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• W2945784804 abstract "•Checkpoint inhibition is now commonplace in the treatment of metastatic SCCHN.•Integrating immunotherapy into radical management of LAHNSCC seems to be safe.•There is great need for robust response biomarkers to tailor treatments.•Adjuvant trials will reveal where immunotherapy will sit in managing LASCCHN. Radical treatment strategies for locally advanced squamous cell carcinoma of the head and neck (LASCCHN) are centred on a multidisciplinary approach with options ranging from primary chemoradiotherapy (CRT) to surgical resection, followed by radiotherapy or CRT depending on pathological risk factors. Such intensive regimens have reduced recurrence rates, often at the cost of organ dysfunction and reduced quality of life [1Pignon J.P. Maître A le 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.Radiother Oncol. 2009; 92: 4-14Abstract Full Text Full Text PDF PubMed Scopus (2189) Google Scholar, 2So W.K.W. Chan R.J. Chan D.N.S. Hughes B.G.M. Chair S.Y. Choi K.C. et al.Quality-of-life among head and neck cancer survivors at one year after treatment – a systematic review.Eur J Cancer. 2012; 48: 2391-2408Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar]. Indeed, there have been moves to de-escalate treatment in those with human papillomavirus (HPV)-positive tumours who have better prognosis [[3]Ang K.K. Harris J. Wheeler R. Weber R. Rosenthal D.I. Nguyen-Tan P.F. et al.Human papillomavirus and survival of patients with oropharyngeal cancer.N Engl J Med. 2010; 363: 24-35Crossref PubMed Scopus (4666) Google Scholar], with trials geared towards reducing toxicities while maintaining cure rates. De-escalation strategies including less invasive surgical techniques, tailored dose radiotherapy/chemotherapy and substitution of alternative agents for cisplatin are being investigated [4Bonner J.A. Harari P.M. Giralt J. Azarnia N. Shin D.M. Cohen R.B. et al.Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck.N Engl J Med. 2006; 354: 567-578Crossref PubMed Scopus (4188) Google Scholar, 5Mirghani H. Blanchard P. Treatment de-escalation for HPV-driven oropharyngeal cancer: where do we stand?.Clin Transl Radiat Oncol. 2017; 8: 4-11Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar]. De-ESCALaTE and RTOG 1016 are the first to report after substituting cetuximab for cisplatin and describe inferior survival in the cetuximab arm with no benefit in terms of adverse events [6Gillison M.L. Trotti A.M. Harris J. Eisbruch A. Harari P.M. Adelstein D.J. et al.Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial.Lancet. 2019; 393: 40-50Abstract Full Text Full Text PDF PubMed Scopus (660) Google Scholar, 7Mehanna H. Robinson M. Hartley A. Kong A. Foran B. Fulton-Lieuw T. et al.Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial.Lancet. 2019; 393: 51-60Abstract Full Text Full Text PDF PubMed Scopus (531) Google Scholar]. Despite this, upwards of 50% of patients with LASCCHN relapse, and there is therefore a need for intensification of therapy in some patient groups. Immune checkpoint inhibitors (ICI) are a relatively new class of agent that have activity in metastatic squamous cell carcinoma of the head and neck (SCCHN). Most evidence around their use involves programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors, which are generally well tolerated and are associated with better quality of life compared with chemotherapy [[8]Ferris R.L. Blumenschein G. Fayette J. Guigay J. Colevas A.D. Licitra L. et al.Nivolumab for recurrent squamous-cell carcinoma of the head and neck.N Engl J Med. 2016; 375: 1856-1867Crossref PubMed Scopus (2901) Google Scholar]. These agents may be ideal candidates for intensification in radical therapy for LASCCHN. Until recently, standard of care for patients with relapsed/metastatic SCCHN had remained first-line platinum and 5-fluorouracil chemotherapy with or without cetuximab (following the EXTREME study) and taxane/methotrexate or single-agent cetuximab in the second line [9Forastiere A.A. Metch B. Schuller D.E. Ensley J.F. Hutchins L.F. Triozzi P. et al.Randomised comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous cell carcinoma of head and neck, a southwest oncology group study.J Clin Oncol. 