Publications by authors named "Pol Specenier"

62 Publications

A phase II study of monalizumab in patients with recurrent/metastatic squamous cell carcinoma of the head and neck: The I1 cohort of the EORTC-HNCG-1559 UPSTREAM trial.

Eur J Cancer 2021 Oct 9;158:17-26. Epub 2021 Oct 9.

Service d'Oncologie Médicale, Institut Roi Albert II, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale, Université Catholique de Louvain (UCLouvain), Avenue Hippocrate 10, 1200 Brussels, Belgium. Electronic address:

Purpose: Monalizumab is a monoclonal antibody targeting the inhibitory natural killer group 2A (NKG2A) receptor localised on natural killer (NK) and T cells. Its ligand, the human leukocyte antigen E (HLA-E), is overexpressed in squamous cell carcinoma of the head and neck (SCCHN). By targeting the HLA-E-NKG2A pathway, monalizumab may enhance NK and T cell activity.

Experimental Design: The UPSTREAM trial is a biomarker-driven umbrella trial studying targeted therapies and immunotherapies in patients with recurrent/metastatic (R/M) SCCHN progressing after platinum therapy. The immunotherapy 1 (I1) cohort was a phase II, single-arm substudy evaluating monalizumab (10 mg/kg intravenously on day 1 of a 14-day cycle). The primary end-point was the objective response (OR) rate (Response Evaluation Criteria in Solid Tumours 1.1) over the first 16 weeks. A two-stage Simon design was used (H1 15%, H0 3%, α 8%, power 90%) with pre-planned interruption of accrual if no OR was observed after the first 25 patients.

Results: Twenty-six eligible patients were enrolled. Seventeen (65%) patients had received ≥2 previous lines of systemic treatment, and 15 (58%) patients were PD(-L)1 inhibitor pretreated. No OR was observed. Stable disease was observed in 6 patients (23%) with a median duration of 3.8 months (95% confidence interval [CI]: 2.7-NE). The median progression-free survival and overall survival were 1.7 months (95% CI: 1.5-1.8) and 6.7 months (95% CI: 3.0-9.6), respectively. The most frequent treatment-related adverse event was grade I/II fatigue (19%).

Conclusions: Monalizumab monotherapy has limited activity in R/M SCCHN. The I1 cohort did not meet its primary objective. Monalizumab combined with durvalumab is under investigation within UPSTREAM.
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http://dx.doi.org/10.1016/j.ejca.2021.09.003DOI Listing
October 2021

Epidermal growth factor as a potential prognostic and predictive biomarker of response to platinum-based chemotherapy.

PLoS One 2021 11;16(6):e0252646. Epub 2021 Jun 11.

Laboratorium of Experimental Medicine and Pediatrics and Member of the Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium.

In this study, we investigated serum epidermal growth factor (EGF) in an oncological population of head- and neck and pulmonary neoplasms and whether serum EGF could serve as a prognostic marker of survival and as a predictive marker for treatment response to platinum-based chemotherapy. A total of 59 oncological patients and a control group of age- and sex-matched healthy volunteers were included in this study. Pre-treatment serum EGF from both groups was determined. Patient's and tumour characteristics and mortality were recorded during a 5-year follow up period. Baseline serum EGF significantly differed between the oncological patients and the healthy volunteers (p<0.001). Serum EGF was associated with lymph node metastasis (p = 0.004) but not with sex (p = 0.753), age (p = 1.00), TNM stage (p = 0.191) or tumour size (p = 0.077). Neither serum EGF (p = 0.81) nor age (p = 0.55) showed an effect on the patient's survival. Tumour location was significantly associated with overall 5-year survival (p = 0.003). The predictive capacity of serum EGF of response to chemotherapy was limited (AUC = 0.606), a sensitivity of 80% and a specificity of 56% was observed resulting in a likelihood ratio of a positive and negative test equal to 1.81 and 0.36, respectively. In conclusion, serum EGF levels are 5.5 times higher in an oncological population compared to a control group. Within the oncological population, low serum EGF values are associated with the presence of lymph node metastasis. Further investigation is necessary to determine if the serum EGF levels could serve as a diagnostic biomarker.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252646PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195347PMC
June 2021

Tipifarnib in Head and Neck Squamous Cell Carcinoma With Mutations.

J Clin Oncol 2021 06 22;39(17):1856-1864. Epub 2021 Mar 22.

Kura Oncology, Boston, MA.

Purpose: Mutations in the (m) proto-oncogene occur in 4%-8% of patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Tipifarnib is a farnesyltransferase inhibitor that disrupts function. We evaluated the efficacy of tipifarnib in patients with R/M m HNSCC.

Methods: We enrolled 30 patients with R/M HNSCC in a single-arm, open-label phase II trial of tipifarnib for m malignancies; one additional patient was treated on an expanded access program. After an ad hoc analysis of the first 16 patients with HNSCC with m variant allele frequency (VAF) data, enrollment was limited to those with a m VAF of ≥ 20% (high VAF). The primary end point was objective response rate. Secondary end points included assessing safety and tolerability. Patients received tipifarnib 600 or 900 mg orally twice daily on days 1-7 and 15-21 of 28-day cycles.

Results: Of the 22 patients with HNSCC with high VAF, 20 were evaluable for response at the time of data cutoff. Objective response rate for evaluable patients with high-VAF HNSCC was 55% (95% CI, 31.5 to 76.9). Median progression-free survival on tipifarnib was 5.6 months (95% CI, 3.6 to 16.4) versus 3.6 months (95% CI, 1.3 to 5.2) on last prior therapy. Median overall survival was 15.4 months (95% CI, 7.0 to 29.7). The most frequent treatment-emergent adverse events among the 30 patients with HNSCC were anemia (37%) and lymphopenia (13%).

Conclusion: Tipifarnib demonstrated encouraging efficacy in patients with R/M HNSCC with mutations for whom limited therapeutic options exist (NCT02383927).
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http://dx.doi.org/10.1200/JCO.20.02903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189627PMC
June 2021

Immunotherapy for head and neck cancer: from recurrent/metastatic disease to (neo)adjuvant treatment in surgically resectable tumors.

Authors:
Pol Specenier

Curr Opin Otolaryngol Head Neck Surg 2021 Apr;29(2):168-177

Department of Oncology, University Hospital Antwerp, Edegem, Belgium.

Purpose Of Review: We aim to summarize the current evidence on the role of immune checkpoint inhibitors in the (neo)adjuvant treatment of squamous cell carcinoma of the head and neck (HNSCC), with a particular focus on surgically treated patients.

