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Background: Effective treatments are needed to improve outcomes for high-grade glioma and low-grade glioma. The activity and safety of dabrafenib plus trametinib were evaluated in adult patients with recurrent or progressive BRAFV600E mutation-positive high-grade glioma and low-grade glioma.Methods: This study is part of an ongoing open-label, single-arm, phase 2 Rare Oncology Agnostic Research (ROAR) basket trial at 27 community and academic cancer centres in 13 countries (Austria, Belgium, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, South Korea, Spain, Sweden, and the USA). The study enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Patients with BRAFV600E mutation-positive high-grade glioma and low-grade glioma received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally until unacceptable toxicity, disease progression, or death. In the high-grade glioma cohort, patients were required to have measurable disease at baseline using the Response Assessment in Neuro-Oncology high-grade glioma response criteria and have been treated previously with radiotherapy and first-line chemotherapy or concurrent chemoradiotherapy. Patients with low-grade glioma were required to have measurable non-enhancing disease (except pilocytic astrocytoma) at baseline using the Response Assessment in Neuro-Oncology low-grade glioma criteria. The primary endpoint, in the evaluable intention-to-treat population, was investigator-assessed objective response rate (complete response plus partial response for high-grade glioma and complete response plus partial response plus minor response for low-grade glioma). This trial is ongoing, but is closed for enrolment, NCT02034110.Findings: Between April 17, 2014, and July 25, 2018, 45 patients (31 with glioblastoma) were enrolled into the high-grade glioma cohort and 13 patients were enrolled into the low-grade glioma cohort. The results presented here are based on interim analysis 16 (data cutoff Sept 14, 2020). In the high-grade glioma cohort, median follow-up was 12·7 months (IQR 5·4-32·3) and 15 (33%; 95% CI 20-49) of 45 patients had an objective response by investigator assessment, including three complete responses and 12 partial responses. In the low-grade glioma cohort, median follow-up was 32·2 months (IQR 25·1-47·8). Nine (69%; 95% CI 39-91) of 13 patients had an objective response by investigator assessment, including one complete response, six partial responses, and two minor responses. Grade 3 or worse adverse events were reported in 31 (53%) patients, the most common being fatigue (five [9%]), decreased neutrophil count (five [9%]), headache (three [5%]), and neutropenia (three [5%]).Interpretation: Dabrafenib plus trametinib showed clinically meaningful activity in patients with BRAFV600E mutation-positive recurrent or refractory high-grade glioma and low-grade glioma, with a safety profile consistent with that in other indications. BRAFV600E testing could potentially be adopted in clinical practice for patients with glioma.Funding: Novartis. [ABSTRACT FROM AUTHOR]

Successful drug development for people with cancers of the CNS has been challenging. There are multiple barriers to successful drug development including biological factors, rarity of the disease, and ineffective use of clinical trials. Based upon a series of presentations at the First Central Nervous System Clinical Trials Conference hosted by the American Society of Clinical Oncology and the Society for Neuro-Oncology, we provide an overview on drug development and novel trial designs in neuro-oncology. This Review discusses the challenges of therapeutic development in neuro-oncology and proposes strategies to improve the drug discovery process by enriching the pipeline of promising therapies, optimising trial design, incorporating biomarkers, using external data, and maximising efficacy and reproducibility of clinical trials. [ABSTRACT FROM AUTHOR]

