Επιστημονικά Ογκολογικά Νέα

Axumin is a radiopharmaceutical agent for functional imaging of prostate cancer recurrence

In February 2019, NICE published a Medtech innovation briefing [MIB172] on Axumin for functional imaging of prostate cancer recurrence.The technology described in the briefing is Axumin, a radiopharmaceutical agent. It is intended for use in positron emission tomography (PET) to detect suspected prostate cancer recurrence in patients who have elevated prostate-specific antigen (PSA) levels after primary curative treatment. It is currently the only licensed PET tracer indicated for use in recurrent prostate cancer.

The innovative aspects are that it is a prostate cancer-specific PET tracer with a novel mechanism of action based on amino acid transport. Its longer half-life and shorter uptake period may allow use in more patients with suspected prostate cancer recurrence compared with other PET tracers.

Axumin (Blue Earth Diagnostics Ltd) is given as an intravenous injection in the arm 3 to 5 minutes before a PET scan. A CT scan is used to provide information about the patient anatomy and the combined scan is termed PET/CT.

Axumin contains the active ingredient ¹⁸F‑fluciclovine (anti-1-amino-3-¹⁸F-fluorocyclobutane-1-carboxylic acid or FACBC). This is a radiolabelled synthetic amino acid that is taken up into cells by transporters (LAT‑1 and ASCT2) known to be present in high numbers on the surface of prostate cancer cells. Once inside the cancer cells, it emits radiation that is detected on the PET scan, with the aim of identifying local and distant areas of recurrence. The preferential uptake of the tracer into prostate cancer cells compared with the surrounding non-cancerous tissue enables cancerous areas to be reliably located.

Axumin is the only PET tracer currently licensed for clinical use in recurrent prostate cancer. Prostate-specific membrane antigen (⁶⁸Ga‑PSMA) and choline-based (¹¹C- and ¹⁸F‑labelled) PET tracers are available only on a special licence basis or for use in research. Expert advice indicates that these tracers are increasingly used in UK practice and that ¹⁸F‑choline PET/CT is currently the only scan commissioned by NHS England in the national PET/CT tender. Axumin is designed to more effectively identify recurrent disease across a wide range of PSA levels compared with standard-of-care imaging (pelvic CT or MRI and bone scans). These lack the sensitivity and specificity to detect prostate cancer when PSA levels are low. The short uptake period for Axumin allows scans to be done 3 to 5 minutes after administration, compared with alternative PET tracers, which may need about 1 hour for optimal tracer uptake. Also, the technology’s shelf life of 7 to 10 hours may offer potential for wider use compared with ¹¹C‑choline. This has a half-life of 20 minutes, meaning that it can only be done in PET centres with on-site cyclotron and radiopharmacy facilities.

The intended place in therapy is in addition to bone scans or MRI to detect suspected prostate cancer recurrence in adults. It may be used as an alternative to choline or prostate-specific membrane antigen PET/CT in centres where these scans are available.

The main points from the evidence summarised in the briefing are from 1 meta-analysis and 5 studies (2 randomised trials and 3 non-randomised observational studies) including more than 1200 men with suspected prostate cancer recurrence. The evidence reported that Axumin PET/CT detected prostate cancer recurrence with good diagnostic accuracy and frequently led to changes in patients’ management plans.

Key uncertainties around the evidence or technology are the lack of comparative studies with other PET tracers. There are no head-to-head studies comparing Axumin with ¹⁸F‑choline. Also, the effects of Axumin PET on earlier diagnosis and on quality of life have not been evaluated.

The per-patient cost for a single dose of Axumin tracer is 950 GBP (excluding VAT), plus transport costs estimated at 50 GBP to 250 GBP per shipment. The resource impact would be a cost increase per scan. The technology has the potential to free up resources if it reduces the number of imaging tests needed to confirm diagnosis or if fewer patients are referred for radiotherapy.

