KRAS mutations in non-small-cell lung cancer (NSCLC) are associated with poor prognosis. Trametinib, a selective inhibitor of MEK1/MEK2, demonstrated similar efficacy to docetaxel in patients with advanced KRAS-mutant NSCLC, with median progression-free survival of 12 and 11 weeks, respectively. With moderate activity as a monotherapy, trametinib-based combination regimens may show improve efficacy.
Keywords: trametinib, MEK inhibitor, docetaxel, NSCLC, KRAS, progression-free survival
Abstract
Background
KRAS mutations are detected in 25% of non-small-cell lung cancer (NSCLC) and no targeted therapies are approved for this subset population. Trametinib, a selective allosteric inhibitor of MEK1/MEK2, demonstrated preclinical and clinical activity in KRAS-mutant NSCLC. We report a phase II trial comparing trametinib with docetaxel in patients with advanced KRAS-mutant NSCLC.
Patients and methods
Eligible patients with histologically confirmed KRAS-mutant NSCLC previously treated with one prior platinum-based chemotherapy were randomly assigned in a ratio of 2 : 1 to trametinib (2 mg orally once daily) or docetaxel (75 mg/m2 i.v. every 3 weeks). Crossover to the other arm after disease progression was allowed. Primary end point was progression-free survival (PFS). The study was prematurely terminated after the interim analysis of 92 PFS events, which showed the comparison of trametinib versus docetaxel for PFS crossed the futility boundary.
Results
One hundred and twenty-nine patients with KRAS-mutant NSCLC were randomized; of which, 86 patients received trametinib and 43 received docetaxel. Median PFS was 12 weeks in the trametinib arm and 11 weeks in the docetaxel arm (hazard ratio [HR] 1.14; 95% CI 0.75–1.75; P = 0.5197). Median overall survival, while the data are immature, was 8 months in the trametinib arm and was not reached in the docetaxel arm (HR 0.97; 95% CI 0.52–1.83; P = 0.934). There were 10 (12%) partial responses (PRs) in the trametinib arm and 5 (12%) PRs in the docetaxel arm (P = 1.0000). The most frequent adverse events (AEs) in ≥20% of trametinib patients were rash, diarrhea, nausea, vomiting, and fatigue. The most frequent grade 3 treatment-related AEs in the trametinib arm were hypertension, rash, diarrhea, and asthenia.
Conclusion
Trametinib showed similar PFS and a response rate as docetaxel in patients with previously treated KRAS-mutant-positive NSCLC.
Clinicaltrials.gov registration number
introduction
Major advances in the understanding of the molecular pathology of lung cancer have led to the clinical success and use of targeted agents, for specific genetically defined subsets, including non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor gene (EGFR) mutation (gefitinib, erlotinib, and afatinib) and anaplastic lymphoma kinase gene (ALK) rearrangement (crizotinib). EGFR mutations are found in 8%–10% of Caucasians, but in a higher proportion of East Asians; echinoderm microtubule-like protein 4 (EML4)-ALK translocation occurs in ∼5% of lung adenocarcinoma [1]. In contrast, KRAS mutations are detected in 25% of lung adenocarcinomas but with limited therapeutic progress in this population [2–4]. KRAS mutations correlate with reduced survival in NSCLC and are associated with resistance to EGFR tyrosine kinase inhibitors [2, 5–11]. Currently, no targeted therapies for KRAS-mutant NSCLC are approved and few trials have specifically addressed this population, limiting options to second-line treatment with single-agent pemetrexed (in non-squamous lung cancer) or docetaxel [2, 7–10, 12].
The mitogen-activated protein kinase (MAPK) pathway is critical to the pathogenesis in many human cancers, and signals through MEK1/2, which phosphorylates and activates ERK1/2. Trametinib (GSK1120212), an oral, reversible, highly selective allosteric inhibitor of MEK1/2 activation and kinase activity, showed preclinical activity in KRAS-mutant NSCLC lines [13–15]. Clinical monotherapy activity was observed in a first-in-human trial in KRAS-mutant NSCLC patients (partial response [PR]: 7% [2/30]; stable disease: 53% [16/30]); and dose-dependent changes in pERK, Ki67, and p27 on tumor tissues were noted [16]. Based on preclinical and encouraging early clinical findings with trametinib in NSCLC, we conducted a randomized phase II trial comparing trametinib with docetaxel as second-line therapy in previously-treated KRAS-mutant NSCLC.
