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Clinical trials to establish the efficacy of new agents in the adjuvant cancer setting typically take many years to complete. During that time, external factors can impact recruitment and reporting plans. An example is a new standard of care becoming available during the recruitment period.In this paper we describe how we modified the design of the RAMPART trial (NCT03288532) which was set up to investigate immune checkpoint inhibitor therapy in the adjuvant renal cancer setting. The trial had been initiated when no globally accepted adjuvant strategy after nephrectomy existed. A subsequent change in the standard of care for many patients with early renal cancer meant it was no longer feasible to continue to recruit. We needed to find a way to maximise the contribution that RAMPART participants could make to the evidence base for immune checkpoint inhibitor therapy without introducing bias or detriment to the integrity of the trial results. We describe how we agreed and incorporated all design and timeline changes while remaining blinded to accumulating data within the trial, thus protecting the reliability of the future results. We share details of our design modifications to guide others who may have similar experiences, particularly as more agents and combinations of agents are developed and investigated in similar adjuvant settings.

Background There is interest in using treatment breaks in oncology, to reduce toxicity without compromising efficacy. Trial design A Phase II/III multicentre, open-label, parallel-group, randomised controlled non-inferiority trial assessing treatment breaks in patients with renal cell carcinoma. Methods Participants Patients with locally advanced or metastatic renal cell carcinoma, starting tyrosine kinase inhibitor as first-line treatment at United Kingdom National Health Service hospitals. Interventions At trial entry, patients were randomised (1 : 1) to a drug-free interval strategy or a conventional continuation strategy. After 24 weeks of treatment with sunitinib/pazopanib, drug-free interval strategy patients took up a treatment break until disease progression with additional breaks dependent on disease response and patient choice. Conventional continuation strategy patients continued on treatment. Both trial strategies continued until treatment intolerance, disease progression on treatment, withdrawal or death. Objective To determine if a drug-free interval strategy is non-inferior to a conventional continuation strategy in terms of the co-primary outcomes of overall survival and quality-adjusted life-years. Co-primary outcomes For non-inferiority to be concluded, a margin of ≤ 7.5% in overall survival and ≤ 10% in quality-adjusted life-years was required in both intention-to-treat and per-protocol analyses. This equated to the 95% confidence interval of the estimates being above 0.812 and −0.156, respectively. Quality-adjusted life-years were calculated using the utility index of the EuroQol-5 Dimensions questionnaire. Results Nine hundred and twenty patients were randomised (461 conventional continuation strategy vs. 459 drug-free interval strategy) from 13 January 2012 to 12 September 2017. Trial treatment and follow-up stopped on 31 December 2020. Four hundred and eighty-eight (53.0%) patients [240 (52.1%) vs. 248 (54.0%)] continued on trial post week 24. The median treatment-break length was 87 days. Nine hundred and nineteen patients were included in the intention-to-treat analysis (461 vs. 458) and 871 patients in the per-protocol analysis (453 vs. 418). For overall survival, non-inferiority was concluded in the intention-to-treat analysis but not in the per-protocol analysis [hazard ratio (95% confidence interval) intention to treat 0.97 (0.83 to 1.12); per-protocol 0.94 (0.80 to 1.09) non-inferiority margin: 95% confidence interval ≥ 0.812, intention to treat: 0.83 > 0.812 non-inferior, per-protocol: 0.80 < 0.812 not non-inferior]. Therefore, a drug-free interval strategy was not concluded to be non-inferior to a conventional continuation strategy in terms of overall survival. For quality-adjusted life-years, non-inferiority was concluded in both the intention-to-treat and per-protocol analyses [marginal effect (95% confidence interval) intention to treat −0.05 (−0.15 to 0.05); per-protocol 0.04 (−0.14 to 0.21) non-inferiority margin: 95% confidence interval ≥ −0.156]. Therefore, a drug-free interval strategy was concluded to be non-inferior to a conventional continuation strategy in terms of quality-adjusted life-years. Limitations The main limitation of the study is the fewer than expected overall survival events, resulting in lower power for the non-inferiority comparison. Future work Future studies should investigate treatment breaks with more contemporary treatments for renal cell carcinoma. Conclusions Non-inferiority was shown for the quality-adjusted life-year end point but not for overall survival as pre-defined. Nevertheless, despite not meeting the primary end point of non-inferiority as per protocol, the study suggested that a treatment-break strategy may not meaningfully reduce life expectancy, does not reduce quality of life and has economic benefits. Although the treating clinicians’ perspectives were not formally collected, the fact that clinicians recruited a large number of patients over a long period suggests support for the study and provides clear evidence that a treatment-break strategy for patients with renal cell carcinoma receiving tyrosine kinase inhibitor therapy is feasible. Trial registration This trial is registered as ISRCTN06473203. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Programme (NIHR award ref: 09/91/21) and is published in full in Health Technology Assessment; Vol. 28, No. 45. See the NIHR Funding and Awards website for further award information. Plain language summary Treatment breaks in cancer are of significant interest to patients and health professionals. Renal cell carcinoma is the most common type of kidney cancer. Sunitinib and pazopanib are both targeted treatments. They were commonly used to treat advanced kidney cancer but often cause side effects, sometimes requiring use of a reduced dose or even stopping treatment. The STAR trial was designed to see whether planned treatment breaks made patients with advanced kidney cancer being treated with sunitinib and pazopanib feel better, without substantially affecting how well the treatment worked. After 24 weeks of treatment, patients took sunitinib and pazopanib either as they normally would or in the alternative way with planned treatment breaks. Treating patients in this way was continued until drug-related side effects stopped treatment, patients’ disease worsened while taking treatment or the patient died. The trial compared how well the different treatment strategies worked in terms of how long patients lived and their quality of life over that time. This trial is the largest United Kingdom trial in advanced renal cell carcinoma. Patients took part from 60 United Kingdom centres between 2012 and 2017. It was funded by the National Institute for Health and Care Research Health Technology Assessment Programme and run by the Leeds Clinical Trials Research Unit. In total, 920 patients took part. Four hundred and sixty-one patients were allocated to continue treatment and 459 were allocated to start at least one treatment break. Treatment breaks lasted on average 87 days. The length of time patients lived in both arms of the trial appeared similar, but this cannot be concluded due to insufficient information. Being allocated to have treatment breaks rather than continuing treatment did not negatively impact a patient’s quality of life. Additionally, allocating patients to have treatment breaks was shown to have significant cost savings compared to just continuing treatment. Importantly planned treatment breaks were shown to be feasible. Scientific summary Background There is increasing interest in using treatment breaks in oncology, to reduce toxicity without compromising efficacy. STAR was designed to determine if a tyrosine kinase inhibitor (TKI) drug-free interval strategy (DFIS) was non-inferior to a conventional continuation strategy (CCS) in the first-line treatment of advanced renal cell carcinoma (RCC). Objectives The overall primary objective was to determine whether a sunitinib or pazopanib DFIS is non-inferior in terms of overall survival (OS) and quality-adjusted life-year (QALY) compared to a sunitinib or pazopanib CCS in patients with locally advanced and/or metastatic clear cell RCC. Secondary objectives included comparing a DFIS to a CCS in terms of summative progression-free interval, time to strategy failure, time to treatment failure, toxicity (common terminology criteria for adverse events v.4.0), quality of life (QoL) [Functional Assessment of Cancer Therapy – Kidney Symptom Index (FKSI-15), Functional Assessment of Cancer Therapy-G (FACT-G), EuroQol-5 Dimensions (EQ-5DTM) and EQ-Visual Analogue Scale (VASTM)], cost effectiveness, progression-free survival (PFS). Three ancillary studies were also included in the trial. The Patient Preference and Understanding Study was designed to understand the participants’ experiences of taking part in the trial. The dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) substudy was designed to investigate whether early DCE-MRI could predict progressive disease (PD) at 24 weeks. The computerised tomography (CT) substudy was designed to determine CT as a potential biomarker and predictor of PD at 24 weeks. Methods STAR was a UK Phase II/III multicentre, open-label, parallel-group, randomised controlled non-inferiority (NI) trial. The trial recruited adults, with histologically confirmed locally advanced or metastatic clear cell, uni-dimensionally measurable, RCC who required but had not received prior systemic therapy. Participants were required to have an Eastern Cooperative Oncology Group performance status of 0–1, meet pre-specified blood parameters prior to randomisation, provide written informed consent, be able and willing to comply with the terms of the protocol and follow approved pregnancy prevention guidelines. Exclusion criteria included pulmonary or mediastinal disease, life expectancy < 6 months, previous treatment with or known contraindications or hypersensitivity to TKIs, untreated brain metastases, concurrent or previous invasive cancers which could confuse diagnosis or end points, use of contraindicated concomitant medication or substances and poorly controlled hypertension. At trial entry, participants were randomised (1 : 1) centrally by Leeds CTRU to a CCS or a DFIS. Randomisation was stratified by Motzer prognostic group (favourable, intermediate, poor), trial site, gender, age (< 60, ≥ 60 years), disease status (metastatic, locally advanced), previous nephrectomy (yes, no), TKI (sunitinib, pazopanib). Both strategies received an initial 4 cycles of trial treatment [sunitinib: 1 cycle of treatment refers to 50 mg (starting dose) on days 1–28, repeated every 42 days; pazopanib: 1 cycle of treatment refers to 800 mg (starting dose) on days 1–42, repeated every 42 days] following which participants in the DFIS arm took up their first treatment break. Following disease progression on a treatment break, DFIS participants restarted their treatment. Additional breaks were permitted following a further 4 cycles of treatment at the treating clinician’s discretion. The trial strategy continued until death, progression while receiving treatment, unacceptable toxicity (clinical withdrawal) or participant withdrawal. Following cessation of the trial strategy, participants were followed up after 6 months and then annually thereafter until death, patient withdrawal or the end of the trial. All trial data were collected on trial-specific case report forms (CRFs). All CRFs, apart from the questionnaires for the patient-reported outcome measures (FSKI-15, FACT-G, EQ-5D and EQ-VAS) were completed by research staff at the site. Overall survival was defined as time from randomisation to death from any cause. For NI to be concluded, a margin of ≤ 7.5% in OS was pre-specified. The survival at 2 years in the CCS arm was assumed to be 48.5%. A 7.5% NI margin led to the survival at 2 years in the DFIS arm assumed to be at least 41%, leading to a hazard ratio (HR) of 0.812. This along with a one-sided 2.5% significance level, 5% dropout rate and 80% power required 920 participants. Where 80% power would be attained when 720 events were observed. Quality-adjusted life-years were defined as the time spent in each health state over trial and follow-up, calculated as the utility index of the EQ-5D questionnaire, which was collected frequently (6-weekly for 24 weeks, 2-weekly for 24 weeks, 6-weekly while on study, 6 months post end of trial strategy and annually thereafter). For NI to be concluded a margin of ≤ 10% in mean QALYs was pre-specified. The power for the QALY comparison was derived using simulations. Under the assumptions of a 0.9 HR in favour of CCS, a sample size of 920, 5.83 years of recruitment and 3.25 years of follow-up a CCS QALY estimate of 1.56 was derived along with a power of 69.94%. The CCS QALY estimate of 1.56 in conjunction with the 10% margin equates to a NI boundary of −0.156 for the difference in mean QALYs. It was pre-specified that NI was required in both intention-to-treat (ITT) and per-protocol (PP) analyses, in both end points, to be concluded overall. An in-depth qualitative inductive study of 11 patients on the DFIS arm was conducted to better understand their acceptability of extended treatment breaks. A thematic analysis using a comparative and contrastive approach was employed. An economic evaluation was also conducted which estimated the cost effectiveness of DFIS versus CCS at 2 years (within-trial analysis) and over the patients’ lifetime (decision modelling analysis). Results Participant flow Two thousand one hundred and ninety-seven patients were screened; of these, 920 were randomised (CCS: 461, DFIS: 459). In total, 878 (95.4%) participants ceased trial treatment prior to the end of follow-up. Radiological disease progression was the most frequent reason for treatment discontinuation at 43.7% (CCS: 48.4%, DFIS: 39.0%). Overall, 13,147 (78.6%, n = 16,726) (CCS: 5764/7401, 77.9%; DFIS: 7383/9327, 79.2%) of QoL questionnaire booklets were returned on the trial. The proportions of reasons for missing booklets were similar between the two arms, where the highest reason was ‘missed by site in error’ (overall: 27%, CCS: 28.4%, DFIS: 25.8%). However, the majority of reasons for missing were missing (overall: 52.1%, CCS: 50.6%, DFIS: 53.4%). Overall, 63 participants (6.8%, n = 920) withdrew from some aspect of the trial. This resulted in 21 (2.82%, n = 920) participants being formally lost to follow-up (CCS: 11, 2.4%; DFIS: 10, 2.2%). An additional DFIS participant was lost to follow-up due to the participant moving away. However, all participants were included in the analysis. Numbers analysed Nine hundred and nineteen participants (CCS: 461, DFIS: 458) were included in the ITT population as one DFIS participant did not have RCC. Similarly, 871 participants (CCS: 453, DFIS: 418) were included in the PP population, 916 participants (CCS: 485, DFIS: 431) were included in the safety population, 869 participants (CCS: 438, DFIS: 431) were included in the EuroQol-5 Dimensions, three-level version (EQ-5D-3L) population, 856 participants (CCS: 425, DFIS: 431) were included in the FACT-G population and 882 participants (CCS: 436, DFIS: 446) were included in the FKSI population. Baseline characteristics and treatment (on trial and in follow-up) Key demographic and disease-related characteristics were similar across both randomisation allocation and randomised under TKI for all analysis populations. STAR participants were predominantly white (ITT – 96.3%), male (ITT – 72.7%) and aged ≥ 60 at randomisation (ITT – 73.4%). On average, participants in both arms received a similar number of treatment cycles [ITT median (interquartile range, IQR): 5 (2, 10) vs. 4 (2, 9)]. Overall, 248 participants (56.3%, n = 459) in the DFIS arm continued on the trial after week 24. The majority of these (127, 51.2%) only started one treatment break. Thirty-eight (15.3%) of these had 2 treatment breaks and 68 (27.4%) took 3 or more treatment breaks. The maximum number of treatment breaks taken by 1 participant was 9, and 15 participants (6%) did not take up a treatment break despite continuing on study after week 24. Overall, 61.6% of participants