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ObjectivesThe impact of cGAS/STING tumor expression on PD-1/L1 inhibitor efficacy and the tumor microenvironment remain to be elucidated.MethodsIn a post-hoc analysis of a prospective biomarker study with 106 advanced NSCLC patients treated with PD-1/L1 inhibitors from December 2015 to September 2018, tumor tissue before treatment from 68 patients was analyzed. cGAS and STING expression were measured using immunohistochemical staining and H-scores. Additionally, 40 serum proteins were quantified before and 4–6 weeks after treatment initiation.ResultsMedian cGAS and STING H-scores were 220 (range, 5–300) and 190 (range, 0–300), respectively. There were no differences in cGAS or STING H-scores between the high (tumor proportion score [TPS] ≥ 50) and low (TPS < 50) PD-L1groups (p = 0.990 and 0.283, respectively). Unexpectedly, patients with high cGAS (H-score ≥ 220) demonstrated significantly shorter progression-free survival (PFS) of PD-1/L1 inhibitors when the PD-L1 TPS was high (median PFS: 143 days vs. not reached; p = 0.028); PFS at 18 months was 7% and 53% in the high and low cGAS groups, respectively while STING expression did not impact PFS. In serum protein analyses, high cGAS H-score was associated with significantly higher TGF-β1 and TGF-β2 before PD-1/L1 inhibition (47.5 vs. 22.3 ng/l, p = 0.023; 2118 vs. 882 pg/ml, p = 0.037); additionally, the cGAS H-score significantly correlated with TGF-β1 (r = 0.451, p = 0.009) and TGF-β2 (r = 0.375, p = 0.031) basal levels.ConclusioncGAS expression, but not STING, predicts poor PD-1/L1 inhibitor efficacy in NSCLC with high PD-L1, potentially due to a TGF-β-mediated immunosuppressive environment (UMIN000024414).

Background: ALK-tyrosine kinase inhibitors (ALK-TKIs) are effective for treating non-small-cell lung cancer with ALK gene rearrangement; however, resistance is inevitable. Brigatinib is a unique ALK-TKI that is effective against many resistance mutations. However, data on factors associated with its efficacy and resistance mechanisms are limited. Objectives: This study will evaluate the efficacy and safety of brigatinib in the real world and explore factors related to its efficacy, safety, and resistance mechanisms. Design: Prospective observational study. Ethics: This study is approved by the Ethics Committee of Wakayama Medical University. Written informed consent will be obtained from all patients before study-related procedures. Methods and analysis: This study comprises three cohorts. Cohorts A, B, and 0 will enroll patients receiving alectinib as the first ALK-TKI, receiving alectinib as the first ALK-TKI and subsequently cytotoxic agents and/or lorlatinib after alectinib, and without a history of ALK-TKI, respectively. Overall, 100, 30, and 50 patients will be enrolled in Cohorts A, B, and 0, respectively. Circulating tumor DNA before starting brigatinib and at disease progression will be analyzed in all cohorts using a hypersensitive next-generation sequencing (NGS) PGDx Elio plasma resolve panel. Serum protein levels will be analyzed using the Milliplex xMAP assay system with a Luminex 200 (Luminex, Austin, USA). The enrollment period is 31 months and the patients will be observed for 2 years after enrollment. Archived tissues will be collected for NGS analysis, gene expression analysis, and immunohistochemistry staining 1 year after completion of registration. Quality of life and safety evaluation using electronic patient-reported outcomes will be investigated. Discussion: This study will elucidate predictors of ALK-TKI efficacy and resistance mechanisms and evaluate the efficacy and safety of brigatinib in a real-world setting. The results will provide crucial information for establishing treatment strategies, discovering novel biomarkers, and developing new therapeutic agents. Trial registration: UMIN000042439.

