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Considering the increasing number of identified driver oncogene alterations, additional genetic tests are required to determine the treatment for advanced non‐small‐cell lung cancer (NSCLC). Next‐generation sequencing can detect multiple driver oncogenes simultaneously, enabling the analysis of limited amounts of biopsied tissue samples. In this retrospective, multicenter study (UMIN ID000039523), we evaluated real‐world clinical data using the Oncomine Dx Target Test Multi‐CDx System (Oncomine DxTT) as a companion diagnostic system. Patients with NSCLC who were tested for a panel of 46 genes using the Oncomine DxTT between June 2019 and January 2020 were eligible for enrollment. Patients from 19 institutions affiliated to the West Japan Oncology Group were recruited. The primary endpoint of the study was the success rate of genetic alteration testing in four driver genes (EGFR, ALK, ROS1, and BRAF) using the Oncomine DxTT. In total, 533 patients were enrolled in the study. The success rate of genetic alteration testing for all four genes was 80.1% (95% CI 76.5%‐83.4%). Surgical resection was associated with the highest success rate (88.0%), which was significantly higher than that for bronchoscopic biopsy (76.8%, P = .005). Multivariate analysis revealed a significant difference for surgical resection alone (P = .006, 95% CI 1.36‐6.18, odds ratio 2.90). Although the success rate of genetic alteration testing immediately after Oncomine DxTT induction was not sufficient in this study, optimizing specimen quantity and quality may improve the use of driver gene testing in clinical settings., The mutation identification success rate for all four genes was 80.1%. Surgical resection was associated with the highest success rate. Multivariate analysis showed a significant difference for surgical resection alone.

Introduction Despite the extensive use of the combination of cytotoxic chemotherapy and programmed cell death protein 1/programmed death-ligand 1 checkpoint inhibitors for cancer treatment, the incidence and characteristics of pneumonitis caused by this combination therapy have not been examined in clinical settings. Methods We conducted a 36-centre, retrospective cohort study in patients with chemo-naive advanced non-squamous non-small cell lung cancer who received a combination of platinum, pemetrexed and pembrolizumab between December 2018 and June 2019. Results The study comprised 299 patients. The most frequent grade ≥3 non-hematologic adverse event was pneumonitis. There were 37 patients (12.4%, 95% CI 8.9–16.7) with all-grade pneumonitis and 10 (3.3%, 95% CI 1.6–6.1) with grade ≥3 pneumonitis. Of these, 21 (7.0%, 95% CI 4.4–10.5) and 9 patients (3.0%, 95% CI 1.4–5.6) developed all-grade and grade ≥3 pneumonitis within 90 days after initiating the combination therapy, respectively. The median time to treatment failure and progression-free survival was 5.9 (95% CI 5.0–6.8) and 7.5 (95% CI 6.5–8.7) months, respectively. In the survival analysis after adjusting for immortal time bias, pneumonitis was independently associated with shorter progression-free survival (HR 1.99, 95% CI 1.07–3.69, P = 0.03) and overall survival (HR 3.03, 95% CI 1.12–8.20, P = 0.03). Conclusions Treatment-related pneumonitis occurred at a higher rate in the real-world population than that reported previously; it led to worse survival outcomes. Pneumonitis requires more attention. Additional studies are required to improve the safety of this combination therapy. Trial registration number UMIN000038084

Noninvasive diagnostics using circulating tumor cells (CTCs) are expected to be useful for decision making in precision cancer therapy. AXL, a receptor tyrosine kinase is associated with tumor progression, epithelial‐to‐mesenchymal transition (EMT), and drug resistance, and is a potential therapeutic target. However, the epithelial markers generally used for CTC detection may be not enough to detect AXL‐expressing CTCs due to EMT. Here, we evaluated the detection of AXL‐expressing CTCs using the mesenchymal marker vimentin with a microcavity array system. To evaluate the recovery of cancer cells, spike‐in experiments were performed using cell lines with varying cytokeratin (CK) or vimentin (VM) expression levels. With high CK and low VM‐expressing cell lines, PC‐9 and HCC827, the recovery rate of AXL‐expressing cancer cells was 1%‐17% using either CK or VM as markers. Whereas, with low CK and high VM‐expressing cell lines, MDA‐MB231 and H1299, it was 52%‐75% using CK and 72%‐88% using VM as a marker. For clinical evaluation, peripheral blood was collected from 20 non–small cell lung cancer patients and CTCs were detected using CK or VM as markers in parallel. Significantly more AXL‐expressing single CTCs were detected in VM‐positive than CK‐positive CTCs (P, We established the detection of AXL‐expressing in circulating tumor cells of lung cancer patients incorporating vimentin as a CTC marker in addition to cytokeratin. Significantly more AXL‐expressing CTCs were detected in patients who had prior treatment history than those did not, suggesting the involvement of AXL in drug resistance.