Recent Findings: Pembrolizumab +/- chemotherapy improves the outcome in patients with previously untreated recurrent/metastatic HNSCC. Nivolumab is superior to chemotherapy after platinum failure. The addition of avelumab to chemoradiation failed to improve the outcome in patients with locally advanced HNSCC. Neoadjuvant presurgical programmed cell death 1 receptor (PD-1) blockade is safe and associated with encouraging overall response rate. KEYNOTE-689 randomizes patients with resectable stage III/IVA HNSCC to surgery and adjuvant standard of care +/- neoadjuvant and adjuvant pembrolizumab. ADHERE assigns surgically treated HNSCC at high risk of recurrence to chemoradiotherapy (CRT) and either durvalumab or placebo. MK-3475-689 evaluates the role of pembrolizumab in patients with resectable HNSCC. NIVOPOSTOP evaluates the addition of nivolumab to CRT in patients with surgically treated pStage III/IV HNSCC or pT3N1/pT4N1 oropharyngeal cancer with at least 20 packs/year at high risk of relapse.

Summary: Multiple trials are currently evaluating the role of immunotherapy in HNSCC amenable to surgery. Neoadjuvant presurgical PD-1 blockade is feasible and safe and is associated with an encouraging overall response rate.
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http://dx.doi.org/10.1097/MOO.0000000000000700DOI Listing
April 2021

Cost-effectiveness of nivolumab in advanced melanoma: a drug review.

Authors:
Pol Specenier

Expert Rev Pharmacoecon Outcomes Res 2021 Feb 6;21(1):13-28. Epub 2020 Dec 6.

Department of Oncology, Antwerp University Hospital, Belgium and Faculty of Medicine and Health Sciences , Edegem, Wilrijk, Belgium.

The immune checkpoint inhibitors, including nivolumab, and targeted agents have dramatically improved the outcome for patients with unresectable advanced melanoma. This is a narrative review of the published evidence on nivolumab in metastatic melanoma. In ipilimumab pre-treated patients (CheckMate 037), nivolumab was associated with a higher response rate and a longer duration of response when compared to chemotherapy. In previously untreated patients, nivolumab improves survival when compared to chemotherapy (CheckMate 066) or to ipilimumab (CheckMate 067). The combination of nivolumab and ipilimumab also improves survival when compared to ipilimumab (CheckMate 067). CheckMate 067 was not designed to compare the nivolumab-ipilimumab combination to nivolumab alone. A modified regimen using a lower dose of ipilimumab in combination with standard dose nivolumab is better tolerated than nivolumab in combination with standard dose ipilimumab (CheckMate 511). In patients with previously untreated metastatic melanoma, the anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab improve survival when compared to ipilimumab. Nivolumab is equally active in BRAF mutated and BRAF wild type melanoma. The optimal sequence of checkpoint inhibitors and BRAF/MEK inhibitors in BRAF mutated patients has not been established.
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http://dx.doi.org/10.1080/14737167.2021.1845144DOI Listing
February 2021

Unplanned hospitalizations in older patients with cancer: Occurrence and predictive factors.

J Geriatr Oncol 2021 04 19;12(3):368-374. Epub 2020 Nov 19.

Department of Medical Oncology, Oncologisch Centrum, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium. Electronic address:

Background: This study aims to investigate the occurrence of unplanned hospitalizations in older patients with cancer and to determine predictive factors.

Methods: A prospective Belgian multicentre (n = 22), observational cohort study was performed. Patients ≥70 years with a malignant tumor were included. Patients underwent G8 screening followed by geriatric assessment (GA) if abnormal at baseline and were followed for unplanned hospitalizations at approximately three months. Uni- and multivariable regression models were performed to determine predictive factors associated with unplanned hospitalizations in older patients with an abnormal G8.

Results: In total, 7763 patients were included in the current analysis of which 2409 (31%) patients with a normal G8 score and 5354 (69%) with an abnormal G8 score. Patients with an abnormal G8 were hospitalized more frequently than patients with a normal G8 (22.9% versus 12.4%; p < 0.0001). Reasons for unplanned hospitalizations were most frequently cancer related (25.7%) or cancer therapy related (28%). In multivariable analysis, predictive factors for unplanned hospitalizations in older patients with cancer and an abnormal G8 were female gender, absence of surgery, chemotherapy, ADL dependency, malnutrition and presence of comorbidities.

Conclusion: Older patients with cancer and an abnormal G8 screening present a higher risk (23%) for unplanned hospitalizations. Predictive factors for these patients were identified and include not only patient and treatment related factors but also GA related factors.
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http://dx.doi.org/10.1016/j.jgo.2020.11.004DOI Listing
April 2021

A Literature Review of the Potential Diagnostic Biomarkers of Head and Neck Neoplasms.

Front Oncol 2020 26;10:1020. Epub 2020 Jun 26.

Laboratorium of Experimental Medicine and Pediatrics and Member of the Infla-Med Centre of Excellence, University of Antwerp, Antwerp, Belgium.

Head and neck neoplasms have a poor prognosis because of their late diagnosis. Finding a biomarker to detect these tumors in an early phase could improve the prognosis and survival rate. This literature review provides an overview of biomarkers, covering the different -omics fields to diagnose head and neck neoplasms in the early phase. To date, not a single biomarker, nor a panel of biomarkers for the detection of head and neck tumors has been detected with clinical applicability. Limitations for the clinical implementation of the investigated biomarkers are mainly the heterogeneity of the study groups (e.g., small population in which the biomarker was tested, and/or only including high-risk populations) and a low sensitivity and/or specificity of the biomarkers under study. Further research on biomarkers to diagnose head and neck neoplasms in an early stage, is therefore needed.
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http://dx.doi.org/10.3389/fonc.2020.01020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332560PMC
June 2020

The prognostic value of patient-reported Health-Related Quality of Life and Geriatric Assessment in predicting early death in 6769 older (≥70 years) patients with different cancer tumors.

J Geriatr Oncol 2020 07 16;11(6):926-936. Epub 2020 Apr 16.

Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium.

Objectives: We aimed to determine the prognostic value of baseline Health-Related Quality Of Life (HRQOL) and geriatric assessment (GA) to predict three-month mortality in older patients with cancer undergoing treatment.

