; Royal North Shore Hospital and Mater Hospitals, Sydney, Australia. Electronic address:

Background: Combination ipilimumab and nivolumab is approved for several malignancies. Toxicity most often occurs 6-10 weeks into treatment. Whether very early toxicity is harder to manage or influences efficacy is unknown.

Methods: Consecutive metastatic melanoma patients who developed hyperacute toxicity, defined as Grade 2+ irAE within 21 days of receiving ipilimumab + anti-PD-1 were retrospectively identified from nine centres.

Results: A total of 82 patients developed hyperacute toxicity (estimated incidence 9%), at a median 10 days (range 1-21). Toxicities included colitis (N = 23), rash (17), hepatitis (9), endocrine (9), pneumonitis (6) and neurotoxicity (4) and were G2 (38%), G3 (52%), G4 (6%) and G5 (2% myocarditis). Fifty-nine percent required treatment beyond oral steroids, including IV steroids (28%), infliximab and other immunosuppression (30%). A total of 29% patients developed an additional hyperacute toxicity and 26% another toxicity >21 days after treatment commencement but before further immunotherapy. The objective response rate (ORR) was 54%, and after a median 11.6 mo follow-up, median PFS was 7.4 mo. Increasing levels of immunosuppression was associated with a reduced PFS (12-month PFS 62% no immunosuppression versus 49% oral steroids versus 33% IV steroids versus 20% further immunosuppressants, p = 0.006). There was no significant difference in ORR or PFS by duration of immunosuppression.

Conclusions: Hyperacute toxicities from combination immunotherapy have a wide spectrum and can be severe. Many patients require significant immunosuppression for prolonged durations and remain at risk of further severe toxicity. Melanoma outcomes in such patients appear similar to those of trial populations, although greater immunosuppression requirements may be associated with inferior outcomes.
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http://dx.doi.org/10.1016/j.ejca.2021.04.045DOI Listing
August 2021

5-Year Outcomes with Cobimetinib plus Vemurafenib in Mutation-Positive Advanced Melanoma: Extended Follow-up of the coBRIM Study.

Clin Cancer Res 2021 Jun 22. Epub 2021 Jun 22.

Peter MacCallum Cancer Centre and the University of Melbourne, Melbourne, Victoria, Australia.

Purpose: The randomized phase III coBRIM study (NCT01689519) demonstrated improved progression-free survival (PFS) and overall survival (OS) with addition of cobimetinib to vemurafenib compared with vemurafenib in patients with previously untreated mutation-positive advanced melanoma. We report long-term follow-up of coBRIM, with at least 5 years since the last patient was randomized.

Experimental Design: Eligible patients were randomized 1:1 to receive either oral cobimetinib (60 mg once daily on days 1-21 in each 28-day cycle) or placebo in combination with oral vemurafenib (960 mg twice daily).

Results: 495 patients were randomized to cobimetinib plus vemurafenib ( = 247) or placebo plus vemurafenib ( = 248). Median follow-up was 21.2 months for cobimetinib plus vemurafenib and 16.6 months for placebo plus vemurafenib. Median OS was 22.5 months (95% CI, 20.3-28.8) with cobimetinib plus vemurafenib and 17.4 months (95% CI, 15.0-19.8) with placebo plus vemurafenib; 5-year OS rates were 31% and 26%, respectively. Median PFS was 12.6 months (95% CI, 9.5-14.8) with cobimetinib plus vemurafenib and 7.2 months (95% CI, 5.6-7.5) with placebo plus vemurafenib; 5-year PFS rates were 14% and 10%, respectively. OS and PFS were longest in patients with normal baseline lactate dehydrogenase levels and low tumor burden, and in those achieving complete response. The safety profile remained consistent with previously published reports.

Conclusions: Extended follow-up of coBRIM confirms the long-term clinical benefit and safety profile of cobimetinib plus vemurafenib compared with vemurafenib monotherapy in patients with mutation-positive advanced melanoma.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0809DOI Listing
June 2021

Cytokine release syndrome in a patient with colorectal cancer after vaccination with BNT162b2.

Nat Med 2021 08 26;27(8):1362-1366. Epub 2021 May 26.

