landmark trials in head and neck cancer ppt

J Clin Oncol. A meta-analysis by Pignon et al. In the neoadjuvant setting, the NeoSphere trial demonstrated significantly improved pathological complete response rates [23] and a trend favouring improved PFS and OS at 5years [24]. Molica S. Targeted therapy in the treatment of chronic lymphocytic leukemia: facts, shortcomings and hopes for the future. Cohen EEW, Bell RB, Bifulco CB, Burtness B, Gillison ML, Harrington KJ, et al. doi: 10.1016/S0360-3016(96)00430-0, 5. Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, et al. N Engl J Med (2004) 350(19):194552. reported on findings from a clinical trial where neoadjuvant nivolumab (240 mg on days 1 and 15) with or without tadalafil was tested. Remon J, Besse B, Soria JC. Lancet (2019) 394(10212):191528. The data and subsequent meta-analysis showed the superiority of CCRT to preserve the larynx in advanced laryngeal cancer patients (8, 23). Lancet Oncol. Expert Rev Hematol. N Engl J Med (1991) 324(24):168590. The current mainstay of advanced head and neck squamous cell carcinoma (HNSCC) treatment remains surgery and radiotherapy with/without conventional chemotherapy. 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). The importance of BTK inhibitors in the first-line setting has been recently investigated in the RESONATE-2 study [33], a head-to-head clinical trial in which outcomes were shown to be superior for patients who received ibrutinib in comparison to patients treated with chlorambucil single agent. 1991;324:168590. Major pathological responses were seen in 1 HPV-positive tumor with none in the HPV-negative tumors. Google Scholar. 2015;372(4):32030. Uppaluri R, Chernock R, Mansour M, Jackson R, Rich J, Pipkorn P, et al. Oncoimmunology (2019) 8(5):e1581530. 2018. IC continues to be used at some centers with defined indications including advanced or borderline resectable tumors. 2010;11:218. Combenefit: an interactive platform for the analysis and visualization of drug combinations. doi: 10.1158/1078-0432.CCR-16-1761, 43. Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi G, Szado T, Ratnayake J, Ross G, Valagussa P. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. doi: 10.1158/1078-0432.CCR-19-2209, 39. Nature (2013) 500(7463):41521. Biomarkers in Head and Neck Cancer an Update - PubMed doi: 10.1093/annonc/mdy507, 41. There were no treatment related delays thus achieving the primary safety endpoint. Bernier J, et al. Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefbvre JL, Greiner RH, et al. N Engl J Med (2003) 349(22):20918. Blood. The CD8+ T cell data was correlated with preclinical models, where anti-PD-1 and anti-CTLA4 combinatorial therapy increased tumor-infiltrating CD8+ T cells (71). Ther Adv Med Oncol (2021) 13:1758835920984061. doi: 10.1177/1758835920984061, 40. By contrast, neoadjuvant immunotherapy is fundamentally distinct as it targets the host immune system to attack tumor cells in a durable fashion. 2015;373:162739. 2015;373(1):2334. Yamazaki H, et al. Lancet. Thus, targeting immune suppression pathways with checkpoint inhibitors has been broadened to the exploration of therapeutic options in all HNSCC treatment settings. Chalabi M, Fanchi LF, Dijkstra KK, Van den Berg JG, Aalbers AG, Sikorska K, et al. Springer Nature. Notably, other work has contradicted the above studies on TMB and concluded that that high TMB failed to predict the effect of ICI (53). Hillmen P, Robak T, Janssens A, Babu KG, Kloczko J, Grosicki S, Doubek M, Panagiotidis P, Kimby E, Schuh A, Pettitt AR, Boyd T, Montillo M, Gupta IV, Wright O, Dixon I, Carey JL, Chang CN, Lisby S, McKeown A, Offner F, COMPLEMENT 1 Study Investigators. doi: 10.1080/2162402X.2019.1581530, 34. Cancer Discov. Schoenfeld etal. Landmark Trials. SM does not have any conflict of interest to disclose. 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). SM is Chief of the Department Hematology-Oncology at the Azienda Ospedaliera Pugliese-Ciaccio Catanzaro, Italy. It remains the fifth leading cause of cancer in the United States and constitutes 10% or more of all cancers worldwide. Google Scholar. Front. In the era of precision cancer medicine, innovative trial designs will also require the matching of novel drugs with putative targets. Bioinformatics. doi: 10.1038/nature14129, 11. Rare Driver Mutations in Head and Neck Squamous Cell Carcinomas Converge on NOTCH Signaling. Historically, surgery and radiotherapy with/without conventional chemotherapy including platinum, taxanes or fluorouracil, were applied to treat HNSCC. Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al. PD-1 and CTLA-4 Combination Blockade Expands Infiltrating T Cells and Reduces Regulatory T and Myeloid Cells Within B16 Melanoma Tumors. Understanding Patterns of Pathologic Response Following Neoadjuvant Immunotherapy for Solid Tumors. All authors read and approved the final manuscript. doi: 10.1056/NEJMoa1602252, 13. Although a total of 21 patients experienced AEs, including grade 3/4 AEs in 2 (N) and 5 (N+I) patients, there were no surgical delays. He works very closely with national patient advocacy groups for GIST and sarcoma and is Chairman of the Melanoma Academy in Poland. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. Redman JM, Gibney GT, Atkins MB. Ferrarotto R, Bell D, Rubin ML, Hutcheson KA, Johnson JM, Goepfert RP, et al. Epidemiology. Combinations of chlorambucil with an anti-CD2O monoclonal antibody, such as rituximab, ofatumumab or obinutuzumab, are now the standard of care in patients unsuited to receive fludarabine, cyclophosphamide and rituximab [34,35,36]. doi: 10.1038/nature13988, 16. This overview examines the treatment history of neoadjuvant approaches for HNSCC, and especially focuses on the recent topics of neoadjuvant immunotherapy for HNSCC. However, as immunotherapy has associated toxicities (see section on this below) and is expensive, careful patient selection to determine who may benefit from these approaches is critical. 2012;13(1):2532. I. 2014;370(12):110110. These data suggest clinical tolerability and effectiveness of neoadjuvant immunotherapy. Lancet Oncol (2014) 15(1):e4250. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. Subsequently the Keynote-048 study, a randomized multi-center phase III study from 37 countries, examined pembrolizumab alone or with chemotherapy (platinum plus fluorouracil) versus cetuximab with chemotherapy (the EXTREME regimen (32)) for first-line treatment of R/M HNSCC (14). Science (2020) 367(6477):19. Di Veroli GY, Fornari C, Wang D, Mollard S, Bramhall JL, Richards FM, Jodrell DI. Lancet. Ruffin AT, Cillo AR, Tabib T, Liu A, Onkar S, Kunning SR, et al. J Clin Oncol. Although these Level 1 data established a new postoperative standard of care to treat high-risk HNSCC patients, the five-year survival rate in for these patients remains suboptimal. Exclusive: combination of drugs causes tumours to vanish in some terminally ill patients, study finds A new cancer treatment can wipe out tumours in terminally ill head and neck cancer patients, scientists have discovered. Lancet Oncol. Nat Commun (2021) 12(1):3349. doi: 10.1038/s41467-021-23355-x, 56. 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. Haddad R, et al. This was nearly double what we saw with one dose of pembrolizumab. 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. doi: 10.1016/0360-3016(92)90027-F, 19. SS: editing the manuscript. 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. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. In addition, in the KEYNOTE-040 phase III study, the correlation of clinical outcome and PD-L1 expression on tumor (PD-L1 tumor proportion score 50%) was evident (13). Another meta-analysis showed that HPV positive HNSCC patients display significant improved outcomes with PD-1/PD-L1 axis blockage treatment compared to HPV negative HNSCC patients (46). An important consideration in neoadjuvant immunotherapy approaches is appropriate patient selection. is discussed which was the first prospective randomized trial to study hypofractionation versus standard fractionation in early-stage larynx cancer. This is multi-institutional trial enrolled 92 patients and 76 patients were evaluable for DFS. 