Background: Post-bronchoscopy sputum cytology (PBS) is traditionally considered a supplementary diagnostic tool for lung cancer; however, its prognostic relevance in bronchoscopically confirmed cases remains unclear. This study evaluated the clinicopathological characteristics and prognostic value of PBS positivity in patients with bronchoscopically diagnosed lung cancer. Methods: This single-center retrospective cohort study included 625 patients with newly diagnosed, bronchoscopically confirmed lung cancer, who underwent PBS between May 2007 and December 2024. Patients were classified as PBS-positive and PBS-negative. Clinical characteristics, tumor features, and overall survival (OS) were compared. Factors associated with PBS positivity were evaluated using multivariate logistic regression. Prognostic factors for OS were assessed using univariate and multivariate Cox proportional hazards models. Survival was estimated using the Kaplan-Meier method. Results: Among the 625 patients, 82 (13.1%) were PBS-positive. PBS-positive patients were significantly younger and more likely to have advanced T-factor tumors, larger primary tumors, and proximal airway involvement. Younger age and advanced T-factor were independently associated with PBS positivity. Median OS was significantly shorter in the PBS-positive group than in the PBS-negative group (median 14.3 vs. 25.3 months; log-rank P<0.001). In the multivariate analysis, PBS positivity remained an independent predictor of poor OS, along with sex, performance status, nodal status, and histological subtype. Conclusions: PBS positivity was associated with aggressive tumor characteristics and independently predicted poor OS in bronchoscopically confirmed lung cancer. Although its diagnostic value may be limited, PBS positivity represents a simple, noninvasive prognostic marker that may support risk stratification and clinical decision-making.

8606 Background: As survival improves in ALK-rearranged NSCLC, patients increasingly receive multiple lines of therapy; however, evidence to guide later-line ALK-TKI sequencing in the third line and beyond remains limited. Brigatinib has activity against multiple ALK resistance mutations, yet data on its effectiveness after progression on first-line alectinib and subsequent lorlatinib and/or chemotherapy—and on associated plasma ctDNA biomarkers—remain scarce. Methods: WJOG11919L/ABRAID Cohort B is a prospective, multicenter observational study enrolling patients with ALK-rearranged NSCLC who received brigatinib after lorlatinib and/or chemotherapy following first-line alectinib. Effectiveness and safety were summarized descriptively. Pretreatment plasma ctDNA was analyzed with the PGDx Elio Plasma Resolve panel. The data cutoff was September 26, 2024. Results: Twenty-five patients were analyzed (median age, 64 years; all adenocarcinoma); ECOG PS was 0-1/2-3 in 22 (88.0%)/3 (12.0%). Baseline CNS metastases were present in 10 patients. After alectinib, 13 patients received lorlatinib and 14 received platinum-based chemotherapy (overlap, n=2). Median follow-up was 12.7 months. Efficacy outcomes overall and by prior lorlatinib exposure are summarized in the Table. 23 patients had discontinued brigatinib, including 21 due to PD. Pretreatment ctDNA was evaluable in 24 patients: ALK mutations were detected in 4 (including 3 with prior lorlatinib), and compound ALK mutations (G1202R/I1171M/L1204V and D1203N/L1196M) were identified in 2, both after lorlatinib. In exploratory analyses, among the 3 patients with prior lorlatinib and detectable ALK mutations, all experienced early progression or death within 10 weeks of brigatinib initiation. Pneumonitis/ILD occurred in 1 patient (4%; grade 4). No new safety signals were observed. Conclusions: Brigatinib showed clinically meaningful activity with a manageable safety profile, providing durable disease control in a subset of patients previously treated with alectinib followed by lorlatinib and/or chemotherapy. Outcomes appeared less favorable after prior lorlatinib, although some patients derived benefit. In exploratory plasma ctDNA analyses among patients with prior lorlatinib, detectable ALK mutations were associated with less favorable outcomes and should be validated in larger cohorts. Clinical trial information: UMIN000042439. Efficacy outcomes overall and by prior lorlatinib exposure. Endpoint Overall (n=25) Prior lorlatinib (n=13) No prior lorlatinib (n=12) ORR, % (95% CI) 32.0 (14.9–53.5) 30.8 (12.7–57.6) 33.3 (13.8–60.9) DCR, % (95% CI) 60.0 (38.7–78.9) 38.5 (17.7–64.5) 83.3 (55.2–95.3) mPFS, mo (95% CI) 4.8 (2.2–12.7) 2.2 (1.2–18.8) 8.9 (2.3–15.6) 12-mo PFS, % 32.0 30.8 33.3 mOS, mo (95% CI) 13.7 (7.29–NR) 10.8 (3.7–NR) 16.2 (7.1–NR) 12-mo OS, % 56.0 38.5 75.0