received further systemic anticancer therapy treatment during follow-up, with a higher proportion in the CCS arm (68.5%, n = 461) compared to the DFIS arm (54.6%, n = 458). Co-primary end points Median (IQR) follow-up for OS in the PP population was 58 months (46, 72). In total 648 (74.4%, n = 871) of PP participants died prior to the end of follow-up (31 December 2020) [CCS: 330 (72.8%, n = 453), DFIS: 318 (76.1%, n = 418)]. Renal cancer was related to the cause of 607 (93.7%, n = 648) deaths [CCS: 314 (95.2%, n = 330), DFIS: 293 (92.1%, n = 318)]. Median OS [95% confidence interval (CI)] in the CCS arm was 28 months (24, 32) and 27 months (23, 31) in the DFIS arm. At 2 years post randomisation (95% CI), 54.2% (50.8%, 57.5%) of PP participants were alive. This was similar between the two arms [CCS: 55.2% (50.5%, 59.7%), DFIS: 53.1% (48.2%, 57.8%)]. On application of a Cox proportional hazards (PH) model adjusted for the stratification factors of the trial, the HR for randomisation allocation, CCS versus DFIS (95% CI) was 0.94 (0.80 to 1.09). Comparing the lower bound of the CI to the NI boundary of 0.812. At the 2.5% significance level, we do not reject the null hypothesis that DFIS is not non-inferior to CCS in terms of OS. There is insufficient evidence to conclude NI. However, the analyses conducted in the ITT population along with the sensitivity analysis conducted in the PP population using a piecewise hazards model and a Cox regression model where Motzer Score at randomisation was considered as two categories did conclude NI between the two arms. The mean QALY (95% CI) for PP participants in the CCS arm was 1.73 (1.60 to 1.86) and 1.80 (1.65 to 1.95) in the DFIS arm derived by combining the results across 52 imputed data sets. The marginal effect (95% CI) of randomisation allocation, DFIS versus CCS was 0.04 (−0.14 to 0.21). Comparing the lower bound of the CI to the NI boundary of 0.156. As the lower bound of the CI is above −0.156, we conclude that the DFIS arm is non-inferior to the CCS arm in terms of QALYs in the PP population. This conclusion remained consistent across all the sensitivity analyses; ITT population, derived from week 24, measured up to 12, 24 and 36 months post randomisation, complete case analysis, analysis conducted using a multivariate linear regression analysis and analysis conducted under missing not at random scenario 1 (worst-case scenario). Secondary end points All secondary time to event end-point analysis was conducted in the ITT population. With the exception of PFS, all analyses showed a significant difference in favour of the DFIS compared to the CCS when applied in a Cox PH model adjusted for the stratification factors of the trial. As PFS measures to the first progression and does therefore not account for successful rechallenge of TKI in the DFIS arm post progression this was expected. There was little difference in the summary statistics of the various QoL questionnaire scores and subscales (FKSI-15, FACT-G, EQ-5D-3L and EQ5D-VAS) when considered by randomisation allocation in each of their populations. A difference only appeared around week 294 when few participants remained on the CCS arm. The multilevel modelling conducted on the FKSI-15 and the FACT-G questionnaires concluded some significant differences between the DFIS and the CCS in favour of the DFIS. However, these differences were small and not consistently observed in the sensitivity analysis, which modelled the questionnaires up to regular intervals post randomisation. The within-trial economic evaluation at 2 years indicated that DFIS was highly likely to be cost-effective. DFIS was found to provide a small QALY benefit (0.049) and substantial cost savings (£3235) over CCS. The value-for-money metric was principally driven by savings in medicine costs. There were relatively minor differences in resource use between arms. The lifetime cost-effectiveness modelling led to the same conclusion yielding QALY gains of 0.08 and cost savings of £2420 (both probabilistic values) in favour of DFIS. The probabilistic sensitivity analyses indicated that DFIS had a 96% chance of being cost saving and a 68% chance of yielding QALY gains versus CCS. The conclusions of both the trial- and model-based analyses were relatively robust to a series of supplementary and sensitivity analyses. Safety All participants bar three in the safety population (CCS: 1, DFIS: 2) experienced an adverse event (AE) during the course of the trial. Overall, a higher proportion of participants in the DFIS arm experienced an AE grade 3 or above (CCS: 70.7%, n = 485, DFIS: 76.1%, n = 431). This difference between arms continues when considering serious adverse events (SAEs) by arm overall and pre and post week 24 (overall – CCS: 45.8%, n = 485, DFIS: 54.1%, n = 431, pre CCS: 32.8%, n = 485, DFIS: 35.5%, n = 431, post CCS: 32.8%, n = 265, DFIS: 48.4%, n = 223). However, this may be explained through the reporting requirements. Participants on DFIS will have reported AEs and SAEs for longer due to their increased time on trial strategy. On consideration of serious AEs deemed to be related to the participants TKI [serious adverse reactions (SARs)], which were collected for the duration of the trial, the difference, in favour of CCS, is more evident prior to week 24 when both strategies are the same (overall – CCS: 18.8%, n = 485, DFIS: 23.4%, n = 431, pre CCS: 13.2%, n = 485, DFIS: 19.3%, n = 431, post CCS: 11.7%, n = 265, DFIS: 9.4%, n = 223). The majority of SAEs and SARs resulted in recovery or recovery with sequelae (SAEs: 80.1%, n = 744, SARs: 87.6%, n = 226). There were 13 suspected unexpected serious adverse reactions (CCS: 5, DFIS: 8) on the trial. Substudies The qualitative substudy concluded that if a DFIS approach was implemented in practice some thought should be given to how patients should be supported during the extended break to cope with and alleviate worries related to ongoing monitoring and tumour growth. The magnetic resonance imaging (MRI) feasibility study demonstrated that DCE-MRI-derived biomarkers of tumour perfusion (perfused tumour volume, Ktrans and extracellular volume) as potential surrogate biomarkers to predict disease progression following TKI therapy in metastatic RCC and the technique of DCE-MRI assessment is reproducible. The CT substudy demonstrated that assessment of enhancement as well as size change alters the categorisation of response. Use of modified Choi (mChoi) criteria may allow for earlier detection of disease progression, and more representative separation of participants with partial response versus stable disease. While published literature has suggested an association of mChoi criteria with time to progression, in terms of prediction of early progression within 6 months of treatment initiation, no association was shown in this cohort. Conclusions Implications for health care The STAR trial is an exemplar trial, being one of the first to be powered on a QALY end point. It demonstrated no substantial detriment in terms of OS and QALY from a DFIS compared to a CCS. However, NI between the two arms cannot be concluded due to a lack of statistical power for the analysis of OS, as a result of fewer than expected OS events due to the changing landscape of effective treatments for relapsed advanced RCC during the trial. These results provide evidence-based reassurance for people who received National Institute for Health and Care Excellence (NICE)-approved treatment breaks in this setting during the COVID-19 pandemic. Through compliance with the protocol, treatment breaks within the trial were shown to be acceptable to patients and health professionals. Future research implications Further discussion is required with patient and public involvement (PPI) and NICE regarding the implications of these results after the NHS interim treatment options following the COVID-19 pandemic end. The STAR trial has provided significant learning regarding the development, design and delivery of intermittent therapy trials. Trial registration This trial is registered as ISRCTN06473203. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Programme (NIHR award ref: 09/91/21) and is published in full in Health Technology Assessment; Vol. 28, No. 45. See the NIHR Funding and Awards website for further award information.

