Visualization of Multi-indication Randomized Control Trial Evidence to Support Decision Making in Oncology: A Case Study on Bevacizumab

Medical Decision Making · 2026-03-31

BackgroundAs an increasing number of oncology drugs are licensed for multiple indications, sharing information across indications may help improve the precision of estimates for a target indication where evidence may be immature. Visualizing the accumulation of evidence and its characteristics across all indications can help inform policy makers as to whether multi-indication synthesis methods should be considered and guide expert elicitation on appropriate cross-indication assumptions.MethodsThe multi-indication oncology drug bevacizumab was selected as a case study. We used visualization methods including timeline, ridgeline, and split-violin plots to display evidence and synthesis results across 7 licensed cancer types, focusing on the evidence on overall and progression-free survival and the display of results from models with and without information sharing.ResultsThe proposed displays allow for visualization of key characteristics of the evidence to support the assessment of heterogeneity within and across indications and inform the feasibility of information-sharing models.LimitationsThe lack of consistent reporting of data in trial reports limits the visualization of some study characteristics. Tradeoffs between plot readability and the level of detail to include were required.ConclusionsClear graphical representations of the evolution and accumulation of evidence and synthesis results can provide a better understanding of the entire multi-indication evidence base, which can inform judgments regarding the appropriate use of data within and across indications. Interactive plots could help overcome some of the current limitations.ImplicationsThe proposed displays should be used to facilitate discussion with experts on the judgments required to assess the feasibility of using information-sharing methods to improve the estimation of relative treatment effects in evidence synthesis approaches and health technology assessment.HighlightsAn increasing number of oncology drugs are licensed for multiple indications; we developed visualization methods for multi-indication evidence that consider key characteristics unique to oncology.Graphical displays can be used to show the evolution of evidence within and across multiple indications.Clear evidence visualizations can be used as a tool to support evidence synthesis approaches, support policy makers, or guide expert elicitation.

Early outcomes of the PLATO ACT5 randomised trial: Personalizing anal cancer radiotherapy dose.

Journal of Clinical Oncology · 2026-01-10

1 Background: The optimal dose of radiotherapy (RT) in advanced anal squamous cell carcinoma (ASCC) is uncertain. Cure rates need to improve, but higher dose RT may result in significant morbidity. Methods: PLATO ACT5 is a seamless pilot/phII/phIII prospective, multi-centre, 3-arm RCT investigating dose-escalated intensity modulated radiotherapy (de-IMRT) with chemotherapy in patients (pts) with T3/4N0 and TanyN+ ASCC. Primary outcome is 3-year locoregional failure (LRF). We report planned 6-month endpoints: acute toxicity (CTCAEv5), treatment compliance, radiological and clinical complete response rates (cCR) and patient reported outcomes (PROs; EORTC-QLQ C30 and ANL27). Pts were randomised 1:1:1 in 28 fractions to standard dose IMRT (sd-IMRT; 53.2Gy), de1-IMRT (58.8Gy) or de2-IMRT (61.6 Gy) with concurrent mitomycin 12mg/m2 day (D) 1 & capecitabine (CAP) 825mg/m2 BD on RT days or 5FU 1000mg/m2 D1-4 & D29-32. 459 pts including 10% drop out were required to compare each experimental arm against sd-IMRT for 3-year LRF-free survival. Results: 463 pts were recruited from 34 UK sites (sd-IMRT n=154; de1-IMRT n=155; de2-IMRT n=154) between Feb 2017 – Aug 2023. 82% received CAP RT and 18% received 5FU RT. Pts characteristics were balanced across 3 arms: Overall median age was 62 years (range 29-81); 73% ECOG 0; 73% female; 30% T4; 45%/18%/21% N1/2/3 respectively; 21% required pre-RT stoma; 1.5% HIV positive. ≥G3 acute toxicity was reported in 57% (sd-IMRT; n=90), 56% (de1-IMRT n=86) and 58, and at 6 mo 19 patients (5/5/9 respectively) reported ≥G3. 460 completed per protocol RT. RT interruptions: sd-IMRT n=40 (26.1%), de1-IMRT n=33 (21.4%), de2-IMRT n=39 (25.7%) of which 25% were due toxicity. 70 (36%) had CAP reduction/omission (sd-IMRT n=13/50; de1-IMRT n=12/47 de2-IMRT n=39/9 respectively); the majority were due to toxicity (46-58%). 6 mo cCR: (MRI TRG 1&2 with no visible T2 weighted pelvic lymph nodes) are: sd-IMRT =100 (65%); de1-IMRT =103 (67%); de2-IMRT= 101 (66%). For PROs, there was a similar large deterioration in pain, fatigue, bowel function, quality of life, physical, role and social function at the end of CRT across all arms which resolved to baseline by 6 months in all arms. Conclusions: Dose escalation has similar toxicity, but does not improve early outcomes. Further stage stratification and novel biology approaches for personalisation are needed. Clinical trial information: ISRCTN88455282.