Gastrointestinal and Lymphoma Unit, The Royal Marsden NHS Foundation Trust, Sutton, UK.

Patients with cancer are currently prioritized in coronavirus disease 2019 (COVID-19) vaccination programs globally, which includes administration of mRNA vaccines. Cytokine release syndrome (CRS) has not been reported with mRNA vaccines and is an extremely rare immune-related adverse event of immune checkpoint inhibitors. We present a case of CRS that occurred 5 d after vaccination with BTN162b2 (tozinameran)-the Pfizer-BioNTech mRNA COVID-19 vaccine-in a patient with colorectal cancer on long-standing anti-PD-1 monotherapy. The CRS was evidenced by raised inflammatory markers, thrombocytopenia, elevated cytokine levels (IFN-γ/IL-2R/IL-18/IL-16/IL-10) and steroid responsiveness. The close temporal association of vaccination and diagnosis of CRS in this case suggests that CRS was a vaccine-related adverse event; with anti-PD1 blockade as a potential contributor. Overall, further prospective pharmacovigillence data are needed in patients with cancer, but the benefit-risk profile remains strongly in favor of COVID-19 vaccination in this population.
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http://dx.doi.org/10.1038/s41591-021-01387-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363501PMC
August 2021

Selection of metastasis competent subclones in the tumour interior.

Nat Ecol Evol 2021 07 17;5(7):1033-1045. Epub 2021 May 17.

Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.

The genetic evolutionary features of solid tumour growth are becoming increasingly well described, but the spatial and physical nature of subclonal growth remains unclear. Here, we utilize 102 macroscopic whole-tumour images from clear cell renal cell carcinoma patients, with matched genetic and phenotypic data from 756 biopsies. Utilizing a digital image processing pipeline, a renal pathologist marked the boundaries between tumour and normal tissue and extracted positions of boundary line and biopsy regions to X and Y coordinates. We then integrated coordinates with genomic data to map exact spatial subclone locations, revealing how genetically distinct subclones grow and evolve spatially. We observed a phenotype of advanced and more aggressive subclonal growth in the tumour centre, characterized by an elevated burden of somatic copy number alterations and higher necrosis, proliferation rate and Fuhrman grade. Moreover, we found that metastasizing subclones preferentially originate from the tumour centre. Collectively, these observations suggest a model of accelerated evolution in the tumour interior, with harsh hypoxic environmental conditions leading to a greater opportunity for driver somatic copy number alterations to arise and expand due to selective advantage. Tumour subclone growth is predominantly spatially contiguous in nature. We found only two cases of subclone dispersal, one of which was associated with metastasis. The largest subclones spatially were dominated by driver somatic copy number alterations, suggesting that a large selective advantage can be conferred to subclones upon acquisition of these alterations. In conclusion, spatial dynamics is strongly associated with genomic alterations and plays an important role in tumour evolution.
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http://dx.doi.org/10.1038/s41559-021-01456-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611703PMC
July 2021

Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma.

J Clin Oncol 2021 Aug 12;39(24):2656-2666. Epub 2021 May 12.

James Graham Brown Cancer Center, University of Louisville, Louisville, KY.

Purpose: Effective treatment options are limited for patients with advanced (metastatic or unresectable) melanoma who progress after immune checkpoint inhibitors and targeted therapies. Adoptive cell therapy using tumor-infiltrating lymphocytes has demonstrated efficacy in advanced melanoma. Lifileucel is an autologous, centrally manufactured tumor-infiltrating lymphocyte product.

Methods: We conducted a phase II open-label, single-arm, multicenter study in patients with advanced melanoma who had been previously treated with checkpoint inhibitor(s) and BRAF ± MEK targeted agents. Lifileucel was produced from harvested tumor specimens in central Good Manufacturing Practice facilities using a streamlined 22-day process. Patients received a nonmyeloablative lymphodepletion regimen, a single infusion of lifileucel, and up to six doses of high-dose interleukin-2. The primary end point was investigator-assessed objective response rate (ORR) per RECIST, version 1.1.

