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Maintenance Defactinib Versus Placebo After First-Line Chemotherapy in Patients With Merlin-Stratified Pleural Mesothelioma: COMMAND—A Double-Blind, Randomized, Phase II Study

Publication: Journal of Clinical Oncology

Abstract

Purpose

Inhibition of focal adhesion kinase has been shown to selectively kill mesothelioma cells that express low levels of moesin-ezrin-radixin-like protein (merlin). On this basis, we designed a randomized, phase II trial to investigate whether defactinib as maintenance therapy after standard first-line chemotherapy could improve progression-free survival (PFS) in patients with malignant pleural mesothelioma (MPM).

Methods

This global, double-blind, randomized, placebo-controlled trial was conducted in patients with advanced MPM and disease control after at least four cycles of first-line chemotherapy. Patients were stratified for merlin and then randomly assigned (in a 1:1 fashion) to receive either oral defactinib or placebo until disease progression, unacceptable toxicity, or withdrawal occurred. The coprimary end points were PFS and overall survival (OS). Quality of life (QoL) was assessed using the Lung Cancer Symptom Scale for Mesothelioma tool.

Results

Three hundred forty-four patients were randomly assigned to receive either defactinib (n = 173) or placebo (n = 171). The median PFS was 4.1 months (95% CI, 2.9 to 5.6 months) for defactinib versus 4.0 months (95% CI, 2.9 to 4.2 months) for placebo. The median OS was 12.7 months (95% CI, 9.1 to 21 months) for defactinib versus 13.6 months (95% CI, 9.6 to 21.2 months) for placebo (hazard ratio, 1.0; 95% CI, 0.7 to 1.4). Although shorter survival for both defactinib- and placebo-treated patients was observed, in the patients who had merlin-low MPM compared with the patients who had merlin-high MPM, there were no statistical differences in response rate, PFS, OS, or QoL between the treatment groups. The most common grade 3 or worse adverse events were nausea, diarrhea, fatigue, dyspnea, and decreased appetite.

Conclusion

Neither PFS nor OS was improved by defactinib after first-line chemotherapy in patients with merlin-low MPM. Defactinib cannot be recommended as maintenance therapy for advanced MPM.

Introduction

Malignant pleural mesothelioma (MPM) is an aggressive, incurable cancer that is the consequence of occupational and/or environmental asbestos exposure.1 Treatment options for MPM are limited, and combined pemetrexed with cisplatin is the only licensed therapy.2 Treatment is usually to a maximum of six cycles, and efficacy is limited; PFS is approximately 6 months. There is currently no approved maintenance treatment, nor is there any approved therapy upon disease progression.
Recently, addition of bevacizumab to chemotherapy has been reported to increase both overall survival (OS) and progression-free survival (PFS) compared with pemetrexed plus cisplatin alone; this study incorporated maintenance bevacizumab until progression occurred.3 Individual patient meta-analyses have repeatedly shown that disease control after initial chemotherapy correlates with longer survival.4 This suggests that targeted strategies could improve clinical outcomes.
Personalized treatment strategies for MPM have been underexplored. The somatic mutational landscape of MPM is characterized by a preponderance of common tumor suppressor losses that include NF2 (which encodes merlin),5,6 BAP-17 and CDKN2A.8-10 In preclinical studies, NF2 inactivation is associated with loss of merlin expression and with sensitivity to inhibition of focal adhesion kinase (FAK).11,12
FAK (also known as protein tyrokinase 2, or PTK2) is a FERM domain, containing focal adhesion associated kinase that is elevated in several cancers, and is involved in the spread of cellular adhesion and inhibition of apoptosis. Because the FAK-merlin synthetic lethal interaction has been demonstrated both in vitro and in vivo, it warrants clinical exploration.11,12 Given the frequent NF2 inactivation rate of approximately 50% in mesothelioma, it was hypothesized that FAK inhibition would be effective in this disease.
Defactinib is an orally bioavailable FAK inhibitor with an excellent safety and tolerability profile.13 Accordingly, a global, molecularly stratified, randomized, trial—COMMAND (ClinicalTrials.gov identifier: NCT01870609)—was undertaken to evaluate the efficacy of defactinib in patients with merlin-low MPM as maintenance therapy after standard first-line chemotherapy.

