Satoshi Wada

Figure S1 from Efficacy and Safety of Necitumumab and Pembrolizumab Combination Therapy in Advanced Non–Small Cell Lung Cancer with ≥50% PD-L1 Expression: A Nonrandomized Phase II Trial

Background/Objectives: Evidence regarding associations between local therapy before an indexed systemic regimen and subsequent outcomes in advanced soft tissue sarcoma (STS) remains limited. We evaluated outcomes within four regimen-defined cohorts and explored associations with prior local-therapy history. Methods: This retrospective cohort included 75 patients with recurrent or metastatic STS who contributed 155 treatment episodes: doxorubicin (n = 44), trabectedin (n = 31), pazopanib (n = 42), and eribulin (n = 38). Progression-free survival (PFS) and overall survival (OS) were measured from initiation of the indexed regimen. Surgery, local ablative therapy, and radiation therapy were assessed separately and in combined categories. Post hoc analyses were restricted to leiomyosarcoma. Results: Median PFS was 3.4, 3.1, 5.1, and 3.9 months, respectively. PFS was longer with any local therapy and surgery and/or ablation in the trabectedin cohort (p = 0.0342 and p = 0.0111) and with surgery and/or ablation in the eribulin cohort (p = 0.0352). Longer indexed-regimen OS was observed in surgery-containing categories in the doxorubicin and eribulin cohorts. In selected multivariable models, local therapy was associated with OS in doxorubicin- and eribulin-treated episodes and with PFS in eribulin-treated episodes. Leiomyosarcoma-restricted analyses did not consistently reproduce the full-cohort findings. Conclusions: Prior local-therapy history was associated with PFS or OS in selected within-cohort analyses. The associations may reflect local-treatment effects, differences among selected patients, or both; however, the study cannot distinguish these contributions. No between-regimen differences were formally tested. These findings support individualized multidisciplinary assessment and external validation.

Purpose: This study investigated the efficacy and safety of pembrolizumab and necitumumab as first-line therapy for patients with advanced non–small cell lung cancer (NSCLC) who had ≥50% programmed death-ligand 1 (PD-L1) expression. Patients and Methods: This nonrandomized, multicenter, open-label, single-arm phase II trial included patients with previously untreated advanced NSCLC who had a PD-L1 tumor proportion score of ≥50%. Patients received pembrolizumab and necitumumab every 3 weeks for up to 35 cycles. The primary endpoint was the investigator-assessed objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Results: The sample comprised 50 patients (38 men, 12 women; median age, 72 years; range, 51–90 years). The ORR was 76% (95% confidence interval, 61.9–86.9; P < 0.0001), with complete and partial response rates of 2% and 74%, respectively. Moreover, 10% and 8% of the patients had stable and progressive disease, respectively, whereas 6% could not be evaluated. The median PFS was 15.7 months, whereas the median OS was not reached at the time of analysis. The most common treatment-related adverse events were rash (64%) and hypomagnesemia (60%). Grade 3 interstitial lung disease occurred in five patients (10%), and grade 5 cardiac arrest occurred in one patient (2%). Conclusions: The pembrolizumab and necitumumab combination exhibited a promising ORR of 76% with a manageable safety profile in patients with NSCLC who had high PD-L1 expression. These findings highlight the need for further research on this regimen for patients with advanced NSCLC who have high PD-L1 expression.