Cost‐effectiveness of <i>DPYD</i> genotyping prior to fluoropyrimidine‐based treatment for colorectal cancer in Wales

British Journal of Clinical Pharmacology · 2026-05-22

BACKGROUND: Regulatory guidance in the United Kingdom advises DPYD genotyping prior to fluoropyrimidine-based treatment. This economic evaluation estimated the costs and outcomes associated with DPYD screening prior to prescribing fluoropyrimidines for colorectal cancer in Wales and also considers additional variants to those included in standard DPYD testing. METHODS: Decision-analytic models were developed to compare the cost-effectiveness of pharmacogenomic-guided prescribing, where patients with actionable variants are prescribed reduced-dose fluoropyrimidines or an alternative drug, against a strategy of prescribing a standard licensed dose irrespective of genetic status. Incremental net health benefit (INHB) was assessed at a cost-effectiveness threshold of £20 000 per quality-adjusted life year (QALY) gained. Probabilistic and univariate sensitivity and scenario analyses characterized modelling uncertainty and assessed the responsiveness of the results to a range of assumptions. RESULTS: Screening prior to prescribing was modelled to be cost-saving, result in fewer adverse drug reactions and be associated with more QALYs than prescribing all patients standard dose fluoropyrimidines. Testing for c.1905+1G>A, c.1679T>G, c.2846A>T, c.1129-5923C>G and c.1236G>A was associated with an estimated INHB of 0.0118 QALYs (95% central range -0.0490, 0.0575) and 0.96 probability of being cost-effective. Screening for additional variants, including c.557A>G increased the INHB. The results were robust across a range of sensitivity analyses. CONCLUSION: DPYD screening prior to the prescription of fluoropyrimidines is likely to be a cost-effective use of National Health Service resources. Testing for additional variants at minimal additional cost has important implications for reducing the burden of adverse drug reactions and health inequalities in ethnically diverse societies.

ABC-12: exploring the microbiome in patients with advanced biliary tract cancer in a first-line study of durvalumab (MEDI4736) in combination with cisplatin/gemcitabine

Future Oncology · 2025-07-29

Until recently, cisplatin/gemcitabine was standard of care for the first-line treatment of patients with advanced biliary tract cancer (BTC). The addition of durvalumab, an immune checkpoint inhibitor, to the combination of cisplatin/gemcitabine has demonstrated an overall survival (OS) benefit and is now a standard of care first-line treatment option. BTCs exhibit immunogenic features may develop through an accumulation of genetic and epigenetic alterations, and can be influenced by microbial exposure. Microbiota can influence inflammation and immunity, and its disruption may impair tumor response to immunotherapy and chemotherapy. Here, the rationale and design of the multi-center, single-arm ABC-12 trial (ISRCTN11210442) is described, which investigates the role of the microbiome in patients with advanced BTC in a first-line study of durvalumab (MEDI4736) in combination with cisplatin/gemcitabine. The primary objective is to determine the difference in baseline alpha diversity between "responders" (partial or complete response) and "non-responders" at 18 weeks (RECIST 1.1) in patients treated with cisplatin/gemcitabine/durvalumab. Secondary objectives include investigating the association between microbiome parameters and objective response rate, tumor control (partial, complete response, and stable disease), progression-free and OS, and investigating the interaction between treatment effect and microbiome parameters on clinical outcomes.

Neoadjuvant Treatment of Rectal Cancer: A Repeat UK-wide Survey After Implementation of National Intensity Modulated Radiotherapy Guidance

Clinical Oncology · 2025-03-22 · 1 citations

1116 PRIME-RT: Durvalumab with extended neoadjuvant regimens in locally advanced rectal cancer (LARC): a randomised phase II trial

Radiotherapy and Oncology · 2025-05-01 · 6 citations

A Phase Ia/b study of MEK1/2 inhibitor binimetinib with MET inhibitor crizotinib in patients with RAS mutant advanced colorectal cancer (MErCuRIC)

