Pembrolizumab and radiotherapy in immunologically cold non-small cell lung cancer

A new study recently published on Nature Cancer show that radiotherapy may sensitize immunologically cold non-small cell lung cancer to immune checkpoint inhibition with pembrolizumab, opening a new therapeutic window of opportunity to overcome immunotherapy resistance.

The potential for therapeutic synergy between radiotherapy and immune checkpoint inhibitors has been evidenced by numerous preclinical studies and a variety of mechanisms can explain how radiation can enhance systemic immune responses. In this study, the immunostimulatory effects of radiotherapy were studied by performing serial comprehensive multiomic analyses of nonirradiated tumors and their tumor microenvironment together with dynamic temporal investigation of the intratumoral and peripheral T cell repertoire; data were collected leveraging the randomized, phase 2 PEMBRO-RT trial of pembrolizumab after stereotactic body radiation therapy compared with pembrolizumab monotherapy in patients with non-small cell lung cancer. Clinical results showed a significantly longer progression-free survival in patients with immunologically cold tumors treated with radioimmunotherapy; results of the analyses showed that induction of interferon-γ, interferon-α and antigen processing and presentation gene sets was significantly enriched after stereotactic body radiation therapy in non-irradiated tumor sites. Significant on-therapy expansions of new and pre-existing T cell clones in both the tumor and the blood compartments were noted alongside clonal neoantigen-reactive autologous T cell responses in participants with long-term survival after radioimmunotherapy. «Our study supports the abscopal effect of radioimmunotherapy in persons with metastatic non-small cell lung cancer, including persons with immunologically cold tumors. Our findings suggest that radioimmunotherapy may be a promising avenue of further exploration for persons with therapeutic resistance to immune checkpoint inhibitors; future efforts will specifically investigate the benefit of radioimmunotherapy in selected populations», authors conclude.