The Christie NHS Foundation Trust

The CALYPSO study demonstrated activity of savolitinib and durvalumab in MET-driven papillary renal cancer (PRC). We report final efficacy outcomes and exploratory circulating tumor DNA (ctDNA) biomarker analysis. This single-arm phase II study evaluated savolitinib and durvalumab in treatment-naïve or pretreated PRC. End points included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). FoundationOne CDx assessed DNA alterations and MET/PD-L1 or MET/tumor mutational burden (TMB) copositivity. ctDNA collected at baseline and on treatment was correlated with outcomes. At 41-months median follow-up, ORR was 34% (95% CI, 20.0 to 51.0) in the intention-to-treat (ITT) population (N = 41) and 53% (95% CI, 28.0 to 77.0) in MET-driven patients (n = 17). Median PFS was 6.5 (95% CI, 2.7 to 12.0) versus 13.9 months (95% CI, 2.9 to 23.8), and OS was 18.3 (95% CI, 7.3 to 30.7) versus 27.4 months (95% CI, 9.3 to 37.4), in the ITT population and the MET-driven population, respectively. PD-L1 (66% positive) and TMB (median 2.5 mut/Mb) status did not correlate with response. Baseline ctDNA positivity (10/21) correlated with shorter OS (median 7.3 v 33.3 months), while ctDNA clearance and mean variant allele frequency reduction correlated with improved OS (median 31.3 v 7.2 and 31.3 v 15.5 months, respectively). Savolitinib plus durvalumab shows OS in MET-driven PRC, supporting the ongoing SAMETA RIII trial (ClinicalTrials.gov identifier: NCT05043090). ctDNA may be a useful predictive biomarker.

Amivantamab is an EGFR-MET bispecific antibody approved as an intravenous formulation for EGFR-mutated advanced non-small cell lung cancer (NSCLC). Intravenous delivery is frequently associated with infusion-related reaction (IRRs), which require adopting slow infusion rates and splitting the first dose over 2 days. The PALOMA study assessed the safety and feasibility of subcutaneous amivantamab administration and identified the formulation and recommended phase II doses (RP2Ds) for multiple dosing schedules. PALOMA is a phase Ib dose-escalation study in 158 participants with advanced solid malignancies. Primary objectives included pharmacokinetics, safety, and determining RP2Ds for every-2-week (Q2W), every-3-week (Q3W), and every-4-week (Q4W) administration. The safety profile of subcutaneous amivantamab was largely consistent with intravenous monotherapy; most common toxicities reflected on-target EGFR/MET inhibition. Subcutaneous amivantamab resulted in meaningfully shorter administration time (≤ 10 minutes vs. 2.3 hours for intravenous beyond cycle 3) and lower incidence and severity of IRRs versus historical intravenous data, which eliminates the need for split-dose administration. Pharmacokinetic analyses and population pharmacokinetic modeling/simulation were used to estimate subcutaneous amivantamab RP2Ds of 1600 mg (2240 mg, ≥ 80 kg), 2400 mg (3360 mg, ≥ 80 kg), and 3520 mg (4640 mg, ≥ 80 kg) for Q2W, Q3W, and Q4W schedules, respectively. The observed efficacy was consistent with intravenous amivantamab monotherapy. Subcutaneous amivantamab administration substantially reduced IRRs, obviating the need for prolonged infusions and 2-day split-dosing at first administration. The identified RP2Ds for subcutaneous amivantamab are implemented in ongoing studies evaluating amivantamab regimens in NSCLC, colorectal cancer, and head and neck squamous cell carcinoma.

<h3>Introduction</h3> Virtual reality (VR) has rapidly advanced over the last twenty years. Its role in pain management has been explored, but there are no guidelines about how to implement this as part of routine practice. The aim of this work was to develop guidelines that describe the inputs, processes, and outputs required to implement VR as a pain management option for people living with advanced cancer. <h3>Methods</h3> The study had three phases across 2 hospices and 2 hospitals in England and Wales: 1. Interviews with people who are living with advanced cancer and experience pain (scoring over 0 when asked about their pain score). (n=37) 2. Focus groups with staff at each site. The results from the first phase were presented and the theory of change was developed and refined following each meeting. (n=37) 3. User-testing (at two sites) for up to 8 weeks to further refine the theory and develop the guidance manual. (recruitment ending November 2025) A thematic framework analysis of phase 1 and 2 led to the development of the theory of change model, depicting the components required to move successfully from inputs to impact. <h3>Results</h3> The theory of change describes the inputs (planning [training, technology], set up [e.g. identification of people who might benefit from using VR], evaluation of use [for further refining]) and processes required (personalisation, to reach the output (the use of VR). The noted outcomes were the physical and psychological improvements of using the headset, along with some potential risks. <h3>Conclusion</h3> We have developed a theory of change model and guidance that could help sites that are interested in offering VR as a pain management option. The offering of VR could help to provide a more holistic approach to pain management for those living with advanced cancer.