patients and methods
patient selection
Eligible patients were ≥18 years of age with histologically or cytologically confirmed adenocarcinoma stage IV NSCLC with a positive mutational status for KRAS, NRAS, BRAF, or MEK1, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 and 1 [17]. Patients must have received only one prior approved platinum-containing chemotherapy regimen for advanced stage/metastatic NSCLC and had measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST) [18]. Adequate bone marrow, renal, liver, and cardiac (LVEF ≥ LLN) functions were required. Patients were ineligible if they had received any previous treatment with a BRAF or MEK inhibitor or a docetaxel-containing regimen, were at risk of retinal vein occlusion or central serous retinopathy, and any brain metastasis. Patients provided written informed consent, and the protocol was approved by local ethics committees. This study (NCT01362296) was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki.
randomization and masking
This was an open-label, multicenter, randomized phase II study comparing the efficacy and safety of trametinib with docetaxel as second-line treatment in patients with advanced or metastatic NSCLC harboring a KRAS mutation who failed one prior platinum-containing chemotherapy regimen. Additionally, an exploratory subset of patients with NSCLC harboring non-KRAS mutations (NRAS, BRAF, and MEK1) was randomized to understand the potential effect of trametinib in this population. Patients were randomly assigned in a 2 : 1 ratio to trametinib 2 mg orally once daily or docetaxel 75 mg/m2 i.v. every 3 weeks until disease progression, death, or unacceptable toxic effects occurred. Randomization was stratified by mutational status (KRAS versus NRAS/BRAF/MEK1 mutation) and sex. Patients were allowed to crossover to the alternative treatment at disease progression following an appropriate washout period.
assessments
KRAS/BRAF/NRAS/MEK1 mutational status in tumor tissue was analyzed using allele-specific polymerase chain reaction (PCR) in a local Clinical Laboratory Improvement Amendments (CLIA)-certified or equivalent laboratory (supplementary Table S1, available at Annals of Oncology online). Patients with unknown mutational status had tissue biopsies submitted for testing at screening.
Patients underwent laboratory testing, medical history, and physical examination, including ophthalmologic and cardiac assessments, within 14 days of treatment initiation. During study treatment, laboratory assessments were carried out on days 1, 8, and 15 of cycle 1 and then day 1 of every cycle thereafter. An echocardiogram or a Multi-Gated Acquisition Scan (MUGA) was carried out on day 1 of cycle 1, and then electrocardiography scans (ECGs; 12-lead) and echocardiograms or MUGA were carried out every 9 weeks thereafter. Pharmacokinetic (PK) blood sampling was obtained within time windows (e.g. 2–4 h) on day 15 of cycle 1 and pre-dose on day 1 of cycles 2 through 4.
Disease assessments were carried out at baseline and every 6 weeks until progression. Patients discontinuing study treatment before disease progression continued disease assessments every 12 weeks until progression or initiation of alternate anticancer therapy. Safety assessments were carried out throughout the study, and adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE). The dose-reduction algorithm in the study allowed for trametinib: 1.5 mg once daily, 1.0 mg once daily, and no more than two trametinib reductions were allowed. Separate dose modification guidelines and stopping criteria were present for docetaxel.
statistical analysis
The primary end point was progression-free survival (PFS), and the secondary end points included safety and tolerability, response rate, duration of response, overall survival (OS), and steady-state PKs of trametinib. The modified intent-to-treat (mITT) population comprised all randomized patients with KRAS mutation-positive NSCLC regardless of whether or not treatment was received and was the primary population for the analysis of patient demographics and efficacy data. The ITT population comprised of all randomized patients, including those with NRAS/BRAF/MEK1 mutations, regardless of whether or not treatment was administered and are included in the safety analysis. This trial compared PFS between treatment with a 90% power and one-sided alpha of 0.025 to detect a 50% reduction in risk of progression or death (corresponding to a hazard ratio [HR] of 0.5) in patients receiving trametinib compared with patients receiving docetaxel (median PFS of 4 versus 2 months). A formal interim analysis was planned at the time 50% of events occurred to assess efficacy and safety. The stopping boundary for futility was P ≥ 0.2056 (HR >0.8031) for the comparison of PFS.
PFS and OS were summarized using Kaplan–Meier estimates for median and quartiles, and compared between treatments using a stratified log-rank test (stratifying for sex). Tumor response (confirmed or unconfirmed response) was based on investigator assessment of target and non-target lesions using computed tomography (CT) or magnetic resonance imaging (MRI). Fisher's exact test was used to compare response rates between treatments, and the Kaplan–Meier method to calculate medians and quartiles for the duration of response. Summary statistics for trametinib plasma concentrations were reported by visit and time. A statistical reporting and analysis plan was written and approved before any analyses carried out by GlaxoSmithKline. All authors reviewed the data analyses and results presented.
results
patient characteristics
Between September 2011 and July 2012, 134 patients were randomly assigned to trametinib (N = 89) or docetaxel (N = 45). All, but five patients, had KRAS-mutant NSCLC (Table 1) and were included in the mITT population. These five patients had NRAS (N = 1) or BRAF (N = 4) mutations. Four patients, two in each treatment arm, were randomly assigned, but did not receive a dose of study treatment; two patients withdrew consent, one patient was randomized in error and the remaining patient was lost to follow-up (Figure 1). For the mITT population, demographic and disease characteristics were generally well balanced between the treatment arms (Table 1). The majority of patients were white (84%), male (53%), and had an ECOG performance status of 1 (74%). KRAS G12C was the most common subtype of KRAS mutation in both arms consistent with prior studies [19]. All patients received one prior platinum-containing chemotherapy regimen (supplementary Table S2, available at Annals of Oncology online). Approximately, half of the patients underwent prior surgery; however, more patients receiving trametinib had prior radiotherapy (37%) or surgery (58%) compared with docetaxel (21% and 44%, respectively).
Table 1.
Patient demographics and disease characteristics
| Characteristicsa | Trametinib (N = 86) | Docetaxel (N = 43) |
|---|---|---|
| Age (years) | ||
| Median (range) | 63.0 (40–79) | 63.0 (34–79) |
| Sex, n (%) | ||
| Female | 40 (47) | 20 (47) |
| Male | 46 (53) | 23 (53) |
| Race, n (%) | ||
| White | 74 (87) | 34 (79) |
| Asian | 8 (9) | 9 (21) |
| Other | 4 (4) | 0 |
| Smoking history, n (%) | ||
| Never-smoked | 6 (7) | 7 (16) |
| Current smoker | 13 (15) | 13 (30) |
| Former smoker | 67 (78) | 23 (53) |
| Baseline LDH, IU/l | ||
| Median (range) | 211.0 (124–1297) | 200.0 (114–429) |
| Prior therapies, n (%) | ||
| Chemotherapy | 86 (100) | 43 (100) |
| Surgery | 50 (58) | 19 (44) |
| Radiotherapy | 32 (37) | 9 (21) |
| Biologic therapy | 5 (6) | 2 (5) |
| Immunotherapy | 3 (3) | 0 |
| Small molecule-targeted therapy | 2 (2) | 1 (2) |
| ECOG performance statusb, n (%) | ||
| 0 | 25 (29) | 8 (19) |
| 1 | 61 (71) | 34 (79) |
| 2 | 0 | 1 (2) |
| Histology, n (%) | ||
| Adenocarcinoma | 85 (99) | 42 (98) |
| Adenosquamous carcinoma—predominantly squamous | 0 | 1 (2) |
| Other | 1 (1) | 0 |
| Histological grade, n (%) | ||
| Grade cannot be assessed | 48 (56) | 18 (42) |
| Well differentiated | 11 (13) | 4 (9) |
| Moderately differentiated | 9 (10) | 7 (16) |
| Poorly differentiated | 13 (15) | 11 (26) |
| Undifferentiated | 3 (3) | 3 (7) |
| Mutation type, n (%) | 89 | 45 |
| KRAS | ||
| G12A | 13 (15) | 8 (18) |
| G12C | 31 (35) | 18 (40) |
| G12D | 13 (15) | 6 (13) |
| G12F | 2 (2) | 0 |
| G12R | 4 (4) | 0 |
| G12V | 16 (18) | 8 (18) |
| G13C | 4 (4) | 2 (4) |
| G13D | 2 (2) | 1 (2) |
| Non-KRAS | ||
| NRAS | 0 | 1 (2) |
| BRAF | 3 (3) | 1 (2) |
| Unknown | 1 (1) | 0 |
aThere were no significant differences between the two groups at baseline.
bOn the ECOG scale, a performance status of 0 indicates that the patient is fully active and able to carry on all predisease activities without restriction, and a status of 1 indicates that the patient is restricted in physically strenuous activity, but is ambulatory and able to carry out work of a light or sedentary nature, such as light housework or office work.
ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase.
Figure 1.
