Paul Lorigan

The COMBI-I trial (ClinicalTrials.gov identifier: NCT02967692 ) evaluating spartalizumab plus dabrafenib and trametinib (sparta-DabTram, n = 267) versus placebo plus dabrafenib and trametinib (placebo-DabTram, n = 265) for BRAF V600–mutant unresectable or metastatic melanoma failed to reach its primary end point of progression-free survival at 24 months. This final analysis reports overall survival (OS) during at least 5 years of extended follow-up. At the end of the trial (August 21, 2024), the median duration of follow-up was 76.9 months (range, 73.7-83.3 months). The median OS was 61.5 months (95% CI, 41.6 to not evaluable) for the sparta-DabTram arm and 41.6 months (95% CI, 30.6 to 56.9) for the placebo-DabTram arm (hazard ratio, 0.760 [95% CI, 0.598 to 0.966]). The safety findings were consistent with the known safety profile for sparta-DabTram. The most common treatment-related adverse event (TRAE) was pyrexia (65.9% v 46.2%, respectively, in the two study arms). Grade ≥3 TRAEs were reported in 57.3% and 36.7% of patients in the two arms, respectively. The combination of sparta-DabTram appears to improve OS compared with dabrafenib and trametinib alone in patients with BRAF V600–mutant metastatic melanoma.

Background: Immune checkpoint inhibitors (ICIs) have revolutionised cancer treatment. Previous studies suggested that early time-of-day administration is associated with better outcomes. We performed a retrospective study in patients treated at a large tertiary cancer centre. Methods: Patients receiving ICIs between January 2018 and December 2023 were grouped according to whether they had ≥50% (“late group”) or <50% (“early group”) of cycles after the median time of all treatments. The endpoint was overall survival (OS). Hazard ratios (HRs) were estimated using Cox models with and without time-dependent variables. Results: 2631 patients with advanced/metastatic lung cancer (45%), melanoma (23%), renal carcinoma (18%), head and neck (9%), and urothelial cancer (5%) were included. Median age was 68.2 years and median infusion time was 12:49 h. At a median follow-up of 32 months, median OS was 13.1 (95% CI 11.8–14.4) vs 21.4 (19.8–24.5) months for late and early group. Late group was associated with shorter OS on both the standard analysis (HR 1.48, 1.33–1.63) and the time-dependent model (HR 1.30, 1.16–1.44). Conclusions: This study provides further evidence in favour of early ICIs administration with a large sample size and a time-dependent model, which reduces the risk of immortal time bias. Data from randomised trials are required to confirm these findings.

A false-negative diagnosis of cancer can lead to a delay in effective treatment and a poorer prognosis. Here, we use the example of cutaneous melanoma to examine how many years of life are lost after a false-negative diagnosis compared to a primarily correct diagnosis. From 1996 to 2015, 9,063 patients are prospectively registered in the German Central Malignant Melanoma Registry and followed up until December 2023. A false-negative diagnosis is found in 206 (2.3%) patients. The median time to correct diagnosis is 24.0 months. The 10-year recurrence-free survival probabilities are 32.9% for false-negative diagnoses and 76.2% for correct diagnoses (p < 0.001). The 10-year melanoma-specific survival probabilities are 62.1% versus 85.0% (p < 0.001). On average, each person with an initial false-negative diagnosis loses 8.2 years of life compared to people with a correct diagnosis. This high number of years of life lost raises the question of whether similar results also apply to other types of cancer.

