Pragmatic nationwide master observational trial based on genomic alterations in advanced solid tumors: KOrean Precision Medicine Networking Group Study of MOlecular profiling guided therapy based on genomic alterations in advanced Solid tumors (KOSMOS)-II study protocol KCSG AL-22-09.

BACKGROUND: Next-generation sequencing (NGS) has been introduced to many Korean institutions to support molecular diagnostics in cancer since 2017, when it became eligible for reimbursement by the National Health Insurance Service. However, the uptake of molecularly guided treatment (MGT) based on NGS results has been limited because of stringent regulations regarding prescriptions outside of approved indications, a lack of clinical trial opportunities, and limited access to molecular tumor boards (MTB) at most institutions. The KOSMOS-II study was designed to demonstrate the feasibility and effectiveness of MGT, informed by MTBs, using a nationwide precision medicine platform. METHODS: The KOSMOS-II trial is a large-scale nationwide master observational study. It involves a framework for screening patients with metastatic solid tumors for actionable genetic alterations based on local NGS testing. It recommends MGT through a remote and centralized MTB meeting held biweekly. MGT can include one of the following options: Tier 1, the therapeutic use of investigational drugs targeting genetic alterations such as ALK, EGFR, ERBB2, BRAF, FH, ROS1, and RET, or those with high tumor mutational burden; Tier 2, comprising drugs with approved indications or those permitted for treatment outside of the indications approved by the Health Insurance Review and Assessment Service of Korea; Tier 3, involving clinical trials matching the genetic alterations recommended by the MTB. Given the anticipated proportion of patients receiving MGT in the range of 50% ± 3.25%, this study aims to enroll 1,000 patients. Patients must have progressed to one or more lines of therapy and undergone NGS before enrollment. DISCUSSION: This pragmatic master protocol provides a mass-screening platform for rare genetic alterations and high-quality real-world data. Collateral clinical trials, translational studies, and clinico-genomic databases will contribute to generating evidence for drug repositioning and the development of new biomarkers. TRIAL REGISTRATION: NCT05525858.

Lipocalin-2 as a prognostic biomarker and its association with systemic inflammation in small cell lung cancer.

BACKGROUND: Systemic inflammation is believed to contribute to small cell lung cancer (SCLC) progression, but the underlying relationship remains unclear. Lipocalin-2, a potential biomarker of inflammation, has been implicated in various cancers but its prognostic value in SCLC is underexplored. METHODS: We retrospectively analyzed 191 patients with SCLC (72 with limited-stage [LD] and 119 with extensive-stage) treated using platinum-based chemotherapy. Lipocalin-2 expression was evaluated using immunohistochemistry. Optimal cutoff values for lipocalin-2 and neutrophil-to-lymphocyte ratio (NLR) were determined using time-dependent receiver operating characteristic curve analysis. The pectoralis muscle index was used to assess sarcopenia. RESULTS: In LD-SCLC, high lipocalin-2 expression was associated with worse progression-free survival (PFS; median: 7.0 vs. 15.9 months, p = 0.015) and overall survival (OS; median: 12.9 vs. 30.3 months, p = 0.035) compared with low lipocalin-2 expression. Patients were stratified into three prognostic groups by combining lipocalin-2 with NLR: low lipocalin-2/low NLR, high lipocalin-2/low NLR or low lipocalin-2/high NLR, and high lipocalin-2/high NLR (median PFS: 17.3 vs. 11.0 vs. 6.3 months, p = 0.004; median OS: 30.5 vs. 17.3 vs. 8.6 months, p = 0.002). Similar trends were observed when combining lipocalin-2 with the pectoralis muscle index. High lipocalin-2 expression was also associated with lower complete response rates (18.9% vs. 34.3%, p = 0.035). No significant prognostic implications were found for lipocalin-2 in extensive-stage SCLC. CONCLUSIONS: High lipocalin-2 expression is potentially associated with poorer survival in LD-SCLC. Combining lipocalin-2 with other inflammation-related markers could improve prognostic stratification.

3D bioprinting of stromal cells-laden artificial cornea based on visible light-crosslinkable bioinks forming multilength networks.

