The Christie School of Oncology: Christie Research Publications Repository
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A comprehensive analysis of High Grade Appendiceal Mucinous Neoplasm (HAMN)-15 years' experience from a peritoneal oncology centre
No full textVirtual reality distraction therapy in paediatric proton beam and photon therapy treatment
No full textEvaluation of clinical parameters associated with response and resistance to cemiplimab in locally advanced and metastatic cutaneous squamous cell carcinoma: a multi-Institutional retrospective cohort study
No full textCutaneous squamous cell carcinoma (cSCC) is a common cancer with increasing incidence and 5% of patients develop incurable disease, often resistant to chemotherapy. The anti-PD-1 therapy cemiplimab has shown high efficacy in clinical trials. This retrospective study evaluated the real-world effectiveness of cemiplimab in incurable cSCC and examined factors influencing response and toxicity. Data from 86 patients across three UK healthcare providers were analysed. Median progression-free survival (PFS) and overall survival (OS) were not reached, with 38% showing durable responses beyond 12 months. The overall response rate was 60.8% (95% CI 49-71), and the clinical benefit rate was 74.3% (95% CI 63-83). A head and neck primary site was associated with improved PFS (p = 0.008) and OS (p = 0.023), while concurrent immunosuppression was associated with worse PFS (p < 0.001). These findings align with clinical trials, suggesting cemiplimab is effective and safe in the recurrent/metastatic setting
An integrative multiparametric approach stratifies putative distinct phenotypes of blast phase chronic myelomonocytic leukemia
No full textApproximately 30% of patients with chronic myelomonocytic leukemia (CMML) undergo transformation to a chemo-refractory blastic phase (BP-CMML). Seeking novel therapeutic approaches, we profiled blast transcriptomes from 42 BP-CMMLs, observing extensive transcriptional heterogeneity and poor alignment to current acute myeloid leukemia (AML) classifications. BP-CMMLs display distinctive transcriptomic profiles, including enrichment for quiescence and variability in drug response signatures. Integrating clinical, immunophenotype, and transcriptome parameters, Random Forest unsupervised clustering distinguishes immature and mature subtypes characterized by differential expression of transcriptional modules, oncogenes, apoptotic regulators, and patterns of surface marker expression. Subtypes differ in predicted response to AML drugs, validated ex vivo in primary samples. Iteratively refined stratification resolves a classification structure comprising five subtypes along a maturation spectrum, predictive of response to novel agents including consistent patterns for receptor tyrosine kinase (RTK), cyclin-dependent kinase (CDK), mechanistic target of rapamycin (MTOR), and mitogen-activated protein kinase (MAPK) inhibitors. Finally, we generate a prototype decision tree to stratify BP-CMML with high specificity and sensitivity, requiring validation but with potential clinical applicability to guide personalized drug selection for improved outcomes
INTERLINK-1: A phase III, randomized, placebo-controlled study of monalizumab plus cetuximab in recurrent/metastatic head and neck squamous cell carcinoma
No full textPURPOSE: Treatment options for recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) after failure of immune checkpoint inhibitor treatment and platinum-based chemotherapy are limited. Preliminary data suggested that monalizumab plus cetuximab had clinical activity in R/M HNSCC. PATIENTS AND METHODS: INTERLINK-1 (NCT04590963) was a double-blind, phase III study. Participants with R/M HNSCC who had received immune checkpoint inhibitor therapy and progressed despite platinum-based chemotherapy were randomized 2:1 to monalizumab (750 mg, every 2 weeks) or placebo, plus cetuximab (400 mg/m2 loading dose, then 250 mg/m2, weekly). The primary endpoint was overall survival (OS) in participants with non-oropharyngeal cancer or human papillomavirus (HPV)-negative oropharyngeal cancer (HPV-unrelated analysis set). Secondary endpoints included progression-free survival and objective response rate. RESULTS: At data cutoff, 216 participants were randomized in the HPV-unrelated analysis set: 145 to monalizumab plus cetuximab and 71 to placebo plus cetuximab. Median OS was 8.8 months for monalizumab plus cetuximab versus 8.6 months for placebo plus cetuximab (HR, 1.00; 95% confidence interval, 0.66-1.54); median progression-free survival was 3.6 versus 3.8 months, respectively (HR, 1.11; 95% confidence interval, 0.79-1.57); and the objective response rate was 15.2% versus 23.9%, respectively. INTERLINK-1 was terminated after a preplanned interim analysis showed that futility criteria were met (predetermined futility HR >0.874). Grade 3/4 treatment-related adverse events were reported in 18.3% and 17.2% of participants treated in the monalizumab and placebo arms, respectively. CONCLUSIONS: Monalizumab plus cetuximab did not improve OS compared with placebo plus cetuximab. The safety profile of the combination was consistent with safety observations for cetuximab monotherapy
Treatment approaches and survival outcomes from a large international cohort study of secondary CNS lymphoma
No full textCapivasertib plus abiraterone in PTEN-deficient metastatic hormone-sensitive prostate cancer: CAPItello-281 Phase III study
No full textBACKGROUND: In metastatic hormone-sensitive prostate cancer (mHSPC), PTEN deficiency results in PI3K/AKT pathway activation, providing an independent proliferative drive, which cannot be suppressed by androgen receptor pathway inhibitors (ARPIs), resulting in worse outcomes. Dual inhibition of PI3K/AKT and AR pathways with capivasertib and abiraterone may delay progression and improve disease outcomes. PATIENTS AND METHODS: In CAPItello-281 (NCT04493853), patients with PTEN-deficient mHSPC (diagnostic cut-off: ≥90% viable malignant cells with no specific cytoplasmic PTEN immunohistochemistry staining) received capivasertib or placebo (1:1) plus abiraterone, prednisone/prednisolone and androgen deprivation therapy (ADT). Primary endpoint was investigator-assessed radiographic progression-free survival (rPFS); overall survival (OS) was a key secondary endpoint. Post-hoc exploratory subgroups at increasing PTEN cut-off thresholds were also assessed. RESULTS: 25.3% (1519/6003) of patients with valid tumor test results had PTEN-deficient tumors. In the randomized PTEN-deficient population, a statistically significant improvement in rPFS was observed with capivasertib plus abiraterone (n=507, median 33.2 months) versus placebo plus abiraterone (n=505, 25.7 months; Hazard Ratio [HR] 0.81, 95% CI 0.66-0.98, P=0.034). Post-hoc rPFS analyses for loss of PTEN cut-offs of ≥95%, ≥99%, and 100% showed the capivasertib plus abiraterone arm performed consistently across cutoffs, but the placebo plus abiraterone arm performed progressively worse as the cut-off for the degree of PTEN loss was increased, resulting in a numerically improved treatment effect. In the overall population studied, the HR for OS (26.4% maturity) was 0.90, 95% CI 0.71-1.15, P=0.401. The most common adverse events (AEs) for capivasertib plus abiraterone were diarrhea (51.9%; 8.0% placebo plus abiraterone), hyperglycemia (38.0%; 12.9%) and rash (35.4%; 7.0%). Deaths associated with an AE were reported in 36 (7.2%) and 26 (5.2%) patients in the capivasertib plus abiraterone and placebo plus abiraterone arms, respectively. CONCLUSIONS: Capivasertib plus abiraterone improves rPFS versus placebo plus abiraterone in PTEN-deficient mHSPC, on a background of ADT, with a 7.5-month improvement in median rPFS. AE profile was consistent with that of the individual agents. Patients with PTEN-deficient mHSPC benefit from dual blockade of the PI3K/AKT and AR pathways with capivasertib plus abiraterone
