doi: 10.1016/S0140-6736(18)31999-8, 14. Int J Radiat Oncol Biol Phys. 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). Lancet Oncol. van der Graaf WT, Blay JY, Chawla SP, Kim DW, Bui-Nguyen B, Casali PG, Schffski P, Aglietta M, Staddon AP, Beppu Y, Le Cesne A, Gelderblom H, Judson IR, Araki N, Ouali M, Marreaud S, Hodge R, Dewji MR, Coens C, Demetri GD, Fletcher CD, Dei Tos AP, Hohenberger P, EORTC Soft Tissue and Bone Sarcoma Group; PALETTE study group. This was followed by BATTLE-2 [42], testing combination treatments in the same disease. Notably, the treatments were safe and 16/26 patients (61.5%) had pathologic responses (>20%) and 8/26 (31%) of patients experienced complete response (72). More effective and cost-efficient phase II trial designs would rapidly lead to landmark trials and practice-changing results. Cancer Discov (2016) 6(12):138299. doi: 10.1200/JCO.2019.37.15_suppl.2575, 73. Definition and Impact of Pathologic Complete Response on Prognosis After Neoadjuvant Chemotherapy in Various Intrinsic Breast Cancer Subtypes. doi: 10.1056/NEJMoa031317, 24. Landmark Trials in Oncology pp 217239Cite as. The study is aimed at establishing the purpose of tumour markers, their application, classification, diagnostic and therapeutic roles in the management of head and neck cancer. However, cancer research also faces challenges in the effective development and assessment of targeted therapeutics [1], including the need for early evaluation of potential biomarkers by translational and correlative studies. J Clin Oncol. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Article No new safety signals were observed and there were no surgical delays. These data indicate that PD-L1 expression on tumor cells is not a perfect biomarker to predict the clinical outcome. The landmark oncology trials highlighted in the BMC Medicine series Spotlight on landmark oncology trials and this editorial are recent trials that have produced practice-changing results for patients. As mentioned above, to date neoadjuvant immunotherapy has been shown to be safe and has not resulted in surgical delays. HPV-related oropharyngeal HNSCC shows better survival related to HPV-negative oropharyngeal HNSCCs. 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. volume15, Articlenumber:111 (2017) 2015;385(9980):187383. Notably, four patients (N, n=1; N+I, n=3) had major/complete response (greater than 90%). doi: 10.1016/S0360-3016(96)00430-0, 5. Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, et al. Programmed Death-1/Programmed Death-Ligand 1-Axis Blockade in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma Stratified by Human Papillomavirus Status: A Systematic Review and Meta-Analysis. These results clearly demonstrate the superiority of dual HER2-directed therapy. Nivolumab Plus Ipilimumab in Lung Cancer With a High Tumor Mutational Burden. She has also received unrestricted educational grants to support investigator initiated clinical trials from Lilly, Roche and Sanofi Aventis, and has received free gemcitabine from Lilly and free bevacizumab from Roche for clinical trials. Head Neck (2005) 27(10):84350. Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, et al. Secondary endpoints are OS, complete pathological response, and assessment of safety and tolerability. 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. Bernier J, et al. evaluated the role of measuring plasma EBV DNA and is included. 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. The data and subsequent meta-analysis showed the superiority of CCRT to preserve the larynx in advanced laryngeal cancer patients (8, 23). The phase II Checkpoint Inhibitors Assessment in Oropharynx cancer (CIAO) trial (NCT03144778) tested a combination of durvalumab (1500 mg) and tremelimumab (75 mg) in the neoadjuvant setting, preceding SOC (surgery with or without radiation therapy) (70). This was nearly double what we saw with one dose of pembrolizumab. Chalabi M, Fanchi LF, Dijkstra KK, Van den Berg JG, Aalbers AG, Sikorska K, et al. Immune cells phenotypes in TME may also be important topredict the response to CPIs. All authors contributed to the article and approved the submitted version. 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 [], and head and neck cancer [].Recent developments and approvals in immunotherapy have significantly changed the landscape of melanoma and NSCLC . McLaughlin J, Han G, Schalper KA, Carvajal-Hausdorf D, Pelekanou V, Rehman J, et al. Science (2018) 362(6411):110. Mandal R, enbabaolu Y, Desrichard A, Havel JJ, Dalin MG, Riaz N, et al. Discordant Responses Between Primary Head and Neck Tumors and Nodal Metastases Treated With Neoadjuvant Nivolumab: Correlation of Radiographic and Pathologic Treatment Effect. This enhanced function acts to destroy micro-metastasis in clinically advanced tumors, decreasing loco-regional or distant metastasis after primary therapies. 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). Sholl LM. Therefore, in absence of data from this and similar trials, either therapeutic choice is adequate in the day-to-day practice. 