BMC Cancer · 2025-04-10 · 5 citations

BACKGROUND: Targeting RAS mutant (MT) colorectal cancer (CRC) remains a difficult challenge, mainly due to the pervasiveness of RAS/MEK-mediated feedback loops. Preclinical studies identified MET/STAT3 as an important mediator of resistance to KRAS-MEK1/2 blockade in RASMT CRC. This dose escalation/expansion study assessed safety and initial efficacy of the MEK1/2 inhibitor binimetinib with MET inhibitor crizotinib in RASMT advanced CRC patients. METHODS: In the dose escalation phase, patients with advanced solid tumours received binimetinib with crizotinib, using a rolling- 6 design to determine the maximum tolerable dose (MTD) and safety/tolerability. A subsequent dose expansion in RASMT CRC patients assessed treatment response. Blood samples for pharmacokinetics, MET biomarker and ctDNA analyses, and skin/tumour biopsies for pharmacodynamics, c-MET immunohistochemistry (IHC), MET in situ hybridisation (ISH) and MET DNA-ISH analyses were collected. RESULTS: Twenty patients were recruited in 3 cohorts in the dose escalation. The MTD was binimetinib 30 mg B.D, days 1-21 every 28 days, with crizotinib 250 mg O.D continuously. Dose-limiting toxicities included grade ≥ 3 transaminitis, creatinine phosphokinase increases and fatigue. Thirty-six RASMT metastatic CRC patients were enrolled in the dose expansion. Pharmacokinetic and pharmacodynamic parameters showed evidence of target engagement. Across the entire study, the most frequent treatment-related adverse events (TR-AE) were rash (80.4%), fatigue (53.4%) and diarrhoea (51.8%) with grade ≥ 3 TR-AE occurring in 44.6%. Best clinical response within the RASMT CRC cohort was stable disease in seven patients (24%). Tumour MET super-expression (IHC H-score > 180 and MET ISH + 3) was observed in 7 patients (24.1%), with MET-amplification only present in 1 of these patients. This patient discontinued treatment early during cycle 1 due to toxicity. Patients with high baseline RASMT allele frequency had a significant shorter median overall survival compared with that seen for patients with low baseline KRASMT allele frequency. CONCLUSIONS: Combination binimetinib/crizotinib showed a poor tolerability with no objective responses observed in RASMT advanced CRC patients. EudraCT-Number: 2014-000463 - 40 (20/06/2014: A Sequential Phase I study of MEK1/2 inhibitors PD- 0325901 or Binimetinib combined with cMET inhibitor Crizotinib in RAS Mutant and RAS Wild Type with aberrant c-MET).

A phase Ia study of the MEK1/2 inhibitor PD-0325901 with the c-MET inhibitor crizotinib in patients with advanced solid cancers

BJC Reports · 2025-03-26 · 3 citations

BACKGROUND: Single-agent MEK1/2 inhibition has been disappointing in clinical trials targeting RAS mutant (MT) cancers, probably due to upstream receptor activation, resulting in resistance. We previously found that dual c-MET/MEK1/2 inhibition attenuated RASMT colorectal cancer (CRC) xenograft growth. In this study, we assessed safety of MEK1/2 inhibitor PD-0325901 with c-MET inhibitor crizotinib and determined the optimal biological doses for subsequent clinical trials. METHODS: In this dose-escalation phase I trial, patients with advanced solid tumours received PD-0325901 with crizotinib, using a rolling-6 design to determine the maximum tolerable dose (MTD) and safety/tolerability. Blood samples for pharmacokinetics and skin biopsies were collected. RESULTS: Twenty-five patients were recruited in 4 cohorts up to doses of crizotinib 200 mg B.D continuously with PD-0325901 8 mg B.D, days 1-21 every 28 days. One in six patients exhibited a dose-limiting toxicity at this dose level. Drug-related adverse events were in keeping with single-agent toxicity profiles. The best clinical response was stable disease in seven patients (29%). CONCLUSIONS: PD-0325901/crizotinib can be given together at pharmacologically-active doses. The MTD for PD-0325901/crizotinib was 8 mg B.D (days 1-21) and 200 mg B.D continuously in a 28-days cycle. The combination was further explored with an alternate MEK1/2 inhibitor in RASMT CRC patients. EUDRACT-NUMBER: 2014-000463-40.

2186 ARISTOTLE: Mature results of a phase 3 trial evaluating the addition of irinotecan to capecitabine chemoradiation in locally advanced rectal cancer

Radiotherapy and Oncology · 2025-05-01

Mississippi, Conflict and Change

University Press of Mississippi eBooks · 2025-07-20