Hidehito Horinouchi

Purpose: Nivolumab plus ipilimumab is a standard first-line therapy for unresectable malignant pleural mesothelioma (MPM), yet biomarkers predicting immune checkpoint inhibitor (ICI) efficacy remain undefined. We aimed to identify genomic and tumor immune microenvironmental features associated with ICI response in MPM. Experimental Design: We analyzed two independent MPM cohorts. The discovery cohort included patients at the National Cancer Center Hospital (2012–2022) with frozen tumor tissues available for whole-genome sequencing (WGS) and RNA sequencing. Genomic alterations, transcriptomic profiles, immune cell composition, and T-cell receptor repertoire were analyzed, and key findings were validated in a nationwide Center for Cancer Genomics and Advanced Therapeutics (C-CAT) cohort. Results: The WGS cohort comprised 52 patients. Among ICI-treated patients, overall response rates were 30% in the WGS cohort and 29.4% in the C-CAT cohort. Genomic analyses identified frequent alterations in BAP1 and NF2, across both cohorts. ICI responders showed higher T-cell receptor diversity, increased CD8⁺ T-cell infiltration, and enrichment of M1 macrophages compared with non-responders. MTAP loss was associated with higher CD8⁺ T-cell infiltration and T-cell receptor diversity, and was linked to a higher ICI response rate in the C-CAT cohort. In contrast, BAP1 and NF2 alterations showed no consistent association with immune features or ICI efficacy. Conclusions: An immune-active tumor microenvironment characterized by high T-cell receptor diversity, CD8⁺ T-cell infiltration, and M1 macrophage enrichment was associated with favorable ICI responses in MPM. MTAP loss was linked to immune-related features and a higher ICI response, supporting further investigation of MTAP loss as a candidate biomarker.

Background: Osimertinib is used across treatment settings for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Dose reduction is sometimes required for tolerability; however, efficacy is often maintained. We evaluated longitudinal plasma trough concentrations (C_trough) in patients receiving osimertinib. Methods: Patients with EGFR-mutant NSCLC receiving osimertinib who provided informed consent for a prospective observational study between March 2022 and May 2024 were included. Blood samples were obtained at each visit, and plasma concentrations were quantified using a validated assay. Among the patients initiated on 80 mg once daily, the association between the initial C_trough and subsequent dose reduction for toxicity was evaluated. Clinical correlates of exposure were assessed by relating the dose-normalized concentration (C/D ratio) to baseline characteristics. Results: Twenty-five patients were evaluated. Patients requiring dose reduction (n = 6) had a higher initial C_trough on days 6–14 than did those who did not (median, 466.5 versus 224 ng/mL; P = .0094). Among 15 patients treated ≥18 months, long-term therapy was sustained across a wide concentration range. Of the 70 long-term samples, 96% were ≤ 268.5 ng/mL. The C/D ratio was higher in females than males, inversely correlated with body weight and body surface area, and positively correlated with the neutrophil-to-lymphocyte ratio. Conclusions: Higher early osimertinib exposure was observed in patients who subsequently required dose reduction because of toxicity. Plasma concentration measurement may provide complementary information on individual drug exposure when assessing tolerability. Long-term treatment was observed across a broad concentration range following dose modification.

In advanced non‐squamous non‐small cell lung cancer (non‐sq NSCLC), companion diagnostic testing (CDx) identifies actionable driver alterations and guides initial targeted therapy. However, disease progression inevitably occurs through acquired resistance, including activation of bypass signaling pathways. Although comprehensive genomic profiling (CGP) can identify emerging resistance alterations, its clinical utility in patients with known actionable driver alterations remains unclear. We retrospectively analyzed 227 patients who underwent CGP between June 2019 and August 2025. Patients with actionable driver alterations identified by CDx before CGP formed the known driver group. We also analyzed the nationwide C‐CAT registry to assess registry‐recorded therapeutic implementation. Among 227 patients, 74 (32.6%) had known actionable driver alterations. CGP identified additional clinically relevant genomic findings, including ESCAT Tier I–III or V alterations, in 34 patients (45.9%), comparable to that in patients without known actionable driver alterations (77/153, 50.3%). In the EGFR ‐mutated ( EGFR m) subgroup, CGP frequently identified alterations consistent with potential bypass resistance mechanisms, including MET amplification, RET fusions, and BRAF V600E mutations. Overall, 10 patients (13.5%) received CGP‐guided therapy based on additional findings, all within the EGFR m subgroup, whereas no patients with non‐ EGFR driver alterations did. In the C‐CAT registry, CGP‐associated therapy was documented in 21 of 381 (5.5%) in the EGFR m subgroup, 6 of 155 (3.9%) in the non‐ EGFR driver subgroup, and 195 of 2132 (9.1%) without registry‐defined driver alterations. These findings indicate that CGP provides molecular re‐evaluation during disease progression, particularly by identifying alterations consistent with potentially actionable resistance or bypass mechanisms in EGFR m NSCLC.

