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SummarySquamous cell carcinoma of the head and neck (HNSCC) is the sixth most common cancer and accounts for 890.000 cases 450.000 deaths worldwide annually. HNSCC is a heterogeneous disease affecting mainly elderly patients, who frequently suffer from significant comorbidities. Due to the aggressive tumor biology and high recurrence rates after curative treatment, it is essential to follow the evidence-based treatment recommendations outlined in the international guidelines, although it has to be emphasized that relevant data gaps and controversies exist such as the role of induction chemotherapy, de-intensification strategies or the role of immunotherapy in the locally advanced and recurrent/metastatic setting. These topics will be addressed in this article. Most importantly, interdisciplinary management of HNSCC patients is key for the optimal management at all disease stages.

Purpose Clinical research relies on data from patients and volunteers, yet the target sample size is often not achieved. Here, we assessed the perception of clinical research among clinical trial participants to improve the recruitment process for future studies. Methods We conducted a single-center descriptive and exploratory study of 300 current or former participants in various phase I–III clinical trials. Questionnaires were either distributed to current clinical trial participants or emailed to former subjects. Results Subjects strongly agreed or agreed that contributing to improving medical care (> 81%), contributing to scientific research (> 79%), and trusting their treating physicians (> 77%) were motives for study participation. Among healthy volunteers, financial motives positively correlated with the number of clinical trials they had participated in (p p Conclusion Altruistic motives and trust in treating physicians were predominant motives for clinical trial participation. Older patients expected to receive the best available treatment during participation. Healthy volunteers who reported financial motives had participated in more clinical trials. Consistent with great trust in medical staff and government research institutions, little concern was expressed about the misuse of personal data during the trial.

Purpose: In this study, we tested the antitumor activity of the dual phosphoinositide 3-kinase (PI3K)/mTOR inhibitor BEZ235 against gastric cancer in vitro and in vivo.Experimental Design: Gastric cancer cell lines (N87, MKN45, and MKN28) were incubated with BEZ235 and assessed for cell viability, cell cycle, and PI3K/mTOR target inhibition. In vivo, athymic nude mice were inoculated with N87, MKN28, or MKN45 cells and treated daily with BEZ235. 3′-Deoxy-3′-[18F]fluorothymidine ([18F]FLT) uptake was measured via small animal positron emission tomography (PET).Results:In vitro, BEZ235 dose dependently decreased the cell viability of gastric cancer cell lines. The antiproliferative activity of BEZ235 was linked to a G1 cell-cycle arrest. In vivo, BEZ235 treatment resulted in PI3K/mTOR target inhibition as shown by dephosphorylation of AKT and S6 protein in all xenograft models. However, BEZ235 treatment only inhibited tumor growth of N87 xenografts, whereas no antitumor effect was observed in the MKN28 and MKN45 xenograft models. Sensitivity to BEZ235 in vivo correlated with downregulation of the proliferation marker thymidine kinase 1. Accordingly, [18F]FLT uptake was only significantly reduced in the BEZ235-sensitive N87 xenograft model as measured by PET.Conclusion: In conclusion, in vivo sensitivity of gastric cancer xenografts to BEZ235 did not correlate with in vitro antiproliferative activity or in vivo PI3K/mTOR target inhibition by BEZ235. In contrast, [18F]FLT uptake was linked to BEZ235 in vivo sensitivity. Noninvasive [18F]FLT PET imaging might qualify as a novel marker for optimizing future clinical testing of dual PI3K/mTOR inhibitors. Clin Cancer Res; 17(16); 5322–32. ©2011 AACR.

