mFOLFOX indicates oxaliplatin + fluorouracil.
eTable 1. Baseline characteristics of subjects enrolled in the trial
eTable 2. Treatment related adverse events
eTable 3. Dose delays and dose reductions due to adverse events
eTable 4. Treatment Summary
Customize your JAMA Network experience by selecting one or more topics from the list below.
Chung V, McDonough S, Philip PA, et al. Effect of Selumetinib and MK-2206 vs Oxaliplatin and Fluorouracil in Patients With Metastatic Pancreatic Cancer After Prior Therapy: SWOG S1115 Study Randomized Clinical Trial . JAMA Oncol. 2017;3(4):516–522. doi:10.1001/jamaoncol.2016.5383
Copyright 2016 American Medical Association. All Rights Reserved.
What is the clinical effectiveness of dual-target inhibition of the MEK and AKT pathways as a treatment strategy for KRAS-mutant tumors compared with cytotoxic oxaliplatin plus fluorouracil (modified FOLFOX) chemotherapy?
In this phase 2 randomized clinical trial, selumetinib and MK-2206 did not improve overall survival compared with modified FOLFOX chemotherapy.
This study is informative for the design of future trials with targeted agents especially for clinical testing of multitargeted strategies.
KRAS mutations are common in pancreatic cancer, but directly targeting the KRAS protein has thus far been unsuccessful. The aim of this trial was to block the MEK and PI3K/AKT pathways downstream of the KRAS protein as an alternate treatment strategy to slow cancer growth and prolong survival. This was the first cooperative group trial to evaluate this strategy using molecularly targeted oral combination therapy for the treatment of chemotherapy-refractory pancreatic cancer.
To compare selumetinib and MK-2206 vs modified FOLFOX (mFOLFOX) in patients with metastatic pancreatic cancer for whom gemcitabine-based therapy had failed.
Design, Setting, and Participants
SWOG S1115 was a randomized phase 2 clinical trial. Between September 2012 and May 2014, 137 patients with metastatic pancreatic adenocarcinoma for whom gemcitabine-based chemotherapy had failed were randomized to selumetinib plus MK-2206 or mFOLFOX. Patients were randomized in a 1:1 fashion and stratified according to duration of prior systemic therapy and presence of liver metastases.
Patients received selumetinib 100 mg orally per day plus MK-2206 135 mg orally once per week or mFOLFOX (oxaliplatin, 85 mg/m2 intravenous, and fluorouracil, 2400 mg/m2 intravenous infusion over 46-48 hours) on days 1 and 15 of a 28-day cycle.
Main Outcomes and Measures
The primary end point of the study was overall survival. Secondary objectives included evaluating toxic effects, objective tumor response, and progression-free survival.
There were 58 patients in the selumetinib plus MK-2206 (experimental) arm (60% male; median [range] age, 69 [54-88] years) and 62 patients in the mFOLFOX arm (35% male; median [range] age, 65 [34-82] years). In the experimental arm, median overall survival was shorter (3.9 vs 6.7 months; HR, 1.37; 95% CI, 0.90-2.08; P = .15), as was median progression-free survival (1.9 vs 2.0 months; HR, 1.61; 95% CI, 1.07-2.43; P = .02). One vs 5 patients had a partial response and 12 vs 14 patients had stable disease in the experimental arm vs mFOLFOX arm. Grade 3 or higher toxic effects were observed in 39 patients treated with selumetinib and MK-2206 vs 23 patients treated with mFOLFOX. More patients in the experimental arm discontinued therapy due to adverse events (13 vs 7 patients).
Conclusions and Relevance
Dual targeting of the MEK and PI3K/AKT pathways downstream of KRAS by selumetinib plus MK-2206 did not improve overall survival in patients with metastatic pancreatic adenocarcinoma for whom gemcitabine-based chemotherapy had failed. This was the first randomized prospective evaluation of mFOLFOX in the US population that showed comparable results to CONKO-003 and PANCREOX.