Methods: Logistic regressions analysed HRQOL, as measured with the EORTC Global Health Status (GHS) scale, and geriatric information prognostic for early mortality controlling for oncology variables. The assessment was established with the odds ratio (OR), 95% confidence interval (CI) and level of significance set at p < 0.05. Discriminative power was evaluated with area under the curve (AUC).

Results: In total, 6769 patients were included in the study, of whom 1259 (18.60%) died at three months. Our model showed higher odds of early death for patients with lower HRQOL (GHS, OR 0.98, 95% CI 0.98-0.99; p < 0.001), a geriatric risk profile (G8 Screening Tool, 1.94, 1.14-3.29; p = 0.014), cognitive decline (Mini Mental State Examination, 1.41, 1.15-1.72; p = 0.001), being at risk for malnutrition (Mini Nutritional Assessment-Short Form, 1.54, 1.21-1.98; p = 0.001), fatigue (Visual Analogue Scale for Fatigue, 1.45, 1.16-1.82; p = 0.012) and comorbidities (Charlson Comorbidity index, 1.23, 1.02-1.49; p = 0.033). Additionally, older age, poor ECOG PS and being male increased the odds of early death, although the magnitude differed depending on tumor site and stage, and treatment (all p < 0.05). Predictive accuracy increased with 3.7% when including HRQOL and GA in the model.

Conclusion: The results suggest that, in addition to traditional clinical measures, HRQOL and GA provide additional prognostic information for early death, but the odds differ by patient and tumor characteristics.
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http://dx.doi.org/10.1016/j.jgo.2020.03.017DOI Listing
July 2020

Study protocol for a randomized controlled trial: prophylactic swallowing exercises in head-and-neck cancer patients treated with (chemo)radiotherapy (PRESTO trial).

Trials 2020 Mar 2;21(1):237. Epub 2020 Mar 2.

Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1 Wilrijk, 2610, Antwerp, Belgium.

Background: Dysphagia is a common and serious complication after (chemo)radiotherapy (CRT) for head-and-neck cancer (HNC) patients. Prophylactic swallowing exercises (PSE) can have a significantly positive effect on post-treatment swallowing function. However, low adherence rates are a key issue in undermining this positive effect. This current randomized trial will investigate the effect of adherence-improving measures on patients' swallowing function, adherence and quality of life (QOL).

Methods: This ongoing trial will explore the difference in adherence and swallowing-related outcome variables during and after PSE in HNC patients performing the same therapy schedule, receiving different delivery methods. One hundred and fifty patients treated in various hospitals will be divided into three groups. Group 1 performs PSE at home, group 2 practices at home with continuous counseling through an app and group 3 receives face-to-face therapy by a speech and language pathologist. The exercises consist of tongue-strengthening exercises and chin-tuck against resistance with effortful swallow. The Iowa Oral Performance Instrument and the Swallowing Exercise Aid are used for practicing. Patients are evaluated before, during and after treatment by means of strength measurements, swallowing and QOL questionnaires.

Discussion: Since low adherence rates undermine the positive impact of PSE on post-treatment swallowing function, there is need to develop an efficient PSE protocol maximizing adherence rates.

Trial Registration: ISRCTN, ID: ISRCTN98243550. Registered retrospectively on 21 December 2018.
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http://dx.doi.org/10.1186/s13063-020-4171-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053144PMC
March 2020

An overview of binimetinib for the treatment of melanoma.

Authors:
Pol Specenier

Expert Opin Pharmacother 2020 May 26;21(7):747-754. Epub 2020 Feb 26.

Department of Oncology, Antwerp University Hospital , Edegem, Belgium.

Introduction: Approximately 50% of patients with metastatic melanoma have mutations in BRAF. Based on the results of prior phase III trials, the combination of a BRAF inhibitor (BRAFi) and a MEK inhibitor (MEKi) is the standard of care in patients with BRAF-mutant metastatic melanoma.

Areas Covered: The author summarizes the available data on binimetinib, a reversible inhibitor of the kinase activity of MEK1 and MEK2, in BRAF- and NRAS-mutated melanoma.

Expert Opinion: With the advent of binimetinib and encorafenib, clinicians can choose between three BRAFi/MEKi combinations. Indirect comparison and a network meta-analysis suggest that binimetinib plus encorafenib is at least as active as the other two BRAFi/MEKi combinations and that safety is similar. The choice should be guided by the slightly different toxicity profile, local availability, and product experience. The optimal sequence of immunotherapy and BRAFi/MEKi in patients with BRAF-mutated tumors is unclear. As the response to BRAF/MEK inhibition is usually prompt and response to immunotherapy can be delayed, clinicians often choose a BRAFi/MEKi combination as first-line therapy in patients with rapidly evolving and threatening disease. Single-agent binimetinib almost doubled median progression-free survival when compared to dacarbazine in patients with NRAS-mutated melanoma.
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http://dx.doi.org/10.1080/14656566.2020.1729122DOI Listing
May 2020

Quantification of 18F-fluorodeoxyglucose uptake to detect residual nodal disease in locally advanced head and neck squamous cell carcinoma after chemoradiotherapy: results from the ECLYPS study.

Eur J Nucl Med Mol Imaging 2020 05 10;47(5):1075-1082. Epub 2020 Feb 10.

Department of Nuclear Medicine, Antwerp University Hospital, Edegem, Belgium.

Background: The Hopkins criteria were introduced for nodal response evaluation after therapy in head and neck cancer, but its superiority over quantification is not yet confirmed.

Methods: SUV thresholds and lesion-to-background ratios were explored in a prospective multicenter study of standardized FDG-PET/CT 12 weeks after CRT in newly diagnosed locally advanced head and neck squamous cell carcinoma (LAHNSCC) patients (ECLYPS). Reference standard was histology, negative FDG-PET/CT at 12 months after treatment or ≥ 2 years of negative follow-up. Area under the receiver operator characteristics curves (AUROC) were estimated and obtained thresholds were validated in an independent cohort of HNSCC patients (n = 127).

Results: In ECLYPS, 124 patients were available for quantification. With a median follow-up of 20.4 months, 23 (18.5%) nodal neck recurrences were observed. A SUV threshold of 2.2 (AUROC = 0.89; sensitivity = 79.7%; specificity = 80.8%) was identified as optimal metric to identify nodal recurrence within 1 year after therapy. For lesion-to-background ratios, an SUV/SUV threshold of 0.96 (AUROC = 0.89; sensitivity = 79.7%; specificity = 82.8%) had the best performance. Compared with Hopkins criteria (AUROC = 0.81), SUV and SUV/SUV provided a borderline significant (p = 0.040 and p = 0.094, respectively) improvement. Validation of thresholds yielded similar AUROC values (SUV = 0.93, SUV/SUV = 0.95), and were comparable to the Hopkins score (AUROC = 0.91; not statistically significant).