The incidence of real-world pneumonitis and durvalumab rechallenge during chemoradiotherapy and durvalumab consolidation for non-small cell lung cancer is unknown.We retrospectively evaluated the medical records of 302 consecutive patients diagnosed with non-small cell lung cancer who started chemoradiotherapy between May 2018 and May 2019.Median age was 70 (range: 40-87) years. Volume of lung parenchyma that received 20 Gy (V20) exceeded 35% in 2% and mean lung dose exceeded 20 Gy in 1% of patients. Durvalumab consolidation was delivered to 225 patients (75%). Overall, 83% (n = 251), 34% (n = 103), 7% (n = 21), and 1% (n = 4) of the patients developed any grade of pneumonitis, symptomatic pneumonitis, ≥grade 3 pneumonitis, and fatal (grade 5) pneumonitis, respectively. Corticosteroids were administered to 25% of the patients to treat pneumonitis. Multivariate analysis identified the predictive factors for the development of symptomatic pneumonitis: V20 Gy or more ≥ 25% (odds ratio [OR]: 2.37, P = 0.008) and mean lung dose (MLD) ≥ 10 Gy (OR: 1.93, P 0.0047). Of the 52 patients who received corticosteroids for pneumonitis after durvalumab initiation, 21 were rechallenged with durvalumab. Overall, 81% of patients met the PACIFIC study's rechallenge criteria and did not experience a severe pneumonitis relapse.High V20 and MLD were independent risk factors of symptomatic pneumonitis. More than 80% of the patients who were rechallenged with durvalumab after pneumonitis met the PACIFIC study's rechallenge criteria. Consequently, severe relapse did not occur. Cooperation between radiation and medical oncologists is important for safe chemoradiotherapy and the safe completion of durvalumab consolidation therapy.

Background Although predictive value of immune‐related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) have been suggested by several studies, their assessments were insufficient because patients were categorized only by the occurrence of irAEs. It has not been elucidated whether irAEs also play a significant role even in responders. Materials and Methods Between December 2015 and September 2018, 106 patients with advanced non‐small cell lung cancer treated with ICIs were enrolled in our prospective biomarker study. Twenty‐three of these were responders, defined as those with complete or partial response. We investigated the proportion of irAEs among overall and responders. For responders, progression‐free survival (PFS) and overall survival of ICIs were compared between those with and without irAEs. As an exploratory analysis, we measured 41 proteins from peripheral blood before and after ICI treatment. Results The proportion of irAEs was significantly higher in responders than nonresponders (65.2% vs. 19.3%, p < .01). Among responders, clinical characteristics did not differ regardless of the occurrence of irAEs. However, there was a significant difference in PFS among responders (irAE group 19.1 months vs. non‐irAE group 5.6 months; hazard ratio: 0.30 [95% confidence interval: 0.10–0.85]; p = .02). Of 41 protein analyses, fibroblast growth factor‐2 at baseline and monocyte chemoattractant protein fold change showed significant differences between them (p < .04). Conclusion Although this is a small sample–sized study, irAE might be a predictive factor of durable efficacy, even in patients who responded to ICIs. Investigation into the significance of irAEs in responders will contribute to the establishment of optimal administration of ICI. Implications for Practice Although the predictive value of immune‐related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) has been suggested by several studies, it has not been elucidated whether irAEs also play a significant role even in responders. This study showed that more than 60% of responders had irAEs. It demonstrated the strong correlation between irAEs and efficacy even in responders. Investigation into the significance of irAEs in responders will contribute to the establishment of optimal administration of ICI., Immune‐related adverse events might be a predictive factor of efficacy, even I patients who respond to immune checkpoint inhibitor therapy. This study investigated the significance of immune‐related adverse events in patients with non‐small cell lung cancer who had complete or partial response after treatment with immune checkpoint inhibitors.