This study investigated the clinical characteristics and predictive factors for developing acute extended radiation pneumonitis with a focus on the presence and radiological characteristics of preexisting interstitial lung disease. Of 1429 irradiations for lung cancer from May 2006 to August 2013, we reviewed 651 irradiations involving the lung field. The presence, compatibility with usual interstitial pneumonia, and occupying area of preexisting interstitial lung disease were retrospectively evaluated by pretreatment computed tomography. Cases of non-infectious, non-cardiogenic, acute respiratory failure with an extended bilateral shadow developing within 30 days after the last irradiation were defined as acute extended radiation pneumonitis. Nine (1.4%) patients developed acute extended radiation pneumonitis a mean of 6.7 days after the last irradiation. Although preexisting interstitial lung disease was found in 13% of patients (84 patients), 78% of patients (7 patients) with acute extended radiation pneumonitis cases had preexisting interstitial lung disease, which resulted in incidences of acute extended radiation pneumonitis of 0.35 and 8.3% in patients without and with preexisting interstitial lung disease, respectively. Multivariate logistic analysis indicated that the presence of preexisting interstitial lung disease (odds ratio = 22.6; 95% confidence interval = 5.29-155; p < 0.001) and performance status (≥2; odds ratio = 4.22; 95% confidence interval = 1.06-20.8; p = 0.049) were significant predictive factors. Further analysis of the 84 patients with preexisting interstitial lung disease revealed that involvement of more than 10% of the lung field was the only independent predictive factor associated with the risk of acute extended radiation pneumonitis (odds ratio = 6.14; 95% confidence interval = 1.0-37.4); p = 0.038). Pretreatment computed tomography evaluations of the presence of and area size occupied by preexisting interstitial lung disease should be assessed for safer irradiation of areas involving the lung field.

Background Conquering acquired resistance to osimertinib remains a major challenge in treating patients with epidermal growth factor receptor ( EGFR ) mutation-positive non-small-cell lung cancer (NSCLC). Thus, we aimed to determine the safety and efficacy of combination treatment with osimertinib and afatinib for patients with acquired resistance to osimertinib. Methods This open-label phase I study was a feasibility study of the combination of afatinib and osimertinib for patients with advanced EGFR -positive NSCLC who had progressive disease after receiving osimertinib. The primary endpoint was to determine the maximum tolerated dose (MTD). We enrolled patients who received afatinib at three different dose levels (level 1, 20 mg; level 2, 30 mg; level 3, 40 mg) combined with osimertinib at a standard dose of 80 mg once per day. Results Thirteen patients were enrolled in this study. The MTD was defined as 30 mg afatinib when combined with daily oral administration of osimertinib (80 mg). The most frequent adverse events were diarrhea (76.9%), anemia (76.9%), and rash (69.2%). Considering the toxicity profiles during all treatment periods, the recommended oral dose of afatinib was determined as 20 mg daily, with an osimertinib dose of 80 mg. For all evaluable patients ( n  = 12), the response rate was 7.7% and the disease-control rate was 46.2%. Conclusion Combination therapy with osimertinib and afatinib was tolerable; however, the synergistic effect of afatinib with osimertinib may be limited in osimertinib-resistant patients. Trial registration Japan Registry of Clinical Trials ID: jRCTs051180008, registered date: 08/11/2018.

SummaryOsimertinib is a molecularly targeted agent used to treat non-small cell lung cancer (NSCLC) patients with an epidermal growth factor receptor (EGFR) T790M mutation. However, its efficacy and safety profile when patients have poor performance status (PS) is unknown. Therefore, we conducted an open-label, multi-center, single-arm phase II study to evaluate its efficacy and safety in EGFR T790M mutation-positive NSCLC patients with Eastern Cooperative Oncology Group PS scores of between 2 and 4. Patients received 80 mg of osimertinib once daily. Our primary endpoint was progression-free survival. Eighteen patients were enrolled between June 2017 and November 2018. The median age was 77 years (range: 55–85 years). Ten, six, and two patients had PS scores of 2, 3, and 4, respectively. All patients had adenocarcinoma with common EGFR mutations and had been treated with first- or second-generation EGFR- tyrosine kinase inhibitors previously. The overall median progression-free survival was 7.0 months (90% confidence interval: 5.5–8.9 months). The overall response rate and median overall survival were 53% and 12.7 months, respectively. Moreover, improved PS scores were observed in 72% of the patients. Although the incidence of grade 3 adverse events was low, with no grade 4 or 5 events observed, three patients required treatment cessation due to the development of interstitial lung disease. Osimertinib therapy could be beneficial for EGFR T790M mutation-positive advanced NSCLC patients with poor PS. This trial was registered with the Japan Registry of Clinical Trials on March 12, 2019 (trial no. jRCT1041180081).