Objective We report post hoc analyses of efficacy with first-line avelumab plus axitinib or sunitinib according to baseline neutrophil-to-eosinophil ratio (NER) in patients with advanced renal cell carcinoma (aRCC) from the JAVELIN Renal 101 phase 3 trial.Methods and analysis Progression-free survival (PFS), overall survival (OS) and objective response per baseline NER were analysed in the overall population and in patients with programmed death ligand 1 (PD-L1+) tumours. Multivariable Cox regression analyses to assess the effect of NER after adjustment for other baseline variables were conducted.Results In NER

Background Tebentafusp, a bispecific (gp100×CD3) ImmTAC, significantly improved overall survival (OS) outcomes for HLA-A*02:01+ adult patients with untreated metastatic uveal melanoma (mUM) and showed promising survival in previously treated mUM with 1-year OS of 62% in the primary analysis of study IMCgp100-102. Here we report long-term outcomes from this phase 1/2 study in pretreated mUM.Patients and methods Patients with previously treated mUM received tebentafusp weekly intravenous at 20 µg dose 1, 30 µg dose 2 and either 54, 64, 68, or 73 µg (phase 1) or 68 µg (phase 2) dose 3+. The primary objective was overall response rate. Secondary objectives included OS and safety. OS was estimated by Kaplan-Meier methods. Association between OS and baseline covariates, on-treatment Response Evaluation Criteria in Solid Tumors (RECIST) response, baseline tumor biopsy and circulating-tumor DNA (ctDNA) changes were assessed.Results 146 patients were treated with tebentafusp: 19 in phase 1 and 127 in phase 2. With a median follow-up duration of 48.5 months, the median OS was 17.4 months (95% CI, 13.1 to 22.8), and the 1-year, 2-year, 3-year and 4-year OS rates were 62%, 40%, 23% and 14%, respectively. Improved survival was associated with lower ctDNA baseline levels and greater ctDNA reductions by week 9 on-treatment, with 100% 1-year, 73% 2-year and 45% 3-year OS rates for patients with ctDNA clearance. Baseline gp100 expression was not associated with survival, despite more RECIST responses among patients with higher expression. No new safety signals were reported with long-term dosing.Conclusions This study represents the longest follow-up of a Tcell receptor bispecific to date and confirms the durable survival benefits achieved with tebentafusp in previously treated mUM with good tolerability long-term. A role for ctDNA reduction as an early indicator of clinical benefit was again suggested for patients treated with tebentafusp.