1992; 10: 1245-1251Crossref PubMed Scopus (645) Google Scholar, 10Jacobs C. Lyman G. Velez-Garcia E. Sridhar K. Knight W. Hochster H. et al.A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck.J Clin Oncol. 1992; 10: 257-263Crossref PubMed Scopus (539) Google Scholar, 11Vermorken J.B. Mesia R. Rivera F. Remenar E. Kawecki A. Rottey S. et al.Platinum-based chemotherapy plus cetuximab in head and neck cancer.N Engl J Med. 2008; 359: 1116-1127Crossref PubMed Scopus (2543) Google Scholar]. There is increasing evidence that ICI such as the PD-1 inhibitors (e.g. pembrolizumab and nivolumab) and PD-L1 inhibitors (e.g. durvalumab) have activity in this setting. These agents target and abrogate key immune evasion mechanisms, in turn activating the immune response against malignant cells [[12]Ferris R.L. Immunology and immunotherapy of head and neck cancer.J Clin Oncol. 2015; 33: 3293-3304Crossref PubMed Scopus (409) Google Scholar]. The Keynote-012 trial showed response rates of 18% for pembrolizumab in patients whose tumours were PD-L1 positive, while retaining a tolerable side-effect profile (grade ≥3 adverse events 17%) [[13]Seiwert T.Y. Burtness B. Mehra R. Weiss J. Berger R. Eder J.P. et al.Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial.Lancet Oncol. 2017; 17: 956-965Abstract Full Text Full Text PDF Scopus (1085) Google Scholar]. These findings were echoed in the Keynote-055 study, with similar response rates and toxicity [[14]Bauml J. Seiwert T.Y. Pfister D.G. Worden F. Liu S.V. Gilbert J. et al.Pembrolizumab for platinum- and cetuximab-refractory head and neck cancer: results from a single-arm, phase II study.J Clin Oncol. 2017; 35: 1542-1549Crossref PubMed Scopus (419) Google Scholar]. Durvalumab has also proven to be efficacious and safe in a heavily pretreated population [[15]Segal N.H. Ou S.I. Balmanoukian A.S. Massarelli E. Brahmer J.R. Weiss J. et al.949O - Updated safety and efficacy of durvalumab (MEDI4736), an anti-PD-L1 antibody, in patients from a squamous cell carcinoma of the head and neck. Presented at ESMO 2016 Congress.Ann Oncol. 2016; 27: 328-350Abstract Full Text Full Text PDF Google Scholar]. The CheckMate 141 study subsequently showed a survival benefit for nivolumab in patients with recurrent/metastatic SCCHN previously treated with cisplatin, compared with single-agent methotrexate, docetaxel or cetuximab. The median overall survival was 7.5 months (95% confidence interval 5.5–9.1) in the nivolumab group versus 5.1 months (95% confidence interval 4.0–6.0) on standard therapy, with fewer grade 3/4 side-effects together with delayed time to deterioration in quality of life [8Ferris R.L. Blumenschein G. Fayette J. Guigay J. Colevas A.D. Licitra L. et al.Nivolumab for recurrent squamous-cell carcinoma of the head and neck.N Engl J Med. 2016; 375: 1856-1867Crossref PubMed Scopus (2901) Google Scholar, 16Harrington K.J. Ferris R.L. Blumenschein G. Colevas A.D. Fayette J. Licitra L. et al.Nivolumab versus standard, single-agent therapy of investigator’s choice in recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141): health-related quality-of-life results from a randomised, phase 3 trial.Lancet Oncol. 