# Radiotherapy and Immunotherapy--A Future Partnership towards a New Standard
## 4 Radiotherapy and Immunotherapy--From Research to Clinical Practice  
An analysis that evaluated 20 clinical trials including 2027 patients with NSCLC concluded that compared to uncombined therapy, treatment that combined PD-1/PD-L1 inhibitors and radiotherapy improved overall survival (OS) and objective response rate (ORR) without significantly increasing the risk of \(\geq\)grade 3 toxicities but with an increased risk of mild pneumonitis. The therapeutic sequence in which PD-1/PD-L1 inhibitors followed radiotherapy offered superior results in relation to the sequence that include immunotherapy delivered before radiotherapy. Stereotactic radiosurgery (SRT) and SBRT also demonstrated superior synergistic potential compared to conventional radiotherapy [45]. The necessity to use a double combination of immunotherapy is justified by a low number of TILs and low expression of immune markers. One such case is triple-negative breast cancer (TNBC) which, although considered an immunogenic tumor, will not generate an immune-mediated antitumor response using a single inhibitory checkpoint, thus falling into the \"cold\" phenotype. Two other types of cancer, malignant melanoma and kidney cancer, are considered \"hot\" due to the infiltration of TILs, being responsive both to single-agent immunotherapy and double ICI [46; 47]. The phase 2 and phase 1/2 trials PEMBRO-RT (NCT02492568) and MDACC (NCT02444741) (phase 1/2) evaluated the benefit of adding radiotherapy to immunotherapy for patients with metastatic small cell lung cancer. Three phenomena (T cells infiltration, tumor antigen release, and antigen presentation) are the basis of the study concept proposed by [PERSON] et al. in the PEMBRO-RT trial. Even if the results were not statistically significant in the arm that combined radiotherapy and pembrolizumab, a benefit of \"abscopal\" irradiation was observed. The inclusion criteria were similar in the two studies, PEMBRO-RT including cases previously treated with chemotherapy, and MDACC cases treatment-naive or previously treated. In the PEMBRO-RT study, immunotherapy with pembrolizumab was administered in a dose of 200 mg every 3 weeks, the initiation of ICI being less than a week after the last dose of stereotactic body radiotherapy (SBRT) in a dose of 24 Gy in 3 fractions. The regimen proposed by MDACC included the concurrent administration of pembrolizumab with radiotherapy (50 Gy in 4 fractions or 45 Gy in 15 fractions). The abscopal response rate was significantly higher (41.7%) and was obtained at 12 weeks in cases that combined radiotherapy with ICI, compared to only 19.7% in cases treated only with pembrolizumab. A more than double PFS (9 months vs. 44.4 months) was associated with the administration of the combination of immunotherapy and radiotherapy, and the median OS of 19.2 months vs. 8.7 months in favor of the combined regimen are arguments for evaluating the regimen in phase III trials [48]. Without intending to carry out a detailed review of all the cases of abscopal effect reported in clinical practice, we briefly presented some examples of associations of some radiotherapy protocols in combination with immunotherapy as inducers of the synergistic abscopal effect in different types of cancer (Table 1), [48; 49; 50; 51; 52; 53; 54; 55; 56]. The combination of pembrolizumab with chemoradiotherapy in advanced unresectable stage II-III esophageal and gastroesophageal junction cancer were evaluated in the phase III study KEYNOTE-975. The trial proposes 3 treatment sequences including platinum-fluorouracil chemotherapy protocols and radiotherapy in a total dose of 50 Gy or 60 Gy or the FOLOFOX chemotherapy regimen. Immunotherapy with pembrolizumab vs. placebo is proposed up to 13 cycles in 1:1 randomization, the endpoints being OS and event-free survival PD-L1 with a combined positive score \(\geq\)10. The trial could provide new data regarding the role of radiotherapy and the preferred dose in generating a synergistic response [57].