CONSORT diagram. AE, adverse event; ITT, intent-to-treat; mITT, modified intent-to-treat; PD, progressive disease; PFS, progression-free survival.
treatment
The median duration of trametinib treatment was 8.4 weeks (range: 0.6–44.7 weeks). The median duration of docetaxel treatment was 10 weeks (range: 3.0–30.0 weeks). Due to disease progression, 55 (63%) patients discontinued trametinib, and 18 patients (21%) discontinued due to AEs. The most common AEs (occurred in ≥2 patients each) leading to permanent discontinuation were dyspnea, decreased ejection fraction, nausea, pneumonia, rash, and vomiting. In the docetaxel arm, 28 (65%) of patients discontinued treatment due to disease progression, and 4 patients (9%) discontinued due to AEs. More patients receiving trametinib had dose interruptions/delays (38%) and dose reductions (28%) compared with docetaxel (14% and 9%, respectively).
efficacy at interim analysis
Interim analysis results were reviewed by the Independent Safety Committee when 59 events (disease progressions or deaths) due to any cause occurred. The comparison of trametinib versus docetaxel for PFS crossed the futility boundary (HR 1.21; 95% CI 0.71–2.04) and the safety profile did not favor trametinib. Consequently, the study was terminated early and the clinical data cut-off date for the final analysis of the primary end point, PFS, was on 13 September 2013; a formal communication of the interim analysis was submitted to all participating investigators at this time.
overall efficacy
progression-free survival
The median follow-up at the final analysis was 3.7 months (range: 0–11 months). In the mITT population, no statistically significant or clinically meaningful difference in PFS was observed between the treatment arms. The median PFS was 12 weeks in the trametinib arm and 11 weeks in the docetaxel arm with an HR of 1.14 (95% CI 0.75–1.75; P = 0.5197) (Figure 2). In the ITT population, PFS was similar to that observed for the primary analysis (mITT population) with neither statistically nor clinically significant difference between the treatment arms (HR 1.23; 95% CI 0.81–1.87; P = 0.3160). No statistically significant difference was observed for KRAS mutational status (refer to supplementary Figure S1, available at Annals of Oncology online).
Figure 2.
Investigator-assessed Kaplan–Meier estimated progression-free survival (PFS). Data are for the KRAS-mutant population. The vertical lines indicate censoring of data.
overall survival
The median OS was 8 months in the trametinib arm and was not reached in the docetaxel arm (HR 0.97; 95% CI 0.52–1.83; P = 0.9324) (supplementary Figure S2, available at Annals of Oncology online). While these data are still immature, 31% of patients in the trametinib arm and 35% in docetaxel arm have died. In the trametinib arm 22% of patients received third-line plus anticancer therapy, compared with 12% of patients randomized to docetaxel.
response rate
The overall response rate (ORR) was 12% in the trametinib arm and 12% in the docetaxel arm (supplementary Table S3, available at Annals of Oncology online). No patients achieved a complete response (CR); however three patients (two on the trametinib arm and one on the docetaxel arm) had tumor measurement reductions from baseline >80%. Tumor measurement reductions from baseline were observed in the both the trametinib and docetaxel arms across several KRAS mutational subtypes (Figure 3). The median duration of response was shorter in the trametinib arm (7 weeks) compared with docetaxel (12 weeks); however, the 95% CI was large and the number of patients who responded and then progressed was small. In the crossover population (N = 25), one patient had a PR after crossing over to trametinib.
Figure 3.
Best percentage change from baseline in target lesions for the trametinib arm (A) and the docetaxel arm (B). The best tumor response for each patient who had undergone at least one tumor assessment after treatment. Each bar represents data for an individual patient. Colors indicate KRAS mutation status for each patient. The percentage change from baseline in the sum of the diameters of the target lesions is shown on the y-axis. Negative values indicate tumor shrinkage.
