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ObjectivesTo estimate the impact of the COVID-19 pandemic on cancer care services and overall (direct and indirect) excess deaths in people with cancer.MethodsWe employed near real-time weekly data on cancer care to determine the adverse effect of the pandemic on cancer services. We also used these data, together with national death registrations until June 2020 to model deaths, in excess of background (pre-COVID-19) mortality, in people with cancer. Background mortality risks for 24 cancers with and without COVID-19-relevant comorbidities were obtained from population-based primary care cohort (Clinical Practice Research Datalink) on 3 862 012 adults in England.ResultsDeclines in urgent referrals (median=−70.4%) and chemotherapy attendances (median=−41.5%) to a nadir (lowest point) in the pandemic were observed. By 31 May, these declines have only partially recovered; urgent referrals (median=−44.5%) and chemotherapy attendances (median=−31.2%). There were short-term excess death registrations for cancer (without COVID-19), with peak relative risk (RR) of 1.17 at week ending on 3 April. The peak RR for all-cause deaths was 2.1 from week ending on 17 April. Based on these findings and recent literature, we modelled 40% and 80% of cancer patients being affected by the pandemic in the long-term. At 40% affected, we estimated 1-year total (direct and indirect) excess deaths in people with cancer as between 7165 and 17 910, using RRs of 1.2 and 1.5, respectively, where 78% of excess deaths occured in patients with ≥1 comorbidity.ConclusionsDramatic reductions were detected in the demand for, and supply of, cancer services which have not fully recovered with lockdown easing. These may contribute, over a 1-year time horizon, to substantial excess mortality among people with cancer and multimorbidity. It is urgent to understand how the recovery of general practitioner, oncology and other hospital services might best mitigate these long-term excess mortality risks.

Among patients with cancers bearing the KRAS G12C mutation who received divarasib at a 400-mg dose, 56% with lung cancer, 36% with colorectal cancer, and 36% with other tumor types had a confirmed response.

A comprehensive evaluation of the total burden of morbidity endured by cancer survivors remains unavailable. This study quantified the burden of 144 health conditions and critical care admissions across 26 adult cancers and treatment modalities in 243,767 adults. By age 60, top conditions ranked by fold difference (cumulative burden in survivors divided by cumulative burden in controls) were haematology, immunology/infection and pulmonary conditions. Patients who had all three forms of treatment (chemotherapy, radiotherapy and surgery) experienced a high cumulative burden of late morbidities compared with patients who received radiotherapy alone. The top five cancers with the highest cumulative burden of critical care admissions by age 60 were bone (12.4 events per 100 individuals [CI: 11.6-13.1]), brain (9.0 [7.5-10.5]), spinal cord and nervous system (7.2 [6.7-7.8]), testis (6.7 [4.9-8.4]) and Hodgkin lymphoma (4.4 [3.6-5.1]). Conditions that were associated with high excess years-of-life-lost were haematological conditions (9.6 years), pulmonary conditions (8.6 years) and immunological conditions or infections (7.8 years). As the population of cancer survivors continues to grow, our results indicate that it is important to tackle long-term health consequences through enacting data-driven policies. Here the authors evaluate the burden of 144 health conditions in adult cancer survivors, and show that the magnitude of late morbidities experienced by survivors varies according to the type of cancer and treatment, highlighting opportunities for optimising patient care