The clinical benefits of intensity-modulated proton therapy (IMPT) compared with intensity-modulated radiation therapy (IMRT) for patients with oropharyngeal squamous cell carcinoma remain uncertain with respect to treatment-related effects on physical function and quality of life. We aimed to compare late functional, patient-reported, disease control, and survival outcomes between IMPT and IMRT. We did a phase 3 trial (TORPEdO) in 20 UK National Health Service hospitals. We randomly assigned (2:1) patients with locally advanced oropharyngeal squamous cell carcinoma to IMPT or IMRT (70 Gy in 33 fractions, for 6·5 weeks) with two cycles of high-dose cisplatin (100 mg/m2, every 3 weeks). Co-primary endpoints at 12 months were gastrostomy-tube dependence (use of feeding tube for nutrition) or severe weight loss (≥20% from baseline) and University of Washington quality of life (UW-QoL) mean physical composite score for saliva, taste, chewing, swallowing, speech and appearance. The study was registered with the ISRCTN registry, ISRCTN16424014; recruitment is complete and follow-up is ongoing. Between Feb 25, 2020, and June 13, 2023, we randomly assigned 205 patients (99 [48%] with T3 or T4 disease and 44 [22%] with bilateral neck lymph node involvement (N2[c]); 136 [66%] to IMPT and 69 [34%] to IMRT). 163 (80%) patients were male and 42 (20%) were female. Ethnicity data were self-reported by 177 (86%) patients; most were White British (167 [94%]). At 12 months, gastrostomy-tube dependence occurred in two (2%) of 119 patients in the IMPT group and in one (2%) of 59 patients in the IMRT group and severe weight loss occurred in 20 (18% [97·5% CI 11 to 28]) of 110 patients in the IMPT group and in three (6% [1 to 17]) of 53 patients in the IMRT group (combined odds ratio 2·80 [97·5% CI 0·75 to 10·4]; p=0·079). Mean UW-QoL physical composite scores at 12 months were 78·3 in the IMPT group versus 77·1 in the IMRT group (difference 1·3 [97·5% CI -3·7 to 6·2]; p=0·56). There were 14 serious adverse events in 12 patients (nine assessed as unrelated to the study treatment [four in the IMPT group and five in the IMRT group] and five study treatment-related [one IMPT vs four IMRT]); the most common events were acute kidney injury (five [36%]) and thromboembolism (four [29%]). There were no treatment-related deaths. At a median follow-up of 28·3 months (IQR 26·5 to 39·3), 24-month freedom from loco-regional recurrence rates were 94% (99% CI 86-98) in the IMPT group versus 97% (82-100) in the IMRT group (hazard ratio [HR] 2·6 [99% CI 0·3 to 20·3; 95% CI 0·5-12·4]; p=0·24), and overall survival rates were 95% (86 to 98) in the IMPT group versus 95% (81-99) in the IMRT group (HR 1·6 [99% CI 0·3 to 8·8; 95% CI 0·4 to 5·9; p=0·47). IMPT and IMRT had similar late physical quality of life scores, gastrostomy-tube dependence, local control, and overall survival. In health-care settings where IMPT is not used routinely for oropharyngeal squamous cell carcinoma, IMRT remains the standard of care. Cancer Research UK.