According to rapid development of chemotherapy in advanced non-small cell lung cancer (NSCLC), the Japan Lung Cancer Society has been updated its own guideline annually since 2010. In this latest version, all of the procedure was carried out in accordance with grading of recommendations assessment, development and evaluation (GRADE) system. It includes comprehensive literature search, systematic review, and determination of the recommendation by multidisciplinary expert panel which consisted of medical doctors, pharmacists, nurses, statisticians, and patients from patient advocacy group. Recently, we have had various types of chemotherapeutic drugs like kinase inhibitors or immune-checkpoint inhibitors. Thus, the guideline proposes to categorize patients into three entities: (1) driver oncogene-positive, (2) PD-L1 ≥ 50%, and (3) others. Based on this subgroup, 31 clinical questions were described. We believe that this attempt enables clinicians to choose appropriate treatment easier. Here, we report an English version of the Japan Lung Cancer Society Guidelines 2018 for NSCLC, stages IV.

Although programmed cell death-ligand-1 (PD-L1) expression in tumor tissue has been established as predictive biomarker for the anti-programmed cell death-1 (PD-1) antibody treatment of non-small-cell lung cancer (NSCLC), additional biomarkers are critically needed. We evaluated serum proteins relevant to immune checkpoint blockade in patients with NSCLC treated with nivolumab to identify novel non-invasive predictive biomarkers.Patients with advanced NSCLC, who had failed at least one prior chemotherapy regimen, received nivolumab monotherapy (3 mg/kg, Q2W) until progressive disease (PD) or unacceptable toxicity was observed. Blood samples were collected at baseline and week 4. Fifty-seven serum protein levels were quantified with a Milliplex MAP assay. The associations of both clinical benefit (CB) and the onset of immune related adverse events (irAEs) with serum proteins levels were evaluated.Thirty-eight patients with advanced NSCLC were enrolled in the study, with 38 and 32 paired serum samples at baseline and week 4 being available for efficacy analysis and irAE analysis, respectively. In durable CB (DCB) patients compared with non-DCB patients, the baseline serum levels of BMP-9 were significantly higher, whereas the follistatin, IL-8, IP-10, and TNF-α levels were significantly lower. In irAE patients compared with non-irAE patients the serum levels of G-CSF and RANTES at week 4 were significantly higher, whereas the levels of leptin were significantly lower. A multivariate analysis revealed that follistatin and IP-10 were statistically associated with DCB (p 0.05) and RANTES was associated with irAE onset (p 0.05). In a subset of irAE-developed patients, RANTES levels decreased after steroid administration, supporting its involvement in irAE.Serum proteins have the potential to be predictive markers for DCB and irAEs onset in patients with NSCLC treated with nivolumab. In addition, antitumor activity and irAEs may not be regulated by the same mechanisms.

Aim The emergency department requires simple and useful clinical indicators to identify bacteremia. This retrospective study explored the Systemic Inflammatory Response Syndrome (SIRS) and quick Sequential Organ Failure Assessment (qSOFA) scores for predicting bacteremia. Methods Between April and September 2017, we assessed blood cultures of 307 patients in our emergency department. We calculated the SIRS and qSOFA scores for these patients and evaluated their correlation with bacteremia. Results Of 307 patients, 66 (21.5%) had bacteremia, 237 (77.2%) were SIRS‐positive, and 123 (40.0%) were qSOFA‐positive. The sensitivity and specificity of the SIRS score for predicting bacteremia were 87.9% and 25.7%, respectively. The sensitivity and specificity of the qSOFA score were 47.0% and 61.8%, respectively. Multivariate analysis revealed that body temperature (odds ratio, 2.16; 95% confidence interval, 1.22–3.84; P = 0.009) and blood pressure (odds ratio, 2.72; 95% confidence interval, 1.39–5.35; P = 0.004) significantly associated with bacteremia. Conclusions The SIRS score was a more sensitive indicator than the qSOFA score for predicting bacteremia., We compared the Systemic Inflammatory Response Syndrome (SIRS) and quick Sequential Organ Failure Assessment (qSOFA) scores in predicting bacteremia. SIRS had higher sensitivity (87.9%) than qSOFA (47.0%). Body temperature significantly correlated with bacteremia and SIRS sensitivity in predicting bacteremia was lower in the antipyretic group.