With increasing attention on the essential roles of the tumour microenvironment in recent years, the nervous system has emerged as a novel and crucial facilitator of cancer growth. In this Review, we describe the foundational, translational, and clinical advances illustrating how nerves contribute to tumour proliferation, stress adaptation, immunomodulation, metastasis, electrical hyperactivity and seizures, and neuropathic pain. Collectively, this expanding knowledge base reveals multiple therapeutic avenues for cancer neuroscience that warrant further exploration in clinical studies. We discuss the available clinical data, including ongoing trials investigating novel agents targeting the tumour-nerve axis, and the therapeutic potential for repurposing existing neuroactive drugs as an anti-cancer approach, particularly in combination with established treatment regimens. Lastly, we discuss the clinical challenges of these treatment strategies and highlight unanswered questions and future directions in the burgeoning field of cancer neuroscience. [ABSTRACT FROM AUTHOR]

Integration of external control data, with patient-level information, in clinical trials has the potential to accelerate the development of new treatments in neuro-oncology by contextualising single-arm studies and improving decision making (eg, early stopping decisions). Based on a series of presentations at the 2020 Clinical Trials Think Tank hosted by the Society of Neuro-Oncology, we provide an overview on the use of external control data representative of the standard of care in the design and analysis of clinical trials. High-quality patient-level records, rigorous methods, and validation analyses are necessary to effectively leverage external data. We review study designs, statistical methods, risks, and potential distortions in using external data from completed trials and real-world data, as well as data sources, data sharing models, ongoing work, and applications in glioblastoma. [ABSTRACT FROM AUTHOR]

Background: Effective treatments for patients with cholangiocarcinoma after progression on gemcitabine-based chemotherapy are urgently needed. Mutations in the BRAF gene have been found in 5% of biliary tract tumours. The combination of dabrafenib and trametinib has shown activity in several BRAFV600E-mutated cancers. We aimed to assess the activity and safety of dabrafenib and trametinib combination therapy in patients with BRAFV600E-mutated biliary tract cancer.Methods: This study is part of an ongoing, phase 2, open-label, single-arm, multicentre, Rare Oncology Agnostic Research (ROAR) basket trial in patients with BRAFV600E-mutated rare cancers. Patients were eligible for the biliary tract cancer cohort if they were aged 18 years or older, had BRAFV600E-mutated, unresectable, metastatic, locally advanced, or recurrent biliary tract cancer, an Eastern Cooperative Oncology Group performance status of 0-2, and had received previous systemic treatment. All patients were treated with oral dabrafenib 150 mg twice daily and oral trametinib 2 mg once daily until disease progression or intolerance of treatment. The primary endpoint was the overall response rate, which was determined by Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat evaluable population, which comprised all enrolled patients regardless of receiving treatment who were evaluable (ie, had progression, began a new anticancer treatment, withdrew consent, died, had stable disease for 6 weeks or longer, or had two or more post-baseline assessments). The ROAR trial is registered with ClinicalTrials.gov, NCT02034110. These results are based on an interim analysis; the study is active but not recruiting.Findings: Between March 12, 2014, and July 18, 2018, 43 patients with BRAFV600E-mutated biliary tract cancer were enrolled to the study and were evaluable. Median follow-up was 10 months (IQR 6-15). An investigator-assessed overall response was achieved by 22 (51%, 95% CI 36-67) of 43 patients. An independent reviewer-assessed overall response was achieved by 20 (47%, 95% CI 31-62) of 43 patients. The most common grade 3 or worse adverse event was increased γ-glutamyltransferase in five (12%) patients. 17 (40%) patients had serious adverse events and nine (21%) had treatment-related serious adverse events, the most frequent of which was pyrexia (eight [19%]). No treatment-related deaths were reported.Interpretation: Dabrafenib plus trametinib combination treatment showed promising activity in patients with BRAFV600E-mutated biliary tract cancer, with a manageable safety profile. Routine testing for BRAFV600E mutations should be considered in patients with biliary tract cancer.Funding: GlaxoSmithKline and Novartis. [ABSTRACT FROM AUTHOR]