Background Parenting programs have the potential to improve population health, if widely disseminated. However, wide-scale dissemination is challenging. Also, more knowledge is needed of whether parenting programs are effective for the variability of families in the general population. Methods This study aimed to investigate who the universal parenting program All Children in Focus (ABC) reaches when offered in routine care in Sweden. A second aim was to investigate if the outcomes were predicted by factors related to family background, group leader experience, and homework completion. Questionnaires were collected before and after ABC from 1420 parents. Hierarchical regression analyses were performed to examine predictors of disruptive child behavior, parenting practices, and satisfaction. Results ABC was available in about 40% of Swedish municipalities and reached a fairly representative population sample, with the exception that fewer fathers than mothers participated. The examined predictors explained a small proportion of the variance in the outcomes (2.5, 3.5 and 14.7%, respectively). Still, the effect on disruptive child behavior was statistically significantly larger for parents born in Sweden, with higher education, and older children. The effect on parenting practices was also larger for parents born in Sweden, for mothers, and for those practicing homework more frequently. Most examined predictors showed no statistically significant association with child and parenting outcomes. Parents were generally satisfied with ABC and the significant predictors of satisfaction had little practical meaning. Conclusions A fairly representative group of parents across Sweden were reached by ABC. Background variables, homework completion, and group leaders’ experience explained a small proportion of variance in the outcomes. Meanwhile, the slightly lower intervention effects found for preschool children and parents born abroad calls for further investigation, since even small differences in effects can have an impact at a population level. The study also points to the importance of stressing homework completion and to increase the reach of universal parenting interventions to some underrepresented groups.

Treatment options for malignant pleural mesothelioma are scarce. Tazemetostat, a selective oral enhancer of zeste homolog 2 (EZH2) inhibitor, has shown antitumour activity in several haematological cancers and solid tumours. We aimed to evaluate the anti-tumour activity and safety of tazemetostat in patients with measurable relapsed or refractory malignant pleural mesothelioma. We conducted an open-label, single-arm phase 2 study at 16 hospitals in France, the UK, and the USA. Eligible patients were aged 18 years or older with malignant pleural mesothelioma of any histology that was relapsed or refractory after treatment with at least one pemetrexed-containing regimen, an Eastern Cooperative Oncology Group performance status of 0 or 1, and a life expectancy of greater than 3 months. In part 1 of the study, participants received oral tazemetostat 800 mg once on day 1 and then twice daily from day 2 onwards. In part 2, participants received oral tazemetostat 800 mg twice daily starting on day 1 of cycle 1, using a two-stage Green-Dahlberg design. Tazemetostat was administered in 21-day cycles for approximately 17 cycles. The primary endpoint of part 1 was the pharmacokinetics of tazemetostat and its metabolite at day 15 after administration of 800 mg tazemetostat, as measured by maximum serum concentration (Cmax), time to Cmax (Tmax), area under the concentration-time curve (AUC) to day 15 (AUC0–t), area under the curve from time 0 extrapolated to infinity (AUC0–∞), and the half-life (t1/2) of tazemetostat, assessed in all patients enrolled in part 1. The primary endpoint of part 2 was the disease control rate (the proportion of patients with a complete response, partial response, or stable disease) at week 12 in patients with malignant pleural mesothelioma per protocol with BAP1 inactivation determined by immunohistochemistry. The safety population included all the patients who had at least one post-dose safety assessment. This trial is now complete and is registered with ClinicalTrials.gov, NCT02860286. Between July 29, 2016, and June 2, 2017, 74 patients were enrolled (13 in part 1 and 61 in part 2) and received tazemetostat, 73 (99%) of whom had BAP1-inactivated tumours. In part 1, following repeat dosing of tazemetostat at steady state, on day 15 of cycle 1, the mean Cmax was 829 ng/mL (coefficient of variation 56·3%), median Tmax was 2 h (range 1–4), mean AUC0–twas 3310 h·ng/mL (coefficient of variation 50·4%), mean AUC0–∞ was 3180 h·ng/mL (46·6%), and the geometric mean t1/2 was 3·1 h (13·9%). After a median follow-up of 35·9 weeks (IQR 20·6–85·9), the disease control rate in part 2 in patients with BAP1-inactivated malignant pleural mesothelioma was 54% (95% CI 42–67; 33 of 61 patients) at week 12. No patients had a confirmed complete response. Two patients had a confirmed partial response: one had an ongoing partial response with a duration of 18 weeks and the other had a duration of 42 weeks. The most common grade 3–4 treatment-emergent adverse events were hyperglycaemia (five [7%] patients), hyponatraemia (five [7%]), and anaemia (four [5%]); serious adverse events were reported in 25 (34%) of 74 patients. Five (7%) of 74 patients died while on study; no treatment-related deaths occurred. Further refinement of biomarkers for tazemetostat activity in malignant pleural mesothelioma beyond BAP1 inactivation could help identify a subset of tumours that are most likely to derive prolonged benefit or shrinkage from this therapy. Epizyme.