BACKGROUND:Optimal management of advanced thymoma remains uncertain. We compared the efficacy of first-line platinum-anthracycline chemotherapy with other platinum-based regimens in a large Japanese cohort. METHODS:We retrospectively analyzed 157 patients with unresectable or recurrent thymoma treated at 39 institutions (2000-2020). Regimens were categorized as platinum-anthracycline (n = 104) or non-anthracycline platinum (n = 53). Propensity score matching (PSM) balanced baseline characteristics (46 pairs). The primary endpoint was overall response rate (ORR); secondary endpoints were real-world progression-free survival (rwPFS) and overall survival (OS). RESULTS:Median age was 58 years (24-79) and 53% were male; 62% had recurrent disease. Before PSM, ORR was higher with platinum-anthracycline than with non-anthracycline platinum (57% vs 31%; p = 0.0024), while rwPFS (median 15.0 vs 13.4 months; HR 1.07; p = 0.72) and OS (median 84.9 vs 111.9 months; HR 1.36; p = 0.24) did not differ. After PSM, ORR remained higher (58% vs 32%; p = 0.0014) with comparable rwPFS (12.1 vs 11.7 months; HR 0.98; p = 0.98) and OS (93.8 vs 113.5 months; HR 1.41; p = 0.31). Overall, 70% of patients received subsequent local therapy. Among fatal cases, paraneoplastic syndromes occurred in 50%, and infections and cardiovascular events were frequent causes of death in addition to tumour progression. CONCLUSIONS:Although platinum-anthracycline regimens achieved higher response rates, this did not translate into longer rwPFS or OS. Non-anthracycline platinum regimens may be reasonable for selected patients, particularly when treatment tolerability is a priority, within individualized multidisciplinary long-term management. TRIAL REGISTRATION:UMIN000048181.

e15105 Background: Large Amino Acid Transporter 1 (LAT1) is critical for transporting essential amino acids, enabling the growth and proliferation of cancer cells. LAT1 is overexpressed via oncogene Myc-pathway in aggressive tumors, making it a promising therapeutic target. LAT1 inhibition disrupts mTORC1 pathway and the metabolic programs, vital for cancer progression. To address the limitations of currently developed reversible inhibitors, we developed APL1101, a first-in-class LAT1 inhibitor that achieves an effectively irreversible, noncovalent “locking” mechanism to durably block amino acid transport. Methods: Preclinical efficacy studies of APL1101 involved in vitro and in vivo models, including LAT1-overexpressing xenograft tumors such as non-small cell lung cancer and triple-negative breast cancer. Toxicity, and pharmacokinetics (PK) were evaluated in rodents and canines to assess safety, drug distribution, and LAT1 occupancy. Combination studies were also performed to explore synergy with existing therapies. Results: APL1101 demonstrated potent and selective LAT1 inhibition in vitro (Ki < 20 nM), significantly reducing tumor cell proliferation. In vivo, it achieved more than 70% tumor growth suppression in xenograft models without causing systemic toxicity or weight loss. PK studies revealed sufficient Cmax and a long half-life, supporting sustained efficacy. Toxicology studies in rodents and canines confirmed a favorable safety profile, with no off-target effects and high tolerability. Notably, preclinical data suggest that combining APL1101 with immune checkpoint inhibitors or standard chemotherapy agents can synergistically enhance anti-tumor efficacy. Clinical Development: Preparations for a Phase 1/2a clinical trial are underway, with Phase 1 scheduled to begin in Q4 2026. The trial will evaluate safety, tolerability, and efficacy in patients with advanced solid tumors. Phase 2a will focus on LAT1-overexpressing cancers using biomarker-driven stratification. APL1101’s mechanism of action, targeting mTORC1 pathway and metabolic programs, underscores its broader potential across multiple solid and hematologic malignancies. Conclusions: APL1101’s innovative irreversible LAT1 inhibition mechanism demonstrates robust preclinical efficacy and safety, supporting its potential as a transformative therapy for aggressive cancers. Its versatility as a monotherapy or in combination regimens with chemotherapeutics and immunotherapies offers significant promise for broader cancer treatment. The upcoming clinical trials will provide critical insights into its full therapeutic potential.

