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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 3 - 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: 2020-01-01 to 2021-06-30

Worldwide, primary lung cancer and breast cancer are the most commonly diagnosed malignancies in 2020, with over 2.2 million new patients. Lung cancer is the most frequently diagnosed cancer and the leading cause of cancer death in males worldwide whereas in females it was the second and third cause, Non-small cell lung cancer (NSCLC) accounts for 80%–90% of all lung cancers. The majority of patients are diagnosed at the time of metastatic disease (stage IV), when treatment options are limited. For those without an oncogenic driver 5-year survival rates are low. These patients rely mainly on palliative treatment with (combinations of) systemic cytotoxic chemotherapy, with a median progression free survival (PFS) of only 3-6 months and almost no chance for long-term benefit. Radiotherapy is often added to these treatments. Even in selected patients stereotactic ablative body radiotherapy (SABR), results 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. This is preferably with new immunotherapeutical strategies, as an activated immune system can result in long-term responses as is shown for a minority of patients treated with first line ICI. 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 is 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 (3) with or without anti-PD(L)1 standard of care treatment. 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 combined with or without anti-PD(L)1 treatment.

It is a multicentre, randomised controlled open-label phase II clinical trial. Some patients who already receive stand of care anti-PD(L)1 treatment, will receive in this case triple treatment “Pushing the accelerator releasing the brake”. Releasing the brakes of tumor immunity with anti-PD-L1 and pushing its accelerator with L19-IL2 cures poorly immunogenic tumors when combined with radiotherapy.
Patients will be divided into two groups according to their metastatic load (oligo= up to 5 metastases, diffuse= 6 to 10 metastases). Patients are eligible if treated in first, second or third line in the IMMUNOSABR trial. After randomisation by minimization, patients will be assigned either to the experimental arm (E-arm) or to the control arm (C-arm) for standard treatment. E-arm patients belonging to oligo metastatic group will receive SABR to all lesions followed by L19-IL2 therapy. Patients with Poly-metastatic NSCLC, will receive SABR to maximal 5 metastatic lesions, with either no previous treatment or following chemo- and/or immunotherapy first line or second line, followed by L19-IL2 therapy. The main objective of the trial is to test if the combination of (SAB)R and the immunocytokine L19-IL2 will result in improved progression-free survival (PFS) at 1.5 years after randomisation, compared to the SOC. The secondary objectives will be assessment of 5-years PFS, 1.5-year and 5-year overall survival, and 1.5-year toxicity, Quality of Life, Out of Field Radio-Immune (OFRI) response, and In Field Radio-Immune (IFRI) response. Exploratory analyses will be performed to investigate biomarkers (e.g. EDB expression on tumour biopsies and blood), diversity of the microbiota of faeces, CT radiomics, iRECIST, tumour grow kinetics, and the changes of immunologic markers in repeated peripheral blood samples.
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 is ongoing and active at 10 sites; Maastricht, Amsterdam, Nijmegen, Rotterdam, Leuven, Brussel, Gent, Antwerpen, Lille, Montpellier. Sites that are ready to start recruitment soon; Dresden, Heidelberg, Londen, Tubbingen and Rome.
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 finished with very promising results. The currently ongoing randomised Phase II study is the first randomised study that generates 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 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 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. In the current challenging COVID-19 situation IMMUNOSABR might be preferred above chemotherapy because it stimulates the immune system instead of weakening it. We plan to report on this at the end of the project.
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