Methods

Study Design

This multicenter, double-blind, placebo-controlled, randomized, phase II trial enrolled patients from 72 study centers across 15 countries worldwide. Patients had unresectable MPM and had achieved either partial response or stable disease after standard chemotherapy with pemetrexed combined with either cisplatin or carboplatin. Patients were stratified by merlin status and then randomly assigned to either maintenance defactinib or placebo. It was hypothesized that patients with merlin-low disease would respond to defactinib better than those with merlin-high disease. To account for possible differential response, an adaptive enrichment design was used,14 whereby enrollment would be restricted to patients in the merlin-low stratum after an interim analysis that was based on PFS. A subsequent sample size re-estimation for the primary efficacy end point of OS was to be performed with the enrichment. The main purpose of the interim analyses was to establish whether prespecified criteria to trigger the adaptive enrichment of the merlin subpopulation were met or if the study should be stopped for futility.

Patients

Eligible patients had a histologically confirmed diagnosis of MPM with available biopsy material sufficient for determination of merlin status before enrolment. Patients ≥ 18 years of age with a Karnofsky performance status of 70% or greater (after palliative measures, such as pleural drainage) and a life expectancy of at least 3 months were required to have evaluable MPM as assessed by RECIST version 1.1. Eligible patients had to have completed only one prior chemotherapy regimen that consisted of pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2) or pemetrexed plus carboplatin (area under the curve [AUC] 5) repeated every 3 weeks, with evidence of disease control (confirmed partial response or stable disease), after four or more cycles.
All prior chemotherapy-associated toxicities had to resolve to grade 1 or less before random assignment, and the last dose of chemotherapy had to have been received within 6 weeks of the first dose of defactinib. Other inclusion criteria included adequate bone marrow, renal, and hepatic functions and a corrected QT interval (QTc) less than 470 ms, as calculated by the Fridericia correction formula.
Key exclusion criteria were: known uncontrolled or severe concurrent medical conditions (including brain metastases; cardiovascular or cerebrovascular disease; Gilbert syndrome; any active infections—including hepatitis A, B or C, or HIV; and a history of upper GI bleeding, ulceration, or perforation) within 12 months of receipt of defactinib.

Random Assignment and Masking

Random assignment (1:1) was performed centrally in a double-blind manner (Fig 1) to either defactinib or placebo. The random assignment was stratified by merlin status (high v low), as determined by centralized immunohistochemistry (IHC; Labcorp Clinical Trials; Los Angeles, CA) using the monoclonal antibody D1D8 (Cell Signaling Technologies, Danvers, MA) and Leica bond polymer refine detection kit (Thermo Fisher Scientific, Waltham, MA), per standard protocols. Positive and negative tissue controls and a negative reagent control were run with every IHC assay. The merlin IHC was read by pathology H-score (0 to 300 scale) for tumor cell merlin protein levels. On the basis of the comparability of 350 mesothelioma specimens co-evaluated by merlin IHC and NF2 fluorescent in situ hybridization (FISH), an H-score cutoff was delineated as merlin high (H-score, 151 to 300) and merlin low (H-score, 0 to 150).
Fig 1. Trial schema.
The random assignment process provided balance between treatment groups within each of the stratification categories. The total number of patients enrolled within a randomly assigned stratum was not restricted overall or by site.

Study Treatment

The initial dose of defactinib was 400 mg twice a day in continuous 21-day cycles until evidence of disease progression. Patients who reported unacceptable adverse effects of grade 3 or 4 neutropenia or thrombocytopenia could have their dosages reduced to 200 mg twice a day and continue at this dosage until disease progression or unacceptable toxicity occurred. If toxicity returned to grade 3 or greater, defactinib was discontinued. After the dose had been reduced, it was not re-escalated.
Clinical laboratory testing was performed at the investigational site before administration of defactinib, and data could be collected up to 24 hours beforehand. A 12-lead electrocardiogram was conducted at each scheduled clinic visit. Blood samples for pharmacokinetics were taken at the week-4 visit immediately before administration (in the clinic to ensure accuracy of collection time points) and then at 1 and 4 hours after defactinib. At week 7, this sampling was repeated before administration and then 2 and 6 hours after the dose. Finally, at weeks 10 and 13, sampling was conducted immediately before administration of defactinib.