Response criteria for paediatric high-grade glioma vary historically and across different cooperative groups. The Response Assessment in Neuro-Oncology working group developed response criteria for adult high-grade glioma, but these were not created to meet the unique challenges in children with the disease. The Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group, consisting of an international panel of paediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address issues and unique challenges in assessing response in children with CNS tumours. We established a subcommittee to develop response assessment criteria for paediatric high-grade glioma. Current practice and literature were reviewed to identify major challenges in assessing the response of paediatric high-grade gliomas to various treatments. For areas in which scientific investigation was scarce, consensus was reached through an iterative process. RAPNO response assessment recommendations include the use of MRI of the brain and the spine, assessment of clinical status, and the use of corticosteroids or antiangiogenics. Imaging standards for brain and spine are defined. Compared with the recommendations for the management of adult high-grade glioma, for paediatrics there is inclusion of diffusion-weighted imaging and a higher reliance on T2-weighted fluid-attenuated inversion recovery. Consensus recommendations and response definitions have been established and, similar to other RAPNO recommendations, prospective validation in clinical trials is warranted. [ABSTRACT FROM AUTHOR]

Clinical trials of treatments for high-grade gliomas have traditionally relied on measures of response or time-dependent metrics; however, these endpoints have limitations because they do not characterise the functional or symptomatic effect of the condition on the person. Including clinical outcome assessments, such as patient- reported outcomes (PROs), to determine net clinical benefit of a treatment strategy is needed because of the substantial burden of symptoms and impaired functioning in this patient population. The US National Cancer Institute convened a meeting to review previous recommendations and existing PRO measures of symptoms and function that can be applied to current trials and clinical practice for high-grade gliomas. Measures were assessed for relevance, relationship to disease and therapy, sensitivity to change, psychometric properties, response format, patient acceptability, and use of self-report. The group also relied on patient input including the results of an online survey, a literature review on available clinical outcomes, expert opinion, and alignment with work done by other organisations. A core set of priority constructs was proposed that allows more comprehensive evaluation of therapies and comparison of outcomes among studies, and enhances efforts to improve the measurement of these core clinical outcomes. The proposed set of constructs was then presented to the Society for Neuro-Oncology Response Assessment in Neuro-Oncology Working Group and feedback was solicited. [ABSTRACT FROM AUTHOR]

The Response Assessment in Neuro-Oncology-Patient-Reported Outcome (RANO-PRO) working group is an international multidisciplinary collaboration that provides guidance on the use of patient-reported outcome (PRO) measures in clinical trials and practice for adult patients with brain tumours. Findings from both PROs and traditional outcome measures, such as survival, and clinical or radiological response, are essential to inform the research community, policy makers, physicians, and patients in the treatment decision-making process. Previous initiatives in oncology have focused on guidelines concerning the collection, analysis, interpretation, and reporting of PRO data. However, we recommend the application of appropriate PRO instruments, with respect to its content and measurement properties (ie, research question, content validity, and other measurement properties), in brain tumour research. PROs should be well defined and reliable to generate high-quality evidence, and our recommendations on the use of specific PRO measures could help to improve the quality of PRO evidence derived from neuro-oncological studies, and might add a new dimension in how the value of therapeutics is assessed in patients with brain tumours. In this Policy Review, we present the RANO-PRO working plan for the use of PROs in adults with brain tumours. [ABSTRACT FROM AUTHOR]