Background: Osimertinib is the standard first-line treatment for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC); however, clinical outcomes vary widely even among patients receiving uniform therapy. Reliable baseline prognostic biomarkers beyond EGFR mutation subtype remain limited. Trophoblast cell-surface antigen 2 (TROP2) has been implicated in tumor progression and therapeutic resistance, but its prognostic relevance in EGFR-mutated NSCLC treated with first-line osimertinib remains unclear. Therefore, this study aimed to evaluate the prognostic significance of TROP2 expression in patients with EGFR-mutated NSCLC treated with first-line osimertinib. Methods: We retrospectively analyzed 155 patients with recurrent or metastatic EGFR-mutated NSCLC who received first-line osimertinib monotherapy between August 2018 and December 2023. TROP2 expression was evaluated by immunohistochemistry using a semi-quantitative scoring system calculated as the product of staining intensity (0-3) and proportion score (1-4), yielding a total score ranging from 0 to 12. TROP2 overexpression was defined as a total score of 12. Progression-free survival (PFS) and overall survival (OS) were assessed using the Kaplan-Meier method and Cox proportional hazards models. Results: TROP2 overexpression was observed in 72 patients (46.5%). While TROP2 overexpression was not independently associated with PFS, it was associated with shorter OS in the overall cohort. In multivariate analysis, age, performance status, clinical stage, liver metastasis, and TROP2 overexpression were identified as independent prognostic factors for OS. Subgroup analysis showed that TROP2 overexpression was associated with worse OS in patients with EGFR exon 19 deletion, whereas this association was not evident in those with L858R mutation. TROP2 intensity score showed stronger prognostic relevance than the proportion score. Conclusions: TROP2 overexpression is an independent predictor of poor OS in patients with EGFR-mutated NSCLC receiving first-line osimertinib. These findings suggest that baseline TROP2 expression may reflect biologically aggressive disease and support further exploration of TROP2-targeted strategies after EGFR-TKI resistance.

Abstract Background: Precursor-exhausted CD8+ T cells (Tpex) are self-renewing, stem-like CD8+ T cells that give rise to terminally exhausted (Tex) cells and maintain long-term antitumor immunity. Within the tumor microenvironment (TME), Tpex localize to tertiary lymphoid structures (TLSs) and high endothelial venules (HEVs) and trigger the CD8+ T-cell burst after PD-1 blockade. However, the CD4+ T-cell subsets that support Tpex generation and maintenance remain unclear. We previously identified Th7R cells, a Th1-like CD4+ T-cell subset (CCR4-CCR6+, expressing IL7R and TCF7) in lung cancer, associated with immune checkpoint inhibitor (ICI) responsiveness. Th7R and Tpex share stem-like signatures, suggesting a potential partnership. Objective: To test whether Th7R cells function as CD4+ partners sustaining Tpex and long-term antitumor immunity, and to evaluate the antitumor efficacy of Th7R adoptive transfer. Methods: We analyzed 55 early-stage lung cancer patients undergoing resection and 20 stage II-III patients treated with neoadjuvant anti-PD-1 therapy. Peripheral blood, tumor-infiltrating lymphocytes (TILs), and lymph node T cells were profiled by mass and imaging mass cytometry to assess the spatial and numerical relationship between Th7R and Tpex. In a mouse MCA205 model, CCR4-CCR6+ Th7R cells sorted and expanded from tumor-draining lymph nodes were adoptively transferred to evaluate antitumor effects and their impact on TILs. Results: Patients with high preoperative Th7R frequency showed better disease-free survival. Th7R—but not other CD4+ subsets—decreased after tumor resection, indicating tumor antigen-driven expansion. In neoadjuvant cases, complete or major pathological responders had higher proportions of Th7R cells. Th7R and Tpex showed a positive correlation in both blood and lymph nodes. Imaging mass cytometry showed Th7R cells located near Tpex within TLSs. In mice, Th7R transfer induced tumor regression and specifically expanded both Tpex and Tex subsets. Conclusion: Th7R cells are numerically and spatially associated with Tpex and crucial for sustaining long-term antitumor immunity. They may promote asymmetric Tpex division, maintaining renewal and effector supply. Th7R adoptive transfer, alone or with ICIs, represents a promising approach to enhance durable antitumor immunity. Citation Format: Shota Takei, Ou Yamaguchi, Satoshi Yamasaki, Atsuhito Mouri, Ayako Shiono, Yu Miura, Kosuke Hashimoto, Hisao Imai, Kyoichi Kaira, Ichiki Yoshinobu, Hiroyuki Nitanda, Tomoyuki Hishida, Katsuhisa Horimoto, Hiroshi Kagamu, . Th7R cells: CD4+ T-cell partners that drive Tpex-mediated antitumor immunity in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4251.