Introduction In patients with relapsed SCLC, amrubicin (AMR) is the current standard treatment in Japan. Nevertheless, its efficacy is not satisfactory and prognosis is poor. Preclinical study suggested that anthracycline agent might induce immunogenic cell death and work synergistically with immune checkpoint inhibitors. Methods Patients with relapsed SCLC who relapsed after completion of platinum-containing regimen were registered. Patients were treated with pembrolizumab (200 mg, flat dose on d 1, every 3 wk for 2 y) plus AMR (40 mg/m2 on d 1–3, every 3 wk until progression). Primary end point was overall response rate (ORR). Secondary end points consisted of progression-free survival (PFS), overall survival, and safety. On the basis of the hypothesis that this treatment will improve ORR from 20% to 40% (0.1 of one-sided α and power of 0.8), 25 patients are required (trial identifier: NCT03253068). Results Between November 2017 and October 2019, a total of 25 patients were enrolled. Most participants (88%) relapsed within 90 days after platinum-containing therapy and all patients were immune checkpoint inhibitor-naive. ORR, the primary end point, was 52.0% (95% confidence interval [CI]: 31.3%–72.2%). Median PFS was 4.0 months (95% CI: 2.8–7.0 mo), and PFS rate at 1 year was 14.4%. Median overall survival was 10.6 months (95% CI: 7.3–21.3 mo). Common adverse events greater than or equal to grade 3 were neutropenia (64%), leukopenia (40%), and febrile neutropenia (16%). No treatment-related deaths occurred. Conclusions Among patients with relapsed SCLC, pembrolizumab plus AMR was effective and tolerable.

BACKGROUND Programmed cell death ligand 1 is a biomarker of immune checkpoint inhibitors (ICIs) for treating advanced non-small-cell lung cancer (NSCLC). Here, we evaluated serum proteins from patients with advanced NSCLC treated with ICIs to determine their potential as noninvasive predictive biomarkers for efficacy and immune-related adverse events (irAEs). PATIENTS AND METHODS Patients with advanced NSCLC who received nivolumab or pembrolizumab monotherapy until disease progression or unacceptable toxicity were integrated with previously reported nivolumab-treated patients. Blood samples were collected serially from baseline until the disease progressed. Serum protein levels were quantified using the Luminex assay. Associations of clinical benefit (CB) and onset of irAEs with serum protein levels were evaluated. RESULTS Sixty-three patients with advanced NSCLC were studied, and we used 63 and 47 paired serum samples at baseline and the second sampling point, respectively, for efficacy analysis. Baseline growth-regulated oncogene 1 (GRO-1) levels were significantly lower in durable CB (DCB) patients than in non-DCB patients (P < .05). Changes in monocyte chemoattractant protein 1 (MCP-1) levels significantly decreased between baseline and the second sampling point (P < .05). Patients with the low GRO-1/decreased MCP-1 subtype showed significantly longer progression-free survival (PFS) and overall survival (OS) than the high GRO-1/increased MCP-1 subgroup did (median PFS, not reached vs. 47 days, P < .0001; median OS, 985 days vs. 148 days, P = .0002, respectively). Elevated GRO-1 levels were associated with immune-related adverse event onset. CONCLUSIONS Serum GRO-1 and MCP-1 levels can identify patients with advanced NSCLC who are likely to benefit from ICI treatment. Time-course tracing of these protein levels might be valuable in ICI treatment.

Importance Although treatment with first-generation epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) plus antiangiogenic inhibitor has shown promising efficacies in patients withEGFR-mutated lung adenocarcinoma, recent single-arm studies have suggested that osimertinib plus antiangiogenic inhibitor might not work synergistically. Objective To explore the efficacy and safety of osimertinib plus bevacizumab compared with osimertinib alone in patients with lung adenocarcinoma withEGFRT790M mutation. Design, Setting, and Participants Patients with advanced lung adenocarcinoma that progressed with prior EGFR-TKI treatment (other than third-generation TKI) and acquiredEGFR T790M mutation were enrolled. This study comprises a lead-in part with 6 patients and a subsequent phase 2 part. In phase 2, patients were randomized to osimertinib plus bevacizumab or osimertinib alone in a 1:1 ratio. Interventions The combination arm received oral osimertinib (80 mg, every day) plus intravenous bevacizumab (15 mg/kg, every 3 weeks) until progression or unacceptable toxic effects. The control arm received osimertinib monotherapy. Main Outcomes and Measures The primary end point was progression-free survival (PFS) assessed by investigators. Secondary end points consisted of overall response rate, time to treatment failure, overall survival, and safety. Results From August 2017 through September 2018, a total of 87 patients were registered (6 in the lead-in part and 81 in the phase 2 part [intention-to-treat population]). Among those randomized, the median (range) age was 68 (41-82) years; 33 (41%) were male; 37 (46%) had an Eastern Cooperative Oncology Group performance status of 0; and 21 (26%) had brain metastasis. Although the overall response rate was better with osimertinib plus bevacizumab than osimertinib alone (68% vs 54%), median PFS was not longer with osimertinib plus bevacizumab (9.4 months vs 13.5 months; adjusted hazard ratio, 1.44; 80% CI, 1.00 to 2.08;P = .20). Median time to treatment failure was also shorter in the combination arm vs the osimertinib arm (8.4 months vs 11.2 months;P = .12). Median overall survival was not different in the combination arm vs osimertinib arm (not reached vs 22.1 months;P = .96). In the combination arm, common adverse events of grade 3 or higher were proteinuria (n = 9; 23%), hypertension (n = 8; 20%). Conclusions and Relevance In this randomized clinical trial comparing osimertinib plus bevacizumab vs osimertinib alone, the combination arm failed to show prolongation of PFS in patients with advanced lung adenocarcinoma withEGFR T790M mutation. Trial Registration UMIN Clinical Trials Registry Identifier:UMIN000023761

