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. doi: 10.1056/NEJMoa1801946, 48. 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). She has been an expert advisor for NHS NICE Health Technology Assessments. Ang KK, et al. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. Contact: Elizabeth Akoth, 240-858-3154. Phase III Randomized Trial of Induction Chemotherapy in Patients With N2 or N3 Locally Advanced Head and Neck Cancer. DCruz A, et al. N Engl J Med. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. 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. 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. Induction Chemotherapy in Advanced Head and Neck Tumors. Xiong Y, Neskey DM, Horton JD, Paulos CM, Knochelmann HM, Armeson KE, et al. Nature (2014) 515(7528):57781. - 50.249.249.18. 2014;32(12):123641. Br J Cancer. Yearley JH, Gibson C, Yu N, Moon C, Murphy E, Juco J, et al. HE has received research funding from Cancer Research UK and the NIHR HTA, and is funded by the NIHR Cambridge Biomedical Research Centre. 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). Head and Neck Cancer Center - Clinical trials - Mayo Clinic The indications for IC are limited to those with significantly advanced disease and may result in a high frequency of severe adverse events. Neoadjuvant PD-1 Immune Checkpoint Blockade Reverses Functional Immunodominance Among Tumor Antigen-Specific T Cells. Rochester, Minn., Jacksonville, Fla. Readers are encouraged to refer to the full manuscript of these trials for a greater understanding. Future Sci OA (2016) 2(1):Fso88. 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. Provided by the Springer Nature SharedIt content-sharing initiative, Over 10 million scientific documents at your fingertips, Not logged in doi: 10.1016/S1470-2045(13)70011-1, 20. The significant impact of checkpoint inhibitor therapy for R/M HNSCC has proven the existence of anti-cancer immunity in HNSCC (1214). Lancet Oncol (2014) 15(1):e4250. Considering the high-frequency of severe adverse events and lack of significant effect OS prolongation with induction chemotherapy, neoadjuvant immunotherapy thus represents an attractive option for advanced HNSCC treatment. 2016;14(4):45073. Lancet (2019) 393(10167):15667. 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 the phase I setting, there is a pressing need to develop better trial methodologies for novel combinations, often of a standard chemotherapy with a novel targeted agent. 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. doi: 10.1093/annonc/mdy495, 49. TMB is a potential predictive biomarker that also needs further exploration. N Engl J Med. The team lead by Professor Jean-Charles Soria discussed the successes and failures of immunotherapy in the first-line treatment of NSCLC [2]. Ann Oncol (2019) 30(1):5767. Lancet. Kwok M, Rawstron AC, Varghese A, Evans PA, OConnor SJ, Doughty C, Newton DJ, Moreton P, Hillmen P. Minimal residual disease is an independent predictor for 10-year survival in CLL. Spotlight on landmark oncology trials: the latest evidence and novel IC resulted in larynx preservation but did not contribute to improved survival. 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. Cookies policy. Patients also received 6 months of adjuvant nivolumab and lirilumab. PubMed 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. Concurrent Chemotherapy and Radiotherapy for Organ Preservation in Advanced Laryngeal Cancer. 2018. doi: 10.1200/JCO.2014.58.6412, 3. The Neoadjuvant Immuno-RadioTherapy (NIRT) phase Ib trial tested neoadjuvant stereotactic body radiation therapy (SBRT) with nivolumab (240 mg, q2 weeks x 3) prior to surgery in HNSCC patients (NCT03247712) (66). Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomized trials and 17,346 patients. Spotlight on landmark oncology trials: the latest evidence and novel trial designs, https://doi.org/10.1186/s12916-017-0884-7, http://creativecommons.org/licenses/by/4.0/, http://creativecommons.org/publicdomain/zero/1.0/. Geoffrois L, Martin L, De Raucourt D, Sun XS, Tao Y, Maingon P, et al. The checkmate 141 phase III trial evaluated the effect of anti-PD-1 (nivolumab) for R/M HNSCC patients (12). In the era of precision cancer medicine, innovative trial designs will also require the matching of novel drugs with putative targets. 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 [2], and head and neck cancer [6]. Timing of Neoadjuvant Immunotherapy in Relation to Surgery Is Crucial for Outcome. 2006;64(1):7782. PubMed Beitler J, et al. doi: 10.1200/JCO.2021.39.15_suppl.6053, 74. PubMedGoogle Scholar. 