landmark trials in head and neck cancer ppt

doi: 10.1038/s41591-020-0805-8, 36. 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). - 50.249.249.18. In the neoadjuvant setting, the NeoSphere trial demonstrated significantly improved pathological complete response rates [23] and a trend favouring improved PFS and OS at 5years [24]. 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%. 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. Bonner J, et al. Although this study didnt report pathologic responses or clinical efficacy, the proportion of CD8+ T cells, especially granzyme B positive cells, increased after treatment. 2016;34(Suppl; abstr 9504). Despite this multi-modality treatment, advanced human papillomavirus (HPV)-negative HNSCC shows poor prognosis. 2015;113(5):699705. doi: 10.1158/1078-0432.CCR-16-1761, 43. Cottrell TR, Thompson ED, Forde PM, Stein JE, Duffield AS, Anagnostou V, et al. Topalian SL, Taube JM, Pardoll DM. Lancet Oncol. Lancet Oncol. 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. They used pathological response (PR) criteria which was defined tumor necrosis and/or histiocytic inflammation and giant cell reaction to keratinaceous debris (74). These encouraging findings have led to numerous ongoing studies testing combinations to improve CPI response rates and also testing these agents in other settings. Forde PM, Chaft JE, Smith KN, Anagnostou V, Cottrell TR, Hellmann MD, et al. Google Scholar. doi: 10.1126/science.aax0902, 10. 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. N Engl J Med. Marur S, DSouza G, Westra WH, Forastiere AA. Yearley JH, Gibson C, Yu N, Moon C, Murphy E, Juco J, et al. There are now numerous studies introducing neoadjuvant immunotherapy in diverse cancer types (3436). ID: NCT03803774. 2016;375(1):1122. doi: 10.1200/JCO.2021.39.15_suppl.6053, 74. Demetri GD, von Mehren M, Jones RL, Hensley ML, Schuetze SM, Staddon A, Milhem M, Elias A, Ganjoo K, Tawbi H, Van Tine BA, Spira A, Dean A, Khokhar NZ, Park YC, Knoblauch RE, Parekh TV, Maki RG, Patel SR. Efficacy and safety of trabectedin or dacarbazine for metastatic liposarcoma or leiomyosarcoma after failure of conventional chemotherapy: results of a phase III randomized multicenter clinical trial. There was an 86% MPR rate and a 67% pCR rate. Future Sci OA (2016) 2(1):Fso88. 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). These patients have the worst prognosis despite multimodality approaches and may benefit from neoadjuvant/adjuvant immunotherapy. The VA Larynx study, RTOG 91-11, a study by Bonner et al. Price KAR, Nichols AC, Shen CJ, Rammal A, Lang P, Palma DA, et al. 2016;375(19):184555. Economic burden of chronic lymphocytic leukemia in the era of oral targeted therapies in the United States. 2015;373(25):242537. N Engl J Med (2013) 369(2):13444. doi: 10.1158/1078-0432.CCR-19-2209, 39. All authors contributed to the article and approved the submitted version. J Clin Oncol (2013) 31(6):74451. Landmark Trials in Oncology pp 217239Cite as. Cancer Discov. Clin Cancer Res (2020) 26(13):32119. Below are current clinical trials. Three HPV-positive tumors and one HPV-negative tumor had partial pathologic responses. doi: 10.1200/JCO.2012.43.8820, 28. First published on Mon 11 Oct 2021 07.19 EDT. Curran MA, Montalvo W, Yagita H, Allison JP. Haddad R, et al. 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. In this trial, safety, pTR, and relapse rate with pembrolizumab were evaluated. reported on findings from a clinical trial where neoadjuvant nivolumab (240 mg on days 1 and 15) with or without tadalafil was tested. 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. 2013;14:25764. Huang SH, Xu W, Waldron J, Siu L, Shen X, Tong L, et al. Any pTR was seen in 44% and pTR-2 was seen in 22% of patients. 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. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. Table1 Completed neoadjuvant immunotherapy clinical trials. on behalf of the MAC-NPC Collaborative Group. Key pathological findings after neoadjuvant immunotherapy include 1) keratinous debris, 2) giant cells, histiocytic reaction and 3) tumor necrosis. However, the proportion of CD4+ T cells were decreased while the rate of CD4+FoxP3+ regulatory T cells was increased with treatment. JAMA Oncol (2016) 2(1):4654. 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. doi: 10.1126/science.aax0182, 35. 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. doi: 10.1001/jamaoncol.2015.3638, 42. Immune Biomarkers of Response to Immune-Checkpoint Inhibitors in Head and Neck Squamous Cell Carcinoma. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. doi: 10.1056/NEJMoa1716078, 37. All authors read and approved the final manuscript. 