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. These trials led to US Food and Drug Administration (FDA) approval of the use of anti-PD-1 (nivolumab and pembrolizumab) for second-line for recurrent and metastatic HNSCC patients who had already experienced platinum-based therapies (31). Int J Radiat Oncol Biol Phys (1992) 23(4):70513. Notably, the timing of immune checkpoint inhibitors may influence the outcome of cancer treatment (33). Clinical outcomes were better than historical with 70% 1-year disease free survival and 85% 1-year overall survival. Refining American Joint Committee on Cancer/Union for International Cancer Control TNM Stage and Prognostic Groups for Human Papillomavirus-Related Oropharyngeal Carcinomas. Menzies AM, Amaria RN, Rozeman EA, Huang AC, Tetzlaff MT, van de Wiel BA, et al. 1998;16:13107. Analysis of the data gathered from these large trials continues to contribute valuable understanding about related issues, including . Cancer Discov (2016) 6(12):138299. Landmark Trials in Selected Head and Neck Cancers. For example, radiological tumor examination is widely used in Response Evaluation Criteria In Solid Tumors (RECIST) after organ preservation therapy including radiotherapy and chemotherapy. All authors contributed to the article and approved the submitted version. cancer [2], melanoma [3, 4], STS [5], head and neck cancer [6]). 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. Patients received two cycles of drug therapy. doi: 10.1136/jitc-2021-002485, 67. However, translational research did not discover any predictive biomarker subgroups [27] for the palbociclib effect. Importantly, phase III clinical trials which examined the clinical efficacy of IC treatment prior to surgery also failed to show suppression of loco-regional relapse and distant metastasis or extend OS (2628). Br J Cancer. Forastiere A, et al. Palbociclib in hormone-receptor-positive advanced breast cancer. doi: 10.1093/annonc/mdt555, 29. Successes and failures: what did we learn from recent first-line treatment immunotherapy trials in non-small cell lung cancer? Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. . Clin Cancer Res (2020) 26(19):514052. BMC Medicine However, PD-L1 negative tumors sometimes respond to CPI treatment, suggestingthe existence of other mechanisms. Hanna GJ, Lizotte P, Cavanaugh M, Kuo FC, Shivdasani P, Frieden A, et al. Programmed Death-1/Programmed Death-Ligand 1-Axis Blockade in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma Stratified by Human Papillomavirus Status: A Systematic Review and Meta-Analysis. He has authored or co-authored over 120 scientific papers in Polish and international journals (with an impact factor of above 1200, index-H: 32, citation index>4000), and is co-author of national and international recommendations for sarcoma and melanoma. Agreement on Major Pathological Response in NSCLC Patients Receiving Neoadjuvant Chemotherapy. J Clin Oncol (2018) 36(9):8508. RU is funded by NIH/NIDCR R01DE024403, R01DE027736, and NIH/NCI/NIDCR U01DE029188. doi: 10.1038/s41591-020-0805-8, 36. Recently we reported an extension of this study with an additional 29 HNSCC patients treated with two cycles of neoadjuvant pembrolizumab. 2017;15(4):50435. - 50.249.249.18. Provided by the Springer Nature SharedIt content-sharing initiative. A natural extension of this work has led several groups to test whether neoadjuvant chemotherapy prior to surgery would improve clinical outcomes. However, cancer research also faces challenges in the effective development and assessment of targeted therapeutics [1], including the need for early evaluation of potential biomarkers by translational and correlative studies. Immune checkpoint blockade therapies, especially anti-PD-1 and anti-CTLA4, were first approved in advanced melanoma patients (29) and then applied for various cancers (30), which has dramatically impacted the cancer treatment algorithm. He has published more than 180 peer-reviewed papers primarily in the field of CLL and CLL-related disorders. JCI Insight (2018) 3(4):113. PubMed Central 2014;14:31723. The probability of response to CPIs has at least in part been linked to TMB across cancer types, including HNSCC (16). Intriguing findings from this study reported discordant responses between primary tumor and regional metastatic lymph nodes (NCT03238365) (65). PubMed Notably, the treatments were safe and 16/26 patients (61.5%) had pathologic responses (>20%) and 8/26 (31%) of patients experienced complete response (72). is included that studied the role of chemotherapy in patients undergoing definitive locoregional treatment.

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