landmark trials in head and neck cancer ppt

N Engl J Med (2018) 378(21):197686. These patients have the worst prognosis despite multimodality approaches and may benefit from neoadjuvant/adjuvant immunotherapy. Ruffin AT, Cillo AR, Tabib T, Liu A, Onkar S, Kunning SR, et al. Int J Radiat Oncol Biol Phys (1996) 36(5):9991004. doi: 10.1093/annonc/mdt461, 25. This enhanced function acts to destroy micro-metastasis in clinically advanced tumors, decreasing loco-regional or distant metastasis after primary therapies. N Engl J Med. 2014;14:31723. PubMed J Clin Oncol (2019) 37(15_suppl):25755. Clin Cancer Res (2020) 26(3):67989. Pathological Response and Survival With Neoadjuvant Therapy in Melanoma: A Pooled Analysis From the International Neoadjuvant Melanoma Consortium (INMC). Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. Histological Assessment. Ann Oncol (2019) 30(1):5767. doi: 10.1073/pnas.0915174107, 72. Piotr Rutkowski. Lancet (2019) 394(10212):191528. PR is Professor of Surgical Oncology at the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology in Warsaw, Poland. Science (2011) 333(6046):115760. Immunotherapy in head and neck cancer: aiming at EXTREME precision. doi: 10.1200/EDBK_280687, Keywords: head and neck squamous cell carcinoma, neoadjuvant immunotherapy, clinical trial, biomarker, pathological tumor response, Citation: Shibata H, Saito S and Uppaluri R (2021) Immunotherapy for Head and Neck Cancer: A Paradigm Shift From Induction Chemotherapy to Neoadjuvant Immunotherapy. Lancet Oncol. 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). Agreement on Major Pathological Response in NSCLC Patients Receiving Neoadjuvant Chemotherapy. IC resulted in larynx preservation but did not contribute to improved survival. In addition, as other checkpoints are testing, further improvements in pathologic responses and clinical outcomes are expected. These data highlight the difficulty of interpreting peripheral lymphocyte populations with clinical responses in HNSCC patients treated with neoadjuvant immunotherapy. doi: 10.1038/nature12634, 50. From a clinical standpoint, he is actively involved in the management and treatment of patients with hematological malignancies and, particularly, those suffering from lymphoproliferative disorders. Although only 15-20% of patients benefit, immunotherapies have been approved and widely used for recurrent and metastatic HNSCC. Pan-Tumor Genomic Biomarkers for PD-1 Checkpoint Blockade-Based Immunotherapy. 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 Al-Saraff M, et al. quantification of plasma epstein-barr virus DNA in patients with advanced nasopharyngeal carcinoma. 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]. 2012;379:187986. BMC Med. In this trial, pembrolizumab monotherapy significantly improved the OS of PD-L1 positive (CPS 20 or CPS 1) HNSCC. Science (2020) 367(6483):12649. Contact: Elizabeth Akoth, 240-858-3154. 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. The Head and Neck Cancer Immune Landscape and Its Immunotherapeutic Implications. Harrington JA, Wheeler GM, Sweeting MJ, Mander AP, Jodrell DI. Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Corts J, CLEOPATRA Study Group. PubMed However, the proportion of CD4+ T cells were decreased while the rate of CD4+FoxP3+ regulatory T cells was increased with treatment. NEngl J Med (2008) 359(11):111627. Refining American Joint Committee on Cancer/Union for International Cancer Control TNM Stage and Prognostic Groups for Human Papillomavirus-Related Oropharyngeal Carcinomas. Rochester, Minn., Jacksonville, Fla. Forastiere A, et al. These successes have led to checkpoint blockade therapies being testing in earlier treatment settings. Patients with high-TMB have more effective clinical responses with improved survival in lung, bladder, and head and neck cancer patients (47, 48). J Clin Oncol. Pembrolizumab versus ipilimumab in advanced melanoma. BMC Med. Lancet. Clin Cancer Res (2020) 26(19):514052. 