clinicaltrials.gov Identifier: NCT01658943
Metastatic pancreatic cancer remains resistant to conventional systemic treatments, with median overall survival (OS) being less than 1 year. Due to toxic effects of combination cytotoxic therapies, rational approaches with targeted therapies have been attempted in hope of minimizing toxic effects. Erlotinib hydrochloride is the only US Food and Drug Administration–approved molecularly targeted treatment for pancreatic cancer; however, the combination with gemcitabine hydrochloride improved median OS by only 2 weeks compared with gemcitabine alone.1 Therefore, traditional cytotoxics have been the mainstay of treatment. FOLFIRINOX (oxaliplatin, irinotecan hydrochloride, leucovorin calcium, and fluorouracil) has the highest reported objective response rate, with a median OS just under 1 year, but at the cost of increased toxic effects.2 The applicability of FOLFIRINOX is therefore limited to younger patients with a good performance status, near-normal liver function, and a willingness to undergo aggressive therapy for metastatic disease. Gemcitabine and nab-paclitaxel provides another treatment option, albeit with a shorter median OS.3
The KRAS protein is a guanosine triphosphatase that regulates cell growth, angiogenesis, and survival. More than 90% of pancreatic ductal adenocarcinomas have activating mutations in this protein, which is also one of the earliest genetic alterations resulting in neoplastic transformation.4,5 Many attempts have been made to target mutant KRAS.6 Earlier studies targeting RAS were directed against its farnesylation, a critical step in its activation. Unfortunately, there was no evidence of benefit to patients, partly because of the alternate activation of RAS by geranylgeranylation.7 Because there are currently no drugs that directly target mutant RAS, inhibiting its downstream canonical RAF/MEK/ERK and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways was a rational alternate treatment strategy.8,9 An earlier trial of trametinib, an orally bioavailable, reversible inhibitor of MEK 1/2, in combination with gemcitabine showed improved survival, although this result was not significant, suggesting that single-pathway blockade was not sufficient for a clinically worthwhile benefit that was suggested by preclinical studies.10 Subsequent preclinical studies explored the cross-talk between pathways downstream of RAS to determine mechanisms to overcome resistance.11,12 Indeed, there was evidence that inhibition of MEK led to upregulation of AKT phosphorylation that in turn allowed continued cell survival and proliferation.13,14 Furthermore, enhanced cytotoxicity in pancreatic cancer cell lines was demonstrated by blocking both MEK and AKT.15,16
Selumetinib is a potent, selective, adenosine triphosphate–uncompetitive inhibitor of MEK 1/2 with a maximum tolerated dose of 200 mg twice per day as a single agent. The phase 1 trial showed substantial rash at this dose, and it was therefore decreased to the well-tolerated 100 mg twice per day. The median half-life was 8 hours, and treatment tumor biopsies demonstrated inhibition of ERK phosphorylation.17,18 MK-2206 was the first allosteric AKT inhibitor and, at nanomolar concentrations, inhibited all 3 isoforms of AKT. In a phase 1 study, the maximum tolerated dose was determined to be 60 mg every other day with a mean half-life of 63 to 76 hours. Due to its dose-limiting toxic effects of rash and mucositis,19 when combined with selumetinib, the dosing schedule had to be modified because of overlapping toxic effects. Selumetinib could only be given at a dose of 100 mg per day rather than twice per day and MK-2206 was given at a dose of 135 mg per week rather than every other day. Despite the decreased dose density, there were 2 patients with pancreatic cancer who had stable disease, 1 of whom had a KRAS-mutated tumor.15
KRAS mutation is the most frequent genomic alteration in pancreatic cancer and considered essential in the mechanism of this disease.4 Previous attempts at targeting this mutant protein have been unsuccessful; therefore, we embarked on this novel trial using the combination of selumetinib and MK2206 to target downstream effectors. Our hypothesis was that blockade of signaling downstream of KRAS by dual targeting of MEK and AKT pathways would slow tumor growth and prolong survival of patients with metastatic pancreatic cancer. This was the first second-line pancreas cancer trial exploring a noncytotoxic combination regimen conducted by SWOG. This was also the first study to prospectively evaluate oxaliplatin plus fluorouracil (mFOLFOX) in the US population.
S1115 (NCT01658943; protocol available in Supplement 1) was an open-label randomized phase 2 study completed within the National Cancer Institute’s National Clinical Trials Network groups SWOG, ECOG-ACRIN, and Alliance (Figure 1). Sixty-one sites participated, with SWOG being the coordinating group. The participating sites obtained institutional review board approval, and informed, written consent was obtained from all patients prior to enrollment.