Results: Sixty-six patients received a mean of 3.3 prior therapies (anti-programmed death 1 [PD-1] or programmed death ligand 1 [PD-L1]: 100%; anticytotoxic T-lymphocyte-associated protein-4: 80%; BRAF ± MEK inhibitor: 23%). The ORR was 36% (95% CI, 25 to 49), with two complete responses and 22 partial responses. Disease control rate was 80% (95% CI, 69 to 89). Median duration of response was not reached after 18.7-month median study follow-up (range, 0.2-34.1 months). In the primary refractory to anti-PD-1 or PD-L1 therapy subset, the ORR and disease control rate were 41% (95% CI, 26 to 57) and 81% (95% CI, 66 to 91), respectively. Safety profile was consistent with known adverse events associated with nonmyeloablative lymphodepletion and interleukin-2.

Conclusion: Lifileucel demonstrated durable responses and addresses a major unmet need in patients with metastatic melanoma with limited treatment options after approved therapy, including the primary refractory to anti-PD-1 or PD-L1 therapy subset.
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http://dx.doi.org/10.1200/JCO.21.00612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376325PMC
August 2021

'This is not part of my life plan': A qualitative study on the psychosocial experiences and practical challenges in young adults with cancer age 25 to 39 years at diagnosis.

Eur J Cancer Care (Engl) 2021 Sep 3;30(5):e13458. Epub 2021 May 3.

Institute of Cancer Research, London, UK.

Objective: Adolescents and young adults with cancer face unique psychosocial and practical issues. However, patients across this group encounter different life experiences, cancer diagnoses and treatment settings given the tailored services for patients ages 15 to 24. Here, we qualitatively explore the psychosocial experiences and practical challenges of young adults (YAs) with cancer diagnosed between ages 25 and 39 in the United Kingdom.

Methods: We invited YAs diagnosed with cancer in the 5 years prior to enrolment at participating sites to take part in semi-structured interviews or focus groups. Transcripts were analysed using inductive thematic analysis. Two YA patients reviewed the results to ensure robustness.

Results: Sixty-five YAs with varied diagnoses participated. Participants struggled to balance work, childcare and financial solvency with treatment. The halt in family and work life as well as changes in image and ability threatened participants' identity and perceived 'normality' as a YA, however, these also stimulated positive changes. YAs experienced social isolation from friends and family, including children. Many struggled to cope with uncertainty around treatment outcomes and disease recurrence.

Conclusion: The disruption of family and work life can lead to age-specific issues in YAs diagnosed with cancer. Age-tailored psychological and practical services must be considered.
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http://dx.doi.org/10.1111/ecc.13458DOI Listing
September 2021

Promoting physical health among people with enduring mental illness: a qualitative study of healthcare providers' perspectives.

BMJ Open 2021 04 21;11(4):e044855. Epub 2021 Apr 21.

Research Centre, Irish College of General Practitioners, Dublin, Ireland.

Background: People with enduring mental illness (EMI) have higher morbidity and mortality from chronic diseases than the general population, and this results in a significantly reduced relative life expectancy-accounted for primarily by physical illness. This gap may be partly influenced by the reduced likelihood of access to and uptake of regular physical health screening.

Aim: To establish Irish service providers' perspectives regarding the care of the physical health of people with EMI in an effort to inform future service developments aimed at improving the physical health of people with EMI.

Design And Setting: Qualitative study of healthcare providers-general practitioners (GPs) and members of the community mental health teams-in Ireland.

Participants: GPs and mental health service providers.

Methods: Qualitative semi-structured interviews were conducted with 34 service providers. Thematic analysis was undertaken.

Results: Participants considered that the physical health of people with EMI is not currently regularly addressed by the patient's GP or the mental health team. Factors associated with this include patient compliance with attendance, time constraints in consultations to adequately support patient self-management, communication difficulties with the patient and between primary and secondary care, and lack of clarity as to whose responsibility it is to ensure physical health is monitored. In participants' view, a barrier to improvement is the present funding approach.

Conclusion: The evidence from this study has the potential to form the basis for innovation and change in service delivery for people with an EMI in Ireland and internationally, specifically in countries where it is not clear who has the overall responsibility to monitor the physical health of patients with EMI. This role requires time and regular contact, and both the organisation and the funding of the health system need to support it.
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http://dx.doi.org/10.1136/bmjopen-2020-044855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061849PMC
April 2021

Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): health-related quality-of-life results from a double-blind, randomised, controlled, phase 3 trial.