safety
All patients had at least one AE and most AEs were grade 1 or 2. In the trametinib arm, the most common AEs were rash (59%), diarrhea (47%), hypertension (34%), nausea (34%), dyspnea (33%), and fatigue (26%). Notably, more patients in the trametinib arm had dyspnea (33%), cough (23%), and pneumonia (11%), compared with docetaxel (19%, 16%, and 2%, respectively) (Table 2). The most common grade 3 treatment-related AEs in the trametinib arm were hypertension, rash, diarrhea, and asthenia. While in the docetaxel arm neutropenia was the principle grade 3–4 AE (Table 2). The grade 4 AEs in the trametinib arm (in more than two patients) were rash (3%), dyspnea (3%), pneumonia (2%), and sepsis (5%). More patients in the trametinib arm (37%) had at least one serious AE (SAE) compared with the docetaxel arm (21%). There were more respiratory-related SAEs on the trametinib arm, including pneumonia (7%), dyspnea (2%), and pulmonary embolism (2%), compared with docetaxel (2%, 2%, and 0%, respectively). Four patients in the trametinib arm had fatal SAEs; one death due to unknown cause was considered related to study treatment. In addition, one patient who crossed over to the trametinib arm had a fatal SAE, general physical health deterioration, which was considered to be not related to study treatment (supplementary Table S4, available at Annals of Oncology online). No fatal SAEs were reported in the docetaxel arm. The safety profile of trametinib in patients who crossed over after disease progression was consistent with that observed in those randomized to trametinib (data not shown).
Table 2.
Treatment-related adverse events occurring in ≥10% of patients
| Adverse eventa | Trametinib (N = 87) |
Docetaxel (N = 43) |
||||
|---|---|---|---|---|---|---|
| Grade 3 | Grade 4 | Any grade | Grade 3 | Grade 4 | Any grade | |
| Patients with any event, n (%) | 36 (41) | 3 (3) | 84 (97) | 16 (37) | 13 (30) | 38 (88) |
| Rash | 5 (6) | 3 (3) | 50 (57) | 0 | 0 | 4 (9) |
| Diarrhea | 4 (5) | 0 | 38 (44) | 1 (2) | 0 | 6 (14) |
| Nausea | 1 (1) | 0 | 23 (26) | 0 | 0 | 9 (21) |
| Vomiting | 2 (2) | 0 | 18 (21) | 1 (2) | 0 | 3 (7) |
| Fatigue | 3 (3) | 0 | 16 (18) | 1 (2) | 0 | 11 (26) |
| Pruritus | 1 (1) | 0 | 15 (17) | 0 | 0 | 2 (5) |
| Asthenia | 4 (5) | 0 | 14 (16) | 0 | 0 | 7 (16) |
| Hypertension | 8 (9) | 0 | 13 (15) | 0 | 0 | 1 (2) |
| Dermatitis acneiform | 0 | 0 | 11 (13) | 0 | 0 | 1 (2) |
| Dry skin | 0 | 0 | 11 (13) | 0 | 0 | 1 (2) |
| Edema peripheral | 0 | 0 | 11 (13) | 0 | 0 | 5 (12) |
| Alopecia | 0 | 0 | 1 (1) | 1 (2) | 0 | 16 (37) |
| Neutropenia | 0 | 0 | 0 | 6 (14) | 9 (21) | 16 (37) |
| Myalgia | 1 (1) | 0 | 2 (2) | 0 | 0 | 8 (19) |
| Neuropathy peripheral | 0 | 0 | 1 (1) | 0 | 0 | 8 (19) |
| Neutrophil count decreased | 0 | 0 | 0 | 3 (7) | 3 (7) | 7 (16) |
| Decreased appetite | 0 | 0 | 8 (9) | 0 | 0 | 6 (14) |
| Dysgeusia | 0 | 0 | 2 (2) | 0 | 0 | 5 (12) |
| Mucosal inflammation | 0 | 0 | 5 (6) | 0 | 0 | 5 (12) |
aTreatment-related adverse events with an overall incidence of ≥10% in at least one treatment group are displayed.
Steady-state PKs
The arithmetic mean pre-dose concentration of trametinib was 16.1 ng/ml in cycle 1, day 15. In cycles 2, 3, and 4 mean pre-dose plasma concentrations of trametinib ranged from 12.9 to 16.7, depicting no large differences between cycles. Concentrations of trametinib were highest (29.7 ng/ml) in the 2- to 4-h collection interval relative to other time windows, relatively consistent with the time-to-peak concentrations of ∼1.5–2.0 h. The peak/trough ratio calculated based on mean concentrations in cycle 1 (day 15) is ∼1.8, which is consistent with the long half-life of the compound (refer to supplementary Table S5, available at Annals of Oncology online).
discussion
KRAS, the most frequently mutated oncogene in NSCLC, is associated with a poor prognosis in lung cancer patients. Following demonstrated single-agent activity in a phase I study (NCT01192165) in KRAS-mutant NSCLC refractory to multiagent chemotherapy [16], trametinib was compared with docetaxel in this phase II study of patients with KRAS-mutant stage IV NSCLC who failed first-line, platinum-containing therapy.
