landmark trials in head and neck cancer ppt

Park JW, Liu MC, Yee D, Yau C, van t Veer LJ, Symmans WF, Paoloni M, Perlmutter J, Hylton NM, Hogarth M, DeMichele A, Buxton MB, Chien AJ, Wallace AM, Boughey JC, Haddad TC, Chui SY, Kemmer KA, Kaplan HG, Isaacs C, Nanda R, Tripathy D, Albain KS, Edmiston KK, Elias AD, Northfelt DW, Pusztai L, Moulder SL, Lang JE, Viscusi RK, Euhus DM, Haley BB, Khan QJ, Wood WC, Melisko M, Schwab R, Helsten T, Lyandres J, Davis SE, Hirst GL, Sanil A, Esserman LJ, Berry DA, I-SPY 2 Investigators. 2016;387:154050. A clinical trial studying the side effects of chemotherapy for patients with locally recurrent head and neck squamous cell carcinoma. HE has received research funding from Cancer Research UK and the NIHR HTA, and is funded by the NIHR Cambridge Biomedical Research Centre. doi: 10.1158/1078-0432.CCR-19-3977, 71. N Engl J Med. 2012;379:187986. These studies with previously untreated tumors may enable establishment of predictive biomarkers to select appropriate patients and also define mechanistic pathways. 2015;373(1):2334. Combenefit: an interactive platform for the analysis and visualization of drug combinations. 2015;373(25):242537. J Clin Oncol. Analysis of the data gathered from these large trials continues to contribute valuable understanding about related issues, including . Springer, Cham. Barker AD, Sigman CC, Kelloff GJ, Hylton NM, Berry DA, Esserman LJ. N Engl J Med. Nevertheless, the selection of systemic therapy must be strictly individualised and based upon several factors, including the histology and biological behaviour of the disease. Google Scholar. Head And Neck Cancer - SlideShare doi: 10.1056/NEJMoa1305133, 30. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. His current research is focused on investigating the impact of novel laboratory parameters for assessing prognosis of CLL. Considering the high-frequency of severe adverse events and lack of significant effect OS prolongation with induction chemotherapy, neoadjuvant immunotherapy thus represents an attractive option for advanced HNSCC treatment. Updated results of a phase II neoadjuvant pembrolizumab trial prior to surgery followed by adjuvant concurrent pembrolizumab and radiation along with cisplatin for clinically high-risk (T3/4 stage and/or 2+ LNs) HPV-negative HNSCC patients (NCT02641093) were recently presented (74). For example, in a phase II trial, platinum combined with immunotherapy (nivolumab) followed by transoral robotic surgery (TORS) or RT/CRT is being examined in oropharyngeal cancer patients (NCT03107182). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. van der Graaf WT, Blay JY, Chawla SP, Kim DW, Bui-Nguyen B, Casali PG, Schffski P, Aglietta M, Staddon AP, Beppu Y, Le Cesne A, Gelderblom H, Judson IR, Araki N, Ouali M, Marreaud S, Hodge R, Dewji MR, Coens C, Demetri GD, Fletcher CD, Dei Tos AP, Hohenberger P, EORTC Soft Tissue and Bone Sarcoma Group; PALETTE study group. It is meant to be an educational resource . Pembrolizumab versus ipilimumab in advanced melanoma. doi: 10.1200/JCO.2021.39.15_suppl.6008, 76. Bertrand Baujat et al. It has become clear that neoadjuvant immunotherapy, especially checkpoint inhibitors, are safe and have shown signals of clinical efficacy in HNSCC. doi: 10.1016/S0140-6736(13)62422-8, 61. Table1 Completed neoadjuvant immunotherapy clinical trials. 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). Bonner J, et al. Part of Springer Nature. doi: 10.1080/2162402X.2019.1581530, 34. Immunological Effects of Nivolumab Immunotherapy in Patients With Oral Cavity Squamous Cell Carcinoma. Nature (2015) 517(7536):57682. Ann Oncol (2019) 30(1):5767. Clin Pharmacol Ther. 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. Cohen EEW, Soulires D, Le Tourneau C, Dinis J, Licitra L, Ahn MJ, et al. In the phase I setting, there is a pressing need to develop better trial methodologies for novel combinations, often of a standard chemotherapy with a novel targeted agent. Terms and Conditions, Google Scholar. He works very closely with national patient advocacy groups for GIST and sarcoma and is Chairman of the Melanoma Academy in Poland. doi: 10.1056/NEJMoa2002788, 31. Proc Natl Acad Sci USA (2010) 107(9):427580. doi: 10.1200/JCO.2014.58.6412, 3. Ann Oncol (2018) 29(8):185360. With the positive responses in the R/M HNSCC setting, several trials have reported results with neoadjuvant checkpoint immunotherapy prior to surgery (Table1). 14 Articles, This article is part of the Research Topic, Rationale of Neoadjuvant Immunotherapy for HNSCC, Patient Selection for Neoadjuvant Immunotherapy, Biomarker Candidates for Neoadjuvant Immunotherapy, Pathologic Response Criteria for Neoadjuvant Immunotherapy, Clinical Studies of Neoadjuvant Immunotherapy for HNSCC, Immune Related Adverse Events in Neoadjuvant Immunotherapy Treated Patients, Creative Commons Attribution License (CC BY). He has participated in several investigator-driven trials in melanoma and sarcoma. 