Lancet Oncol 2021 05 12;22(5):655-664. Epub 2021 Apr 12.

EORTC Headquarters, Brussels, Belgium.

Background: The European Organisation for Research and Treatment of Cancer (EORTC) 1325-MG/KEYNOTE-054 trial in patients with resected, high-risk stage III melanoma demonstrated improved recurrence-free survival with adjuvant pembrolizumab compared with placebo (hazard ratio 0·57 [98·4% CI 0·43-0·74]; p<0·0001). This study reports the results from the health-related quality-of-life (HRQOL) exploratory endpoint.

Methods: This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with previously untreated histologically confirmed stage IIIA, IIIB, or IIIC resected cutaneous melanoma, and an Eastern Cooperative Oncology Group performance status score of 1 or 0 were eligible. Patients were randomly assigned (1:1) using a central interactive voice-response system on the basis of a minimisation technique stratified for stage and geographic region to receive intravenously 200 mg pembrolizumab or placebo. Treatment was administered every 3 weeks for 1 year, or until disease recurrence, unacceptable toxicity, or death. The primary endpoint of the trial was recurrence-free survival (reported elsewhere). HRQOL was a prespecified exploratory endpoint, with global health/quality of life (GHQ) over 2 years measured by the EORTC QLQ-C30 as the primary analysis. Analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37, and long-term follow-up is ongoing.

Findings: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to pembrolizumab (n=514) or placebo (n=505). Median follow-up was 15·1 months (IQR 12·8-16·9) at the time of this analysis. HRQOL compliance was greater than 90% at baseline, greater than 70% during the first year, and greater than 60% thereafter for both groups. Because of low absolute compliance numbers at later follow-up, the analysis was truncated to week 84. Baseline GHQ scores were similar between groups (77·55 [SD 18·20] in the pembrolizumab group and 76·54 [17·81] in the placebo group) and remained stable over time. The difference in average GHQ score between the two groups over the 2 years was -2·2 points (95% CI -4·3 to -0·2). The difference in average score during treatment was -1·1 points (95% CI -3·2 to 0·9) and the difference in average score after treatment was -2·2 points (-4·8 to 0·4). These differences are within the 5-point clinical relevance threshold for the QLQ-C30 and are therefore clinically non-significant.

Interpretation: Pembrolizumab does not result in a clinically significant decrease in HRQOL compared with placebo when given as adjuvant therapy for patients with resected, high-risk stage III melanoma. These results support the use of adjuvant pembrolizumab in this setting.

Funding: Merck Sharp & Dohme.
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http://dx.doi.org/10.1016/S1470-2045(21)00081-4DOI Listing
May 2021

Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial.

Lancet Oncol 2021 05 12;22(5):643-654. Epub 2021 Apr 12.

EORTC Headquarters, Brussels, Belgium.

Background: The European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial assessed pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. At 15-month median follow-up, pembrolizumab improved recurrence-free survival (hazard ratio [HR] 0·57 [98·4% CI 0·43-0·74], p<0·0001) compared with placebo, leading to its approval in the USA and Europe. This report provides the final results for the secondary efficacy endpoint, distant metastasis-free survival and an update of the recurrence-free survival results.

Methods: This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with complete resection of cutaneous melanoma metastatic to lymph node, classified as American Joint Committee on Cancer staging system, seventh edition (AJCC-7) stage IIIA (at least one lymph node metastasis >1 mm), IIIB, or IIIC (without in-transit metastasis), and with an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) via a central interactive voice response system to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for up to 18 doses or until disease recurrence or unacceptable toxicity. Randomisation was stratified according to disease stage and region, using a minimisation technique, and clinical investigators, patients, and those collecting or analysing the data were masked to treatment assignment. The two coprimary endpoints were recurrence-free survival in the intention-to-treat (ITT) population and in patients with PD-L1-positive tumours. The secondary endpoint reported here was distant metastasis-free survival in the ITT and PD-L1-positive populations. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37.