Abstract Background Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of melanoma and other cancers. However, no reliable biomarker of survival or response has entered the clinic to identify those patients with melanoma who are most likely to benefit from ICIs. Glycosylation affects proteins and lipids’ structure and functions. Tumours are characterized by aberrant glycosylation which may contribute to their progression and hinder an effective antitumour immune response. Methods We aim at identifying novel glyco-markers of response and survival by leveraging the N-glycome of total serum proteins collected in 88 ICI-naive patients with advanced melanoma from two European countries. Samples were collected before and during ICI treatment. Results We observe that responders to ICIs present with a pre-treatment N-glycome profile significantly shifted towards higher abundancy of low-branched structures containing lower abundances of antennary fucose, and that this profile is positively associated with survival and a better predictor of response than clinical variables alone. Conclusion While changes in serum protein glycosylation have been previously implicated in a pro-metastatic melanoma behaviour, we show here that they are also associated with response to ICI, opening new avenues for the stratification of patients and the design of adjunct therapies aiming at improving immune response.

Background: Approximately 30% of childhood cancer survivors (CCSs) will develop chronic kidney disease (CKD) or hypertension 15 to 20 years after treatment ends. The incidence of CKD and hypertension in the 5-year window after cancer therapy is unknown. Moreover, extent of monitoring of CCS with CKD and associated complications in current practice is underexplored. To inform the development of new and existing care guidelines for CCS, the epidemiology and monitoring of CKD and hypertension in the early period following cancer therapy warrants further investigation. Objective: To describe the design and methods of the KIdney aNd blooD prESsure ouTcomes in Childhood Cancer Survivors study, which aims to evaluate the burden of late kidney and blood pressure outcomes in the first ~10 years after cancer therapy, the extent of appropriate screening and complications monitoring for CKD and hypertension, and whether patient, disease/treatment, or system factors are associated with these outcomes. Design: Two distinct, but related studies; a prospective cohort study and a retrospective cohort study. Setting: Five Ontario pediatric oncology centers. Patients: The prospective study will involve 500 CCS at high risk for these late effects due to cancer therapy, and the retrospective study involves 5,000 CCS ≤ 18 years old treated for cancer between January 2008 and December 2020. Measurements: Chronic kidney disease is defined as Estimated glomerular filtration rate