TPS8667 Background: The standard of care for stage IV non-small cell lung cancer (NSCLC) patients without actionable driver mutations is immune-checkpoint inhibitors (ICIs) with or without platinum-based chemotherapy. For patients with synchronous oligometastatic disease, local ablative therapy (LAT) to all lesions, including primary sites, may improve survival based on several randomized phase II trials. Furthermore, combining LAT with ICIs may enhance anti-tumor immune responses by reducing tumor burden. However, a recent large phase II/III study failed to demonstrate a survival benefit for adding LAT to systemic therapy in patients with synchronous or induced oligometastatic NSCLC. Consequently, it remains unclear whether LAT provides a survival benefit in synchronous oligometastatic NSCLC. Based on the promising results from our preceding phase II trial (TRAP-OLIGO; WJOG11118L), we initiated this phase III trial to definitively evaluate the benefit of adding LAT to pembrolizumab plus platinum-based chemotherapy specifically for synchronous oligometastatic NSCLC. Methods: J-OLIGO is a multicenter, open-label, randomized phase III intergroup trial. Eligible patients have untreated stage IV NSCLC, ECOG PS 0-1, 1–3 metastases, and no actionable driver mutations. During the induction phase, patients receive 4 cycles of pembrolizumab plus platinum-based chemotherapy. Patients who achieve disease control with induction therapy and remain eligible for LAT to all residual lesions are randomized (1:1) to either the LAT group (Intervention) or the standard group (Control). The feasibility and appropriateness of LAT for each patient are evaluated by a multidisciplinary tumor board, consisting of medical oncologists, radiation oncologists, and thoracic surgeons, to ensure definitive treatment of all viable lesions. The LAT group receives definitive surgery and/or definitive radiotherapy to all sites, followed by maintenance pembrolizumab (±pemetrexed). Stratification factors include number of metastases, PD-L1 TPS, histology, and induction response. The primary endpoint is overall survival (OS), defined as the time from randomization. Secondary endpoints include progression-free survival (PFS), objective response rate (ORR), and the safety. Based on results from previous studies, the study has 80% power to detect a hazard ratio of 0.55 for OS (median OS: 20 vs. 36 months) with a one-sided alpha of 0.05. The target sample size is 150 patients for primary registration and 100 for secondary registration. Accrual began in October 2025 and is planned for 4 years, followed by a 4-year follow-up period. This trial is supported by the Japan Agency for Medical Research and Development (AMED) under the Project for Innovative Cancer Research. Clinical trial information: jRCTs041250114.

PURPOSE:NRG Oncology/Alliance LU005 (ClinicalTrials.gov identifier: NCT03811002) tested the addition of atezolizumab to concurrent chemoradiation (CRT) in this open-label, phase III international trial. METHODS:Patients with limited-stage small cell lung cancer (LS-SCLC), stage Tx-IV, N0-3, and M0 with Eastern Cooperative Group performance status (PS) 0-2 received one cycle of chemotherapy (platinum/etoposide) before study registration and were randomly assigned to CRT alone versus CRT plus concurrent and adjuvant atezolizumab, 1,200 mg once daily, every 3 weeks until investigator-assessed progression or intolerable side effects for a maximum of 17 cycles. Patients were stratified by choice of chemotherapy (cisplatin v carboplatin), radiation fractionation schedule (66 Gy once daily v 45 Gy twice daily), sex, and PS (0/1 v 2). The primary end point was overall survival (OS). Secondary end points included investigator-assessed progression-free survival (PFS), objective response rate, local control, and distant-metastasis-free survival (DMFS). RESULTS:patients were randomly assigned from May 2019 to December 2023. The median OS was 36.1 months (95% CI, 28.1 to 42.5) for the CRT-alone arm and 31.1 months (95% CI, 28.5 to 44.7) for the CRT + atezolizumab arm, respectively (hazard ratio [HR], 1.03 [95% CI, 0.80 to 1.32]). The median PFS was 11.4 months (95% CI, 10.3 to 13.2) for the CRT-alone arm and 12.1 months (95% CI, 10.9 to 15.2) for the CRT + atezolizumab arm, respectively (HR, 0.98 [95% CI, 0.79 to 1.22]). The median DMFS was 13.0 months (95% CI, 11.3 to 18.2) for the CRT-alone arm and 16.8 months (95% CI, 12.1 to 21.6) for the CRT + atezolizumab arm (HR, 0.96 [95% CI, 0.76 to 1.21]). No unexpected safety signals with concurrent atezolizumab were observed. CONCLUSION:Concurrent and adjuvant atezolizumab with chemoradiation did not improve survival in patients with LS-SCLC.

CD4⁺ T cells support the priming, expansion, and function of CD8⁺ T cells through dendritic cells. Precursor exhausted T cells (Tpex) maintain self-renewal and supply cytotoxic CD8⁺ T cells in the tumor microenvironment (TME), but the identity of their CD4⁺ T-cell partners remains unclear. Here, we perform scRNA-seq, scTCR-seq, and mass cytometry analysis on peripheral blood, tumor, and lymph nodes primarily from lung cancer patients and, in part, renal cell carcinoma. We identify an IL-7Rhigh CCR6⁺ Th1-like CD4⁺ T cell-population, named Th7R, that is numerically and spatially partnered with Tpex. Th7R cells express lymphotoxin-β and CXCL13, correlate with high endothelial venules, and co-localize with Tpex in tertiary lymphoid structures. Th7R cell abundance correlates with Tpex numbers in the TME and lymph nodes, and adoptive transfer of Th7R increases Tpex in a preclinical mouse model. Intratumoral Th7R and Tpex associate with improved response to neoadjuvant PD-1 blockade therapy. These results suggest that Th7R cells act as partners of Tpex to sustain antitumor T-cell immunity.