Findings: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to receive either pembrolizumab (n=514) or placebo (n=505). At an overall median follow-up of 42·3 months (IQR 40·5-45·9), 3·5-year distant metastasis-free survival was higher in the pembrolizumab group than in the placebo group in the ITT population (65·3% [95% CI 60·9-69·5] in the pembrolizumab group vs 49·4% [44·8-53·8] in the placebo group; HR 0·60 [95% CI 0·49-0·73]; p<0·0001). In the 853 patients with PD-L1-positive tumours, 3·5-year distant metastasis-free survival was 66·7% (95% CI 61·8-71·2) in the pembrolizumab group and 51·6% (46·6-56·4) in the placebo group (HR 0·61 [95% CI 0·49-0·76]; p<0·0001). Recurrence-free survival remained longer in the pembrolizumab group 59·8% (95% CI 55·3-64·1) than the placebo group 41·4% (37·0-45·8) at this 3·5-year follow-up in the ITT population (HR 0·59 [95% CI 0·49-0·70]) and in those with PD-L1-positive tumours 61·4% (56·3-66·1) in the pembrolizumab group and 44·1% (39·2-48·8) in the placebo group (HR 0·59 [95% CI 0·49-0·73]).

Interpretation: Pembrolizumab adjuvant therapy provided a significant and clinically meaningful improvement in distant metastasis-free survival at a 3·5-year median follow-up, which was consistent with the improvement in recurrence-free survival. Therefore, the results of this trial support the indication to use adjuvant pembrolizumab therapy in patients with resected high risk stage III cutaneous melanoma.

Funding: Merck Sharp & Dohme.
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http://dx.doi.org/10.1016/S1470-2045(21)00065-6DOI Listing
May 2021

Predictive biomarkers for response to immune checkpoint inhibition.

Semin Cancer Biol 2021 Apr 2. Epub 2021 Apr 2.

Renal and Skin Units, The Royal Marsden Hospital, London SW3 6JJ, UK; Cancer Dynamics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. Electronic address:

Immune checkpoint inhibitors have transformed the prognosis and treatment paradigm of many cancer types, through the potential for durable responses. However, the majority of patients still do not benefit. Response to checkpoint inhibition is determined by dynamic host, tumour and tumour microenvironment factors that display spatial and temporal variability, but our understanding of these interactions is incomplete. Through investigating biomarkers of resistance and response, opportunities arise to discover new therapeutic targets and shape personalised treatment strategies. Here we review approved and emerging biomarkers of response to immune checkpoint inhibitors, in particular the recent rapid progress in host and tumour genomics. It is unlikely that a single biomarker will precisely predict response, but multivariate multiomic markers may provide a balanced assessment of these factors and more accurately identify patients who will benefit. Further efforts are required to translate these groundbreaking discoveries into novel therapeutics and biomarker driven clinical trials, to provide durable treatment response to a greater population of patients.
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http://dx.doi.org/10.1016/j.semcancer.2021.03.036DOI Listing
April 2021

Systematic literature review for the association of biomarkers with efficacy of anti-PD-1 inhibitors in advanced melanoma.

Future Oncol 2021 Jul 30;17(20):2683-2692. Epub 2021 Mar 30.

The Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK.

Summarize the literature assessing biomarkers in predicting efficacy of anti-PD-1 therapy for patients with high-risk unresectable or metastatic melanoma. Relevant studies were identified via a systematic literature review. About 334 unique biomarkers or biomarker combinations were identified from 121 citations. Neutrophil-to-lymphocyte ratio was the most frequently studied biomarker, followed by C-reactive protein. Fifty-nine biomarkers were significantly associated with overall survival (OS), 51 with progression-free survival (PFS) and 44 with response. Twenty biomarkers were associated with both OS and PFS; two were associated with OS, PFS and response (MHC-II and tumor mutational burden). Numerous biomarkers could potentially predict the efficacy of anti-PD-1-based therapy for melanoma patients. However, confirmatory studies are needed as well as determination of implications for clinical decision-making.
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http://dx.doi.org/10.2217/fon-2021-0154DOI Listing
July 2021
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