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. doi: 10.1093/annonc/mdy218, 59. von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, et al. Earl, H., Molica, S. & Rutkowski, P. Spotlight on landmark oncology trials: the latest evidence and novel trial designs. Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott CL, Meier W, Shapira-Frommer R, Safra T, Matei D, Fielding A, Spencer S, Dougherty B, Orr M, Hodgson D, Barrett JC, Matulonis U. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. 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). J Clin Oncol (2021) 39(15_suppl):60533. Recent developments and approvals in immunotherapy have significantly changed the landscape of melanoma and NSCLC therapy in the metastatic setting, and open various possibilities for adjuvant treatment in high-risk locoregional disease [7,8,9,10]. 2014;89(1):1320. Clin Cancer Res (2017) 23(12):315867. These findings highlight the clinical importance to establish standard pathological criteria to accurately evaluate the therapeutic effect of neoadjuvant immunotherapy after definitive surgery. 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. doi: 10.1016/0360-3016(92)90642-U, 4. J Clin Oncol. 2015;373(1):2334. 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). 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%. 1. reported on findings from a clinical trial where neoadjuvant nivolumab (240 mg on days 1 and 15) with or without tadalafil was tested. Clinical outcomes were better than historical with 70% 1-year disease free survival and 85% 1-year overall survival. Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, Fabbro M, Ledermann JA, Lorusso D, Vergote I, Ben-Baruch NE, Marth C, Mdry R, Christensen RD, Berek JS, Drum A, Tinker AV, du Bois A, Gonzlez-Martn A, Follana P, Benigno B, Rosenberg P, Gilbert L, Rimel BJ, Buscema J, Balser JP, Agarwal S, Matulonis UA, ENGOT-OV16/NOVA Investigators. They used pathological response (PR) criteria which was defined tumor necrosis and/or histiocytic inflammation and giant cell reaction to keratinaceous debris (74). Preoperative Chemotherapy in Advanced Resectable OCSCC: Long-Term Results of a Randomized Phase III Trial. We classified pTR into pTR-0 (10%), pTR-1 (10-49%), and pTR-2 (50%) (54). Clin Lung Cancer (2020) 21(4):3418. Immune-Modified Response Evaluation Criteria In Solid Tumors (imRECIST): Refining Guidelines to Assess the Clinical Benefit of Cancer Immunotherapy. 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). Frameshift Events Predict Anti-PD-1/L1 Response in Head and Neck Cancer. Improved Efficacy of Neoadjuvant Compared to Adjuvant Immunotherapy to Eradicate Metastatic Disease. Schachter J, Ribas A, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil CM, Lotem M, Larkin JMG, Lorigan P, Neyns B, Blank CU, Petrella TM, Hamid O, Zhou H, Ebbinghaus S, Ibrahim N, Robert C. Pembrolizumab versus ipilimumab for advanced melanoma: Final overall survival analysis of KEYNOTE-006. Then, we focus on the rationale and clinical trials of neoadjuvant immunotherapy and its potential impact on HNSCC treatment. He is the current Head of the Department of Soft Tissue/Bone Sarcoma and Melanoma, the Plenipotentiary Director of Institute for Clinical Trials at the Maria Sklodowska-Curie Memorial Cancer Center as well as the President of the Scientific Council of Maria Sklodowska-Curie Memorial Cancer Center. 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. NIRT did impact healing of wounds that all ultimately resolved. However, PD-L1 negative tumors sometimes respond to CPI treatment, suggestingthe existence of other mechanisms. RU serves on an advisory board for Merck, Inc. N Engl J Med. Furthermore, tertiary lymphoid structures (TLS) in the tumor bed are suggested tocontribute favorable outcome (55). Nature (2013) 500(7463):41521. 2018. Nat Med (2020) 26(4):56676. doi: 10.1200/JCO.2012.43.8820, 28. Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, et al. J Clin Oncol (2003) 21(2):32733. She has been an expert advisor for NHS NICE Health Technology Assessments. CAS Therefore, in absence of data from this and similar trials, either therapeutic choice is adequate in the day-to-day practice. Schffski P, Chawla S, Maki RG, Italiano A, Gelderblom H, Choy E, Grignani G, Camargo V, Bauer S, Rha SY, Blay JY, Hohenberger P, DAdamo D, Guo M, Chmielowski B, Le Cesne A, Demetri GD, Patel SR. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial. A more recent niraparib study had similar results [30], where patients in the niraparib group had a significantly longer PFS than the placebo group in all cohorts tested (21.0 vs. 5.5months in the gBRCA cohort; 12.9 vs. 3.8months in the non-gBRCA cohort for patients who had tumours with homologous recombination deficiency; and 9.3 vs. 3.9months in the overall non-gBRCA cohort; P<0.001). A. Lorch J, et al. To test the sequencing of these therapies in the laryngeal cancer setting, RTOG 91-11 compared the clinical efficacy of 1) IC followed by RT, 2) CCRT and 3) RT alone for advanced laryngeal cancer patients (23). To be eligible, patients had to have N2 or N3 adenopathy. Immune cells phenotypes in TME may also be important topredict the response to CPIs. Immune Biomarkers of Response to Immune-Checkpoint Inhibitors in Head and Neck Squamous Cell Carcinoma. Indeed, ibrutinib demonstrated a survival advantage over chlorambucil despite the studys crossover design. J Clin Oncol (2015) 33(8):83645. Intriguing findings from this study reported discordant responses between primary tumor and regional metastatic lymph nodes (NCT03238365) (65). doi: 10.1080/2162402X.2019.1581530, 34. Nat Commun (2021) 12(1):3349. doi: 10.1038/s41467-021-23355-x, 56. There are now numerous studies introducing neoadjuvant immunotherapy in diverse cancer types (3436). 2004;350:246170. PubMed These trials will test the important topic of whether there is synergy in combination approaches with RT, immunotherapy and/or chemotherapy. The published and ongoing trials described above focused on single agent checkpoint blockade immunotherapy prior to surgery. evaluated the role of measuring plasma EBV DNA and is included. 1998;16:13107. doi: 10.1158/1078-0432.CCR-16-1761, 43. chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized intergroup study 0099. A trial done by Tata Memorial Centre is included that randomized patients with mostly oral tongue carcinoma to elective neck dissection at the time of primary cancer surgery or watchful waiting with therapeutic neck dissection for nodal relapse. Status: Open - Recruiting. J Clin Oncol (2012) 30(15):1796804. Nat Rev Clin Oncol. Google Scholar. Lancet Oncol. Turner NC, Ro J, Andr F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Huang Bartlett C, Zhang K, Giorgetti C, Randolph S, Koehler M, Cristofanilli M, PALOMA3 Study Group. N Engl J Med. The Department of Veterans Affairs Laryngeal Cancer Study Group. doi: 10.1016/S0140-6736(13)62422-8, 61. safer and more-effective approaches to head and neck radiation therapy. 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. Epidemiology. Notably, any pTR after neoadjuvant pembrolizumab correlated with baseline tumor PD-L1, immune infiltration, and IFN- activity, but not TMB. Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K, Sivachenko A, et al. Zhong LP, Zhang CP, Ren GX, Guo W, William WN Jr., Sun J, et al. Cancer Discov. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. In the neoadjuvant immunotherapy context, immune-modified RECIST (imRECIST) criteria have been proposed (56). Byrd JC, Brown JR, OBrien S, Barrientos JC, Kay NE, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Devereux S, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Pocock C, Thornton P, Caligaris-Cappio F, Robak T, Delgado J, Schuster SJ, Montillo M, Schuh A, de Vos S, Gill D, Bloor A, Dearden C, Moreno C, Jones JJ, Chu AD, Fardis M, McGreivy J, Clow F, James DF, Hillmen P, RESONATE Investigators. Neoadjuvant Nivolumab or Nivolumab Plus Ipilimumab in Untreated Oral Cavity Squamous Cell Carcinoma: A Phase 2 Open-Label Randomized Clinical Trial. doi: 10.1136/jitc-2021-002568corr1, 68. Tumour Regression in Non-Small-Cell Lung Cancer Following Neoadjuvant Therapy. The RTOG 90-03 trial . Di Veroli GY, Fornari C, Wang D, Mollard S, Bramhall JL, Richards FM, Jodrell DI. Science (2018) 362(6411):110. Ferris RL, Blumenschein G Jr., Fayette J, Guigay J, Colevas AD, Licitra L, et al. Bertrand Baujat et al. However, translational research did not discover any predictive biomarker subgroups [27] for the palbociclib effect. Impact of Neoadjuvant Durvalumab With or Without Tremelimumab on CD8(+) Tumor Lymphocyte Density, Safety, and Efficacy in Patients With Oropharynx Cancer: CIAO Trial Results. A summary of recent pivotal trials for systemic therapy in advanced STS is presented in Table2 [19,20,21,22]. The significant impact of checkpoint inhibitor therapy for R/M HNSCC has proven the existence of anti-cancer immunity in HNSCC (1214). 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. Bossi P, Lo Vullo S, Guzzo M, Mariani L, Granata R, Orlandi E, et al. doi: 10.1056/NEJMoa1305133, 30. PubMedGoogle Scholar, Yajnik, S. (2019). In addition, the dynamic expression change of PD-L1 with tumor heterogeneity also makes it difficult to evaluate the expression of PD-L1 (41). 2015;372(26):252132. PD-1 and CTLA-4 Combination Blockade Expands Infiltrating T Cells and Reduces Regulatory T and Myeloid Cells Within B16 Melanoma Tumors. doi: 10.1016/j.cllc.2019.11.003, 62. Three trials are discussed that studied various forms of treatment de-intensification in patients with HPV-positive oropharyngeal carcinoma, including a phase 2 study by ECOG, RTOG 1016, and the De-ESCALaTE trial. N Engl J Med. N Engl J Med (2018) 378(22):2093104. Neoadjuvant Checkpoint Blockade for Cancer Immunotherapy. Curran MA, Montalvo W, Yagita H, Allison JP. 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. doi: 10.1016/0360-3016(92)90027-F, 19. 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. Lancet Oncol. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Adjuvant Chemotherapy for Resectable Squamous Cell Carcinomas of the Head and Neck: Report on Intergroup Study 0034. Head Neck (2005) 27(10):84350. Pembrolizumab for Platinum- and Cetuximab-Refractory Head and Neck Cancer: Results From a Single-Arm, Phase II Study. 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. Huang SH, Xu W, Waldron J, Siu L, Shen X, Tong L, et al. Ang KK, et al. Phase III Randomized Trial of Induction Chemotherapy in Patients With N2 or N3 Locally Advanced Head and Neck Cancer. Timing of Neoadjuvant Immunotherapy in Relation to Surgery Is Crucial for Outcome. 2011;1(1):4453. CrossRef Spotlight on landmark oncology trials: the latest evidence and novel trial designs, https://doi.org/10.1186/s12916-017-0884-7, http://creativecommons.org/licenses/by/4.0/, http://creativecommons.org/publicdomain/zero/1.0/. We defined pathological tumor response (pTR) as one such approach which is quantified as the proportion of the resection bed with tumor necrosis, keratinous debris, and giant cell/histiocytic reaction were distinct from growing tumor and only seen after therapy (Figure1). Ferrarotto R, Bell D, Rubin ML, Hutcheson KA, Johnson JM, Goepfert RP, et al. Lancet. These results underscore that TPF IC is not recommended for survival benefit. Ann Oncol (2018) 29(8):185360. In support of this, neoadjuvant anti-PD-1 treatment in a mouse HNSCC model resulted in conversion of functional immune-dominance and induced robust anti-cancer responses, supporting the application of neoadjuvant immunotherapy for HNSCC (38). N Engl J Med. Molica S. Targeted therapy in the treatment of chronic lymphocytic leukemia: facts, shortcomings and hopes for the future. An important consideration in neoadjuvant immunotherapy approaches is clinical safety as the possibility of lifelong autoimmune complications in the definitive surgical setting needs to be weighed carefully. Kiong KL, Yao C, Lin FY, Bell D, Ferrarotto R, Weber RS, et al. NEngl J Med (2016) 375(19):185667. This was nearly double what we saw with one dose of pembrolizumab. A new cancer treatment can wipe out tumours in terminally ill head and neck cancer patients, scientists have discovered. 