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. Google Scholar. Head and Neck Cancer | NEJM A Study to Evaluate Fractionated Radiation Therapy Utilizing GRID Therapy for Locally-advanced Bulky Tumors. PR is Professor of Surgical Oncology at the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology in Warsaw, Poland. 2017;15:57. How to accurately evaluate the effect of neoadjuvant immunotherapy is an evolving area. Historically, surgery and radiotherapy with/without conventional chemotherapy including platinum, taxanes or fluorouracil, were applied to treat HNSCC. Topalian SL, Taube JM, Pardoll DM. Recent landmark immunotherapy trials - melanoma, Study 19 [28, 29] used olaparib against placebo and demonstrated a PFS of 11.2months in BRCA-mutated patients compared with 4.3months for wild-type patients (hazard ratio, 0.18; P<0.0001). Immune Biomarkers of Response to Immune-Checkpoint Inhibitors in Head and Neck Squamous Cell Carcinoma. High Tumor Mutation Burden Fails to Predict Immune Checkpoint Blockade Response Across All Cancer Types. Indeed, ibrutinib demonstrated a survival advantage over chlorambucil despite the studys crossover design. 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). Wise-Draper TM, Takiar V, Mierzwa ML, Casper K, Palackdharry S, Worden FP, et al. The establishment of the best pathological method to evaluate the response of neoadjuvant immunotherapy is still evolving as the ultimate clinical impact of histologic changes is understood. Hodi FS, Ballinger M, Lyons B, Soria JC, Nishino M, Tabernero J, et al. 2009;86(1):97100. In conclusion, we provided here an overview of the history of neoadjuvant immunotherapies in HNSCC starting with chemotherapy extending to exciting frontiers using immunotherapy. 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. Table1 Completed neoadjuvant immunotherapy clinical trials. He has authored or co-authored over 120 scientific papers in Polish and international journals (with an impact factor of above 1200, index-H: 32, citation index>4000), and is co-author of national and international recommendations for sarcoma and melanoma. 2010;11:218. PD-L2 Expression in Human Tumors: Relevance to Anti-PD-1 Therapy in Cancer. Terms and Conditions, Landmark Trials in Oncology pp 217239Cite as. Pathological Response After Neoadjuvant Chemotherapy in Resectable Non-Small-Cell Lung Cancers: Proposal for the Use of Major Pathological Response as a Surrogate Endpoint. Both trials did not show a significant extension of OS and DFS, consistent with the subsequent studies (24, 25). PubMed N Engl J Med. Improved Efficacy of Neoadjuvant Compared to Adjuvant Immunotherapy to Eradicate Metastatic Disease. Indeed, BATTLE, a landmark phase II trial using an adaptive randomised design, tested four novel drugs and biomarker pairings in NSCLC [41]. Nivolumab (3 mg/kg) was administered on weeks 1 and 3, while ipilimumab (1 mg/kg) was given on week 1 only. 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. Despite optimal local treatment, approximately 50% of adult patients with localised STS develop distant metastases and die of metastatic disease. Haddad R, ONeill A, Rabinowits G, Tishler R, Khuri F, Adkins D, et al. A. These trials led to US Food and Drug Administration (FDA) approval of the use of anti-PD-1 (nivolumab and pembrolizumab) for second-line for recurrent and metastatic HNSCC patients who had already experienced platinum-based therapies (31). Lancet. 2017;35(2):16674. Agreement on Major Pathological Response in NSCLC Patients Receiving Neoadjuvant Chemotherapy. Radiother Oncol. elective versus therapeutic neck dissection in node-negative oral cancer. To speed up the introduction of targeted therapy for cancer patients, novel phase II trials are being designed, and may likely form the basis for the landmark trials of the future. Lancet. 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. In conclusion, neoadjuvant approaches provide a potential exciting new treatment paradigm for HNSCC patients. doi: 10.1073/pnas.0915174107, 72. https://doi.org/10.1007/978-3-030-14405-0_7, DOI: https://doi.org/10.1007/978-3-030-14405-0_7. 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). 11:727433. doi: 10.3389/fonc.2021.727433. Intriguing findings from this study reported discordant responses between primary tumor and regional metastatic lymph nodes (NCT03238365) (65). Furthermore, the one-year relapse rate in high-risk patients was 16.7%, which was lower than historical data. doi: 10.1200/JCO.2017.76.2591, 26. Ther Adv Med Oncol (2021) 13:1758835920984061. doi: 10.1177/1758835920984061, 40. The landmark phase III CheckMate 141 trial resulted in the approval of nivolumab in the R/M second-line HNSCC setting (12). 