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Background Statins are a common class of cholesterol-lowering drugs prescribed for the prevention and treatment of cardiovascular disease. Moreover, it was suggested that statins may possess anti-cancer properties and interact with RANK ligand expression. Therefore, we aimed at evaluating a hypothetical synergistic effect of statins with denosumab in early-stage breast cancer (BC) patients from the Austrian Breast and Colorectal Cancer Study Group (ABCSG) trial 18. Methods ABCSG-18 (NCT00556374) is a prospective, randomized, double-blind, phase III study; postmenopausal patients with hormone receptor (HR) positive BC receiving a non-steroidal aromatase inhibitor were randomly assigned to denosumab or placebo. In this post-hoc analysis, we investigated the potential effects of concomitant statin therapy on recurrence risk of BC, fracture risk and bone mineral density (BMD) using time-dependent Cox proportional hazards models. Sensitivity analyses accounting for immortal time and confounding bias were performed. Results In the analysis of the study population (n=3,420), statin therapy (n=824) was associated with worse disease-free survival (DFS) (HR 1.35, 95%; CI 1.04-1.75; p=0.023). Sensitivity analysis relativized these results (HR 1.22, 95% CI 0.94 - 1.59; p=0.14). While there was no significant effect of lipophilic statins (n=710) on recurrence risk (HR 1.30, 95% CI 0.99 - 1.72; p=0.062), patients on hydrophilic statins (n=87) had worse DFS compared with patients not receiving any statins (HR 2.00, 95% CI 1.09-3.66; p=0.026). This finding was mainly driven by the effect of hydrophilic statins on DFS in the denosumab arm (HR 2.63, 95% CI 1.21 - 5.68; p=0.014). No association between statin use and fracture risk or osteoporosis was observed. Conclusion In this population of early-stage breast cancer patients from a prospective randomized study, an association of hydrophilic statins with increased recurrence risk was observed. According to this retrospective analysis hydrophilic statins may increase recurrence risk especially in patients treated with denosumab. Still, our data need to be interpreted with caution due to their retrospective nature and the low number of patients receiving hydrophilic statins. Therefore, no final conclusion is possible. This hypothesis generating result warrants further exploration. Citation Format: Christoph Minichsdorfer, Thorsten Fuereder, Michael Leutner, Christian F. Singer, Stephanie Kacerovsky-Strobl, Daniel Egle, Richard Greil, Marija Balic, Florian Fitzal, Georg Pfeiler, Sophie Frantal, Rupert A. Bartsch, Michael Gnant. Effect of concomitant statin treatment in postmenopausal patients with hormone-receptor positive early-stage breast cancer receiving adjuvant denosumab or placebo: A post-hoc analysis of ABCSG-18 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-15-01.

Objectives: Pathophysiology of medication-related osteonecrosis of the jaw (MRONJ) is still unclear, and disease development is associated with adverse reaction of bisphosphonates and denosumab, and Actinomyces spp. as well. In this study, we evaluated the abundance of Actinomyces spp. in breast cancer patients undergoing chemotherapy compared to healthy controls. Methods: Oropharyngeal samples were collected from treatment-naive early-stage breast cancer patients, who were scheduled for standard of care therapy (eight samples throughout chemotherapy, one prior to radiotherapy and one after a year of start), as well as from healthy controls at matched timepoints. We quantified Actinomyces spp. in the samples with a highly sensitive and specific quantitative polymerase chain reaction. Results: Twenty-one patients and 16 healthy subjects were enrolled. Forty-eight percent of patients suffered from estrogen receptor-positive/progesterone receptor-positive or -negative/human epidermal growth factor receptor 2 (HER2)-negative disease, 38% were HER2-positive, and 14% were triple-negative. Comparison of Actinomyces spp. loads in cancer patients and healthy controls did not reveal significant difference. Fluctuations on bacterial quantity were observed in both groups over time. Tumor receptor status or different chemotherapy schemes of patients were not correlated with a particular pattern on abundance of Actinomyces spp. Conclusions: We suggest that Actinomyces spp. are not the initiative factors in MRONJ development. These bacteria are not altered in abundance during chemotherapy, but they behave opportunistic when there is a bone disruption in the oropharynx in the first place caused by antiresorptive drugs or dental trauma and proliferate in their new niche. Thus, Actinomyces spp. plays a latter role in MRONJ development, rather than a primary causative one.

SummaryDuring the ASCO 2021 virtual meeting, multiple clinically relevant studies were presented addressing open questions regarding the therapy of nasopharyngeal carcinomas (NPC): Is immunotherapy plus chemotherapy the new first line standard of care for patients in the recurrent/metastatic setting? Is adjuvant therapy with capecitabine in high risk NPC patients post chemoradiation (CRT) beneficial? Is there a role for treatment intensification by adjuvant metronomic capecitabine in NPC patients post induction chemotherapy and CRT? This article summarizes the most significant NPC studies presented at the ASCO 2021 virtual meeting and discusses the data in the context of the current literature.

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.

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.

