Journal of Thoracic Oncology最新文献

Introduction: Thyroid transcription factor-1 (TTF-1) expression, routinely assessed through immunohistochemistry in the diagnostic evaluation of lung adenocarcinomas (LUADs), is negative (TTF-1^Neg) in approximately 15% to 20% of cases. Although worse outcomes have been reported for these tumors compared with TTF-1-positive (TTF-1^Pos) LUAD, a comprehensive characterization of TTF-1 negativity is currently lacking.

Methods: Patients with LUAD and available TTF-1 immunohistochemistry from five institutions, The Cancer Genome Atlas, the Stand Up To Cancer-Mark Foundation, and the POPLAR/OAK data sets, were included. Features and outcomes were analyzed according to TTF-1 expression.

Results: Among 3297 patients, TTF-1^Neg (15%, n = 496), compared with TTF-1^Pos (85%, n = 2801), was associated with a more frequent tobacco use history and lower PD-L1 expression. TTF-1^Neg LUAD was enriched for STK11, KEAP1, SMARCA4, NKX2-1, CDKN2A, and KRAS mutations (q < 0.05). Patients with metastatic TTF-1^Neg LUAD treated with immune checkpoint inhibitors (n = 233), compared with TTF-1^Pos cases (n = 1179), had worse objective response rates (ORR, 17% versus 28%, p = 0.001), median progression-free survival (mPFS, 2.5 versus 4.4 mo, p < 0.0001), and median overall survival (mOS, 9.6 versus 20.2 mo, p < 0.0001). Similarly, TTF-1^Neg cases had worse outcomes to chemoimmunotherapy (ORR, 26% versus 41%, p < 0.0001; mPFS, 4.6 versus 8.2 mo, p < 0.0001; mOS, 11.2 versus 23.4 mo, p < 0.0001), durvalumab after chemoradiation for unresectable stage III disease (mPFS, 8.0 versus 24.8 mo, p = 0.016; mOS, 20.0 mo versus not reached, p = 0.004), and KRAS^G12C inhibitors in KRAS^G12C-mutant LUAD (ORR, 13% versus 36%, p = 0.03; mPFS, 2.7 versus 5.9 mo, p < 0.0001; mOS, 4.4 versus 12.1 mo, p < 0.0001).

Conclusions: TTF-1 negativity identifies a subset of LUAD with worse outcomes to immunotherapy, chemoimmunotherapy, and KRAS^G12C inhibitors.

Introduction: Optimal first-line immunotherapy duration in metastatic NSCLC with controlled disease remains unclear. We evaluated 6-month nivolumab-ipilimumab (Nivo-Ipi) in patients with disease control (DC).

Methods: This randomized, open-label, noninferiority trial enrolled treatment-naive patients with metastatic NSCLC (aged 18-75 y, Eastern Cooperative Oncology Group performance status 0-1, no actionable genomic alterations). After 6-month induction treatment with Nivo (3 mg/kg biweekly) plus Ipi (1 mg/kg every 6 wk), patients with DC were randomized to continue treatment or stop and resume at disease progression. The primary outcome was progression-free survival (PFS).

Results: Among 265 patients enrolled, 71 were randomized to the continuation control arm (n = 36) or to the experimental arm (n = 35), with trial premature interruption because of the lack of European filing for the immunotherapy combination. Median PFS follow-up was 47.8 months (95% confidence interval [CI]: 43.1-51.0). In the per-protocol population, median PFS was 18.7 months (95% CI: 7.1-37.1) in the continuation arm versus not reached (NR) (95% CI: 16.1-NR) in the experimental arm. Median OS was 55.5 months (95% CI: 32.4-NR) in the continuation arm versus NR in the experimental group. The 18-month OS was 80.6% (95% CI: 63.5-90.2) and 93.8% (95% CI: 77.3-98.4), respectively. Grade 3 to 5 treatment-related adverse event rates were higher in the continuation arm (54.3% versus 23.5%). Median time until definitive quality-of-life deterioration was 15.5 months (95% CI: 10.0-NR) for the continuation arm but NR in the experimental arm (hazard ratio = 0.36, 95% CI: 0.14-0.92, p = 0.03).

Conclusions: Stopping Nivo-Ipi combination at 6 months in DC patients demonstrated no survival harm at 4 years, reduced severe immune-related adverse events, and delayed quality-of-life deterioration.

Introduction: Acquired resistance to third-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs) is a major challenge in NSCLC, with approximately 50% of cases lacking precise resistance mechanisms. This study investigates the immunosuppressive tumor microenvironment (TME) driving resistance and develops a novel triple-combination therapy to restore T-cell antitumor activity.

Methods: Single-cell RNA sequencing and multicolor fluorescence staining were performed on NSCLC patient samples to analyze TME changes post-EGFR-TKI resistance. A triple therapy combining BC3448 (EGFR and CD3 bispecific T-cell engager), tucidinostat (histone deacetylase inhibitor), and WBP3425 (4-1BB agonist) was tested using in vitro co-culture assays, syngeneic cell-derived xenograft models in humanized NOG-EXL mice, and multi-omics analyses.

Results: Single-cell RNA sequencing revealed reduced T-cell infiltration or activation and increased immunosuppressive myeloid cells in resistant NSCLC. BC3448 monotherapy activated T cells and induced tumor cell apoptosis in vitro but was limited in vivo because of myeloid-driven immunosuppression. The triple therapy significantly enhanced tumor regression in osimertinib-resistant models (tumor growth inhibition >70%, p < 0.001), promoted CD8+ effector T-cell differentiation, and suppressed Tregs and M2 macrophages. CD40-CD40L axis activation between T cells and monocyte-derived macrophages was critical for TME remodeling, with spatial profiling revealing increased CD40L+ T-cell and CD40+ macrophage proximity, correlating with higher IFN-γ and reduced angiogenesis. A durable response to BC3448 monotherapy was observed in an immunotherapy-resistant patient with NSCLC (>2 y of stable disease), presenting a translational potential of this approach.

Conclusions: This study establishes a novel triple therapy that overcomes the limitations of bispecific T-cell engagers in cold and immunosuppressive TMEs and provides an immunomodulatory approach to addressing third-generation EGFR-TKI resistance.