The goals of therapeutic and biomarker development form the foundation of clinical trial design, and change considerably from early-phase to late-phase trials. From these goals, decisions on specific clinical trial design elements, such as endpoint selection and statistical approaches, are formed. Whereas early-phase trials might focus on finding a therapeutic signal to make decisions on further development, late-phase trials focus on the confirmation of therapeutic impact by considering clinically meaningful endpoints. In this guideline from the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group, we highlight issues related to, and provide recommendations for, the design of clinical trials on local therapies for CNS metastases from solid tumours. We discuss endpoint selection criteria, the analysis appropriate for early-phase and late-phase trials, the association between tumour-specific and clinically meaningful endpoints, and possible issues related to the estimation of local control in the context of competing risks. In light of these discussions, we make specific recommendations on the clinical trial design of local therapies for brain metastases. [ABSTRACT FROM AUTHOR]

Patients with active CNS disease are often excluded from clinical trials, and data regarding the CNS efficacy of systemic agents are usually obtained late in the drug development process or not at all. In this guideline from the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group, we provide detailed recommendations on when patients with brain metastases from solid tumours should be included or excluded in clinical trials of systemic agents. We also discuss the limitations of retrospective studies in determining the CNS efficacy of systemic drugs. Inclusion of patients with brain metastases early on in the clinical development of a drug or a regimen is needed to generate appropriate CNS efficacy or non-efficacy signals. We consider how to optimally incorporate or exclude such patients in systemic therapy trials depending on the likelihood of CNS activity of the agent by considering three scenarios: drugs that are considered very unlikely to have CNS antitumour activity or efficacy; drugs that are considered very likely to have CNS activity or efficacy; and drugs with minimal baseline information on CNS activity or efficacy. We also address trial design issues unique to patients with brain metastases, including the selection of appropriate CNS endpoints in systemic therapy trials. [ABSTRACT FROM AUTHOR]

Immunotherapy is a promising area of therapy in patients with neuro-oncological malignancies. However, early-phase studies show unique challenges associated with the assessment of radiological changes in response to immunotherapy reflecting delayed responses or therapy-induced inflammation. Clinical benefit, including long-term survival and tumour regression, can still occur after initial disease progression or after the appearance of new lesions. Refinement of the response assessment criteria for patients with neuro-oncological malignancies undergoing immunotherapy is therefore warranted. Herein, a multinational and multidisciplinary panel of neuro-oncology immunotherapy experts describe immunotherapy Response Assessment for Neuro-Oncology (iRANO) criteria based on guidance for the determination of tumour progression outlined by the immune-related response criteria and the RANO working group. Among patients who demonstrate imaging findings meeting RANO criteria for progressive disease within 6 months of initiating immunotherapy, including the development of new lesions, confirmation of radiographic progression on follow-up imaging is recommended provided that the patient is not significantly worse clinically. The proposed criteria also include guidelines for the use of corticosteroids. We review the role of advanced imaging techniques and the role of measurement of clinical benefit endpoints including neurological and immunological functions. The iRANO guidelines put forth in this Review will evolve successively to improve their usefulness as further experience from immunotherapy trials in neuro-oncology accumulate. [ABSTRACT FROM AUTHOR]