Immune checkpoint control is one of several mechanisms that negatively influence the immune system and contribute to the development and progression of cancer. To enhance anti-tumor immune responses in patients with advanced solid tumors, we employ a novel autologous cancer cell therapy, APN401, which allows transient and highly specific silencing of Casitas B-lineage lymphoma-b (Cbl-b) in patients’ peripheral mononuclear cells (PBMCs). Cbl-b is an E3 ubiquitin protein ligase that plays a central role in both innate and adaptive immune responses. Here we present two patients with advanced, metastatic solid tumors: one patient diagnosed with appendix carcinoma, and one patient diagnosed with head and neck squamous cell carcinoma (HNSCC). Both showed stable disease (SD) during treatment with APN401. In an open-label, multicenter Phase Ib trial, two increasing dose levels of APN401 were evaluated in patients with advanced solid tumors. Using invIOs’s closed cell-processing platform - Enhancement Platform for immune Cells (EPiC) - patients’ PBMCs were purified from leukapheresis products and subsequently transfected with a small interfering ribonucleic acid (siRNA) to specifically block Cbl-b expression. The entire manufacturing process required less than six hours, and the drug product could be reinfused on the same day. The trial evaluated safety and clinical outcomes, as well as the activity and potency of the drug product. Additionally, various biomarkers were analyzed in patients’ peripheral blood, which was collected prior to each treatment cycle. Two patients, one with appendix carcinoma and one with HNSCC, showed stable disease after repeated APN401 treatments at the lowest and/or intermediate dose levels. Subsequent drug product analyses revealed increased IL-2 levels and elevated CD8/CD4 ratios, suggesting potential cytotoxic efficacy. In stimulation assays with HLA class I-restricted viral or tumor antigens, increased IFN-γ levels were detected and served as surrogate markers for improved immunity and tumor reactivity. 10X genomics and TCR clonotyping revealed clonal expansion of T cell subsets throughout the course of the treatment. Taken together, these initial results indicate that APN401, a novel personalized cancer cell therapy based on targeted silencing of Cbl-b in PBMCs, may be a safe and effective immunotherapy for solid tumors. This cell therapy will be further evaluated as a monotherapy along with potential combinations in clinical trials in various solid tumors. Ethics approval: The clinical trial was approved by the Medical University of Vienna institution’s independent Ethics Committee, approval number 1778/2020. Citation Format: Mario Kuttke, Alexander Dohnal, Andreas Tanzmann, Beate Pribitzer, Felix Batrina, Stefan Bunka, Sophia Spagl, Manuela Branka, Sarah Bischof, Kathrin Thell, Maria Urban, Hannes Muehleisen, Bernhard Peball, Bianca Gapp, Angela Halfmann, Markus Raderer, Gerald Prager, Thorsten Fuereder, Romana Gugenberger, Nina Worel. Case report: APN401, a novel cancer therapy using Cbl-b silenced autologous PBMCs, induced stable disease in two patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB187.

SummaryAt the ASCO 2020 virtual meeting, multiple clinically relevant studies were presented addressing open questions in the head and neck cancer field: Are de-escalation strategies feasible in low risk patients? What is the appropriate platinum dose in combination with radiotherapy in high-risk patients suffering from locally advanced disease? Is immunotherapy the first line standard of care for all patient in the recurrent/metastatic setting? This article summarizes the most significant head and neck cancer studies presented at the ASCO 2020 virtual meeting and discusses the data in the context of the current literature.

Trastuzumab deruxtecan is an antibody–drug conjugate with high extracranial activity in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. We conducted the prospective, open-label, single-arm, phase 2 TUXEDO-1 trial. We enrolled patients aged ≥18 years with HER2-positive breast cancer and newly diagnosed untreated brain metastases or brain metastases progressing after previous local therapy, previous exposure to trastuzumab and pertuzumab and no indication for immediate local therapy. Patients received trastuzumab deruxtecan intravenously at the standard dose of 5.4 mg per kg bodyweight once every 3 weeks. The primary endpoint was intracranial response rate measured according to the response assessment in neuro-oncology brain metastases criteria. A Simon two-stage design was used to compare a null hypothesis of