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). Friedman J, Moore EC, Zolkind P, Robbins Y, Clavijo PE, Sun L, et al. Redman JM, Gibney GT, Atkins MB. 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. SM is Chief of the Department Hematology-Oncology at the Azienda Ospedaliera Pugliese-Ciaccio Catanzaro, Italy. (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). Notably, the timing of immune checkpoint inhibitors may influence the outcome of cancer treatment (33). By using this website, you agree to our 2016;17(4):42539. 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. This overview examines the treatment history of neoadjuvant approaches for HNSCC, and especially focuses on the recent topics of neoadjuvant immunotherapy for HNSCC. Tap WD, Jones RL, Van Tine BA, Chmielowski B, Elias AD, Adkins D, Agulnik M, Cooney MM, Livingston MB, Pennock G, Hameed MR, Shah GD, Qin A, Shahir A, Cronier DM, Ilaria Jr R, Conti I, Cosaert J, Schwartz GK. statement and Marur S, et al. Papadimitrakopoulou V, Lee JJ, Wistuba II, Tsao AS, Fossella FV, Kalhor N, Gupta S, Byers LA, Izzo JG, Gettinger SN, Goldberg SB, Tang X, Miller VA, Skoulidis F, Gibbons DL, Shen L, Wei C, Diao L, Peng SA, Wang J, Tam AL, Coombes KR, Koo JS, Mauro DJ, Rubin EH, Heymach JV, Hong WK, Herbst RS. - 50.249.249.18. 2016;34(30):363847. Lancet (2014) 384(9938):16472. 2017;5(10):42532. Therapeutically, HPV-positive HNSCC demonstrates sensitivity to chemoradiotherapy, and offers a better prognosis (2). 2017;35(2):16674. Sci Rep (2019) 9(1):13404. doi: 10.1038/s41598-019-49771-0, 46. [39] published an interesting software to provide information in terms of synergy and/or antagonism between two compounds. Feasibility and Toxicity of Neoadjuvant Nivolumab With or Without Ipilimumab Prior to Extensive (Salvage) Surgery in Patients With Advanced Head and Neck Cancer (the IMCISION Trial, NCT03003637). Di Veroli et al. The pTR rate is calculated as the area of regions 1-3/(1-3)+area of any remaining tumor. 2011;12(2):1539. Chemotherapy in locally advanced nasopharyngeal carcinoma: an individual patient data meta-analysis of eight randomized trials and 1753 patients. HE, SM and PR contributed equally to drafting, editing and revision of the manuscript. doi: 10.1016/j.annonc.2021.02.006, 54. Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus-Unrelated Head and Neck Cancer: A Multicenter, Phase II Trial. doi: 10.1016/S0360-3016(96)00430-0, 5. Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, et al. 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). 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 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). 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. J Clin Oncol. Comprehensive Genomic Characterization of Head and Neck Squamous Cell Carcinomas. JAMA Oncol (2016) 2(1):4654. doi: 10.1126/science.aar3593, 52. doi: 10.1200/JCO.2021.39.15_suppl.6008, 76. These results clearly demonstrate the superiority of dual HER2-directed therapy. doi: 10.1200/JCO.2011.38.8595, 60. Ettinger DS, Wood DE, Aisner DL, Akerley W, Bauman J, Chirieac LR, DAmico TA, DeCamp MM, Dilling TJ, Dobelbower M, Doebele RC, Govindan R, Gubens MA, Hennon M, Horn L, Komaki R, Lackner RP, Lanuti M, Leal TA, Leisch LJ, Lilenbaum R, Lin J, Loo Jr BW, Martins R, Otterson GA, Reckamp K, Riely GJ, Schild SE, Shapiro TA, Stevenson J, Swanson SJ, Tauer K, Yang SC, Gregory K, Hughes M. Non-Small Cell Lung Cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology.
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