Patients with NSCLC in East Asia, including Japan, frequently contain EGFR mutations. In 2018, we published the latest full clinical practice guidelines on the basis of those provided by the Japanese Lung Cancer Society Guidelines Committee. The purpose of this study was to update those recommendations, especially for the treatment of metastatic or recurrent EGFR-mutated NSCLC. We conducted a literature search of systematic reviews of randomized controlled and nonrandomized trials published between 2018 and 2019 that multiple physicians had reviewed independently. On the basis of those studies and the advice from the Japanese Society of Lung Cancer Expert Panel, we developed updated guidelines according to the Grading of Recommendations, Assessment, Development, and Evaluation system. We also evaluated the benefits of overall and progression-free survival, end points, toxicities, and patients' reported outcomes. For patients with NSCLC harboring EGFR-activating mutations, the use of EGFR tyrosine kinase inhibitors (EGFR TKIs), especially osimertinib, had the best recommendation as to first-line treatment. We also recommended the combination of EGFR TKI with other agents (platinum-based chemotherapy or antiangiogenic agents); however, it can lead to toxicity. In the presence of EGFR uncommon mutations, except for an exon 20 insertion, we also recommended the EGFR TKI treatment. However, we could not provide recommendations for the treatment of EGFR mutations with immune checkpoint inhibitors, including monotherapy, and its combination with cytotoxic chemotherapy, because of the limited evidence present in the literature. The 2020 Japanese Lung Cancer Society Guidelines can help community-based physicians to determine the most appropriate treatments and adequately provide medical care to their patients.

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, 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

In the WJOG8815L phase II clinical study, we monitored EGFR mutation fractions (MFs) in the circulating tumor DNA (ctDNA) of EGFR T790M mutation‐positive patients with non‐small cell lung cancer (NSCLC) that received treatment with the tyrosine kinase inhibitor (TKI) osimertinib. The MF values of TKI‐sensitizing EGFR mutations in ctDNA at day 1 of cycle 4 of osimertinib treatment could predict osimertinib treatment outcomes., The WJOG8815L phase II clinical study involves patients with non‐small cell lung cancer (NSCLC) that harbored the EGFR T790M mutation, which confers resistance to EGFR tyrosine kinase inhibitors (TKIs). The purpose of this study was to assess the predictive value of monitoring EGFR genomic alterations in circulating tumor DNA (ctDNA) from patients with NSCLC that undergo treatment with the third‐generation EGFR‐TKI osimertinib. Plasma samples of 52 patients harboring the EGFR T790M mutation were obtained pretreatment (Pre), on day 1 of treatment cycle 4 (C4) or cycle 9 (C9), and at diagnosis of disease progression or treatment discontinuation (PD/stop). CtDNA was screened for EGFR‐TKI‐sensitizing mutations, the EGFR T790M mutation, and other genomic alterations using the cobas EGFR Mutation Test v2 (cobas), droplet digital PCR (ddPCR), and targeted deep sequencing. Analysis of the sensitizing—and T790M—EGFR mutant fractions (MFs) was used to determine tumor mutational burden. Both MFs were found to decrease during treatment, whereas rebound of the sensitizing EGFR MF was observed at PD/stop, suggesting that osimertinib targeted both T790M mutation‐positive tumors and tumors with sensitizing EGFR mutations. Significant differences in the response rates and progression‐free survival were observed between the sensitizing EGFR MF‐high and sensitizing EGFR MF‐low groups (cutoff: median) at C4. In conclusion, ctDNA monitoring for sensitizing EGFR mutations at C4 is suitable for predicting the treatment outcomes in NSCLC patients receiving osimertinib (Clinical Trial Registration No.: UMIN000022076).