The majority of targeted therapies for non-small-cell lung cancer (NSCLC) are directed against oncogenic drivers that are more prevalent in patients with light exposure to tobacco smoke 1 – 3 . As this group represents around 20% of all patients with lung cancer, the discovery of stratified medicine options for tobacco-associated NSCLC is a high priority. Umbrella trials seek to streamline the investigation of genotype-based treatments by screening tumours for multiple genomic alterations and triaging patients to one of several genotype-matched therapeutic agents. Here we report the current outcomes of 19 drug–biomarker cohorts from the ongoing National Lung Matrix Trial, the largest umbrella trial in NSCLC. We use next-generation sequencing to match patients to appropriate targeted therapies on the basis of their tumour genotype. The Bayesian trial design enables outcome data from open cohorts that are still recruiting to be reported alongside data from closed cohorts. Of the 5,467 patients that were screened, 2,007 were molecularly eligible for entry into the trial, and 302 entered the trial to receive genotype-matched therapy—including 14 that re-registered to the trial for a sequential trial drug. Despite pre-clinical data supporting the drug–biomarker combinations, current evidence shows that a limited number of combinations demonstrate clinically relevant benefits, which remain concentrated in patients with lung cancers that are associated with minimal exposure to tobacco smoke. Current outcomes are reported from the ongoing National Lung Matrix Trial, an umbrella trial for the treatment of non-small-cell lung cancer in which patients are triaged according to their tumour genotype and matched with targeted therapeutic agents.

Tisotumab vedotin is a first-in-human antibody–drug conjugate directed against tissue factor, which is expressed across multiple solid tumour types and is associated with poor clinical outcomes. We aimed to establish the safety, tolerability, pharmacokinetic profile, and antitumour activity of tisotumab vedotin in a mixed population of patients with locally advanced or metastatic (or both) solid tumours known to express tissue factor. InnovaTV 201 is a phase 1–2, open-label, dose-escalation and dose-expansion study done at 21 centres in the USA and Europe. Patients (aged ≥18 years) had relapsed, advanced, or metastatic cancer of the ovary, cervix, endometrium, bladder, prostate, oesophagus, squamous cell carcinoma of the head and neck or non-small-cell lung cancer; an Eastern Cooperative Oncology Group performance status of 0–1; and had relapsed after or were not eligible to receive the available standard of care. No specific tissue factor expression level was required for inclusion. In the dose-escalation phase, patients were treated with tisotumab vedotin between 0·3 and 2·2 mg/kg intravenously once every 3 weeks in a traditional 3 + 3 design. In the dose-expansion phase, patients were treated at the recommended phase 2 dose. The primary endpoint was the incidence of adverse events, including serious adverse events, infusion-related, treatment-related and those of grade 3 or worse, and study drug-related adverse events, analysed in all patients who received at least one dose of tisotumab vedotin (full analysis population). This trial is registered with ClinicalTrials.gov, number NCT02001623, and is closed to new participants with follow-up ongoing. Between Dec 9, 2013, and May 18, 2015, 27 eligible patients were enrolled to the dose-escalation phase. Dose-limiting toxicities, including grade 3 type 2 diabetes mellitus, mucositis, and neutropenic fever, were seen at the 2·2 mg/kg dose; therefore, 2·0 mg/kg of tisotumab vedotin intravenously once every 3 weeks was established as the recommended phase 2 dose. Between Oct 8, 2015, and April 26, 2018, 147 eligible patients were enrolled to the dose-expansion phase. The most common (in ≥20% of patients) treatment-emergent adverse events of any grade were epistaxis (102 [69%] of 147 patients), fatigue (82 [56%]), nausea (77 [52%]), alopecia (64 [44%]), conjunctivitis (63 [43%]), decreased appetite (53 [36%]), constipation (52 [35%]), diarrhoea (44 [30%]), vomiting (42 [29%]), peripheral neuropathy (33 [22%]), dry eye (32 [22%]), and abdominal pain (30 [20%]). The most common adverse events of grade 3 or worse were fatigue (14 [10%] of 147 patients), anaemia (eight [5%]), abdominal pain (six [4%]), hypokalaemia (six [4%]), conjunctivitis (five [3%]), hyponatraemia (five [3%]), and vomiting (five [3%]). 67 (46%) of 147 patients had a treatment-emergent serious adverse event. 39 (27%) of 147 patients had a treatment-emergent serious adverse event related to the study drug. Infusion-related reactions occurred in 17 (12%) of 147 patients. Across tumour types, the confirmed proportion of patients who achieved an objective response was 15·6% (95% CI 10·2–22·5; 23 of 147 patients). There were nine deaths across all study phases (three in the dose-escalation phase and six in the dose-expansion phase); only one case of pneumonia in the dose-expansion phase was considered possibly related to study treatment. Tisotumab vedotin has a manageable safety profile with encouraging preliminary antitumour activity across multiple tumour types in heavily pretreated patients. Continued evaluation of tisotumab vedotin is warranted in solid tumours. Genmab A/S.

