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Safety and Impact of Low-dose Methotrexate on Endothelial Function and Inflammation in Individuals With Treated Human Immunodeficiency Virus: AIDS Clinical Trials Group Study A5314.
Hsue, PY, Ribaudo, HJ, Deeks, SG, Bell, T, Ridker, PM, Fichtenbaum, C, Daar, ES, Havlir, D, Yeh, E, Tawakol, A, et al
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2019;(11):1877-1886
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BACKGROUND Chronic inflammation in treated HIV infection is associated with mortality and atherosclerotic cardiovascular disease (ASCVD). We evaluated the safety and potential efficacy of low-dose methotrexate (LDMTX) in treated HIV. METHODS This was a phase 2 randomized, double-blind, multicenter trial in adults ≥40 years old with treated HIV, with CD4+ T-cell count ≥400 cells/μL and with/at increased risk for ASCVD. Participants received LDMTX (5-15 mg/week) or placebo (plus folic acid) for 24 weeks and were followed for an additional 12 weeks. Primary endpoints were safety and brachial artery flow-mediated dilation (FMD). RESULTS The 176 participants (90% male) had a median (Q1, Q3) age of 54 (49, 59) years. LDMTX was associated with decreases in CD4+ T cells at week 24 and CD8+ T cells at weeks 8, 12, and 24. Eleven participants (12.8%) experienced safety events in the LDMTX group vs 5 (5.6%) in placebo (Δ = 7.2%, upper 1-sided 90% CI, 13.4%; Pnoninferiority = .037). Week 24 change in FMD was 0.47% with LDMTX and 0.09% with placebo (P = .55). No inflammatory markers changed differentially with LDMTX compared to placebo. CONCLUSIONS Adults with HIV and increased ASCVD risk treated with LDMTX had more safety events than with placebo, but the prespecified noninferiority margin of 15% was not exceeded. LDMTX had no significant effect on endothelial function or inflammatory biomarkers but was associated with a significant decrease in CD8+ T cells. The balance of risks and potential benefits of LDMTX in this population will require additional investigation. CLINICAL TRIALS REGISTRATION NCT01949116.
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An intensified dosing schedule of subcutaneous methotrexate in patients with moderate to severe plaque-type psoriasis (METOP): a 52 week, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.
Warren, RB, Mrowietz, U, von Kiedrowski, R, Niesmann, J, Wilsmann-Theis, D, Ghoreschi, K, Zschocke, I, Falk, TM, Blödorn-Schlicht, N, Reich, K
Lancet (London, England). 2017;(10068):528-537
Abstract
BACKGROUND Methotrexate is one of the most commonly used systemic drugs for the treatment of moderate to severe psoriasis; however, high-quality evidence for its use is sparse and limited to use of oral dosing. We aimed to assess the effect of an intensified dosing schedule of subcutaneous methotrexate in patients with moderate to severe plaque-type psoriasis. METHODS We did this prospective, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial (METOP) at 16 sites in Germany, France, the Netherlands, and the UK. Eligible patients were aged 18 years or older, had a diagnosis of chronic plaque psoriasis for at least 6 months before baseline, had currently moderate to severe disease, and were methotrexate treatment-naive. Participants were randomly assigned (3:1), via a computer-generated random number sequence integrated into an electronic data capture system, to receive either methotrexate at a starting dose of 17·5 mg/week or placebo for the first 16 weeks, followed by methotrexate treatment of all patients up to 52 weeks (methotrexate-methotrexate vs placebo-methotrexate groups). Dose escalation to 22·5 mg/week was allowed after 8 weeks of methotrexate treatment if patients had not achieved at least a 50% reduction in baseline Psoriasis Area and Severity Index score (PASI), with corresponding volume increases in placebo injections. Treatment was combined with folic acid 5 mg/week. Group allocation was concealed from participants and investigators from the time of randomisation until an interim database lock at week 16, and was open label from week 16 onwards, with no masking of participants or investigators. The primary efficacy endpoint was a 75% reduction in PASI score (PASI 75) from baseline to week 16. We did analysis by modified intention to treat, with non-responder imputation. This study is registered with EudraCT, number 2012-002716-10. FINDINGS Between Feb 22, 2013, and May 13, 2015, we randomly assigned 120 patients to receive methotrexate (n=91) or placebo (n=29). At week 16, a PASI 75 response was achieved in 37 (41%) patients in the methotrexate group compared with three (10%) patients in the placebo group (relative risk 3·93, 95% CI 1·31-11·81; p=0·0026). Subcutaneous methotrexate was generally well tolerated; no patients died or had serious infections, malignancies, or major adverse cardiovascular events. Serious adverse events were recorded in three (3%) patients who received methotrexate for the full 52 week treatment period. INTERPRETATION Our findings show a favourable 52 week risk-benefit profile of subcutaneous methotrexate in patients with psoriasis. The route of administration and the intensified dosing schedule should be considered when methotrexate is used in this patient group. FUNDING Medac.
