California Privacy Statement, Advances in immunotherapy for melanoma. Di Veroli et al. doi:10.1080/17474086.2017.1313108. Of eighty evaluated patients, 32 patients (40%) showed a PR [26 partial PR ( 20% and <90%) and 6 with major PR (>90%)]. doi: 10.1038/nature12634, 50. 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. 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. Pathological complete response (pCR) and major pathologic response (MPR) are widely used as surrogate clinical endpoints for long-term survival (5962). Therapeutically, HPV-positive HNSCC demonstrates sensitivity to chemoradiotherapy, and offers a better prognosis (2). Neoadjuvant Nivolumab for Patients With Resectable HPV-Positive and HPV-Negative Squamous Cell Carcinomas of the Head and Neck in the CheckMate 358 Trial. Wang J, Sun H, Zeng Q, Guo XJ, Wang H, Liu HH, et al. JCI Insight (2016) 1(17):e89829. Ann Oncol (2014) 25(1):21625. N Engl J Med. Remon J, Besse B, Soria JC. J Clin Oncol (2014) 32(25):273543. Am Soc Clin Oncol Educ Book (2020) 40:113. Although neither baseline CD8+ T cell infiltration status nor PD-L1 expression level correlated with overall response, there was a trend in which greater CD8+ T cells infiltrated patients tended to show MPR. As trials mature, patient selection for neoadjuvant immunotherapy will need to be defined further. 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). 2014;32(12):123641. J Clin Oncol (2021) 39(15_suppl):60533. doi: 10.1002/cncr.33471, 22. 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). Neoadjuvant PD-1 Immune Checkpoint Blockade Reverses Functional Immunodominance Among Tumor Antigen-Specific T Cells. Blood. These encouraging findings have led to numerous ongoing studies testing combinations to improve CPI response rates and also testing these agents in other settings. These findings highlight the clinical importance to establish standard pathological criteria to accurately evaluate the therapeutic effect of neoadjuvant immunotherapy after definitive surgery. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomized trials and 17,346 patients. Frameshift Events Predict Anti-PD-1/L1 Response in Head and Neck Cancer. PubMed 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. In this review, we present a brief overview of the history of neoadjuvant (induction) chemotherapy in the definitive surgical management of HNSCC. These results underscore that TPF IC is not recommended for survival benefit. 2012;31:84552. She is an Editorial Board Member for BMC Medicine. However, although IC may help with surgical management, Phase III trial results showed no improvements in survival. doi: 10.1093/annonc/mdy507, 41. 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. N Engl J Med. doi: 10.1093/annonc/mdy495, 49. 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. 2016;375(1):1122. A study by Lin et al. J Clin Oncol (2015) 33(8):83645. Neoadjuvant Immunotherapy Leads to Pathological Responses in MMR-Proficient and MMR-Deficient Early-Stage Colon Cancers. Cancer Discov. There are three major potential benefits to use CPIs in the neoadjuvant setting. J Clin Oncol (2003) 21(2):32733. doi: 10.1200/JCO.2016.70.1524, 45. Ferrarotto R, Bell D, Rubin ML, Hutcheson KA, Johnson JM, Goepfert RP, et al. Proc Natl Acad Sci USA (2010) 107(9):427580. A potential shortcoming with the upfront use of ibrutinib includes cost and indefinite treatment course [37]. 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. The pTR rate is calculated as the area of regions 1-3/(1-3)+area of any remaining tumor. Intriguingly, in preclinical mouse models, a specific interval between neoadjuvant immunotherapy and subsequent surgery was important to establish potent systemic T cell response (33), suggesting that it will be important to establish the optimal duration in the clinical setting. 