Background The development and rapid uptake of immune checkpoint inhibitors (CPI) has changed the outlook for patients with cancer. However, CPIs have different adverse event (AE) profiles to other systemic therapies, and prompt AE management is essential to assure optimal outcomes. In order to understand what and when adverse events are experienced, reported and managed during CPI treatment, a mixed methods study was conducted, including a case note review of patients who were receiving immunotherapy and semi-structured interviews with patients to understand their experience, management and reporting of AEs after receiving immune CPI treatment. Methods This mixed methods study was conducted at a large cancer hospital in the United Kingdom. A case note review identified how and where patients reported AEs. Data relating to patients with lung, bladder, prostate and head & neck cancers who received CPI treatment between 01/04/2015 and 31/07/2018 were extracted from e-prescribing databases and clinical data were included for analysis at a single time point (31 July 2018). Semi-structured interviews were conducted with patients receiving CPI treatment, exploring experience of AEs and reasons for delays in AE reporting and management. Results Sixty-two patients were included in the case note review, with 78 AEs being experienced by 36 patients (58%), including one patient experiencing 10 AEs. Serious AEs were experienced by 12 patients (19%) and ten AEs (17%) required oral steroids as treatment. The majority of AEs were reported to clinicians prior to further dosing, although milder AEs were often not addressed until subsequent clinic appointments. Interviews with 13 patients yielded major themes: variability, causality, decision making and impact. Conclusion Most CPI-associated AEs are manageable if reported and treated promptly. Both the case note review and interviews found that reporting of non-serious AEs is often left until routine clinic visits, despite impacting patient experience, leaving the opportunity for AEs to be left unreported and implying a potential benefit for real time monitoring. Our study highlights a need to provide patients with reminders around AEs and their timely reporting even when apparently innocuous; patients must understand that AEs can occur at any cycle and even following treatment completion.

