First, neoadjuvant immunotherapies will enhance systemic T cell responses for tumor-specific antigens before surgery (34). E1308: phase II trial of induction chemotherapy followed by reduced-dose radiation and weekly cetuximab in patients with HPV-associated resectable squamous cell carcinoma of the oropharynxECOG-ACRIN Cancer Research Group. Hanna GJ, ONeill AM, Jo VY, Wong K, Lizotte PH, Annino DJ, et al. There are now numerous studies introducing neoadjuvant immunotherapy in diverse cancer types (3436). N Engl J Med. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. By contrast, neoadjuvant immunotherapy is fundamentally distinct as it targets the host immune system to attack tumor cells in a durable fashion. 2012;366(15):138292. Pathologic complete response means the ablation of all cancer cells in resected tumor after the treatment. Marur S, et al. doi: 10.4155/fso.15.88, 44. Head and Neck Cancer Center - Clinical trials - Mayo Clinic PD-1 and CTLA-4 Combination Blockade Expands Infiltrating T Cells and Reduces Regulatory T and Myeloid Cells Within B16 Melanoma Tumors. Uppaluri R, Chernock R, Mansour M, Jackson R, Rich J, Pipkorn P, et al. Pembrolizumab versus ipilimumab in advanced melanoma. The IMCISION study (NCT03003637) presented at ESMO 2020 is examining neoadjuvant nivolumab and ipilimumab for stage II-IVa HNSCC patients. 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. IC continues to be used at some centers with defined indications including advanced or borderline resectable tumors. 2016;375(19):184555. 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. Article doi: 10.1093/annonc/mdy218, 59. von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, et al. Tumour Regression in Non-Small-Cell Lung Cancer Following Neoadjuvant Therapy. He has participated in several investigator-driven trials in melanoma and sarcoma. Head Neck. We and others have focused on the definitive surgical setting with integration of neoadjuvant immunotherapy and in this review focus on historical and current approaches. Neoadjuvant Immunotherapy Leads to Pathological Responses in MMR-Proficient and MMR-Deficient Early-Stage Colon Cancers. Association of Pathological Response to Neoadjuvant Pembrolizumab With Tumor PD-L1 Expression and High Disease-Free Survival (DFS) in Patients With Resectable, Local-Regionally Advanced, Head and Neck Squamous Cell Carcinoma (HNSCC). They used pathological response (PR) criteria which was defined tumor necrosis and/or histiocytic inflammation and giant cell reaction to keratinaceous debris (74). Lin J-C, et al. BMC Med 15, 111 (2017). Status: Open - Recruiting. Cottrell TR, Thompson ED, Forde PM, Stein JE, Duffield AS, Anagnostou V, et al. However, negative Phase III trials (19, 20) in this setting have reduced enthusiasm for these approaches. doi:10.1080/17474086.2017.1313108. https://doi.org/10.1186/s12916-017-0884-7, DOI: https://doi.org/10.1186/s12916-017-0884-7. 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). 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). Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K, Sivachenko A, et al. No use, distribution or reproduction is permitted which does not comply with these terms. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. I. Mutational Landscape and Significance Across 12 Major Cancer Types. He is also an active member of the EORTC Melanoma Group and the Global Melanoma Task Force. Palbociclib in hormone-receptor-positive advanced breast cancer. 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. This is a preview of subscription content, access via your institution. Notably, four patients (N, n=1; N+I, n=3) had major/complete response (greater than 90%). Forastiere A, et al. All authors contributed to the article and approved the submitted version. N Engl J Med. In addition, there was evidence of response in both arms. 2009;86(1):97100. Ther Adv Med Oncol (2021) 13:1758835920984061. doi: 10.1177/1758835920984061, 40. Nivolumab Plus Ipilimumab in Lung Cancer With a High Tumor Mutational Burden. Haddad R, et al. Redman JM, Gibney GT, Atkins MB. 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). Our own group is developing a novel Bayesian, adaptive randomised methodology [47]. The RTOG 90-03 trial compared four radiation therapy fractionation schemes for locoregionally advanced patients undergoing radiation therapy alone and is discussed. 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. PubMedGoogle Scholar. doi: 10.1126/science.aax0902, 10. Phase III Randomized Trial of Induction Chemotherapy in Patients With N2 or N3 Locally Advanced Head and Neck Cancer. Table2 Ongoing neoadjuvant immunotherapy clinical trials. PR reports personal fees (honoraria for lectures and Advisory Board Member) from Novartis, BMS, Roche, MSD, GSK, Pfizer, and Amgen outside the submitted work. J Natl Compr Canc Netw. Bossi P, Lo Vullo S, Guzzo M, Mariani L, Granata R, Orlandi E, et al. Copyright 2021 Shibata, Saito and Uppaluri. Hillmen P, Gribben JG, Follows GA, Milligan D, Sayala HA, Moreton P, Oscier DG, Dearden CE, Kennedy DB, Pettitt AR, Nathwani A, Varghese A, Cohen D, Rawstron A, Oertel S, Pocock CF. Three HPV-positive tumors and one HPV-negative tumor had partial pathologic responses. 