doi: 10.1016/S0140-6736(13)62422-8, 61. Table1 Completed neoadjuvant immunotherapy clinical trials. In: Proceedings from the American Association for Cancer Research Annual Meeting, April 25, 2017, Washington DC. Understanding Patterns of Pathologic Response Following Neoadjuvant Immunotherapy for Solid Tumors. Cancer Discov (2016) 6(12):138299. Ther Adv Med Oncol (2021) 13:1758835920984061. doi: 10.1177/1758835920984061, 40. Marur S, DSouza G, Westra WH, Forastiere AA. N Engl J Med. All authors contributed to the article and approved the submitted version. Given that CPIs are still expensive drugs and sometimes induce severe immune-related toxicities, it is important to establish the appropriate markers which can predict efficacy of CPIs (39, 40). Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, Chagorova T, de la Serna J, Dilhuydy MS, Illmer T, Opat S, Owen CJ, Samoylova O, Kreuzer KA, Stilgenbauer S, Dhner H, Langerak AW, Ritgen M, Kneba M, Asikanius E, Humphrey K, Wenger M, Hallek M. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. PubMed Article These are the first clear data in HNSCC supporting the finding that neoadjuvant anti-PD1 induced PR is a predictor of clinical outcomes. N Engl J Med (2004) 350(19):194552. Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers. McGrail DJ, Pili PG, Rashid NU, Voorwerk L, Slagter M, Kok M, et al. Kim ES, Herbst RS, Wistuba II, Lee JJ, Blumenschein GR, Tsao A, Stewart DJ, Hicks ME, Erasmus J, Gupta S. The BATTLE trial: personalizing therapy for lung cancer. 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. Google Scholar. N Engl J Med. 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. Study 19 [28, 29] used olaparib against placebo and demonstrated a PFS of 11.2months in BRCA-mutated patients compared with 4.3months for wild-type patients (hazard ratio, 0.18; P<0.0001). cancer [2], melanoma [3, 4], STS [5], head and neck cancer [6]). 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. BMC Cancer (2020) 20(1):229. doi: 10.1186/s12885-020-06726-3, 70. Head Neck. The Annals of Surgical Oncology (ASO) is pleased to announce, The Landmark Series. Article Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Given that the genomic analyses of HNSCC has not identified widely shared oncogenic driver mutations but shows relatively high TMB (49, 50), the relationship between TMB and response to CPIs is promising. 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. 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. 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. Burtness B, Harrington KJ, Greil R, Soulires D, Tahara M, de Castro G Jr, et al. 2013;31(36):45628. His current research is focused on investigating the impact of novel laboratory parameters for assessing prognosis of CLL. Article 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. Saad ED, Paoletti X, Burzykowski T, Buyse M. Precision medicine needs randomized clinical trials. Figure1 Representative figure of pathological tumor response (pTR). doi: 10.1200/JCO.2014.58.6412, 3. Clinical outcomes were better than historical with 70% 1-year disease free survival and 85% 1-year overall survival. This is a preview of subscription content, access via your institution. These data suggest that virus infection status impacts TMB as a biomarker. Di Veroli et al. doi: 10.1126/science.aar3593, 52. Indeed, ibrutinib demonstrated a survival advantage over chlorambucil despite the studys crossover design. Landmark Trials in Oncology pp 217239Cite as. 1991;324:168590. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. PD-1 and CTLA-4 Combination Blockade Expands Infiltrating T Cells and Reduces Regulatory T and Myeloid Cells Within B16 Melanoma Tumors. Bossi P, Lo Vullo S, Guzzo M, Mariani L, Granata R, Orlandi E, et al. 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. 2017;15:57. Bioinformatics. For all cohorts, there was a 90% clinical to pathologic down staging. doi: 10.1016/S0360-3016(96)00430-0, 5. Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, et al. Below are current clinical trials. In addition to ongoing Phase II trials, KEYNOTE-689 is an international phase III study (NCT03765918) where surgically resectable locally advanced HPV-negative HNSCC patients are randomized to receive upfront surgery with SOC adjuvant treatment or neoadjuvant pembrolizumab (two doses) followed by surgery and SOC adjuvant treatment with pembrolizumab (76). In this editorial, we discuss the special article collection entitled Spotlight on landmark oncology trials recently published in BMC Medicine, which focuses on the core clinical trials of selected solid tumours (lung cancer [2], melanoma [3, 4], STS [5], head and neck cancer [6]). doi: 10.1016/j.annonc.2021.02.006, 54. The current results of anti-PD-1 therapy with pembrolizumab or nivolumab monotherapy in melanoma indicated a median overall survival (OS) of approximately 2years, but the combination of anti-PD-1 and anti-CTLA-4 (nivolumab with ipilimumab) was shown to be superior in terms of progression-free survival (PFS) and OS (Table1) [11,12,13,14,15]. HS: writing original draft, tables, and figure. 