Background: Thymic epithelial tumors (TETs) are rare neoplasms; however, optimal predictors after initial treatment are unclear. 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) is useful for differentiating malignant from benign lesions and has the potential to serve as a prognostic predictor. This retrospective study investigated the prognostic significance of 18F-FDG PET in patients with TETs. Methods: A total of 108 consecutive patients with TETs classified as thymoma or thymic carcinoma (TC) who received 18F-FDG PET before any treatment between August 2007 and March 2020 were eligible for this study. For 18F-FDG uptake, the maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were assessed for prognostic prediction. Results: Univariate analysis identified performance status (PS), smoking, disease stage, histology, SUVmax, MTV, and TLG as significant predictors of progression-free survival (PFS) and overall survival (OS). In the multivariate analysis, TLG was an independent prognostic factor for predicting worse PFS, and histology emerged as a significant predictor for OS. In patients with thymoma, univariate analysis identified disease stage, SUVmax, MTV, and TLG as significant predictors for PFS but not OS. In patients with TC, univariate analysis identified PS, disease stage, smoking status, SUVmax, MTV, and TLG as significant predictors for both PFS and OS. Conclusions: Indicators of 18F-FDG uptake, including SUVmax, MTV, and TLG, can predict poor outcomes in patients with TETs. Increased accumulation of 18F-FDG was closely associated with poor PFS in specific populations, such as those with thymoma or TC, but not OS.

PURPOSE:Thyroid transcription factor 1 (TTF-1) expression is a useful predictor of treatment efficacy in advanced non-squamous non-small cell lung cancer (NSCLC). This study aimed to evaluate whether TTF-1 could predict the effectiveness of chemotherapy versus chemoimmunotherapy in patients with non-squamous NSCLC with programmed death ligand-1 (PD-L1) expression between 1% and 49%. MATERIALS AND METHODS:We conducted a retrospective study of patients with NSCLC who were treated with chemotherapy or chemoimmunotherapy between March 2016 and May 2023. The patients had histologically confirmed NSCLC, stage III-IV or postoperative recurrence, TTF-1 measurements, and PD-L1 expression levels between 1% and 49%. Clinical data were analyzed to evaluate the effect of TTF-1 expression on treatment efficacy. RESULTS:This study included 283 of 624 patients. TTF-1-positive patients showed longer progression-free survival (PFS) and overall survival (OS) (PFS: 6.4 months [95% confidence interval (CI), 5.0 to 9.4] vs. 4.1 months [95% CI, 2.7 to 6.1], p=0.03; OS: 17.9 months [95% CI, 15.2 to 28.1] vs. 9.4 months [95% CI, 6.3 to 17.0], p < 0.01) in the chemotherapy cohorts (n=93). In the chemoimmunotherapy cohort (n=190), there was no significant difference in PFS and OS between TTF-1-positive and -negative groups (PFS: 7.6 months [95% CI, 6.4 to 11.0] vs. 6.0 months [95% CI, 3.6 to 12.6], p=0.59; OS: 25.0 months [95% CI, 18.0 to 49.2] vs. 21.3 months [95% CI, 9.8 to 28.8], p=0.09). CONCLUSION:In patients with NSCLC with PD-L1 expression between 1% and 49%, TTF-1 expression was a predictor of chemotherapeutic, but not chemoimmunotherapeutic, efficacy.

Abstract Background: Anti-tumor T-cell immunity is strongly influenced by the host immune state, known as the cancer-immune set point, in which gut immunity plays an essential role. Kawanabe-Matsuda et al. demonstrated in tumor-bearing mice that oral intake of purified exopolysaccharides derived from Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1 (R-1 EPS) induces CCR6+ T cells in Peyer’s patches and enhances the antitumor efficacy of immune checkpoint inhibitors. A randomized controlled study also reported that 4-week continuous consumption of yogurt containing R-1 EPS increases CCR6+ T-cell subsets in the peripheral blood of healthy volunteers. We previously identified a novel CCR4-CCR6+ CD4+ T-cell cluster, Th7R, enriched in advanced non-small cell lung cancer (NSCLC) patients who responded to PD-1 blockade therapy. Pre-treatment Th7R predicted ICI efficacy, and long-term survivors maintained a high proportion of Th7R after therapy. Objective: To analyze longitudinal changes in T-cell subsets in patients with histologically confirmed lung cancer who consumed yogurt fermented by L. bulgaricus OLL1073R-1 containing R-1 EPS. Methods: Peripheral blood was collected before intake, after 4 weeks of yogurt consumption, and 4 weeks after discontinuation. Changes in T-cell immune markers were evaluated using the Welch test and correlation analyses. Adverse events and the influence of concurrent cancer treatments were assessed. Results: By August 15, 2025, 91 NSCLC patients were enrolled (median age 73 years; 70 males). Participants included stage II-III patients who received neoadjuvant therapy plus surgery or chemoradiotherapy, and patients with advanced or recurrent disease receiving systemic therapy. Treatments included targeted therapy (n=5), pembrolizumab (n=15), ipilimumab plus nivolumab (n=51), cytotoxic agents plus pembrolizumab (n=2), chemoradiotherapy (n=3), and neoadjuvant cytotoxic therapy plus nivolumab (n=9). In the PD-1 inhibitor group, an increase in peripheral GZMB+ CD8+ T cells was observed. Moreover, compared with historical data, the pembrolizumab-induced reduction of Th7R cells was attenuated. In the pembrolizumab subgroup with PD-L1 TPS ≥50%, treatment efficacy was favorable relative to historical controls (ORR 58.3%; DCR 91.7%). Notably, the neoadjuvant cohort achieved a 100% response rate. Conclusion: Intake of yogurt containing R-1 EPS may enhance the efficacy of immuno-oncology therapies by suppressing the decline of Th7R cells. Citation Format: Hiroshi Kagamu, Ayako Shiono, Hisao Imai, Atsuto Mouri, Ou Yamaguchi, Kosuke Hashimoto, Shota Takei, Hirotaka Kawanabe-Matsuda, Kyoichi Kaira. An exopolysaccharide-containing yogurt preserves CCR6+ CD4+ T Cells: Th7R, and may enhance immunotherapy responses in lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7776.