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MethotrexaTE THerapy in ST-Segment Elevation MYocardial InfarctionS: A Randomized Double-Blind, Placebo-Controlled Trial (TETHYS Trial).
Moreira, DM, Lueneberg, ME, da Silva, RL, Fattah, T, Gottschall, CAM
Journal of cardiovascular pharmacology and therapeutics. 2017;(6):538-545
Abstract
PURPOSE Methotrexate is an anti-inflammatory drug that has been shown to have anti-ischemic effects. Our aim was to evaluate if methotrexate could reduce infarct size in patients with ST-segment elevation myocardial infarction (STEMI). METHODS We randomly assigned patients with STEMI to receive either methotrexate or placebo. Primary outcome was infarct size determined by calculating the area under the curve (AUC) for creatine kinase (CK) release. Secondary outcomes were AUC of CK MB (CK-MB) and AUC of troponin I; peak CK, peak CK-MB, and troponin I; B-type natriuretic peptide (BNP) level, high-sensitivity C-reactive protein (hsCRP) result, and erythrocyte sedimentation rate (ESR); left ventricular ejection fraction (LVEF); thrombolysis in myocardial infarction (TIMI) frame count; Killip score; mortality and reinfarction incidence; and incidence of adverse reactions. RESULTS We included 84 patients. Median AUC of CK was 78 861.0 in the methotrexate group and 68 088.0 in the placebo group ( P = .10). Patients given methotrexate and placebo exhibited, respectively, median AUC for CK-MB of 9803.4 and 8037.0 ( P = .42); median AUC for troponin of 3691.1 and 2132.6 ( P = .09); peak CK of 2806.0 and 2147.0 ( P = .05); peak CK-MB of 516.0 and 462.3 ( P = .25); and peak troponin of 121.0 and 85.1 ( P = .06). At 3 months, LVEF was lower in patients who received methotrexate (49.0% ± 14.1%) than in patients given placebo (56.4% ± 10.0%; P = .01). There were no differences in hsCRP, ESR, BNP, Killip scores, TIMI frame count, reinfarction, and mortality rates. There was a higher median serum glutamic-pyruvic transaminase levels in the methotrexate group. CONCLUSION Methotrexate did not reduce infarction size and worsened LVEF at 3 months ( Clinicaltrials.gov identifier NCT01741558).
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Peficitinib, a JAK Inhibitor, in the Treatment of Moderate-to-Severe Rheumatoid Arthritis in Patients With an Inadequate Response to Methotrexate.
Kivitz, AJ, Gutierrez-Ureña, SR, Poiley, J, Genovese, MC, Kristy, R, Shay, K, Wang, X, Garg, JP, Zubrzycka-Sienkiewicz, A
Arthritis & rheumatology (Hoboken, N.J.). 2017;(4):709-719
Abstract
OBJECTIVE To evaluate the efficacy and safety of orally administered once-daily peficitinib in combination with methotrexate (MTX) in patients with moderate-to-severe rheumatoid arthritis (RA) who had an inadequate response to MTX. METHODS In this multinational, phase IIb, randomized, double-blind, placebo-controlled, dose-ranging trial, patients with RA (n = 378) were treated with peficitinib 25 mg, 50 mg, 100 mg, or 150 mg plus MTX, or matching placebo plus MTX once daily for 12 weeks. The primary end point was the percentage of patients who met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at week 12. RESULTS ACR20 response rates at week 12 were 43.9%, 61.5% (P < 0.05 versus placebo), 46.4%, 57.7%, and 44.4% in the peficitinib 25 mg, 50 mg, 100 mg, 150 mg, and placebo groups, respectively. Significant decreases from baseline in the Disease Activity Score in 28 joints using the C-reactive protein level were seen in the peficitinib 50 mg (P < 0.05) and 150 mg (P < 0.01) groups compared with placebo at week 12. Overall, the incidence of adverse events (AEs) was similar between peficitinib and placebo. The most common AEs were urinary tract infection (n = 22 [6%]), upper respiratory tract infection (n = 16 [4%]), and diarrhea (n = 16 [4%]). There were 3 cases of herpes zoster infection (2 in the peficitinib 100 mg group and 1 in the 150 mg group) and 2 cases of serious infection (viral infection in the peficitinib 100 mg group and erysipelas in the 150 mg group). CONCLUSION The ACR20 response rate in the group receiving peficitinib 50 mg plus MTX was significantly different compared with the rate in patients receiving placebo, but there were no apparent dose-dependent responses, and the placebo response rate was high. Peficitinib plus MTX in patients with moderate-to-severe RA was well tolerated, with limited safety signals emerging.
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Efficacy and Safety of ABT-494, a Selective JAK-1 Inhibitor, in a Phase IIb Study in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate.
Genovese, MC, Smolen, JS, Weinblatt, ME, Burmester, GR, Meerwein, S, Camp, HS, Wang, L, Othman, AA, Khan, N, Pangan, AL, et al
Arthritis & rheumatology (Hoboken, N.J.). 2016;(12):2857-2866
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OBJECTIVE To evaluate the efficacy and safety of ABT-494, a selective JAK-1 inhibitor, in patients with moderate-to-severe rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX). METHODS Three hundred RA patients receiving stable doses of MTX were randomly assigned equally to receive immediate-release ABT-494 at 3, 6, 12, or 18 mg twice daily, 24 mg once daily, or placebo for 12 weeks. The primary efficacy end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 12, as determined using the last observation carried forward method. RESULTS At week 12, the proportion of ACR20 responses was higher with ABT-494 (62%, 68%, 80%, 64%, and 76% for the 3, 6, 12, 18, and 24 mg doses, respectively) than with placebo (46%) (using nonresponder imputation) (P < 0.05 for the 6, 12, and 24 mg doses). There was a significant dose-response relationship among all ABT-494 doses (P < 0.001). The proportions of patients achieving ACR50 and ACR70 responses were significantly higher for all ABT-494 doses (except the 12 mg dose for the ACR70 response) than for placebo, as were changes in the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP). Rapid improvement was demonstrated by significant differences in ACR20 response rates and changes in the DAS28-CRP for all doses compared with placebo at week 2 (the first postbaseline visit). The incidence of adverse events was similar across groups; most were mild, and infections were the most frequent. One serious infection (community-acquired pneumonia) occurred with ABT-494 at 12 mg. There were dose-dependent increases in high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, but the LDL cholesterol:HDL cholesterol ratios were unchanged through week 12. Mean hemoglobin levels remained stable at lower doses, but decreases were observed at higher doses. CONCLUSION This study evaluated a broad range of doses of ABT-494 in RA patients with an inadequate response to MTX. ABT-494 demonstrated efficacy, with a safety and tolerability profile similar to that of other JAK inhibitors.
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Effect of denosumab on Japanese patients with rheumatoid arthritis: a dose-response study of AMG 162 (Denosumab) in patients with RheumatoId arthritis on methotrexate to Validate inhibitory effect on bone Erosion (DRIVE)-a 12-month, multicentre, randomised, double-blind, placebo-controlled, phase II clinical trial.