Patients 18 years and older with a Zubrod performance status of 0 to 1 were eligible if they had a histologically or cytologically confirmed diagnosis of pancreatic adenocarcinoma that was metastatic. Patients with neuroendocrine tumors, lymphoma, or ampullary adenocarcinoma were excluded. Prior gemcitabine-based chemotherapy must have been completed at least 14 days prior to registration, and toxic effects from therapy must have recovered to Common Terminology Criteria for Adverse Events grade 1 or less. If prior treatment included FOLFIRINOX, FOLFOX, other oxaliplatin-based chemotherapy or MEK, PI3K, or AKT inhibitors, the patient was deemed ineligible. Normal cardiac and renal functions were required. In patients with hepatic metastases, the total bilirubin level was required to be no more than the institutional upper limit of normal (IULN); aspartate aminotransferase and alanine aminotransferase levels both to be no more than 2.5 times IULN and serum alkaline phosphatase level to be no more than 3 times IULN. Patients were required to have a serum albumin level at least 2.5 g/dL (to convert to grams per liter, multiply by 10), and uncontrolled diarrhea was an exclusion criterion. Patients with any visual abnormalities except myopia, hyperopia, and presbyopia were excluded.
Patients were randomized 1:1 to selumetinib plus MK-2206 or mFOLFOX by the SWOG Statistical Center using a dynamic balancing algorithm20 with stratification based on duration of prior systemic chemotherapy (≤4 or >4 months) and presence or absence of liver metastases.
Baseline evaluation including history and physical examination, laboratory evaluations, and imaging by computed tomography or magnetic resonance imaging were completed prior to registration. Laboratory tests were performed within 14 days whereas imaging was within 28 days of registration. Patients received selumetinib 100 mg orally per day plus MK-2206 135 mg orally once per week or mFOLFOX (oxaliplatin 85 mg/m2 intravenous and fluorouracil 2400 mg/m2 intravenous infusion over 46-48 hours) on days 1 and 15, with each cycle being 28 days. Hematopoietic growth factors were allowed per American Society of Clinical Oncology guidelines, and antiemetic medications were prescribed per institutional guidelines. Tumor assessments by computed tomography or magnetic resonance imaging scan were performed every 2 cycles until disease progression.
The primary objective of this study was to estimate the OS in patients receiving selumetinib plus MK-2206 or mFOLFOX after failure of gemcitabine-based chemotherapy. Secondary objectives included evaluating toxic effects per National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0, objective tumor response, and progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors 1.0. The OS and PFS end points were measured from the time of randomization, and censoring time was defined as the date of last contact. Patients were observed until death or 3 years after registration, whichever occurred first.
Median OS was assumed to be 6 months for the mFOLFOX arm based on previously published results of the CONKO-003 and PANCREOX trials.21,22 Assuming a 1-sided type I error of 10%, approximately 2 years of accrual, and 1.5 years of follow-up, 120 eligible patients provided 80% power to detect a 0.66 hazard ratio.23 An interim analysis of OS was planned once 34% of the expected events in the mFOLFOX arm were observed. The study was to close early if the alternative hypothesis was rejected at a 1-sided .05 α level. According to the intent-to-treat principle, all eligible patients were included in the analyses according to randomized treatment assignment, regardless of treatments received.
Probabilities of OS and PFS were estimated using the Kaplan-Meier method. Statistical differences in event rates between treatment arms were assessed via Cox proportional hazards model. Rates of objective tumor response (confirmed and unconfirmed complete and partial response) were compared via Fisher exact test, in the subset of patients with measurable disease. Heterogeneity between treatment arms was tested using a 2-sample t test for age and χ2 tests for sex, race, prior systemic therapy duration, and presence of liver metastases.
We instituted careful adverse event monitoring for the first 20 patients randomized to the experimental arm because of limited preexisting clinical data on the safety of selumetinib combined with MK-2206. Toxic effects were closely monitored by the study coordinator, study statistician, disease committee chair, and SWOG gastrointestinal executive officer, in conjunction with the SWOG Data and Safety Monitoring Committee and Cancer Therapy Evaluation Program.
