Stereotactic ablative body radiotherapy (SABR) combined with immunotherapy (L19-IL2) versus standard of care in stage IV NSCLC patients, ImmunoSABR: a multicentre, randomised controlled open-label phase II trial

Relinde I Y Lieverse, Evert J Van Limbergen, Cary J G Oberije, Esther G C Troost, Sine R Hadrup, Anne-Marie C Dingemans, Lizza E L Hendriks, Franziska Eckert, Crispin Hiley, Christophe Dooms, Yolande Lievens, Monique C de Jong, Johan Bussink, Xavier Geets, Vincenzo Valentini, Giuliano Elia, Dario Neri, Charlotte Billiet, Amir Abdollahi, David Pasquier, Pierre Boisselier, Ala Yaromina, Dirk De Ruysscher, Ludwig J Dubois, Philippe Lambin, Relinde I Y Lieverse, Evert J Van Limbergen, Cary J G Oberije, Esther G C Troost, Sine R Hadrup, Anne-Marie C Dingemans, Lizza E L Hendriks, Franziska Eckert, Crispin Hiley, Christophe Dooms, Yolande Lievens, Monique C de Jong, Johan Bussink, Xavier Geets, Vincenzo Valentini, Giuliano Elia, Dario Neri, Charlotte Billiet, Amir Abdollahi, David Pasquier, Pierre Boisselier, Ala Yaromina, Dirk De Ruysscher, Ludwig J Dubois, Philippe Lambin

Abstract

Background: 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 needed. We previously demonstrated clinical safety of the tumour-selective immunocytokine L19-IL2, consisting of the anti-ED-B scFv L19 antibody coupled to IL2, combined with stereotactic ablative radiotherapy (SABR).

Methods: This investigator-initiated, multicentric, randomised controlled open-label phase II clinical trial will test the hypothesis that the combination of SABR and L19-IL2 increases progression free survival (PFS) in patients with limited metastatic NSCLC. One hundred twenty-six patients will be stratified according to their metastatic load (oligo-metastatic: ≤5 or poly-metastatic: 6 to 10) and randomised to the experimental-arm (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 SABR to all lesions followed by L19-IL2 therapy; radiotherapy for poly-metastatic patients consists of irradiation of one (symptomatic) to a maximum of 5 lesions (including ICI in both arms if this is the SOC). The accrual period will be 2.5-years, starting after the first centre is initiated and active. 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, immune monitoring, CT-based radiomics, stool collection, iRECIST and tumour growth rate will be performed.

Discussion: The combination of SABR with or without ICI and the immunocytokine L19-IL2 will be tested as 1st, 2nd or 3rd line treatment in stage IV NSCLC patients in 14 centres located in 6 countries. This bimodal and trimodal 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. The first results are expected end 2023.

Trial registration: ImmunoSABR Protocol Code: NL67629.068.18; EudraCT: 2018-002583-11; Clinicaltrials.gov: NCT03705403; ISRCTN ID: ISRCTN49817477; Date of registration: 03-April-2019.

Keywords: Anti-PD-1; Anti-PD-L1; Immunotherapy; L19-IL2; Multicentre; NSCLC; Phase 2; Radiotherapy; SABR; Stage IV.

Conflict of interest statement

PL reports, inside the submitted work, grants/sponsored research from Oncoradiomics, ptTheragnostic/DNAmito; advisor (SAB)/presentor fee from Oncoradiomics, Varian medical and Elekta. Furthermore, he is the inventor of two patents on radiomics and one non-patentable invention (software), licensed to Oncoradiomics and has (minority) shares in the company Oncoradiomics and MedC2. LH: none related to the current manuscript, outside of current manuscript: research funding Roche, Boehringer Ingelheim, AstraZeneca (all institution), the advisory board: Boehringer, BMS, Lilly, Takeda, Pfizer, MSD (all institution), travel reimbursement: Roche, BMS (self); mentorship program with key opinion leaders: funded by AstraZeneca; fees for educational webinars: Quadia (self). Philogen S.P.A supplies L19-IL2 (darleukin). Philogen had only influence on the drug-related topics in the study protocol, e.g. description, preparation, labelling, and justification of administration and dosage. DN: reports he is a co-Founder and Board Member in Philogen. DdR: none related to the current manuscript, outside of the current manuscript: advisory board of Bristol-Myers-Squibb, Astra Zeneca, Roche/Genentech, Merck/Pfizer and Celgene. Research grants have been received from Bristol-Myers Squibb and Boehringer Ingelheim. All income from the advisory board and from the research grants went integrally to the institution. AD: none related to the current manuscript, outside of the current manuscript: advisory board BMS, MSD, Roche, Eli Lilly, Takeda, Pfizer, Boehringer Ingelheim (all institution). Research grant: BMS (institution). YL: personal fees from Astra Zeneca, personal fees from RayStation, outside the submitted work. AA reports grants and other benefits from Merck, EMD and Fibrogen, and other benefits from BMS, BioMedX and Roche, outside the submitted work. All other authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Study design of ImmunoSABR phase II trial
Fig. 2
Fig. 2
Timeline of study treatment and follow-up

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