Periodic Reporting for period 6 - 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: 2024-01-01 to 2024-12-31
About 50% of non-small cell lung cancer (NSCLC) patients have metastatic disease at initial diagnosis, which limits their treatment options and, consequently, the 5-year survival rate (15%). Immune checkpoint inhibitors (ICI), either alone or in combination with chemotherapy, have become standard of care (SOC) for most good performance status patients. However, most patients will not obtain long-term benefit, and new treatment strategies are therefore still needed. Before this project, we demonstrated clinical safety of the tumour-selective immunocytokine L19-IL2, consisting of the anti-EDB scFv L19 antibody coupled to IL2, combined with (stereotactic ablative) radiotherapy (RT).
Within this randomized phase II ImmunoSABR trial, the combination of RT with or without the immunocytokine L19-IL2 with or without ICI has been tested as 1st, 2nd or 3rd line treatment in stage IV NSCLC patients. This bi-modal and triple treatment approach was based on the direct cytotoxic effect of radiotherapy, the tumour selective immunocytokine L19-IL2, the abscopal effect observed distant from the irradiated metastatic site(s), and the memory effect.
The multicentric, randomised controlled open-label phase II clinical trial (NCT03705403) was carried out to test the hypothesis that the combination of RT and L19-IL2 increases the progression free survival (PFS) in patients with limited metastatic NSCLC.
ImmunoSABR’s consortium consists of 14 participating centres located in 6 countries. Primary endpoint was PFS at 1.5 years based, and secondary endpoints were overall survival, toxicity, quality of life and abscopal response. Associative biomarker studies, blood and tumour cell immune monitoring, CT-based radiomics, stool collection, iRECIST, and tumour growth rate have been performed.
Patients were stratified according to their metastatic load (oligo-metastatic: up to 5, or poly-metastatic: 6 to 10 metastases). Patients have been randomised by minimisation to the experimental (E-arm) or the control arm (C-arm). The C-arm received SOC, according to the local protocol. E-arm oligo-metastatic patients received RT to all lesions followed by L19-IL2 therapy; radiotherapy for poly-metastatic patients consisted of irradiation of at least one (symptomatic) to a maximum of 5 lesions (including ICI in both arms if this is the SOC).
Within this randomized phase II ImmunoSABR trial, the combination of RT with or without the immunocytokine L19-IL2 with or without ICI has been tested as 1st, 2nd or 3rd line treatment in stage IV NSCLC patients. This bi-modal and triple treatment approach was based on the direct cytotoxic effect of radiotherapy, the tumour selective immunocytokine L19-IL2, the abscopal effect observed distant from the irradiated metastatic site(s), and the memory effect.
The multicentric, randomised controlled open-label phase II clinical trial (NCT03705403) was carried out to test the hypothesis that the combination of RT and L19-IL2 increases the progression free survival (PFS) in patients with limited metastatic NSCLC.
ImmunoSABR’s consortium consists of 14 participating centres located in 6 countries. Primary endpoint was PFS at 1.5 years based, and secondary endpoints were overall survival, toxicity, quality of life and abscopal response. Associative biomarker studies, blood and tumour cell immune monitoring, CT-based radiomics, stool collection, iRECIST, and tumour growth rate have been performed.
Patients were stratified according to their metastatic load (oligo-metastatic: up to 5, or poly-metastatic: 6 to 10 metastases). Patients have been randomised by minimisation to the experimental (E-arm) or the control arm (C-arm). The C-arm received SOC, according to the local protocol. E-arm oligo-metastatic patients received RT to all lesions followed by L19-IL2 therapy; radiotherapy for poly-metastatic patients consisted of irradiation of at least one (symptomatic) to a maximum of 5 lesions (including ICI in both arms if this is the SOC).
In this European Commission-funded project, we successfully completed a multi-center Phase 2 clinical trial involving 88 patients with metastatic non-small cell lung cancer. Participants were randomly assigned to receive either the current standard treatment or an experimental approach that combined radiotherapy with a targeted immunotherapy (L19-IL2), with or without additional immune checkpoint inhibitors. Beyond the clinical trial itself, the project led to significant scientific and technological advances. So far, it has resulted in two patents, 12 peer-reviewed publications (published or accepted), with five more in progress. We also developed a new therapeutic concept that combines radiotherapy with two types of immunotherapy: one that blocks regulatory T cells and another that activates CD8+ T cells, enhancing the body’s immune response against cancer. Seven innovations from the project have been highlighted in the EU Innovation Radar. Notably, two patents were filed—one for a technique called “lymphocyte-sparing radiotherapy,” which has already been licensed to a commercial partner outside the consortium. The project also generated valuable research resources, including a biobank with patient blood and stool samples, as well as curated sequential medical imaging. Early findings from these materials are promising. In summary, this project not only advanced clinical cancer treatment but also contributed to cutting-edge innovation with potential real-world impact. The final analysis by treatment arm will be conducted following data curation, starting from July 2025.
Immune checkpoint inhibitors revolutionized the therapy for patients with metastatic NSCLC, but only a minority of patients obtain long-term benefit. The large majority of therapies for metastatic lung cancer patients are palliative and have disappointing survival rates. IMMUNOSABR has designed a powerful bi/tri-modal treatment strategy that has major clinical potential to improve survival. A Phase I study has been completed with very promising results. The randomised Phase II study is the first randomised study that intended to generate a reliable evidence base to change clinical practice for patients with limited metastatic NSCLC, by providing additional treatment options besides ICI to change clinical practice from palliative to curative treatment for additional patients. There have been several non-randomised studies that demonstrate that Stereotactic Ablative Radiotherapy (SABR) for patients with limited metastatic disease is safe and effective, with local control rates of about 80%. The main goal is to prolong PFS 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 are 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 used this innovative approach in metastatic diseases for the development of a powerful strategy with curative intent. IMMUNOSABR aimed to prolong survival (increase PFS) with an acceptable toxicity profile in patients with limited tumour metastases. IMMUNOSABR intended to 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. After multiple challenging factors (such as the COVID-19pandemy ) IMMUNOSABR had to close recruitment after enrolling 88 patients instead of the intended 126 patients. Several innovations developed through this project will be adopted by companies for clinical implementation, ultimately improving patient outcomes and contributing to the growth of Europe’s knowledge-based economy.
The large majority of patients with metastatic cancer are 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 used this innovative approach in metastatic diseases for the development of a powerful strategy with curative intent. IMMUNOSABR aimed to prolong survival (increase PFS) with an acceptable toxicity profile in patients with limited tumour metastases. IMMUNOSABR intended to 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. After multiple challenging factors (such as the COVID-19pandemy ) IMMUNOSABR had to close recruitment after enrolling 88 patients instead of the intended 126 patients. Several innovations developed through this project will be adopted by companies for clinical implementation, ultimately improving patient outcomes and contributing to the growth of Europe’s knowledge-based economy.