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PURPOSE Pembrolizumab and pembrolizumab-chemotherapy demonstrated efficacy in recurrent/metastatic head and neck squamous cell carcinoma in KEYNOTE-048. Post hoc analysis of long-term efficacy and progression-free survival on next-line therapy (PFS2) is presented. METHODS Patients were randomly assigned (1:1:1) to pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy. Efficacy was evaluated in programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥ 20, CPS ≥ 1, and total populations, with no multiplicity or alpha adjustment. RESULTS The median study follow-up was 45.0 months (interquartile range, 41.0-49.2; n = 882). At data cutoff (February 18, 2020), overall survival improved with pembrolizumab in the PD-L1 CPS ≥ 20 (hazard ratio [HR], 0.61; 95% CI, 0.46 to 0.81) and CPS ≥ 1 populations (HR, 0.74; 95% CI, 0.61 to 0.89) and was noninferior in the total population (HR, 0.81; 95% CI, 0.68 to 0.97). Overall survival improved with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.62; 95% CI, 0.46 to 0.84), CPS ≥ 1 (HR, 0.64; 95% CI, 0.53 to 0.78), and total (HR, 0.71; 95% CI, 0.59 to 0.85) populations. The objective response rate on second-course pembrolizumab was 27.3% (3 of 11). PFS2 improved with pembrolizumab in the PD-L1 CPS ≥ 20 (HR, 0.64; 95% CI, 0.48 to 0.84) and CPS ≥ 1 (HR, 0.79; 95% CI, 0.66 to 0.95) populations and with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.64; 95% CI, 0.48 to 0.86), CPS ≥ 1 (HR, 0.66; 95% CI, 0.55 to 0.81), and total (HR, 0.73; 95% CI, 0.61 to 0.88) populations. PFS2 was similar after pembrolizumab and longer after pembrolizumab-chemotherapy on next-line taxanes and shorter after pembrolizumab and similar after pembrolizumab-chemotherapy on next-line nontaxanes. CONCLUSION With a 4-year follow-up, first-line pembrolizumab and pembrolizumab-chemotherapy continued to demonstrate survival benefit versus cetuximab-chemotherapy in recurrent/metastatic head and neck squamous cell carcinoma. Patients responded well to subsequent treatment after pembrolizumab-based therapy.

Pembrolizumab; Immunoteràpia; Carcinoma cèl·lules escamotes de cap i coll Pembrolizumab; Inmunoterapia; Carcinoma células escamotas de cabeza y cuello Pembrolizumab; Immunotherapy; Squamous cell carcinoma of the head and neck El càncer de cap i coll (CCC) inclou nombroses localitzacions anatòmiques amb múltiples sub-localitzacions. Engloba les neoplàsies localitzades a la cavitat nasal, sins paranasals, nasofaringe, hipofaringe, laringe, tràquea, cavitat oral, orofaringe, glàndules salivals, tumors odontogènics, oïda i tumors del sistema paraganglionar, amb diferents estratègies terapèutiques segons la localització. D'aquesta definició s'exclouen els tumors d'esòfag, tumors de la pell, tumors cerebrals, del sistema nerviós i de la glàndula tiroides.

Quimioteràpia; Carcinoma de cèl·lules escamoses de cap i coll Quimioterapia; Carcinoma de células escamosas de cabeza y cuello Chemotherapy; Head and neck squamous cell carcinoma PURPOSE The phase III KEYNOTE-048 (ClinicalTrials.gov identifier: NCT02358031) trial of pembrolizumab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) included planned efficacy analyses in the total population and in participants with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 1 and CPS ≥ 20. To further characterize the predictive value of PD-L1 expression on outcome, we conducted efficacy analyses in the PD-L1 CPS < 1 and CPS 1-19 subgroups in KEYNOTE-048. METHODS Participants with R/M HNSCC and no prior systemic therapy for R/M disease were randomly assigned 1:1:1 to pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy. Post hoc efficacy analyses of the PD-L1 CPS < 1 and CPS 1-19 subgroups were performed. RESULTS Of 882 participants enrolled, 128 had PD-L1 CPS < 1 and 373 had CPS 1-19. For pembrolizumab versus cetuximab-chemotherapy, the median overall survival was 7.9 versus 11.3 months in the PD-L1 CPS < 1 subgroup (hazard ratio [HR], 1.51 [95% CI, 0.96 to 2.37]) and 10.8 versus 10.1 months in the CPS 1-19 subgroup (HR, 0.86 [95% CI, 0.66 to 1.12]). For pembrolizumab-chemotherapy versus cetuximab-chemotherapy, the median overall survival was 11.3 versus 10.7 months in the PD-L1 CPS < 1 subgroup (HR, 1.21 [95% CI, 0.76 to 1.94]) and 12.7 versus 9.9 months in the CPS 1-19 subgroup (HR, 0.71 [95% CI, 0.54 to 0.94]). CONCLUSION Increased efficacy of pembrolizumab or pembrolizumab-chemotherapy was observed with increasing PD-L1 expression. PD-L1 CPS < 1 subgroup analysis was limited by small participant numbers. Results from the PD-L1 CPS 1-19 subgroup support previous findings of treatment benefit with pembrolizumab monotherapy and pembrolizumab-chemotherapy in patients with PD-L1 CPS ≥ 1 tumors. Although PD-L1 expression is informative, exploration of additional predictive biomarkers is needed for low PD-L1–expressing HNSCC. Funding for this research was provided by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co Inc, Kenilworth, NJ.

Immunotherapy; Pembrolizumab; Quality of life Inmunoterapia; Pembrolizumab; Calidad de vida Immunoteràpia; Pembrolizumab; Qualitat de vida Objectives To assess health-related quality of life (HRQoL) with first-line pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) in the phase 3 KEYNOTE-048 trial (NCT02358031). Materials and Methods HRQoL was measured using the European Organisation for Research and Treatment of Cancer 30-question quality-of-life (EORTC QLQ-C30), the EORTC 35-question quality-of-life head and neck cancer–specific module (EORTC QLQ-H&N35), and the EuroQol 5-dimension 3-level instruments (EQ-5D-3L). Secondary endpoints included mean change from baseline in EORTC QLQ-C30 global health status/quality of life (GHS/QoL) at week 15 and time to deterioration (TTD) in EORTC QLQ-C30 GHS/QoL and EORTC QLQ-H&N35 pain and swallowing. Results Of 882 enrolled participants, 844 received ≥ 1 dose of study treatment and completed ≥ 1 HRQoL assessment; adherence was ≥ 79% at week 15 across treatment groups. At week 15, EORTC QLQ-C30 GHS/QoL scores remained stable; no clinically meaningful between-group differences were observed (least squares mean difference, pembrolizumab vs cetuximab-chemotherapy, 0.24; 95% CI, −3.34 to 3.82; pembrolizumab-chemotherapy vs cetuximab-chemotherapy, 0.40; 95% CI, −3.46 to 4.26). Median TTD in EORTC QLQ-C30 GHS/QoL and EORTC QLQ-H&N35 pain and swallowing scores was not reached over 51 weeks across groups, showing stable HRQoL. TTD was similar between groups for EORTC QLQ-C30 GHS/QoL (pembrolizumab vs cetuximab-chemotherapy: HR, 1.38; 95% CI, 0.95–2.00; pembrolizumab-chemotherapy vs cetuximab-chemotherapy: HR, 1.37; 95% CI, 0.94–2.00), as was TTD in EORTC QLQ-H&N35 pain and swallowing scores. Conclusions Pembrolizumab monotherapy and pembrolizumab-chemotherapy extended OS while maintaining HRQoL, further supporting first-line use for R/M HNSCC. Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Simple Summary Drug resistance is the principal limiting factor to achieving good survival rates in patients with cancer. The identification of potential biomarkers for diagnosis and prognostic prediction, as well as the design of new molecular-targeted treatments, will be essential to improving head and neck squamous cell carcinoma (HNSCC) patient outcomes. In this sense, the sensitization of resistant cells and cancer stem cells (CSCs) represents a major challenge in cancer therapy. We conducted a proteomic study involving cisplatin-resistance and CSCs with the aim to unravel the molecular and cellular mechanisms by which tumor cells acquire resistance to chemotherapy. Syntenin-1 (SDCBP) was identified as an important protein involved in the chemoresistance and stemness of HNSCC tumors. Abstract To characterize the mechanisms that govern chemoresistance, we performed a comparative proteomic study analyzing head and neck squamous cell carcinoma (HNSCC) cells: CCL-138 (parental), CCL-138-R (cisplatin-resistant), and cancer stem cells (CSCs). Syntenin-1 (SDCBP) was upregulated in CCL-138-R cells and CSCs over parental cells. SDCBP depletion sensitized biopsy-derived and established HNSCC cell lines to cisplatin (CDDP) and reduced CSC markers, Src activation being the main SDCBP downstream target. In mice, SDCBP-depleted cells formed tumors with decreased mitosis, Ki-67 positivity, and metastasis over controls. Moreover, the fusocellular pattern of CCL-138-R cell-derived tumors reverted to a more epithelial morphology upon SDCBP silencing. Importantly, SDCBP expression was associated with Src activation, poor differentiated tumor grade, advanced tumor stage, and shorter survival rates in a series of 382 HNSCC patients. Our results reveal that SDCBP might be a promising therapeutic target for effectively eliminating CSCs and CDDP resistance.

Càncer de cèl·lules escatoses de cap i coll; Tractament en platí; Pacients adults Cáncer de células escamosas de cabeza y cuello; Tratamiento en platino; Pacientes adultos Cancer of scaly cells of head and neck; Platinum treatment; Adult patients El càncer de cap i coll (CCC) és una patologia heterogènia que agrupa als càncers de la cavitat nasal, sinus paranasals, oïda, glàndules salivars, cavitat oral, nasofaringe, orofaringe, hipofaringe i laringe. La histologia epidermoide o escatosa és la més freqüent (90% dels casos) i les seves localitzacions més freqüents són cavitat oral, orofaringe, hipofaringe i laringe. Els principals factors de risc relacionats amb el CCC són el consum de tabac i alcohol. També s'ha relacionat amb la infecció del virus del papil·loma humà subtipus 16 (VPH-16), en el cas de CCC d'orofaringe, constituint un factor pronòstic. Head and neck cancer (HCC) is a heterogeneous pathology that groups the cancers of the nasal cavity, sinuses, ear, salivary glands, oral cavity, nasopharynx, oropharynx, hypopharynx and larynx. Epidermoid or scratchy histology is the most frequent (90% of cases) and its most frequent locations are oral cavity, oropharynx, hypopharynx and larynx. The main risk factors related to the HCC are the consumption of tobacco and alcohol. Also it has been related to the infection of the human papilloma virus subtype 16 (HPV-16), in the case of HCC of oropharynx, constituting a prognostic factor El cáncer de cabeza y cuello (CCC) es una patología heterogénea que agrupa a los cánceres de la cavidad nasal, senos paranasales, oído, glándulas salivares, cavidad oral, nasofaringe, orofaringe, hipofaringe y laringe. La histología epidermoide o escamosa es la más frecuente (90% de los casos) y sus localizaciones más frecuentes son cavidad oral, orofaringe, hipofaringe y laringe. Los principales factores de riesgo relacionados con el CCC son el consumo de tabaco y alcohol. También se ha relacionado con la infección del virus del papiloma humano subtipo 16 (VPH-16), en el caso de CCC de orofaringe, constituyendo un factor pronóstico.

Tractament mèdic; Tractament amb irradiació; Càncer de cap i coll; Carcinoma de nasofaringe Tratamiento médico; Tratamiento con irradiación; Cáncer de cabeza y cuello; Carcinoma de nasofaringe Medical treatment; Irradiation treatment; Head and neck cancer; Nasopharyngeal carcinoma L’anomenat càncer de cap i coll engloba un grup de tumors malignes localitzats en diverses zones de les vies aerodigestives superiors: sins paranasals, nasofaringe, orofaringe (amígdala, paladar tou, base de la llengua), hipofaringe, laringe, cavitat oral (mucosa oral, geniva, paladar dur, llengua i terra de la boca) i glàndules salivals. L'objectiu d'aquest document és - Desenvolupar, difondre, implementar i avaluar resultats de la ICO-ICSPraxi per al tractament del càncer d’orofaringe, hipofaringe, laringe i nasofaringe. - Disminuir la variabilitat terapèutica entre els pacients tractats en els diversos centres d’aquesta institució. - Implementar els resultats de la terapèutica en els pacients amb càncer de càvum, orofaringe, hipofaringe o laringe tractats d’acord amb les recomanacions d’aquesta guia.