Between September 2012 and May 2014, 137 patients with metastatic pancreatic cancer for whom gemcitabine-based chemotherapy had failed were randomized to selumetinib plus MK-2206 or mFOLFOX (Figure 1). Sixteen patients were ineligible after not meeting protocol-specified eligibility criteria. One additional patient withdrew consent prior to protocol treatment. Thus, 58 patients in the selumetinib plus MK-2206 arm and 62 patients in the mFOLFOX arm were available for toxicity and efficacy analyses. eTable 1 in Supplement 2 provides the patient characteristics. In the experimental arm, patients were older, with more men compared with the mFOLFOX arm (P = .001 and P = .01, respectively). Overall, 50% of patients (n = 60) had received combination, rather than single-agent, gemcitabine-based chemotherapy (28 [48%] in the experimental arm and 32 [52%] in the mFOLFOX arm). Since the approval of nab-paclitaxel for pancreatic cancer in 2013, this was the most commonly used combination with gemcitabine. Prior systemic therapy duration and percentage of patients with liver metastases was not significantly different between treatment arms (P = .99 and .24, respectively).
eTable 2 in Supplement 2 compares the frequency of treatment-related adverse events occurring in at least 10% of patients. The most common toxic effects observed in selumetinib plus MK-2206–treated patients were nausea and vomiting, occurring in 24 (41%) and 18 (31%) patients, respectively. The frequency of nausea and vomiting for mFOLFOX was higher, at 37 (60%) and 19 (31%) patients, with a higher incidence of grade 3 toxic effects compared with the oral therapy arm. In the experimental arm, fatigue and anorexia occurred in 24 (41%) and 19 (33%) patients, compared with 35 (56%) and 20 (32%) patients in the mFOLFOX arm. Overall, more patients in the experimental arm vs the mFOLFOX arm experienced grade 3 or higher toxic effects (39 [67%] vs 23 [37%]). Rash and mucositis, which are common adverse effects for this class of drugs, occurred in 30 (52%) and 13 (22%) patients in the experimental arm. In the experimental arm, 26 (45%) patients required dose modifications or delays in the first cycle compared with 6 (10%) for mFOLFOX (eTable 3 in Supplement 2). In addition, more patients in the experimental arm discontinued treatment compared with mFOLFOX (13 [22%] vs 6 [10%]) (eTable 4 in Supplement 2).
Based on the assumptions made at the beginning of the study, the interim analysis was expected to occur at 15 months with approximately 62% of accrual met. Due to robust accrual and a lower than expected event rate, we completed accrual to the trial prior to the prespecified interim analysis. After the data were analyzed, the futility boundary was crossed and the results were released early to the public. The median PFS was 1.9 months in the selumetinib plus MK-2206 arm and 2.0 months in the mFOLFOX arm, with a hazard ratio of 1.61 (95% CI, 1.07-2.43; P = .02) (Figure 2). The median OS was 3.9 months in the selumetinib plus MK-2206 arm and 6.7 months in the mFOLFOX arm (Figure 3). The estimated hazard ratio for the comparison of the selumetinib plus MK-2206 arm to the mFOLFOX arm was 1.37 (95% CI, 0.90-2.08; P = .15). Of the 55 and 57 evaluable patients with measurable disease in the selumetinib plus MK-2206 and mFOLFOX arms, no complete responses were seen. In the selumetinib plus MK-2206 arm vs mFOLFOX, there were 1 vs 4 patients with a partial response (P = .21) and 12 vs 14 patients with stable disease, respectively.
The modest advances in the treatment of pancreatic cancer were made exclusively with conventional cytotoxic drugs. Targeted agents inhibiting a single pathway such as insulin-like growth factor 1 receptor or MEK, although promising in the preclinical setting, failed to improve survival in a variety of cancers.24,25 This study addresses mutant RAS signaling, specifically targeting downstream survival and proliferation pathways using a dual inhibitory strategy with 2 oral molecularly targeted drugs, selumetinib and MK-2206. The results of this trial did not meet its primary end point of improving survival over a standard treatment with modified FOLFOX. However, our trial showed that in a US population, efficacy of mFOLFOX was similar to those obtained in the CONKO-003 and PANCREOX trials. With oxaliplatin + fluorouracil + leucovorin and mFOLFOX6 chemotherapy, the median OS was 5.9 and 6.1 months, respectively, which is comparable to our survival of 6.7 months. To our knowledge, this was the first trial to prospectively evaluate and show efficacy of this regimen in the US population.