Background: Boron neutron capture therapy (BNCT) is a type of targeted radiotherapy with considerable therapeutic potential that may be combined with immune checkpoint inhibitors (ICIs) to enhance systemic antitumor immunity. Its efficacy relies on the efficient and safe delivery of boron to cancer cells. This study evaluated the acute toxicity of a self-assembling peptide-based boron carrier composed of A6K and sodium borocaptate (BSH) at a 1:10 molar ratio (A6K/BSH boron drug), which had previously shown excellent tumor-selective accumulation and prolonged intracellular retention. Methods: A single-dose intraperitoneal toxicity study was performed in 6-week-old BALB/c mice (n = 6 per group; 3 males and 3 females). Animals received BSH-equivalent doses of 0, 30, 100, 300, or 600 mg/kg and were observed for 14 days. Mortality, clinical signs, body weight, gross necropsy findings, and histopathological characteristics of major organs were then assessed. Results: No mortality or treatment-related clinical signs were observed. Body weight changes were comparable between the control and treated groups. Gross necropsy revealed no treatment-related abnormalities. Histopathology showed mild hepatocellular hypertrophy and granular degeneration without dose dependency. No other organ toxicities or sex-related differences were detected. Conclusions: A single intraperitoneal administration of the A6K/BSH boron drug up to 600 mg/kg (BSH-equivalent) produced no evident acute systemic toxicity, suggesting that the approximate lethal dose exceeds 600 mg/kg for both sexes. This initial safety assessment supports the further development of the A6K/BSH boron drug as a boron delivery agent for BNCT. Further studies are needed to confirm its safety under clinically relevant conditions.

Immune checkpoint inhibitors (ICIs) targeting PD-1 improve outcomes in advanced non-small cell lung cancer (NSCLC), but responses are heterogeneous and tissue biomarkers are imperfect. Circulating immunoglobulins integrate B- and T-cell function and may reflect systemic immune competence. We investigated whether plasma immunoglobulin levels during ICI therapy are associated with clinical outcomes in stage IV NSCLC. In this single-center retrospective study, 55 patients received anti-PD-1-based regimens: anti-PD-1 monotherapy (n = 31), chemotherapy plus anti-PD-1 (n = 18), or ipilimumab plus nivolumab (n = 6). Plasma IgG, IgA, and IgM were measured at baseline and after 1–4 cycles, and associations with objective response, progression-free survival (PFS), and overall survival (OS) were evaluated. In the chemotherapy plus anti-PD-1 group, IgG decreased significantly on treatment (p = 0.0030), whereas no significant changes in any isotype were observed with anti-PD-1 monotherapy. In the monotherapy cohort, post-treatment IgG was higher in responders than in non-responders (p = 0.0262) and was associated with longer PFS (p = 0.0218) and OS (p = 0.0166). In multivariable Cox models in the monotherapy cohort, higher post-treatment IgG remained independently associated with longer PFS (adjusted HR 0.28, 95% CI 0.11–0.75; p = 0.011) and OS (adjusted HR 0.29, 95% CI 0.09–0.87; p = 0.028). Sensitivity analyses incorporating PD-L1 status and 6-week landmark analyses showed similar trends. In exploratory pooled analyses, no significant association between post-treatment IgG and PFS or OS was observed across all 55 patients. IgA and IgM were not significantly associated with outcomes. Higher early on-treatment plasma IgG may serve as a non-invasive biomarker of favorable outcome, particularly in the anti-PD-1 monotherapy setting, warranting prospective validation and mechanistic studies.

Background/Objectives: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy; however, their efficacy varies among patients. Eosinophils have been reported as prognostic markers in chemotherapy-treated pancreatic cancer; however, these studies are limited mainly to single cancer types and relatively small cohorts. Therefore, we aimed to examine the relationship between eosinophil count and the effectiveness of ICIs across various cancer types. Methods: We retrospectively analyzed 138 patients treated with ICI monotherapy, ICI plus chemotherapy, or chemotherapy alone at our institution between December 2015 and September 2024. Peripheral blood parameters, including eosinophil counts and albumin levels, were collected at baseline and after two cycles of treatment. Associations between overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan–Meier analysis and Cox proportional hazards regression. Results: In the ICI monotherapy group, patients with higher baseline eosinophil counts had significantly longer OS (HR 0.26, p = 0.007) and PFS (HR 0.30, p = 0.005). No significant associations were observed between the ICI plus chemotherapy and chemotherapy-alone groups. Changes in eosinophil counts between baseline and after two cycles were not associated with outcomes in any group. Conclusions: Baseline eosinophil counts were significantly associated with survival outcomes in patients receiving ICI monotherapy and may serve as a promising predictive biomarker.