2017; 18: 1104-1115Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar]. Updated follow-up data reported a maintained benefit for nivolumab, with an estimated 24 month overall survival rate of 16.9% (95% confidence interval 12.4–22.0%) [[17]Ferris R.L. Blumenschein G. Fayette J. Guigay J. Colevas A.D. Licitra L. et al.Nivolumab vs investigator’s choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression.Oral Oncol. 2018; 81: 45-51Crossref PubMed Scopus (432) Google Scholar]. Outcomes were also analysed by HPV status and expression of PD-L1; high expression of which has been shown to enrich the response to PD-1/PD-L1 agents in different tumour groups. Both HPV-positive and -negative patients gained benefit from nivolumab in the 2 year analysis (hazard ratio 0.60 and 0.59, respectively). Expression of PD-L1 was more strongly associated with a positive outcome; hazard ratio 0.55 (95% confidence interval 0.39–0.78) and 0.73 (95% confidence interval 0.49–1.09) with PD-L1 expression >1% and <1%, respectively [[17]Ferris R.L. Blumenschein G. Fayette J. Guigay J. Colevas A.D. Licitra L. et al.Nivolumab vs investigator’s choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression.Oral Oncol. 2018; 81: 45-51Crossref PubMed Scopus (432) Google Scholar]. A further phase III study (Keynote-040) in the same setting examined pembrolizumab versus the investigator's choice of chemotherapy and showed similar results, with an updated survival analysis reporting an improvement in median overall survival (8.4 versus 6.9 months; hazard ratio 0.8, 95% confidence interval 0.65–0.98) [18Cohen E.E. Harrington J. Le Tourneau C. Dinis J. Licitra L. Ahn M. et al.Abstract LBA45_PR. Pembrolizumab (pembro) vs standard of care (SOC) for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC): phase 3 KEYNOTE-040 trial. ESMO 2017 Congress.Ann Oncol. 2017; 28: v605-v649Google Scholar, 19Soulieres D. Cohen E. Le Tourneau C. Dinis J. Licitra L. Ahn M. et al.Abstract CT115 - Updated survival results of the KEYNOTE-040 study of pembrolizumab vs standard-of-care chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma.in: Presented at: American association for cancer research annual meeting. 14–18 April 2018http://www.abstractsonline.com/pp8/#!/4562/presentation/11149Crossref Google Scholar]. Recently, Keynote-048 has provided early evidence for the use of first-line pembrolizumab alone or in combination with cisplatin and 5-fluorouracil when compared with the EXTREME regimen. These regimens showed non-inferiority and improved overall survival, respectively, in an interim analysis [[20]Burtness B. Harrington K.J. Greil R. Soulieres D. Tahara M. De Castro G. et al.Abstract LBA8_PR First-line pembrolizumab for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC): interim results from the phase 3 KEYNOTE-048 study.Ann Oncol. 2018; 29: 729Abstract Full Text Full Text PDF Google Scholar]. Although the final analysis is awaited, these promising results suggest that Keynote-048 will be practice changing. Preclinical studies have shown that combining ICI and radiotherapy can alter the balance within the tumour microenvironment in an immunostimulatory direction, promote auto-immunisation and subsequent immunogenic cell death [21Sharabi A. Lim M. DeWeese T. Drake C.G. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy.Lancet Oncol. 2015; 16: e498-e509Abstract Full Text Full Text PDF PubMed Scopus (511) Google Scholar, 22Chajon E. Castelli J. Marsiglia H. De Crevoisier R. The synergistic effect of radiotherapy and immunotherapy: a promising but not simple partnership.Crit Rev Oncol Hematol. 2017; 111: 124-132Crossref PubMed Scopus (81) Google Scholar, 23Kang J. Demaria S. Formenti S. Current clinical trials testing the combination of immunotherapy with radiotherapy.J Immunother Cancer. 