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). Additionally, R/M HNSCC patients treated with pembrolizumab plus chemotherapy had significantly prolonged OS compared to the cetuximab with chemotherapy group. A natural extension of this work has led several groups to test whether neoadjuvant chemotherapy prior to surgery would improve clinical outcomes. Concurrent Chemotherapy and Radiotherapy for Organ Preservation in Advanced Laryngeal Cancer. doi: 10.1126/science.1208130, 12. However, PD-L1 negative tumors sometimes respond to CPI treatment, suggestingthe existence of other mechanisms. An important consideration in neoadjuvant immunotherapy approaches is appropriate patient selection. 2016;35:4907. Using a primary radiation based approach, several ongoing clinical trials aim to de-intensify the treatment impact by adding immunotherapy (77). doi: 10.1056/NEJMoa0802656, 33. Notably, four patients (N, n=1; N+I, n=3) had major/complete response (greater than 90%). Haddad R, ONeill A, Rabinowits G, Tishler R, Khuri F, Adkins D, 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. 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. Therefore, in absence of data from this and similar trials, either therapeutic choice is adequate in the day-to-day practice. Lorch J, et al. 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. doi: 10.1136/jitc-2021-002485, 67. 2015;373:5219. 2016;375(1):2334. doi: 10.1016/S1470-2045(13)70334-6, 64. https://doi.org/10.1186/s12916-017-0884-7, DOI: https://doi.org/10.1186/s12916-017-0884-7. In addition to radiation and immunotherapy combinations, other trials are testing chemotherapy/immunotherapy combinations. Epidemiology. Barker AD, Sigman CC, Kelloff GJ, Hylton NM, Berry DA, Esserman LJ. Di Veroli GY, Fornari C, Wang D, Mollard S, Bramhall JL, Richards FM, Jodrell DI. Radiother Oncol. J Clin Oncol. There are hundreds of trials to choose from, and therefore, no claim toward completeness can be made in the current format. Weissferdt A, Pataer A, Vaporciyan AA, Correa AM, Sepesi B, Moran CA, et al. Recent landmark trials in HER2-positive breast cancer include those using dual HER2-targeted therapy pertuzumab and trastuzumab with docetaxel. Rare Driver Mutations in Head and Neck Squamous Cell Carcinomas Converge on NOTCH Signaling. The primary cancer (oral cavity) invades in various directions, which are color-coded vectors (arrows) representing stage of progression: Tis, yellow; T1, green; T2, blue; T3, purple; T4A, red; and T4B, black. N Engl J Med. I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. 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). PD-1 and CTLA-4 Combination Blockade Expands Infiltrating T Cells and Reduces Regulatory T and Myeloid Cells Within B16 Melanoma Tumors. Curran MA, Montalvo W, Yagita H, Allison JP. NEngl J Med (2008) 359(11):111627. 2015;113(5):699705. 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. Discordant Responses Between Primary Head and Neck Tumors and Nodal Metastases Treated With Neoadjuvant Nivolumab: Correlation of Radiographic and Pathologic Treatment Effect. She has been an expert advisor for NHS NICE Health Technology Assessments. Nat Rev Clin Oncol. IC continues to be used at some centers with defined indications including advanced or borderline resectable tumors. Checkpoint Blockade Cancer Immunotherapy Targets Tumour-Specific Mutant Antigens. doi: 10.1093/annonc/mdt555, 29. Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott C, Meier W, Shapira-Frommer R, Safra T, Matei D, Macpherson E, Watkins C, Carmichael J, Matulonis U. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. 2016;14:20. This diverse patient selection has been used primarily to define a signal of activity. Lancet Oncol. Article In a landmark trial, a cocktail of immunotherapy medications harnessed patients' immune systems to kill their own cancer cells and prompted "a positive trend in survival . 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). 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. The Head and Neck Cancer Immune Landscape and Its Immunotherapeutic Implications. In addition, as other checkpoints are testing, further improvements in pathologic responses and clinical outcomes are expected. Springer Nature. Eur J Cancer. Clin Cancer Res (2017) 23(12):315867. Huang SH, Xu W, Waldron J, Siu L, Shen X, Tong L, et al. These data suggest that virus infection status impacts TMB as a biomarker. Article In Checkmate-141 phase III trial, there wasno correlation of survival extension and PD-L1 expression on tumors (PD-L1+ >1%, 5% and 10%) (12). J Clin Oncol. 