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. BMC Med. Although a total of 21 patients experienced AEs, including grade 3/4 AEs in 2 (N) and 5 (N+I) patients, there were no surgical delays. doi: 10.1172/jci.insight.98811, 53. Pembrolizumab versus ipilimumab in advanced melanoma. Bonner J, et al. TMB is a potential predictive biomarker that also needs further exploration. JAMA Oncol (2016) 2(1):4654. These findings highlight the clinical importance to establish standard pathological criteria to accurately evaluate the therapeutic effect of neoadjuvant immunotherapy after definitive surgery. Palbociclib in hormone-receptor-positive advanced breast cancer. BMC Cancer (2020) 20(1):229. doi: 10.1186/s12885-020-06726-3, 70. 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). 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. 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. Signatures of Mutational Processes in Human Cancer. Lancet Oncol. 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. Expert Rev Hematol. Lawrence MS, Sougnez C, Lichtenstein L, Cibulskis K, Lander E, Gabriel SB, et al. Eur J Cancer. Lancet. 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. 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. PubMed HPV infection results in production of virus-related proteins, which may induce de novo T cell response and more CD8+ T cell infiltration in tumor (43). 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. doi: 10.1038/nature12477, 51. J Immunother Cancer (2021) 9(6):111. 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). doi: 10.1016/0360-3016(92)90027-F, 19. Ther Adv Med Oncol (2021) 13:1758835920984061. doi: 10.1177/1758835920984061, 40. 2015;373(25):242537. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomized trials and 17,346 patients. Ang KK, et al. doi: 10.1038/s41591-020-0805-8, 36. A Randomized Phase III Trial Comparing Induction Chemotherapy Followed by Chemoradiotherapy Versus Chemoradiotherapy Alone as Treatment of Unresectable Head and Neck Cancer. Following this, the phase III KEYNOTE-048 trial established a new paradigm for first-line R/M HNSCC patients (14). doi: 10.1001/jamaoncol.2015.3638, 42. A meta-analysis by Pignon et al. 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. Molica S. Targeted therapy in the treatment of chronic lymphocytic leukemia: facts, shortcomings and hopes for the future. With the positive responses in the R/M HNSCC setting, several trials have reported results with neoadjuvant checkpoint immunotherapy prior to surgery (Table1). HS: writing original draft, tables, and figure. Nature (2013) 502(7471):3339. N Engl J Med (2018) 378(21):197686. Front. 2015;113(5):699705. Induction Chemotherapy Plus Radiation Compared With Surgery Plus Radiation in Patients With Advanced Laryngeal Cancer. It is meant to be an educational resource . A natural extension of this work has led several groups to test whether neoadjuvant chemotherapy prior to surgery would improve clinical outcomes. doi: 10.1038/nature12634, 50. Coit DG, Thompson JA, Algazi A, Andtbacka R, Bichakjian CK, Carson 3rd WE, Daniels GA, DiMaio D, Ernstoff M, Fields RC, Fleming MD, Gonzalez R, Guild V, Halpern AC, Hodi Jr FS, Joseph RW, Lange JR, Martini MC, Materin MA, Olszanski AJ, Ross MI, Salama AK, Skitzki J, Sosman J, Swetter SM, Tanabe KK, Torres-Roca JF, Trisal V, Urist MM, McMillian N, Melanoma EA. Pathologic treatment effect (PTE) is another similar scale, which is evaluated by the area showing fibrosis or lymphohistiocytic inflammation divided by total tumor area (65). In: Proceedings from the American Association for Cancer Research Annual Meeting, April 25, 2017, Washington DC. Weissferdt A, Pataer A, Vaporciyan AA, Correa AM, Sepesi B, Moran CA, et al. The expression level of PD-L1 in the tumor does not necessarily correlate withthe response to CPIs. Head and Neck Cancer Clinical Trials and Research Timing of Neoadjuvant Immunotherapy in Relation to Surgery Is Crucial for Outcome. Cottrell TR, Thompson ED, Forde PM, Stein JE, Duffield AS, Anagnostou V, et al. doi: 10.1158/1078-0432.CCR-20-1695, 55. 2011;1(1):4453. Below are current clinical trials. Recent landmark immunotherapy trials - melanoma, Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A. KEYNOTE-006 investigators. He is also an active member of the EORTC Melanoma Group and the Global Melanoma Task Force. 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. 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. doi: 10.1056/NEJMoa0802656, 33. 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. In addition, there was evidence of response in both arms. Other work showed that PD-L2 expression was significantly correlated with PD-L1 expression in HNSCC clinical samples (42). Int J Radiat Oncol Biol Phys (1992) 23(3):6712; discussion 6778. A new cancer treatment can wipe out tumours in terminally ill head and neck cancer patients, scientists have discovered. Lancet Oncol. 