# Radiotherapy and Immunotherapy--A Future Partnership towards a New Standard
## 4 Radiotherapy and Immunotherapy--From Research to Clinical Practice
Even if the median duration of response was not obtained, a proportion of more than 75% of response at 12 months and an average rate of grade 3 or higher pneumonia of 8% and 6.9% in the group with squamous and non-squamous histology, respectively, the study demonstrates the feasibility of combining pembrolizumab with radiochemotherapy, the adverse effects being considered manageable [59]. A significantly longer PFS and OS for lung patients who previously received radiotherapy is demonstrated by a secondary analysis of the results of the KEYNOTE-001 trial [60]. The efficacy and safety of pembrolizumab are currently evaluated by the KEYNOTE-992 trial in urothelial bladder cancer in association with trimodal treatment including maximal transurethral resection of the bladder followed by radio-chemotherapy [61]. The addition of avelumab (anti-PD-L1) to chemoradiotherapy, the standard treatment in locally advanced unresectable head and neck squamous cell carcinoma (HNSCC) was evaluated in a randomized phase 3 study including 907 cases for the potential to improve the prognosis of these patients. An amount of 10 mg/kg intravenous avelumab every 2 weeks was added to the standard treatment (concurrent chemoradiotherapy with cisplatin 100 mg\(\cdot\)m\({}^{2}\) every 3 weeks and radiotherapy using the intensity-modulated radiotherapy (IMRT) technique in a dose of 70 Gy in 35 daily fractions over 7 weeks. Even if the rate of treatment-related toxicities was not significant, the primary objective of median progression-free survival was not achieved, and the study was discontinued. CD8+ T depletion due to elective nodal irradiation in HNSCC, but also the concurrent therapeutic sequence used in the Javelin Head Neck 100 trial were possible causes of the failure of this trial [62]. Selective depletion of host immune cells, mentioning here the 60% risk 3-4 lymphopenia reported in a trial with a similar design by [PERSON] et al., but also the surprising flow cytometry results that demonstrated a reduction of CD4 T cells and B cells in the case of the concurrent association of pembrolizumab, but not CD8 T cells, are data that must be taken into account in the design of trials that associate immunotherapy with radiotherapy [63]. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer demonstrated benefit in PFS compared to the standard treatment of chemoradiotherapy-apy followed by surgery. A nivolumab dose of 240 mg every 2 weeks for 16 weeks, followed by a dose of 480 mg every 4 weeks was administered for up to one year. A 22.4-month median disease-free survival in the active treatment arm compared to 11 months in the placebo arm represents a net benefit of the adjuvant immunotherapy regimen, but adverse events of 13%, more than double compared to the placebo arm, led to the discontinuation of the trial [58; 64; 65]. However, the results of the PACIFIC trial are clear evidence of the benefit brought by conventional radiotherapy and standard fractionation, or more precisely, proof of the advantage brought by the triple combination of chemotherapy and radiotherapy. Analyzing the data from the PACIFIC trial, [PERSON] and collaborators note the value of this study that opens a new ERA, but at the same time opened a series of questions and unknown concepts that the future will have to answer. If, regarding the therapeutic sequence, the data supporting the advantage of \"consolidation\" immunotherapy treatment are confirmed, the study also suggests the optimal time interval, a real \"window of opportunity\" for immunotherapy administration. From the point of view of the time factor, a \"too soon\" or \"too late\" after radio-chemotherapy can tilt the advantage in favor of immunosuppressivefactors in the TME, leading to an unfavorable response of the tumor to immunotherapy [61].