In conclusion, neoadjuvant approaches provide a potential exciting new treatment paradigm for HNSCC patients. 2023 Springer Nature Switzerland AG. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomized controlled trial. This material is provided for educational purposes only and with the goal of encouraging further study about the landmark trials that have impacted oncology. HS received funding from the Uehara Foundation (201941070). We defined pathological tumor response (pTR) as one such approach which is quantified as the proportion of the resection bed with tumor necrosis, keratinous debris, and giant cell/histiocytic reaction were distinct from growing tumor and only seen after therapy (Figure1). 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. Ann Oncol (2019) 30(1):5767. These results clearly demonstrate the superiority of dual HER2-directed therapy. Lin J-C, et al. For example, radiological tumor examination is widely used in Response Evaluation Criteria In Solid Tumors (RECIST) after organ preservation therapy including radiotherapy and chemotherapy. Bayesian adaptive designs for biomarker trials with biomarker discovery. 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. Importantly, phase III clinical trials which examined the clinical efficacy of IC treatment prior to surgery also failed to show suppression of loco-regional relapse and distant metastasis or extend OS (2628). To determine the survival benefit of IC using docetaxel plus cisplatin and fluorouracil (TPF) regimen followed by CCRT, two-phase III randomized trials were completed: the PARADIGM trial reported in 2013 (19) and DeCIDE trial reported in 2014 (20). Postoperative Irradiation With or Without Concomitant Chemotherapy for Locally Advanced Head and Neck Cancer. Wang J, Sun H, Zeng Q, Guo XJ, Wang H, Liu HH, et al. 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). 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. Results from the CLEOPATRA trial in the metastatic setting of the same treatment have produced remarkable results [25]; the same combination produced a 56.5-month median OS compared with 40.8months achieved with trastuzumab and docetaxel alone, showing an increase of 15.7months to OS in the pertuzumab group. Head Neck (2005) 27(10):84350. A Randomized Phase III Trial Comparing Induction Chemotherapy Followed by Chemoradiotherapy Versus Chemoradiotherapy Alone as Treatment of Unresectable Head and Neck Cancer. Chen Q, Jain N, Ayer T, Wierda WG, Flowers CR, OBrien SM, Keating MJ, Kantarjian HM, Chhatwal J. J Radiat Oncol Biol Phys. N Engl J Med. 11:727433. doi: 10.3389/fonc.2021.727433. 2016;375(22):215464. doi: 10.1172/jci.insight.89829, 18. Cooper JS. PR is Professor of Surgical Oncology at the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology in Warsaw, Poland. doi: 10.1016/S0140-6736(19)32591-7, 15. This chapter contains a summary of some key findings from a selection of 18 trials related to oral cavity, nasopharynx, oropharynx, larynx, and hypopharynx cancer. 2016;388(10043):48897. J Immunother Cancer (2021) 9(5):115. Earl, H., Molica, S. & Rutkowski, P. Spotlight on landmark oncology trials: the latest evidence and novel trial designs. (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). reported on findings from a clinical trial where neoadjuvant nivolumab (240 mg on days 1 and 15) with or without tadalafil was tested. Adaptive randomization of neratinib in early breast cancer. 2014;32:294050. Zuur CL, Elbers JBW, Vos JL, Avd L, Qiao X, Karakullukcu B, et al. Schoenfeld etal. Both trials did not show a significant extension of OS and DFS, consistent with the subsequent studies (24, 25). 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). 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). Improved Efficacy of Neoadjuvant Compared to Adjuvant Immunotherapy to Eradicate Metastatic Disease. Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al. Completed and ongoing trials have focused on a diverse group of HNSCC patients including early and advanced stage and HPV-positive and negative patients. Lancet Oncol. Lancet Oncol. 2017. doi:10.1186/s12916-017-0879-4. HPV infection might also be a clinical biomarker to predict the response to CPIs. The IMCISION study (NCT03003637) presented at ESMO 2020 is examining neoadjuvant nivolumab and ipilimumab for stage II-IVa HNSCC patients. We and others have focused on HPV-negative, locally advanced disease patients with high-risk pathologic features (positive surgical margins or extra-nodal extension). Neoadjuvant and Adjuvant Nivolumab and Lirilumab in Patients With Recurrent, Resectable Squamous Cell Carcinoma of the Head and Neck. Novel Strategies to Effectively De-Escalate Curative-Intent Therapy for Patients With HPV-Associated Oropharyngeal Cancer: Current and Future Directions. elective versus therapeutic neck dissection in node-negative oral cancer. Di Veroli et al. Pembrolizumab Versus Methotrexate, Docetaxel, or Cetuximab for Recurrent or Metastatic Head-and-Neck Squamous Cell Carcinoma (KEYNOTE-040): A Randomised, Open-Label, Phase 3 Study. N Engl J Med. JAMA Oncol (2020) 6(10):156370. 