Takeuchi, T, Tanaka, Y, Ishiguro, N, Yamanaka, H, Yoneda, T, Ohira, T, Okubo, N, Genant, HK, van der Heijde, D
Annals of the rheumatic diseases. 2016;(6):983-90
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OBJECTIVES To evaluate efficacy and safety of three different regimens of denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor kappa B (RANK) ligand (RANKL), for Japanese patients with rheumatoid arthritis (RA). METHODS In this multicentre, randomised, placebo-controlled phase II study, 350 Japanese patients with RA between 6 months and <5 years, stratified by glucocorticoid use and rheumatoid factor status, were randomly assigned to subcutaneous injections of placebo or denosumab 60 mg every 6 months (Q6M), every 3 months (Q3M) or every 2 months (Q2M). All patients basically continued methotrexate treatment and had a supplement of calcium and vitamin D throughout the study. The primary endpoint was change in the modified Sharp erosion score from baseline to 12 months. RESULTS Denosumab significantly inhibited the progression of bone erosion at 12 months compared with the placebo, and the mean changes of the modified Sharp erosion score at 12 months from baseline were 0.99, 0.27 (compared with placebo, p=0.0082), 0.14 (p=0.0036) and 0.09 (p<0.0001) in the placebo, Q6M, Q3M and Q2M, respectively. Secondary endpoint analysis revealed that denosumab also significantly inhibited the increase of the modified total Sharp score compared with the placebo, with no obvious evidence of an effect on joint space narrowing for denosumab. As shown in previous studies, denosumab increased bone mineral density. No apparent difference was observed in the safety profiles of denosumab and placebo. CONCLUSIONS Addition of denosumab to methotrexate has potential as a new therapeutic option for patients with RA with risk factors of joint destruction. TRIAL REGISTRATION NUMBER JapicCTI-101263.
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Association of Triple Therapy With Improvement in Cholesterol Profiles Over Two-Year Followup in the Treatment of Early Aggressive Rheumatoid Arthritis Trial.
Charles-Schoeman, C, Wang, X, Lee, YY, Shahbazian, A, Navarro-Millán, I, Yang, S, Chen, L, Cofield, SS, Moreland, LW, O'Dell, J, et al
Arthritis & rheumatology (Hoboken, N.J.). 2016;(3):577-86
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OBJECTIVE To evaluate long-term changes in cholesterol levels in patients with early rheumatoid arthritis (RA) who were randomized to begin treatment with methotrexate (MTX) monotherapy, MTX plus etanercept, or triple therapy (MTX plus sulfasalazine plus hydroxychloroquine) in the Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) trial. METHODS Levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol were analyzed in 416 patients participating in the TEAR trial, during 102 weeks of followup. Associations of cholesterol changes with disease activity and drug treatment were evaluated using repeated-measures analysis with mixed-effect linear models to model within-subject covariance over time. RESULTS Mixed-effect models controlling for traditional cardiovascular (CV) risk factors, TEAR treatment, and baseline prednisone and statin use demonstrated significant inverse associations of RA disease activity with changes in cholesterol over time. Decreases in the 28-joint Disease Activity Score, the C-reactive protein level, or the erythrocyte sedimentation rate were associated with increases in levels of HDL cholesterol, LDL cholesterol, and total cholesterol in all treatment groups (P < 0.001-0.035). Triple therapy was strongly associated with higher levels of HDL cholesterol, lower levels of LDL cholesterol, and higher ratios of total cholesterol:HDL cholesterol (P < 0.001 for all) compared to MTX monotherapy or MTX plus etanercept therapy over the 2-year followup. CONCLUSION Decreases in RA disease activity over long-term followup were associated with increases in cholesterol levels in patients with early RA treated with either biologic or nonbiologic therapies. The use of triple therapy during 2 years of followup was associated with higher HDL cholesterol levels, lower LDL cholesterol levels, and lower total cholesterol:HDL cholesterol ratios compared to those observed in patients who received MTX monotherapy or MTX plus etanercept combination therapy. Additional studies are needed to assess the effects of these cholesterol changes on CV events in patients with RA.