2016; 4: 1-20Google Scholar]. In addition, potential synergies have been reported between immunotherapy and chemotherapy [[24]Emens L.A. Middleton G. The interplay of immunotherapy and chemotherapy: harnessing potential synergies.Cancer Immunol Res. 2015; 3: 436-443Crossref PubMed Scopus (491) Google Scholar]. These findings, and the flattening of survival curves often seen in ICI trials (which suggest cure in a proportion of cases), has underpinned a move towards utilising ICI in earlier disease, i.e. the neo/adjuvant setting. Although trials set in this context are yet to report in SCCHN, proof of concept has been provided in melanoma and lung cancer. The EORTC 18071 trial investigated patients with stage III melanoma who received up to 3 years of adjuvant ipilimumab (anti CTLA-4 monoclonal antibody) and reported 5 year overall survival rates of 65.4% in the treatment arm compared with 54.4% in placebo (hazard ratio for death 0.72; P = 0.001) [[25]Eggermont A.M.M. Chiarion-Sileni V. Grob J.J. Dummer R. Wolchok J.D. Schmidt H. et al.Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy.N Engl J Med. 2016; 375: 1845-1855Crossref PubMed Scopus (953) Google Scholar]. Subsequently, CheckMate 238 randomised 906 patients to either adjuvant nivolumab or ipilimumab for up to 12 months. Nivolumab proved superior; with recurrence-free survival rates of 70.5% (95% confidence interval 66.1–74.5) compared with 60.8% (95% confidence interval 56.0–65.2) [[26]Weber J. Mandala M. Del Vecchio M. Gogas H.J. Arance A.M. Cowey C.L. et al.Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma.N Engl J Med. 2017; 377: 1824-1835Crossref PubMed Scopus (1350) Google Scholar]. As adjuvant PD-1 inhibitors become standard of care [27https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm590004.htmDate accessed: August 10, 2018Google Scholar, 28https://www.ema.europa.eu/documents/smop/chmp-post-authorisation-summary-positive-opinion-opdivo_en-1.pdfDate accessed: August 10, 2018Google Scholar] there is emerging evidence that ICI in the neoadjuvant setting are beneficial in stage III melanoma, with early results from OpACIN (NCT02437279) and NCT02519322 reporting a reduction in tumour burden with nivolumab plus ipilimumab prior to lymph node resection [29Blank C. Akkooi van A. Rozeman E.A. Kvistborg P. Theinen van H.V. Stegenga B. et al.LBA-39 – (Neo-)adjuvant ipilimumab + nivolumab (IPI + NIVO) in palpable stage 3 melanoma – initial data from the OpACIN trial.Ann Oncol. 2016; 27: 1-36PubMed Google Scholar, 30Reddy S.M. Amaria R.N. Spencer M.T. Reuben A. Andrews M. Wang L. et al.Neoadjuvant nivolumab versus combination ipilimumab and nivolumab followed by adjuvant nivolumab in patients with resectable stage III and oligometastatic stage IV melanoma: preliminary findings.in: 32nd SITC annual meeting. November 2017Google Scholar]. Evidence is also accumulating in non-small cell lung cancer (NSCLC), with the PACIFIC trial using 12 months of durvalumab versus placebo in patients with stage III NSCLC who had a complete response following CRT. Progression-free survival was dramatically improved by 11.2 months (hazard ratio for disease progression/death 0.52; P = 0.001) [[31]Antonia S.J. Villegas A. Daniel D. Vicente D. Murakami S. Hui R. et al.Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer.N Engl J Med. 2017; 377: 1919-1929Crossref PubMed Scopus (2478) Google Scholar]. Results of other trials examining alternative PD-1/PD-L1 agents in the adjuvant setting (e.g. PEARLS NCT02504372) are eagerly awaited [[32]https://clinicaltrials.gov/ct2/show/NCT02504372Date accessed: May 11, 2018Google Scholar]. As in melanoma, there is evidence that neoadjuvant ICI have activity and in a small trial Chaft et al. [[33]Chaft J.E. Forde P.M. Smith K.N. Anagnostou V. Cottrell T. Taube J.M. Neoadjuvant nivolumab in early-stage, resectable non-small cell lung cancers.J Clin Oncol. 