Outcome Measures

Mesothelioma burden was assessed via computed tomography scan at baseline within 28 days of defactinib administration and every 6 weeks. The burden also was centrally assessed by RECIST version 1.1 for the first 25 weeks and every 8 weeks thereafter.
PFS was calculated for all patients from the date of random assignment to the date of radiologic progression, which was defined in the target lesions as at least a 20% increase in the sum of the target lesion measurements compared with the smallest sum during the study (including at baseline). For nontarget lesions, unequivocal progression was evaluated as a whole regardless of the status of target lesions. For PFS, patients who had not had disease progression or whose disease was not evaluable at the interim or final analyses were censored on the date of last evaluation by a central reading of images.
OS was calculated for all patients from the date of random assignment to the date of death. Patients who were still alive at the time of analysis or who dropped out before the end of the study were censored at the day they were last known to be alive. Adverse events were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03.

Quality-of-Life Analysis

QoL was measured using the lung cancer symptom scale–mesothelioma (LCSS-Meso) tool, which included a patient scale and a health care professional observer scale. Secondary efficacy analyses were based on the patient scale only. Formal efficacy analyses with the health care professional observer scale were not performed.

Statistical Analysis

The primary analyses of PFS and OS were based on the stratified log-rank test, and Kaplan-Meier methods were used for estimation of summary statistics. Hypothesis tests were performed in a sequential manner to avoid the need to adjust type-I error rates for multiplicity but with the requisite restrictions on claims of significance, for which a statistically significant improvement in PFS must be observed to warrant a subsequent, formal efficacy analysis of OS.
Given an assumed median OS of 12 months for placebo versus 16.1 months for defactinib, which would correspond to a hazard ratio of 0.7, 372 events were required to assess superiority of survival with 80% power and a one-sided type-I error rate of .025. If patients were accrued over 24 months, a sample size of 372 patients (with a maximum of 256 PFS events), would provide 90% power to assess the second primary efficacy end point of PFS with a one-sided type-I error rate of .025, given a median PFS of 4 months for placebo and a median PFS of 6 months for defactinib, and if 15% of patients was not evaluable.
Two interim analyses were planned—the first was an initial PFS analysis to determine whether to enrich the sample and the second was to perform sample size re-estimation for OS. The first interim analysis was planned for when half of the maximum PFS events were observed (128 of a maximum of 256 events). Planned decision rules about whether to continue or enrich the sample for the remainder of the study were based on conditional power (defined as the probability of observing a significant result at the end of the study on the basis of the results observed at the interim) for the log-rank test to assess PFS in the full sample enrolled to that point (both overall and in the low-merlin expression group). On the basis of the results, the study would fall into one of four categories at the interim analysis—futile, unfavorable, enrich, or favorable. If the conditional power in the full sample was less than 10%, the study was categorized as futile.
A sensitivity analysis was performed on OS, and patients who received any chemotherapy during follow-up were censored. Kaplan-Meier methods were used, and patients were censored at the first date of chemotherapy after the end of study drug administration. Additional exploratory Cox models were used to determine the effect of other prognostic factors overall and within low- and high-merlin expression strata.
Exploratory Cox models also were used to determine the effect of other potential prognostic factors, including sex, age, histology, and prior surgery. The additional exploratory Cox models were used to determine the effect of other prognostic factors overall and within low- and high-merlin expression strata.
The LCSS-Meso total score was analyzed through a comparison of median AUC between the two treatment groups using a Wilcoxon test. The average AUC for each patient was computed as the sum of the AUC of LCSS-Meso total scores divided by the total number of days between the first and last LCSS-Meso total scores recorded.