Squamous cell carcinoma of the head and neck accounts for 330 000 deaths and 650 000 cases worldwide annually. Systemic therapy is an essential pillar of multimodal therapy despite being accompanied with substantial toxicity. This article reviews the latest advances in systemic therapy for the treatment of locoregionally advanced and reccurent/metastatic head and neck cancer from a tolerability perspective.Multiple recent attempts have been made to optimize tolerability (and efficacy) of systemic therapy utilizing new regimens, modified prescription doses, drugs such as immunotherapies or genotyping to tailor the systemic therapy to the individual patient.Although treatment benefit has to be weighed against potential toxicity, it is reasonable to anticipate potential side effects of systemic therapies. In a vulnerable elderly or Asian patient population upfront dose modifications of cytotoxic chemotherapies might be reasonable. Special attention should be laid on the patient's nutritional status and early intervention recommended. Dihydropyrimidine dehydrogenase genotyping can predict 5-fluorouracil toxicity and identify patients for whom alternative regimens are more suitable. As for immune checkpoint inhibitor therapy, despite being well tolerated, the identification of biomarkers to predict reduced tolerability or severe toxicity would be highly desirable.

BackgroundBiomarkers for response prediction to anti-programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICI) in patients with head and neck squamous cell carcinoma (HNSCC) are urgently needed for a personalized therapy approach. We investigated the predictive potential of inflammatory parameters and DNA methylation profiling in patients with HNSCC treated with anti-PD-1 ICI.MethodsWe identified patients with HNSCC that were treated with anti-PD-1 ICI therapy in the recurrent or metastatic setting after progression to platinum-based chemotherapy in two independent centers. We analyzed DNA methylation profiles of >850.000 CpG sites in tumor specimens of these patients by Infinium MethylationEPIC microarrays, immune cell density in the tumor microenvironment (CD8, CD3, CD45RO, forkhead box P3 (FOXP3), CD68), PD-1 and programmed cell death ligand 1 (PD-L1) expression by immunohistochemistry, and blood inflammation markers (platelet-to-lymphocyte ratio, leucocyte-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio). DNA methylation profiles and immunological markers were bioinformatically and statistically correlated with radiological response to anti-PD-1 ICI.Results37 patients with HNSCC (median age of 62 years; range 49–83; 8 (21.6%) women, 29 (78.4%) men) were included (Center 1 N=26, 70.3%; Center 2 N=11, 29.7%). Median number of prior systemic therapies was 1 (range 1–4). Five out of 37 (13.5%) patients achieved an objective response to ICI. Median progression-free survival and median overall survival times were 3.7 months (range 0–22.9) and 9.0 months (range 0–38.8), respectively. Microarray analyses revealed a methylation signature including both hypomethylation and hypermethylation which was predictive for response to ICI and included several genes involved in cancer-related molecular pathways. Over-represented differentially methylated genes between responders and non-responders were associated with ‘Axon guidance’, ‘Hippo signaling’, ‘Pathways in cancer’ and ‘MAPK signaling’. A statistically significant correlation of PD-L1 expression and response was present (p=0.0498).ConclusionsOur findings suggest that tumor DNA methylation profiling may be useful to predict response to ICI in patients with HNSCC.

Background Due to potentially immune-escaping virus variants and waning immunity, a third SARS-CoV-2 vaccination dose is increasingly recommended. However, data in patients with cancer are limited. Patients and methods We measured anti-SARS-CoV-2 spike protein antibody levels after the third vaccination dose in 439 patients with cancer and 41 health care workers (HCW) at an academic center in Austria and a rural community hospital in Italy. Adverse events were retrieved from questionnaires. Results Overall, 439 patients and 41 HCW were included. SARS-CoV-2 infections were observed in 62/439 (14.1%) patients before vaccination and in 5/439 (1.1%) patients after ≥1 dose. Longitudinal analysis revealed a decrease of antibody levels between 3 and 6 months after second vaccination in patients with solid tumors (p