2017; 35: 8508Crossref Google Scholar] used two doses of nivolumab prior to surgical resection in patients with stage IB–IIIA NSCLC. There were no delays to surgery and 86% of patients were alive without recurrence at 9 months [[33]Chaft J.E. Forde P.M. Smith K.N. Anagnostou V. Cottrell T. Taube J.M. Neoadjuvant nivolumab in early-stage, resectable non-small cell lung cancers.J Clin Oncol. 2017; 35: 8508Crossref Google Scholar]. Although there are similarities between NSCLC and SCCHN patient demographics and disease course, the presence of key differences (role of viruses etc.) should invoke a degree of caution when drawing comparisons. There are many questions to be answered with regards to the ideal approach for integrating ICI into the management of LASCCHN, namely treatment duration and timing. The wide range of regimens applied within clinical trials reflects this uncertainty; some encourage immune priming with (neo)adjuvant ICI (e.g. CompARE, CRUK/13/026 [[34]https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-trial-looking-at-different-treatments-for-people-with-oropharyngeal-cancer-compareDate accessed: January 18, 2019Google Scholar]), whereas others seek to test concurrent ICI with CRT and varying lengths of adjuvant therapy (e.g. 6 months in Keynote-412 NCT03040999 and 12 months in JAVELIN NCT02952586 [35Machiels J.-P.H. Licitra L. Rischin D. Waldron J. Burtness B. Gregoire G. et al.KEYNOTE-412: Pembrolizumab (pembro) in combination with chemoradiation versus chemoradiation alone in locally advanced head and neck squamous cell carcinoma (LA-HNSCC).J Clin Oncol. 2017; 35 (TPS6090)Google Scholar, 36Lee N.Y. Ferris R.L. Beck T. Harrington K. Haddad R.I. Bourhis J. et al.JAVELIN head and neck 100: a phase 3 trial of avelumab in combination with chemoradiotherapy (CRT) vs CRT for 1st-line treatment of locally advanced squamous cell carcinoma of the head and neck (LA SCCHN).J Clin Oncol. 2017; 35 (TPS6093)Google Scholar]) (see Table 1). In addition, studies such as NICO (neoadjuvant and adjuvant nivolumab for surgically managed locally advanced oral cavity cancer) seek to exploit potential adjuvant benefit while utilising the surgical window of opportunity (and its rich bioresource) in search of biomarkers for a response capable of guiding future clinical decision making [[37]https://www.lctu.org.uk/LCTU_NET/frontend/core/Features/trialinfo.aspx?Data=W1tkSEpw WVd4bmNtOTFjQT09XV1bTWc9PV1bW2RISnBZV3hwWkE9PV1dW016YzBdW1tiRzlqWVd4bF1dW01RPT1dDate accessed: May 11, 2018Google Scholar]. Although this could revolutionise the treatment of SCCHN, specific barriers cannot be ignored; particularly whether adding further systemic anticancer drugs to CRT could induce intolerable side-effects or, in the case of neoadjuvant treatment, prevent the commencement of standard of care therapy. Preliminary trial results (NCT02586207) have, however, reported manageable toxicities. Of 27 patients with LASCCHN treated with pembrolizumab in conjunction with primary CRT, three stopped pembrolizumab due to side-effects and all completed their radiotherapy without significant delay [[38]Powell S.F. Gitau M.M. Sumey C.J. Reynolds J.T. Lohr M. McGraw S. et al.Safety of pembrolizumab with chemoradiation (CRT) in locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN).J Clin Oncol. 2017; 35: 6011Crossref Google Scholar].Table 1Listed phase II/III neoadjuvant, adjuvant and concurrent trials utilising immune checkpoint inhibitors in the management of locally advanced squamous cell carcinoma of the head and neck (SCCHN)Clinical trial identifierTrial nameSponsor/collaboratorPhaseEligibilityTreatment armsOutcome measureNeoadjuvant/adjuvant trialsNCT03317327REPORTOslo University Hospital/Bristol-Myers SquibbI/IIRecurrent or second primary SCCHN following prior radiotherapy suitable for re-irradiationRadiotherapy plus concurrent and adjuvant nivolumab (up to 12 months)Incidence