The lack of clinical activity of this combined targeted strategy in advanced pancreatic cancer may be attributed to a number of factors related to sustained blockage of signaling pathways in vivo. In single-agent phase 1 studies of selumetinib and MK-2206, target inhibition was achieved with twice-daily dosing of selumetinib and alternate-day dosing of MK-2206.18,19 However, the maximum tolerated dose of the phase 1 study using the combination of the 2 drugs was only 100 mg daily for selumetinib and 135 mg once per week for MK2206. The lower dose intensity was because of their overlapping toxic effects.15 It is reasonable to assume that a noncytotoxic regimen must be given at an optimal dose intensity for sustained inhibition of signaling pathways that are necessary for an effective clinical outcome. This was demonstrated in a biomarker trial studying this drug combination in patients with colorectal cancer.26 Pre- and posttreatment biopsies were obtained to evaluate pAKT and pERK inhibition. In their trial, target inhibition of 70% was prespecified and considered necessary for clinical activity based on preclinical data. Dual-target inhibition at the specified levels was not seen using selumetinib, 75 mg daily, and MK-2206, 90 mg weekly. Escalation to doses similar to those used in our study also did not produce worthwhile dual-target inhibition, and there were no clinical responses in this population of patients with advanced colorectal cancer.26 This indicates that the strategy of using 2 or more kinase inhibitors, although scientifically justified, is challenged by the overlapping toxic effects that would significantly influence the delivery of effective inhibitory doses of both drugs in vivo.
A major contributing factor to the lack of benefit was the frequency of toxicity-related treatment delays and dose reductions in the experimental arm, undermining sustained signaling inhibition. Dose delays or dose reductions occurred in 45% of patients in the experimental arms compared with only 10% in the mFOLFOX arm. Mucositis and rash were more frequently observed in the experimental arm, and although these were managed symptomatically, ultimately dose modifications were required. The self-limiting nature of these toxic effects in the mFOLFOX arm with every-2-week infusions made it more tolerable to patients.
Results of this trial can also be explained by alternate signaling pathways that drive pancreatic cell growth and survival. As an example, effectors such as Ral protein signaling may be relevant to tumor progression. Recently, Miller et al27 reported on posttranslational modification of the cell surface as a mechanism of resistance to targeting MAPK signaling. Normally, proteolytic shedding of cell surface receptors can provide negative feedback on signaling activity; however, MAPK inhibition decreases this posttranslational event by enhancing the signaling of sheddase substrates. Decreased proteolysis leads to surface accumulation of receptor tyrosine kinases (RTK) and increased signaling through other pathways such as JNK to promote cellular proliferation. The RTK shedding also effects the tumor microenvironment, amplifying prosurvival and prometastatic tumor-stroma interactions.27 This illustrates the complexity of the signaling pathways, whereby multiple ones must be blocked before clinical benefit can accrue. However, the challenge lies in combining multiple inhibitors that will be tolerable to the patient.
This study is informative for the design of future trials with targeted agents especially for clinical testing of multitargeted strategies. Despite preclinical models that demonstrated synergy and target inhibition of MEK and AKT signaling, this did not translate into a clinical benefit in patients with refractory metastatic pancreatic cancer.15,28,29 To determine whether this was due to inadequate target inhibition because of suboptimal dosing, additional preclinical studies need to be performed. An alternative treatment schedule with intermittent (higher intensity) dosing of the targeted agents may be considered. Inclusion of a proapoptotic cytotoxic agent may also be necessary because the selumetinib and MK-2206 combination is not synthetically lethal. Even as newer formulations of drugs blocking the PI3K/AKT and RAF/MEK/ERK pathways with improved therapeutic index are developed, targeting these pathways downstream of KRAS may lead to additional resistant phenotypes. For example, in melanoma cell lines, inhibition of MEK and BRAF induced STAT3 signaling, potentially leading to increased invasion and metastasis.13,30 STAT3 has been associated with a poor prognosis in pancreatic cancer, and preclinical studies have shown that the loss of p53 function activates JAK2-STAT3 signaling.31
KRAS mutations differ across tumor types, and understanding which pathways are specifically activated may be predictive of response to targeted therapies. For example, PI3K/Pdk1 signaling is required for tumor initiation in KRAS-driven pancreatic cancer but not in non–small-cell lung cancer models. In murine lung cancer models, inhibition of the MEK/PI3K pathways showed pronounced and sustained responses.29 However, pancreatic cancer models showed transient benefit to MEK/PI3K inhibition potentially due to the differing genetic and epigenetic changes.8,28 Pancreatic cancer can also be subdivided into epithelial and mesenchymal subtypes, and a synergistic effect of MEK and EGFR inhibition was only seen in the epithelial subtype with HER3 knockdown.32
This study has limitations due to the lack of serial biopsies during treatment. Target inhibition was not observed in patients with colon cancer treated with the same experimental therapy, but the desmoplasia seen with pancreatic cancer creates a unique environment. Analyzing serial treatment biopsies would be essential for determining on-target effects of these small-molecule inhibitors but also potentially define biomarkers of response.
