RU: editing and supervising the manuscript, tables and figure. doi: 10.1038/s41591-020-0805-8, 36. These data indicate that PD-L1 expression on tumor cells is not a perfect biomarker to predict the clinical outcome. Landmark Trials. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomized controlled trial. Differences in T-Cell Infiltrates and Survival Between HPV+ and HPV- Oropharyngeal Squamous Cell Carcinoma. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. He is also an active member of the EORTC Melanoma Group and the Global Melanoma Task Force. As described by ASO Editor-in-Chief, Kelly M. McMasters, MD, PhD, "The Landmark Series is designed to trace the origins of current multidisciplinary therapy for each type of solid tumor, and demonstrate the logical progression of clinical trials and other key evidence. Recent developments in the classification of STS, insights into their molecular pathogenesis and the optimal treatment strategies have evolved considerably during the past decades and have led to the introduction of new therapies. N Engl J Med (2003) 349(22):20918. Di Veroli GY, Fornari C, Wang D, Mollard S, Bramhall JL, Richards FM, Jodrell DI. Other work showed that PD-L2 expression was significantly correlated with PD-L1 expression in HNSCC clinical samples (42). safer and more-effective approaches to head and neck radiation therapy. J Clin Oncol (2021) 39(15_suppl):60088. doi: 10.1093/annonc/mdy227, 58. Earl, H., Molica, S. & Rutkowski, P. Spotlight on landmark oncology trials: the latest evidence and novel trial designs. Matlung SE, Wilhelmina van Kempen PM, Bovenschen N, van Baarle D, Willems SM. ID: NCT03803774. N Engl J Med. Definition and Impact of Pathologic Complete Response on Prognosis After Neoadjuvant Chemotherapy in Various Intrinsic Breast Cancer Subtypes. HE has received research funding from Cancer Research UK and the NIHR HTA, and is funded by the NIHR Cambridge Biomedical Research Centre. A study by Yamazaki et al. McGrail DJ, Pili PG, Rashid NU, Voorwerk L, Slagter M, Kok M, et al. Oncoimmunology (2019) 8(5):e1581530. Google Scholar. A special article collection in BMC Medicine, Spotlight on landmark oncology trials, features articles from invited experts on recent clinical practice-changing trials. HNSCC patients with high CD8+ T cells infiltration showed better anti-PD-1 response in the adjuvant setting (52, 54). chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized intergroup study 0099. Nivolumab Plus Ipilimumab in Lung Cancer With a High Tumor Mutational Burden. Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, et al. Patients received two cycles of drug therapy. Checkpoint inhibitors (CPI) targeting the programmed death 1 (PD-1) pathway have been approved for recurrent and metastatic (R/M) HNSCC patients in the first- and second-line settings (1214) and have dramatically changed the treatment algorithm of HNSCC. Kiong KL, Yao C, Lin FY, Bell D, Ferrarotto R, Weber RS, et al. Notably, four patients (N, n=1; N+I, n=3) had major/complete response (greater than 90%). In a phase II neoadjuvant immunotherapy clinical trial for oral cavity cancer patients which treated with nivolumab (N, n=14) or nivolumab and ipilimumab (N+I, n=15), two (N) and five (N+I) patients showed grade 3/4 AEs. This trial included both definitive and salvage surgery patients. Front Oncol (2020) 10:566315. doi: 10.3389/fonc.2020.566315, 66. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. 2018. Cohen E, et al. Lancet (2019) 394(10212):191528. In the KEYNOTE-048 phase III trial, significant survival benefit of pembrolizumab for patients was seen with PD-L1 expression 1% and 20% by CPS (14). She has been an expert advisor for NHS NICE Health Technology Assessments. doi: 10.1002/hed.20279, 7. 2006;64(1):4756. The first articles in the special article collection focus on landmark clinical trials in selected advanced solid tumours, with special attention on the most studied tumours with regards to immunotherapy development, namely melanoma [3, 4], NSCLC [], and head and neck cancer [].Recent developments and approvals in immunotherapy have significantly changed the landscape of melanoma and NSCLC . Br J Cancer. volume15, Articlenumber:111 (2017) In fact, a study evaluating 20 resected non-small cell lung cancer (NSCLC) tumors after neoadjuvant anti-PD-1 treatment showed a discrepancy between radiological and pathological evaluation (58). Received: 18 June 2021; Accepted: 19 August 2021;Published: 06 September 2021. These successes have led to checkpoint blockade therapies being testing