BACKGROUND: Pembrolizumab is active in head and neck squamous cell carcinoma (HNSCC), with programmed cell death ligand 1 (PD-L1) expression associated with improved response.METHODS: KEYNOTE-048 was a randomised, phase 3 study of participants with untreated locally incurable recurrent or metastatic HNSCC done at 200 sites in 37 countries. Participants were stratified by PD-L1 expression, p16 status, and performance status and randomly allocated (1:1:1) to pembrolizumab alone, pembrolizumab plus a platinum and 5-fluorouracil (pembrolizumab with chemotherapy), or cetuximab plus a platinum and 5-fluorouracil (cetuximab with chemotherapy). Investigators and participants were aware of treatment assignment. Investigators, participants, and representatives of the sponsor were masked to the PD-L1 combined positive score (CPS) results; PD-L1 positivity was not required for study entry. The primary endpoints were overall survival (time from randomisation to death from any cause) and progression-free survival (time from randomisation to radiographically confirmed disease progression or death from any cause, whichever came first) in the intention-to-treat population (all participants randomly allocated to a treatment group). There were 14 primary hypotheses: superiority of pembrolizumab alone and of pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival and progression-free survival in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations and non-inferiority (non-inferiority margin: 1·2) of pembrolizumab alone and pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival in the total population. The definitive findings for each hypothesis were obtained when statistical testing was completed for that hypothesis; this occurred at the second interim analysis for 11 hypotheses and at final analysis for three hypotheses. Safety was assessed in the as-treated population (all participants who received at least one dose of allocated treatment). This study is registered at ClinicalTrials.gov, number NCT02358031.FINDINGS: Between April 20, 2015, and Jan 17, 2017, 882 participants were allocated to receive pembrolizumab alone (n=301), pembrolizumab with chemotherapy (n=281), or cetuximab with chemotherapy (n=300); of these, 754 (85%) had CPS of 1 or more and 381 (43%) had CPS of 20 or more. At the second interim analysis, pembrolizumab alone improved overall survival versus cetuximab with chemotherapy in the CPS of 20 or more population (median 14·9 months vs 10·7 months, hazard ratio [HR] 0·61 [95% CI 0·45-0·83], p=0·0007) and CPS of 1 or more population (12·3 vs 10·3, 0·78 [0·64-0·96], p=0·0086) and was non-inferior in the total population (11·6 vs 10·7, 0·85 [0·71-1·03]). Pembrolizumab with chemotherapy improved overall survival versus cetuximab with chemotherapy in the total population (13·0 months vs 10·7 months, HR 0·77 [95% CI 0·63-0·93], p=0·0034) at the second interim analysis and in the CPS of 20 or more population (14·7 vs 11·0, 0·60 [0·45-0·82], p=0·0004) and CPS of 1 or more population (13·6 vs 10·4, 0·65 [0·53-0·80], pINTERPRETATION: Based on the observed efficacy and safety, pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for recurrent or metastatic HNSCC and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC.FUNDING: Merck Sharp & Dohme.

Importance: To our knowledge, little is known about antibody development after SARS-CoV-2 vaccination in immunocompromised individuals, such as patients with cancer. Objective: To determine whether hematooncological patients develop anti-SARS-CoV-2 antibodies after vaccination. Design, Setting, and Participants: This retrospective cohort study included 2 independent cohorts of patients who were treated for hematological and solid malignant tumors between October 2020 and May 2021, comprising 901 samples from 595 patients and 58 health care workers (HCWs). Serum samples were collected from patients who were treated at an academic center and a community hospital in a rural area and a control group of HCWs, all of whom received SARS-CoV-2 vaccination. Main Outcomes and Measures: Total anti-SARS-CoV-2 nucleocapsid (anti-NC) and antispike protein (anti-S) antibodies were measured retrospectively. Results: In total, 595 patients (320 women [53.8%] and 275 men [46.2%]; median [range] age, 67 [19-96] years) and 58 HCWs (40 women [69.0%] and 18 men [31.0%]; median [range] age, 42 [24-60] years) were included. Previous SARS-CoV-2 infection was documented in 43 of 595 (7.2%), while anti-NC antibodies that suggested previous infections were observed in 49 of 573 evaluable patients (8.6%). In both cohorts, anti-S antibody levels were higher in fully vaccinated patients compared with patients who received 1 dose. After the first vaccination, patients with hematological cancer who received B cell-targeting agents had lower anti-S levels (median, 1.6 AU/mL; range: 0-17 244 AU/mL) than patients who received other therapies (median, 191.6 AU/mL; range, 0-40 000; P < .001) or patients with solid tumors (median, 246.4 AU/mL; range, 0-40 000 AU/mL; P < .001). Anti-S levels after the first vaccination differed according to ongoing antineoplastic treatment modalities, with the lowest median levels in patients who received chemotherapy alone (157.7 AU/mL; range, 0-40 000 AU/mL) or in combination with immunotherapy (118.7 AU/mL; range, 14.1-38 727 AU/mL) and the highest levels in patients with no ongoing antineoplastic treatment (median, 634.3 AU/mL; range, 0-40 000 AU/mL; P = .01). Antibody levels after full immunization were higher in HCWs (median, 2500 U/mL; range, 485-2500 U/mL) than in patients with cancer (median, 117.0 U/mL; range, 0-2500 U/mL; P < .001). Conclusions and Relevance: In this cohort study of patients with hematooncological diseases and a control group of HCWs, anti-SARS-CoV-2 antibodies after vaccination could be detected in patients with cancer. Lower antibody levels compared with HCWs and differences in seroconversion in specific subgroups underscore the need for further studies on SARS-CoV-2 vaccination in patients with hematooncological disease.