and severity of adverse eventsNCT03247712Providence Health & ServicesI/IISCCHN planned for surgical resectionNeoadjuvant radiotherapy plus nivolumab ± surgical resection then 6 months of adjuvant nivolumabUnplanned delay to surgery, decrease in tumour size or number of involved nodesNCT03051906Ducro-HNAzienda Ospedaliero-Universitaria CareggiI/IILocally advanced SCCHN ineligible for surgical resectionDurvalumab, cetuximab and radiotherapy plus adjuvant durvalumab (6 months)2 year progression-free survivalNCT03003637IMCISIONThe Netherlands Cancer InstituteI/IILocally advanced SCCHN suitable for surgical resectionNeoadjuvant nivolumab plus ipilimumab followed by surgical resectionDelay to surgery, tumour pathological responseNCT02841748PATHWayUniversity of ChicagoIIStage III–IVb SCCHN with high risk of recurrence following curative therapy12 months of adjuvant pembrolizumab versus 12 months of adjuvant placebo2 year progression-free survivalNCT03355560University of Cincinnati/Bristol-Myers SquibbIILocal recurrence of SCCHN treated with salvage surgical resection (previous curative treatment)12 months of adjuvant nivolumabGrade 3 or 4 adverse eventsNCT02919683Dana-Farber Cancer Institute/Bristol-Myers SquibbIIT2 or greater and/or nodal involved oral cavity SCC planned for curative treatmentNeoadjuvant nivolumab, 1 dose versus neoadjuvant nivolumab plus Ipilimumab, 1 doseResponse rates2017-005015-13 (EudraCT number)NICOClatterbridge Cancer Centre NHS Foundation Trust/Aintree University Hospital NHS Foundation Trust/Liverpool Cancer Trials Unit/Bristol-Myers SquibbIILocally advanced SCC oral cavity planned for surgical resectionNeoadjuvant nivolumab, radical surgery and subsequent risk-stratified adjuvant radiotherapy or chemoradiotherapy, then 6 months of adjuvant nivolumab1 year progression-free survivalNCT02777385University of Pittsburgh/Merck Sharp & DohmeIILocally advanced SCCHN not undergoing surgical resectionChemoradiotherapy with concurrent pembrolizumab versus chemoradiotherapy with 6 months of adjuvant pembrolizumab1 year progression-free survival, 1 year failure rate, acute toxicity rateNCT02289209Dan Zandberg/Merck Sharp & DohmeIILocoregional recurrent SCCHN which is unresectable, suitable for re-irradiationRadiotherapy plus concurrent and adjuvant pembrolizumab (3–24 months based on response)Progression-free survivalNCT03383094Loren Mell, University of California/Merck Sharp & DohmeIIP16-positive SCCHN with high/intermediate risk diseaseRadiotherapy with concurrent cisplatin versus radiotherapy with concurrent and adjuvant pembrolizumab (20 cycles)Progression-free survivalNCT03107182Optima-IIUniversity of ChicagoIIHPV-positive SCCHN. No previous surgery or radiation therapyInduction nab-paclitaxel, carboplatin, nivolumab. Following this: surgery and adjuvant radiotherapy depending on risk factors versus de-escalated chemoradiotherapy versus standard dose chemoradiotherapy.All patients 6 months of adjuvant nivolumabTumour shrinkage (%), deep response rateNCT03342911Sidney Kimmel Cancer Centre at Thomas Jefferson University/Bristol-Myers SquibbIIStage III–IV SCCHN surgically resectable at baseline3 cycles of induction paclitaxel, carboplatin and nivolumab prior to surgical resectionPathological complete responseNCT02769520Ezra Cohen/Merck Sharp & DohmeIILocal and/or locoregional recurrent SCCHN amenable to salvage surgery. Disease-free interval 18 months post-curative therapySalvage surgery with 12 months of adjuvant pembrolizumabDisease-free survival at 12 monthsNCT02296684Washington University School of Medicine/Merck Sharp & DohmeIILocally advanced surgically resectable SCCHNNeoadjuvant pembrolizumab, surgical resection with adjuvant risk-based radiotherapy or chemoradiotherapy plus 6 cycles of adjuvant pembrolizumab versus neoadjuvant