PD-L2 Expression in Human Tumors: Relevance to Anti-PD-1 Therapy in Cancer. 2013;31(36):45628. HS: writing original draft, tables, and figure. Harrington JA, Wheeler GM, Sweeting MJ, Mander AP, Jodrell DI. 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. 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). Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer. Oliva M, Spreafico A, Taberna M, Alemany L, Coburn B, Mesia R, et al. HE, SM and PR contributed equally to drafting, editing and revision of the manuscript. Lancet Oncol. A total of 28 patients were eligible, and 24 (86%) of patients were HPV positive. doi: 10.1136/jitc-2021-002568corr1, 68. Google Scholar. doi: 10.1016/j.annonc.2021.02.006, 54. Epidemiology. Radiation Oncology Consultants (ROC), Chicago, IL, USA, You can also search for this author in Article Pan-Tumor Genomic Biomarkers for PD-1 Checkpoint Blockade-Based Immunotherapy. The probability of response to CPIs has at least in part been linked to TMB across cancer types, including HNSCC (16). As opposed to the CIAO and IMCISION trials where some patients enrolled were undergoing salvage surgery, a third trial recently presented at ASCO 2021 focused exclusively on challenging recurrent, surgically resectable HNSCC patients (NCT03341936) (73). 2005;27:84350. The published and ongoing trials described above focused on single agent checkpoint blockade immunotherapy prior to surgery. Liu J, ODonnell JS, Yan J, Madore J, Allen S, Smyth MJ, et al. 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). IC continues to be used at some centers with defined indications including advanced or borderline resectable tumors. J Clin Oncol (2021) 39(15_suppl):60088. PDF Spotlight on landmark oncology trials: the latest evidence and novel Int J Radiat Oncol Biol Phys. In addition, IC may increase the possibility of severe AEs as compared to CCRT in non-surgical locally, advanced HNSCC treatment. 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. Matlung SE, Wilhelmina van Kempen PM, Bovenschen N, van Baarle D, Willems SM. 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. Uppaluri R, Chernock R, Mansour M, Jackson R, Rich J, Pipkorn P, et al. PubMed Central 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. that compared radiation therapy plus or minus cetuximab, and RTOG 0522 are included as landmark trials in the development of an organ preservation approach for the management of locoregionally advanced disease. 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. 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. 2015;385(9980):187383. J Clin Oncol. 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). Received: 18 June 2021; Accepted: 19 August 2021;Published: 06 September 2021. 2014;15(8):85261. Hanna GJ, ONeill AM, Jo VY, Wong K, Lizotte PH, Annino DJ, et al. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. 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). 2016;387:154050. Despite this multi-modality treatment, advanced human papillomavirus (HPV)-negative HNSCC shows poor prognosis. 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. Our own group is developing a novel Bayesian, adaptive randomised methodology [47]. I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. The effects of checkpoint inhibitors are mainly derived from reinvigoration and activation of tumor-oriented antigen-specific T cells (15). Lancet Oncol. Filter this list of studies by location, status and more. N Engl J Med. Pembrolizumab Alone or With Chemotherapy Versus Cetuximab With Chemotherapy for Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (KEYNOTE-048): A Randomised, Open-Label, Phase 3 Study. 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. Yamazaki H, et al. He was/is member of the editorial board of Leukemia and Lymphoma, BMC Medicine, ISRN Hematology and International Journal of Hematologic Oncology. 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 . 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. 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. 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. 2012;379:187986. Proc Natl Acad Sci USA (2010) 107(9):427580. The RTOG 90-03 trial . 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. Rochester, Minn., Jacksonville, Fla. 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. Lancet (2019) 394(10212):191528. Quantitative Assessment of the Heterogeneity of PD-L1 Expression in Non-Small-Cell Lung Cancer. Remon J, Besse B, Soria JC. Lancet. Am Soc Clin Oncol Educ Book (2020) 40:113. Enhanced Pathologic Tumor Response With Two Cycles of Neoadjuvant Pembrolizumab in Surgically Resectable, Locally Advanced HPV-Negative Head and Neck Squamous Cell Carcinoma (HNSCC). Cristescu R, Mogg R, Ayers M, Albright A, Murphy E, Yearley J, et al. Recent clinical trials of neoadjuvant immunotherapy show promising results and this methodology has the potential to change the treatment algorithm of HNSCC. N Engl J Med. These data suggest clinical tolerability and effectiveness of neoadjuvant immunotherapy. In: Proceedings from the American Association for Cancer Research Annual Meeting, April 25, 2017, Washington DC. Uppaluri R, Lee NY, Westra W, Cohen EEW, Haddad RI, Temam S, et al. 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. New Treatment for Head/Neck Tumours | Tissuepathology.com Bauml J, Seiwert TY, Pfister DG, Worden F, Liu SV, Gilbert J, et al. Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, et al. doi: 10.1158/1535-7163.MCT-17-0386, 17. Notably, four patients (N, n=1; N+I, n=3) had major/complete response (greater than 90%). In this trial, primary endpoints are rate of major pathological response (10% tumor cells in resected primary and lymph nodes on central review) and event-free survival (EFS). 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). 2012;13(1):2532. Completed and ongoing trials have focused on a diverse group of HNSCC patients including early and advanced stage and HPV-positive and negative patients. Table2 Ongoing neoadjuvant immunotherapy clinical trials. 2011;12(2):1539. 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). Cancer Discov. ID: NCT03803774. 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). Tumors with both PD-L1 and PD-L2 expression responded better than tumors with only PD-L1 expression, indicating that combinatorial scoring may be an attractive approach. 20 studies in Head and Neck Cancer Center (open studies only). N Engl J Med (2013) 369(2):13444. 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). This trial highlighted the effectiveness of combination immunotherapy and chemotherapy for subsets of HNSCC patients. doi: 10.4155/fso.15.88, 44. A new cancer treatment can wipe out tumours in terminally ill head and neck cancer patients, scientists have discovered. 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). doi: 10.1200/JCO.2003.06.146, 27. 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. Advances in immunotherapy for melanoma. Note that MPR was observed in 8 (29%) patients in either the primary tumor or lymph node metastasis. 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). JCI Insight (2018) 3(4):113. Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al. In Cambridge, she is the cancer lead in the collaborative work stream for novel adaptive trial designs. Lancet Oncol. Pathological Response and Survival With Neoadjuvant Therapy in Melanoma: A Pooled Analysis From the International Neoadjuvant Melanoma Consortium (INMC). Marur S, DSouza G, Westra WH, Forastiere AA. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebb C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA. Nivolumab in previously untreated melanoma without BRAF mutation. Gutirrez Caldern V, Cantero Gonzlez A, Glvez Carvajal L, Aguilar Lizarralde Y, Rueda Domnguez A. Neoadjuvant Immunotherapy in Resectable Head and Neck Cancer: Oral Cavity Carcinoma as a Potential Research Model. Furthermore, tertiary lymphoid structures (TLS) in the tumor bed are suggested tocontribute favorable outcome (55). 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).
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