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. 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. HE, SM and PR contributed equally to drafting, editing and revision of the manuscript. The Annals of Surgical Oncology (ASO) is pleased to announce, The Landmark Series. 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). 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 . doi: 10.1093/annonc/mdy218, 59. von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, et al. Status: Open - Recruiting. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. N Engl J Med. HE has provided clinical advice at Advisory Board meetings for Roche, Pfizer and Astra Zeneca. Recent landmark trials in HER2-positive breast cancer include those using dual HER2-targeted therapy pertuzumab and trastuzumab with docetaxel. N Engl J Med. Immunological Effects of Nivolumab Immunotherapy in Patients With Oral Cavity Squamous Cell Carcinoma. Finally, we recently reported a second cohort of our neoadjuvant pembrolizumab trial where instead of one dose, patients received two doses of drug similar to the neoadjuvant phase of the KEYNOTE-689 Phase II trial (75). Merlino DJ, Johnson JM, Tuluc M, Gargano S, Stapp R, Harshyne L Jr., et al. By using this website, you agree to our 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. CrossRef In addition, in the KEYNOTE-040 phase III study, the correlation of clinical outcome and PD-L1 expression on tumor (PD-L1 tumor proportion score 50%) was evident (13). Nivolumab (3 mg/kg) was administered on weeks 1 and 3, while ipilimumab (1 mg/kg) was given on week 1 only. Lancet. 2005;27:84350. Int J Radiat Oncol Biol Phys (1992) 23(4):70513. doi: 10.1016/0360-3016(92)90642-U, 4. In conclusion, the RESONATE-2 trial demonstrates that ibrutinib is a new important player in the treatment of elderly unfit patients and in those with high-risk disease. Head Neck (2005) 27(10):84350. The head and neck region is anatomically complex and serves essential functions such as eating, speaking, and breathing. BMC Med. Completed and ongoing trials have focused on a diverse group of HNSCC patients including early and advanced stage and HPV-positive and negative patients. radiotherapy for early glottic carcinoma (T1N0M): results of prospective randomized study of radiation fraction size and overall treatment time. 2009;92:414. Pathological Response and Survival With Neoadjuvant Therapy in Melanoma: A Pooled Analysis From the International Neoadjuvant Melanoma Consortium (INMC). . Combinations of chlorambucil with an anti-CD2O monoclonal antibody, such as rituximab, ofatumumab or obinutuzumab, are now the standard of care in patients unsuited to receive fludarabine, cyclophosphamide and rituximab [34,35,36]. Di Veroli GY, Fornari C, Wang D, Mollard S, Bramhall JL, Richards FM, Jodrell DI. Recently we reported an extension of this study with an additional 29 HNSCC patients treated with two cycles of neoadjuvant pembrolizumab. Di Veroli et al. N Engl J Med. Am Soc Clin Oncol Educ Book (2020) 40:113. doi: 10.1007/BF01192200, 63. doi: 10.1016/S1470-2045(13)70011-1, 20. Ugurel S, Roehmel J, Ascierto PA, Flaherty KT, Grob JJ, Hauschild A, Larkin J, Long GV, Lorigan P, McArthur GA, Ribas A, Robert C, Schadendorf D, Garbe C. Survival of patient s with advanced metastatic melanoma: the impact of novel therapies. 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). All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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). 2014;32:294050. Article Nature (2013) 500(7463):41521. These encouraging findings have led to numerous ongoing studies testing combinations to improve CPI response rates and also testing these agents in other settings. 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. Bonner J, et al. With the positive responses in the R/M HNSCC setting, several trials have reported results with neoadjuvant checkpoint immunotherapy prior to surgery (Table1). HNSCC patients with high CD8+ T cells infiltration showed better anti-PD-1 response in the adjuvant setting (52, 54). J Clin Oncol (2021) 39(15_suppl):60088. Hanna GJ, Lizotte P, Cavanaugh M, Kuo FC, Shivdasani P, Frieden A, et al. Cohen EE, Karrison TG, Kocherginsky M, Mueller J, Egan R, Huang CH, et al. Lancet Oncol. 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). Curran MA, Montalvo W, Yagita H, Allison JP. In ER-positive, HER2-negative metastatic disease, the landmark trial (PALOMA 3) uses the CDK 4/6 inhibitor, palbociclib [26, 27]. Nat Commun (2021) 12(1):3349. doi: 10.1038/s41467-021-23355-x, 56. 2016;14:20. Nat Rev Clin Oncol. 2015;373(1):2334. Chalabi M, Fanchi LF, Dijkstra KK, Van den Berg JG, Aalbers AG, Sikorska K, et al. Provided by the Springer Nature SharedIt content-sharing initiative. doi: 10.1126/science.aax0182, 35. NEngl J Med (2008) 359(11):111627. Long term results of TAX324, a randomized phase III trial of sequential therapy with TPF versus PF in locally advanced squamous cell cancer of the head and neck. These data indicate that PD-L1 expression on tumor cells is not a perfect biomarker to predict the clinical outcome. Cookies policy. There are several questions about how this approach would integrate with current SOC including whether this treatment intensification is necessary especially in good prognosis HPV+ disease and the role of nivolumab as SBRT alone conferred a high rate of pathologic responses. Enhanced Pathologic Tumor Response With Two Cycles of Neoadjuvant Pembrolizumab in Surgically Resectable, Locally Advanced HPV-Negative Head and Neck Squamous Cell Carcinoma (HNSCC). 2016;32(18):28668. Mutational Landscape and Significance Across 12 Major Cancer Types. JClin Oncol (2018) 36(31):307783. Br J Cancer. doi: 10.1016/S0140-6736(13)62422-8, 61. Neoadjuvant Nivolumab for Patients With Resectable HPV-Positive and HPV-Negative Squamous Cell Carcinomas of the Head and Neck in the CheckMate 358 Trial. Price KAR, Nichols AC, Shen CJ, Rammal A, Lang P, Palma DA, et al. Pignon J-P, et al. Below are current clinical trials. This trial highlighted the effectiveness of combination immunotherapy and chemotherapy for subsets of HNSCC patients. Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, et al. Immune-Modified Response Evaluation Criteria In Solid Tumors (imRECIST): Refining Guidelines to Assess the Clinical Benefit of Cancer Immunotherapy. 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. TMB is a potential predictive biomarker that also needs further exploration. Cohen EEW, Soulires D, Le Tourneau C, Dinis J, Licitra L, Ahn MJ, et al. 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). 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. 2016;34(8):78693. Lancet Oncol. J Immunother Cancer (2021) 9(5):115. PR is Professor of Surgical Oncology at the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology in Warsaw, Poland. doi: 10.1073/pnas.0915174107, 72. elective versus therapeutic neck dissection in node-negative oral cancer. PubMed Radiother Oncol. A summary of recent pivotal trials for systemic therapy in advanced STS is presented in Table2 [19,20,21,22]. 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. Definition and Impact of Pathologic Complete Response on Prognosis After Neoadjuvant Chemotherapy in Various Intrinsic Breast Cancer Subtypes. The November 3, 2021 "Clinical Trial Endpoint Development" (12pm - 5:00 pm ET) will address Locally Advanced Head and Neck Squamous Cell Carcinoma (HNSCC) Bayesian adaptive designs for biomarker trials with biomarker discovery. Second, in contrast to conventional chemotherapy, immunotherapy is much better tolerated by patients. evaluated the role of measuring plasma EBV DNA and is included. doi: 10.1200/JCO.2014.58.6412, 3. Notably, other work has contradicted the above studies on TMB and concluded that that high TMB failed to predict the effect of ICI (53). A total of 36 patients (T3/T4; 80%, stage IV; 92%) were enrolled and received one time dose of neoadjuvant pembrolizumab (200 mg) followed by surgery two or three weeks after the immunotherapy. The primary endpoint of this trial was comparison between arms of a change in the CD8+ tumor infiltrating lymphocyte (TIL) density. Similarly, the Keynote-040 randomized phase III trial compared the efficacy of pembrolizumab (anti-PD-1) versus SOC (methotrexate, docetaxel, or cetuximab) (13) for R/M HNSCC patients after platinum-containing treatment. 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. 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%. 2018. Although these Level 1 data established a new postoperative standard of care to treat high-risk HNSCC patients, the five-year survival rate in for these patients remains suboptimal. Neoadjuvant Immunoradiotherapy Results in High Rate of Complete Pathological Response and Clinical to Pathological Downstaging in Locally Advanced Head and Neck Squamous Cell Carcinoma. 2017;5(10):42532. I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Science (2018) 362(6411):110. (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). CrossRef However, translational research did not discover any predictive biomarker subgroups [27] for the palbociclib effect. J Clin Oncol (2003) 21(2):32733. 2013;31(36):45628. Forastiere A, et al. Following this, the phase III KEYNOTE-048 trial established a new paradigm for first-line R/M HNSCC patients (14). 2016;128(24):27703. 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. A Randomized Phase III Trial Comparing Induction Chemotherapy Followed by Chemoradiotherapy Versus Chemoradiotherapy Alone as Treatment of Unresectable Head and Neck Cancer. This material is provided for educational purposes only and with the goal of encouraging further study about the landmark trials that have impacted oncology. J Clin Oncol. J Clin Oncol (2014) 32(25):273543. In this article series, worldwide renowned experts in their fields provided an extensive overview on the state of the art in immunotherapy and discussed the possible future paths in these, still difficult, types of malignancies. 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. There was an 86% MPR rate and a 67% pCR rate. However, negative Phase III trials (19, 20) in this setting have reduced enthusiasm for these approaches. PD-L2 Expression in Human Tumors: Relevance to Anti-PD-1 Therapy in Cancer. RU is funded by NIH/NIDCR R01DE024403, R01DE027736, and NIH/NCI/NIDCR U01DE029188. CAS 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. However, the proportion of CD4+ T cells were decreased while the rate of CD4+FoxP3+ regulatory T cells was increased with treatment. Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefbvre JL, Greiner RH, et al. However, PD-L1 negative tumors sometimes respond to CPI treatment, suggestingthe existence of other mechanisms. 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]. Int J Radiat Oncol Biol Phys (1992) 23(3):6712; discussion 6778. N Engl J Med. Several landmark trials established the clinical benefit of using cisplatin-based chemoradiotherapy after surgery for locally advanced, . doi: 10.1016/S0140-6736(19)32591-7, 15. The expression level of PD-L1 in the tumor does not necessarily correlate withthe response to CPIs. 2016;375(22):215464. 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 three-planar views are crucial to understanding the malignant gradient. In addition to radiation and immunotherapy combinations, other trials are testing chemotherapy/immunotherapy combinations. 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). HNSCC shows a relatively high tumor-mutational burden (TMB) (16) and immune infiltration (17), consistent with a potential to achieve therapeutic efficacy from cancer immunotherapy. Article It has become clear that neoadjuvant immunotherapy, especially checkpoint inhibitors, are safe and have shown signals of clinical efficacy in HNSCC. Lin J-C, et al. J Clin Oncol (2021) 39(15_suppl):60066. doi: 10.1038/s41591-020-0805-8, 36. doi: 10.1200/JCO.2013.54.6309, 21. Cottrell TR, Thompson ED, Forde PM, Stein JE, Duffield AS, Anagnostou V, et al. doi: 10.1056/NEJMoa032646, 6. N Engl J Med. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. J Clin Oncol. 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.