While PD-1/L1 inhibitors are characterized by durable tumor control, they also prolong survival without prolongation of progression-free survival (PFS) in part of patients. However, little is known about the factors and mechanisms involved in this. Between December 2015 and September 2018, 106 patients with advanced non-small cell lung cancer treated with ICI monotherapy were enrolled in a prospective-observational study. Sixty-nine of whom progressed or died within 6 months after ICI initiation were defined as patients without durable clinical benefit (NDBs). Clinical factors and 39 serum proteins before ICI initiation and at the time of progressive disease (PD) were explored for an association with overall survival (OS) and OS after PD (OS-PD). As a result, median PFS, OS, and OS-PD were 44 days [95% confidence interval (CI): 39–56), 211 days (95% CI: 158–425), and 193 days (95% CI: 118–349), respectively. By multivariate analysis for OS, CRP (> 1.44 mg/dl) [HR 2.59 (95% CI:1.33–5.04), P = 0.005] and follistatin (> 685 pg/ml) [HR 2.29 (95% CI:1.12–4.69), P = 0.023] before ICI initiation were significantly predictive. Notably, no serum protein at the time of PD was predictive for OS-PD. There were also no serum predictive factors of OS in the 33 patients with durable clinical benefit. In conclusion, serum levels of CRP and follistatin before ICI initiation, not at the time of PD, are predictive for OS in NDBs, suggesting long-term survivor in NDBs are predetermined by the immune status before ICI initiation.

A multistep sorting method for enrichment of rare cells, such as circulating tumor cells, in the blood without cumbersome pretreatments required by most flow cytometry-based methods, which lead to high cost and decreased detection efficiency, was developed. After only hemolysis and cell staining, cancer cells are enriched by repetitive sorting (3×) based on nuclear-positive, cytokeratin-positive, and CD45-negative expression. Experiments using spikes of PC-9 cells showed a mean recovery of 65% and mean purity of 83%, which was retained up to 72 hours after blood draw using preservative tubes. Significant differences in expression level of programmed death-ligand 1 or vimentin were observed between high- and low-expressing cell lines, concurrently with enrichment. Next-generation sequencing analysis of recovered PC-9, A549, and MDA-MB231 cells successfully detected all known mutations. This novel isolation method applicable for preserved samples with sufficient recovery and purity may be substantially beneficial for recovering cells for subsequent molecular analysis.

CD24, a heavily glycosylated glycosylphosphatidylinositol–anchored surface protein, inhibits phagocytosis as potently as CD47. The relationship between such anti‐phagocytic factors and the immune response with immune–checkpoint inhibitors (ICI) remains unexplored. We evaluated CD24 and CD47 tumor proportion scores (TPS) in 68 of the 106 patients with advanced non–small‐cell lung cancer who participated in a prospective observational study of ICI treatment. We also explored the impact of CD24 TPS and CD47 TPS on ICI efficacy and serum cytokine changes. CD24 positivity (TPS ≥ 1) was negatively associated with progression–free survival (PFS) of ICI when PD‐L1 TPS was < 50 (median PFS; 37 vs 127 d, P = .033), but there was no association when PD‐L1 TPS was ≥ 50 (median PFS; 494 vs 144 d, P = .168). CD24 positivity was also related to significantly higher increase of CCL2 from baseline to 4‐6 wk later, and such increase was notably observed only when PD‐L1 TPS < 50 (P = .0004). CCL2 increase after ICI initiation was negatively predictive for survival after initiation of ICI (median survival time; not reached vs 233 d; P = .028). CD47 TPS high (≥60) significantly suppressed the increase in vascular endothelial growth factor (VEGF)‐A, D and PDGF‐AB/BB after ICI initiation. There was no association, however, between CD47 tumor expression and the efficacy of ICI. In conclusion, CD24, not CD47, is a candidate negative predictive marker of ICI in advanced, non–small‐cell lung cancer with PD‐L1 TPS < 50. Tumor expression of both CD24 and CD47 was associated with changes in factors related to monocytes and angiogenesis after ICI initiation (UMIN000024414). We evaluated tumor proportion score (TPS) of CD24 and CD47 in 68 patients with advanced, non–small‐cell lung cancer who participated in a prospective observational study for treatment with ICI, and we also explored the impact of CD24 TPS and CD47 TPS on the efficacy of ICI and serum cytokine alterations. CD24 positivity (TPS ≥ 1) was negatively associated with progression–free survival of ICI when PD‐L1 TPS < 50 (median PFS; 37 vs 127 d, P = .033), but there was no association between CD47 tumor expression and the efficacy of ICI. CD24 positivity was also related to significantly higher increases in CCL2 from baseline to 4‐6 wk later, and such increase was notably observed only when PD‐L1 TPS was < 50 (P = .0004).