Conclusion: FDG quantification detects nodal relapse in LAHNSCC patients. When using EARL standardized PET acquisitions and reconstruction, absolute SUV metrics (SUV threshold 2.2) prove robust, yet ratios (SUV/SUV, threshold 0.96) may be more useful in routine clinical care. In this setting, the diagnostic value of quantification is comparable to the Hopkins criteria.

Trial Registration: US National Library for Medicine, NCT01179360. Registered 11 August 2010, https://clinicaltrials.gov/ct2/show/NCT01179360.
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http://dx.doi.org/10.1007/s00259-020-04710-4DOI Listing
May 2020

Radiosensitization of Non-Small Cell Lung Cancer Cells by the Plk1 Inhibitor Volasertib Is Dependent on the p53 Status.

Cancers (Basel) 2019 Nov 28;11(12). Epub 2019 Nov 28.

Center for Oncological Research (CORE), University of Antwerp, 2610 Wilrijk, Belgium.

Polo-like kinase 1 (Plk1), a master regulator of mitotic cell division, is highly expressed in non-small cell lung cancer (NSCLC) making it an interesting drug target. We examined the in vitro therapeutic effects of volasertib, a Plk1 inhibitor, in combination with irradiation in a panel of NSCLC cell lines with different p53 backgrounds. Pretreatment with volasertib efficiently sensitized p53 wild type cells to irradiation. Flow cytometric analysis revealed that significantly more cells were arrested in the G/M phase of the cell cycle after the combination therapy compared to either treatment alone ( < 0.005). No significant synergistic induction of apoptotic cell death was observed, but, importantly, significantly more senescent cells were detected when cells were pretreated with volasertib before irradiation compared to both monotherapies alone ( < 0.001), especially in cells with functional p53. Consequently, while most cells with functional p53 showed permanent growth arrest, more p53 knockdown/mutant cells could re-enter the cell cycle, resulting in colony formation and cell survival. Our findings assign functional p53 as a determining factor for the observed radiosensitizing effect of volasertib in combination with radiotherapy for the treatment of NSCLC.
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http://dx.doi.org/10.3390/cancers11121893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966428PMC
November 2019

Health related quality of life in older patients with solid tumors and prognostic factors for decline.

J Geriatr Oncol 2019 11 18;10(6):895-903. Epub 2019 Apr 18.

Department of General Medical Oncology, University Hospitals Leuven, Department of Oncology, KU Leuven, Leuven, Belgium.

Objectives: This study aims to investigate health-related quality of life (HRQOL) at baseline and at follow-up in older patients with cancer and to determine prognostic factors for HRQOL decline.

Methods: A prospective Belgian multicentre (n = 22) study was performed. Patients ≥70 years with a malignant tumor and abnormal G8 (≤14/17) screening tool were included. Patients underwent geriatric assessment (GA) and HRQOL evaluation with follow up at three months. Uni- and multivariate regression models were performed to determine factors associated (p < .05) with baseline HRQOL and HRQOL decline at follow-up.

Results: Results reflect data collected from 3673 patients. A multivariate analysis showed that younger patients, and those with poor Eastern Cooperative Oncology Group - Performance Status (ECOG-PS), specific tumor types (gastrointestinal, gynaecological and thorax) and higher stage had lower baseline HRQOL. In addition worse functional status and presence of pain, fatigue, depression and malnutrition were associated with lower baseline HRQOL. During treatment (n = 2972), improvement in HRQOL was observed in 1037 patients (35%) and a decline in 838 patients (28.2%). In multivariate analysis, stage and presence of baseline comorbidities, pain, fatigue or malnutrition were associated with HRQOL evolution.

Conclusion: Baseline HRQOL in older patients with cancer and an abnormal G8 depends on tumor and age related parameters. During follow-up, HRQOL improved in one third of patients, indicating that they may benefit from cancer treatment while one quarter demonstrated a HRQOL decline for which prognostic factors were identified.
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http://dx.doi.org/10.1016/j.jgo.2019.03.018DOI Listing
November 2019

In vitro study of the Polo-like kinase 1 inhibitor volasertib in non-small-cell lung cancer reveals a role for the tumor suppressor p53.

Mol Oncol 2019 05 5;13(5):1196-1213. Epub 2019 Apr 5.

Center for Oncological Research (CORE), University of Antwerp, Wilrijk, Belgium.

Polo-like kinase 1 (Plk1), a master regulator of mitosis and the DNA damage response, is considered to be an intriguing target in the research field of mitotic intervention. The observation that Plk1 is overexpressed in multiple human malignancies, including non-small-cell lung cancer (NSCLC), gave rise to the development of several small-molecule inhibitors. Volasertib, presently the most extensively studied Plk1 inhibitor, has been validated to efficiently reduce tumor growth in preclinical settings. Unfortunately, only modest antitumor activity against solid tumors was reported in clinical trials. This discrepancy prompted research into the identification of predictive biomarkers. In this study, we investigated the therapeutic effect of volasertib monotherapy (i.e., cytotoxicity, cell cycle distribution, apoptotic cell death, cellular senescence, and migration) in a panel of NSCLC cell lines differing in p53 status under both normal and reduced oxygen tension (<0.1% O ). A strong growth inhibitory effect was observed in p53 wild-type cells (A549 and A549-NTC), with IC values significantly lower than those in p53 knockdown/mutant cells (A549-920 and NCI-H1975) (P < 0.001). While mitotic arrest was significantly greater in cells with nonfunctional p53 (P < 0.005), apoptotic cell death (P < 0.026) and cellular senescence (P < 0.021) were predominantly induced in p53 wild-type cells. Overall, the therapeutic effect of volasertib was reduced under hypoxia (P < 0.050). Remarkably, volasertib inhibited cell migration in all cell lines tested (P < 0.040), with the exception of for the NCI-H1975 p53 mutant cell line. In conclusion, our results show an important difference in the therapeutic effect of Plk1 inhibition in NSCLC cells with versus without functional p53. Overall, the p53 wild-type cell lines were more sensitive to volasertib treatment, suggesting that p53 might be a predictive biomarker for Plk1 inhibition in NSCLC. Moreover, our results pave the way for new combination strategies with Plk1 inhibitors to enhance antitumor activity.
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http://dx.doi.org/10.1002/1878-0261.12477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487694PMC
May 2019

Evolution of self-perceived swallowing function, tongue strength and swallow-related quality of life during radiotherapy in head and neck cancer patients.