2023 BioMed Central Ltd unless otherwise stated. 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. A Study to Evaluate Fractionated Radiation Therapy Utilizing GRID Therapy for Locally-advanced Bulky Tumors. This enhanced function acts to destroy micro-metastasis in clinically advanced tumors, decreasing loco-regional or distant metastasis after primary therapies. 2016;34(8):78693. McLaughlin J, Han G, Schalper KA, Carvajal-Hausdorf D, Pelekanou V, Rehman J, et al. 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. evaluated the role of measuring plasma EBV DNA and is included. Lancet Oncol. These results underscore that TPF IC is not recommended for survival benefit. Schoenfeld JD, Hanna GJ, Jo VY, Rawal B, Chen YH, Catalano PS, et al. doi: 10.1172/jci.insight.89829, 18. Cooper JS. In addition to radiation and immunotherapy combinations, other trials are testing chemotherapy/immunotherapy combinations. Lancet. Several landmark trials established the clinical benefit of using cisplatin-based chemoradiotherapy after surgery for locally advanced, . For larynx cancer, this approach was initially focused on reducing metastases, and preserving laryngeal function including speech and swallowing. Furthermore, although distinct tumor-suppressor mutations including TP53, CDKN2A, NOTCH have been reported in HNSCC, cancer-promoting driver oncogenic mutations have not been detected (911), which makes it challenging to apply molecular targeted therapies. doi: 10.1038/nature12634, 50. Bioinformatics. However, IC remains an attractive approach for specific cases of advanced disease with a high risk for local or distant failure or to debulk rapidly growing tumors (19). Pembrolizumab for Platinum- and Cetuximab-Refractory Head and Neck Cancer: Results From a Single-Arm, Phase II Study. 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). 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. Int J Radiat Oncol Biol Phys (1992) 23(4):70513. quantification of plasma epstein-barr virus DNA in patients with advanced nasopharyngeal carcinoma. Finally, considering the ease of biopsies in the head and neck region, compared to adjuvant immunotherapy, neoadjuvant immunotherapy has the benefit to enable translational efforts such as TCR analysis, gene-expression profiling, and cytokine evaluation in the primary tumor which is not affected by other treatments including chemotherapeutics or radiation. 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. https://doi.org/10.1007/978-3-030-14405-0_7, DOI: https://doi.org/10.1007/978-3-030-14405-0_7. Licitra L, Grandi C, Guzzo M, Mariani L, Lo Vullo S, Valvo F, et al. Biomarkers in Head and Neck Cancer an Update - PubMed Cancer Discov. J Clin Oncol (2021) 39(15_suppl):60066. These encouraging findings have led to numerous ongoing studies testing combinations to improve CPI response rates and also testing these agents in other settings. defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (#9501). doi: 10.1126/science.aax0182, 35. Ferris RL, Spanos WC, Leidner R, Gonalves A, Martens UM, Kyi C, et al. HS received funding from the Uehara Foundation (201941070). Mol Cancer Ther (2017) 16(11):2598608. Note that MPR was observed in 8 (29%) patients in either the primary tumor or lymph node metastasis. Rochester, Minn., Jacksonville, Fla. Bauml J, Seiwert TY, Pfister DG, Worden F, Liu SV, Gilbert J, et al. BMC Cancer (2020) 20(1):229. doi: 10.1186/s12885-020-06726-3, 70. JClin Oncol (2018) 36(31):307783. Although this study didnt report pathologic responses or clinical efficacy, the proportion of CD8+ T cells, especially granzyme B positive cells, increased after treatment. 2018. Pathological Complete Response and Long-Term Clinical Benefit in Breast Cancer: The CTNeoBC Pooled Analysis. Int J Radiat Oncol Biol Phys (1996) 36(5):9991004. Saad ED, Paoletti X, Burzykowski T, Buyse M. Precision medicine needs randomized clinical trials. Provided by the Springer Nature SharedIt content-sharing initiative. Pathologic responses were seen in 12/28 (43%) of patients with 4 having MPR. 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. Timing of Neoadjuvant Immunotherapy in Relation to Surgery Is Crucial for Outcome. Then, we focus on the rationale and clinical trials of neoadjuvant immunotherapy and its potential impact on HNSCC treatment. 2014;15(8):85261. N Engl J Med. doi: 10.1056/NEJMoa032646, 6. This trial included both definitive and salvage surgery patients. The published and ongoing trials described above focused on single agent checkpoint blockade immunotherapy prior to surgery. However, while pCR and MPR are considered the gold standard, they do not take into account lesser degrees of immunological reaction in the tumor that may still impact clinical outcomes. doi: 10.1001/jamaoncol.2015.3638, 42. Therapeutically, HPV-positive HNSCC demonstrates sensitivity to chemoradiotherapy, and offers a better prognosis (2). N Engl J Med. Note, there are institution specific protocols where induction chemotherapy prior to surgery is still used for larger tumors to achieve more rapid control (21). 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.
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