IntroductionTriplet regimen of carboplatin or cisplatin with pemetrexed and pembrolizumab is a standard treatment for patients with advanced, chemo-naïve, non-squamous non-small cell lung cancer. However, subgroup analysis for patients aged ≥75 years indicated that elderly patients who received the triplet regimen may have had shorter survival times than if they had chemotherapy alone (HR of 2.09). Treatments in the elderly are not always as effective or safe as for non-elderly patients, so there remains concern over whether the triplet regimen can be widely used in the elderly.Methods and analysisThis is a single-arm, prospective, multicentre phase II study. The primary endpoint is set as the overall response rate according to Response Evaluation Criteria in Solid Tumors V.1.1. Secondary endpoints are progression-free survival, disease control rate and safety. This trial will enrol 22 patients.Ethics and disseminationThis study was approved by the Wakayama Medical University Central Review Board on 2 December 2019 (approval number: W-32). Patients have been enrolled since February 2020. As the study will complete accrual in January 2022, results will be submitted for publication in peer-reviewed medical journals within 2023 and international scientific meetings. This study will provide significant information on whether the triplet regimens are clinically beneficial to elderly patients.Trial registration numberJapan Registry of Clinical Trials (jRCTs051190095).

Background First‐generation epidermal growth factor receptor‐tyrosine kinase inhibitor (EGFR‐TKI) sometimes causes lung injury, thereby affecting survival. Although pre‐existing interstitial lung abnormal shadow (pre‐ILS) increases the risk of lung injury by EGFR‐TKIs, its impact on osimertinib, a third‐generation EGFR‐TKI, remains unknown. Patients and Methods This retrospective cohort study consecutively enrolled patients of EGFR‐mutated non‐small cell lung cancer treated with osimertinib. Computed tomography images were obtained and evaluated independently by three pulmonologists in a blinded manner. Factors associated with lung injury were assessed using a logistic regression model. Survival curves were calculated by the Kaplan–Meier method and compared using a log‐rank test. Results Of the 195 patients, 40 had pre‐ILS, and 21 (8 with and 13 without pre‐ILS) developed lung injury during the observation period. Multivariate analysis revealed that pre‐ILS was independently associated with lung injury (odds ratio, 3.1; 95% confidence interval [CI], 1.1–8.2; p = 0.025). Severe (≥Grade 3) lung injury was observed in eight (4.1%) patients, of whom, two (5%) and six (3.9%) had and did not have pre‐ILS (p = 0.67), respectively. Grade 5 lung injury was not observed, and survival curves were similar between the patients who developed lung injury and those who did not (median 11 vs. 12 months; hazard ratio, 1.2; 95% CI, 0.56–2.7; p = 0.60). Conclusions Pre‐ILS increased the risk of lung injury in patients of non‐small cell lung cancer treated with osimertinib, while the severity of lung injury was not clearly affected by the presence of pre‐ILS. Although pre‐existing interstitial lung abnormal (pre‐ILS) shadow has been known to be a risk factor of lung injury by EGFR‐TKIs, data on osimertinib are lacking. Current results demonstrated that pre‐ILS increases the risk of lung injury (odds ratio, 3.1; 95% confidence interval, 1.1–8.2; p = 0.025) in the treatment with osimertinib. Notably, the incidence of grade ≥3 was similar between patients with and without pre‐ILS, which was 5% and 3.9%, respectively. The overall survival was similar for patients who developed lung injury and those who did not. However, we still need to be cautious during treatment with osimertinib in patients with pre‐ILS; further studies are warranted in this field.