Head Neck 2019 07 14;41(7):2197-2207. Epub 2019 Feb 14.

Department of Otolaryngology and Head and Neck Surgery - Rehabilitation Center for Communication Disorders, Antwerp University Hospital, Antwerp, Belgium.

Background: Radiation-associated-dysphagia is a serious side effect of radiotherapy (RT) for head and neck cancer (HNC).

Methods: Seventy-six patients had a weekly prospective follow-up from baseline until one week post-RT. Combined mixed model analysis (n = 43) determined the evolution of self-perceived swallowing function, isometric tongue strength (MIP), tongue strength (TS) during swallowing (Pswal), and quality of life (QoL) in these patients during RT.

Results: Swallowing deteriorated from the third week on, resulting in an increase of tube dependency from 10% at baseline toward 31% post-RT. Both MIP and Pswal are reduced, with anterior MIP decreasing in 29% of patients and posterior MIP in 17%. Pswal decreases for saliva and a bolus swallow. All QoL subscales except "sleep" were affected during RT.

Conclusions: Self-perceived swallowing function, TS and QoL decrease during RT for HNC. Current findings highlight the need for early monitoring of these parameters.
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http://dx.doi.org/10.1002/hed.25684DOI Listing
July 2019

Authors' response letter: Quality of life in oropharyngeal cancer: a structured review of the literature.

Support Care Cancer 2019 05 14;27(5):1583. Epub 2019 Feb 14.

University of Antwerp, Universiteitsplein, 12610, Wilrijk, Belgium.

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http://dx.doi.org/10.1007/s00520-019-04691-7DOI Listing
May 2019

Efficacy of nab-paclitaxel in treating metastatic melanoma.

Authors:
Pol Specenier

Expert Opin Pharmacother 2019 Apr 28;20(5):495-500. Epub 2019 Jan 28.

a Department of Oncology , Antwerp University Hospital , Edegem , Belgium.

Introduction: Systemic treatment of metastatic melanoma has been revolutionized by the advent of checkpoint inhibitors and targeted agents which are widely accepted as standard front-line therapies. However, despite these major advances, a substantial portion of patients still fail checkpoint inhibitors and/or targeted agents and are not candidates for clinical trials. Commonly used cytotoxics in these patients include paclitaxel, dacarbazine, platins, and temozolomide. The overall response rates of these agents are usually disappointing and short-lived. Areas covered: Herein, the author provides a literature review of the role of nab-paclitaxel in metastatic melanoma including coverage of its pharmacokinetics, pharmacodynamics and efficacy. Expert opinion: The role of chemotherapy in the treatment of metastatic melanoma is limited to patients who failed checkpoint inhibitors and, when applicable, targeted agents, and those not appropriate for clinical trials. nab-Paclitaxel has single agent activity in chemotherapy-naïve untreated metastatic melanoma which compares favorably to the activity of weekly paclitaxel or single agent dacarbazine. However, the activity in chemotherapy-pretreated patients is modest. Data on nab-paclitaxel in patients pretreated with targeted agents or check point inhibitors are lacking. Further advances are expected from new checkpoint inhibitors and targeted agents for the treatment of metastatic melanoma in addition to the optimal combination and sequencing of these agents.
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http://dx.doi.org/10.1080/14656566.2019.1569628DOI Listing
April 2019

Optimizing treatments for recurrent or metastatic head and neck squamous cell carcinoma.

Expert Rev Anticancer Ther 2018 09 16;18(9):901-915. Epub 2018 Jul 16.

a Department of Oncology , Antwerp University Hospital , Edegem , Belgium.

Introduction: The majority of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) will recur. The treatment of patients with recurrent/metastatic (R/M HNSCC) is rapidly evolving. Areas covered: This article will comprehensively review the current systemic treatment of R/M HNSCC. Expert commentary: For the time being, the EXTREME regimen (cetuximab in combination with platinum and 5-fluorouracil) still remains standard of care in previously untreated R/M HNSCC patients who are candidates for combination chemotherapy. Single agents with well documented activity in HNSCC include methotrexate, cisplatin, 5-FU, docetaxel, and paclitaxel. The anti-PD-1 monoclonal antibody nivolumab can be considered the current standard of care in patients with R/M HNSCC progressing after platinum-based therapy based on the results of CheckMate 141 showing a survival benefit over standard of care drugs, such as single agent weekly cetuximab, methotrexate, or docetaxel. Multiple randomized phase III trials comparing anti-PD(L)-antibodies either as single agent or in combination with chemotherapy or an anti-CTLA-4 with the EXTREME as fist line treatment are ongoing or planned. The outcome of these trials might change the current treatment paradigm in previously untreated R/M HNSCC. Immunotherapeutic agents under active investigation include Toll-like receptor 8 agonists and inhibitors of IDO1.
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http://dx.doi.org/10.1080/14737140.2018.1493925DOI Listing
September 2018

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus.

J Clin Endocrinol Metab 2018 09;103(9):3144-3154

Department of Endocrinology, Diabetology & Metabolism, Antwerp University Hospital, Edegem, Belgium.

Context: Pembrolizumab (Keytruda; Merck Sharp & Dohme) is a humanized IgG4 monoclonal antibody used in cancer immunotherapy. It targets the programmed cell death-1 (PD-1) receptor, which is important in maintaining self-tolerance. However, immune checkpoint blockade is associated with a risk for immune-related adverse events (irAEs) potentially affecting the endocrine organs. Type 1 diabetes mellitus is a rare irAE of PD-1 inhibitors, occurring in 0.2% of cases.

Evidence Acquisition: Systematic search of four databases (MEDLINE, Embase, Web of Science, and Cochrane Library) using the search terms "diabetes" or "ketoacidosis" and "pembrolizumab," "nivolumab," "PD-1 inhibitor," or "immunotherapy." Included were articles published in English between 1 January 2012 and 1 January 2018. The search was supplemented by bibliographic searches of the complete reference lists of all included papers.

Evidence Synthesis: We provide an overview of all published cases (n = 42) of PD-1 inhibitor-induced type 1 diabetes mellitus to date, including a well-characterized case of islet cell antibody and glutamic acid decarboxylase antibody-positive diabetes mellitus, in a patient with a diabetes-prone HLA genotype. She presented with diabetic ketoacidosis during pembrolizumab therapy for a metastatic uveal melanoma. Furthermore, we discuss potential pathogenic mechanisms, clinical presentation, prognostic markers (β-cell antibodies and HLA type), treatment, and a screening protocol.