PURPOSE: Tiragolumab plus atezolizumab has shown encouraging survival outcomes in metastatic non–small cell lung cancer (NSCLC), primarily in patients with PD-L1–high tumors. We further evaluated the combination of tiragolumab plus atezolizumab in the phase III SKYSCRAPER-01 study. METHODS: Patients with untreated, locally advanced unresectable/metastatic PD-L1–high (by central laboratory testing) NSCLC were randomly assigned 1:1 to receive either tiragolumab (600 mg) plus atezolizumab (1,200 mg) or placebo plus atezolizumab (1,200 mg) intravenously in 21-day cycles until disease progression, loss of clinical benefit, or unacceptable toxicity. Primary end points were investigator-assessed progression-free survival (INV-PFS) and overall survival (OS) in the primary analysis set (PD-L1–high per 22C3 assay). RESULTS: Five hundred twenty-one patients were randomly assigned to either the tiragolumab plus atezolizumab group (n = 262) or the placebo plus atezolizumab group (n = 259). At the primary PFS analysis (Mar 12, 2022; median follow-up 9.9 months [IQR, 6.2-13.8]), median INV-PFS was 7.0 months (95% CI, 5.6 to 9.8) with tiragolumab plus atezolizumab and 5.6 months (95% CI, 4.4 to 7.0) with placebo plus atezolizumab (hazard ratio [HR], 0.78 [95% CI, 0.63 to 0.97]; P = .02 [nonsignificant]). At the final OS analysis (Sept 24, 2024; median follow-up 17.9 months [IQR, 6.7-39.0]), median OS was 23.1 months (95% CI, 17.7 to 28.8) with tiragolumab plus atezolizumab and 16.9 months (95% CI, 14.6 to 21.3) with placebo plus atezolizumab (HR, 0.87 [95% CI, 0.7 to 1.1]; P = .22 [nonsignificant]). Overall, 41.2% (n = 110/267) and 33.8% (n = 89/263) of patients experienced grade 3-4 adverse events with tiragolumab plus atezolizumab and placebo plus atezolizumab, respectively. Four and two treatment-related deaths occurred in each group, respectively. CONCLUSION: Tiragolumab plus atezolizumab did not demonstrate a statistically significant INV-PFS or OS benefit over atezolizumab in patients with previously untreated PD-L1–high NSCLC.

This guideline has been updated. This ASCO Living Guideline is reviewed on an eight-week cycle. Please see the online dynamic version for the latest updates. Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the ASCO Guidelines Methodology Manual . ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines . Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating clinician and do not account for individual variation among patients. See appendix for disclaimers and other important information ( Appendix 1 and Appendix 2 , online only). Updates are published regularly and can be found on the ASCO Publications website .

Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the ASCO Guidelines Methodology Manual . ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines . Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating clinician and do not account for individual variation among patients. See appendix for disclaimers and other important information ( Appendix 1 and Appendix 2 , online only). Updates are published regularly and can be found at https://ascopubs.org/nsclc-non-da-living-guideline .

Dual inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways may improve outcomes in metastatic EGFR-mutant NSCLC, but VEGF inhibitors are not universally effective. We evaluated the impact of VEGFA and VEGFR2 expressions on EGFR-TKI outcomes. EGFR-mutant NSCLC patients from the National Cancer Center Hospital, were retrospectively analysed. The early-stage cohort comprised stage I-IIIA patients (1997-2019). The advanced-stage cohort included metastatic patients (2018-2022). VEGFA/VEGFR2 expressions were dichotomised by median transcripts per million. Among 447 early-stage patients (median age 66), high VEGFA was associated with smoking, TP53 co-mutation, higher Brinkman Index, and higher tumour mutation burden (all p < 0.01). High VEGFA predicted shorter relapse-free survival (HR 2.10, 95% CI 1.63-2.71, p < 0.01) and overall survival (HR 2.07, 95% CI 1.46-2.95, p < 0.01). VEGFR2 expression showed no prognostic impact. In 146 relapsed patients receiving first-line EGFR-TKIs, high VEGFA was linked to shorter progression-free survival (PFS) overall (HR 1.70,95%CI 1.13-2.56, p = 0.009), particularly for first/second-generation EGFR-TKIs (HR 1.66,95%CI 1.08-2.54 p = 0.023), but not for osimertinib (p = 0.491). In 60 advanced-stage patients on osimertinib, PFS was unaffected by VEGFA (p = 0.102). High VEGFA is associated with aggressive biology and inferior outcomes, correlating with shorter PFS for first/second-generation EGFR-TKIs but not for osimertinib.