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Clinical proof of concept through a randomised phase II study: a combination of immunotherapy and stereotactic ablative radiotherapy as a curative treatment for limited metastatic lung cancer

Periodic Reporting for period 2 - IMMUNOSABR (Clinical proof of concept through a randomised phase II study: a combination of immunotherapy and stereotactic ablative radiotherapy as a curative treatment for limited metastatic lung cancer)

Reporting period: 2018-07-01 to 2019-12-31

Metastatic cancer is responsible for 90% of all 8.2 million cancer deaths worldwide. [1] Non-small cell lung cancer (NSCLC) comprises 85% of all lung cancer cases. The majority of patients are diagnosed at the time of metastatic disease (stage IV), when treatment options are limited and 5-year survival rates are drastically reduced (<5% in stage IV). These patients nearly always develop multidrug resistance to many forms of chemotherapy, and targeted agents or immunotherapy work only for small fraction of patients. At present, a significant minority of lung cancer patients benefit from immunotherapy, which remains non-curative when delivered alone. These patients rely mainly on palliative treatment with a combination of systemic cytotoxic chemotherapy, hormonal deprivation, and/or targeted agents. Current treatment strategies, including stereotactic ablative body radiotherapy (SABR), result in a median progression-free survival (PFS) of only 2-12 months. Together, these facts call for a major transformation of the current thinking and therapeutic management of metastatic cancer.
Interleukin-2 (IL2) plays an essential role in the activation phase of both specific and natural immune responses, while inducing tumour regression by stimulating a potent cell-mediated response. To avoid systemic toxicity while delivering IL2 to the tumour, we have added the anti-EDB scFv L19 antibody for a more targeted approach. ImmunoSABR will be a phase II clinical trial in which (1) high precision SABR will be combined with a promising and well tolerated (2) tumour selective immunocytokine (L19-IL2) to form a powerful synergistic immuno-radio-therapeutic strategy. This approach will rely on the direct cytotoxic effect of radiotherapy, the abscopal effect observed distant from the irradiated metastatic site(s), and the tumour selective immunocytokine L19-IL2.
It is a multicentre, randomised controlled open-label phase II clinical trial testing the hypothesis that a combination of SABR (for eligible patients, otherwise standard high-precision radiotherapy - (SAB)R) and immunocytokine L19-IL2 increases the progression-free survival in patients with limited metastatic NSCLC. Patients will be divided into two groups according to their metastatic load (oligo= up to 3 metastases, diffuse= 4 to 10 metastases). After randomisation by minimization, patients will be assigned either to the experimental arm (E-arm) or to the control arm. E-arm patients belonging to the lower metastatic load group will receive SABR to all lesions followed by L19-IL2 therapy and finally standard of care treatment (SOC); the higher metatstatic load group will enter the study after completing first or second line platinum doublet treatment and will receive radiotherapy to at least one (symptomatic) lesion, followed by L19-IL2 and finally SOC. After treatment, there will be a follow-up CT-scan every 12 weeks with and quality of life (QOL) questionnaires for 1.5 years.
Results / conclusion
The main objective of this trial is to test if the combination of (SAB)R and the immunocytokine L19-IL2 will result in improved PFS at 1.5 years after last treatment The secondary objectives will be overall survival, QOL (EORTC QLQ-C30), and abscopal response. In an exploratory analysis, associative biomarker studies (EDB expression on tumour biopsies and blood), immune monitoring on peripheral blood samples and tumour tissue, radiomics on CT and cone beam CT with prospective validation of existing signatures (including hypoxia radiomics signature), non-synonymous mutational burden and stool collection (optional), will be performed.
The immunotherapeutic drug L19-IL2 was produced as a clear, colorless liquid solution containing the fusion protein, purified from conditioned cell culture medium by subsequent chromatographic steps and dissolved. L19-IL2 was obtained through different manufacturing steps, sterile filtration and aseptic filling.

The scan protocols for CT and PET were finalized.

We finalized the medical protocol. The submission of the clinical trial documents to the Medical Ethical Committees will soon take place in different countries. We hope to start with the recruitment of patients at the end of September/begin November.
Cancer metastasis is a complex chronic non communicable disease and responsible for 90% of all 8.2 million cancer-related death in the world 1. Lung cancer is the most common cause of death from cancer worldwide with 1.59 million deaths annually. The large majority of therapies for these patients are palliative and have disappointing survival rates. IMMUNOSABR has designed a powerful bi-modal treatment strategy that has major clinical potential to improve survival. A Phase I study is already ongoing and actively recruiting participants. The randomised Phase II study proposed here will be the first randomised study that generates a reliable evidence base to change clinical practice from palliative to a curative treatment strategy in patients with limited metastatic NSCLC. There have been several non-randomised studies that demonstrate that SABR for patients with limited metastatic disease is safe and effective, with local control rates of about 80%. Importantly, these studies also suggest that the disease course changes, as we observe 2 year progression-free survival in ~20% of SABR-treated patients. The main goal is to prolong progression-free survival with at least 25% in patients with limited metastatic disease, ready for further development in clinical Phase III studies.

The large majority of patients with metastatic cancer is treated with palliative intent. The IMMUNOSABR consortium identifies the ‘limited disease state’ as a unique subset of metastatic cancer patients with ≤10 metastatic sites for which curative treatment regimens such as SABR show very promising results. IMMUNOSABR will use this innovative approach in metastatic diseases for the development of a powerful strategy with curative intent. IMMUNOSABR will aim to prolong survival (increase PFS) with an acceptable toxicity profile in patients with limited tumour metastases. A curative treatment strategy presented by IMMUNOSABR will have major impact on patients and their families as it will improve the quality of life. IMMUNOSABR will have a profound impact on the cancer care by offering a curative treatment strategy for metastatic cancer complemented with a biomarker strategy to identify patients who will benefit from treatment. As patients will be treated according to their diseases state and sensitivity to treatment they will have better health outcomes, avoiding unnecessary healthcare costs and distress for the patient and family.