Conclusions: Because the use of immunotherapy will increase, it is essential that all clinicians are aware of diabetic ketoacidosis as a rare and life-threatening side effect of immunotherapy. Blood glucose monitoring during anti-PD-1 therapy is necessary.
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http://dx.doi.org/10.1210/jc.2018-00728DOI Listing
September 2018

Quality of life in oropharyngeal cancer: a structured review of the literature.

Support Care Cancer 2018 Aug 3;26(8):2511-2518. Epub 2018 May 3.

Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.

Purpose: To summarize the literature on quality of life (QoL) in patients with oropharyngeal squamous cell carcinoma (OPSCC).

Methods: The PubMed database was searched using the inclusion criteria "oropharyngeal cancer," "quality of life," "human," and "English," the exclusion criterion "recurrent," and publication date between January 1, 2005 and October 26, 2015.

Results: The search yielded 98 articles of which 17 fulfilled all selection criteria. Intensity-modulated radiotherapy (IMRT) showed a better outcome for several QoL domains and was superior to chemoradiotherapy (CRT) in some studies. At 12-month follow up, deterioration of QoL was seen in a smaller proportion of patients after surgery and postoperative radiotherapy (S&PORT) in comparison to CRT. For all treatment modalities, the most important worsening for several QoL domains was seen at 3 months. Stage III/IV patients experienced a greater deterioration of QoL scores for most scores. No consistent results were reported for the correlation between xerostomia assessed with QoL questionnaires and objective swallowing function assessed with modified barium swallow videofluoroscopy.

Conclusion: The different tools used for the assessment of patient-reported QoL and objective measurement of functional outcome make it difficult to evaluate the effect of different treatment modalities. In general, we can conclude that a non-surgical approach is associated with worse QoL scores. IMRT minimizes radiation to the surrounding tissue and therefore has a better outcome in several QoL domains in comparison to conventional RT.
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http://dx.doi.org/10.1007/s00520-018-4227-9DOI Listing
August 2018

Nivolumab in squamous cell carcinoma of the head and neck.

Authors:
Pol Specenier

Expert Rev Anticancer Ther 2018 05 2;18(5):409-420. Epub 2018 Apr 2.

a Department of Oncology , Antwerp University Hospital , Edegem , Belgium.

Introduction: The prognosis of recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (HNSCC) after failure of first line chemotherapy is dismal. Until the publication of the results of CheckMate 141, not a single agent provided any survival benefit as a second line treatment for R/M HNSCC. Areas covered: A comprehensive review of the literature was conducted on the role of nivolumab in HNSCC. Expert commentary: Nivolumab is approved by the Food and Drug Administration for the treatment of patients based on the results of CheckMate 141 showing an overall survival benefit as compared to standard care (single agent docetaxel, methotrexate, or cetuximab). Of particular interest are immune-related adverse events which should be managed according to published guidelines.
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http://dx.doi.org/10.1080/14737140.2018.1456337DOI Listing
May 2018

Feasibility of tongue strength measurements during (chemo)radiotherapy in head and neck cancer patients.

Support Care Cancer 2017 11 2;25(11):3417-3423. Epub 2017 Jun 2.

Department of Otolaryngology and Head and Neck Surgery-Rehabilitation Center for Communication Disorders, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Antwerp, Belgium.

Purpose: The aim of this study was to investigate the feasibility of tongue strength measures (TSMs) and the influence of bulb location, sex, and self-perceived pain and mucositis in head and neck cancer (HNC) patients during chemoradiotherapy (CRT).

Methods: Twenty-six newly diagnosed HNC patients treated with CRT performed anterior and posterior maximal isometric tongue pressures by means of the Iowa Oral Performance Instrument (IOPI). The Oral Mucositis Weekly Questionnaire (OMWQ) and a Visual Analogue Scale (VAS) for pain during swallowing were completed weekly from baseline to 1 week post CRT.

Results: Feasibility of TSMs during CRT declines significantly from 96 to 100% at baseline to 46% after 6 weeks of CRT. But post-hoc analyses reveal only significant differences in feasibility between baseline and measurements after 4 weeks of treatment. No effect of gender or bulb location was established, but feasibility is influenced by pain and mucositis.

Conclusions: Feasibility of TSMs declines during CRT and is influenced by mucositis and pain. For the majority of subjects, TSMs were feasible within the first 4 weeks, which provides a window of scientific and clinical opportunities in this patient population.
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http://dx.doi.org/10.1007/s00520-017-3761-1DOI Listing
November 2017

Biomarker and Histopathology Evaluation of Patients with Recurrent Glioblastoma Treated with Galunisertib, Lomustine, or the Combination of Galunisertib and Lomustine.

Int J Mol Sci 2017 May 6;18(5). Epub 2017 May 6.

Department of Neurology, University Hospital Heidelberg, 69120 Heidelberg, Germany.

Galunisertib, a Transforming growth factor-βRI (TGF-βRI) kinase inhibitor, blocks TGF-β-mediated tumor growth in glioblastoma. In a three-arm study of galunisertib (300 mg/day) monotherapy (intermittent dosing; each cycle =14 days on/14 days off), lomustine monotherapy, and galunisertib plus lomustine therapy, baseline tumor tissue was evaluated to identify markers associated with tumor stage (e.g., histopathology, Ki67, glial fibrillary acidic protein) and TGF-β-related signaling (e.g., pSMAD2). Other pharmacodynamic assessments included chemokine, cytokine, and T cell subsets alterations. 158 patients were randomized to galunisertib plus lomustine ( = 79), galunisertib ( = 39) and placebo+lomustine ( = 40). In 127 of these patients, tissue was adequate for central pathology review and biomarker work. Isocitrate dehydrogenase () negative glioblastoma patients with baseline pSMAD2⁺ in cytoplasm had median overall survival (OS) 9.5 months vs. 6.9 months for patients with no tumor pSMAD2 expression ( = 0.4574). Eight patients were IDH1 R132H⁺ and had a median OS of 10.4 months compared to 6.9 months for patients with negative IDH1 R132H ( = 0.5452). IDH1 status was associated with numerically higher plasma macrophage-derived chemokine (MDC/CCL22), higher whole blood FOXP3, and reduced tumor CD3⁺ T cell counts. Compared to the baseline, treatment with galunisertib monotherapy preserved CD4⁺ T cell counts, eosinophils, lymphocytes, and the CD4/CD8 ratio. The T-regulatory cell compartment was associated with better OS with MDC/CCL22 as a prominent prognostic marker.
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http://dx.doi.org/10.3390/ijms18050995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5454908PMC
May 2017

Pembrolizumab use for the treatment of advanced melanoma.

