Phase I Study of Afatinib and Selumetinib in Patients with KRAS-Mutated Colorectal,Non-Small Cell Lung,and Pancreatic Cancer

Lessons Learned

• Afatinib and selumetinib can be combined in continuous and intermittent dosing schedules, albeit at lower doses than approved for monotherapy.
• Maximum tolerated dose for continuous and intermittent schedules is afatinib 20 mg once daily and selumetinib 25 mg b.i.d.
• Because the anticancer activity was limited, further development of this combination is not recommended until better biomarkers for response and resistance are defined.

BackgroundAntitumor effects of MEK inhibitors are limited in KRAS‐mutated tumors because of feedback activation of upstream epidermal growth factor receptors, which reactivates the MAPK and the phosphoinositide 3‐kinase–AKT pathway. Therefore, this phase I trial was initiated with the pan‐HER inhibitor afatinib plus the MEK inhibitor selumetinib in patients with KRAS mutant, PIK3CA wild‐type tumors.MethodsAfatinib and selumetinib were administered according to a 3+3 design in continuous and intermittent schedules. The primary objective was safety, and the secondary objective was clinical efficacy.ResultsTwenty‐six patients were enrolled with colorectal cancer (n = 19), non‐small cell lung cancer (NSCLC) (n = 6), and pancreatic cancer (n = 1). Dose‐limiting toxicities occurred in six patients, including grade 3 diarrhea, dehydration, decreased appetite, nausea, vomiting, and mucositis. The recommended phase II dose (RP2D) was 20 mg afatinib once daily (QD) and 25 mg selumetinib b.i.d. (21 days on/7 days off) for continuous afatinib dosing and for intermittent dosing with both drugs 5 days on/2 days off. Efficacy was limited with disease stabilization for 221 days in a patient with NSCLC as best response.ConclusionAfatinib and selumetinib can be combined in continuous and intermittent schedules in patients with KRAS mutant tumors. Although target engagement was observed, the clinical efficacy was limited.     

Research methods in performance validity testing studies: Criterion grouping approach impacts study outcomes

Objective: Performance validity test (PVT) research studies commonly utilize a known-groups design, but the criterion grouping approaches within the design vary greatly from one study to another. At the present time, it is unclear as to what degree different criterion grouping approaches might impact PVT classification accuracy statistics. Method: To analyze this, the authors used three different criterion grouping approaches to examine how classification accuracy statistics of a PVT (Word Choice Test; WCT) would differ. The three criterion grouping approaches included: (1) failure of 2+ PVTs versus failure of 0 PVTs, (2) failure of 2+ PVTs versus failure of 0–1 PVT, and (3) failure of a stand-alone PVT versus passing of a stand-alone PVT (Test of Memory Malingering). Results: When setting specificity at ≥.90, WCT cutoff scores ranged from 41 to 44 and associated sensitivity values ranged from .64 to .88, depending on the criterion grouping approach that was utilized. Conclusions: When using a stand-alone PVT to define criterion group status, classification accuracy rates of the WCT were higher than expected, likely due to strong correlations between the reference PVT and the WCT. This held true even when considering evidence that this grouping approach results in higher rates of criterion group misclassification. Conversely, when using criterion grouping approaches that utilized failure of 2+ PVTs, accuracy rates were more consistent with expectations. These findings demonstrate that criterion grouping approaches can impact PVT classification accuracy rates and resultant cutoff scores. Strengths, weaknesses, and practical implications of each of the criterion grouping approaches are discussed.     

Sample size re-estimation for clinical trials with longitudinal negative binomial counts including time trends

In some diseases, such as multiple sclerosis, lesion counts obtained from magnetic resonance imaging (MRI) are used as markers of disease progression. This leads to longitudinal, and typically overdispersed, count data outcomes in clinical trials. Models for such data invariably include a number of nuisance parameters, which can be difficult to specify at the planning stage, leading to considerable uncertainty in sample size specification. Consequently, blinded sample size re-estimation procedures are used, allowing for an adjustment of the sample size within an ongoing trial by estimating relevant nuisance parameters at an interim point, without compromising trial integrity. To date, the methods available for re-estimation have required an assumption that the mean count is time-constant within patients. We propose a new modeling approach that maintains the advantages of established procedures but allows for general underlying and treatment-specific time trends in the mean response. A simulation study is conducted to assess the effectiveness of blinded sample size re-estimation methods over fixed designs. Sample sizes attained through blinded sample size re-estimation procedures are shown to maintain the desired study power without inflating the Type I error rate and the procedure is demonstrated on MRI data from a recent study in multiple sclerosis.