2016;34(Suppl; abstr 9504). We also highlight selected and recent practice-changing trials in chronic lymphocytic leu-kaemia as well as breast and gynaecological cancers, and review the advances offered by the development of novel clinical trial designs. Ann Oncol (2021) 32(5):66172. Intriguing findings from this study reported discordant responses between primary tumor and regional metastatic lymph nodes (NCT03238365) (65). Frezza AM, Stacchiotti S, Gronchi A. Neoadjuvant and Adjuvant Nivolumab and Lirilumab in Patients With Recurrent, Resectable Squamous Cell Carcinoma of the Head and Neck. 2016;34(30):363847. Second, in contrast to conventional chemotherapy, immunotherapy is much better tolerated by patients. Neoadjuvant immunotherapy has the potential to enhance clinical outcomes by increasing anti-tumor immune responses in the presence of abundant tumor-derived antigen in an immune microenvironment that has not been exposed to previous therapy. 1. Cookies policy. A meta-analysis which examined the results of clinical trials including Checkmate 141, KEYNOTE-012, KEYNOTE-055 showed that HPV infection status was associated with the response rate to anti-PD-1 treatment independently of PD-L1 expression and TMB in HNSCC (45). Filter this list of studies by location, status and more. Therapeutically, HPV-positive HNSCC demonstrates sensitivity to chemoradiotherapy, and offers a better prognosis (2). doi: 10.1172/jci.insight.89829, 18. Cooper JS. Chan TA, Yarchoan M, Jaffee E, Swanton C, Quezada SA, Stenzinger A, et al. 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). Further clinical trials are under way to determine how best to integrate combination immunotherapy and other treatment modalities as well as to establish the correct sequence of therapy with targeted treatment in BRAF-mutated cases. Head Neck (2005) 27(10):84350. doi: 10.1126/science.1208130, 12. Postoperative Concurrent Radiotherapy and Chemotherapy for High-Risk Squamous-Cell Carcinoma of the Head and Neck. on behalf of the MAC-NPC Collaborative Group. I. doi: 10.1158/1078-0432.CCR-19-2209, 39. Article Neoadjuvant Nivolumab or Nivolumab Plus Ipilimumab in Untreated Oral Cavity Squamous Cell Carcinoma: A Phase 2 Open-Label Randomized Clinical Trial. In addition to this design, immunotherapy is being integrated in several neoadjuvant combinations with radiation or chemotherapy prior to surgery. Therefore, in absence of data from this and similar trials, either therapeutic choice is adequate in the day-to-day practice. 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. NEngl J Med (2016) 375(19):185667. Lancet (2014) 384(9938):16472. Xiong Y, Neskey DM, Horton JD, Paulos CM, Knochelmann HM, Armeson KE, et al. CAS KEYNOTE-689: Phase 3 Study of Adjuvant and Neoadjuvant Pembrolizumab Combined With Standard of Care (SOC) in Patients With Resectable, Locally Advanced Head and Neck Squamous Cell Carcinoma. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A. KEYNOTE-006 investigators. These included oral mucositis and one patient with autoimmune diabetes (68) and there were no surgical delays. He is a member of several Polish and international scientific societies (Board member and Past-President of Polish Society Surgical Oncology and Ex-member of the Board of Directors of the Connective Tissue Oncology Society). Haddad R, ONeill A, Rabinowits G, Tishler R, Khuri F, Adkins D, et al. A phase II trial was reported by Xiong etal. J Clin Oncol (2021) 39(15_suppl):60533. Cancer Discov. N Engl J Med (2018) 378(21):197686. Pathologic complete response means the ablation of all cancer cells in resected tumor after the treatment. Bonner J, et al. However, the proportion of CD4+ T cells were decreased while the rate of CD4+FoxP3+ regulatory T cells was increased with treatment. Lancet. doi: 10.1056/NEJMoa1305133, 30. We classified pTR into pTR-0 (10%), pTR-1 (10-49%), and pTR-2 (50%) (54). J Clin Oncol (2014) 32(25):273543. IC continues to be used at some centers with defined indications including advanced or borderline resectable tumors. Gianni L, Pienkowski T, Im YH, Tseng LM, Liu MC, Lluch A, Starosawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi GV, Magazz D, McNally V, Douthwaite H, Ross G, Valagussa P. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Key pathological findings after neoadjuvant immunotherapy include 1) keratinous debris, 2) giant cells, histiocytic reaction and 3) tumor necrosis. Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, et al. B Cell Signatures and Tertiary Lymphoid Structures Contribute to Outcome in Head and Neck Squamous Cell Carcinoma. Manage cookies/Do not sell my data we use in the preference centre. In fact, meta-analysis of melanoma neoadjuvant immunotherapy trials has shown that any degree of pathologic response and not just MPR/pCR, was correlated with better clinical outcomes (64). 2014;15(8):85261. Adaptive designs for dual-agent phase I dose-escalation studies. Checkpoint Blockade Cancer Immunotherapy Targets Tumour-Specific Mutant Antigens. SS: editing the manuscript. doi: 10.1172/jci.insight.98811, 53. statement and The goals of induction chemotherapy are to achieve rapid tumor responses in particular with large volume disease and to chemo-select patients prior for definitive (chemo)radiotherapy or surgery. There were no treatment related delays thus achieving the primary safety endpoint. In another phase II neoadjuvant pembrolizumab clinical trial, we reported no severe grade 3/4 AEs and no surgical delays in a total of 36 treated HNSCC patients (54). (NCT03021993), in which a total of 10 locally advanced OSCC patients were treated with neoadjuvant nivolumab (3 mg/kg on days 1, 14 and 28) (69). Safety and Tumor Responses With Lambrolizumab (Anti-PD-1) in Melanoma. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebb C, Ferraresi V, Smylie M, Weber JS, Maio M, Bastholt L, Mortier L, Thomas L, Tahir S, Hauschild A, Hassel JC, Hodi FS, Taitt C, de Pril V, de Schaetzen G, Suciu S, Testori A. doi: 10.1080/2162402X.2019.1581530, 34. Head and neck cancer is growing in incidence. Rituximab plus chlorambucil as first-line treatment for chronic lymphocytic leukemia: Final analysis of an open-label phase II study. 2015;385(9980):187383. Redman JM, Gibney GT, Atkins MB. doi: 10.1200/JCO.2021.39.15_suppl.6006, 75. Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus-Unrelated Head and Neck Cancer: A Multicenter, Phase II Trial. PR is Professor of Surgical Oncology at the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology in Warsaw, Poland. Any pTR was seen in 44% and pTR-2 was seen in 22% of patients. 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). Economic burden of chronic lymphocytic leukemia in the era of oral targeted therapies in the United States. doi: 10.1126/science.aax0902, 10. In a spontaneous mouse metastatic breast cancer model, neoadjuvant checkpoint inhibitors showed an enhanced survival compared to the adjuvant setting by suppressing metastatic lesions (37). Forde PM, Chaft JE, Smith KN, Anagnostou V, Cottrell TR, Hellmann MD, et al. In a landmark trial, a . Induction Chemotherapy Followed by Cetuximab Radiotherapy Is Not Superior to Concurrent Chemoradiotherapy for Head and Neck Carcinomas: Results of the GORTEC 2007-02 Phase III Randomized Trial. This overview examines the treatment history of neoadjuvant approaches for HNSCC, and especially focuses on the recent topics of neoadjuvant immunotherapy for HNSCC. The RTOG 90-03 trial compared four radiation therapy fractionation schemes for locoregionally advanced patients undergoing radiation therapy alone and is discussed. BMC Med. Lancet Oncol. Impact of Neoadjuvant Durvalumab With or Without Tremelimumab on CD8(+) Tumor Lymphocyte Density, Safety, and Efficacy in Patients With Oropharynx Cancer: CIAO Trial Results. J Clin Oncol (2012) 30(15):1796804. elective versus therapeutic neck dissection in node-negative oral cancer. N Engl J Med. As mentioned above, to date neoadjuvant immunotherapy has been shown to be safe and has not resulted in surgical delays. 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. Quantitative Assessment of the Heterogeneity of PD-L1 Expression in Non-Small-Cell Lung Cancer. Google Scholar. On the other hand, MPR represents 10% of residual viable tumor (63). doi: 10.1200/JCO.2016.70.1524, 45. A Randomized Phase III Trial Comparing Induction Chemotherapy Followed by Chemoradiotherapy Versus Chemoradiotherapy Alone as Treatment of Unresectable Head and Neck Cancer. This was followed by BATTLE-2 [42], testing combination treatments in the same disease. doi: 10.1016/0360-3016(92)90027-F, 19. Improved Efficacy of Neoadjuvant Compared to Adjuvant Immunotherapy to Eradicate Metastatic Disease. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomized phase 3 trial. Induction Chemotherapy Plus Radiation Compared With Surgery Plus Radiation in Patients With Advanced Laryngeal Cancer. Lancet Oncol. Barker AD, Sigman CC, Kelloff GJ, Hylton NM, Berry DA, Esserman LJ. Lancet. Moreover, three anti-PD-1/anti-PD-L1 agents, pembrolizumab, nivolumab and atezolizumab, have been approved for second-line therapy of NSCLC [16,17,18]; however, contrary to melanoma, patient selection to therapy should be based on PD-L1 expression level of tumour cells. Nivolumab (3 mg/kg) was administered on weeks 1 and 3, while ipilimumab (1 mg/kg) was given on week 1 only. BMC Med 15, 111 (2017). Friedman J, Moore EC, Zolkind P, Robbins Y, Clavijo PE, Sun L, et al. Indeed, BATTLE, a landmark phase II trial using an adaptive randomised design, tested four novel drugs and biomarker pairings in NSCLC [41]. TMB is a potential predictive biomarker that also needs further exploration. There are hundreds of trials to choose from, and therefore, no claim toward completeness can be made in the current format. In this review, we present a brief overview of the history of neoadjuvant (induction) chemotherapy in the definitive surgical management of HNSCC. California Privacy Statement, The checkmate 141 phase III trial evaluated the effect of anti-PD-1 (nivolumab) for R/M HNSCC patients (12). Google Scholar. 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. Both trials demonstrated significant benefit for maintenance PARP inhibitors in all subgroups of platinum-sensitive relapsed high-grade serous ovarian cancer. Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol. 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). Completed and ongoing trials have focused on a diverse group of HNSCC patients including early and advanced stage and HPV-positive and negative patients. Immune-Modified Response Evaluation Criteria In Solid Tumors (imRECIST): Refining Guidelines to Assess the Clinical Benefit of Cancer Immunotherapy. Furthermore, tertiary lymphoid structures (TLS) in the tumor bed are suggested tocontribute favorable outcome (55). Patients with high-TMB have more effective clinical responses with improved survival in lung, bladder, and head and neck cancer patients (47, 48). These results underscore that TPF IC is not recommended for survival benefit. 2006;64(1):7782. Notably, patients with PR (partial plus major) showed significantly improved 1-year DFS compared to patients with no PR (100% versus 68%, p = 0.01; HR = 0.23). doi: 10.1200/JCO.2021.39.15_suppl.6008, 76. Compared to our initial cohort with one dose, we found that 50% of patients had any pTR and 44% of patients exhibited pTR2. Zuur CL, Elbers JBW, Vos JL, Avd L, Qiao X, Karakullukcu B, et al. Median PFS was 9.5months in the fulvestrant plus palbociclib group and 4.6months in the fulvestrant plus placebo group with a hazard ratio of 0.46, which was highly statistically significant. Received: 18 June 2021; Accepted: 19 August 2021;Published: 06 September 2021. Szturz P, Vermorken JB. doi: 10.1093/annonc/mdy507, 41. Novel trial designs could potentially lead to a different type of landmark trial that would accelerate the process and allow cancer patients to access new treatments faster. Bernier J, et al. Considering the treatment nave situation and the absence of treatment-resistant cells compared with the R/M setting, neoadjuvant immunotherapy is hypothetically likely able to result in a strong and durable therapeutic effect. The era of precision medicine has led to significant developments in the therapy of advanced soft tissue sarcomas (STS), breast cancer, ovarian cancer and haematological neoplasms, among others. Definition and Impact of Pathologic Complete Response on Prognosis After Neoadjuvant Chemotherapy in Various Intrinsic Breast Cancer Subtypes. 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 These patients have the worst prognosis despite multimodality approaches and may benefit from neoadjuvant/adjuvant immunotherapy. 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. PubMed Central BMC Med. Despite this multi-modality treatment, advanced human papillomavirus (HPV)-negative HNSCC shows poor prognosis. Differences in T-Cell Infiltrates and Survival Between HPV+ and HPV- Oropharyngeal Squamous Cell Carcinoma. J Clin Oncol (2017) 35(14):15429. Histological Assessment. 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. Lancet Oncol (2014) 15(1):e4250. [39] published an interesting software to provide information in terms of synergy and/or antagonism between two compounds. Haddad R, et al. A potential shortcoming with the upfront use of ibrutinib includes cost and indefinite treatment course [37]. https://doi.org/10.1007/978-3-030-14405-0_7, DOI: https://doi.org/10.1007/978-3-030-14405-0_7. DCruz A, et al. doi: 10.1056/NEJMoa1801946, 48. Following this, the phase III KEYNOTE-048 trial established a new paradigm for first-line R/M HNSCC patients (14). Thus, targeting immune suppression pathways with checkpoint inhibitors has been broadened to the exploration of therapeutic options in all HNSCC treatment settings. Ann Oncol (2019) 30(1):5767. 