Authors:
Pol Specenier

Expert Opin Biol Ther 2017 06 3;17(6):765-780. Epub 2017 Apr 3.

a Department of Medical Oncology , Antwerp University Hospital , Edegem , Belgium.

Introduction: Until recently, overall long term survival in patients with stage IV melanoma was lower than 10%. However, the treatment of melanoma has evolved rapidly over the last few years, with the advent of inhibitors of BRAF and MEK and of immunotherapeutic agents including ipilimumab, nivolumab, and pembrolizumab. Areas covered: This is a comprehensive review of the literature on the role of pembrolizumab in melanoma. Pembrolizumab is a Programmed Death Receptor 1 (PD-1) directed monoclonal antibody which is approved by FDA and EMA for the treatment of patients with metastatic melanoma. Expert opinion: Phase II and III trials demonstrated that pembrolizumab is superior to ipilimumab in previously untreated patients and to chemotherapy in ipilimumab pre-treated patients. Unfortunately, prospectively validated predictive markers are lacking. Immune-related adverse events are particularly interesting and should be managed per the published guidelines. There are still many issues that remain unresolved including: when to stop treatment, biomarkers for choosing a single agent or combination therapy, the optimal schedule of ipilimumab in combination with anti-PD1 monoclonal antibodies, optimal management of adverse events, the role of immunotherapy in specific populations, the optimal sequence of immunotherapy and the BRAF/MEK inhibitor combination in patients.
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http://dx.doi.org/10.1080/14712598.2017.1309388DOI Listing
June 2017

CONCERT-1, an additional piece in the puzzle of (bio)-(chemo)-radiation.

Ann Transl Med 2016 Nov;4(21):432

Faculty of Medicine and Health Sciences, Antwerp University, Wilrijk, Belgium; ; Department of Oncology, Antwerp University Hospital, Edegem, Belgium.

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http://dx.doi.org/10.21037/atm.2016.11.25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5124631PMC
November 2016

Nivolumab in melanoma.

Authors:
Pol Specenier

Expert Rev Anticancer Ther 2016 Dec 7;16(12):1247-1261. Epub 2016 Nov 7.

a Faculty of Medicine and Health Sciences , University of Antwerp , Antwerp , Belgium.

Introduction: The treatment of melanoma is evolving rapidly over the past few years. Areas covered: We conducted a comprehensive review of the literature on the role of nivolumab in melanoma Expert commentary: Nivolumab is approved by FDA and EMA for the treatment of patients with metastatic melanoma. Nivolumab is superior to chemotherapy and to ipilimumab in previously untreated patients and to chemotherapy in ipilimumab pre-treated patients. The addition ipilimumab to nivolumab is associated with a higher response rate and a better PFS, particularly in patients with PD-L1 negative tumors, albeit at the cost of an increase in grade 3-4 adverse event rate. Definitive survival data on this combination are pending and the selection of patients most likely to benefit from this combination and its pharmacoeconomics are to be elucidated. Prospectively validated predictive markers are lacking. Of particular interest are immune-related adverse events which should be managed according to published guidelines.
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http://dx.doi.org/10.1080/14737140.2016.1249856DOI Listing
December 2016

Phase Ib study of duligotuzumab (MEHD7945A) plus cisplatin/5-fluorouracil or carboplatin/paclitaxel for first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck.

Cancer 2016 Dec 15;122(24):3803-3811. Epub 2016 Aug 15.

Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium.

Background: This open-label, multicenter, phase Ib study assessed the safety and preliminary activity of duligotuzumab, a dual-action antibody that blocks ligand binding to human epidermal growth factor receptor 3 (HER3) and epidermal growth factor receptor, in combination with chemotherapy, in the first-line treatment of patients with recurrent/metastatic squamous cell cancer of the head and neck.

Methods: On day 1, duligotuzumab at a dose of 1650 mg intravenously was combined with cisplatin at a dose of 100 mg/m and 5-fluorouracil at a dose of 1000 mg/m /day on days 1 to 4 in treatment arm A, or carboplatin (area under the curve, 6 mg/mL/min) and paclitaxel (at a dose of 200 mg/m ) in treatment arm B. Up to 6 cycles (21 days/cycle) were followed by duligotuzumab maintenance until disease progression or intolerable toxicity occurred.

Results: Nine patients in arm A and 15 patients in arm B received a median of 6 cycles of chemotherapy, and a median of 11 cycles (arm A) and 9 cycles (arm B) of duligotuzumab. Dose-limiting toxicities occurred in 3 patients in arm A and 1 patient in arm B. Grade ≥ 3 treatment-related adverse events (graded according to graded according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]) in ≥ 3 patients were neutropenia (5 patients), hypokalemia (4 patients), dehydration (3 patients), anemia (3 patients), and diarrhea (3 patients) in arm A, and neutropenia (8 patients), anemia (5 patients), febrile neutropenia (4 patients), leukopenia (3 patients), thrombocytopenia (3 patients), and hypomagnesemia (3 patients) in arm B. The chemotherapy dose was reduced in 19 of 24 patients. Sixteen patients (67%) demonstrated objective responses regardless of human papillomavirus status or neuregulin 1 (NRG1) mRNA expression (arm A: 2 confirmed complete responses and 4 confirmed partial responses; arm B: 2 confirmed complete responses and 8 confirmed partial responses).

Conclusions: Duligotuzumab in combination with cisplatin/5-fluorouracil or carboplatin/paclitaxel demonstrated encouraging activity in patients with recurrent/metastatic squamous cell cancer of the head and neck; an association with increased frequency and severity of select adverse events relative to historical data was suggestive of the potentiation of chemotherapy-related adverse events. Cancer 2016;122:3803-3811. © 2016 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30256DOI Listing
December 2016

Ipilimumab in melanoma.

Authors:
Pol Specenier

Expert Rev Anticancer Ther 2016 Aug 25;16(8):811-26. Epub 2016 Jul 25.

a Oncology , Universitair Ziekenhuis Antwerpen , Edegem , Belgium.