Source: https://www.esmo.org/Oncology-News/

Approval is based on results from the EORTC1325/KEYNOTE 054 study

On 15 February 2019, the US Food and Drug Administration (FDA) approved pembrolizumab (KEYTRUDA, Merck) for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.
Approval was based on EORTC1325/KEYNOTE‑054 (NCT02362594), a randomised, double-blind, placebo-controlled, trial in 1019 patients with completely resected, stage IIIA (>1 mm lymph node metastasis), IIIB or IIIC melanoma (AJCC 7th ed). Patients with mucosal or ocular melanoma were not eligible. Patients were randomly allocated (1:1) to receive pembrolizumab 200 mg every three weeks or placebo for up to 1 year until disease recurrence or unacceptable toxicity. Enrolment required complete resection of melanoma with negative margins, lymph node dissection, and completion of radiotherapy, if indicated, within 13 weeks prior to starting treatment.

The primary efficacy outcome measure was recurrence‑free survival (RFS), as assessed by investigators per RECIST version 1.1. The RFS was defined as the time between the date of randomisation and first recurrence (local, regional, or distant metastasis) or death from any cause, whichever occurred first. Patients receiving pembrolizumab experienced fewer recurrences/deaths, 26% (n=135), compared with 43% (n=216) on the placebo arm (hazard ratio 0.57; 95% CI: 0.46, 0.70; p < 0.001). The RFS benefit for pembrolizumab compared with placebo was observed regardless of tumour PD-L1 expression. Median RFS was 20.4 months in the placebo arm and not reached for those receiving pembrolizumab.

Seventy-six percent of patients received pembrolizumab for 6 months or longer. Pembrolizumab was discontinued for adverse reactions in 14% of patients. The most common adverse reactions (reported in at least 10% of pembrolizumab-treated patients) were diarrhea, pruritus, nausea, arthralgia, hypothyroidism, cough, rash, asthenia, influenza-like illness, weight loss, and hyperthyroidism.

The recommended pembrolizumab dose and schedule for the adjuvant treatment of melanoma is 200 mg administered as an i.v. infusion over 30 minutes every 3 weeks until disease recurrence or unacceptable toxicity, for a maximum of 1 year.

Full prescribing information for KEYTRUDA is available here.

FDA granted this application standard review and Orphan Designation.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System.

Sourch: https://www.esmo.org/Oncology-News/

Life Time and RESTORE among shortlisted projects

The European Commission announced on 8 February that has selected 6 research projects in areas from health and energy to artificial intelligence and cultural heritage to compete to become one of its next billion EUR flagship science initiatives. On 1 March 2019, each team will receive €1 million to develop a detailed feasibility proposal over the next year. Up to three will be chosen to become fully fledged initiatives to launch in 2021.

The European Commission already supports three scientific mega-projects known as Future and Emerging Technologies Flagships which are each funded to the tune of around €1 billion over 10 years. The high-profile projects aim to make paradigm-shifting advances in their field — by bringing together expertise and funding from scores of academic and industrial sources across the continent.

Among the 6 newly shortlisted initiatives there is a project that would explore how artificial intelligence can enhance human capabilities, one to hasten clinical availability of cell and gene therapies, and a personalised medicine initiative.

One of the two health projects that were shortlisted, German-led consortium LifeTime, would create innovative platforms for personalised medicine. The platforms would measure how the molecular functions of individual cells and tissues change during the course of a disease and treatment, and use artificial intelligence and machine learning would reveal significant patterns in the data that might be biologically meaningful. LifeTime also proposes to develop tailored organoids that can model an individual patient’s disease.

Single-cell technologies will be applied to experimental model systems such as organoids. Combined with the genome editing tool CRISPR/Cas as well as state-of-the-art microscopy, these models will help to understand how cells stay healthy or progress towards disease and react to therapeutics. Importantly, LifeTime scientists will also develop computational strategies such as powerful machine-learning and artificial intelligence methods that help to understand molecular mechanisms and predict the future of a patient’s tissue or even means to steer the tissue towards health. This strategy is expected to improve early diagnoses and intervention, predict the course of a disease, identify new drug targets and select the most effective therapies for individual patients.

LifeTime is jointly coordinated by the Max Delbrück Center for Molecular Medicine in the Helmholtz Association in Berlin and the Institut Curie in Paris. Currently the LifeTime consortium consists of over 60 leading single-cell biologists, computer scientists, mathematicians, clinicians, pathologists, imaging experts, and physicists from over 50 European institutions in 18 countries. They are pioneers in their disciplines, working towards a common vision of future medicine, and would like LifeTime to be an open endeavour that will attract new talents and integrate all scientists in Europe who can make a significant contribution. Their unique collective network will transcend institutional boundaries and improve the overall infrastructure for the life sciences in Europe, with a focus on training for the next generation of scientists.

Both the Helmholtz Association of German Research Centres and the French National Center for Scientific Research CNRS – two of the biggest science organisations in Europe – have pledged their strong support. Furthermore, the consortium is endorsed by Science Academies such as the German National Academy of Sciences Leopoldina, the French Academy of Sciences, the Royal Society and the Royal Netherlands Academy of Sciences and Arts and the EU-life Alliance.

The LifeTime consortium will build on the achievements of the Human Cell Atlas. However, LifeTime proposes to go far beyond; many technologies at the centre of LifeTime are key European research strengths that the Flagship could boost. These include single-cell technologies combined with advanced imaging, artificial intelligence and patient-matched organoids, or organ-on-a-chip disease models to study the progression of an illness and develop novel therapeutics. New mathematical and computational tools will be required to understand the movement and relationships of those cells.

Participating institutions are Helmholtz Association, CNRS, Institute of Molecular Biotechnology, Research Center for Molecular Medicine of the Austrian Academy of Sciences, VIB-KU Leuven, Friedrich Miescher Institute for Biomedical Research, University of Basel, University of Zurich, Central European Institute of Technology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Institute for  Molecular Genetics, German Cancer Research Center, Max Delbrück Center for Molecular Medicine, German Center for Neurodegenerative Diseases, Helmholtz Zentrum München, Max Planck Institute for Evolutionary Anthropology, Helmholtz Institute of RNA-based Infection Research, Saarland University, Technical University Munich, University of Würzburg, Biotech Research & Innovation Centre, Interdisciplinary Nanoscience Center, University of Copenhagen, Centre for Genomic Regulation, Institut Curie, Université de Montpellier, Inserm, Université Toulouse III – Paul Sabatier, École nationale supérieure des mines de Paris, Institute for Molecular Medicine Finland, The Biomedical Research Foundation, Academy of Athens, Weizmann Institute of Science, Hebrew University, Sapienza – University of Rome, Instituto Nazionale Genetica Molecolare, University of Napoli, University of Padua, University of Milan, European Institute of Oncology, Netherlands Cancer Institute, Radboud University, University Medical Center Utrecht, Hubrecht Institute, Instituto Gulbenkian de Ciência, Institute of Bioorganic Chemistry of the Polish Academy of Sciences, Romanian Center for Systems Immunology, Karolinska Institute, MRC Human Genetics Unit, University of Edinburgh, Wellcome Sanger Institute, The Babraham Institute, European Molecular Biology Laboratory – European Bioinformatics Institute.

The other health project, RESTORE, led from the Berlin university hospital Charité, proposes developing the multiple steps needed to speed the translation of advanced cell and gene therapies to the clinic. These treatments hold great promise for common diseases such as cancer and diabetes, but are notoriously complicated and expensive to bring to the market.

Large-Scale-Research Initiative RESTORE will promote groundbreaking research, nurture innovative companies and engage the public; its concept is supported by a broad international and interdisciplinary community of stakeholders, who united behind the mission to make patient-centred value at high ethical and quality standards a reality.

The implementation of newly developed Advanced Therapy Medicinal Products and Biologised Medical Devices in clinical routine holds tremendous promise and is the unifying goal of the RESTORE initiative. It is formed by eminent leaders from European academia, clinics and industry.

The RESTORE core team are world leaders from basic and clinical research and biotech industry: Charité – Universitätsmedizin Berlin (Germany), University of Zurich (Switzerland), Cell and Gene Therapy Catapult (United Kingdom), TissUse GmbH (Germany), Pluristem Ltd (Israel), Miltenyi Biotec GmbH (Germany), INSERM – Institut National de la Santé et de la Recherche (France), Innovation Acta S.r.l. (Italy), Fondazione Telethon Milan (Italy) and University Minho (Portugal). More than 250 stakeholders from basic and clinical science, industry, non-profit organisations and patient advocates throughout Europe and beyond have pledged support for RESTORE’s urgent mission, underlining the potential of Advanced Therapies for science, the economy and public health.

Source: https://www.esmo.org/Oncology-News/

Increase in accrual capacity and the quality standards

On 11 February 2019, Gustave Roussy  and Institut Bergonié announced that they have signed an agreement intended to widen the range of therapeutic innovation for cancer patients and to increase even more their accrual capacity and their quality standards in the conduction of early phase trials.

The two institutions thus formalise cooperation and partnership axes allowing the development of knowledge in oncology in the context of early phase clinical research, onco-immunology as well as in strategic therapeutic areas such as thoracic cancers and rare tumours.

Among the strategic objectives of the partnership agreement:

• The development of clinical research – in particular early phase trials, in order to offer patients the widest possible portfolio of innovative therapeutics while guaranteeing industrial promoters a simplified procedure for signing agreements, a broad potential for inclusion and the best data quality standards.
• The development of precision medicine through common molecular tumour boards by developing the portfolio of clinical trials guided by the genomic and immunological profiling of tumours.
• Translational research: essential bridge between basic research and clinical research to accelerate innovation for the benefit of patients, particularly in the field of onco-immunology (mechanisms of sensitivity and resistance) but also rare tumours with the use of tools focusing on artificial intelligence.

Professor François-Xavier Mahon, general director of Institut Bergonié said in accompanied press release: “On behalf of the Institut Bergonié, I am particularly proud of the formalization of this long-standing collaboration between Institut Bergonié and GustaveRoussy. This partnership will lead to the constitution of a major strategic axis that will make the Institut Bergonié-Gustave Roussy pole, a European model of innovation in oncology and early phase trials.”

Professor Alexander Eggermont, General Director of Gustave Roussy said in press release: “This collaboration between our two institutes is patient-focused and aims, thanks to a synergy between our clinical research teams to facilitate access of our patients to innovative therapies. It is a concrete and structural response to the need to bring together our scientific and medical forces to address the problems that pose cancer.”

Professor Antoine Italiano, Head of Early Phase Trials Unit, Institut Bergonié said in press release: “I am glad to announce our latest partnership with Gustave Roussy. This agreement will increase the capacity of our both institutions to implement early phase clinical trials through a fast track process allowing contract signatures within an unprecedented short time and with an ultimate goal of making sure the accrual target and the data collected meets the highest quality, integrity and reliability standards to industrial sponsors.”

Dr Christophe MASSARD, Head of DITEP said in press release: “The agreement between Institut Bergonié and Gustave Roussy allows us to create an unique network of expertise in France the field of oncology early-phase clinical studies, precision medicine and immunotherapy. This allows us to increase access to early phase trials for cancer patients.”

Institut Bergonié is labelled by the French National Cancer Institute as a reference centre for early-phase clinical trials (CLIP2) in oncology and a national referral centre for the diagnosis and management of patients with sarcomas. Between 2015 and 2018, the early phase clinical trial unit led by Professor Antoine Italiano enabled more than 3,000 patients with advanced cancer to benefit from an early phase clinical trial, making the Institut Bergonié a European leader in the field of therapeutic innovation.

The Early Phase Clinical Trials Unit supports industry-sponsored research in patients with all types of solid tumours and haematological cancers. The clinical space comprising of 10 beds is highly rated by patients as delivering quality care in a comfortable environment.

There is a dedicated interventional radiology unit co-located on the ward which enables high quality sequential tumour biopsies with record keeping, to demonstrate custodianship of the samples (conformity > 92%).