Checkpoint inhibitor immunotherapy (CPI) for BRAF mutant advanced melanoma first-line results in a better long-term survival compared to targeted therapy (TT), however TT induction may benefit poor prognosis groups. The parallel-arm, randomised phase II, multicentre, feasibility CAcTUS trial (Clinicaltrials.gov NCT03808441) randomised 21 patients to receive standard of care investigators choice TT or CPI, switching to the alternative upon progression ( n = 10), or commencing TT and switching to CPI upon an ≥80% reduction of BRAF variant allele frequency ( VAF) in circulating tumour DNA (ctDNA; n = 11). The study achieved its primary endpoints with 100% (95% confidence interval [CI]: 94-100%) of critical results provided within 7 days to inform a decision to switch and 100% of patients commencing TT achieving an ≥80% reduction of BRAF VAF (95% CI: 80-100%). Secondary outcomes included progression-free survival and overall survival. No new safety signals were observed for TT/CPI. Post-hoc analysis of clinical features, circulating cytokines and chemokines at ctDNA nadir following TT induction suggested a more favourable profile prior to CPI initiation. Longitudinal ctDNA dynamics revealed ctDNA provided an early signal of CPI benefit and that rechallenge with TT following CPI progression resulted in a further ctDNA response. These data support the utility of ctDNA to guide treatment decision-making within a clinically relevant timeframe to optimise treatment scheduling strategies.

Background: People with an intellectual disability (ID) are at increased risk of bowel cancer. However, evidence on their presenting symptoms, diagnostic pathways, treatments and survival remains limited. Methods: A matched cohort study was conducted using linked primary care (Clinical Practice Research Datalink), hospital, cancer, and mortality records. Outcomes included symptoms associated with bowel cancer, faecal immunochemical or faecal occult blood (FIT/FOB) testing, urgent suspected cancer (USC) referral, endoscopy, surgery, systemic anticancer therapy (SACT), and bowel cancer-specific mortality. Adjusted incidence rate ratios (aIRRs), risk ratios (aRRs), and hazard ratios (aHRs) were estimated using Poisson, modified Poisson and Cox regression. Results: A total of 111,034 individuals with an ID were matched to 1,964,420 comparators. ID was associated with increased risk of bowel cancer (aHR 1.30, 1.18-1.44), particularly before age 50 years (aRR 2.19, 1.68-2.85). People with an ID presented more frequently with symptoms associated with bowel cancer (aIRR 2.59, 2.53-2.65) but, following such symptoms, were less likely to undergo FIT/FOB testing (aRR 0.74, 0.67-0.83), USC referral (aRR 0.57, 0.52-0.62), endoscopy (aRR 0.45, 0.42-0.49), or receive a diagnosis within 56 days (aRR 0.52, 0.41-0.67). They were also less likely to be diagnosed via screening (aRR 0.27, 0.14-0.50) or USC referral (aRR 0.62, 0.50-0.76), and more likely to be diagnosed via emergency presentation (aRR 1.76, 1.52-2.02), on the date of death (aRR 5.08, 2.92-8.84), or with stage IV disease (aRR 1.25, 1.01-1.56). ID was associated with similar proportions receiving curative surgery for stage I-III disease (aRR 0.98, 0.79-1.19), but markedly lower proportions receiving SACT for stage IV (aRR 0.15, 0.05-0.46), and higher bowel cancer-specific mortality across all stages (aHR 2.00, 1.71-2.33). Conclusions: People with an ID experience worse outcomes across nearly all stages of the bowel cancer care pathway, including referral, investigation, treatment and survival. Earlier screening may be justified given the elevated risk in those under age 50 years.

Tumour infiltrating lymphocyte (TIL) therapy offers the potential for durable clinical benefit in select patients with advanced melanoma, especially after progression on treatment with immune checkpoint inhibitors and/or targeted therapies. The 2024 FDA approval of Lifileucel (Amtagvi), a commercially manufactured autologous TIL product, marks a key milestone in integrating advanced therapy medicinal products (ATMPs) into routine care for solid tumours. Health Canada has since approved Lifileucel, with regulatory and funding decisions across the UK and Europe still pending. In this Perspective, we review the evidence base and outline key considerations for national adoption of TIL therapy. Despite promising results from clinical trials, TIL therapy requires complex coordination, including patient selection, tumour procurement, manufacturing logistics, lymphodepletion, and IL-2 administration; all contingent on specialised infrastructure and well-considered integrated care pathways. While commercial centralisation may ease logistical barriers, the high cost of TIL therapy necessitates careful health economic evaluation. A nationally coordinated effort is required to harmonise clinical prioritisation strategies, maintain oversight by multidisciplinary specialist tumour boards, and consider investment in future-proof decentralised manufacturing capacity. Collaborations and peer support such as through the Advanced Therapy Treatment Centre (ATTC) Network will facilitate phased, experience-led rollout with equity-focused service design.