BackgroundSurvivors of childhood cancer are at lifelong risk of morbidity (such as new cancers or heart failure) and premature mortality due to their cancer treatment. These are termed late effects. Therefore, they require lifelong, risk-tailored surveillance. However, most adult survivors of childhood cancer do not complete recommended surveillance tests such as mammograms or echocardiograms. ObjectiveIn partnership with survivors, family physicians, and health system partners, we are designing a provincial support system for high-priority tests informed by principles of implementation science, behavioral science, and design thinking. MethodsOur multiphase process was structured as follows. Step 1 consisted of a qualitative study to explore intervention components essential to accessing surveillance tests. Step 2 comprised a workshop with childhood cancer survivors, family physicians, and health system stakeholders that used the Step 1 findings and “personas” (a series of fictional but data-informed characters) to develop and tailor the intervention for different survivor groups. Step 3 consisted of intervention prototype development, and Step 4 involved iterative user testing. ResultsThe qualitative study of 30 survivors and 7 family physicians found a high desire for information on surveillance for late effects. Respondents indicated that the intervention should help patients book appointments when they are due in addition to providing personalized information. Insights from the workshop included the importance of partnering with both family physicians and survivorship clinics and providing emotional support for survivors who may experience distress upon learning of their risk for late effects. In our user-testing process, prototypes went through iterations that incorporated feedback from users regarding acceptability, usability, and functionality. We sought to address the needs of survivors and physicians while balancing the capacity and infrastructure available for a lifelong intervention via our health system partners. ConclusionsIn partnership with childhood cancer survivors, family physicians, and health system partners, we elucidated the barriers and enablers to accessing guideline-recommended surveillance tests and designed a multifaceted solution that will support survivors and their family physicians. The next step is to evaluate the intervention in a pragmatic randomized controlled trial.

Summary: Background: Inflammation can modulate tumour growth and progression, and influence clinical response to treatment. We investigated the potential of circulating inflammatory proteins for response stratification of immune checkpoint inhibitor (ICI) therapy for advanced melanoma. Methods: Study subjects were 87 patients with unresectable stage III or IV cutaneous melanoma from the multiple centres across the United Kingdom (UK) and the Netherlands (NL) who received ipilimumab, nivolumab, or pembrolizumab, or a combination of ipilimumab and nivolumab. Serum samples were collected before and during ICI therapy at follow-up visits scheduled every third week over a 12-week period. We performed targeted quantification of 92 proteins involved in inflammation and tested for association of their pre-treatment and on-treatment levels, as well as longitudinal changes, with overall response rate, progression-free survival, and overall survival. Findings: We observed consistently higher pre-treatment levels of interleukin-6 (IL-6), hepatocyte growth factor (HGF), and monocyte chemotactic protein 2 (MCP-2), in non-responders compared to responders (meta-analysis p=3.31 × 10−4, 2.29 × 10−4, and 1.02 × 10−3, respectively). Patients' stratification according to the median value of IL-6, HGF, and MCP-2 highlighted a cumulative negative effect of pre-treatment levels of the three proteins on response (p=1.13 × 10−2), with overall response rate among patients presenting with combined elevated IL-6, HGF, and MCP-2 levels being three-fold lower (26.7%) compared to patients with none of the three proteins elevated (80.0%, p=9.22 × 10−3). Longitudinal data analysis showed that on-treatment changes in circulating inflammatory proteins are not correlated with response. Interpretation: Our findings are in line with an increasing body of evidence that the pro-inflammatory cytokine IL-6 can influence response to ICI in advanced melanoma, and further support a role of circulating HGF and MCP-2 levels as prognostic biomarkers as suggested by previous smaller studies. Inflammatory proteins may serve as predictive biomarkers of ICI response and valuable targets for combination therapy. Funding: This work was supported by the Seerave Foundation and Dutch Cancer Society.

Abstract Over the last few years, numerous clinical trials and real-world experience have provided a large amount of evidence demonstrating the potential for long-term survival with immunotherapy agents across various malignancies, beginning with melanoma and extending to other tumours. The clinical success of immune checkpoint blockade has encouraged increasing development of other immunotherapies. It has been estimated that there are over 3000 immuno-oncology trials ongoing, targeting hundreds of disease and immune pathways. Evolving topics on cancer immunotherapy, including the state of the art of immunotherapy across various malignancies, were the focus of discussions at the Immunotherapy Bridge meeting (4–5 December, 2019, Naples, Italy), and are summarised in this report.

This Viewpoint paper presents a timely and constructive critique of mainstream SIDS research. It is concerning that twenty-first century medical science has not provided an answer to the tragic enigma of SIDS. The paper helps explain why this is so and illustrates possible shortcomings in the investigation of Sudden Infant Death Syndrome/Sudden Unexplained Infant Death (SIDS/SUID) by mainstream researchers. Mainstream findings are often based on questionable and dogmatic assumptions that return to founding notions such as the Triple Risk Hypothesis and the contention that the mechanisms underlying SIDS/SUID are heterogeneous in nature. The paper illustrates how the pathological findings in SIDS have been under-investigated (or ignored) and that key epidemiological risk factors have slipped from memory. This apparent amnesia has resulted in failure to use these established SIDS facts to substantiate the significance of various neuropathological, neurochemical, or other research findings. These unsupported findings and their derivative hypotheses are therefore ill-founded and lack scientific rigor.ConclusionThe deficits of SIDS “science” revealed in this paper explain why the SIDS enigma has not yet been solved. To make progress in understanding SIDS, it is important that researchers, as scientists, uphold standards of research. Encouragement for new directions of research is offered.

