Phase 2 study of osimertinib in combination with platinum and pemetrexed in patients with previously untreated EGFR-mutated advanced non-squamous non-small cell lung cancer: The OPAL Study.

BACKGROUND: This multicenter phase 2 trial evaluated the safety and efficacy of osimertinib and platinum-based chemotherapy (OPP) in patients with previously untreated EGFR-mutated advanced non-squamous non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients received osimertinib 80 mg once daily (QD), with either cisplatin 75 mg/m2 (arm A) or carboplatin (area under the curve [AUC] = 5; arm B), plus pemetrexed 500 mg/m2 for four cycles and maintenance therapy of osimertinib 80 mg QD with pemetrexed 500 mg/m2 every 3 weeks. The primary end-points were safety and objective response rate (ORR), and the secondary end-points were complete response rate (CRR), disease control rate (DCR), and progression-free survival (PFS). RESULTS: In total, 67 patients (34 in arm A and 33 in arm B) were enrolled between July 2019 and February 2020. At the data cutoff (28th February 2022), 35 (52.2%) patients had discontinued the protocol treatment, including 10 (14.9%) due to adverse events. No treatment-related deaths occurred. In the full analysis set, the ORR, CRR, and DCR were 90.9% (95% confidence interval [CI], 84.0-97.8), 3.0% (0.0-7.2), and 97.0% (92.8-100.0), respectively. Based on updated survival data (data cutoff on August 31, 2022, median follow-up time: 33.4 months), the median PFS was 31.0 months (95% CI, 26.8 months-not reached) and median overall survival was not reached. CONCLUSIONS: This is the first study to show that OPP has excellent efficacy with acceptable toxicity in previously untreated EGFR-mutated advanced non-squamous NSCLC patients.

Delayed antigen-specific CD4+ T cell induction correlates with impaired immune responses to SARS-COV-2 mRNA vaccination in the elderly

Despite the clinical efficacy of coronavirus disease 2019 mRNA vaccines, the elderly demonstrate lower IgG levels and neutralizing titers and a higher risk of severe diseases. CD4+ T cells play a central role in regulating antigen-specific antibody and CD8+ T-cell responses; however, because their composition and functionality change significantly with age, relationships between age-associated defects in T cells and the immunogenicity of or reactogenicity to mRNA vaccines are unclear. Using a vaccine cohort (n = 216), we found that the elderly (aged [≥]65 years) showed delayed induction and early contraction of vaccine-specific CD4+ T cells, and that the compromised C-X-C motif chemokine receptor 3+ circulating T follicular helper cell response after the first dose was associated with the lower IgG levels. Additionally, the elderly experienced significantly fewer systemic adverse effects (AEs) after the second dose, with those exhibiting few AEs showing lower cytokine+ CD4+ T cells after the first dose and lower antibody levels after the second dose. Furthermore, T helper 1 cells in the elderly expressed higher levels of programmed cell death protein-1, a negative regulator of the T-cell response, which was associated with less production of vaccine-specific CD4+ T cells and impaired CD8+ T-cell expansion. Thus, efficient induction of vaccine-specific effector/memory CD4+ T cells after the first dose may trigger robust cytokine production after the second dose, leading to effective vaccine responses and higher systemic reactogenicity. These results suggested that an enhanced CD4+ T-cell response after the first dose is key to improved vaccination efficacy in the elderly. One Sentence SummaryWe compared immunogenicity and reactogenicity to COVID-19 mRNA vaccine in 107 adults (aged <65 years) and 109 elderly (aged [≥]65) individuals.

Statistical Contribution to Quality of Life (QOL) Evaluation / 薬剤疫学

Quality of life (QOL) evaluated by patients themselves has become one of the important outcomes in clinical practice as well as clinical trials. Recently clinicians have attempted to gather QOL evaluation data in their clinical practice setting and integrate the findings into the medical decision-making process. To date, several multidimensional generic questionnaires consisting of multiple domains such as functional, physical, mental and social well-being, have been developed and utilized for generic QOL evaluation in clinical trials, especially in the oncology area. To develop a well-constructed and valid QOL questionnaire, its psychometric characteristics such as reliability, validity, responsiveness and feasibility must be adequately assessed in the research setting.<BR>In clinical trials, QOL data are generally measured in a longitudinal fashion and there are two prominent embarrassing statistical problems : one is the multiplicity due to replication (in time) of statistical tests and the other is the occurrence of missing data due to a variety of reasons. Non-random missing data which occurs because of any reasons related to a patient's present status and/or future prognosis possibly leads to bias and misinterpretation of the results of a trial. To solve the multiplicity problem, the repeated-measures ANOVA-type data analysis or summarization of a repeated measures into an appropriate summary measure can be applied. Missing data can be prevented to some extent by allocating/training coordinators at each participating institute and establishing a communication network between a data center and participating institutes. However, missing data will occur inevitably due to the deterioration of a patient's physical status in the area of life threatening diseases suchas advanced cancer or other diseases with poor prognosis. Although several statistical approaches to cope with missing data even including non-random one have been proposed, there is no single complete analytical solution that can handle the non-random missing problem. The best remedy would be to collect information about reasons why the missing data occurred so that we can identify the missing mechanism and take it into account in a statistical analysis. A so-called “sensitivity analysis” of comparing the results of several analytical methods suchas different imputation techniques or newly proposed ideas would also be a useful approach. The QALY (Quality Adjusted Life Year) used the idea of weighting life time by utility evaluated by patients themselves and is coined for incorporating a patient's judgment into the treatment selection. Ultimately, an assessment of QOL should be utilized for “individualized” or “tailor-made” treatment and statistical methodology should be developed further for gathering, analyzing and utilizing QOL data.