Overall, patients on trametinib had more clinically significant AEs, including fatal serious events, than those on docetaxel. The most common AEs in trametinib-treated NSCLC patients were rash, diarrhea, nausea, and hypertension, and are known effects of trametinib. Dyspnea occurred more often with trametinib compared with docetaxel (33% versus 19%), including grade 3/4 events (10% versus 2%). The rate of dyspnea in this study was higher than that in advanced or malignant melanoma with trametinib (NCT01245062) [20] and may be a reflection of natural history of disease of metastatic NSCLC rather than a trametinib-based toxicity unique to NSCLC patients. Five fatal SAEs were reported with trametinib, and no fatal SAEs were reported with docetaxel.
A response rate of 12% in trametinib-treated patients with KRAS-mutant NSCLC demonstrates that there is a single-agent activity in contrast to selumetinib, another allosteric MEK inhibitor (AZD6244, ARRY-142886; AstraZeneca, Alderley Park, Cheshire, UK), where no single-agent activity was observed in KRAS-mutant NSCLC [21]. However, this limited single activity suggests that efforts to both identify subsets of KRAS-mutant patients more likely to respond and/or the development of MEK inhibitor-based combination treatment strategies are needed.
The KRAS-mutant NSCLC patient population is a heterogeneous mix of different point mutations and the identification of the specific KRAS mutation could have important clinical implications in the selection of patients and their therapeutic management [22, 23]. Eight kinds of KRAS mutations were observed in this study with G12C reported in over a third of the population, which was consistent with prior studies [19]. Data from in vitro studies suggest that cell lines harboring KRAS G12C or G12V mutations have a greater dependency on MEK/ERK compared with AKT signaling, and hence may be more sensitive to MEK inhibition [24]. In our study, a trend in improvement in PFS was observed in trametinib-treated patients with KRAS G12V mutation compared with those on the docetaxel arm, but the numbers are relatively small and will require additional investigation. No overall differences in clinical outcome between treatments were observed with G12C and other subtypes of KRAS mutations.
Although trametinib did not demonstrate superiority to docetaxel in this selected patient population, there is strong rationale for combining MEK inhibitors including trametinib with other biologic agents, chemotherapy, or radiation therapy [15, 25]. A randomized phase II trial reported by Janne et al. [19] showed an improvement in both PFS and ORR with the combination of selumetinib and docetaxel, compared with docetaxel alone, in patients with KRAS-mutant NSCLC. Preliminary data from a phase Ib trial combining trametinib and docetaxel provided further evidence supporting this strategy reporting an ORR of 28% in patients with chemotherapy refractory KRAS-mutant NSCLC [26]. Preclinical studies further demonstrate that combining MEK inhibitors with PI3K inhibitors or BCL-XL may also be effective strategies to treat KRAS-mutant lung cancers [27, 28]. Further definitive studies will be necessary to determine the efficacy and tolerability of these MEK inhibitor-based combinations in patients with KRAS-mutant NSCLC.
funding
This study was funded, initiated, administrated, and sponsored by GlaxoSmithKline (NCT01362296), which also provided data analysis services.
disclosure
GRB received funding to his institution from GlaxoSmithKline for conduct of the study. JC received grants for research from Pfizer and personal fees outside the submitted work from Pfizer, Roche, Lilly, Boehringer Ingelheim, Novartis, and Genentech. D-WK received personal fees from Pfizer and Novartis outside the submitted work. PB received grants/compensation for research to his institution outside of the submitted work. PAJ received personal fees from GlaxoSmithKline and AstraZeneca during the conduct of this study and personal fees outside of the submitted work from Genentech, Boehringer Ingelheim, Clovis Oncology, Merrimack Pharmaceuticals, Chugai, and Pfizer. ER, SR, AP, and FSW are employees of GlaxoSmithKline. M-JA, EFS, DP, TDP, FD, NHH, J-HK, JM, KU, and S-WK declare that they have no conflicts of interest.
Supplementary Material
acknowledgements
We thank members of the Independent Safety Review Committee, Steve Hobbiger, Trevor Gibbs, Debbie Hepworth, and Ethan Weiner. Additionally, we thank the Study Team, including Anett Puski, Christine Tucker, Joanna Goh, Michelle Casey, and Mary Richardson from GlaxoSmithKline. Editorial support in the form of graphic services was provided by SciMentum and was funded by GlaxoSmithKline.
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