Despite increasing clinical interest in adapting checkpoint inhibitor (CPI) therapies for patients with gynecologic malignancies, no accurate clinical biomarkers to predict therapy response and prognosis are currently available. Therefore, we aimed to assess the predictive and prognostic value of pretherapeutic body mass index (BMI) for recurrent gynecologic cancer patients as previously validated for other solid tumors. We evaluated patients with programmed cell death ligand 1 (PD-L1) positive and, in endometrial cancer, also mismatch repair deficient (MMR) gynecologic malignancies, who received the PD-1 inhibitor pembrolizumab as monotherapy (200 mg fixed-dose q3 w) from 2017 to 2020 (n = 48). Thirty-six patients receiving at least four courses were included in the final analysis. Associations between a BMI increase per 5 kg/m2 and overall response rate (ORR, complete + partial response), disease control rate (DCR, ORR + stable disease), progression-free (PFS), and overall survival (OS) were assessed. An elevated BMI was univariately associated with ORR (OR 10.93 [CI 2.39–49.82], p = 0.002), DCR (OR 2.19 [CI 0.99–4.83], p = 0.048), prolonged PFS (HR 1.54 [CI 1.03–2.34], p = 0.038), and OS (HR 1.87 [CI 1.07–3.29], p = 0.028). All results could be confirmed in the multivariate analyses. Pretherapeutic BMI therefore appears to be a promising readily available biomarker to identify patients with PD-L1-positive and/or MMR-deficient gynecologic malignancies who could particularly benefit from CPI treatment.

Background We investigated the influence of population‐wide COVID‐19 lockdown measures implemented on 16, March 2020 on routine and emergency care of cancer outpatients at a tertiary care cancer centre in Vienna, Austria. Methods We compared the number/visits of cancer outpatients receiving oncological therapies at the oncologic day clinic (DC) and admissions at the emergency department (ED) of our institution in time periods before (pre‐lockdown period: 1 January – 15 March 2020) and after (post‐lockdown period: 16 March– 31 May 2020) lockdown implementation with the respective reference periods of 2018 and 2019. Additionally, we analysed Emergency Severity Index (ESI) score of unplanned cancer patient presentations to the ED in the same post‐lockdown time periods. Patient outcome was described as 3‐month mortality rate (3‐MM). Results In total, 16 703 visits at the DC and 2664 patient visits for the respective time periods were recorded at the ED. No decrease in patient visits was observed at the DC after lockdown implementation (P = .351), whereas a substantial decrease in patient visits at the ED was seen (P

Immuno-oncology and in particular checkpoint inhibitor (CPI) treatment has become a novel promising cancer therapy strategy in recent years. However, still a minority of patients respond to checkpoint blockade. Primary and secondary resistance to CPI is a challenge in the daily clinical routine. Combination strategies have been tested in various clinical trials in order to address this issue. Data available from these trials indicate improved activity depending on the tumor type. This review article focuses on the molecular background for resistance to CPI, gives an overview of current clinical data of CPI combination studies and points out potential strategies to overcome CPI resistance depending on the immune phenotype.