BackgroundStudies have suggested that chemotherapy after immune checkpoint inhibitors may confer an improved response for non–small cell lung cancer (NSCLC). However, potential selection bias in such studies has not been addressed. We therefore applied propensity score analysis to investigate the efficacy of chemotherapy after PD-1 inhibitor treatment (CAP) compared with chemotherapy alone.MethodsWe conducted a retrospective observational cohort study for patients treated at 47 institutions across Japan between April 1, 2014 and July 31, 2017. Eligible patients had advanced or recurrent NSCLC who have undergone chemotherapy. Patients subsequently treated with chemotherapy (docetaxel with or without ramucirumab, S-1 or pemetrexed) either after PD-1 inhibitor therapy (CAP cohort) or alone (control cohort) were included. The primary end point was objective response rate (ORR). Inverse probability weighting (IPW) was applied to adjust for potential confounding factors.ResultsA total of 1439 patients (243 and 1196 in the CAP and control cohorts, respectively) was available for unadjusted analysis. Several baseline characteristics—including age, histology,EGFRorALKgenetic alterations, and brain metastasis—differed significantly between the two cohorts. After adjustment for patient characteristics with the IPW method, ORR was 18.9% for the CAP cohort and 11.0% for the control cohort (ORR ratio 1.71; 95% CI 1.19 to 2.46; p=0.004). IPW-adjusted Kaplan-Meier curves showed that median progression-free survival (PFS) for the CAP and control cohorts was 2.8 and 2.7 months (IPW-adjusted HR 0.95; 95% CI 0.80 to 1.12; p=0.55), and median overall survival (OS) was 9.2 and 10.4 months (IPW-adjusted HR 1.05; 95% CI 0.86 to 1.28; p=0.63), respectively.ConclusionsAfter accounting for selection bias by propensity score analysis, CAP showed a significantly higher ORR compared with chemotherapy alone, with the primary end point of ORR being achieved. However, these results did not translate into a PFS or OS advantage, suggesting that prior administration of PD-1 inhibitors may result in a synergistic antitumor effect with subsequent chemotherapy, but that such an effect is transient. CAP therefore does not appear to achieve durable tumor control or confer a lasting survival benefit.

Background Most patients with non–small-cell lung cancer (NSCLC) are ineligible for clinical trials. However, few studies have reported on the profiles and treatment outcomes for these patients. Therefore, we investigated the characteristics, outcomes, and survival of patients with advanced NSCLC who were ineligible for clinical trials. Materials and Methods We analyzed the data from a retrospective cohort of 786 consecutive patients with a diagnosis of advanced NSCLC. We reviewed the criteria of phase 1 to 3 clinical trials and classified patients according to the common first-line eligibility criteria for lung cancer. Results Of the 786 patients, 469 (60%) were ineligible for clinical trials. The main reasons for ineligibility were brain metastasis (41%), poor performance status (25%), and respiratory disease (24%). For all patients, ineligibility was identified as an independent predictor of overall survival (hazard ratio, 0.78; 95.0% confidence interval, 0.65-0.93; P = .008), even in those with a good performance status who had received chemotherapy (hazard ratio, 0.80; 95.0% confidence interval, 0.65-0.99; P = .037). In the subgroup analysis of ineligible patients, survival varied depending on the reasons for ineligibility. In particular, a history of cancer was not associated with a poor outcome, although this was a common reason for ineligibility. Conclusion Most patients were ineligible for clinical trials and had a shorter overall survival, although this varied depending on the reason for their ineligibility. These results should be considered when applying clinical trial outcomes to real-world patients. Further studies of ineligible patients are needed to improve the treatment decisions in clinical settings.