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.

Abstract Immunotherapy is now widely established as a potent and effective treatment option across several types of cancer. However, there is increasing recognition that not all patients respond to immunotherapy, focusing attention on the immune contexture of the tumor microenvironment (TME), drivers of the immune response and mechanisms of tumor resistance to immunity. The development of novel immunotherapeutics and their use in combination with checkpoint inhibitors and other standard of care and novel treatment modalities is an area of particular attention across several tumor types, including melanoma, lung, ovarian, breast, pancreatic, renal, head and neck, brain and non-melanoma skin cancers. The 4th Immunotherapy Bridge meeting (28–29 November, 2018, Naples, Italy) focused on a wide range of evolving topics and trends in the field of cancer immunotherapy and key presentations from this meeting are summarised in this report.

Abstract As part of the 2018 Immunotherapy Bridge congress (November 28–29, Naples, Italy), the Great Debate session featured counterpoint views from leading experts on four topical clinical issues in immunotherapy today. These were: the relative importance of adaptive versus innate immunity in the anti-cancer immune response; the merits of combination versus sequential immunotherapy regimens in the treatment of cancer; the advantages and disadvantages of murine models of cancer versus humans in order to evaluate immunotherapy; and whether or not mechanisms of resistance to immunotherapy differ between different cancers. Discussion of these important topics are summarised in this report.

This decade has brought significantly improved outcomes for patients with advanced melanoma with immunotherapies and targeted treatments offering utility in a variety of settings. In 2020, we can hope for durable long-term responses, and complete remission in a subset of patients with metastatic disease. In the adjuvant setting, approximately 50% improvements in recurrence-free survival are seen both with targeted and immunotherapies. Early data from neoadjuvant immunotherapy clinical trials are very promising. However, responses to treatment are heterogeneous and not always durable; further advances are required, and several emerging strategies are of particular interest. We review the systemic treatment of melanoma, discussing the treatment of unresectable stage III–IV and recurrent disease, outlining curative treatment of cutaneous melanoma in the adjuvant setting and briefly discussing neoadjuvant systemic therapies for advanced melanoma.

Abstract Immunotherapy represents the third important wave in the history of the systemic treatment of cancer after chemotherapy and targeted therapy and is now established as a potent and effective treatment option across several cancer types. The clinical success of anti-cytotoxic T-lymphocyte-associated antigen (CTLA)-4, first, and anti-programmed death (PD)-1/PD-ligand (L)1 agents in melanoma and other cancers a few years later, has encouraged increasing focus on the development of other immunotherapies (e.g. monoclonal antibodies with other immune targets, adoptive cell transfer, and vaccines), with over 3000 immuno-oncology trials ongoing, involving hundreds of research institutes across the globe. The potential use of these different immunotherapeutic options in various combinations with one another and with other treatment modalities is an area of particular promise. The third Immunotherapy Bridge meeting (29-30 November, 2017, Naples, Italy) focused on recent advances in immunotherapy across various cancer types and is summarised in this report.

Abstract Background Tyrosine kinase inhibitors are the first line standard of care for treatment of metastatic renal cell carcinoma (RCC). Accurate response assessment in the setting of antiangiogenic therapies remains suboptimal as standard size-related response criteria do not necessarily accurately reflect clinical benefit, as they may be less pronounced or occur later in therapy than devascularisation. The challenge for imaging is providing timely assessment of disease status allowing therapies to be tailored to ensure ongoing clinical benefit. We propose that combined assessment of morphological, physiological and metabolic imaging parameters using 18F–fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F–FDG PET/MRI) will better reflect disease behaviour, improving assessment of response/non-response/relapse. Methods/design The REMAP study is a single-centre prospective observational study. Eligible patients with metastatic renal cell carcinoma, planned for systemic therapy, with at least 2 lesions will undergo an integrated 18F–FDG PET and MRI whole body imaging with diffusion weighted and contrast-enhanced multiphasic as well as standard anatomical MRI sequences at baseline, 12 weeks and 24 weeks of systemic therapy allowing 18F–FDG standardised uptake value (SUV), apparent diffusion co-efficient (ADC) and normalised signal intensity (SI) parameters to be obtained. Standard of care contrast-enhanced computed tomography CT scans will be performed at equivalent time-points. CT response categorisation will be performed using RECIST 1.1 and alternative (modified)Choi and MASS criteria. The reference standard for disease status will be by consensus panel taking into account clinical, biochemical and conventional imaging parameters. Intra- and inter-tumoural heterogeneity in vascular, diffusion and metabolic response/non-response will be assessed by image texture analysis. Imaging will also inform the development of computational methods for automated disease status categorisation. Discussion The REMAP study will demonstrate the ability of integrated 18F–FDG PET-MRI to provide a more personalised approach to therapy. We suggest that 18F–FDG PET/MRI will provide superior sensitivity and specificity in early response/non-response categorisation when compared to standard CT (using RECIST 1.1 and alternative (modified)Choi or MASS criteria) thus facilitating more timely and better informed treatment decisions. Trial registration The trial is approved by the Southeast London Research Ethics Committee reference 16/LO/1499 and registered on the NIHR clinical research network portfolio ISRCTN12114913 .