2016;34(30):363847. Lancet Oncol. J Clin Oncol. Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, et al. N Engl J Med (2003) 349(22):20918. We and others have focused on HPV-negative, locally advanced disease patients with high-risk pathologic features (positive surgical margins or extra-nodal extension). Another topic featured in this article collection is systemic therapy in STS [5], which is a heterogeneous group of rare solid tumours. Google Scholar. 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%. 2014;14:31723. Schoenfeld etal. Liu J, Blake SJ, Yong MC, Harjunp H, Ngiow SF, Takeda K, et al. In addition, adaptive designs for phase I combinations are being developed [40]. Zuur CL, Elbers JBW, Vos JL, Avd L, Qiao X, Karakullukcu B, et al. The three-planar views are crucial to understanding the malignant gradient. Furthermore, tertiary lymphoid structures (TLS) in the tumor bed are suggested tocontribute favorable outcome (55). 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 . 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. 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). doi: 10.1001/jamaoncol.2015.3638, 42. A study by Lin et al. Nat Rev Clin Oncol. Signatures of Mutational Processes in Human Cancer. PubMed Central 2016;35:4907. Compared to our initial cohort with one dose, we found that 50% of patients had any pTR and 44% of patients exhibited pTR2. He is the current Head of the Department of Soft Tissue/Bone Sarcoma and Melanoma, the Plenipotentiary Director of Institute for Clinical Trials at the Maria Sklodowska-Curie Memorial Cancer Center as well as the President of the Scientific Council of Maria Sklodowska-Curie Memorial Cancer Center. Nature (2015) 517(7536):57682. Below are current clinical trials. radiotherapy for early glottic carcinoma (T1N0M): results of prospective randomized study of radiation fraction size and overall treatment time. Wason JMS, Abraham JE, Baird RD, Gounaris I, Vallier A-V, Brenton JD, Earl HM, Mander AP. Head Neck (2005) 27(10):84350. doi: 10.1016/S1470-2045(13)70334-6, 64. These results clearly demonstrate the superiority of dual HER2-directed therapy. J Clin Oncol (2003) 21(2):32733. CrossRef Front Oncol (2020) 10:566315. doi: 10.3389/fonc.2020.566315, 66. doi: 10.1126/science.1208130, 12. Article Both trials demonstrated significant benefit for maintenance PARP inhibitors in all subgroups of platinum-sensitive relapsed high-grade serous ovarian cancer. The primary endpoint of this trial was comparison between arms of a change in the CD8+ tumor infiltrating lymphocyte (TIL) density. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebb C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA. Nivolumab in previously untreated melanoma without BRAF mutation. 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]. CAS 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). N Engl J Med (2020) 383(13):121830. doi: 10.1001/jamaoncol.2020.2955, 69. Enhanced Pathologic Tumor Response With Two Cycles of Neoadjuvant Pembrolizumab in Surgically Resectable, Locally Advanced HPV-Negative Head and Neck Squamous Cell Carcinoma (HNSCC). (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). The current results of anti-PD-1 therapy with pembrolizumab or nivolumab monotherapy in melanoma indicated a median overall survival (OS) of approximately 2years, but the combination of anti-PD-1 and anti-CTLA-4 (nivolumab with ipilimumab) was shown to be superior in terms of progression-free survival (PFS) and OS (Table1) [11,12,13,14,15]. National Cancer Center Hospital East, Japan, University General Hospital Attikon, Greece. 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. Secondary endpoints are OS, complete pathological response, and assessment of safety and tolerability. doi: 10.1200/JCO.2021.39.15_suppl.6006, 75. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. Notably, grade 3/4 serious adverse events or delay of surgery didnt occur, underscoring the safety of neoadjuvant immunotherapy. Ferrarotto R, Bell D, Rubin ML, Hutcheson KA, Johnson JM, Goepfert RP, et al. 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). The goal of cytotoxic chemotherapy in this setting is to directly attack tumor cells to reduce tumor burden. There was an 86% MPR rate and a 67% pCR rate. Leidner R, Crittenden M, Young K, Xiao H, Wu Y, Couey MA, et al. Overall survival results from a phase III trial of nivolumab combined with ipilimumab in treatment-nave patients with advanced melanoma (CheckMate 067). Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. Several landmark trials established the clinical benefit of using cisplatin-based chemoradiotherapy after surgery for locally advanced, high-risk HNSCC patients (3, 4). Lin J-C, et al. 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 (2021) 39(15_suppl):60533. Nat Med (2020) 26(4):56676. Development of Tumor Mutation Burden as an Immunotherapy Biomarker: Utility for the Oncology Clinic. Table2 Ongoing neoadjuvant immunotherapy clinical trials. For all cohorts, there was a 90% clinical to pathologic down staging. The Annals of Surgical Oncology (ASO) is pleased to announce, The Landmark Series. It has become clear that neoadjuvant immunotherapy, especially checkpoint inhibitors, are safe and have shown signals of clinical efficacy in HNSCC. Successes and failures: what did we learn from recent first-line treatment immunotherapy trials in non-small cell lung cancer? doi: 10.1056/NEJM199106133242402, 23. Adaptive designs for dual-agent phase I dose-escalation studies. This enhanced function acts to destroy micro-metastasis in clinically advanced tumors, decreasing loco-regional or distant metastasis after primary therapies. B Cell Signatures and Tertiary Lymphoid Structures Contribute to Outcome in Head and Neck Squamous Cell Carcinoma. These trials will test the important topic of whether there is synergy in combination approaches with RT, immunotherapy and/or chemotherapy. Advances in immunotherapy for melanoma. HNSCC patients with high CD8+ T cells infiltration showed better anti-PD-1 response in the adjuvant setting (52, 54). CAS Kiong KL, Yao C, Lin FY, Bell D, Ferrarotto R, Weber RS, et al. 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. Google Scholar. Note, there are institution specific protocols where induction chemotherapy prior to surgery is still used for larger tumors to achieve more rapid control (21). 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. Di Veroli GY, Fornari C, Wang D, Mollard S, Bramhall JL, Richards FM, Jodrell DI. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet Oncol. 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. Neoadjuvant Checkpoint Blockade for Cancer Immunotherapy. Tap WD, Jones RL, Van Tine BA, Chmielowski B, Elias AD, Adkins D, Agulnik M, Cooney MM, Livingston MB, Pennock G, Hameed MR, Shah GD, Qin A, Shahir A, Cronier DM, Ilaria Jr R, Conti I, Cosaert J, Schwartz GK. 2005;27:84350. Int J Radiat Oncol Biol Phys. University of Cambridge Department of Oncology, NIHR Cambridge Biomedical Research Centre, and Hon Consultant in Medical Oncology, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK, Department Hematology-Oncology, Azienda Ospedaliera Pugliese-Ciaccio, 88100, Catanzaro, Italy, Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Institute - Oncology Center, Roentgena 5, 02-781, Warsaw, Poland, You can also search for this author in J Natl Compr Canc Netw. doi: 10.1016/0360-3016(92)90027-F, 19. Hitt R, Grau JJ, Lpez-Pousa A, Berrocal A, Garca-Girn C, Irigoyen A, et al. These designs would allow recruitment of biomarker-negative patients, often not included in other trials, and have the potential for perpetual designs, in which successful matching of novel drugs and biomarkers would result in graduation of the pair to a phase III trial, along with the rapid rejection of novel drugs that did not work. Licitra L, Grandi C, Guzzo M, Mariani L, Lo Vullo S, Valvo F, et al. Barker AD, Sigman CC, Kelloff GJ, Hylton NM, Berry DA, Esserman LJ. 2015;373(1):2334. J Clin Oncol (2019) 37(15_suppl):25755. Weissferdt A, Pataer A, Vaporciyan AA, Correa AM, Sepesi B, Moran CA, et al. J Natl Compr Canc Netw. Bauml J, Seiwert TY, Pfister DG, Worden F, Liu SV, Gilbert J, et al. 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. 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). Pathologic complete response means the ablation of all cancer cells in resected tumor after the treatment. doi: 10.4155/fso.15.88, 44. 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. [39] published an interesting software to provide information in terms of synergy and/or antagonism between two compounds. Neoadjuvant Immunotherapy Leads to Pathological Responses in MMR-Proficient and MMR-Deficient Early-Stage Colon Cancers. In addition, CD8+ T cells with lymphocyte-activation gene 3 (LAG-3) or T cell immunoglobulin domain and mucin domain-3 (TIM-3) co-expression with PD-1 was higher among non-responders (52).