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). A natural extension of this work has led several groups to test whether neoadjuvant chemotherapy prior to surgery would improve clinical outcomes. Checkpoint inhibitors (CPI) targeting the programmed death 1 (PD-1) pathway have been approved for recurrent and metastatic (R/M) HNSCC patients in the first- and second-line settings (1214) and have dramatically changed the treatment algorithm of HNSCC. 2016;35:4907. Contact: Elizabeth Akoth, 240-858-3154. 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. 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. A limited number of drugs have shown activity in advanced disease, and due to the rarity of these tumours, clinical trials in sarcoma include many subtypes and are mainly initiated by academic research groups. In HNSCC, anti-PD-1 agents (nivolumab, pembrolizumab) were first examined and approved in R/M setting. doi: 10.1038/nature13988, 16. Rare Driver Mutations in Head and Neck Squamous Cell Carcinomas Converge on NOTCH Signaling. California Privacy Statement, doi: 10.1093/annonc/mdy227, 58. A summary of recent pivotal trials for systemic therapy in advanced STS is presented in Table2 [19,20,21,22]. Neoadjuvant Nivolumab or Nivolumab Plus Ipilimumab in Untreated Oral Cavity Squamous Cell Carcinoma: A Phase 2 Open-Label Randomized Clinical Trial. For example, radiological tumor examination is widely used in Response Evaluation Criteria In Solid Tumors (RECIST) after organ preservation therapy including radiotherapy and chemotherapy. Int J Radiat Oncol Biol Phys. 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). Ann Oncol (2018) 29(8):16302. Chemotherapy in locally advanced nasopharyngeal carcinoma: an individual patient data meta-analysis of eight randomized trials and 1753 patients. Lancet. Head and Neck Cancer Clinical Trials and Research In neoadjuvant breast cancer, the I-SPY 1 and 2 trials have successfully matched treatment and biomarkers, using adaptive randomised designs [43, 44]. 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). Adaptive designs for dual-agent phase I dose-escalation studies. doi: 10.1073/pnas.0915174107, 72. 2014;371(3):21323. Mol Cancer Ther (2017) 16(11):2598608. Induction Chemotherapy Followed by Concurrent Chemoradiotherapy (Sequential Chemoradiotherapy) Versus Concurrent Chemoradiotherapy Alone in Locally Advanced Head and Neck Cancer (PARADIGM): A Randomised Phase 3 Trial. Barker AD, Sigman CC, Kelloff GJ, Hylton NM, Berry DA, Esserman LJ. Byrd JC, Brown JR, OBrien S, Barrientos JC, Kay NE, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Devereux S, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Pocock C, Thornton P, Caligaris-Cappio F, Robak T, Delgado J, Schuster SJ, Montillo M, Schuh A, de Vos S, Gill D, Bloor A, Dearden C, Moreno C, Jones JJ, Chu AD, Fardis M, McGreivy J, Clow F, James DF, Hillmen P, RESONATE Investigators. Tumour Regression in Non-Small-Cell Lung Cancer Following Neoadjuvant Therapy. 2012;379:187986. JClin Oncol (2018) 36(31):307783. How to accurately evaluate the effect of neoadjuvant immunotherapy is an evolving area. The RTOG 90-03 trial . volume15, Articlenumber:111 (2017) N Engl J Med. Int J Radiat Oncol Biol Phys (1992) 23(3):6712; discussion 6778. 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). Part of The data and subsequent meta-analysis showed the superiority of CCRT to preserve the larynx in advanced laryngeal cancer patients (8, 23). Zhong LP, Zhang CP, Ren GX, Guo W, William WN Jr., Sun J, et al. 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. *Correspondence: Ravindra Uppaluri, Ravindra_Uppaluri@DFCI.Harvard.edu, ORCID: Hirofumi Shibata, orcid.org/0000-0002-7104-9456Ravindra Uppaluri, orcid.org/0000-0001-5988-6828, Immunology and Immunotherapy of Head and Neck Cancer, View all Both trials demonstrated significant benefit for maintenance PARP inhibitors in all subgroups of platinum-sensitive relapsed high-grade serous ovarian cancer. doi: 10.4155/fso.15.88, 44. Development of Tumor Mutation Burden as an Immunotherapy Biomarker: Utility for the Oncology Clinic. 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. Abstract CT075. Merlino DJ, Johnson JM, Tuluc M, Gargano S, Stapp R, Harshyne L Jr., et al. In this review, we present a brief overview of the history of neoadjuvant (induction) chemotherapy in the definitive surgical management of HNSCC. SM currently serves as referee for several haematology and oncology journals such as Journal Clinical Oncology, Blood, Haematologica, Leukemia Research, Leukemia, Leukemia & Lymphoma, European Journal Haematology, Cancer, British Journal of Haematology, and Lancet Haematology. 2015;373(1):2334. 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). 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. 2016;53:12534. Earl, H., Molica, S. & Rutkowski, P. Spotlight on landmark oncology trials: the latest evidence and novel trial designs. Epidemiology. Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, Fabbro M, Ledermann JA, Lorusso D, Vergote I, Ben-Baruch NE, Marth C, Mdry R, Christensen RD, Berek JS, Drum A, Tinker AV, du Bois A, Gonzlez-Martn A, Follana P, Benigno B, Rosenberg P, Gilbert L, Rimel BJ, Buscema J, Balser JP, Agarwal S, Matulonis UA, ENGOT-OV16/NOVA Investigators. Bertrand Baujat et al. 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. Burtness B, Harrington KJ, Greil R, Soulires D, Tahara M, de Castro G Jr, et al. Systemic treatment in advanced soft tissue sarcoma: what is standard, what is new. HNCA recommends researching head and neck cancer clinical trials either by going to www.ClinicalTrials.gov a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world - or using our Clinical Trial Finder which is designed to be user-friendly for patients. Lancet. 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. 1. J Clin Oncol (2012) 30(15):1796804. Phase 2, Open-Label, Single Arm Study, With BST-236 in Adults With R/R AML or Higher-Risk MDS. 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. I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. doi: 10.1093/annonc/mdt461, 25. In addition to ongoing Phase II trials, KEYNOTE-689 is an international phase III study (NCT03765918) where surgically resectable locally advanced HPV-negative HNSCC patients are randomized to receive upfront surgery with SOC adjuvant treatment or neoadjuvant pembrolizumab (two doses) followed by surgery and SOC adjuvant treatment with pembrolizumab (76). J Clin Oncol (2019) 37(15_suppl):25755. doi: 10.1016/j.cllc.2019.11.003, 62. Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al. High Tumor Mutation Burden Fails to Predict Immune Checkpoint Blockade Response Across All Cancer Types. Cancer Discov (2016) 6(12):138299. Given that CPIs are still expensive drugs and sometimes induce severe immune-related toxicities, it is important to establish the appropriate markers which can predict efficacy of CPIs (39, 40). 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. IC continues to be used at some centers with defined indications including advanced or borderline resectable tumors. doi: 10.1200/JCO.2021.39.15_suppl.6006, 75. Pembrolizumab versus ipilimumab in advanced melanoma. 1991;324:168590. 2016;34(30):363847. Ann Oncol (2019) 30(1):4456. doi: 10.1200/JCO.2016.70.1524, 45. doi: 10.1158/1078-0432.CCR-20-1695, 55. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med. 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). 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). As further investigation of these intriguing results is needed, the SITC HNSCC immunotherapy guidelines does not recommend using HPV status for anti-PD1 treatments in R/M HNSCC (31). Google Scholar. doi: 10.1016/0360-3016(92)90027-F, 19. 2016;32(18):28668. This was nearly double what we saw with one dose of pembrolizumab. Overall survival results from a phase III trial of nivolumab combined with ipilimumab in treatment-nave patients with advanced melanoma (CheckMate 067). BMC Med. 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. doi: 10.1136/jitc-2021-002485, 67. The November 3, 2021 "Clinical Trial Endpoint Development" (12pm - 5:00 pm ET) will address Locally Advanced Head and Neck Squamous Cell Carcinoma (HNSCC) Remon J, Besse B, Soria JC. HPV-Positive Status Associated With Inflamed Immune Microenvironment and Improved Response to Anti-PD-1 Therapy in Head and Neck Squamous Cell Carcinoma. 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. doi: 10.1002/cncr.33471, 22. Clin Pharmacol Ther. J Clin Oncol. Correspondence to 2013;31(36):45628. 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]. As described by ASO Editor-in-Chief, Kelly M. McMasters, MD, PhD, "The Landmark Series is designed to trace the origins of current multidisciplinary therapy for each type of solid tumor, and demonstrate the logical progression of clinical trials and other key evidence. 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). 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. There are three major potential benefits to use CPIs in the neoadjuvant setting. Neoadjuvant Nivolumab for Patients With Resectable HPV-Positive and HPV-Negative Squamous Cell Carcinomas of the Head and Neck in the CheckMate 358 Trial. These trials relate to the multidisciplinary management of head and neck cancer from the perspective of a radiation oncologist. Google Scholar. Clinical Trials - Head and Neck Cancer Alliance J Clin Oncol. doi: 10.1038/nature12634, 50. He works very closely with national patient advocacy groups for GIST and sarcoma and is Chairman of the Melanoma Academy in Poland.

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landmark trials in head and neck cancer ppt

landmark trials in head and neck cancer ppt