3D bioprinting has the potential for the rapid and precise engineering of hydrogel constructs that can mimic the structural and optical complexity of a healthy cornea. However, the use of existing light-activated bioinks for corneal printing is limited by their poor cytocompatibility, use of cytotoxic photoinitiators (PIs), low photo-crosslinking efficiency, and opaque/colored surface of the printed material. Herein, we report a fast-curable, non-cytotoxic, optically transparent bioprinting system using a new water-soluble benzoyl phosphinate-based PI and photocrosslinkable methacrylated hyaluronic acid (HAMA). Compared with commercially available PIs, the newly developed PI, lithium benzoyl (phenyl) phosphinate (BP), demonstrated increased photoinitiation efficiency under visible light and low cytotoxicity. Using a catalytic amount of BP, the HA-based bioinks quickly formed 3D hydrogel constructs under low-energy visible-light irradiation (405 nm, <1 J cm-2). The mechanical properties and printability of photocurable bioinks were further improved by blending low (10 kDa) and high (100 kDa) molecular weight (MW) HAMA by forming multilength networks. For potential applications as corneal scaffolds, stromal cell-laden dome-shaped constructs were fabricated using MW-blended HAMA/BP bioink and a digital light processing printer. The HA-based photocurable bioinks exhibited good cytocompatibility (80%-95%), fast curing kinetics (<5 s), and excellent optical transparency (>90% in the visible range), potentially making them suitable for corneal tissue engineering.

Lazertinib as a frontline treatment in patients with EGFR-mutated advanced non-small cell lung cancer: Long-term follow-up results from LASER201.

OBJECTIVE: This analysis of the first-line cohort of LASER201 study evaluated the efficacy and safety of lazertinib 240 mg as a frontline therapy for epidermal growth factor receptor (EGFR)-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC). METHODS: A total of 43 patients, with EGFR mutation-positive (Exon19Del, n = 24; L858R, n = 18; G719X, n = 1) locally advanced or metastatic NSCLC who had not previously received EGFR tyrosine kinase inhibitor (EGFR TKI) therapy, received once-daily lazertinib 240 mg. EGFR mutation status was confirmed by local or central testing. The primary endpoint was objective response rate (ORR) assessed by blinded independent central review. Secondary efficacy endpoints included duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), tumor shrinkage, and overall survival (OS). RESULTS: At the primary data cut-off (DCO; January 8, 2021), the ORR was 70 % (95 % confidence interval [CI]: 56.0-83.5), DCR was 86 % (95 % CI: 75.7-96.4) and the median DoR was 23.5 (95 % CI: 12.5-not reached) months. The median PFS was 24.6 (95 % CI: 12.2-30.2) months. At the final DCO (March 30, 2023), the median OS was not estimable and the median follow-up duration for OS was 55.2 [95 % CI: 22.8-55.7] months. OS rates at 36 months and 54 months were 66 % (95 % CI: 47.5-79.3 %) and 55 % (95 % CI: 36.6-70.7 %), respectively. The most commonly reported TEAEs were rash (54 %), diarrhea (47 %), pruritus (35 %), and paresthesia (35 %). No drug-related rash or pruritus TEAEs of grade 3 or higher were reported. Diarrhea and paresthesia of grade 3 or higher were reported in 3 (7 %) and 1 (2 %) patients, respectively. CONCLUSION: This analysis demonstrated long-term clinical benefit with lazertinib 240 mg in patients with EGFR-mutated NSCLC who had not previously received EGFR TKIs. The safety profile for lazertinib was tolerable and consistent with that previously reported.

Assessing the Efficacy of Bortezomib and Dexamethasone for Induction and Maintenance Therapy in Relapsed/Refractory Cutaneous T-Cell Lymphoma: A Phase II CISL1701/BIC Study.

Purpose: This multicenter, open-label, phase II trial evaluated the efficacy and safety of bortezomib combined with dexamethasone for the treatment of relapsed/refractory cutaneous T-cell lymphoma (CTCL) in previously treated patients across 14 institutions in South Korea. Patients and Methods: Between September 2017 and July 2020, 29 patients with histologically confirmed CTCL received treatment, consisting of eight 4-week cycles of induction therapy followed by maintenance therapy, contingent upon response, for up to one year. The primary endpoint was the proportion of patients achieving an objective global response. Results: Thirteen (44.8%) of the 29 patients achieved an objective global response, including two complete responses. The median progression-free survival (PFS) was 5.8 months, with responders showing a median PFS of 14.0 months. Treatment-emergent adverse events were generally mild, with a low incidence of peripheral neuropathy and hematologic toxicities. Despite the trend toward shorter PFS in patients with higher mutation burdens, genomic profiling before and after treatment showed no significant emergence of new mutations indicative of disease progression. Conclusion: This study supports the use of bortezomib and dexamethasone as a viable and safe treatment option for previously treated CTCL, demonstrating substantial efficacy and manageability in adverse effects. Further research with a larger cohort is suggested to validate these findings and explore the prognostic value of mutation profiles.