The aim of this study was to compare the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, the immune RECIST (iRECIST) criteria, and the Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) 1.0 in patients with advanced non-small cell lung cancer treated with programmed cell death protein 1 (PD-1)/programmed cell death protein 1 ligand (PD-L1) inhibitors.This prospective study of 42 patients treated with a PD-1/PD-L1 inhibitor was approved by our institutional review board, and all patients gave written, informed consent. Tumor burden dynamics were assessed on F-FDG PET/CT before and after treatment initiation. Immunotherapeutic responses were evaluated according to RECIST 1.1, iRECIST, and PERCIST 1.0 for the dichotomous groups, responders versus nonresponders. Cohen κ and Wilcoxon signed rank tests were used to evaluate concordance among these criteria. We assessed progression-free survival and overall survival using the Kaplan-Meier estimator.The RECIST 1.1 and PERCIST 1.0 response classifications were discordant in 6 patients (14.2%; κ = 0.581). RECIST 1.1 and iRECIST were discordant in 2 patients, who evidenced pseudoprogression after treatment initiation. Median progression-free survival, as well as overall survival, was significantly longer for responders compared with nonresponders for all criteria (P0.001), with no significant difference between the 3 criteria (P0.05).RECIST 1.1 and PERCIST 1.0 show only moderate agreement, but both can predict treatment response to PD-1/PD-L1 inhibitor therapy. In case of pseudoprogression, metabolic tumor activity may help to correctly classify treatment response.

// Gerald W. Prager 1, 8 , Matthias Unseld 1, 8 , Fredrik Waneck 3, 8 , Robert Mader 1, 8 , Fritz Wrba 2, 8 , Markus Raderer 1, 8 , Thorsten Fuereder 1, 8 , Phillip Staber 4, 8 , Ulrich Jager 4, 8 , Markus Kieler 1, 8 , Daniela Bianconi 1, 8 , Mir Alireza Hoda 7, 8 , Lukas Baumann 9 , Alexander Reinthaller 5, 8 , Walter Berger 6, 8 , Christoph Grimm 5, 8 , Heinz Kolbl 5, 8 , Maria Sibilia 6, 8 , Leonhard Mullauer 2, 8 and Christoph Zielinski 1, 8 1 Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria 2 Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria 3 Department of Interventional Radiology, Medical University of Vienna, Vienna, Austria 4 Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria 5 Department of General Gynecology and Gynecological Oncology, Medical University of Vienna, Vienna, Austria 6 Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, Vienna, Austria 7 Department of Surgery, Institute of Cancer Research, Medical University of Vienna, Vienna, Austria 8 Comprehensive Cancer Center of the Medical University of Vienna, Vienna, Austria 9 Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria Correspondence to: Gerald W. Prager, email: gerald.prager@meduniwien.ac.at Keywords: precision medicine; molecular profile Received: May 28, 2018 Accepted: January 02, 2019 Published: January 29, 2019 ABSTRACT Background: The concept of personalized medicine defines a promising approach in cancer care. High-throughput genomic profiling of tumor specimens allows the identification of actionable mutations that potentially lead to tailored treatment for individuals’ benefit. The aim of this study was to prove efficacy of a personalized treatment option in solid tumor patients after failure of standard treatment concepts. Results: Final analysis demonstrates that 34 patients (62%) had a longer PFS upon experimental treatment (PFS1) when compared to previous therapy (PFS0); PFS ratio > 1.0 ( p = 0.002). The median PFS under targeted therapy based on molecular profiling (PFS1) was 112 days (quartiles 66/201) and PFS0 = 61 days (quartiles 51/92; p = 0.002). Of the 55 patients, 31 (56%) showed disease control (DCR), consisting of 2 (4%) patients which achieved a complete remission, 14 (25%) patients with a partial remission and 15 (27%) patients who had a stabilization of disease. Median OS from start of experimental therapy was 348 days (quartiles 177/664). Conclusion: The prospective trial EXACT suggests that treatment based on real-time molecular tumor profiling leads to superior clinical benefit. Materials and Methods: In this prospective clinical phase II trial, 55 cancer patients, after failure of standard treatment options, aimed to achieve a longer progression-free survival on the experimental treatment based on the individual’s molecular profile (PFS1) when compared to the last treatment given before (PFS0). The personalized medicine approach was conceived to be clinical beneficial for patients who show a PFS ratio (PFS 1/PFS0) of > 1.0.