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VX-509 (Decernotinib), an Oral Selective JAK-3 Inhibitor, in Combination With Methotrexate in Patients With Rheumatoid Arthritis.
Genovese, MC, van Vollenhoven, RF, Pacheco-Tena, C, Zhang, Y, Kinnman, N
Arthritis & rheumatology (Hoboken, N.J.). 2016;(1):46-55
Abstract
OBJECTIVE To assess the efficacy and safety of decernotinib (VX-509), an oral selective inhibitor of JAK-3, in patients with rheumatoid arthritis (RA) in whom the response to methotrexate treatment was inadequate. METHODS In this 24-week, double-blind, randomized phase IIb study, 358 patients with active RA received either placebo (n = 71) or VX-509 at dosages of 100 mg/day (n = 71), 150 mg/day (n = 72), 200 mg/day (n = 72), or 100 mg twice daily (n = 72). Primary measures of efficacy at week 12 were the response rate according to the American College of Rheumatology 20% improvement criteria (ACR20) and change from baseline in the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP). RESULTS At week 12, the ACR20 response rates were 46.5%, 66.7%, 56.9%, and 68.1% in the groups receiving VX-509 at dosages of 100 mg/day, 150 mg/day, 200 mg/day, and 100 mg twice daily, respectively, and 18.3% in the placebo group (P < 0.001 for all comparisons). At week 12, the mean change from baseline in the DAS28-CRP was significantly greater in each VX-509 group compared with the placebo group (P < 0.001). Improvements were maintained at week 24, as shown by the ACR20, ACR50, and ACR70 response rates and mean change from baseline in the DAS28-CRP. The most common adverse event in the VX-509 group was headache (8.7%), and elevated levels of transaminases, lipoproteins, and creatinine were observed. CONCLUSION VX-509 significantly improved the signs and symptoms of RA at weeks 12 and 24 compared with the placebo group when it was administered in combination with methotrexate. Safety signals included infection and increases in liver transaminase and lipid levels.
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Sarilumab Plus Methotrexate in Patients With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate: Results of a Phase III Study.
Genovese, MC, Fleischmann, R, Kivitz, AJ, Rell-Bakalarska, M, Martincova, R, Fiore, S, Rohane, P, van Hoogstraten, H, Garg, A, Fan, C, et al
Arthritis & rheumatology (Hoboken, N.J.). 2015;(6):1424-37
Abstract
OBJECTIVE To evaluate the efficacy and safety of sarilumab in combination with methotrexate (MTX) for the treatment of rheumatoid arthritis (RA). METHODS Adults with moderate-to-severe RA and an inadequate response to MTX were randomized (1:1:1) to receive sarilumab (doses of 150 mg or 200 mg) or placebo every 2 weeks in conjunction with weekly MTX for 52 weeks. Co-primary end points were the proportion of patients achieving American College of Rheumatology 20% (ACR20) improvement responses at week 24, change from baseline in the Health Assessment Questionnaire (HAQ) disability index (DI) at week 16, and change from baseline in the modified Sharp/van der Heijde score (SHS) of radiographic damage at week 52. RESULTS Baseline characteristics were similar among the groups. For all 3 co-primary end points, the sarilumab 150 mg and 200 mg groups demonstrated statistically significant improvements as compared with the placebo group (ACR20 response rate at week 24, 58.0%, 66.4%, and 33.4%, respectively [P < 0.0001]; least squares mean change in HAQ DI at week 16, -0.53, -0.55, and -0.29, respectively [P < 0.0001]; and mean change in SHS at week 52, 0.90, 0.25, and 2.78, respectively [P < 0.0001]). The most common treatment-emergent adverse event was infection. In the sarilumab 150 mg, sarilumab 200 mg, and placebo groups, the incidence of serious infections was 2.6%, 4.0%, and 2.3%, respectively. Elevations in alanine aminotransferase levels >3-fold the upper limit of normal occurred in 9.5%, 8.0%, and 2.1% of patients, respectively; in 24 patients, this led to discontinuation of treatment. Elevated total cholesterol levels were observed in 36.8%, 43.0%, and 18.3% of patients, respectively. In patients receiving 150 mg and 200 mg sarilumab, neutrophil counts of 0.5 to <1.0 × 10(9) /liter were observed in 5.1% and 7.8% of patients, respectively, while neutrophil counts of <0.5 × 10(9) /liter were observed in 0.9% and 0.7% of patients, respectively; none of the patients receiving placebo experienced changes in neutrophil counts. CONCLUSION In RA patients treated with sarilumab (150 mg or 200 mg every 2 weeks) in combination with MTX, both doses provided sustained clinical efficacy, as shown by significant improvements in symptomatic, functional, and radiographic outcomes. Sarilumab was generally well tolerated. The adverse events observed in this study were consistent with the effects of interleukin-6 signaling blockade.