Predictive biomarkers for response and post-treatment survival of patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) are limited. The present study aimed to evaluate whether recombinant Oscillatoria agardhii agglutinin (OAA)1-enriched plasma microRNAs (miRNAs/miRs) can serve as predictive and prognostic biomarkers in patients with NSCLC treated with nivolumab. High-mannose glycans, enriched in tumors, were selectively captured using this novel lectin. Pre-treatment plasma samples from 48 patients with NSCLC treated with nivolumab, an ICI, were processed using OAA1 columns. Plasma miRNAs were evaluated for their potential roles as predictive markers of response to nivolumab. The levels of circulating miR-320a, miR-320b and miR-3613-5p, which are associated with nivolumab resistance, were quantified with and without OAA1 enrichment. The three miRNAs were significantly upregulated in patients with stable or progressive disease compared with those with a partial response. For miR-320a, this difference was significant only after OAA1 enrichment. Receiver operating characteristic curve and survival analyses showed improved predictive and prognostic performance for OAA1-enriched miRNAs: The area under the curve for miR-3613-5p improved from 0.837 to 0.897, and the hazard ratio increased from 3.386 to 7.815. In conclusion, OAA1-enriched plasma miRNAs may be associated with resistance to nivolumab and a poor prognosis in NSCLC. This glycan-based enrichment strategy could enhance the clinical value of circulating miRNAs and may complement tissue-based biomarkers of ICI response.

Background: Clinical trial eligible patients with advanced non-small cell lung cancer (aNSCLC) and low programmed cell death ligand 1 (PD-L1) expression achieve greater benefit from immune checkpoint inhibitor (ICI) combination chemotherapy (ICI-Chemo) compared with Chemo alone. We examined whether patients ineligible for clinical trials may benefit from ICI-Chemo. Methods: This multicenter retrospective cohort study enrolled patients with aNSCLC, including unresectable Stage III (IIIB/IIIC) and IV disease with a PD-L1 tumor proportion score of 1-49% treated with ICI-Chemo or Chemo as first-line therapy from 2018 to 2023 in Japan. Treatment outcome and safety of ICI-Chemo versus Chemo groups in trial-eligible and trial-ineligible patients was compared based on criteria from previous phase III clinical trials. Results: Overall, 728 patients were analyzed: 333 trial-eligible and 395 ineligible patients. The median overall survival was 25.1 months in the ICI-Chemo group and 18.5 months in the Chemo group for eligible patients (HR 0.73, 95 %CI: 0.54-0.97) and was 18.2 months in the ICI-Chemo group and 14.9 months in the Chemo group for ineligible patients (HR 0.75, 95 %CI: 0.59-0.95). Median progression-free survival was longer with ICI-Chemo in both groups. For ineligible patients, performance status (PS) >= 2 and squamous cell carcinoma (SqCC) were clinical factors associated with worse survival prognosis, and survival outcomes with ICI-Chemo and Chemo were comparable. The ineligible group had no increase in severe adverse events compared to the eligible group. Conclusions: This study suggests a possible clinical benefit of receiving ICI-Chemo for trial-ineligible patients with low PD-L1 expression, excluding those with PS >= 2 or SqCC.