in earlier treatment settings. HPV infection might also be a clinical biomarker to predict the response to CPIs. 11:727433. doi: 10.3389/fonc.2021.727433. JCI Insight (2016) 1(17):e89829. Long term results of TAX324, a randomized phase III trial of sequential therapy with TPF versus PF in locally advanced squamous cell cancer of the head and neck. The premise of neoadjuvant immunotherapy is to use the existing tumor mass as an in-situ source of tumor-specific antigens to enhance systemic immunity via dendritic cell antigen presentation to rejuvenate T cells and priming especially for cytotoxic T cells (34). Nevertheless, the selection of systemic therapy must be strictly individualised and based upon several factors, including the histology and biological behaviour of the disease. A limited number of drugs have shown activity in advanced disease, and due to the rarity of these tumours, clinical trials in sarcoma include many subtypes and are mainly initiated by academic research groups. As trials mature, patient selection for neoadjuvant immunotherapy will need to be defined further. 2010;11:218. Leidner R, Crittenden M, Young K, Xiao H, Wu Y, Couey MA, et al. 2015;385(9980):187383. doi: 10.1093/annonc/mdy218, 59. von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, et al. This chapter contains a summary of some key findings from a selection of 18 trials related to oral cavity, nasopharynx, oropharynx, larynx, and hypopharynx cancer. Science (2020) 367(6483):12649. Hanna GJ, ONeill AM, Jo VY, Wong K, Lizotte PH, Annino DJ, et al. Nat Rev Clin Oncol. Based on KEYNOTE-048, the FDA approved use of pembrolizumab monotherapy in the first-line for R/M HNSCC with CPS 1 and pembrolizumab plus platinum-based chemotherapy for those with CPS<1 R/M HNSCC (31). In this article series, worldwide renowned experts in their fields provided an extensive overview on the state of the art in immunotherapy and discussed the possible future paths in these, still difficult, types of malignancies. Bachaud JM, Cohen-Jonathan E, Alzieu C, David JM, Serrano E, Daly-Schveitzer N. Combined Postoperative Radiotherapy and Weekly Cisplatin Infusion for Locally Advanced Head and Neck Carcinoma: Final Report of a Randomized Trial. Junker K, Thomas M, Schulmann K, Klinke F, Bosse U, Mller KM. TMB is a potential predictive biomarker that also needs further exploration. Treatment intensification with neoadjuvant (induction) chemotherapies with platinum drugs are insufficient to significantly prolong overall survival. doi: 10.1200/JCO.2016.70.1524, 45. Lancet Oncol. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. [39] published an interesting software to provide information in terms of synergy and/or antagonism between two compounds. Correspondence to 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. 2023 BioMed Central Ltd unless otherwise stated. However, although IC may help with surgical management, Phase III trial results showed no improvements in survival. JAMA Oncol (2020) 6(10):156370. Nature (2013) 502(7471):3339. Google Scholar. a landmark trial conducted by Bonner and colleagues evaluating the role of cetuximab plus radiation vs radiation alone, and several induction trials evaluating TPF vs cisplatin . Curran MA, Montalvo W, Yagita H, Allison JP. Notably, any pTR after neoadjuvant pembrolizumab correlated with baseline tumor PD-L1, immune infiltration, and IFN- activity, but not TMB. Article The phase II Checkpoint Inhibitors Assessment in Oropharynx cancer (CIAO) trial (NCT03144778) tested a combination of durvalumab (1500 mg) and tremelimumab (75 mg) in the neoadjuvant setting, preceding SOC (surgery with or without radiation therapy) (70). Ang KK, et al. J Clin Oncol (2021) 39(15_suppl):60066. N Engl J Med (2004) 350(19):193744. doi: 10.1200/JCO.2017.75.1644, 57. Finally, biomarker and minimal residual disease assessment may ultimately be useful to guide the targeted agent or regimen of choice and the duration of treatment [38]. The IMCISION study (NCT03003637) presented at ESMO 2020 is examining neoadjuvant nivolumab and ipilimumab for stage II-IVa HNSCC patients. Using a primary radiation based approach, several ongoing clinical trials aim to de-intensify the treatment impact by adding immunotherapy (77). Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers. PubMed CrossRef B Cell Signatures and Tertiary Lymphoid Structures Contribute to Outcome in Head and Neck Squamous Cell Carcinoma. Checkpoint Blockade Cancer Immunotherapy Targets Tumour-Specific Mutant Antigens. Overall survival results from a phase III trial of nivolumab combined with ipilimumab in treatment-nave patients with advanced melanoma (CheckMate 067). 