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Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial.
Machiels, JP, Haddad, RI, Fayette, J, Licitra, LF, Tahara, M, Vermorken, JB, Clement, PM, Gauler, T, Cupissol, D, Grau, JJ, et al
The Lancet. Oncology. 2015;(5):583-94
Abstract
BACKGROUND Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (HNSCC) progressing after first-line platinum regimens have a poor prognosis and few treatment options. Afatinib, an irreversible ERBB family blocker, has shown efficacy in a phase 2 study in this setting. We aimed to assess the efficacy and safety of afatinib compared with methotrexate as second-line treatment in patients with recurrent or metastatic HNSCC progressing on or after platinum-based therapy. METHODS In this open-label, phase 3, randomised controlled trial conducted in 101 centres in 19 countries, we enrolled patients aged 18 years or older with histologically or cytologically confirmed HNSCC that was recurrent, metastatic, or both who had progressed on or after first-line platinum-based therapy, were not amenable for salvage surgery or radiotherapy, and who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Previous treatment with more than one systemic regimen in this setting was not allowed; previous treatment with EGFR-targeted antibody therapy (but not EGFR-targeted tyrosine-kinase inhibitors) was allowed. We randomly assigned eligible patients in a 2:1 ratio to receive oral afatinib (40 mg/day) or intravenous methotrexate (40 mg/m(2) per week), stratified by ECOG performance status and previous EGFR-targeted antibody therapy for recurrent or metastatic disease. Randomisation was done centrally with an interactive voice or web-based response system. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. The primary endpoint was progression-free survival as assessed by an independent, central imaging review committee. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01345682. FINDINGS Between Jan 10, 2012, and Dec 12, 2013, we enrolled 483 patients and randomly assigned 322 to afatinib and 161 to methotrexate. After a median follow-up of 6·7 months (IQR 3·1-9·0), progression-free survival was longer in the afatinib group than in the methotrexate group (median 2·6 months [95% CI 2·0-2·7] for the afatinib group vs 1·7 months [1·5-2·4] for the methotrexate group; hazard ratio [HR] 0·80 [95% CI 0·65-0·98], p=0·030). The most frequent grade 3 or 4 drug-related adverse events were rash or acne (31 [10%] of 320 patients in the afatinib group vs none of 160 patients in the methotrexate group), diarrhoea (30 [9%] vs three [2%]), stomatitis (20 [6%] vs 13 [8%]), fatigue (18 [6%] vs five [3%]), and neutropenia (1 [<1%] vs 11 [7%]); serious adverse events occurred in 44 (14%) of afatinib-treated patients and 18 (11%) of methotrexate-treated patients. INTERPRETATION Afatinib was associated with significant improvements in progression-free survival and had a manageable safety profile. These findings provide important new insights into the treatment of this patient population and support further investigations with irreversible ERBB family blockers in HNSCC. FUNDING Boehringer Ingelheim.