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. Tumour Regression in Non-Small-Cell Lung Cancer Following Neoadjuvant Therapy. 2016;17(4):42539. PR is an active member of the EORTC Soft Tissue and Bone Sarcoma Group, where he chaired the Local Treatment Subcommittee and the Membership Committee of the EORTC Board. J Clin Oncol (2015) 33(8):83645. Readers are encouraged to refer to the full manuscript of these trials for a greater understanding. Lorch J, et al. Price KAR, Nichols AC, Shen CJ, Rammal A, Lang P, Palma DA, et al. A. Int J Radiat Oncol Biol Phys (1996) 36(5):9991004. Marur S, et al. There were no delays to surgery and 3/28 patients had Grade 3 AEs. Recent clinical trials of neoadjuvant immunotherapy show promising results and this methodology has the potential to change the treatment algorithm of HNSCC. Cookies policy. 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). Recent developments and approvals in immunotherapy have significantly changed the landscape of melanoma and NSCLC therapy in the metastatic setting, and open various possibilities for adjuvant treatment in high-risk locoregional disease [7,8,9,10]. Impact of Neoadjuvant Durvalumab With or Without Tremelimumab on CD8(+) Tumor Lymphocyte Density, Safety, and Efficacy in Patients With Oropharynx Cancer: CIAO Trial Results. Cohen E, et al. Pembrolizumab for Platinum- and Cetuximab-Refractory Head and Neck Cancer: Results From a Single-Arm, Phase II Study. Pathological Response and Survival With Neoadjuvant Therapy in Melanoma: A Pooled Analysis From the International Neoadjuvant Melanoma Consortium (INMC). J Clin Oncol. Refining American Joint Committee on Cancer/Union for International Cancer Control TNM Stage and Prognostic Groups for Human Papillomavirus-Related Oropharyngeal Carcinomas. More effective and cost-efficient phase II trial designs would rapidly lead to landmark trials and practice-changing results. 2015;373(1):2334. 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. Of eighty evaluated patients, 32 patients (40%) showed a PR [26 partial PR ( 20% and <90%) and 6 with major PR (>90%)]. doi: 10.1126/science.aar3593, 52. Springer Nature. N Engl J Med. 2016;387:154050. BMC Med. 2016;128(24):27703. With the positive responses in the R/M HNSCC setting, several trials have reported results with neoadjuvant checkpoint immunotherapy prior to surgery (Table1). These data suggest the reactivity of neoadjuvant immunotherapy is related to immunogenic phenotype before treatment and highlights the future possibility to select patients for neoadjuvant immunotherapy before surgery. Am Soc Clin Oncol Educ Book (2020) 40:113. Therapeutically, HPV-positive HNSCC demonstrates sensitivity to chemoradiotherapy, and offers a better prognosis (2). Another meta-analysis showed that HPV positive HNSCC patients display significant improved outcomes with PD-1/PD-L1 axis blockage treatment compared to HPV negative HNSCC patients (46). Int J Radiat Oncol Biol Phys. The immunological responses were analyzed using blood before and after treatment. 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). A literature review using Medline, Scopus, Google Scholar, the Cochrane Database of Systematic Reviews and the Cochrane cen NEngl J Med (2016) 375(19):185667. A new cancer treatment can wipe out tumours in terminally ill head and neck cancer patients, scientists have discovered. doi: 10.1200/JCO.2019.37.15_suppl.TPS6090, 77. Moreover, recent trials of immune checkpoint inhibitors in melanoma, non-small cell lung carcinoma, and head and neck cancers have significantly influenced the therapeutic landscape by providing promising evidence for immunotherapy efficacy in the adjuvant setting in high-risk locoregional disease. The landmark VA Larynx study compared IC (cisplatin and fluorouracil) followed by RT versus total laryngectomy followed by RT in advanced laryngeal cancer (22). Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. Clin Cancer Res (2020) 26(19):514052. doi: 10.1126/science.aax0902, 10. Landmark Trials. 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. N Engl J Med. Neoadjuvant Checkpoint Blockade for Cancer Immunotherapy. Based on this study and depending on the programmed death-ligand 1 (PD-L1) combined positive score (CPS) either pembrolizumab alone or with chemotherapy represents the first choice for these patients (14). 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. 