Response Assessment in Neuro-Oncology (RANO) response criteria have been established and were updated in 2023 for MRI-based response evaluation of diffuse gliomas in clinical trials. In addition, PET-based imaging with amino acid tracers is increasingly considered for disease monitoring in both clinical practice and clinical trials. So far, a standardised framework defining timepoints for baseline and follow-up investigations and response evaluation criteria for PET imaging of diffuse gliomas has not been established. Therefore, in this Policy Review, we propose a set of criteria for response assessment based on amino acid PET imaging in clinical trials enrolling participants with diffuse gliomas as defined in the 2021 WHO classification of tumours of the central nervous system. These proposed PET RANO criteria provide a conceptual framework that facilitates the structured implementation of PET imaging into clinical research and, ultimately, clinical routine. To this end, the PET RANO 1.0 criteria are intended to encourage specific investigations of amino acid PET imaging of gliomas., Competing Interests: Declaration of interests NLA has received honoraria for consultation or advisory board participation from Novartis (Advanced Accelerator Applications), Telix Pharmaceuticals, and Servier; and research funding from Novocure. NG received honoraria for lectures from Blue Earth Diagnostics and honoraria for advisory board participation from Telix Pharmaceuticals. BME is on the advisory board and is a paid consultant for Medicenna, MedQIA, Servier Pharmaceuticals, Siemens, Janssen Pharmaceuticals, Imaging Endpoints, Kazia, Chimerix, Sumitomo Dainippon Pharma Oncology, ImmunoGenesis, Ellipses Pharma, Monteris, Neosoma, Alpheus Medical, Sagimet Biosciences, Sapience Therapeutics, Orbus Therapeutics, and the Global Coalition for Adaptive Research. MJvdB has received honoraria from Roche, AstraZeneca, Servier, Boehringer, Genenta, Fore Biotherapeutics, Incyte, and Nerviano. ELR reports personal financial interests as an advisory board member for Bayer, Janssen, Leo Pharma, Pierre Fabre, Roche, Seattle Genetics, and Servier; and institutional funding from Bristol Myers Squibb. MJM has received research support from Bristol Myers Squibb and travel support from Pierre Fabre. GM has received honoraria for lectures from BrainLab. RR has received research grants from Bayer, and honoraria for lectures or consulting from UCB, Novocure, Genenta, Curevac, and Servier. AMS has received research support to his institution from Medimmune, AVID, Telix Pharmaceuticals, ITM, Fusion, Cyclotek, Adalta, TheraMyc, Curis, Humanigen, and Antengene; funding support from the Medical Research Future Fund, Australian Brain Cancer Mission, Cure Brain Cancer Foundation, National Breast Cancer Foundation, Australian Cancer Research Foundation, National Imaging Facility, and Victorian Cancer Agency; and is a National Health and Medical Research Council Investigator. MS has received honoraria for consultancy from Bracco and honoraria for lectures from GE Healthcare, AuntMinnie, and Fondazione Internazionale Menarini (all paid to their institution). BS has received honoraria for lectures and consultation from Novocure. J-CT has received honoraria for lectures, consultation, or advisory board participation from SeagGen, AAA-Novartis, Novocure, and Munich Surgical Imaging. AV has received honoraria for lectures and advisory board participation from Curium, Eisai, and General Electrics. MW has received research grants from Quercis and Versameb; and honoraria for lectures or advisory board participation or consulting from Bayer, Curevac, Medac, Novartis, Novocure, Orbus, Philogen, Roche, and Servier. PYW has received research support from AstraZeneca, Black Diamond, Bristol Myers Squibb, Celgene, Chimerix, Eli Lilly, Erasca, Genentech/Roche, Kazia, MediciNova, Merck, Novartis, Nuvation Bio, Servier, Vascular Biogenics, and VBI Vaccines; and honoraria for serving as a consultant or on advisory boards for AstraZeneca, Black Diamond, Celularity, Chimerix, Day One Bio, Genenta, GSK, Merck, Mundipharma, Novartis, Novocure, Nuvation Bio, Prelude Therapeutics, Sapience, Servier, Sagimet, Vascular Biogenics, and VBI Vaccines. MP has received honoraria for lectures, consultation, or advisory board participation from Bayer, Bristol Myers Squibb, Novartis, Gerson Lehrman Group, CMC Contrast, GSK, Mundipharma, Roche, BMJ Journals, MedMedia, AstraZeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dohme, Tocagen, Adastra, Gan & Lee Pharmaceuticals, and Servier; and travel support from Servier, Roche, and Medsir., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Effective treatments are needed to improve outcomes for high-grade glioma and low-grade glioma. The activity and safety of dabrafenib plus trametinib were evaluated in adult