Introduction Adolescents and young adults (AYA) are an understudied population in cancer research. The Initiative to Maximize Progress in Adolescent and Young Adult Cancer Therapy (IMPACT) cohort includes Ontario individuals aged 15-21 years, diagnosed with a malignancy during 1992-2011. This cohort contains a rich source of patient, disease, and treatment data. Objectives and Approach The IMPACT cohort was created using chart review and linkages to population-based health services databases. The cohort is comprised of AYA with a primary diagnosis of acute leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, sarcoma, or testicular cancer. For the current study, we focused on acute lymphoblastic leukemia (ALL) patients, and examined survival outcomes of those treated at pediatric vs adult centers, with adult vs pediatric protocols. We assessed 5-year event-free survival (first of relapse, progression, secondary malignant neoplasm, or death) and overall survival. Results The IMPACT cohort contains 2,963 patients, of which 152/271 ALL patients were treated at adult centers. The 5-year event-free survival (EFS ± standard error) among those treated at a pediatric vs. adult center was 72%±4% vs. 56%±4% (p = 0.03), respectively. The 5-year overall survival (OS) was 82%±4% vs. 64%±4% (p Conclusion/Implications ALL patients treated with a pediatric protocol at a pediatric center experienced better, crude survival outcomes compared to those at an adult center. The IMPACT cohort offers the opportunity to study a myriad of questions on different cancer groups, with the ultimate goal of improving outcomes among the AYA population.

Recent findings suggest that infection (and sepsis) stand alone as the only plausible mechanism of causation of sudden infant death syndrome (SIDS) and accordingly achieves congruence with all clinicopathological and epidemiological findings. This review examines the role of infection in the pathogenesis of SIDS in the context of the major risk factor of prone sleep position. The study explores how sleep position could interact with the immune system and inflammatory response via vagal neural connections, which could play key roles in gut and immune homeostasis. A plausible and congruent clinicopathological and epidemiological paradigm is suggested.

This review examines the association of strains of Escherichia coli with Sudden Infant Death Syndrome (SIDS) and the possible role of these bacteria play in this enigmatic condition. The review addresses evidence for E. coli in SIDS infants, potential sources of E. coli in the environment, colonisation by commensal and pathogenic strains, the variety of currently accepted pathotypes, and how these pathotypes could compromise intestinal integrity and induce inflammation. Both intestinal and extraintestinal pathotypes are compared in relation to the apparent lability in which virulence traits can be gained or lost by strains of E. coli. The way in which E. coli infections fit with current views on infant sleeping position and other SIDS risk factors is highlighted.

BACKGROUND:Evaluating long-term prognosis is important for physicians, patients and payers. This study reports the results of a model developed to predict long-term survival for UK patients receiving second-line ipilimumab. METHODS:MDX010-20 trial data were used to predict survival for ipilimumab versus UK best supportive care. Two aspects of this analysis required novel approaches: 1) The overall survival Kaplan-Meier data shape is unusual: an initial steep decline is observed before a 'plateau'. 2) The need to extrapolate beyond the trial end (4.6 years). Based upon UK clinician advice, a three-part curve fit was used: from 0-1.5 years, Kaplan-Meier data from the trial; from 1.5-5 years, standard parametric curve fits; after 5 years, long-term data from the American Joint Committee on Cancer registry. RESULTS:This approach provided good internal validity: low mean absolute error and good match to median and mean trial data. Lifetime predicted means were 2.77 years for ipilimumab and 1.07 for best supportive care, driven by increased long-term survival with ipilimumab. CONCLUSION:To understand the full benefit of treatment and to meet reimbursement requirements, accurate estimation of treatment benefit is key. Models, such as the one presented, can be used to extrapolate beyond trials.

A number of imaging modalities are showing promise as predictive and prognostic biomarkers in advanced renal cell carcinoma. This review discusses progress to date in this exciting area and identifies areas of future promise.

Purpose: The purpose of this study was to explore how teacher coaching was implemented across eight schools. Design/methodology/approach: A subjectivist epistemological position was adopted as the most appropriate for this study, and a qualitative approach to methodology, data collection and analysis was used within an evaluative multiple case study framework in order to investigate three research questions. Findings: The findings indicate coaching has the potential to provide schools with a professional learning approach that allows staff to explore a wide variety of challenges of practice. However, inconsistencies in perceptions, staffing and coach development mean positive outcomes for students may not be guaranteed. Research limitations/implications: One limitation of this study is that it provides a snapshot of teacher coaching in relation to a specific group of schools in a constantly changing New Zealand context. Practical implications School leaders implementing teacher coaching programmes are encouraged to consider how they will evaluate whether their programmes are changing teachers' practice and improving outcome for students. School leaders should also plan how to manage changes in personnel. Social implications: The findings show the concept of teacher coaching is a social construct influenced by the unique environmental context and individual perceptions of those involved, leading to variations in its application. Originality/value: This study provides new knowledge in relation to the challenges that can be experienced when implementing teacher coaching across a community of schools.