Takahiro Mimae

Objectives: Bevacizumab (Bev) improves the response and survival rates in patients with advanced non-small cell lung cancer (NSCLC). This phase II trial aimed to assess the feasibility of adding Bev to preoperative chemotherapy in resectable non-squamous NSCLC. Methods: Patients with clinical stage II/IIIA non-squamous NSCLC (n = 30) received three cycles of cisplatin (Cis), pemetrexed (Pem), and Bev, followed by surgical resection. The primary endpoint was the complete resection rate (CRR), defined as the proportion of all eligible enrolled patients who ultimately underwent complete (R0) resection. The sample size was set at 30 patients. Treatment was considered feasible if the CRR exceeded the predefined acceptable threshold of 65%. Results: Radiological tumour reduction was observed in 29 of 30 patients (97%). Twenty-eight patients (93%) completed all three cycles of chemotherapy, and 25 patients (83%) underwent surgery. Five patients discontinued treatment due to adverse events (n = 3), disease progression (n = 1), or patient refusal (n = 1). Complete resection was achieved in all resected patients, yielding an 83% CRR (two-sided 80% confidence interval, 71.3%–91.7%). The objective response rate was 37%, and pathological complete response of the primary tumour was achieved in 3 patients (12%). Grade 3 toxicities included neutropenia (7%), nausea (7%), hypertension (23%), and pulmonary embolism (3%). No grade 4/5 adverse events occurred within 28 days, and no treatment-related deaths occurred within 84 days. Conclusions: Preoperative Cis, Pem, and Bev for clinical stage II/IIIA non-squamous NSCLC met the predefined feasibility criterion, with acceptable safety in this selected population. These findings provide historical insights supporting perioperative anti-vascular endothelial growth factor-based systemic intensification.

BackgroundSegmentectomy has demonstrated favorable long-term outcomes compared with lobectomy in patients with small peripheral non-small cell lung cancer (NSCLC). However, whether similar benefits can be achieved in centrally located, small-sized, radiologically solid-dominant NSCLC remains uncertain. This study aims to confirm the non-inferiority of segmentectomy to lobectomy within this setting.MethodsJCOG2501 is a multi-institutional, open-label, phase III, randomized controlled trial designed to confirm the non-inferiority of segmentectomy to lobectomy in patients with centrally located (within the inner two-thirds of the lung field), small-sized (maximum tumor diameter ≤2 cm), radiologically solid-dominant (consolidation-to-tumor ratio, >0.5 to ≤1) NSCLC. Eligible patients are aged 18–85 years with an Eastern Cooperative Oncology Group performance status of 0–1 and adequate pulmonary function. A two-step registration system is adopted, with preoperative and intraoperative confirmation of patient eligibility. Following confirmation of eligibility at the second registration, patients are randomized 1:1 to either the lobectomy or segmentectomy arm. In both arms, systematic or lobe-specific lymph node dissection is mandatory, and nodal sampling alone is prohibited. The primary endpoint is overall survival, analyzed in all randomized patients. Assuming a non-inferiority margin of 6.5% for 5-year overall survival, 490 patients are required to achieve 70% power with a one-sided α = 5%. The planned sample size is 500 patients at the second registration. JCOG2501 was initiated in February 2026 and is registered with the Japan Registry of Clinical Trials (jRCT1030250727).ConclusionsJCOG2501 will clarify the role of segmentectomy in centrally located small-sized NSCLC and inform future surgical standards.

Objectives: Mediastinal lymph-node dissection (MLND) is recommended for resectable non-small-cell lung cancer (NSCLC); however, its prognostic impact remains controversial. We evaluated whether MLND improves prognosis in patients with radiologically solid-dominant clinical stage I NSCLC. Methods: We retrospectively reviewed 2212 patients who underwent lobectomy for solid-dominant clinical stage I NSCLC between 2010 and 2022. Prognosis and local control were compared between the MLND and non-MLND groups. Results: The MLND and non-MLND groups included 1912 and 300 patients, respectively. After propensity score matching, 5-year overall survival did not show a statistically significant difference between the groups (85.3% vs 79.3%, P = .089). MLND identified occult pN2 metastasis in 7.3% (138/1912) of patients. Notably, 3.6% (68/1912) of the entire MLND cohort had pN2 disease yet remained recurrence-free. Furthermore, the MLND group demonstrated significantly lower mediastinal lymph-node recurrence than the non-MLND group (P = .017). Among patients with pN2 disease in the MLND group, those with recurrence (n = 70) had a higher incidence of intrapulmonary metastases (P = .042), a higher number of mediastinal lymph-node metastases (P = .002), and a lower rate of skip-N2 involvement (P = .031). Conclusions: Mediastinal lymph-node dissection provides superior local control by reducing mediastinal recurrences and enables accurate pathological staging. While this advantage guides appropriate adjuvant therapy selection, the direct impact of MLND on overall survival remains uncertain. Its true survival benefit should be evaluated in future prospective randomized trials.

Supplementary Figure S11 shows schematic illustration of our study.

Immune checkpoint inhibitors (ICI) have improved the prognosis of patients with non–small cell lung cancer (NSCLC), but the cure rate remains low because tolerant persister cancer cells can survive within the tumor during ICI treatment. We have previously reported that plasminogen activator inhibitor-1 (PAI-1) is involved in tolerance acquisition to osimertinib in EGFR-mutated NSCLC. This study aimed to examine the role of PAI-1 in ICI tolerance and whether PAI-1 may be a therapeutic target to overcome this tolerance. In a mouse subcutaneous tumor model using Lewis lung carcinoma or KLN205 cells, cancer cells surviving within the tumor 7 days after anti–PD-1 (aPD-1) antibody treatment were defined as aPD-1 antibody–tolerant persister cells (aPD-1-TP). PAI-1 and mesenchymal gene expression levels were higher in aPD-1-TPs than in control cells. IHC analyses showed higher numbers of tumor-associated macrophages, expression of PD-L1 in cancer cells, and degree of angiogenesis. In contrast, the number of tumor-infiltrating lymphocytes was lower in aPD-1 antibody–tolerant tumors than in control tumors. Combination treatment with an aPD-1 antibody and the PAI-1 inhibitor, TM5614 decreased mesenchymal gene expression, PD-L1 expression, tumor-associated macrophage numbers, and angiogenesis and increased tumor-infiltrating lymphocyte counts in tolerant tumors. Furthermore, it resulted in prolonged inhibition of tumor growth. In conclusion, this study underscores the involvement of PAI-1 in the survival of aPD-1-TPs via epithelial–mesenchymal transition and alteration of the tumor microenvironment. Combination treatment with an aPD-1 antibody and TM5614 can be a new therapeutic strategy for NSCLC.

Supplementary Figure S9 shows tumor microenvironment of tumors composed of LLC and KLN205 cells.

Supplementary Figure S8 shows relationship of TGF-β secretion with TAMs and CAFs.

Supplementary Figure S4 shows that SK-216 significantly increases the antitumor efficacy of aPD-1.