pembrolizumab, surgical resectionLocoregional recurrence rates, distant failure rates, rate of major pathological treatment effectNCT03325465KEOUniversity of ChicagoIILocally advanced SCCHN appropriate for surgical resectionNeoadjuvant pembrolizumab plus epacadostat, surgical resection with 12 months of adjuvant pembrolizumab plus epacadostat versus neoadjuvant pembrolizumab, surgical resection with 12 months of adjuvant pembrolizumabRate of major treatment effect, rate of complete responseNCT03174275UNC Lineberger Comprehensive Cancer Centre/AstraZeneca/CelgeneIIStage III and IV SCCHN amenable to surgical resectionRisk dependent: 5 cycles of neoadjuvant carboplatin, nab-paclitaxel plus durvalumab, surgical resection with adjuvant chemoradiotherapy and subsequent 3 cycles adjuvant durvalumabPathological complete response rateNCT03406247ADJORL1Gustave Roussy, Cancer Campus, Grand ParisIIRecurrent or second primary SCCHN in at previously irradiated site that has received salvage surgery6 months of adjuvant nivolumab versus 6 months of adjuvant nivolumab plus ipilimumab2 year disease-free survivalNCT03114280PICHCentre Antoine Lacassagne/GORTECIIUntreated unresectable locally advanced SCCHN3 cycles of induction docetaxel, cisplatin, 5-fluorouracil plus pembrolizumab followed by chemoradiotherapy with carboplatinProgression-free survivalNCT02827838Wake Forest University Health Sciences/National Cancer InstituteIISCCHN suitable for surgical resectionNeoadjuvant durvalumab followed by surgical resectionImmune responsesNCT03426657University of Erlangen-Nurnberg Medical SchoolIILocally advanced SCCHN (stage III–IVB)Neoadjuvant durvalumab, tremelimumab, cisplatin, docetaxel: stable/decreased CD8+T cell density on biopsy = standard chemoradiotherapyIncreased CD8+ = radiotherapy with concurrent durvalumab plus tremelimumab followed by 8 cycles of adjuvant durvalumabNumber of patients with increased CD8+ T cell densities. Predictive character of changes in T cell densityNCT03258554National Cancer InstituteII/IIILocally advanced SCCHN contraindication to cisplatinRadiotherapy plus concurrent and adjuvant durvalumab versus radiotherapy plus concurrent cetuximabDose-limiting toxicity, overall survival, progression-free survivalNCT02952586JAVELIN Head and Neck 100PfizerIIILocally advanced SCCHN eligible for chemoradiotherapy with curative intentNeoadjuvant avelumab, chemoradiotherapy plus avelumab with 12 months of adjuvant avelumabVersus neoadjuvant placebo, chemoradiotherapy plus placebo with 12 months of adjuvant placeboProgression-free survivalNCT02999087REACHGroupe Oncologie Radiotherapie tete et Cou/Merck KGaA/PfizerIIILocally advanced SCCHN fit for cisplatin and unfit for cisplatinFit for cisplatin: radiotherapy plus concurrent cisplatinversus radiotherapy plus concurrent cetuximab and avelumab, 12 months of adjuvant avelumab Unfit for cisplatin: radiotherapy plus cetuximabversus radiotherapy plus concurrent cetuximab and avelumab with 12 months of adjuvant avelumabProgression-free survivalNCT03040999Keynote 412Merck Sharp & DohmeIIILocally advanced SCCHN eligible for definitive chemoradiotherapyRadiotherapy plus concurrent pembrolizumab and cisplatin with 6 months of adjuvant pembrolizumab versus Radiotherapy plus placebo and cisplatin with 6 months of adjuvant placeboEvent-free survivalCRUK/13/026CompARECancer Research UKExperimental Cancer Medicine Centre (ECMC)NIHR Clinical Research Network: CancerUniversity of BirminghamIIIIntermediate or high risk oropharyngeal SCC suitable for chemoradiotherapyChemoradiotherapy versus high dose radiotherapy with concurrent cisplatin versus surgical resection followed by chemoradiotherapy versus neoadjuvant durvalumab, followed by chemoradiotherapy and 6 months of adjuvant durvalumabProgression-free survivalConcurrent trialsNCT02759575Nooshin