This retrospective study conducted at 19 centers in Japan included 316 patients with advanced nonsquamous non-small cell lung cancer (NSCLC) with a programmed cell death ligand 1 (PD-L1) tumor percentage score (TPS) of 1% to 49% who received chemoimmunotherapy as first-line treatment. The median follow-up time was 39.2 months (7.9-68.9 months) and the results showed comparable survival outcome and all adverse events of grade >= 3 among the combination chemotherapy regimens with PD-1, PD-L1 and PD-1/CTLA-4 inhibitors. The incidence of hematologic and nonhematologic toxicities differed among the regimens, although the differences were not statistically significant. The incidence of grade >= 3 pneumonitis was significantly lower among patients who received anti-PD-L1 antibodies. Thus, clinicians could prioritize patient factors such as avoidable adverse events and pneumonitis when selecting a chemoimmunotherapy regimen for patients with advanced nonsquamous NSCLC with a PD-L1 TPS of 1% to 49%. Background: Although chemoimmunotherapy is recommended for advanced nonsquamous non-small cell lung cancer (NSCLC) with low programmed cell death ligand 1 (PD-L1) expression, no head-to-head comparisons of immune check point inhibitors (ICIs) have been performed. Therefore, we compared the effect and safety of regimens in these patients to guide evidence-based treatment. Methods: This retrospective study included patients with advanced nonsquamous NSCLC with a PD-L1 tumor proportion score of 1% to 49% administered ICI combination platinum-based chemotherapy between May 2018 and May 2023 at 19 institutions in Japan. The main analysis compared survival outcomes and the incidence of grade >= 3 adverse events among regimens. Results: Among 316 included patients (median [range] age, 69 [36-89] years; 242 males; 41 never smokers), 200 (63%), 68 (22%), and 48 (15%) received chemotherapy combined with anti-programmed cell death protein 1 (PD-1), anti-PD-L1, and anti-PD-1/cytotoxic T-lymphocyte associated protein 4 (CTLA-4) antibodies, respectively. The median overall survival times were 28.6, 23.1, and 24.4 months (P = .41), and the median progression-free survival times were 9.4, 7.2, and 8.7 months (P = .28) in the anti-PD-1/Chemo, antiPD-L1/Chemo and anti-PD-1/CTLA-4/Chemo groups, respectively. The anti-PD-1/CTLA-4/Chemo group had the lowest incidence of hematologic toxicity (P = .13) and the highest incidence of nonhematologic toxicity (P = .07). The incidence of grade >= 3 pneumonitis was significantly lower in the anti-PD-L1/Chemo group (P = .049). Conclusions: Despite comparable survival benefits, adverse events differed among three regimens in patients with low PD-L1 expression. Notably, anti-PD-L1 antibody combination chemotherapy may reduce the risk of severe pneumonitis. (c) 2025 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

8633 Background: Osimertinib (Osi) has been established as a standard of care for patients (pts) with EGFR -mutant advanced non-small-cell lung cancer (NSCLC). However, in the FLAURA study, survival superiority of Osi over first-generation EGFR-TKIs was not demonstrated especially in Japanese pts (hazard ratio [HR], 1.39; 95% confidence interval [CI], 0.83 to 2.34; P = 0.22). This is presumably due to the different impact of adverse events or tumor antigen-specific cytotoxicity of T cells on subsequent therapy between both EGFR-TKIs in Japanese pts. On the other hand, there has been no clinical trial comparing second- with third-generation EGFR-TKIs. Therefore, optimal first-line EGFR-TKI may not have been identified in Japanese pts. Methods: This was a randomized, open-label, multicenter, phase II study to compare overall survival (OS) between initial treatment with afatinib (Afa) (n = 50) and Osi (n = 50) in pts with advanced or recurrent EGFR -mutant NSCLC. Exploration of immunomonitoring through peripheral blood mononuclear cells (PBMC) was also performed, before, during, and after treatment. The co-primary endpoints were the superiority of Afa over Osi at 3-year survival rate and the exploration of immunological biomarkers for treatment outcomes. Enrollment started in May 2020 at 28 sites in Japan with a minimum follow-up of 3 years. Results: Overall, 95 eligible pts were analyzed (47 to Afa and 48 to Osi). Objective response rates were 63.8% for Afa vs. 62.5% for Osi. Median progression-free survival (PFS) was 16.7 months (mos) for Afa vs. 14.5 mos for Osi (HR, 1.17; 95% CI, 0.72 to 1.90; P = 0.52). Median OS was 38.8 mos for Afa and not reached for Osi (HR, 1.15; 95% CI, 0.64 to 2.05; P = 0.64), resulting in 54.7% (95% CI, 39.4 to 67.7) for Afa vs. 57.5% (95% CI, 42.2 to 70.1) for Osi at 3-year survival rate. Predominant adverse events with Afa or Osi were diarrhea (92% vs. 31%) and pneumonitis (11% vs. 21%; Grade 5, 0% vs. 6%). Treatment discontinuation rates due to adverse events were 21% with Afa vs. 29% with Osi. The efficacy of Osi varied significantly dependent on the immunological biomarkers, Th7R (stem cell-like CD4 T cells) and Th2. Pts with high Th7R (7.83% or more) had promising PFS (31.0 mos [n = 28] vs. 6.6 mos [n = 20]; HR, 0.38; P = 0.006) and OS (not reached vs. 35.5 mos; HR, 0.56; P = 0.18). In contrast, pts with high Th2 (7.20% or more) had poor PFS (6.6 mos [n = 27] vs. 31.0 mos [n = 21]; HR, 1.78; P = 0.11) and OS (35.5 mos vs. not reached; HR, 2.77; P = 0.03). On the other hand, no immunological biomarkers affected PFS and OS of Afa. Conclusions: Afa and Osi both demonstrated favorable clinical activity as first-line treatment in Japanese NSCLC patients with EGFR mutations. Although their outcomes are comparable, immunological biomarkers (Th7R/Th2) may refine treatment decisions and warrant further prospective validation. Clinical trial information: jRCTs031190221 .