Poly(ADP-ribose) polymerase (PARP) is implicated in DNA repair and transcription regulation. Niraparib (MK4827) is an oral potent, selective PARP-1 and PARP-2 inhibitor that induces synthetic lethality in preclinical tumour models with loss of BRCA and PTEN function. We investigated the safety, tolerability, maximum tolerated dose, pharmacokinetic and pharmacodynamic profiles, and preliminary antitumour activity of niraparib. In a phase 1 dose-escalation study, we enrolled patients with advanced solid tumours at one site in the UK and two sites in the USA. Eligible patients were aged at least 18 years; had a life expectancy of at least 12 weeks; had an Eastern Cooperative Oncology Group performance status of 2 or less; had assessable disease; were not suitable to receive any established treatments; had adequate organ function; and had discontinued any previous anticancer treatments at least 4 weeks previously. In part A, cohorts of three to six patients, enriched for BRCA1 and BRCA2 mutation carriers, received niraparib daily at ten escalating doses from 30 mg to 400 mg in a 21-day cycle to establish the maximum tolerated dose. Dose expansion at the maximum tolerated dose was pursued in 15 patients to confirm tolerability. In part B, we further investigated the maximum tolerated dose in patients with sporadic platinum-resistant high-grade serous ovarian cancer and sporadic prostate cancer. We obtained blood, circulating tumour cells, and optional paired tumour biopsies for pharmacokinetic and pharmacodynamic assessments. Toxic effects were assessed by common toxicity criteria and tumour responses ascribed by Response Evaluation Criteria in Solid Tumors (RECIST). Circulating tumour cells and archival tumour tissue in prostate patients were analysed for exploratory putative predictive biomarkers, such as loss of PTEN expression and ETS rearrangements. This trial is registered with ClinicalTrials.gov, NCT00749502. Between Sept 15, 2008, and Jan 14, 2011, we enrolled 100 patients: 60 in part A and 40 in part B. 300 mg/day was established as the maximum tolerated dose. Dose-limiting toxic effects reported in the first cycle were grade 3 fatigue (one patient given 30 mg/day), grade 3 pneumonitis (one given 60 mg/day), and grade 4 thrombocytopenia (two given 400 mg/day). Common treatment-related toxic effects were anaemia (48 patients [48%]), nausea (42 [42%]), fatigue (42 [42%]), thrombocytopenia (35 [35%]), anorexia (26 [26%]), neutropenia (24 [24%]), constipation (23 [23%]), and vomiting (20 [20%]), and were predominantly grade 1 or 2. Pharmacokinetics were dose proportional and the mean terminal elimination half-life was 36·4 h (range 32·8–46·0). Pharmacodynamic analyses confirmed PARP inhibition exceeded 50% at doses greater than 80 mg/day and antitumour activity was documented beyond doses of 60 mg/day. Eight (40% [95% CI 19–64]) of 20 BRCA1 or BRCA2 mutation carriers with ovarian cancer had RECIST partial responses, as did two (50% [7–93]) of four mutation carriers with breast cancer. Antitumour activity was also reported in sporadic high-grade serous ovarian cancer, non-small-cell lung cancer, and prostate cancer. We recorded no correlation between loss of PTEN expression or ETS rearrangements and measures of antitumour activity in patients with prostate cancer. A recommended phase 2 dose of 300 mg/day niraparib is well tolerated. Niraparib should be further assessed in inherited and sporadic cancers with homologous recombination DNA repair defects and to target PARP-mediated transcription in cancer. Merck Sharp and Dohme.

Background Value-adaptive designs for clinical trials are a novel set of emerging methods for delivering greater value for clinical research. There is increasing interest in using them within publicly funded health systems. A value-adaptive design permits ‘in progress’ changes to be made to the trial according to criteria which reflect its overall value to the healthcare system, including the cost-effectiveness of the technologies under investigation, the cost of running the trial and the total health benefit delivered to patients. These trial designs offer the potential to explicitly balance the costs and benefits of adaptive clinical trials with the health economic benefits expected for populations that are affected by any subsequent health technology adoption decisions. They may also improve the expected value of learning from the budget that is spent within a trial. Main body This paper introduces value-adaptive designs for publicly funded clinical trials. It discusses the idea of delivering ‘value for money’ in health technology assessment, what is meant by being ‘value-adaptive’ and the key features that characterise these designs. The methodology behind one kind of value-adaptive design – the value-based sequential model of a two-armed clinical trial proposed by Chick et al. (2017) – is described and illustrated using three retrospective case studies from the United Kingdom. The paper concludes by reviewing a range of perspectives provided by stakeholders, together with our own thoughts, on the practical opportunities and changes required for implementing a value-adaptive approach. Conclusions Value-adaptive clinical trial designs offer the potential to align health research funding allocations with population health economic goals. Many of the systems required to deploy value-adaptive designs within a publicly funded health system already exist and, with increased application, experience, and refinement they have the potential to deliver improved value for money.