Hashemi-Sadraei, University of Cincinnati/Merck Sharp & DohmeI/IILocally advanced laryngeal SCCChemoradiotherapy with cisplatin plus pembrolizumabTreatment-related adverse events, laryngectomy-free survivalNCT02609503UNC Lindeberger Comprehensive Cancer Centre/Merck Sharp & DohmeIILocally advanced SCCHNRadical radiotherapy plus concomitant pembrolizumabProgression-free survivalNCT02641093Trisha Wise-Draper, University of Cincinnati/Merck Sharp & DohmeIILocally advanced SCCHN suitable for resection and adjuvant radiotherapy/chemoradiotherapyRadiotherapy plus pembrolizumab or chemoradiotherapy plus pembrolizumab depending on pathological risk factorsTreatment-related adverse effects, disease-free survivalNCT02707588Groupe Oncologie Radiotherapie Tete et CouIILocally advanced SCCHN ineligible for cisplatin chemoradiotherapyRadiotherapy with concurrent pembrolizumab versus radiotherapy with concurrent cetuximabLocoregional controlNCT03349710Bristol-Myers SquibbIIILocally advanced unresectable SCCHNUnfit for cisplatin: nivolumab plus placebo plus radiotherapy versus cetuximab plus placebo plus radiotherapy Fit for cisplatin: nivolumab plus cisplatin plus radiotherapy versus placebo plus cisplatin plus radiotherapyEvent-free survivalhttps://www.clinicaltrials.gov/.https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial.https://eudract.ema.europa.eu/.HPV, human papilloma virus; SCC, squamous cell carcinoma. Open table in a new tab https://www.clinicaltrials.gov/. https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial. https://eudract.ema.europa.eu/. HPV, human papilloma virus; SCC, squamous cell carcinoma. On the other hand, (neo)adjuvant ICI has the advantage of reducing the chances of adverse interactions with CRT and has shown survival benefit, albeit in NSCLC rather than HNSCC [[31]Antonia S.J. Villegas A. Daniel D. Vicente D. Murakami S. Hui R. et al.Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer.N Engl J Med. 2017; 377: 1919-1929Crossref PubMed Scopus (2478) Google Scholar]. Ferris et al. [[39]Ferris R.L. Goncalves A. Baxi S.S. Martens U.B. Gauthier H. Langenberg M. et al.LBA46 - an open-label, multicohort, phase 1/2 study in patients with virus-associated cancers (CheckMate 358): safety and efficacy of neoadjuvant nivolumab.Ann Oncol. 2017; 28: v605-v649Google Scholar] presented data from CheckMate 358, which is examining neoadjuvant nivolumab in virus-associated solid tumours. They focused on 29 patients with SCCHN, all of whom received two cycles of nivolumab before surgery. Two patients suffered adverse events of grade 3/4 without delays to resection, leading to the presumption that neoadjuvant ICI is unlikely to impact adversely on current standard of care [[39]Ferris R.L. Goncalves A. Baxi S.S. Martens U.B. Gauthier H. Langenberg M. et al.LBA46 - an open-label, multicohort, phase 1/2 study in patients with virus-associated cancers (CheckMate 358): safety and efficacy of neoadjuvant nivolumab.Ann Oncol. 2017; 28: v605-v649Google Scholar]. 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Sacco J. Using QR codes to enable quick access to information in acute cancer care.Br J Nurs. 2017; 26: S4-S12Crossref PubMed Scopus (9) Google Scholar, 41Kroschinsky F. Stölzel F. von Bonin S. Beutel G. Kochanek M. Kiehl M. et al.New drugs, new toxicities: severe side effects of modern targeted and immunotherapy of cancer and their management.Crit Care. 2017; 21: 1-11Crossref PubMed Scopus (257) Google Scholar]. In a patient population where previous attempts at escalation of therapeutic intensity have failed to achieve significant survival benefit, an opportunity remains to determine what additional benefit might be derived from the inclusion of ICI in treatment paradigms." @default.
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