Overall survival and Progression-free survival of 851 patients according to treatments

Background and Objectives: The comparative efficacy and safety of nivolumab plus ipilimumab (Nivo-Ipi) combination therapy between patients with either postoperative recurrent non-small cell lung cancer (NSCLC) or inoperable stage III/IV NSCLC have yet to be conclusively determined. Materials and Methods: This retrospective study reviewed the medical records of consecutive patients diagnosed with either postoperative recurrent NSCLC or inoperable stage III/IV NSCLC. Both groups, referred to as the postoperative and inoperable cohorts respectively, underwent Nivo-Ipi therapy at four Japanese medical institutions between December 2020 and November 2022. The study’s primary aim was to evaluate and compare the efficacy and safety outcomes across these two groups. Results: A total of 161 patients received Nivo-Ipi therapy (postoperative group, n = 30; inoperable group, n = 131). The objective response rate was comparable between the postoperative and inoperable groups (36.7% vs. 32.1%, p = 0.67). Median progression-free survival did not differ significantly between groups (8.9 months vs. 6.5 months, p = 0.14). However, median overall survival was significantly longer in the postoperative group (not reached vs. 13.0 months, p = 0.012). The incidence of grade ≥ 3 adverse events in the postoperative group included lung injury (13.3%), liver dysfunction (10.0%), adrenal insufficiency (6.7%), and colitis (6.7%). No significant difference was observed in the frequency of grade ≥ 3 treatment-related adverse events between the groups, and no treatment-related deaths occurred in the postoperative group. Conclusions: Patients with postoperative recurrent NSCLC treated with Nivo-Ipi demonstrated significantly longer overall survival compared to those with inoperable NSCLC. Given its favorable efficacy and acceptable toxicity profile, postoperative recurrent disease may warrant consideration as a stratification factor in clinical trials for advanced NSCLC. Nivo-Ipi therapy could serve as a preferred first-line treatment option for patients with postoperative recurrent NSCLC.

Background:Immune checkpoint inhibitors (ICIs) in combination with chemotherapy have demonstrated efficacy in the treatment of non-small cell lung cancer (NSCLC) with a programmed death ligand 1 (PD-L1) tumor proportion score (TPS) of 1-49%. However, older patients remain underrepresented in clinical trials, and optimal treatment strategies for this population remain unclear. This study sought to evaluate the efficacy and safety of first-line treatment with either platinum-based chemotherapy alone (Chemo) or in combination with ICIs (ICI/Chemo) in older patients with NSCLC who have low PD-L1 expression. Methods:This retrospective multicenter study included patients diagnosed with advanced NSCLC (stage IIIB-IV) with a PD-L1 TPS of 1-49% from 19 Japanese institutions. We examined the relationship between baseline patient characteristics and treatment outcomes within each group. Propensity score matching (PSM) was used to balance patient characteristics between the ICI/Chemo and Chemo groups. Results:We evaluated data from 613 patients, finding that the ICI/Chemo group (n=370) exhibited significantly longer median progression-free survival (PFS) and overall survival (OS) compared to the Chemo group (n=243). Among the 613 patients, 152 were aged ≥75 years. Of these, 63 received Chemo, while 89 underwent ICI/Chemo as first-line treatment. In this older cohort, ICI/Chemo significantly improved median PFS; however, no significant difference was observed in OS. Nonetheless, the incidence of grade ≥3 adverse events and pneumonitis of any grade was higher in the ICI/Chemo group compared to the Chemo group among older patients. Multivariate analysis using Cox proportional hazards models indicated that Eastern Cooperative Oncology Group performance status (ECOG PS) was significantly associated with PFS and OS. In older patients with ECOG PS 0, ICI/Chemo showed significant PFS benefits; in those with ECOG PS 1, both the PFS and OS were similar between the two groups. Conclusions:ICI combined with chemotherapy may be a potentially effective treatment strategy for older patients with NSCLC and low PD-L1 expression. However, compared with the overall population, the benefits of adding ICI to chemotherapy were decreased, while the risk of toxicity may increase, making appropriate patient selection crucial for this population. Particularly, in patients with ECOG PS 1, the additional benefit of ICI over chemotherapy was minimal in terms of efficacy, suggesting that the introduction of ICI combined with chemotherapy should be carefully considered for this patient population.