14 Articles, This article is part of the Research Topic, Rationale of Neoadjuvant Immunotherapy for HNSCC, Patient Selection for Neoadjuvant Immunotherapy, Biomarker Candidates for Neoadjuvant Immunotherapy, Pathologic Response Criteria for Neoadjuvant Immunotherapy, Clinical Studies of Neoadjuvant Immunotherapy for HNSCC, Immune Related Adverse Events in Neoadjuvant Immunotherapy Treated Patients, Creative Commons Attribution License (CC BY). In addition to radiation and immunotherapy combinations, other trials are testing chemotherapy/immunotherapy combinations. Abstract CT075. Ferris RL, Blumenschein G Jr., Fayette J, Guigay J, Colevas AD, Licitra L, et al. Merlino etal. 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. Burtness B, Harrington KJ, Greil R, Soulires D, Tahara M, de Castro G Jr, et al. doi: 10.4155/fso.15.88, 44. For all cohorts, there was a 90% clinical to pathologic down staging. 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. CAS RU: editing and supervising the manuscript, tables and figure. How to accurately evaluate the effect of neoadjuvant immunotherapy is an evolving area. 2023 BioMed Central Ltd unless otherwise stated. Gillison ML, et al. J Clin Oncol (2013) 31(6):74451. However, PD-L1 negative tumors sometimes respond to CPI treatment, suggestingthe existence of other mechanisms. The FOCUS 4 trial in metastatic colorectal cancer uses group-sequential multi-arm, multi-stage methodology [46] to achieve similar matching of novel therapy and biomarker groups. Notably, the timing of immune checkpoint inhibitors may influence the outcome of cancer treatment (33). Kim ES, Herbst RS, Wistuba II, Lee JJ, Blumenschein GR, Tsao A, Stewart DJ, Hicks ME, Erasmus J, Gupta S. The BATTLE trial: personalizing therapy for lung cancer. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. This trial highlighted the effectiveness of combination immunotherapy and chemotherapy for subsets of HNSCC patients. HNSCC patients with high CD8+ T cells infiltration showed better anti-PD-1 response in the adjuvant setting (52, 54). 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. Lancet Oncol. Moreover, three anti-PD-1/anti-PD-L1 agents, pembrolizumab, nivolumab and atezolizumab, have been approved for second-line therapy of NSCLC [16,17,18]; however, contrary to melanoma, patient selection to therapy should be based on PD-L1 expression level of tumour cells. Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, et al. doi: 10.1001/jamaoncol.2020.2955, 69. The Mutational Landscape of Head and Neck Squamous Cell Carcinoma. Article A total of 28 patients were eligible, and 24 (86%) of patients were HPV positive. National Cancer Center Hospital East, Japan, University General Hospital Attikon, Greece. Liu J, ODonnell JS, Yan J, Madore J, Allen S, Smyth MJ, et al. 2004;350:246170. doi: 10.1056/NEJMoa032641, 8. PR reports personal fees (honoraria for lectures and Advisory Board Member) from Novartis, BMS, Roche, MSD, GSK, Pfizer, and Amgen outside the submitted work. Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, Chagorova T, de la Serna J, Dilhuydy MS, Illmer T, Opat S, Owen CJ, Samoylova O, Kreuzer KA, Stilgenbauer S, Dhner H, Langerak AW, Ritgen M, Kneba M, Asikanius E, Humphrey K, Wenger M, Hallek M. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. Bayesian adaptive designs for biomarker trials with biomarker discovery. Forastiere AA, Goepfert H, Maor M, Pajak TF, Weber R, Morrison W, et al. CAS These encouraging findings have led to numerous ongoing studies testing combinations to improve CPI response rates and also testing these agents in other settings. Di Veroli et al. The November 3, 2021 "Clinical Trial Endpoint Development" (12pm - 5:00 pm ET) will address Locally Advanced Head and Neck Squamous Cell Carcinoma (HNSCC) N Engl J Med. We also highlight selected and recent practice-changing trials in chronic lymphocytic leukaemia as well as breast and gynaecological cancers, and review the advances offered by the development of novel clinical trial designs. 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. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, et al. A Study to Evaluate Fractionated Radiation Therapy Utilizing GRID Therapy for Locally-advanced Bulky Tumors. Zhong LP, Zhang CP, Ren GX, Guo W, William WN Jr., Sun J, et al. Bertrand Baujat et al. 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. 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. 2016;387:154050. HPV-Associated Head and Neck Cancer: A Virus-Related Cancer Epidemic. It remains the fifth leading cause of cancer in the United States and constitutes 10% or more of all cancers worldwide. 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. Squamous cell carcinoma (SCC) is the predominant malignant histology of the mucosal surfaces of the head and neck (HN) region that includes the oral cavity, pharynx, and larynx. ID: NCT03803774. Pathologic responses were evaluated in 34 patients (17 HPV+ and 17 HPV-negative). Contact: Elizabeth Akoth, 240-858-3154. J Clin Oncol. 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. Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K, Sivachenko A, et al.