patients with recurrent or progressive BRAF V600E mutation-positive high-grade glioma and low-grade glioma., Methods: This study is part of an ongoing open-label, single-arm, phase 2 Rare Oncology Agnostic Research (ROAR) basket trial at 27 community and academic cancer centres in 13 countries (Austria, Belgium, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, South Korea, Spain, Sweden, and the USA). The study enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Patients with BRAF V600E mutation-positive high-grade glioma and low-grade glioma received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally until unacceptable toxicity, disease progression, or death. In the high-grade glioma cohort, patients were required to have measurable disease at baseline using the Response Assessment in Neuro-Oncology high-grade glioma response criteria and have been treated previously with radiotherapy and first-line chemotherapy or concurrent chemoradiotherapy. Patients with low-grade glioma were required to have measurable non-enhancing disease (except pilocytic astrocytoma) at baseline using the Response Assessment in Neuro-Oncology low-grade glioma criteria. The primary endpoint, in the evaluable intention-to-treat population, was investigator-assessed objective response rate (complete response plus partial response for high-grade glioma and complete response plus partial response plus minor response for low-grade glioma). This trial is ongoing, but is closed for enrolment, NCT02034110., Findings: Between April 17, 2014, and July 25, 2018, 45 patients (31 with glioblastoma) were enrolled into the high-grade glioma cohort and 13 patients were enrolled into the low-grade glioma cohort. The results presented here are based on interim analysis 16 (data cutoff Sept 14, 2020). In the high-grade glioma cohort, median follow-up was 12·7 months (IQR 5·4-32·3) and 15 (33%; 95% CI 20-49) of 45 patients had an objective response by investigator assessment, including three complete responses and 12 partial responses. In the low-grade glioma cohort, median follow-up was 32·2 months (IQR 25·1-47·8). Nine (69%; 95% CI 39-91) of 13 patients had an objective response by investigator assessment, including one complete response, six partial responses, and two minor responses. Grade 3 or worse adverse events were reported in 31 (53%) patients, the most common being fatigue (five [9%]), decreased neutrophil count (five [9%]), headache (three [5%]), and neutropenia (three [5%])., Interpretation: Dabrafenib plus trametinib showed clinically meaningful activity in patients with BRAF V600E mutation-positive recurrent or refractory high-grade glioma and low-grade glioma, with a safety profile consistent with that in other indications. BRAF V600E testing could potentially be adopted in clinical practice for patients with glioma., Funding: Novartis., Competing Interests: Declaration of interests PYW reports research support from Agios, AstraZeneca/MedImmune, Bayer, Celgene, Eli Lilly, Genentech/Roche, Kazia Therapeutics, MediciNova, Merck, Novartis, Nuvation Bio, Oncoceutics, Vascular Biogenics, and VBI Vaccines; and has an advisory or board member role in Agios, AstraZeneca, Bayer, Black Diamond, Boston Pharmaceuticals, ElevateBio, Imvax, Karyopharm Therapeutics, Merck, Mundipharma, Novartis, Novocure, Nuvation Bio, Prelude Therapeutics, QED Therapeutics, Sapience, Vascular Biogenics, VBI Vaccines, and Voyager. AS reports grants or research support from Bristol Myers Squibb, German Cancer Aid, Merck KGaA, Roche, Sanofi, and Servier; has advisory or board member role in Amgen, Bristol Myers Squibb, Celgene, Merck KGaA, Merck Sharp & Dohme, Roche, Sanofi, and Servier; and speaker's bureau participation in Amgen, Bristol Myers Squibb, Merck KGaA, Roche, Sanofi, and Servier. MvdB has a consultant or independent role in Agios, CarThera, Celgene, Genenta, Karyopharm Therapeutics, and Nerviano Medical Sciences. FYFLdV reports grants or research support from AbbVie, BioClin Therapeutics, Bristol Myers Squibb, GlaxoSmithKline, Novartis, Octimet Oncology NV, and Vaximm; has an advisory or board member role in Bristol Myers Squibb; and received travel support from Roche Genentech. NvB reports grants or research support and has an advisory or board member role in Novartis; and recieves honorarium from Novartis and Takeda. GWP reports honoraria and being an advisory or board member in Amgen, Bayer, Bristol Myers Squibb, Eli