Results

Between September 25, 2013, and December 4, 2015 a total of 449 patients were screened, and 344 patients were randomly assigned to receive defactinib or placebo (Fig 1). Of 173 patients who received defactinib, 101 and 72 patients were designated to the merlin-high and merlin-low strata, respectively. Of 171 patients randomly assigned to the placebo group, 100 and 71 patients were designated to the merlin-high and merlin-low strata, respectively. Overall, the most common reason for termination of study drug was disease progression (n = 213; 62%). The study was closed after the first interim analysis by the drug safety monitoring board. Ninety-five patients (28%) terminated study drug administration because of closure of the study. One hundred thirteen patients (33%) died before the termination of the study.
The demographic and baseline characteristics were similar between the defactinib and placebo groups (Table 1). Overall, 84% of patients were men. Patients ranged in age from 33 to 87 years, and the overall median age was 68 years. The majority of patients (96%) had a baseline Karnofsky performance score of 80 to 100.
Table 1. Baseline Demographics and Clinical Characteristics
Overall, patient characteristics were comparable between the defactinib and placebo groups (Table 1). The majority of patients (64%) had TNM stage III or IV disease at baseline. The lung was the most frequently reported location of metastatic disease in both groups (n = 16; 4.7%). Of 263 patients for whom histologic subtype was available, the histologies between the defactinib arm (epithelioid, 82.5%; biphasic, 9.5%; sarcomatoid, 8.0%) and placebo arm (epithelioid, 83.9%; biphasic, 9.5%; sarcomatoid, 6.6%) were similarly distributed.
There were no notable differences between the defactinib and placebo groups in prior treatments or surgeries. A total of 54% of patients had received chemotherapy with pemetrexed plus cisplatin, and 46% received pemetrexed plus carboplatin. Fifty-six patients in each treatment group (33% overall) had prior surgery, and 16% had received prior radiation therapy.
The mean duration of exposure to the study drug was 108 days in the defactinib group and was 117 days in the placebo group. The mean number of cycles started was similar in both groups (5.8 and 6.2 cycles, respectively). Compliance with study drug administration was approximately 96% in both treatment groups. Missed doses and dose interruptions were uncommon, and there was only one dose reduction in the defactinib group.

Efficacy

The median PFS was similar in both treatment groups (Fig 2). In the defactinib arm, the median PFS was 4.1 months (95% CI, 2.9 to 5.6 months); it was 4.5 and 2.8 months for patients who had merlin-high and merlin-low disease, respectively. Similarly, in the placebo arm, the median PFS was 4.0 months (95% CI, 2.9 to 4.2 months); it was 4.5 and 2.8 months for patients who had merlin-high and merlin-low disease, respectively.
Fig 2. Progression-free survival (PFS).
The median OS was similar in the defactinib (12.7 months; 95% CI, 9.1 to 21 months) and placebo (13.6 months; 95% CI, 9.6 to 21.2 months) groups (hazard ratio, 1.0; 95% CI, 0.7 to 1.4; Fig 3). The median OS for patients who had merlin-high disease was not reached in the defactinib group and was 16.6 months in the placebo group. In those who had merlin-low disease, the median OS was 9.0 months in the defactinib group and was 9.5 months in the placebo group. The Kaplan-Meier curve for OS is shown in Figure 3.
Fig 3. Overall survival (OS: intent-to-treat population).
At the time of the planned interim analysis (n = 128 events), the median PFS was 3.9 months in the defactinib group and was 3.2 months in the placebo group. On the basis of these results, the probability of observing a significant result at the end of the study was less than 0.10, and the study was stopped for futility. In the final analysis, the median PFS was approximately 4 months in both the defactinib and placebo groups. The median OS was also similar in the defactinib (12.7 months) and placebo (13.6 months) groups.
The best overall response observed was partial, which was reported for seven patients (4.0%) in the defactinib group and five patients (2.9%) in the placebo group. The majority of patients in both groups had a best overall response of stable disease: 101 patients (58.4%) in the defactinib group and 104 patients (60.8%) in the placebo group. The difference in best overall response between groups was not statistically significant (P = .5).
Global QoL, as well as pain and dyspnea scores, were similar between the defactinib and placebo groups at baseline and at all on-study visits. In both treatment groups, the overall QoL score was approximately 77 (in which 0 is the highest and 100 is the lowest intensity of symptoms); the overall difference between treatment groups was not statistically significant (P = .7).