1991;324:168590. Atezolizumab versus docetaxel for patients with previously treated nonsmall-cell lung cancer (POPLAR): a multicentre, open label, phase 2 randomised controlled trial. Immune-Modified Response Evaluation Criteria In Solid Tumors (imRECIST): Refining Guidelines to Assess the Clinical Benefit of Cancer Immunotherapy. In this review, we present a brief overview of the history of neoadjuvant (induction) chemotherapy in the definitive surgical management of HNSCC. Per standard of care, postoperative RT or CCRT were performed, and adjuvant pembrolizumab treatment was used in high-risk patients with positive surgical margins or extra-nodal extension. No use, distribution or reproduction is permitted which does not comply with these terms. Moreover, recent trials of immune checkpoint inhibitors in melanoma, non-small cell lung carcinoma, and head and neck cancers have significantly influenced the therapeutic landscape by providing promising evidence for immunotherapy efficacy in the adjuvant setting in high-risk locoregional disease. A. Historically, surgery and radiotherapy with/without conventional chemotherapy including platinum, taxanes or fluorouracil, were applied to treat HNSCC. Key pathological findings after neoadjuvant immunotherapy include 1) keratinous debris, 2) giant cells, histiocytic reaction and 3) tumor necrosis. doi: 10.1056/NEJMoa032641, 8. Figure1 Representative figure of pathological tumor response (pTR). PubMed Central Licitra L, Grandi C, Guzzo M, Mariani L, Lo Vullo S, Valvo F, et al. 2017;5(10):42532. 2016;17(6):791800. The TAX 324 trial compared two different induction chemotherapy regimens in patients undergoing chemoradiotherapy, and the PARADIGM and DECIDE trials studied the role of induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone. In the neoadjuvant immunotherapy context, immune-modified RECIST (imRECIST) criteria have been proposed (56). doi: 10.1172/jci.insight.98811, 53. The expression level of PD-L1 in the tumor does not necessarily correlate withthe response to CPIs. In: Proceedings from the American Association for Cancer Research Annual Meeting, April 25, 2017, Washington DC. Cookies policy. Zhong LP, Zhang CP, Ren GX, Guo W, William WN Jr., Sun J, et al. Article Postoperative Concurrent Radiotherapy and Chemotherapy for High-Risk Squamous-Cell Carcinoma of the Head and Neck. doi: 10.1158/1078-0432.CCR-19-2209, 39. The probability of response to CPIs has at least in part been linked to TMB across cancer types, including HNSCC (16). Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, Colleoni M, DeMichele A, Loi S, Verma S, Iwata H, Harbeck N, Zhang K, Theall KP, Jiang Y, Bartlett CH, Koehler M, Slamon D. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. 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). Barker AD, Sigman CC, Kelloff GJ, Hylton NM, Berry DA, Esserman LJ. doi: 10.1016/S0140-6736(18)31999-8, 14. Based on this study and depending on the programmed death-ligand 1 (PD-L1) combined positive score (CPS) either pembrolizumab alone or with chemotherapy represents the first choice for these patients (14). Wolf GT, Fisher SG, Hong WK, Hillman R, Spaulding M, Laramore GE, et al. Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al. doi: 10.1126/science.1208130, 12. Landmark Trials in Selected Head and Neck Cancers There are several distinct mechanisms of how radiation and/or chemotherapy can work with immunotherapy and other have covered these topics. The landmark phase III CheckMate 141 trial resulted in the approval of nivolumab in the R/M second-line HNSCC setting (12). doi: 10.1200/JCO.2021.39.15_suppl.6006, 75. 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. JCI Insight (2018) 3(4):113. N Engl J Med. J Clin Oncol (2015) 33(8):83645. Pathological Complete Response and Long-Term Clinical Benefit in Breast Cancer: The CTNeoBC Pooled Analysis. These results clearly demonstrate the superiority of dual HER2-directed therapy. The pTR scores were evaluated by two independent pathologists and graded using the following scale: pTR-0 < 10%, pTR-1; 10-49%, pTR-2 50%. 1998;16:13107. There are now numerous studies introducing neoadjuvant immunotherapy in diverse cancer types (3436). Demetri GD, von Mehren M, Jones RL, Hensley ML, Schuetze SM, Staddon A, Milhem M, Elias A, Ganjoo K, Tawbi H, Van Tine BA, Spira A, Dean A, Khokhar NZ, Park YC, Knoblauch RE, Parekh TV, Maki RG, Patel SR. Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: results of a phase III randomized multicenter clinical trial. Manage cookies/Do not sell my data we use in the preference centre. A meta-analysis by Pignon et al. All authors contributed to the article and approved the submitted version. The study is aimed at establishing the purpose of tumour markers, their application, classification, diagnostic and therapeutic roles in the management of head and neck cancer. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crin L, Blumenschein Jr GR, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. Forastiere A, et al. The current mainstay of advanced head and neck squamous cell carcinoma (HNSCC) treatment remains surgery and radiotherapy with/without conventional chemotherapy. By contrast, neoadjuvant immunotherapy is fundamentally distinct as it targets the host immune system to attack tumor cells in a durable fashion. Int J Radiat Oncol Biol Phys (1992) 23(4):70513. doi: 10.1093/annonc/mdt555, 29. HNCA recommends researching head and neck cancer clinical trials either by going to www.ClinicalTrials.gov a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world - or using our Clinical Trial Finder which is designed to be user-friendly for patients. Landmark results include those in triple negative breast cancer for the combination of velaparib and carboplatin [44] and neratinib in HER2-positive breast cancer [45]. J Radiat Oncol Biol Phys. head neck oncology advances.ppt - Google Slides However, a potential setback is represented by the control arm since chlorambucil is no longer regarded an adequate therapy in CLL [26]. Am Soc Clin Oncol Educ Book (2020) 40:113. PD-L2 Expression in Human Tumors: Relevance to Anti-PD-1 Therapy in Cancer. statement and Hodi FS, Ballinger M, Lyons B, Soria JC, Nishino M, Tabernero J, et al. Filter this list of studies by location, status and more. To speed up the introduction of targeted therapy for cancer patients, novel phase II trials are being designed, and may likely form the basis for the landmark trials of the future. 2015;373(3):20919. doi: 10.1007/BF01192200, 63. Compared to our initial cohort with one dose, we found that 50% of patients had any pTR and 44% of patients exhibited pTR2. There were no treatment related delays thus achieving the primary safety endpoint. J Clin Oncol (2021) 39(15_suppl):60533. Thus, targeting immune suppression pathways with checkpoint inhibitors has been broadened to the exploration of therapeutic options in all HNSCC treatment settings. Combenefit: an interactive platform for the analysis and visualization of drug combinations. In addition, adaptive designs for phase I combinations are being developed [40]. Furthermore, although distinct tumor-suppressor mutations including TP53, CDKN2A, NOTCH have been reported in HNSCC, cancer-promoting driver oncogenic mutations have not been detected (911), which makes it challenging to apply molecular targeted therapies. The Landmark Series - Society of Surgical Oncology Chan TA, Yarchoan M, Jaffee E, Swanton C, Quezada SA, Stenzinger A, et al. Below are current clinical trials. In the KEYNOTE-055 phase II trial, the response rate to pembrolizumab was 22% for p16 positive patients and 16% for p16 negative patients (44). Molica S. Targeted therapy in the treatment of chronic lymphocytic leukemia: facts, shortcomings and hopes for the future. Chalabi M, Fanchi LF, Dijkstra KK, Van den Berg JG, Aalbers AG, Sikorska K, et al. Mutational Landscape and Significance Across 12 Major Cancer Types. Marur S, et al. Spotlight on landmark oncology trials: the latest evidence and novel These data show that two doses or the longer neoadjuvant window (3 versus 6 weeks) resulted in an increased rate of pTR but did not increase the total proportion of patients with pTR. Finally, we recently reported a second cohort of our neoadjuvant pembrolizumab trial where instead of one dose, patients received two doses of drug similar to the neoadjuvant phase of the KEYNOTE-689 Phase II trial (75). Nat Rev Clin Oncol. A Study to Evaluate Fractionated Radiation Therapy Utilizing GRID Therapy for Locally-advanced Bulky Tumors. Abstract. In conclusion, neoadjuvant approaches provide a potential exciting new treatment paradigm for HNSCC patients. These data together support further investigation in Phase III trials such as KEYNOTE-689 to define evidence for survival benefit and identify high-risk patients who may benefit from this approach. National Cancer Center Hospital East, Japan, University General Hospital Attikon, Greece.
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