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). The Checkmate 358 phase I/II study examined clinical safety and efficacy of two doses of neoadjuvant nivolumab in HPV positive or negative HNSCC (NCT02488759) (67). The importance of BTK inhibitors in the first-line setting has been recently investigated in the RESONATE-2 study [33], a head-to-head clinical trial in which outcomes were shown to be superior for patients who received ibrutinib in comparison to patients treated with chlorambucil single agent. Below are current clinical trials. Systemic treatment in advanced soft tissue sarcoma: what is standard, what is new. Median PFS was 9.5months in the fulvestrant plus palbociclib group and 4.6months in the fulvestrant plus placebo group with a hazard ratio of 0.46, which was highly statistically significant. 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. Int J Radiat Oncol Biol Phys. N Engl J Med. This trial highlighted the effectiveness of combination immunotherapy and chemotherapy for subsets of HNSCC patients. Phase 2, Open-Label, Single Arm Study, With BST-236 in Adults With R/R AML or Higher-Risk MDS. 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). In addition to the published studies above, several ongoing neoadjuvant immunotherapy trials with subsequent surgery for locally advanced HNSCC have reported results at major oncology meetings (Table2). The BATTLE-2 Study: a biomarker-integrated targeted therapy study in previously treated patients with advanced nonsmall-cell lung cancer. Pignon JP, le Matre A, Maillard E, Bourhis J. Meta-Analysis of Chemotherapy in Head and Neck Cancer (MACH-NC): An Update on 93 Randomised Trials and 17,346 Patients. These are the first clear data in HNSCC supporting the finding that neoadjuvant anti-PD1 induced PR is a predictor of clinical outcomes. 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). Piotr Rutkowski. CAS Schoenfeld JD, Hanna GJ, Jo VY, Rawal B, Chen YH, Catalano PS, et al. 1991;324:168590. Notably, other work has contradicted the above studies on TMB and concluded that that high TMB failed to predict the effect of ICI (53). Atezolizumab versus docetaxel for patients with previously treated nonsmall-cell lung cancer (POPLAR): a multicentre, open label, phase 2 randomised controlled trial. 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. Treatment intensification with neoadjuvant (induction) chemotherapies with platinum drugs are insufficient to significantly prolong overall survival. 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. PR reports personal fees (honoraria for lectures and Advisory Board Member) from Novartis, BMS, Roche, MSD, GSK, Pfizer, and Amgen outside the submitted work. The primary endpoint of this trial was comparison between arms of a change in the CD8+ tumor infiltrating lymphocyte (TIL) density. 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. N Engl J Med. N Engl J Med (2018) 378(22):2093104. In the neoadjuvant immunotherapy context, immune-modified RECIST (imRECIST) criteria have been proposed (56). 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. Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefbvre JL, Greiner RH, et al. J Clin Oncol. Understanding Patterns of Pathologic Response Following Neoadjuvant Immunotherapy for Solid Tumors. doi: 10.1056/NEJMoa032641, 8. This was followed by BATTLE-2 [42], testing combination treatments in the same disease. Version 2.2016, NCCN Clinical Practice Guidelines in Oncology. Thus, further studies are needed to define the role of TMB as a predictive biomarker. Gillison ML, et al. 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. Post-operative adjuvant treatments for locally advanced HNSCC have been studied for many years as historically surgery alone for locally advanced disease had very poor outcomes. Comprehensive Genomic Characterization of Head and Neck Squamous Cell Carcinomas. Patients with high-TMB have more effective clinical responses with improved survival in lung, bladder, and head and neck cancer patients (47, 48). Following this, the phase III KEYNOTE-048 trial established a new paradigm for first-line R/M HNSCC patients (14). A trial done by Tata Memorial Centre is included that randomized patients with mostly oral tongue carcinoma to elective neck dissection at the time of primary cancer surgery or watchful waiting with therapeutic neck dissection for nodal relapse. Yearley JH, Gibson C, Yu N, Moon C, Murphy E, Juco J, et al. Wolf GT, Fisher SG, Hong WK, Hillman R, Spaulding M, Laramore GE, et al. 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). These trials relate to the multidisciplinary management of head and neck cancer from the perspective of a radiation oncologist. The RTOG 90-03 trial . PD-L1 expression in tumor cells and immune cells remains the most widely used biomarker in HNSCC and other cancers (40, 41). In addition, IC may increase the possibility of severe AEs as compared to CCRT in non-surgical locally, advanced HNSCC treatment. doi: 10.4155/fso.15.88, 44. 