Spot check inspections in 2010 and 2011 revealed poor compliance with legal ultraviolet (UV) radiation limits for sunbeds. The highest UV irradiance was found in North East England. We note that melanoma incidence among 25–49-year-olds in North East England was twice the national average several years after the initial inspections.

Purpose. The diagnosis, management, and therapy of cancer are rapidly advancing and becoming more costly. Data linking the diagnosis, management, and prescription of systemic anticancer therapy (SACT) are not publicly available, are time-consuming to obtain, and are onerous to analyze. We aimed to illustrate how a simple expert elicitation method can be used rapidly to calculate the cost of diagnosing and treating a cancer by stage of disease. We illustrate the method using the example of melanoma. Methods. We designed a simple structured elicitation exercise for melanoma experts from the United Kingdom with the aim of describing the diagnosis, management, and SACT prescription for people with melanoma and the associated proportions offered each option. We modeled experts’ beliefs using scaled beta distributions. We used random-effects meta-analysis to combine the estimates. Published unit costs (£; 2024–2025) were multiplied by estimated proportions to calculate the mean costs for the diagnosis, management, and SACT by disease stage. Results. Seven dermatologists, 5 oncologists, and 4 surgeons participated (2022–2023). There was variation in the estimates of the proportions receiving possible diagnosis, management, or SACT options. Diagnosing suspicious lesions cost £424 to £699 depending on the investigations required. Mean (95% confidence intervals) management costs were £782 (£611, £981) for stage 0, £946 (£776, £1,145) for stage 1a, £4,729 (£4,532, £4,944) for stage 1b/2, £3,719 (£3,213, £4,150) for macroscopic 3, and £2,827 (£2,757, £2,904) for microscopic 3. Mean SACT costs were £65,289 (£50,581, £74,521) for stage 3 and £134,065 (£115,787, £152,938) for stage 4. Conclusions. Our new approach to eliciting and combining estimates balances practical and theoretical considerations. We illustrate how this method produces estimates of the costs, and associated uncertainty, of the diagnosis, management, and SACT for melanoma by stage of disease in the absence of readily accessible diagnosis, management, and prescribing data. These cost estimates were not validated against registry data. Highlights: Linked diagnosis, primary surgical management (hereafter “management”), and prescribing of systemic anticancer therapies (SACT) data describing the number and proportion of people with cancer offered these options are not readily available. The time to obtain data together with the time to conduct onerous analyses are a key barrier to obtaining values for use by decision analysts building economic models for evaluating new options for the early detection or prevention of cancer. We designed a simple expert elicitation exercise, completed in Excel. The exercise was designed to provide estimates of the total cost of cancer by stage of disease and crucially also to understand the extent of uncertainty around these estimates. We used melanoma as an exemplar cancer. Clinical experts (consultant dermatologists, surgeons, and oncologists) estimated the proportions of people offered possible diagnostic, management, or SACT options for melanoma (by stage of disease). Our study suggested that they found the expert elicitation exercise easy to understand and managed to complete the task. Random-effects meta-analysis used to pool the individual estimates indicated substantial heterogeneity across experts’ estimates of most elicited proportions. This finding suggested wide variation in possible approaches to the diagnosis, management, and use of SACT for melanoma.

Paul Lorigan and colleagues argue that despite regulation commercial sunbeds remain popular with young people and are adding to the national skin cancer burden