Lancet (2019) 394(10212):191528. BMC Med. J Immunother Cancer (2021) 9(6):111. In the era of precision cancer medicine, innovative trial designs will also require the matching of novel drugs with putative targets. Rochester, Minn., Jacksonville, Fla. However, some immunological therapeutic effects can induce pseudo-progression or development of new lesions because of infiltration of immune cells into the primary tumor or lymph nodes, which makes it difficult to evaluate the treatment efficacy only with radiographical information (57). Chen Q, Jain N, Ayer T, Wierda WG, Flowers CR, OBrien SM, Keating MJ, Kantarjian HM, Chhatwal J. N Engl J Med. The EORTC 22931 and RTOG 9501 trials were published in 2004 and demonstrated that the addition of concurrent cisplatin chemotherapy to radiation therapy in the postoperative setting improved outcomes for selected (based on pathologic features) patients with squamous cell carcinoma of the oral cavity, oropharynx, larynx, and hypopharynx. doi: 10.1056/NEJMoa032646, 6. . Table2 Ongoing neoadjuvant immunotherapy clinical trials. doi: 10.1172/jci.insight.98811, 53. Thus, targeting immune suppression pathways with checkpoint inhibitors has been broadened to the exploration of therapeutic options in all HNSCC treatment settings. BMC Med 15, 111 (2017). The era of precision oncology is marked with prominent successes in the therapy of advanced soft tissue sarcomas, breast cancer, ovarian cancer and haematological neoplasms, among others. doi: 10.1136/jitc-2021-002568corr1, 68. Lancet (2019) 393(10167):15667. The published and ongoing trials described above focused on single agent checkpoint blockade immunotherapy prior to surgery. National Cancer Center Hospital East, Japan, University General Hospital Attikon, Greece. These trials relate to the multidisciplinary management of head and neck cancer from the perspective of a radiation oncologist. Both trials did not show a significant extension of OS and DFS, consistent with the subsequent studies (24, 25). 2015;373:5219. Lancet Oncol. J Immunother Cancer (2021) 9(5):115. Immune cells phenotypes in TME may also be important topredict the response to CPIs. Science (2020) 367(6477):19. These results underscore that TPF IC is not recommended for survival benefit. Several landmark trials established the clinical benefit of using cisplatin-based chemoradiotherapy after surgery for locally advanced, high-risk HNSCC patients (3, 4). Google Scholar. 2015;372(8):72434. Recent landmark immunotherapy trials - melanoma, Treatment intensification with neoadjuvant (induction) chemotherapies with platinum drugs are insufficient to significantly prolong overall survival. doi: 10.1001/jamaoncol.2015.3638, 42. Positive results from this study established the application of anti-PD-1 for R/M HNSCC treatment, and proved the existence of actionable, efficient anti-cancer immunity in HNSCC tumors. reported on findings from a clinical trial where neoadjuvant nivolumab (240 mg on days 1 and 15) with or without tadalafil was tested. Nat Rev Clin Oncol. Lancet Oncol (2010) 11(8):7819. The data and subsequent meta-analysis showed the superiority of CCRT to preserve the larynx in advanced laryngeal cancer patients (8, 23). There are three major potential benefits to use CPIs in the neoadjuvant setting. Considering the TME will be dramatically changed after therapeutic treatment, neoadjuvant immunotherapy for HNSCC can provide an opportunity to establish immune markers to predict efficacy of subsequent immunotherapy. With the positive responses in the R/M HNSCC setting, several trials have reported results with neoadjuvant checkpoint immunotherapy prior to surgery (Table1).