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 . IC resulted in larynx preservation but did not contribute to improved survival. doi: 10.1073/pnas.0915174107, 72. 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. Differences in T-Cell Infiltrates and Survival Between HPV+ and HPV- Oropharyngeal Squamous Cell Carcinoma. Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer. Google Scholar. First, neoadjuvant immunotherapies will enhance systemic T cell responses for tumor-specific antigens before surgery (34). Furthermore, the one-year relapse rate in high-risk patients was 16.7%, which was lower than historical data. J Clin Oncol. Table1 Completed neoadjuvant immunotherapy clinical trials. Hellmann MD, Chaft JE, William WN Jr, Rusch V, Pisters KM, Kalhor N, et al. 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. These data highlight the difficulty of interpreting peripheral lymphocyte populations with clinical responses in HNSCC patients treated with neoadjuvant immunotherapy. 2015;373(25):242537. Neoadjuvant Nivolumab for Patients With Resectable HPV-Positive and HPV-Negative Squamous Cell Carcinomas of the Head and Neck in the CheckMate 358 Trial. There was an 86% MPR rate and a 67% pCR rate. In neoadjuvant breast cancer, the I-SPY 1 and 2 trials have successfully matched treatment and biomarkers, using adaptive randomised designs [43, 44]. Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus-Unrelated Head and Neck Cancer: A Multicenter, Phase II Trial. Immune Biomarkers of Response to Immune-Checkpoint Inhibitors in Head and Neck Squamous Cell Carcinoma. Further, a trial comparing ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab finished recruiting, but results are not yet mature (ClinicalTrials.gov Identifier: NCT02264574). 2023 BioMed Central Ltd unless otherwise stated. Ang KK, et al. Article The pTR rate is calculated as the area of regions 1-3/(1-3)+area of any remaining tumor. 1. HE is an academic clinician in Medical Oncology and currently Professor of Clinical Cancer Medicine at the University of Cambridge, Department of Oncology and a Principal Investigator of the NIHR Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre. doi: 10.1200/JCO.2013.54.6309, 21. The data and subsequent meta-analysis showed the superiority of CCRT to preserve the larynx in advanced laryngeal cancer patients (8, 23). In conclusion, we provided here an overview of the history of neoadjuvant immunotherapies in HNSCC starting with chemotherapy extending to exciting frontiers using immunotherapy. Head Neck. 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). 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. 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. Hitt R, Grau JJ, Lpez-Pousa A, Berrocal A, Garca-Girn C, Irigoyen A, et al. Preoperative Chemotherapy in Advanced Resectable OCSCC: Long-Term Results of a Randomized Phase III Trial. All authors read and approved the final manuscript. This trial aims to enroll 600 patients. Lawrence MS, Sougnez C, Lichtenstein L, Cibulskis K, Lander E, Gabriel SB, et al. Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K, Sivachenko A, et al. McLaughlin J, Han G, Schalper KA, Carvajal-Hausdorf D, Pelekanou V, Rehman J, et al. Nat Med (2020) 26(4):56676. 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. Recently we reported an extension of this study with an additional 29 HNSCC patients treated with two cycles of neoadjuvant pembrolizumab. doi: 10.1158/1078-0432.CCR-20-1695, 55. 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). 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). statement and An important consideration in neoadjuvant immunotherapy approaches is appropriate patient selection. doi: 10.1200/JCO.2017.75.1644, 57. Although only 15-20% of patients benefit, immunotherapies have been approved and widely used for recurrent and metastatic HNSCC. J Clin Oncol. 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 . Adjuvant Chemotherapy for Resectable Squamous Cell Carcinomas of the Head and Neck: Report on Intergroup Study 0034. Status: Open - Recruiting. Positive results from this study established the application of anti-PD-1 for R/M HNSCC treatment, and proved the existence of actionable, efficient anti-cancer immunity in HNSCC tumors. However, a potential setback is represented by the control arm since chlorambucil is no longer regarded an adequate therapy in CLL [26]. Analysis of the data gathered from these large trials continues to contribute valuable understanding about related issues, including . 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