2014;32(12):123641. doi: 10.1200/JCO.2017.75.1644, 57. Earl, H., Molica, S. & Rutkowski, P. Spotlight on landmark oncology trials: the latest evidence and novel trial designs. The FOCUS 4 trial in metastatic colorectal cancer uses group-sequential multi-arm, multi-stage methodology [46] to achieve similar matching of novel therapy and biomarker groups. The November 3, 2021 "Clinical Trial Endpoint Development" (12pm - 5:00 pm ET) will address Locally Advanced Head and Neck Squamous Cell Carcinoma (HNSCC) 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. 20 studies in Head and Neck Cancer Center (open studies only). There was an 86% MPR rate and a 67% pCR rate. Cohen EEW, Bell RB, Bifulco CB, Burtness B, Gillison ML, Harrington KJ, et al. The head and neck region is anatomically complex and serves essential functions such as eating, speaking, and breathing. The expression level of PD-L1 in the tumor does not necessarily correlate withthe response to CPIs. I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Adaptive designs for dual-agent phase I dose-escalation studies. 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%. RU is funded by NIH/NIDCR R01DE024403, R01DE027736, and NIH/NCI/NIDCR U01DE029188. Notably, the timing of immune checkpoint inhibitors may influence the outcome of cancer treatment (33). Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. She is an Editorial Board Member for BMC Medicine. Improved Efficacy of Neoadjuvant Compared to Adjuvant Immunotherapy to Eradicate Metastatic Disease. Patients with high-TMB have more effective clinical responses with improved survival in lung, bladder, and head and neck cancer patients (47, 48). 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. Chan TA, Yarchoan M, Jaffee E, Swanton C, Quezada SA, Stenzinger A, et al. HPV-Associated Head and Neck Cancer: A Virus-Related Cancer Epidemic. These early studies led to two randomized Phase III trials, which provided Level 1 evidence supporting the use of concurrent chemoradiotherapy in high-risk HNSCC patients (57). PD-1 and CTLA-4 Combination Blockade Expands Infiltrating T Cells and Reduces Regulatory T and Myeloid Cells Within B16 Melanoma Tumors. Correspondence to These data indicate that PD-L1 expression on tumor cells is not a perfect biomarker to predict the clinical outcome. NEngl J Med (2008) 359(11):111627. In this review, we present a brief overview of the history of neoadjuvant (induction) chemotherapy in the definitive surgical management of HNSCC. It remains the fifth leading cause of cancer in the United States and constitutes 10% or more of all cancers worldwide. JAMA Oncol (2016) 2(1):4654. I. Al-Saraff M, et al. head neck oncology advances.ppt - Google Slides This was nearly double what we saw with one dose of pembrolizumab. Another topic featured in this article collection is systemic therapy in STS [5], which is a heterogeneous group of rare solid tumours. Several landmark trials established the clinical benefit of using cisplatin-based chemoradiotherapy after surgery for locally advanced, high-risk HNSCC patients (3, 4). Landmark Trials | Division of Cancer Prevention 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. 2014;15(8):85261. Patients with high-TMB have more effective clinical responses with improved survival in lung, bladder, and head and neck cancer patients (47, 48). By using this website, you agree to our Our doctors are running clinical trials testing: new drug therapies for head and neck cancer, including immunotherapies and targeted therapies, that can boost the effectiveness of your care. Cookies policy. Geoffrois L, Martin L, De Raucourt D, Sun XS, Tao Y, Maingon P, et al. Google Scholar. Nature (2013) 502(7471):3339. 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. evaluated the role of measuring plasma EBV DNA and is included. Ann Oncol (2019) 30(1):4456. These results underscore that TPF IC is not recommended for survival benefit. https://doi.org/10.1007/978-3-030-14405-0_7, Tax calculation will be finalised during checkout. The pTR rate is calculated as the area of regions 1-3/(1-3)+area of any remaining tumor. 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. Landmark Trials in Selected Head and Neck Cancers - ResearchGate Patients also received 6 months of adjuvant nivolumab and lirilumab. An important consideration in neoadjuvant immunotherapy approaches is appropriate patient selection. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. Finally, considering the ease of biopsies in the head and neck region, compared to adjuvant immunotherapy, neoadjuvant immunotherapy has the benefit to enable translational efforts such as TCR analysis, gene-expression profiling, and cytokine evaluation in the primary tumor which is not affected by other treatments including chemotherapeutics or radiation. 2015;372(26):252132. statement and Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, Bairey O, Hillmen P, Bartlett NL, Li J, Simpson D, Grosicki S, Devereux S, McCarthy H, Coutre S, Quach H, Gaidano G, Maslyak Z, Stevens DA, Janssens A, Offner F, Mayer J, ODwyer M, Hellmann A, Schuh A, Siddiqi T, Polliack A, Tam CS, Suri D, Cheng M, Clow F, Styles L, James DF, Kipps TJ, RESONATE-2 Investigators. Defining Risk Levels in Locally Advanced Head and Neck Cancers: AComparative Analysis of Concurrent Postoperative Radiation Plus Chemotherapy Trials of the EORTC (#22931) and RTOG (# 9501). PD-L2 Expression in Human Tumors: Relevance to Anti-PD-1 Therapy in Cancer. The radiographic volumetric response (RVR) and PTE were evaluated, and the results of RVR and PTE was significantly correlated in primary tumor and lymph nodes. Refining American Joint Committee on Cancer/Union for International Cancer Control TNM Stage and Prognostic Groups for Human Papillomavirus-Related Oropharyngeal Carcinomas. Cristescu R, Mogg R, Ayers M, Albright A, Murphy E, Yearley J, et al. Neoadjuvant Nivolumab or Nivolumab Plus Ipilimumab in Untreated Oral Cavity Squamous Cell Carcinoma: A Phase 2 Open-Label Randomized Clinical Trial. 2009;86(1):97100. The strength of the study also relies on the good tolerance profile of ibrutinib, which allows it to be administered continuously and provide indefinite disease suppression even in elderly or unfit CLL patients. The Head and Neck Cancer Immune Landscape and Its Immunotherapeutic Implications. Note, there are institution specific protocols where induction chemotherapy prior to surgery is still used for larger tumors to achieve more rapid control (21). Science (2018) 362(6411):110. University of Cambridge Department of Oncology, NIHR Cambridge Biomedical Research Centre, and Hon Consultant in Medical Oncology, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK, Department Hematology-Oncology, Azienda Ospedaliera Pugliese-Ciaccio, 88100, Catanzaro, Italy, Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Institute - Oncology Center, Roentgena 5, 02-781, Warsaw, Poland, You can also search for this author in doi: 10.1136/jitc-2021-002568corr1, 68. Using a primary radiation based approach, several ongoing clinical trials aim to de-intensify the treatment impact by adding immunotherapy (77). She has also received unrestricted educational grants to support investigator initiated clinical trials from Lilly, Roche and Sanofi Aventis, and has received free gemcitabine from Lilly and free bevacizumab from Roche for clinical trials. Head and Neck Cancer | NEJM 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. Neoadjuvant PD-1 Immune Checkpoint Blockade Reverses Functional Immunodominance Among Tumor Antigen-Specific T Cells. doi: 10.1200/JCO.2012.43.8820, 28. doi: 10.1126/science.1208130, 12. doi: 10.1016/j.radonc.2009.04.014, 9. doi: 10.1016/S0360-3016(96)00430-0, 5. Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, et al. Lancet Oncol (2014) 15(1):e4250. The RTOG 90-03 trial . 2015;372(8):72434. 2006;64(1):4756. The Neoadjuvant Immuno-RadioTherapy (NIRT) phase Ib trial tested neoadjuvant stereotactic body radiation therapy (SBRT) with nivolumab (240 mg, q2 weeks x 3) prior to surgery in HNSCC patients (NCT03247712) (66). These trials will test the important topic of whether there is synergy in combination approaches with RT, immunotherapy and/or chemotherapy. Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, et al. Despite optimal local treatment, approximately 50% of adult patients with localised STS develop distant metastases and die of metastatic disease. Three trials dealing with nasopharynx cancer are discussed including the Intergroup 0099 trial and the MAC-NPC Collaborative Group meta-analysis which studied the role of chemotherapy. Nivolumab (3 mg/kg) was administered on weeks 1 and 3, while ipilimumab (1 mg/kg) was given on week 1 only. Despite these efforts to improve clinical prognosis, the five-year survival rate of locally advanced stage III/IV HNSCC patients is still sub-optimal [53% in postoperative CCRT treated patients (7)], and half of advanced patients show recurrence within three years (8). Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, Park K, Smith D, Artal-Cortes A, Lewanski C, Braiteh F, Waterkamp D, He P, Zou W, Chen DS, Yi J, Sandler A, Rittmeyer A, POPLAR Study Group. The landmark oncology trials highlighted in the BMC Medicine series Spotlight on landmark oncology trials and this editorial are recent trials that have produced practice-changing results for patients. Curran MA, Montalvo W, Yagita H, Allison JP. Pan-Tumor Genomic Biomarkers for PD-1 Checkpoint Blockade-Based Immunotherapy. Our own group is developing a novel Bayesian, adaptive randomised methodology [47]. Final results of local-regional control and late toxicity of RTOG 90-03; a randomized trial of altered fractionation radiation for locally advanced head and neck cancer. Huang SH, Xu W, Waldron J, Siu L, Shen X, Tong L, et al. With the advent of novel oral agents that are well tolerated and highly efficacious, the therapeutic landscape of CLL underwent radical changes [31]. Eur J Cancer. Lancet. Immune cells phenotypes in TME may also be important topredict the response to CPIs. Neoadjuvant Immunotherapy Leads to Pathological Responses in MMR-Proficient and MMR-Deficient Early-Stage Colon Cancers. J Clin Oncol (2019) 37(15_suppl):25755. doi: 10.1158/1078-0432.CCR-20-1695, 55. Induction Chemotherapy Plus Radiation Compared With Surgery Plus Radiation in Patients With Advanced Laryngeal Cancer. Pembrolizumab Versus Methotrexate, Docetaxel, or Cetuximab for Recurrent or Metastatic Head-and-Neck Squamous Cell Carcinoma (KEYNOTE-040): A Randomised, Open-Label, Phase 3 Study. Preoperative Chemotherapy in Advanced Resectable OCSCC: Long-Term Results of a Randomized Phase III Trial. doi: 10.1001/jamaoncol.2020.2955, 69. 2014;89(1):1320. Int J Radiat Oncol Biol Phys. examined neoadjuvant 1) nivolumab (N) or 2) nivolumab plus ipilimumab (N+I) in untreated 29 oral cavity cancer patients in a phase II trial (eligible for T2 or node positive) (NCT02919683) (68). N Engl J Med. Clinical outcomes were better than historical with 70% 1-year disease free survival and 85% 1-year overall survival. However, the five-year survival rate is still below 50% in advanced HPV-negative HNSCC patients (8), and many patients suffer from severe impact on essential functions. In this trial, only one patient showed a grade III AE (rash) while no patients had grade IV AE, consistent with the safety and tolerability of neoadjuvant immunotherapy (75). quantification of plasma epstein-barr virus DNA in patients with advanced nasopharyngeal carcinoma. Despite this multi-modality treatment, advanced human papillomavirus (HPV)-negative HNSCC shows poor prognosis. 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. Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al. A potential shortcoming with the upfront use of ibrutinib includes cost and indefinite treatment course [37]. doi: 10.1016/0360-3016(92)90027-F, 19. Rutkowski P, Kozak K. News from the melanoma sessions of the European Cancer Congress 2017. Zhong LP, Zhang CP, Ren GX, Guo W, William WN Jr., Sun J, et al. There were excellent clinical outcomes and only one patient required adjuvant chemoradiation. Note that MPR was observed in 8 (29%) patients in either the primary tumor or lymph node metastasis. Association of Pathological Response to Neoadjuvant Pembrolizumab With Tumor PD-L1 Expression and High Disease-Free Survival (DFS) in Patients With Resectable, Local-Regionally Advanced, Head and Neck Squamous Cell Carcinoma (HNSCC). J Clin Oncol (2018) 36(9):8508. SM is Chief of the Department Hematology-Oncology at the Azienda Ospedaliera Pugliese-Ciaccio Catanzaro, Italy. Liu J, ODonnell JS, Yan J, Madore J, Allen S, Smyth MJ, et al. Compared to our initial cohort with one dose, we found that 50% of patients had any pTR and 44% of patients exhibited pTR2. A study by Lin et al. Gillison ML, et al. BMC Med. Phase 2, Open-Label, Single Arm Study, With BST-236 in Adults With R/R AML or Higher-Risk MDS. Pembrolizumab for Platinum- and Cetuximab-Refractory Head and Neck Cancer: Results From a Single-Arm, Phase II Study. Treatment intensification with neoadjuvant (induction) chemotherapies with platinum drugs are insufficient to significantly prolong overall survival. doi: 10.1056/NEJMoa1801946, 48. 2013;14:25764. In phase 3 trials, ibrutinib, a first-in-class Bruton tyrosine kinase (BTK) inhibitor, showed efficacy over traditional salvage therapeutic options in patients with relapsed or refractory CLL [32]. Cottrell TR, Thompson ED, Forde PM, Stein JE, Duffield AS, Anagnostou V, et al. In addition, CD8+ T cells with lymphocyte-activation gene 3 (LAG-3) or T cell immunoglobulin domain and mucin domain-3 (TIM-3) co-expression with PD-1 was higher among non-responders (52). The Department of Veterans Affairs Laryngeal Cancer Study Group. 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).
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