2017;15:55. Historically, surgery and radiotherapy with/without conventional chemotherapy including platinum, taxanes or fluorouracil, were applied to treat HNSCC. Furthermore, the one-year relapse rate in high-risk patients was 16.7%, which was lower than historical data. Future Sci OA (2016) 2(1):Fso88. Adaptive randomization of neratinib in early breast cancer. Treatment intensification with neoadjuvant (induction) chemotherapies with platinum drugs are insufficient to significantly prolong overall survival. Being a member of the American Society Clinical Oncology (ASCO), American Society Hematology (ASH), European Society Hematology, he is actively involved in the GIMEMA (Gruppo Italiano Malattie Ematologiche Adulto) lymphoproliferative working group as a member of the working party. Clin Pharmacol Ther. Lancet (2019) 394(10212):191528. Oliva M, Spreafico A, Taberna M, Alemany L, Coburn B, Mesia R, et al. Contact: Elizabeth Akoth, 240-858-3154. Pathological Response After Neoadjuvant Chemotherapy in Resectable Non-Small-Cell Lung Cancers: Proposal for the Use of Major Pathological Response as a Surrogate Endpoint. A study in over 300 patients across 22 solid tumor types from four KEYNOTE trials and an observational study of 126 HNSCC patients revealed HNSCC patients with high TMB showed significantly better anti-PD-1 response (51, 52). As further investigation of these intriguing results is needed, the SITC HNSCC immunotherapy guidelines does not recommend using HPV status for anti-PD1 treatments in R/M HNSCC (31). RU: editing and supervising the manuscript, tables and figure. A pooled analysis of data from these two postoperative trials is included, which was designed to analyze the selection criteria, clinical and pathologic risk factors, and outcomes and to establish precisely which patients benefit from the addition of cisplatin to postoperative radiation therapy. The landmark phase III CheckMate 141 trial resulted in the approval of nivolumab in the R/M second-line HNSCC setting (12). Yamazaki H, et al. 2015;372(26):252132. BMC Med. Both trials did not show a significant extension of OS and DFS, consistent with the subsequent studies (24, 25). 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. Landmark Trials in Selected Head and Neck Cancers. Front. Thus, further studies are needed to define the role of TMB as a predictive biomarker. Recent clinical trials of neoadjuvant immunotherapy show promising results and this methodology has the potential to change the treatment algorithm of HNSCC. doi: 10.1002/hed.20279, 7. Conventional HNSCC is mainly caused by habitual alcohol drinking and smoking, and often occurs in older adults, while human papillomavirus (HPV)-related HNSCC of the oropharyngeal region is rapidly increasing in relatively younger patients (1). Nat Med (2021) 27(2):3019. N Engl J Med (1991) 324(24):168590. Price KAR, Nichols AC, Shen CJ, Rammal A, Lang P, Palma DA, et al. Springer Nature. J Immunother Cancer (2021) 9(5):115. Huang SH, Xu W, Waldron J, Siu L, Shen X, Tong L, et al. 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. 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). doi: 10.1038/nature13988, 16. Expert Rev Hematol. Yearley JH, Gibson C, Yu N, Moon C, Murphy E, Juco J, et al. doi: 10.4155/fso.15.88, 44. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomized trials and 17,346 patients. This is multi-institutional trial enrolled 92 patients and 76 patients were evaluable for DFS. Lancet Oncol. Randomized Phase III Trial of Induction Chemotherapy With Docetaxel, Cisplatin, and Fluorouracil Followed by Surgery Versus Up-Front Surgery in Locally Advanced Resectable Oral Squamous Cell Carcinoma. Recent landmark trials in HER2-positive breast cancer include those using dual HER2-targeted therapy pertuzumab and trastuzumab with docetaxel. Kiong KL, Yao C, Lin FY, Bell D, Ferrarotto R, Weber RS, et al. doi: 10.1056/NEJMoa031317, 24. 2018. 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. We reported a phase II trial, in which neoadjuvant/adjuvant pembrolizumab was tested in locally advanced, resectable HPV-negative HNSCC patients (NCT02296684) (54). 2016;375(22):215464. Ann Oncol (2018) 29(8):16302. https://doi.org/10.1007/978-3-030-14405-0_7, Tax calculation will be finalised during checkout. doi: 10.1038/nature12477, 51. This trial included both definitive and salvage surgery patients. She is an Editorial Board Member for BMC Medicine. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. doi: 10.1200/JCO.2017.75.1644, 57. 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).
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