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. PubMed Patients received two cycles of drug therapy. 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). Nature (2013) 500(7463):41521. Phase III Randomized Trial of Induction Chemotherapy in Patients With N2 or N3 Locally Advanced Head and Neck Cancer. Int J Radiat Oncol Biol Phys (1992) 23(4):70513. 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. RU is funded by NIH/NIDCR R01DE024403, R01DE027736, and NIH/NCI/NIDCR U01DE029188. The first articles in the special article collection focus on landmark clinical trials in selected advanced solid tumours, with special attention on the most studied tumours with regards to immunotherapy development, namely melanoma [3, 4], NSCLC [2], and head and neck cancer [6]. Received: 18 June 2021; Accepted: 19 August 2021;Published: 06 September 2021. Analysis of the data gathered from these large trials continues to contribute valuable understanding about related issues, including . Completed and ongoing trials have focused on a diverse group of HNSCC patients including early and advanced stage and HPV-positive and negative patients. Following this, the phase III KEYNOTE-048 trial established a new paradigm for first-line R/M HNSCC patients (14). Pembrolizumab for Platinum- and Cetuximab-Refractory Head and Neck Cancer: Results From a Single-Arm, Phase II Study. JClin Oncol (2018) 36(31):307783. doi: 10.1016/S1470-2045(13)70011-1, 20. There are several distinct mechanisms of how radiation and/or chemotherapy can work with immunotherapy and other have covered these topics. 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. However, the proportion of CD4+ T cells were decreased while the rate of CD4+FoxP3+ regulatory T cells was increased with treatment. Al-Saraff M, et al. She is co-lead for the Breast Cancer Programme at the Cancer Research UK Cambridge Cancer Centre and significantly contributes to the translational endeavour in precision medicine and the development of personalised treatment pathways in breast cancer. 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). Ferris RL, Blumenschein G Jr., Fayette J, Guigay J, Colevas AD, Licitra L, et al. Lancet Oncol. doi: 10.1016/j.radonc.2009.04.014, 9. Finally, biomarker and minimal residual disease assessment may ultimately be useful to guide the targeted agent or regimen of choice and the duration of treatment [38]. 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. is included that studied the role of chemotherapy in patients undergoing definitive locoregional treatment. The immunological responses were analyzed using blood before and after treatment. Cite this article. Oncol. 2017;15:57. This trial aims to enroll 600 patients. N Engl J Med (1991) 324(24):168590. N Engl J Med. 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. 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. He works very closely with national patient advocacy groups for GIST and sarcoma and is Chairman of the Melanoma Academy in Poland. For example, a phase II/III trial in patients with early-stage HPV-positive HNSCC is testing whether RT plus chemotherapy (cisplatin) or immunotherapy (nivolumab or durvalumab) can be used for de-intensification (NCT03952585, NCT03410615). 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). Compared to our initial cohort with one dose, we found that 50% of patients had any pTR and 44% of patients exhibited pTR2. Chen Q, Jain N, Ayer T, Wierda WG, Flowers CR, OBrien SM, Keating MJ, Kantarjian HM, Chhatwal J. Lancet Oncol. Primary Chemotherapy in Resectable Oral Cavity Squamous Cell Cancer: A Randomized Controlled Trial. J Natl Compr Canc Netw. First published on Mon 11 Oct 2021 07.19 EDT. The IMCISION study (NCT03003637) presented at ESMO 2020 is examining neoadjuvant nivolumab and ipilimumab for stage II-IVa HNSCC patients. https://doi.org/10.1007/978-3-030-14405-0_7, Tax calculation will be finalised during checkout. 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).