A better understanding of the underlying signaling networks driving pancreatic cancer progression and potential escape mechanisms is required. Also, the role of preclinical models of pancreatic cancer and the optimal translation of preclinical successes into trial design must be improved. Moreover, clinical testing of targeted agents must include validation of target modulation in treated patients. Obtaining tissue samples before and after treatment is challenging for this population of patients, but the recent advances in liquid biopsies may help to remove the hurdles of serial tissue sampling.33
Corresponding Author: Vincent Chung, MD, City of Hope National Medical Center, 1500 E Duarte Rd, Duarte, CA 91010 (firstname.lastname@example.org).
Accepted for Publication: October 4, 2016.
Published Online: December 15, 2016. doi:10.1001/jamaoncol.2016.5383
Author Contributions: Dr Chung and Ms McDonough had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Chung, Philip, Doyle, Lowy, Hochster.
Acquisition, analysis, or interpretation of data: Chung, McDonough, Philip, Cardin, Wang-Gillam, Hui, Tejani, Seery, Dy, Al Baghdadi, Hendifar, Guthrie, Blanke, Hochster.
Drafting of the manuscript: Chung, McDonough, Tejani, Dy, Hendifar, Lowy, Guthrie, Hochster.
Critical revision of the manuscript for important intellectual content: Chung, Philip, Cardin, Wang-Gillam, Hui, Seery, Al Baghdadi, Hendifar, Doyle, Lowy, Guthrie, Blanke, Hochster.
Statistical analysis: McDonough, Guthrie.
Administrative, technical, or material support: Chung, Cardin, Dy, Al Baghdadi, Hendifar, Lowy, Blanke, Hochster.
Conflict of Interest Disclosures: Dr Chung has received honoraria, acted in a consulting or advisory role, and been part of the speakers’ bureau for Celgene and received research funding from Novartis. Dr Philip has received honoraria from Celgene, acted in a consulting or advisory role for Celgene, Merrimack, and Halozyme, and received research funding from Celgene and Merck. Dr Wang-Gillam has received honoraria from Axis, acted in a consulting or advisory role for Newlink, Merrimack, and Pfizer, and received research funding from Aduro, Chemocentry, CTI Biopharma, Millennium, Pfizer, Merrimack, Newlink, EMD Precision, and AstraZeneca. Dr Tejani has received research funding from Bayer. Dr Seery has acted in a consulting or advisory role for Bayer and Halozyme. Dr Al Baghdadi holds stock or other ownership in Exelixis, Array Biopharma, Tracon Pharmaceuticals, Cerulean, and Spectrum Pharmaceuticals, has acted in a consulting or advisory role for Seattle Genetics and Incyte, and received travel, accommodations, and expenses from Celgene and Cardinal Health. Dr Doyle holds a patent as co-discoverer of the ABCG2 (BCRP) transporter gene, unrelated to the S1115 trial. Dr Lowy has received honoraria from Pfizer, has acted in a consulting or advisory role for Merck and Halozyme, and has provided expert testimony for Merck. No other disclosures are reported.
Funding/Support: This work was supported by National Institutes of Health/National Cancer Institute/National Clinical Trials Network (grants CA180888, CA180819, CA180820, CA180847, CA180821, CA180835, CA 180846, CA180818, CA180801, CA180828, CA189804, CA180798); National Institutes of Health/National Cancer Institute Community Oncology Research Program (grants CA189821, CA189830, CA189960, CA189971, CA189808, CA189954, CA189822, CA189809, CA189853, CA189953, CA189858); National Institutes of Health/National Cancer Institute legacy (grants CA11083, CA46368, CA58723, CA04919, CA46113); and the Susan E. Riley Foundation. AstraZeneca provided selumetinib, and Merck & Co, Inc, MK-2206.
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We thank the Hope Foundation for sponsoring the SWOG Young Investigators Course.
Create a personal account or sign in to: