Prospective Evaluation of All-lesion Versus Single-lesion Radiotherapy in Combination With PD-1/PD-L1 Immune Checkpoint Inhibitors

Abstract

Background Local ablative treatments improve survival in patients with oligometastatic disease in addition to chemotherapy. The application of immune checkpoint inhibitors prolonged patients’ survival in different tumor entities. This raises the question if patients still benefit from intensified local treatments in combination with a more efficient systemic treatment with immune checkpoint inhibitors. Methods The prospective non-interventional ST-ICI trial investigates treatment with PD-1/PD-L1 (Programmed cell death protein 1/Programmed cell death 1 ligand 1) immune checkpoint inhibitors and radiotherapy in different tumor entities. Patients who started radiotherapy and immunotherapy concomitantly were included in this interim analysis. In this cohort patients with all-lesion radiotherapy (all tumor lesions irradiated, al-RT) were compared to patients with radiotherapy to only a single of their tumor lesions (single-lesion radiotherapy, sl-RT). Endpoints of the interim analysis were progression-free survival (PFS), overall survival (OS) and time to progression (TTP). Results A total of 104 patients were registered between April 2017 and August 2019. Fifty patients started immune checkpoint inhibitor treatment and radiotherapy concomitantly and were included. Most frequent tumor entities were non-small cell lung cancer (62%) followed by head and neck squamous cell cancer (26%). Most frequent location of radiotherapy was lung (34%) and central nervous system (20%). Median duration of follow-up was 8.6 months beginning with first administration of the immune-checkpoint-inhibitor. Median PFS was 9.2 months (95% CI, 5.8 – 12.6) in the al-RT group and 3.0 months (95% CI, 2.5 – 3.5) in the sl-RT group (p<0.001). Median OS was 11.6 months (95% CI, 8.1 - 15.1) in the al-RT group and 4.2 months (95% CI, 3.0 - 5.4) in the sl-RT group (p=0.007). Median TTP was not reached in the al-RT group compared to 4.6 months (95% CI, 1.1–8.0) in the sl-RT group (p=0.028). Univariate Cox regression analyses computed tumor entity, histology, central nervous system metastases, immunotherapy drug and al-RT as predictors of OS (with an effect p-value of ≤ 0.1). In the multivariable analysis only tumor entity and al-RT remained prognostic factors for OS. Conclusion Patients with PD-1/PD-L1 immune checkpoint inhibitor therapy benefit from local radiotherapy to all known lesions compared to single-lesion radiotherapy regarding PFS and OS.

Radiotherapy and the immune system: More than just immune suppression

“…A further promising clinical strategy is to irradiate all metastases of patients with oligometastatic disease in combination with IT 84 . In this field several trials are ongoing, but randomized data are currently not available.…”

A Predictive Biophysical Model of the Combined Action of Radiation Therapy and Immunotherapy of Cancer

“…In that regard, further model investigations will consider the irradiation of multiple lesions, which has been shown to be beneficial in clinical settings. 28,29 From a theoretical perspective a homogeneous dose coverage of the entire lesion sites is not needed to trigger immune response, as has been shown by exploiting the immunogenic action of radiation alone. 19 Hence even a partial volume irradiation of primary tumor and the largest metastatic sites may be sufficient to establish durable systemic antitumor response.…”

Immunotherapy with radiotherapy fails to improve prognosis of patients with stage IV non-small cell lung cancer: a retrospective cohort analysis of the THUNDER-2 study

“…RT on multiple sites of metastases releases a large amount of antigen while reducing the tumor load, thus stimulating the immunogenicity of the tumor. This, in the context of IT, could lead to consider local treatment on all metastatic sites ( 28 ).…”