Background/Objectives: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy; however, reliable biomarkers of therapeutic efficacy remain limited. We investigated the clinical utility of plasma WFDC2 levels in patients receiving anti-PD-1 antibody treatment. Methods: Twenty-one patients with non-small cell lung, gastric, or bladder cancer received nivolumab or pembrolizumab. Plasma WFDC2 concentrations were measured by ELISA before ICI treatment (pre-ICI) and after two and four treatment cycles. Associations between WFDC2 expression changes and overall survival (OS), progression-free survival (PFS), and tumor progression were assessed. ROC curve analyses compared the predictive performance of WFDC2, soluble PD-L1 (sPD-L1), soluble PD-1 (sPD-1), and their combinations, with the area under the curve (AUC) evaluating predictive accuracy. Results: Levels of WFDC2 pre-ICI and those after two cycles were significantly higher than levels in healthy donors. However, no significant differences in WFDC2 levels were found between the time points during treatment. Greater increases in WFDC2 levels were significantly correlated with shorter OS (p = 0.002), shorter PFS (p = 0.037), and tumor progression (p = 0.003). ROC analysis revealed that WFDC2 achieved a higher AUC (0.700) than sPD-L1 (0.538) or sPD-1 (0.650). Combining biomarkers improved the predictive accuracy, with sPD-L1 plus WFDC2 showing the highest AUC (0.825). Conclusions: Serial increases in plasma WFDC2 are associated with poor clinical outcomes, highlighting its potential as a biomarker. Baseline plasma WFDC2 outperformed sPD-L1 and sPD-1 diagnostically. These findings should be interpreted as exploratory and hypothesis-generating, requiring confirmation in larger, tumor-specific cohorts with multivariate adjustment. WFDC2 represents a promising minimally invasive biomarker for the early identification of patients unlikely to benefit from ICI therapy.

Background: Although WAP four-disulfide core domain 2 (WFDC2) is widely recognized as a diagnostic biomarker for ovarian cancer, its function in other cancer types remains unclear. The aim of this study was to evaluate the prognostic potential of WFDC2 across multiple cancers.Methods: Publicly available transcriptomic datasets were analyzed to compare WFDC2 mRNA expression in normal and tumor tissues across various cancer types. Kaplan-Meier survival analysis and Cox proportional hazards regression were used to assess the association between WFDC2 mRNA expression and overall survival (OS). Plasma WFDC2 levels were measured using enzyme-linked immunosorbent assay in healthy donors as well as patients with gastric, lung, colorectal, esophageal, and pancreatic cancers. Receiver operating characteristic (ROC) analysis was performed to evaluate the diagnostic performance of WFDC2. Kaplan–Meier analysis was conducted to evaluate the association between WFDC2 expression and OS. Cox proportional hazards regression analysis was performed to assess the prognostic significance of WFDC2 expression.Results: WFDC2 mRNA expression was significantly elevated in gastric cancer, lung adenocarcinoma (LUAD), esophageal carcinoma, and pancreatic ductal adenocarcinoma (p < 0.01); however, it was significantly lower in colorectal cancer (p < 0.005). Kaplan-Meier analysis indicated that elevated WFDC2 mRNA expression in LUAD was only significantly associated with prolonged OS (p = 0.017), whereas no significant associations were observed in other cancer types. Moreover, plasma WFDC2 levels were significantly higher in all cancer patient groups than in healthy donors (p < 0.0001). ROC analysis revealed potential diagnostic performance, with an area under the curve of 0.890 (95% CI: 0.844–0.936) for distinguishing patients with cancer from healthy donors. Subgroup analysis indicated diagnostic performance across all cancer types. Elevated plasma WFDC2 levels were significantly associated with shorter OS in esophageal cancer (p = 0.0226). Multivariate Cox regression analysis confirmed that plasma WFDC2 concentration was an independent prognostic factor in gastric (HR = 1.04, 95% CI: 1.00–1.07, p = 0.019) and esophageal cancers (HR = 1.08, 95% CI: 1.02–1.13, p = 0.006).Conclusion: Plasma WFDC2 levels demonstrated potential diagnostic performance across multiple cancers and were significantly associated with poor prognosis in gastric and esophageal cancers.