A team of experienced investigators, research nurses and clinical fellows work across the broad portfolio of studies, providing expertise in patient management and protocol compliance. By taking a systematic approach to data capture, data entry is highly compliant and the team is trialling real time data entry.

As a department dedicated to phase I clinical trials at Gustave Roussy, DITEP’s mission is to offer patients in therapeutic failure access to innovative molecules and to accelerate the development of new treatments in oncology. DITEP is one of the largest early testing centres in the world. Created in September 2013, it is labelled by the French National Cancer Institute as an Early Phase Center (CLIP2). The activity of DITEP is led by a multidisciplinary expert committee in medical oncology, immunotherapy, radiotherapy, haematology, imaging, biology and pathology. In 2017, more than 1250 patients were participating in an early phase trial or molecular medicine programme in DITEP, including 460 patients in a phase I trial. Gustave Roussy, the first centre for the fight against cancer in Europe, is a worldwide recognised comprehensive cancer centre dedicated to patient care and clinical research. It brings together 3,100 professionals whose missions are care, research and teaching.

Source: https://www.esmo.org/Oncology-News/

Evaluation of changes in the tumour immune microenvironment

Two letters published on 11 February 2019 in the Nature Medicine reveal feasibility, safety and immunobiological effects of neoadjuvant PD-1 blockade in patients with glioblastoma, while the third letter provides perspective on immune and genomic correlates of response to anti-PD-1 therapy in glioblastoma.

In first letter Ignacio Melero of the Centro de Investigación Biomedica en Red de Oncología, Madrid, Instituto de Investigación Sanitaria de Navarra, Pamplona, and Clínica Universidad de Navarra, Pamplona, Spain and co-authors reported the results of neoadjuvant PD-1 blockade in patients undergoing surgery for glioblastoma from a single-arm phase II clinical trial. In the study, they tested a presurgical dose of nivolumab followed by postsurgical nivolumab until disease progression or unacceptable toxicity in 30 patients. In these patients, 27 salvage surgeries were performed for recurrent cases and primary surgery for newly diagnosed patients in 3 cases.

Availability of tumour tissue pre- and post-nivolumab dosing and from additional patients who did not receive nivolumab allowed the evaluation of changes in the tumour immune microenvironment using multiple molecular and cellular analyses.

Neoadjuvant nivolumab resulted in enhanced expression of chemokine transcripts, higher immune cell infiltration and augmented TCR clonal diversity among tumour infiltrating T lymphocytes, supporting a local immunomodulatory effect of treatment.

Although no obvious clinical benefit was substantiated following salvage surgery, two of the three patients treated with nivolumab before and after primary surgery remain alive 33 and 28 months later.

In the second letter Timothy F. Cloughesy and Robert M. Prins of the David Geffen School of Medicine and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA reported the results from a randomised, multi-institution clinical trial conducted by The Ivy Foundation Early Phase Clinical Trials Consortium in order to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma.

Patients who were randomised to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomised to receive adjuvant, post-surgical PD-1 blockade alone.

Neoadjuvant PD-1 blockade was associated with upregulation of T cell– and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumour, which was not seen in patients that received adjuvant therapy alone. Focal induction of PD-L1 in the tumour microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting.

The authors concluded that the findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response.

In third letter, Fabio M. Iwamoto of the Columbia University Irving Medical Center, New York, Adam M. Sonabend of the Northwestern University Feinberg School of Medicine, Chicago, and Raul Rabadan of the Columbia University, New York, USA and colleagues report molecular determinants of immunotherapeutic response in glioblastoma. They longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors, nivolumab or pembrolizumab.

Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of PTPN11 and BRAF that are MAPK pathway alterations in responders.

Responsive tumours were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumour microenvironment profiles.

The authors concluded that clinical response to anti-PD-1 immunotherapy in glioblastoma is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumour clonal evolution during treatment.

The European Medicines Agency has released two bioequivalence guidance for public consultation:

• Palbociclib hard capsule 75 mg, 100 mg and 125 mg (pdf)
• Alectinib hard capsule 150 mg (pdf)

Source: https://www.esmo.org/Oncology-News/