Introduction Nivolumab has demonstrated efficacy against metastatic NSCLC. Four programmed cell death ligand 1 (PD-L1) immunohistochemistry (IHC) assay systems are available for identification of responders among patients with NSCLC, and these assays show some differing characteristics. Accordingly, in this study, we evaluated the ability of these assays to identify responders to nivolumab therapy. Methods We retrospectively analyzed patients with previously treated advanced NSCLC, who received nivolumab between January 2016 and September 2016. Specimens were stained using four PD-L1 IHC assays (28-8, 22C3, SP142, and SP263). We classified patients as having test results that were strongly positive (tumor proportion score [TPS] ≥50%), weakly positive (TPS 1%–49%), or negative (TPS Results A total of 40 patients with NSCLC and their specimens were analyzed. Analytical comparisons demonstrated good concordance of PD-L1–stained tumor cells among the 28-8, 22C3, and SP263 assays (weighted κ coefficient 0.64–0.71), whereas the SP142 assay showed lower concordance with other assays (weighted κ coefficient 0.39–0.55). Progression-free survival in patients showing strongly positive PD-L1 staining classified by 28-8, 22C3, and SP263 assays was significantly longer than that in patients with a negative result for PD-L1 staining. Predictive performance of response to nivolumab, as assessed by receiver operating characteristic analysis, was also equivalent among the 28-8, 22C3, and SP263 assays (area under the curve 0.75–0.82), whereas the SP142 assay exhibited lower predictive performance (area under the curve 0.68). Conclusions The 28-8, 22C3, and SP263 PD-L1 IHC assays showed equivalent predictive performance, whereas the SP142 assay showed lower predictive performance.

Background: In the past decade, three-dimensional organoid culture derived from various tumors has been applied to cancer research. Compared to the conventional two-dimensional cell culture, organoid culture recapitulates in vivo system and furthermore, its high establishment rate may hold the potential to help decision-making for precision medicine. However, it remains challenging to establish organoids from advanced thoracic malignancies due to a limited amount of biopsy specimens. Here, we report the attempt to establish organoids from endoscopic biopsy specimens and pleural effusions in patients with advanced thoracic malignancies Methods: Organoid culture was attempted using biopsy specimens or pleural effusions from patients who underwent transbronchial biopsy, thoracoscopic biopsy or thoracentesis. After confirming the presence of malignant cells by rapid on-site evaluation, biopsy specimens were digested with collagenase and dispase at 37°C followed by being harvested and cultured in Matrigel. As for pleural effusions, mononuclear cells were isolated by ficoll density gradient centrifugation and CD45+ cells were depleted using anti-CD45 magnetic beads. Then, the resultant cells were cultured in Matrigel. Next-generation sequencing was performed to confirm cancer-related somatic mutations using Ion PGM system. Cell viability assay was performed by resazurin assay. Results:142 patients were registered in the study between May 2019 and October 2020 at Wakayama Medical University. Fifty-one cases were excluded because of negative diagnosis for malignancy, retraction of the consent or risk of bleeding associated with biopsy. We attempted to culture organoids using 98 samples from 91 patients. The types of malignancies were as follows: non-small cell lung cancers (NSCLC)/SCLC/others, 80/8/3. A total of 33 organoids were successfully cultured with sustainable proliferation and 16 were successfully cryopreserved. Established organoids were confirmed to harbor the same mutations as detected by clinical testing with tissue samples and to form tumors in a xenotransplantation model. HLCO-75, established from pleural effusion at disease progression after osimertinib treatment was genotyped and found to gain ERBB2 V777L mutation in exon 20 in addition to original EGFR L858R mutation. Marked growth-inhibitory effect by poziotinib, a HER2 tyrosine kinase inhibitor with IC50 value 6 nM was observed whereas not by TAS6417, another EGFR/HER2 exon 20 inhibitor, suggesting the potential of organoid culture for decision-making in cancer precision medicine. Conclusion: Our results suggest that organoid culture is feasible from small biopsy specimens and these organoids could be applied for personalized medicine. Citation Format: Jun Oyanagi, Yasuhiro Koh, Koichi Sato, Masanori Tanaka, Katsuyuki Furuta, Takeya Sugimoto, Ryota Shibaki, Shunsuke Teraoka, Daichi Fujimoto, Nahomi Tokudome, Hiroaki Akamatsu, Atsushi Hayata, Atsushi Hayata, Yuichi Ozawa, Hiroki Ueda, Nobuyuki Yamamoto. Establishment of organoids derived from patients with advanced thoracic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2976.

Introduction Nivolumab has demonstrated efficacy against metastatic non-small cell lung cancer (NSCLC). However, immune-related adverse events can occur, among which pneumonitis is relatively common. Lung cancer patients with idiopathic interstitial pneumonia (IIP) have a higher risk of pneumonitis associated with anticancer therapy. We hypothesized that the benefit of nivolumab may outweigh the risks of pneumonitis in patients with NSCLC who have mild IIP. We performed a pilot trial to evaluate the safety of nivolumab in NSCLC patients with mild IIP. Methods Previously treated, inoperable NSCLC patients with mild IIP were enrolled. Mild IIP was defined as having a predicted vital capacity ≥80% and a possible usual interstitial pneumonia (UIP) or inconsistent with UIP pattern on chest high-resolution computed tomography. Patients received nivolumab at a dose of 3 mg/kg biweekly. Results Six patients were enrolled in this trial between April 2016 and December 2016. None experienced drug-related nonhematologic grade 3/4 or hematologic grade 4 adverse events in the 12 weeks following the initiation of nivolumab treatment. Furthermore, none of the patients had pneumonitis of any grade. At the time of analysis, all patients were alive, and 3 had experienced a partial response. Conclusions Nivolumab therapy may be feasible in NSCLC patients with mild IIP. (Trial registration number: UMIN000022037)

