Assessing Patient Risk, Benefit, and Outcomes in Drug Development: Insights From Afatinib Clinical Trials Across Diverse Cancer Indications.

PURPOSE: In 2013, afatinib was approved for non-small-cell lung cancer with subsequent indication expansion. We investigated published afatinib clinical trials to assess risk and benefit profiles for the drug in its approved indication of non-small-cell lung cancer as well as in off-label uses. Previous literature demonstrates excessive patient burden and limited benefit as afatinib has spread into more indications. A trial analysis is needed to establish efficacy and risk. METHODS: In this investigation, we screened literature databases and clinical trial registries for trials of afatinib as monotherapy or in combination interventions for cancer treatment. We extracted participant demographics, adverse event characteristics, as well as clinical and surrogate endpoints for each trial. Studies were deemed positive, negative, or indeterminate based on their achieving of primary endpoints as well as their safety. RESULTS: Our search yielded 2444 articles; we excluded 2352 articles for a final inclusion of 92 trials of 8859 patients. Our sample had 49 (53%) positive trials, 27 (29%) negative trials, and 16 (17%) indeterminate trials. The most common off-label indications for afatinib were breast cancer and squamous cell carcinoma of head and neck. The median OS for all trials was 8.4 months, median PFS 3.4 months, and the total ORR was 29.6%. Our study found that trials performed in disease states beyond the initial indications were largely negative with little patient benefit. The adverse events within our trial sample appear to be in line with expectations for toxicity. IMPLICATIONS: These results are consistent with other studies that present similar findings, such as in Carlisle et al which indicate limited efficacy in nonapproved indications. Future trials should keep this potential evidence and patient burden in mind before initiation of those trials. This study contributes to the understanding of afatinib's risk-benefit profile across many clinical applications.

The Influence of Motor Unit Number and Muscle Activation on Early Phase Rate of Torque Development in Younger and Older Men.

This study examined the influence of muscle activation and motor unit number estimation (MUNE) on early phase voluntary rate of torque development (RTD) in younger (YM) and older (OM) men. Thirty-two YM (n = 17; Age = 22 yrs) and OM (n = 15; Age = 74 yrs) volunteered to participate in this study. Early phase RTD (first 50 ms of a rapid isometric contraction; RTD50) and normalized surface electromyography (first 50 ms of muscle excitation; nEMG50) were recorded from the right quadricep muscle group. MUNE was examined from the right vastus lateralis. Multiple linear regression analyses revealed that nEMG50 had a significant effect on RTD50 independent of age group (p ≤ 0.001). nEMG50 had a significant effect on RTD50 in the OM group (p = 0.037). MUNE had no effect on RTD50 independent of age. Older adults may depend more on muscle activation at contraction onset of early phase RTD compared to younger adults.