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Purpose: Unresectable, locally advanced sinonasal epithelial tumours are rare diseases with poor prognosis. Multimodal approach is widely used, although no standard therapy has been established in prospective trials. This study assessed activity and safety of an innovative integration of multimodality treatment-induction chemotherapy (ICT), surgery and radiotherapy (RT)-modulated by histology and response to ICT., Methods: Patients with untreated, unresectable sinonasal epithelial tumours with selected histotypes (squamous cell carcinoma, intestinal-type adenocarcinoma, sinonasal undifferentiated and neuroendocrine carcinoma, olfactory neuroblastoma) were enroled in a single-arm, open-label, phase II, multicentre clinical trial. Patients were treated with up to 5 ICT cycles, whose regimen was selected according to histotype. Photon and/or proton/carbon-ion-based RT was employed according to disease site, stage and ICT response. Primary end-point was 5-years progression-free survival (PFS), secondary end-points were overall survival (OS), ICT objective response rate per RECIST 1.1 and safety., Results: Twenty-five patients were evaluable for primary end-point. Five-year PFS was 26.8% (95% confidence interval [CI]: 12.6-57.1), with a median PFS of 18 months. Five-year OS was 23.8% (95% CI: 9.5-59.3), with a median OS of 27 months. The overall response rate to ICT was 40%. Three-year PFS for patients achieving major volumetric partial response (mPRv) versus non-mPRv was 40% (95% CI: 13.7-100%) versus 23.1% (95% CI: 8.3-64.7%) (P = 0.318) and 3-year OS was 53.3% (95% CI: 21.4-100%) versus 37.7% (95% CI: 20.0-71.0%) (P = 0.114)., Conclusion: Multimodal combination of ICT and innovative RT did not provide a significant improvement in survival rates with respect to previous experiences. This finding underscores the need for future research in this rare disease, still characterised by a heavy burden and poor prognosis. We observed longer survival in subjects achieving response to ICT. The overall treatment safety is acceptable., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lisa Licitra: consulting or advisory role for Astrazeneca, Bayer, BMS, Eisai, MSD, Merck–Serono, Boehringer Ingelheim, Novartis, Roche, Debiopharm International SA, Sobi, Ipsen, Incyte Biosciences Italy srl, Doxa Pharma, Amgen, Nanobiotics Sa and GSK; research funding by Company: Astrazeneca, BMS, Boehringer Ingelheim, Celgene International, Debiopharm International SA, Eisai, Exelixis inc, Hoffmann-La Roche ltd, IRX Therapeutics inc, Medpace inc, Merck–Serono, MSD, Novartis, Pfizer, Roche. Paolo Bossi: consulting or advisory role for Merck, Sanofi, Merck Sharp & Dohme, Sun Pharma, Angelini, Molteni, Bristol-Myers Squibb, GSK; research funding by Gsk, MSD, Sanofi, BMS. Barbara Vischioni: honoraria by Merk. Carlo Resteghini: honoraria by Sun Pharma. All remaining authors have declared no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Sinonasal tumours are rare diseases with poor prognosis. Multimodal approach including surgery is widely used, although no standard therapy has been established in prospective trials. This study assessed activity and safety of an innovative integration of multimodality treatment-induction chemotherapy (ICT), surgery and radiotherapy (RT)-modulated by histology and response to ICT., Methods: Patients with untreated, operable sinonasal tumours with selected histotypes (squamous cell carcinoma, intestinal-type adenocarcinoma, sinonasal undifferentiated and neuroendocrine carcinoma, olfactory neuroblastoma) were enrolled in a single-arm, phase II, multicenter clinical trial. Patients were treated with up to 5 ICT cycles, whose regimen was selected according to histotype, followed either by curative chemo-RT for pts with ≥80% reduction of initial tumour diameter or surgery and adjuvant (chemo)RT. Photon and/or proton/carbon ion-based RT was employed according to the disease site and stage. Primary end-point was 5-year progression-free survival (PFS), secondary end-points were overall survival (OS), ICT objective response rate (ORR) per RECIST 1.1 and safety., Results: Thirty-five patients were evaluable for primary end-point. Fourteen patients (40%) were treated with definitive (CT)RT and 20 (57%) underwent surgery. Five-year PFS was 38% (95% confidence interval [CI], 21-69), with a median PFS of 26 months. Five-year OS was 46% (95% CI, 28-75), with a median OS of 36 months. Three-year PFS-OS for pts achieving PR/CR versus stable disease (SD)/PD to ICT were 49.8-57% versus 43.2-53%, respectively. Three-year PFS for patients achieving major volumetric partial response (≥80% reduction of initial tumour volume, major partial volumetric response [mPRv]) versus non-mPRv were 82% versus 28% and 3-year OS were 92% versus 36% (p value 0.010 and 0.029, respectively). The ORR to ICT was 54% and 60% across all histotypes and in the sinonasal undifferentiated carcinoma (SNUC) subpopulation, respectively, with 6/15 SNUCs (40%) achieving mPRv., Conclusion: Treatment of advanced sinonasal cancer with histology-driven ICT followed by (CT)RT in responsive patients was feasible. Overall, these findings suggest a possible role of ICT as the primary approach in newly diagnosed, resectable sinonasal tumours-especially SNUC-to select patients with favourable prognosis. Histology heterogeneity limits generalisation of trial results., Competing Interests: Declaration of Competing Interest Lisa Licitra: consulting or advisory role for Astrazeneca, Bayer, BMS, Eisai, MSD, Merck–Serono, Boehringer Ingelheim, Novartis, Roche, Debiopharm International SA, Sobi, Ipsen, Incyte Biosciences Italy srl, Doxa Pharma, Amgen, Nanobiotics Sa and GSK; research funding by Company: Astrazeneca, BMS, Boehringer Ingelheim, Celgene International, Debiopharm International SA, Eisai, Exelixis inc, Hoffmann-La Roche Ltd, IRX Therapeutics inc, Medpace Inc, Merck–Serono, MSD, Novartis, Pfizer, Roche. Paolo Bossi: consulting or advisory role for Merck, Sanofi, Merck Sharp & Dohme, Sun Pharma, Angelini, Molteni, Bristol-Myers Squibb, GSK; research funding by Gsk, MSD, Sanofi, BMS. Barbara Vischioni: honoraria by Merk. Carlo Resteghini: honoraria by Sun Pharma. All remaining authors have declared no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Aim: Recommendations for managing patients with nasopharyngeal carcinoma (NPC) in non-endemic areas are largely derived from studies conducted in endemic areas. We analysed the impact of treatment approaches on survival in non-endemic areas., Methods: In an international, multicentre, retrospective study, we analyse consecutive patients with NPC diagnosed between 2004 and 2017 in 36 hospitals from 11 countries. Treatment was categorised as non-intensive (NIT), including radiotherapy alone or concomitant chemoradiotherapy (cCRT), and intensive (IT) including cCRT preceded by and/or followed by chemotherapy (CT). The impact of IT on overall survival (OS) and disease-free survival (DFS) was adjusted for all the available potential confounders., Results: Overall, 1021 and 1113 patients were eligible for overall survival (OS) and disease-free survival (DFS) analyses, respectively; 501 and 554 with Epstein Barr-encoded RNA (EBER) status available. In the whole group, 5-year OS was 84% and DFS 65%. The use of NIT was associated with a risk of death or recurrence 1.37 times higher than patients receiving IT. Patients submitted to NIT and induction CT + concurrent concomitant chemo and three-dimensional Conformal Radiation Therapy (3DCRT) had a risk of death or recurrence 1.5 and 1.7 times higher than patients treated with induction CT + cCRT with intensity-modulated radiotherapy (IMRT), respectively. The IT had no impact on OS in neither patients with EBER+ nor in patients with EBER-; IT showed better DFS in EBER+ but not in patients with EBER-., Conclusions: In low-incidence areas, patients with NPC treated with induction CT followed by concurrent IMRT cCRT achieved the highest DFS rate. The benefit of IT on DFS was restricted to patients with EBER+, suggesting that additional therapy offers no advantages in EBER- cases., Competing Interests: Conflict of interest statement Bossi reports personal fees from Merck, Sanofi Regeneron, BMS, MSD, GSK, Astrazeneca, Sunpharma, Angelini and grants from GSK and Sunpharma, outside the submitted work. Buglione reports personal fees from Meck Serono, outside the submitted work. Cirauqui Cirauqui reports congress support from MSD, Merck, BMS and Roche, and personal fees from BMS and Roche, outside the submitted work. Ursino reports grants from Merck Serono, Nestlé, Kyowakirin and Astra Zeneca, outside the submitted work. D'angelo reports personal fees from Astra Zeneca, Nestlé and Merck Spa, outside the submitted work. Licitra reports personal fees and grants from Astra Zeneca, Bayer, BMS, Boehringer ingelheim, Debiopharm International SA, EISAI, Merck Serono MSD, Novartis, Roche; Personal fee from Bayer, SOBI, IPSEN, GSK, Doxa Pharma srl, Incyte Biosciences Italy srl, Amgen, Nanobiotics Sa; Grants from Celgene International, Exelixis inc, grants Hoffmann-La Roche ltd, IRX Therapeutics incMedpace inc, grants Pfizer, outside the submitted work. Mesia reports Consulting and advisory role for Merck, MSD, Roche, Asta Zeneca, BMS and speaker's Bureau for Merck, MSD, BMS, Roche. All the other authors have nothing to disclose., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Distant metastases in adenoid cystic carcinoma (ACC) are common. There is no consensus on the management of metastatic disease because no therapeutic approach has demonstrated improvement in overall survival (OS) and because of prolonged life expectancy. The aim of this study is to build and validate a prognostic nomogram for metastatic ACC patients., Methods: The study end-point was OS, measured from the date of first metastatic presentation to death/last follow-up. A retrospective analysis including metastatic ACC patients was performed to build the prognostic nomogram at the INT (Milan, Italy). The model was validated on an independent cohort of patients with similar characteristics treated at Leuven (Belgium). Outcome data and covariates were modelled by resorting to a random forest method. This machine-learning approach was used to guide and benchmark the subsequent use of more conventional modelling methods. Cox model performance was assessed in terms of discrimination (Harrell's c-index)., Results: Two hundred ninety-eight patients with metastatic ACC (testing set 259 INT, validation set 39 Leuven) were studied. Akaike Information Criterion-based backward selection yielded a 5-factor model showing a bias-corrected c-index of 0.730. Five independent prognostic factors were found: gender, disease-free interval and presence of lung, liver or bone metastases. Nomogram discrimination in the validation series was c = 0.701., Conclusion: This retrospective analysis allowed the building of an externally validated prognostic nomogram. This tool might help clinicians to discriminate patients requiring prompt management from who can benefit from a 'watchful waiting'. In addition, the nomogram might be useful to stratify patients in clinical trials., Competing Interests: Conflict of interest statement L.D.L. declares grant and other financial relationship with Biogen, Eisai, Ipsen, Lilly, Merck Serono, MSD and BMS. P.B. is on advisory board of Merck, Sanofi, Merck Sharp & Dohme, Sun Pharma, Angelini, AstraZeneca, Bristol-Myers Squibb, Helsinn and received conference honoraria from Bristol-Myers Squibb, Kyowa Hakko Kirin, Angelini, Sanofi, Roche, GSK. L.L. has received funding (for her Institution) for clinical studies and research from AstraZeneca, Boehringer Ingelheim, Eisai, Merck Serono, MSD, Novartis and Roche; has received compensation for service as a consultant/advisor and/or for lectures from AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Debiopharm, Eisai, Merck Serono, MSD, Novartis, Roche and Sobi and she has received travel coverage for medical meetings from Bayer, Bristol-Myers Squibb, Debiopharm, Merck Serono, MSD and Sobi. The remaining authors declare no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: In recurrent or metastatic (R/M) skin squamous cell cancer (sSCC) not amenable to radiotherapy (RT) or surgery, chemotherapy (CT) has a palliative intent and limited clinical responses. The role of oral pan-HER inhibitor dacomitinib in this setting was investigated within a clinical trial., Methods: Patients with diagnosis of R/M sSCC were treated. Dacomitinib was started at a dose of 30 mg daily (QD) for 15 d, followed by 45 mg QD. Primary end-point was response rate (RR). Tumour samples were analysed through next-generation sequencing using a custom panel targeting 36 genes associated with sSCC., Results: Forty-two patients (33 men; median age 77 years) were treated. Most (86%) received previous treatments consisting in surgery (86%), RT (50%) and CT (14%). RR was 28% (2% complete response; 26% partial response), disease control rate was 86%. Median progression-free survival and overall survival were 6 and 11 months, respectively. Most patients (93%) experienced at least one adverse event (AE): diarrhoea, skin rash (71% each), fatigue (36%) and mucositis (31%); AEs grade 3-4 occurred in 36% of pts. In 16% of cases, treatment was discontinued because of drug-related toxicity. TP53, NOTCH1/2, KMT2C/D, FAT1 and HER4 were the most frequently mutated genes. BRAF, NRAS and HRAS mutations were more frequent in non-responders, and KMT2C and CASP8 mutations were restricted to this subgroup., Conclusions: In sSCC, dacomitinib showed activity similar to what was observed with anti-epidermal growth factor receptor agents, and durable clinical benefit was observed. Safety profile was comparable to previous experiences in other cancers. Molecular pt selection could improve therapeutic ratio., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Pre-clinical and clinical evidence suggests a rationale for the use of anti-angiogenic agents, including sorafenib, in recurrent and/or metastatic salivary gland carcinomas (RMSGCs). This study evaluates the activity of sorafenib in patients with RMSGCs and also investigates whether the activity of sorafenib could be related to its main tailored targets (i.e. BRAF, vascular endothelial growth factor receptor 2 [VEGFR2], platelet-derived growth factor receptor α [PDGFRα] and β, RET, KIT)., Patients and Methods: Patients received sorafenib at 400 mg BID. The primary end-point was response rate (RR) including complete response or partial response (PR); secondary end-points included RR according to Choi criteria, disease control rate (DCR), overall survival (OS), and progression-free survival (PFS)., Results: Thirty-seven patients (19 adenoid cystic cancers, ACC) were enrolled. Six PRs were recorded. RR was 16% (95% confidence interval [CI]: 6-32; 11% in ACC and 22% in non-ACC). Choi criteria could be applied in 30 out of 37 cases with a RR of 50% (95% CI: 31-69%); DCR was 76% (95% CI: 59-88%). Incidence of ≥G3 adverse events was 29.7%. Median PFS and OS for the entire population were 5.9 months and 23.4 months, respectively. Median PFS and OS were 8.9 and 26.4 months for ACC versus 4.2 and 12.3 months for non-ACC patients. All the cases showed expression of PDGFRβ in the stroma and VEGFR2 in endothelial cells; PDGFRα positivity was found in the stroma of four (27%) cases. All except for two cases showed no PDGFRβ, VEGFR2 and PDGFRα expression in the tumour cells. KIT expression was restricted to ACC and a weak RET expression was limited to one adenocarcinoma, not otherwise specified (NOS). No BRAF mutation was found. No correlation was observed between the sorafenib activity and the expression of its markers although all six responders (two ACC, one adenocarcinoma, NOS, one salivary duct cancer [SDC], one high-grade mucoepidermoid [HG-MEC] and one poorly-differentiated cancer) are enriched in the stromal component showing a PDGFRβ immunodecoration. In ACCs, immunohistochemistry revealed MYB protein expression in 15/16 cases (94%) and the MYB-NFIB fusion oncogene was observed in 9/14 (64%)., Conclusions: Sorafenib is the first anti-angiogenic agent to demonstrate activity in RMSGC patients, particularly in some histotypes such as HG-MEC, SDC and adenocarcinoma, NOS. The PDGFRβ-positive rich stromal component characterising these histotypes and the lack of correlation between the activity of sorafenib and its targets suggests anti-angiogenic effect as the prevalent mechanism of action of sorafenib in SGCs., (Copyright © 2016 Elsevier Ltd. All rights reserved.)