Toxicity

Defactinib was generally well tolerated (Table 2). The majority of patients, including 161 (93%) in the defactinib group and 139 (81%) in the placebo group, experienced at least one treatment-related adverse effect (TRAE). The incidence of severe adverse events was similar between treatment groups and the most commonly reported severe adverse event (SAE) was disease progression. The most commonly reported TRAEs in the defactinib group were nausea, diarrhea, fatigue, dyspnea, and decreased appetite. These TRAEs were also among the most frequent in the placebo group, as was the incidence of peripheral edema, arthralgia, and hyperbilirubinemia.
Table 2. Treatment-Related Adverse Events
In both treatment groups, most TRAEs were mild or moderate in severity. No grade 3 or greater TRAE was reported in more than 5% of patients in either treatment group. SAEs, including death, were reported in 19 patients (11.0%) in the defactinib group and in 13 patients (7.6%) in the placebo group. In the defactinib group, the only SAE reported in more than one patient was MPM progression (n = 4; 2.3%). In the placebo group, atrial fibrillation was the only SAE reported in more than one patient (n = 2; 1.2%). Study drug–related SAEs in the defactinib group included congestive cardiac failure, syncope, pneumonia, electrocardiogram QT prolongation, musculoskeletal chest pain, and renal failure (each reported in one patient); in the placebo group, diarrhea, nausea, lung infection, influenza-like illness, and vena cava thrombosis each were reported in one patient. A total of seven patients (2.0%) had treatment-emergent adverse events that led to death, including six patients (3.5%) in the defactinib group and one patient (0.6%) in the placebo group. For five of these patients in the defactinib group and for the one patient in the placebo group, the death was a result of disease progression or metastases and was considered unrelated to study drug.

Discussion

In this randomized study, the first to our knowledge to investigate a molecularly stratified switch maintenance treatment strategy for MPM, defactinib did not improve either OS or PFS compared with placebo in patients who had experienced response to first-line chemotherapy. Previously, a randomized, phase II study of thalidomide maintenance failed to show an improvement in clinical outcome.15
Molecularly stratified therapy for mesothelioma is a potentially promising approach to improve outcomes for this aggressive cancer, but the approach is currently in its infancy.16 Recent clinical trials, such as a proof-of-concept study that demonstrated efficacy of arginine deprivation therapy in arginine-succinate synthetase–deficient MPM, suggests that synthetic lethal approaches may be tractable in mesothelioma.17,18
Clinical support for a potential correlation between merlin expression and PFS in a phase I study of the FAK inhibitor GSK2256098 was recently reported. In 29 patients with recurrent mesothelioma, this study suggested a trend to longer PFS in patients with merlin-low (23.4 weeks) versus merlin-positive (11.3 weeks) mesothelioma.19 However, this analysis was retrospective and exploratory, in contrast to the COMMAND trial. Promising in vitro and in vivo preclinical data implicated both the selective targeting of cancer stem cells via FAK inhibition and a synthetic lethal interaction between loss of merlin/NF2 inactivation with FAK inhibition.11,12,20,21 The COMMAND trial failed to confirm merlin expression as a predictive biomarker of defactinib efficacy—the study was underpowered for this analysis because of its termination. Subgroup analysis did not reveal any trends toward specific subgroup benefit.
Loss of merlin protein expression was associated with worse OS. This observation is consistent with genetically modified mouse models that demonstrated NF2 inactivation as a driver of mesothelioma aggressiveness,22 which may be augmented by commutation of LATS2.23 The causal relationship between FAK and merlin expression is poorly defined, but evidence exists of induced silencing of merlin is unable to recapitulate the sensitivity of intrinsic merlin-low ovarian carcinoma cell lines to FAK inhibition.24 KRAS has been proposed as a sensitizing mutation for FAK, in the context of CDKN2A mutation, and this has been explored clinically in KRAS-mutant non–small-cell lung cancer with evidence of clinical activity (ClinicalTrials.gov identifier: NCT01778803).25 In other tumor types, FAK and NF2 may be more directly associated. The National Cancer Institute MATCH (ClinicalTrials.gov identifier: NCT02465060) phase II study is currently underway to evaluate whether defactinib benefit is associated with NF2 mutation or loss in a variety of solid tumor types.
Recent insights into the role of FAK and consequences of its inhibition in cancer have been reported that might shed light on why this study was negative. Nuclear FAK creates an immunosuppressive tumor microenvironment by inhibiting cytotoxic CD8+ T-cell activity through its upregulation of chemokine transcription that drives immunosuppressive regulatory T-cell recruitment.26 FAK deficiency (eg, by small-molecule inhibition of FAK) promotes tumor regression in an immunocompetent host setting by a mechanism dependent on CD8+ T cells. However, enhancement of CD8+ T-cell recruitment and activation can be blocked by expression of the programmed death ligand 1 immune checkpoint, which is expressed in MPMs.27,28 One hypothesis to explain this negative trial result is that the immunosuppressive, postchemotherapy context may be antagonistic to defactinib. Indeed, studies have reported upregulation of programmed death ligand 1 after chemotherapy,29 which could potentially block defactinib-induced CD8+ T-cell anticancer effects. This hypothesis is supported by early data that show promising defactinib monotherapy activity in mesothelioma when administered in the chemotherapy-naïve, neoadjuvant setting.30 On the basis of the synergistic interaction between FAK and programmed death 1 inhibition,27 a phase I/II trial is now underway to evaluate an anti–programmed death 1 therapy (pembrolizumab) in combination with defactinib in patients with relapsed mesothelioma (ClinicalTrials.gov identifier: NCT02758587). In summary, maintenance defactinib after first-line chemotherapy cannot be advised in patients with mesothelioma.
Clinical trial information: NCT01870609.

Authors' Disclosures of Potential Conflicts of Interest

Maintenance Defactinib Versus Placebo After First-Line Chemotherapy in Patients With Merlin-Stratified Pleural Mesothelioma: COMMAND—A Double-Blind, Randomized, Phase II Study

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.

Dean A. Fennell

Honoraria: Bristol-Myers Squibb, Bayer, Lilly, Boehringer Ingelheim, Clovis Oncology, MSD Oncology
Consulting or Advisory Role: Bristol-Myers Squibb, Lilly, MSD Oncology, Roche, Clovis Oncology
Speakers' Bureau: Boehringer Ingelheim
Research Funding: Boehringer Ingelheim (Inst), Bayer, Astex Pharmaceuticals, Fuji Pharma (Inst), Lab21 (Inst)
Travel, Accommodations, Expenses: Bristol-Myers Squibb, MSD Oncology

Paul Baas

Honoraria: Bristol-Myers Squibb
Consulting or Advisory Role: Merck Sharp & Dohme (Inst), Bristol-Myers Squibb (Inst)
Research Funding: Bristol-Myers Squibb (Inst), Merck Sharp & Dohme (Inst)
Travel, Accommodations, Expenses: Merck Sharp & Dohme, Bristol-Myers Squibb
Other Relationship: Bristol-Myers Squibb

Paul Taylor

Travel, Accommodations, Expenses: MSD Oncology, Pierre Fabre, Merck

Anna K. Nowak

Consulting or Advisory Role: Bayer, AstraZeneca, Sellas Life Sciences, Trizell, Boehringer Ingelheim, Epizyme, Roche, Merck Sharp & Dohme, Douglas Pharmaceuticals
Research Funding: AstraZeneca (Inst)
Travel, Accommodations, Expenses: AstraZeneca, Boehringer Ingelheim

Jonathan A. Pachter

Employment: Verastem

David T. Weaver

Employment: Verastem, Agios (I)
Stock or Other Ownership: Verastem, Agios (I)
Patents, Royalties, Other Intellectual Property: Verastem, Agios (I), Ovasciences, Daiamed

Arnaud Scherpereel

Consulting or Advisory Role: MSD Oncology, Roche, Bristol-Myers Squibb, Boehringer Ingelheim, AstraZeneca, MedImmune
Research Funding: Bristol-Myers Squibb (Inst)
Travel, Accommodations, Expenses: MSD Oncology, Roche, Bristol-Myers Squibb

Nick Pavlakis

Honoraria: Roche, Genentech, Pfizer, Novartis, Ipsen
Consulting or Advisory Role: Pfizer, Roche, Ipsen, AstraZeneca, Novartis, Boehringer Ingelheim, Merck Serono, Merck KGaA, Merck Sharp & Dohme, Bristol-Myers Squibb
Research Funding: Bayer (Inst), Pfizer, Roche, Bristol-Myers Squibb, Ipsen, Boehringer Ingelheim

Jan P. van Meerbeeck

Research Funding: AstraZeneca (Inst)
Travel, Accommodations, Expenses: Roche

Susana Cedrés

Consulting or Advisory Role: Bristol-Myers Squibb, Lilly, Boehringer Ingelheim, Roche
Research Funding: Merck Serono (Inst)
Travel, Accommodations, Expenses: Pfizer

Luke Nolan

Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb
Speakers' Bureau: Bristol-Myers Squibb
Travel, Accommodations, Expenses: Bristol-Myers Squibb, Amgen

Hedy Kindler

Consulting or Advisory Role: Aduro Biotech, MedImmune, Bayer, Celgene, GlaxoSmithKline, AstraZeneca, Merck, Bristol-Myers Squibb, Boehringer Ingelheim, Ipsen, Erytech Pharma, Five Prime Therapeutics, Paredox Therapeutics, Kyowa Kirin, Aldeyra Therapeutics
Research Funding: Adura Biotech, AstraZeneca, Bayer, GlaxoSmithKline, Merck, MedImmune, Verastem, Bristol-Myers Squibb, Lilly, Polaris, Deciphera

Joachim G.J.V. Aerts

Stock or Other Ownership: Amphera
Consulting or Advisory Role: Bristol-Myers Squibb, MSD Oncology, Roche, AstraZeneca, Eli Lilly, Amphera, Takeda
Patents, Royalties, Other Intellectual Property: Tumor cell lysate in immunotherapy (Inst); SNP associated with adverse events and clinical activity in PD-1 treated patients with NSCLC (Inst); Kinase activity profiles for predicting NSCLC response to therapy (Inst)
Travel, Accommodations, Expenses: Bristol-Myers Squibb, MSD Oncology
No other potential conflicts of interest were reported.

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Information & Authors

Information

Published In

Journal of Clinical Oncology
Pages: 790 - 798
PubMed: 30785827

History

Published online: February 20, 2019
Published in print: April 01, 2019

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Authors

Affiliations

Dean A. Fennell, FRCP [email protected]
University of Leicester, Leicester, United Kingdom
Paul Baas, MD
Netherlands Cancer Institute, Amsterdam, the Netherlands
Paul Taylor, MD
Wythenshawe Hospital, Manchester, United Kingdom
Anna K. Nowak, MD
University of Western Australia and Sir Charles Gairdner Hospital, Perth, WA, Australia
David Gilligan, MD
Cambridge University Hospitals National Health Service Foundation Trust, Addenbrooke’s Hospital, Cambridge, United Kingdom
Takashi Nakano, MD
Hyogo College of Medicine, Hyogo, Japan
Jonathan A. Pachter, PhD
David T. Weaver, PhD
Arnaud Scherpereel, MD
Calmette Hospital, Regional University Hospital of Lille, Lille Cedex, France
Nick Pavlakis, MD
Northern Cancer Institute, St Leonards, NSW, Australia
Jan P. van Meerbeeck, MD
Universitair Ziekenuis, Antwerp, Belgium
Susana Cedrés, PhMD
Karolinska University Hospital, Stockholm, Sweden
Luke Nolan, MD
University Hospital, Southampton, United Kingdom
Hedy Kindler, MD
University of Chicago Medical Center, Chicago, IL
Joachim G.J.V. Aerts, MD
Erasmus Medical College, Rotterdam, the Netherlands
Vall d’Hebron University Hospital, Barcelona, Spain

Notes

Dean A. Fennell, FRCP, University of Leicester and University Hospitals of Leicester NHS Trust, Robert Kirkpatrick Clinical Sciences Building, Leicester, LE1 5WW United Kingdom; e-mail: [email protected].

Author Contributions

Conception and design: Dean Fennell, Paul Baas, Jonathan A. Pachter, Anna K. Nowak, David T. Weaver, Hedy Kindler
Provision of study materials or patients: All authors
Collection and assembly of data: All authors
Data analysis and interpretation: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors

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Dean A. Fennell, Paul Baas, Paul Taylor, Anna K. Nowak, David Gilligan, Takashi Nakano, Jonathan A. Pachter, David T. Weaver, Arnaud Scherpereel, Nick Pavlakis, Jan P. van Meerbeeck, Susana Cedrés, Luke Nolan, Hedy Kindler, Joachim G.J.V. Aerts
Journal of Clinical Oncology 2019 37:10, 790-798

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