Periodic Reporting for period 5 - 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)
Okres sprawozdawczy: 2022-07-01 do 2023-12-31
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. We previously 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 phase II ImmunoSABR trial, the combination of RT with or without ICI and the immunocytokine L19-IL2 will be tested as 1st, 2nd or 3rd line treatment in stage IV NSCLC patients. This bi-modal and triple treatment approach is 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.
This investigator initiated, multicentric, randomised controlled open-label phase II clinical trial (NCT03705403) will test the hypothesis that the combination of RT and L19-IL2 increases the progression free survival (PFS) in patients with limited metastatic NSCLC. Patients will be stratified according to their metastatic load (oligo-metastatic: up to 5, or poly-metastatic: 6 to 10 metastases). Patients will be randomised by minimisation to the experimental (E-arm) or the control arm (C-arm). The C-arm will receive SOC, according to the local protocol. E-arm oligo-metastatic patients will receive RT to all lesions followed by L19-IL2 therapy; radiotherapy for poly-metastatic patients consists of irradiation of at least one (symptomatic) to a maximum of 5 lesions (including ICI in both arms if this is the SOC).
ImmunoSABR consists of 15 participating centres located in 6 countries. Primary endpoint is PFS at 1.5 years based on blinded radiological review, and secondary endpoints are 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 will be performed. The first results are expected end 2024.
Within this phase II ImmunoSABR trial, the combination of RT with or without ICI and the immunocytokine L19-IL2 will be tested as 1st, 2nd or 3rd line treatment in stage IV NSCLC patients. This bi-modal and triple treatment approach is 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.
This investigator initiated, multicentric, randomised controlled open-label phase II clinical trial (NCT03705403) will test the hypothesis that the combination of RT and L19-IL2 increases the progression free survival (PFS) in patients with limited metastatic NSCLC. Patients will be stratified according to their metastatic load (oligo-metastatic: up to 5, or poly-metastatic: 6 to 10 metastases). Patients will be randomised by minimisation to the experimental (E-arm) or the control arm (C-arm). The C-arm will receive SOC, according to the local protocol. E-arm oligo-metastatic patients will receive RT to all lesions followed by L19-IL2 therapy; radiotherapy for poly-metastatic patients consists of irradiation of at least one (symptomatic) to a maximum of 5 lesions (including ICI in both arms if this is the SOC).
ImmunoSABR consists of 15 participating centres located in 6 countries. Primary endpoint is PFS at 1.5 years based on blinded radiological review, and secondary endpoints are 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 will be performed. The first results are expected end 2024.
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 Medical Ethical Committees accepted the clinical trial documents in different countries. We started with the recruitment of patients in January 2020. Trial was active at 15 sites; Maastricht, Amsterdam, Nijmegen, Rotterdam, Leuven, Brussel, Gent, Antwerpen, Lille, Montpellier, Dresden, Heidelberg, Londen, Tubbingen and Rome. Recruitment was closed December 2023 due to poor enrollment and the decision of the DSMB to stop recruitment.
The scan protocols for CT and PET were finalized.
We finalized the medical protocol. The Medical Ethical Committees accepted the clinical trial documents in different countries. We started with the recruitment of patients in January 2020. Trial was active at 15 sites; Maastricht, Amsterdam, Nijmegen, Rotterdam, Leuven, Brussel, Gent, Antwerpen, Lille, Montpellier, Dresden, Heidelberg, Londen, Tubbingen and Rome. Recruitment was closed December 2023 due to poor enrollment and the decision of the DSMB to stop recruitment.
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%. Importantly, these studies also suggest that the disease course changes, as we observe 2 year PFS in ~20% of SABR-treated patients. 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 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 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-19 situation) IMMUNOSABR had to close recruitment early after enrolling 88 patients instead of the intended 126 patients.
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 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-19 situation) IMMUNOSABR had to close recruitment early after enrolling 88 patients instead of the intended 126 patients.