Kate Wheeler & Guy Blanchard
The International Society of Paediatric Oncology, European Neuroblastoma (SIOPEN), is the grouping of neuroblastoma clinicians from Europe and other affiliated countries. Their major yearly meeting is the Autumn AGM, this year hosted by Dr Isaac Yaniv and Dr Shifra Ash in Jerusalem. Here we report on the major themes of the meeting, focusing on current and recent clinical trials run within SIOPEN.
SIOPEN high risk trial
Until earlier this year, UK children with high risk neuroblastoma would typically receive their treatment whilst enrolled in the SIOPEN high risk trial (HRNBL1). Children were given the best available treatment while also being randomised to answer particular treatment questions. The first randomisation, R0, which was closed in 2005, established that G-CSF is beneficial during COJEC high dose induction treatment. The second randomisation, R1, established that BUMEL was better than CEM (Lancet Oncology, 2017, Vol. 18, p. 500) and BUMEL is now the standard high dose treatment. The results of R2 have just been published (Lancet Oncology, 2018, Vol. 19, p. 1617) showing that the addition of subcutaneous IL-2 to immunotherapy with chimeric 14.18 anti-GD2 monoclonal antibody does not improve outcome. So currently giving the antibody alone is considered standard care. The UK’s National Institute for Health and Care Excellence (NICE) have recently agreed a cost with EUSA Pharma to provide this immunotherapy on the NHS, a favourable outcome that Neuroblastoma UK helped bring about (see https://www.neuroblastoma.org.uk/news/2018/7/11/nice-approves-neuroblastoma-drug).
The SIOPEN HRNBL1 trial is now closed and plans are well underway to open a second high risk trial (HRNBL2). France is the international sponsor of the trial, so it will open there first and is likely then to open in the UK in 2020. Dr Martin Elliot (Leeds) will be the UK trial lead. This trial will include a randomisation between single and tandem high dose chemotherapy and a radiotherapy randomisation. Currently, the plan is for each country to be able to choose its induction therapy, either COJEC or N7. Until this trial opens, all children with high risk neuroblastoma in the UK will receive standard treatment which includes anti-GD2 immunotherapy as maintenance treatment.
The high risk trial, one of the most important activities that SIOPEN coordinates, has been able to complete Phase III trial randomisations across Europe on a reasonable time-scale given the rate of accrual of children with neuroblastoma from its many member countries. An impressive 3317 patients were enrolled into the HRNBL 1 Trial. As an aside, we note that the UK’s involvement in SIOPEN is not directly under threat from Brexit, since SIOPEN is a self-organised organization, funded by member countries and not dependent on EU structures or funding.
Summary of selected other early phase trials (listed alphabetically)
1. The BEACON trial for relapsed and refractory patients, coordinated by Lucas Moreno (Madrid), is about to be amended to introduce a randomisation to receive anti-GD2 to its chemotherapies. Juliet Gray (Southampton) will coordinate this amended trial in the UK, with Giuseppe Barone (GOSH) taking over when a new BEACON 2 trial opens.
2. The Cancer Research UK trial for highly personalised CAR T-cell immunotherapy is coordinated by John Anderson (GOSH). CAR T therapy has shown very encouraging results in leukaemia (ALL) and has shown some response in this Phase II trial. Whether it will be as effective against a solid tumour, where tumour cells are more protected from access by white blood T-cells is not yet clear. There is some neurotoxicity with this treatment, but improvements to CAR T-cell methods are in the pipe-line. For the future, treatment options targeting antigens other than GD are being explored.
3. The MINIVAN trial sponsored by Solving Kids Cancer and coordinated by Juliet Gray (Southampton) opened in the UK in July 2018, with 6 patients recruited so far. This early phase trial is for patients with relapsed or refractory neuroblastoma and the treatment is 131-I mIBG, nivolumab (anti PD-1) and immunotherapy (ch14.18/CHO). This trial is only open in the UK at present, but will open in North America and Germany in due course.
4. The VERITAS trial has enrolled two patients in France and is about to open in the UK, coordinated by Mark Gaze and Guy Makin. This trial involves targeted mIBG and high dose chemotherapy, followed by immunotherapy, and is for those HR patients who don’t respond to induction therapy. It is not currently possible to identify at diagnosis the patients that are very likely not to respond to induction therapy, though defining such an ‘ultra-high risk’ group of patients is being worked on. VERITAS is likely to be the route for patients who don’t respond to treatment in the HRNBL2 trial when it opens.
At the AGM, there were also reports on interesting research developments. Angelika Eggert (Berlin) reported that each patient’s primary tumour is likely to contain many different clones of tumour cells with a variety of different mutations and errors. The tumour clones that are resistant or evolve resistance to treatment are usually small clones in the primary tumour and may often not be picked up in primary tumour biopsies.
There was an interesting Tumour Biology session, in which Jan Molenaar (Utrecht) emphasised that there are lots of possible drugable gene targets in neuroblastoma but each target is rare and only found in a small proportion of patients. Drugs against one of the more common targets, a gene called ALK, has been showing disappointing results in the clinic. There is a lot of molecular interest in ATRX/TERT, but no drugs are yet in trial. Other genes such as CDK, p53, MYCN and BCL2 are the subject of urgent research, with known inhibitor drugs, but all of these are having teething issues in Phase I/II trials.
Finding drug synergies must surely be a route to more effective treatment. Indeed, Paul Sondell (Wisconsin) talked about laboratory evidence for a synergy between radiotherapy and immunotherapy, the former enhancing the effectiveness of the latter. This shows promise, but is not yet in clinical trial, with ongoing questions about how to deliver the immunotherapy.
Regarding the role of surgery in neuroblastoma treatment, Sabine Sarnacki (Paris) is working tirelessly on improving surgical techniques and on developing an international unified reporting system for surgical resections .This work is vital to establish facts in order to try and determine how important a complete surgical resection is in high risk neuroblastoma.
The Children’s Oncology Group (COG) is the equivalent organization to SIOPEN in North America. Julie Park (Seattle) provided a snapshot of recent developments from COG. The COG definition of high risk disease is slightly different from SIOPEN’s, so comparing each other’s trials results is not completely straightforward. A COG trial has recently established that tandem transplant does improve outcome in patients who respond well to induction treatment. COG are considering specific chemotherapies to be given alongside immunotherapy at the end of treatment, during the maintenance phase, adding to the heavy burden of treatment. We hope that this will improve outcome rather than just further worsen quality of life and the after-effects of treatment.
The current SIOPEN president is Dominique Valteau-Couanet (Paris), who has done great work including preparing for the opening of the HR2 trial. In the autumn of 2019 Maja Beck-Popovic (Switzerland) will take over as president of SIOPEN. We wish them both well with SIOPEN’s vitally important work improving the lot of children with neuroblastoma.