173 Background: Sarcopenia is common in advanced prostate cancer and worsened by androgen deprivation therapy (ADT). Routine staging CT scans provide an opportunity to screen for sarcopenia. The STAMPEDE trials have demonstrated treatment intensification beyond ADT improve cancer outcomes; however, benefits are heterogeneous. This study investigates CT-derived skeletal muscle index (SMI), a validated marker of total muscle mass, as a prognostic and predictive biomarker in the STAMPEDE docetaxel and ARPI trials. Methods: Men with newly diagnosed non-metastatic high-risk (M0) and metastatic (M1) hormone-sensitive prostate cancer (HSPC) with available staging CT imaging in the STAMPEDE docetaxel or ARPI trials were included. These trials compared standard of care (SOC) with addition of docetaxel ± zoledronic acid (ZA) or abiraterone acetate with prednisolone (AAP) ± enzalutamide (Enz). SMI (cm²/m²) was calculated as mean muscle area divided by height squared. Outcomes were overall survival (OS) in M1 patients and metastasis-free survival (MFS) in M0. Prognostic utility of SMI was evaluated in Kaplan–Meier analyses and Cox regression models. Predictive value was assessed by comparing hazard ratios of the treatment effect in Cox models for high vs low SMI cohorts. Likelihood ratio tests were used to identify treatment-SMI interactions. Continuous predictive effects were examined using multivariable fractional polynomial interaction (MFPI) models. Results: 2,267 patients (1,578 M1, 689 M0) met inclusion criteria. The median SMI was 47.2cm²/m² (IQR 42-52) in M1 patients and 48.2cm²/m² (IQR 44-54) in M0. SMI and CHAARTED burden were identified as independent prognostic biomarkers in M1 patients, with a 10 cm²/m² increase in SMI associated with a 15% reduction in risk of death (HR 0.85, 95% CI 0.79–0.92, p&lt;0.001). SMI was not an independent prognostic biomarker in M0 patients. SMI was identified as an independent predictive biomarker of MFS benefit upon addition of AAP±Enz in M0 patients; high SMI cohorts had greater MFS benefit from addition of AAP±Enz compared with the low SMI cohort (HR 0.44 [0.3-0.66] vs 0.59 [0.38-0.91]). Likelihood ratio tests confirmed that adding a treatment-SMI interaction improved prediction of treatment benefit (χ²: 4.67, p=0.03). MFPI modelling demonstrated a significant MFS benefit with addition of AAP±Enz in M0 patients (χ²=9.95, p=0.006) with increasing SMI, however this benefit was observed in the range of 41-63 cm 2 /m 2 only. 20% of our cohort lay outside this range (13% lower, 7% higher) and did not observe MFS benefit from addition of AAP±Enz to SOC. Conclusions: SMI is an independent prognostic biomarker in trial patients with de novo metastatic HSPC. SMI is predictive of improved MFS with addition of AAP±Enz to SOC in M0 disease. Further research is required to validate our findings in real-world cohorts.

Evidence from conventional and Mendelian Randomisation epidemiological studies support the conclusion that obesity is causally associated with increased risk of several common cancer types. Some evidence, notably from quasi-experimental bariatric surgery studies, support the concept that sustained long-term weight loss in individuals is associated with reduction of cancer incidence, particularly in women. Yet, there are no authoritative public health policies directed specifically at large-scale weight management interventions to prevent obesity-related cancers. At least two adversities conspire against public health success: (i) awareness of the causal link between obesity and cancer risk; and (ii) lifestyle interventions are associated with only moderate weight loss that is generally not sustained longenough to result in clinically meaningful cancer prevention. However, there is now a revolution of effective pharmacotherapy for obesity, namely glucagon-like-peptide (GLP)-1 agonists and their extended family of dual and triple agonists, which leads to substantial rates of weight loss, sustained while individuals continue to take the drug. There is now a key new cancer prevention research question, whether this drug class might significantly reduce cancer risk with long-term use. The logistics of addressing this question in a clinical trial setting are discussed and potential strategies to overcome these challenges are proposed.

Childhood cancer survivors face an increased risk of dental anomalies with both chemotherapy and radiation therapy (RT) contributing to these late adverse effects (AEs), particularly when RT doses >20 Gy are delivered. This systematic review aims to: (1) provide an overview of late dental AEs reported after childhood RT, (2) report the prevalence of these AEs in survivors who received head and/or neck RT during childhood, and (3) describe dose-response evidence and the use of AE grading protocols. A comprehensive search was conducted in Embase and PubMed. Extracted data included study characteristics, treatment details, and outcomes. Heterogeneity was assessed qualitatively, and risk of bias was evaluated using the Cochrane Childhood Cancer tool. Forty-four studies published between 1985 and 2024 were included, comprising 7299 participants (age range 3-16.5 years). The median prescribed RT dose was 50.4 Gy (range 10.0-67.5 Gy), with a median follow-up of 8.35 years. Reported dental AEs included agenesis, microdontia, and root stunting. Higher prescribed radiation doses were associated with increased AE risk. Dental outcomes were assessed clinically and radiographically. There is a clear need for standardized definitions, assessment methods, grading criteria, and data reporting for late dental AEs in childhood head and/or neck cancer survivors. Accurate documentation of RT regimens and pretreatment dental status is essential to support dose minimization strategies, tailored patient education, and long-term dental follow-up, ultimately improving survivorship care.