Challenges in synergizing radiotherapy with immunotherapy to unlock the abscopal effect in metastatic NSCLC: A systematic review

BACKGROUND: With the recent success of immunotherapy, there is a growing interest in combining radiation with immunotherapy to boost abscopal response rates. Several challenges exist in determining how to synergize these two modalities in the treatment of metastatic NSCLC. METHODS: References for this review were identified through searches of MEDLINE/PubMed and Clinicaltrials.gov databases with the search terms “abscopal”, “radiation OR radiotherapy,” “NSCLC”, and “lung” on the index date of July 2022 from 2000-2022. This systematic review focuses primarily on clinical papers. DISCUSSION: Early work combining radiotherapy with immunotherapy show promise in unlocking the abscopal effect. Preliminary evidence suggests that radiotherapy regimens with <5 fractions and smaller fields may be superior to regimens with 15 fractions and larger fields. There does not appear to be enough evidence to draw conclusions about the optimal timing of radiotherapy in relation to immunotherapy or the optimal anatomical location of radiation to induce the abscopal effect. Several studies suggest selecting patients with a higher absolute lymphocyte count (ALC) and lower neutrophil-to-lymphocyte ratio (NLR) may help to further boost abscopal response rates. Furthermore, selecting tumors with programmed death ligand-1 (PD-L1) expression, mismatch repair deficiency, and higher tumor mutational burden may similarly achieve this goal. Lastly, additional work is needed to minimize and predict for severe toxicity associated with combination therapy.