Lilly, Merck, Merck Sharp & Dohme, Roche, Sanofi, Servier, and Taiho Pharma. MC reports honoraria and advisor or consultant role in AbbVie, Accord, AstraZeneca, GT1, Novartis, Pierre Fabre, Pfizer, Sanofi, and Servier; and speaker's bureau participation in Eli Lilly and Novartis. JAL-M is employed at PharmaMar; and reports advisory or board member role in Amgen, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Novartis, Merck Sharp & Dohme, Pfizer, PharmaMar, Pierre Fabre, and Roche; has a consultant or independent role in Chobani; is a stock shareholder (self-managed) in PharmaMar; is a co-founder, member of the Board of Directors, and former President of GETICA (Spanish Group–Cancer ImmunoBiotherapy); and receives travel support from Bayer, Bristol Myers Squibb, Daiichi Sankyo, Merck Serono, Merck Sharp & Dohme, Novartis, PharmaMar, and Roche. TMK reports grants or research support from AstraZeneca–KHIDI outside the submitted work; has a consultant or independent role in AstraZeneca, Boryung, Eli Lilly, Hanmi, Novartis, Roche–Genentech, Sanofi, and Takeda; and speaker's bureau participation in Takeda. WPM reports participation in GlaxoSmithKline, Ono Pharmaceuticals, Apotex, and Viatris advisory board outside the submitted work. J-YB reports grants or research support from AstraZeneca, Bayer, Bristol Myers Squibb, Deciphera, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, PharmaMar, and Roche; has an advisory or board member role in Innate Pharma; and receives honorarium from Bayer, Deciphera, Novartis, and Roche. DCC reports being a consultant for Amphivena Therapeutics, HUYA Bioscience, Nektar Therapeutics, Pfizer, PureTech, and Werewolf. AG is a principal investigator or sub-investigator in clinical trials for AbbVie, Adaptimmune, Aduro Biotech, Agios Pharmaceuticals, Amgen, arGEN-X BVBA, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca, Aveo, Basilea Pharmaceutica International, Bayer Healthcare, BBB Technologies BV, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Celgene, Chugai Pharmaceutical, Clovis Oncology, Cullinan Apollo, Daiichi Sankyo, Debiopharm, Eisai, Eli Lilly, Exelixis, Faron Pharmaceuticals, Forma Therapeutics, GamaMabs, Genentech, GlaxoSmithKline, H3 Biomedicine, Hoffmann-La Roche, ImCheck Therapeutics, Innate Pharma, Institut de Recherche Pierre Fabre, Iris Servier, Janssen-Cilag, Janssen Research Foundation, Kura Oncology, Kyowa Kirin Pharmaceutical Development, Lilly France, Loxo Oncology, Lytix Biopharma AS, Medicament, MedImmune, Menarini Ricerche, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Molecular Partners, Merck Sharp & Dohme-Chibret, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology NV, Oncoethix, Oncopeptides, Orion Pharma, Ose Pharma, Pfizer, PharmaMar, Pierre Fabre, Roche, Sanofi Aventis, Seattle Genetics, Sotio, Syros Pharmaceuticals, Taiho Pharma, Tesaro, and Xencor; receives research grants from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Janssen-Cilag, Merck, Novartis, Onxeo, Pfizer, Roche, and Sanofi; and receives non-financial support (drug supplied) from AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, MedImmune, Merck, NH TherAguix, Onxeo, Pfizer, and Roche. DP reports an advisory or board member role in Astellas, AstraZeneca, Merck, Pfizer, and Sanofi; receives honorarium from Bristol Myers Squibb, Ipsen, Janssen, and Merck Sharp & Dohme; and receives travel and accommodation support from AstraZeneca, Janssen, and Pfizer. AB is an employee of Novartis and reports stock ownership in Novartis. PB is an employee of Novartis and reports stock ownership in Novartis and GlaxoSmithKline. PI is an employee of Novartis and reports stock ownership in Novartis. EG is a former employee of Novartis and reports stock ownership in Novartis and Innovent Biologics. VS reports grants or research support from AbbVie, Agensys, Alfasigma, Altum, Amgen, Bayer, Berghealth, Blueprint Medicines, Boston Biomedical, Boston Pharmaceuticals, D3 Pharma, Dragonfly Therapeutics, Exelixis, Fujifilm, Idera Pharmaceuticals, Incyte, Inhibrx, Loxo Oncology, MedImmune, MultiVir, National Comprehensive Cancer Network, NCI-Cancer Therapy Evaluation Program, Novartis, Pfizer, PharmaMar, Takeda, The University of Texas MD Anderson Cancer Center, and Turning Point Therapeutics; has an advisory or board member role in Eli Lilly, Helsinn, Incyte, Loxo Oncology, MedImmune, Novartis, QED Therapeutics, and R-Pharma US; is an Andrew Sabin Family Foundation Fellow at The University of Texas MD Anderson Cancer Center; receives financial support from The Jacquelyn A Brady Fund; receives the US National Institutes of Health grant R01CA242845; and is affiliated with University of Texas MD Anderson Cancer Center, which receives the US National Institutes of Health support grant P30 CA016672. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Effective treatments for patients with cholangiocarcinoma after progression on gemcitabine-based chemotherapy are urgently needed. Mutations in the BRAF gene have been found in 5% of biliary tract tumours. The combination of dabrafenib and trametinib has shown activity in several BRAF V600E -mutated cancers. We aimed to assess the activity and safety of dabrafenib and trametinib combination therapy in patients with BRAF V600E -mutated biliary tract cancer., Methods: This study is part of an ongoing, phase 2, open-label, single-arm, multicentre, Rare Oncology Agnostic Research (ROAR) basket trial in patients with BRAF V600E -mutated rare cancers. Patients were eligible for the biliary tract cancer cohort if they were aged 18 years or older, had BRAF V600E -mutated, unresectable, metastatic, locally advanced, or recurrent biliary tract cancer, an Eastern Cooperative Oncology Group performance status of 0-2, and had received previous systemic treatment. All patients were treated with oral dabrafenib 150 mg twice daily and oral trametinib 2 mg once daily until disease progression or intolerance of treatment. The primary endpoint was the overall response rate, which was determined by Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat evaluable population, which comprised all enrolled patients regardless of receiving treatment who were evaluable (ie, had progression, began a new anticancer treatment, withdrew consent, died, had stable disease for 6 weeks or longer, or had two or more post-baseline assessments). The ROAR trial is registered with ClinicalTrials.gov, NCT02034110. These results are based on an interim analysis; the study is active but not recruiting., Findings: Between March 12, 2014, and July 18, 2018, 43 patients with BRAF V600E -mutated biliary tract cancer were enrolled to the study and were evaluable. Median follow-up was 10 months (IQR 6-15). An investigator-assessed overall response was achieved by 22 (51%, 95% CI 36-67) of 43 patients. An independent reviewer-assessed overall response was achieved by 20 (47%, 95% CI 31-62) of 43 patients. The most common grade 3 or worse adverse event was increased γ-glutamyltransferase in five (12%) patients. 17 (40%) patients had serious adverse events and nine (21%) had treatment-related serious adverse events, the most frequent of which was pyrexia (eight [19%]). No treatment-related deaths were reported., Interpretation: Dabrafenib plus trametinib combination treatment showed promising activity in patients with BRAF V600E -mutated biliary tract cancer, with a manageable safety profile. Routine testing for BRAF V600E mutations should be considered in patients with biliary tract cancer., Funding: GlaxoSmithKline and Novartis., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

CNS metastases are the most common cause of malignant brain tumours in adults. Historically, patients with brain metastases have been excluded from most clinical trials, but their inclusion is now becoming more common. The medical literature is difficult to interpret because of substantial variation in the response and progression criteria used across clinical trials. The Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group is an international, multidisciplinary effort to develop standard response and progression criteria for use in clinical trials of treatment for brain metastases. Previous efforts have focused on aspects of trial design, such as patient population, variations in existing response and progression criteria, and challenges when incorporating neurological, neuro-cognitive, and quality-of-life endpoints into trials of patients with brain metastases. Here, we present our recommendations for standard response and progression criteria for the assessment of brain metastases in clinical trials. The proposed criteria will hopefully facilitate the development of novel approaches to this difficult problem by providing more uniformity in the assessment of CNS metastases across trials., (Copyright © 2015 Elsevier Ltd. All rights reserved.)