The risk of venous thromboembolism (VTE) and arterial thromboembolism (ATE) associated with immune checkpoint inhibitors is currently unclear. Our aim was to quantify the risk of VTE/ATE in patients with cancer treated with immune checkpoint inhibitors, explore clinical impact, and investigate potential clinical risk factors. Patients treated with immune checkpoint inhibitors at the Medical University of Vienna from 2015 to 2018 were identified using in-house pharmacy records (n = 672; most frequent entities: 30.4% melanoma, 24.1% non-small cell lung cancer; 86% stage IV disease). A retrospective chart review was performed to screen for VTE and/or ATE. Cumulative incidences and between-group differences were estimated in competing-risk analysis. The impact of VTE/ATE on mortality was studied by multistate modelling. Over a median follow-up of 8.5 months, 47 VTEs and 9 ATEs were observed. Cumulative incidences of VTE and ATE were 12.9% (95% confidence interval [CI], 8.2-18.5) and 1.8% (95% CI, 0.7-3.6). Occurrence of VTE was associated with increased mortality (transition hazard ratio, 3.09; 95% CI, 2.07-4.60). History of VTE predicted VTE occurrence (subdistribution hazard ratio [SHR], 3.69; 95% CI, 2.00-6.81), and distant metastasis was nonsignificantly associated with VTE risk (SHR, 1.71; 95% CI, 0.62-4.73). No association of VTE with Eastern Cooperative Oncology Group performance status, Charlson comorbidity index, or Khorana score was observed, and rates of VTE were comparable between tumor types and checkpoint-inhibitory agents. In conclusion, patients with cancer under immune checkpoint inhibitor therapy are at high risk of thromboembolism, especially VTE. Furthermore, VTE occurrence was associated with increased mortality.

Background Taxane-based checkpoint inhibitor combination therapy might improve the outcome in recurrent/metastatic (R/M) head and neck cancer (HNSCC) patients. Thus, we investigated the efficacy and safety of docetaxel (DTX) plus pembrolizumab (P) in a prospective phase I/II trial. Methods Platinum-resistant R/M HNSCC patients received DTX 75 mg/m^2 plus P 200 mg for up to six cycles followed by P maintenance therapy. The primary endpoint was overall response rate (ORR) and safety. Secondary endpoints comprised disease control rate (DCR), overall survival (OS) and progression free survival (PFS). Results Twenty-two patients were enrolled. Nine patients (40.9%) had a primary tumor in the oropharynx, 8 (36.4%) in the oral cavity, 3 (13.6%) in the hypopharynx and 2 (9.1%) in the larynx. The ORR was 22.7% (95% CI 10.1%-43.4%) and one (4.5%) complete response was achieved. The DCR was 54.6% (95% 34.7%-73.1%). The median PFS was 5.8 months (95% CI 2.7–11.6) and the median OS 21.3 months (95% CI 6.3–31.1). The 1-year PFS and OS rates were 27.3% and 68.2%, respectively. While the most frequent adverse event (AE) was myelosuppression, which was reported in all 22 patients, 3 (13.6%) patients experienced grade 3 febrile neutropenia. The most common immune-related AEs were grade skin rash (40.9%) and hypothyroidism (40.9%). One patient (4.5%) experienced grade 5 immune thrombocytopenia. Conclusion DXT in combination with P shows promising activity accompanied with a manageable side effect profile in pre-treated R/M HNSCC patients.

Background: Nasopharyngeal carcinoma (NPC) is endemic in East Asia but rare in the western world. Programmed death ligand 1 (PD-L1) expression on NPC correlates with clinical outcomes. However, data for Caucasian NPC patients are missing. Thus, we performed this retrospective analysis for investigating the potential association of immune checkpoint protein expression with outcome parameters in Caucasian NPC patients.Methods: Fifty-five patients with NPC treated between 1993 and 2018 at the Medical University of Vienna were identified. After the exclusion of Asian patients, data on baseline demographic, tumor stage, overall survival (OS), and disease-free survival (DFS) of 30 patients were analyzed. Their tumor samples were stained and scored (low vs. high) for PD-L1, programmed death receptor 1 (PD-1), lymphocyte activating gene 3 (LAG3), and cluster of differentiation 8 (CD8) antibodies. Statistical analysis was performed with Kaplan-Meier plots and log-rank test. Estimated hazard ratios of dichotomized analysis were calculated, together with 95% confidence intervals and p-values of Wald tests.Results: PD-L1 expression was ≥50% in 6 (20%) patients, whereas 19 (63%) had ≥1% expression and 5 (17%) tumor samples were PD-L1-negative. While sex and age had no impact on DFS or OS