Introduction: The treatment of melanoma is evolving rapidly over the past few years. Patients with BRAFv600 mutations can be treated with a combination of a BRAF-inhibitor and an MEK-inhibitor. Patients with BRAF wild-type tumors and BRAFv600 mutated tumors can be treated with immunotherapy i.e. check point inhibitors.

Areas Covered: We conducted a comprehensive review of the literature on the efficacy and predictive markers, safety, and pharmacoeconomics of ipilimumab in melanoma Expert commentary: Ipilimumab was the first check point inhibitor reaching the clinic, gaining FDA and EMA approval for metastatic melanoma in 2011. Ipilimumab was also approved by FDA in the adjuvant setting for patients with high risk, stage III melanoma. The anti-PD1 directed antibodies pembrolizumab and nivolumab are superior to single agent ipilimumab, which is no longer considered the standard first line treatment in metastatic melanoma. The addition ipilimumab to nivolumab is associated with a higher response rate and a better PFS, particularly in patients with PD-L1 negative tumors, albeit at the cost of a steep increase in grade 3-4 adverse event rate. Definitive survival data on this combination are pending and the selection of patients potentially requiring the combination and its pharmacoeconomic implications are to be elucidated.
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http://dx.doi.org/10.1080/14737140.2016.1211936DOI Listing
August 2016

Afatinib in squamous cell carcinoma of the head and neck.

Expert Opin Pharmacother 2016 Jun 19;17(9):1295-301. Epub 2016 May 19.

a Department of Medical Oncology , Universitair Ziekenhuis Antwerpen , Edegem , Belgium.

Introduction: Recently new data on the efficacy of afatinib in head and neck squamous cell carcinoma (HNSCC) have been published.

Areas Covered: We searched the literature for published and ongoing studies with afatinib in HNSCC. Phase I data and results of phase II and III studies of afatinib in HNSCC are discussed. The maximum tolerated dose (MTD) of afatinib monotherapy with continuous administration was determined at 40 or 50 mg/day, rash and diarrhea being the principal dose-limiting toxicities. The MTD was lower when combined with chemotherapy. Studies with afatinib have been conducted or are ongoing both in the recurrent or metastatic (R/M) and in the locoregionally advanced (LA) HNSCC disease setting.

Expert Opinion: Comparable disease control and tumor shrinkage rates were observed with cetuximab and afatinib in HNSCC progressing after platinum-containing chemotherapy. In patients with R/M- Squamous cell carcinoma of the head and neck (SCCHN) who had progressed on/after first-line platinum-based therapy, afatinib induced significantly higher disease control rate, longer progression-free survival and improved patient-reported outcome compared to methotrexate. Randomized phase III trials studying the role of adjuvant afatinib after definitive or postoperative chemoradiation in LA-HNSCC are ongoing.
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http://dx.doi.org/10.1080/14656566.2016.1183647DOI Listing
June 2016

A Phase II randomized study of galunisertib monotherapy or galunisertib plus lomustine compared with lomustine monotherapy in patients with recurrent glioblastoma.

Neuro Oncol 2016 08 21;18(8):1146-56. Epub 2016 Feb 21.

Medical Oncology Department, Bellaria-Maggiore Hospitals, Azienda USL - IRCCS Institute of Neurological Sciences, Bologna, Italy (A.A.B.); Hôpital Avicenne, Paris 13 University, Bobigny, France (A.F.C.); University of California San Diego Health System, La Jolla, California (S.K.); Hospital Universitario 12 de Octubre, Madrid, Spain (J.M.S.-S.); Department of Oncology, Royal North Shore Hospital, St Leonards, Australia (H.R.W.); CHU Hôspital De La Timone, Rue Saint Pierre, France (O.C.); Austin Hospital, Heidelberg, Australia (L.C.); Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Frankfurt, Germany (J.P.S.); Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany (D.C.); Antwerp University Hospital, Edegem, Belgium (P.S.); Medical Oncology, Vall d'Hebron University Hospital and Universitat Autònoma de Barcelona, Barcelona, Spain (J.R.); Eli Lilly and Company, Erl Wood, England (A.C., C.S., I.G., C.M.); Eli Lilly and Company, Indianapolis, Indiana (S.C.G., D.D., M.M.L.); Neurology Clinic, University of Heidelberg, Heidelberg, Germany (W.W.).

Background: The combination of galunisertib, a transforming growth factor (TGF)-β receptor (R)1 kinase inhibitor, and lomustine was found to have antitumor activity in murine models of glioblastoma.

Methods: Galunisertib (300 mg/day) was given orally 14 days on/14 days off (intermittent dosing). Lomustine was given as approved. Patients were randomized in a 2:1:1 ratio to galunisertib + lomustine, galunisertib monotherapy, or placebo + lomustine. The primary objective was overall survival (OS); secondary objectives were safety, pharmacokinetics (PKs), and antitumor activity.

Results: One hundred fifty-eight patients were randomized: galunisertib + lomustine (N = 79), galunisertib (N = 39), and placebo + lomustine (N = 40). Baseline characteristics were: male (64.6%), white (75.3%), median age 58 years, ECOG performance status (PS) 1 (63.3%), and primary glioblastoma (93.7%). The PKs of galunisertib were not altered with lomustine, and galunisertib had a median half-life of ∼8 hours. Median OS in months (95% credible interval [CrI]) for galunisertib + lomustine was 6.7 (range: 5.3-8.5), 8.0 (range: 5.7-11.7) for galunisertib alone, and 7.5 (range: 5.6-10.3) for placebo + lomustine. There was no difference in OS for patients treated with galunisertib + lomustine compared with placebo + lomustine [P (HR < 1) = 26%]. Median progression-free survival of ∼2 months was observed in all 3 arms. Among 8 patients with IDH1 mutation, 7 patients were treated with galunisertib (monotherapy or with lomustine); OS ranged from 4 to 17 months. Patients treated with galunisertib alone had fewer drug-related grade 3/4 adverse events (n = 34) compared with lomustine-treated patients (10% vs 26%). Baseline PS, post-discontinuation of bevacizumab, tumor size, and baseline levels of MDC/CCL22 were correlated with OS.

Conclusions: Galunisertib + lomustine failed to demonstrate improved OS relative to placebo + lomustine. Efficacy outcomes were similar in all 3 arms.

Clinical Trial Registration: NCT01582269, ClinicalTrials.gov.
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http://dx.doi.org/10.1093/neuonc/now009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4933481PMC
August 2016
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