Combination of pembrolizumab and radiotherapy induces systemic antitumor immune responses in immunologically cold non-small cell lung cancer

The abscopal effects of radiation may sensitize immunologically cold tumors to immune checkpoint inhibition. We investigated the immunostimulatory effects of radiotherapy leveraging multiomic analyses of serial tissue and blood biospecimens (n = 293) from a phase 2 clinical trial of stereotactic body radiation therapy (SBRT) followed by pembrolizumab in metastatic non-small cell lung cancer ( NCT02492568 ). Participants with immunologically cold tumors (low tumor mutation burden, null programmed death ligand 1 expression or Wnt pathway mutations) had significantly longer progression-free survival in the SBRT arm. Induction of interferon-γ, interferon-α and antigen processing and presentation gene sets was significantly enriched after SBRT in nonirradiated tumor sites. Significant on-therapy expansions of new and pre-existing T cell clones in both the tumor (abscopal) and the blood (systemic) compartments were noted alongside clonal neoantigen-reactive autologous T cell responses in participants with long-term survival after radioimmunotherapy. These findings support the systemic immunomodulatory and antitumor effects of radioimmunotherapy and may open a therapeutic window of opportunity to overcome immunotherapy resistance.