Background Liquid biopsy allows the identification of patients whose tumors harbor specific mutations in a minimally invasive manner. No prospective data have been available for the efficacy of osimertinib in patients with non-small cell lung cancer (NSCLC) who develop resistance to first- or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and who test positive for the TKI resistance-conferring T790M mutation of EGFR by liquid biopsy. Therefore, a phase 2 study was conducted to assess the efficacy and safety of osimertinib in such patients. Methods Eligible patients had advanced or recurrent NSCLC with known TKI-sensitizing mutations of EGFR, had documented disease progression after treatment with at least 1 first- or second-generation EGFR TKI, and were positive for the T790M mutation in plasma according to the Cobas EGFR Mutation Test v2 (Roche Diagnostics) or droplet digital polymerase chain reaction analysis. Patients were treated with osimertinib (80 mg/d) until disease progression. The primary endpoint was the overall response rate (ORR) in patients positive for T790M in plasma by the Cobas assay. Results Between June 2016 and November 2017, 276 patients were screened for their T790M status with a liquid biopsy. Seventy-four patients were positive for T790M in plasma, and 53 of these individuals were enrolled in the study. The ORR for evaluable patients positive for T790M in plasma by the Cobas assay (n = 49) was 55.1% (95% confidence interval [CI], 40.2%-69.3%). The median progression-free survival for all evaluable patients (n = 52) was 8.3 months (95% CI, 6.9-12.6 months). Conclusions The results demonstrate the utility of liquid biopsy for the detection of T790M with the Cobas EGFR Mutation Test v2. Plasma genotyping with this assay is informative for treatment selection in clinical practice when tumor sampling is not feasible.

Objectives Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate that targets delta-like protein 3 (DLL3) on small cell lung cancer (SCLC) tumors, is internalized and releases the toxin pyrrolobenzodiazepine to induce cell death. This open label phase I study was the first study of Rova-T in Japanese patients. The aim of this study was to evaluate, safety, pharmacokinetics, and preliminary efficacy of Rova-T in Japanese patients with advanced recurrent SCLC. Materials and methods Patients received Rova-T (0.2 or 0.3 mg/kg) by intravenous infusion on Day (D) 1 of each 6-week cycle for 2 doses and dexamethasone (8 mg BID oral) on D-1, D1, and D2 of each 6-week cycle. Retreatment with Rova-T was permitted for patients who tolerated their initial doses and then progressed after disease control (defined as stable disease or better) was observed for at least 12 weeks after their last dose of Rova-T. Results Rova-T exhibited toxicity that was generally manageable in Japanese patients (N = 29). No dose-limiting toxicities were experienced. The most common treatment-related adverse events (≥25% of patients, all grades) were platelet count decreased, pleural effusion, peripheral edema, aspartate aminotransferase increased, white blood cell count decreased, neutrophil count decreased, alanine aminotransferase increased, hypoalbuminaemia, anemia and decreased appetite. Safety and pharmacokinetics exposures were similar to previous observations in non-Japanese populations. Per investigator assessment of DLL3 high patients, 17% (3/18) had confirmed partial responses, and the disease control rate was 56%, mPFS was 2.9 months, and mOS was 7.4 months. Conclusions These preliminary data support further exploration of Rova-T treatment in Japanese patients with SCLC in global studies. This trial was registered with ClinicalTrials.gov as NCT03086239.

e21048 Background: The cGAS/STING pathway is an innate immune pathway that promotes cytokine production in response to cytoplasmic DNA, and its activation is important for the induction of anti-tumor immunity. However, predictivity of cGAS/STING tumor expression on the efficacy of PD-1/L1 inhibitors and subsequent immune responses (e.g., changes in serum cytokines) remain to be elucidated. Non-small cell lung cancer with PD-L1 tumor proportion score (TPS) of 50% or higher respond well to immune checkpoint inhibitor (ICI) monotherapy, but there is still a poor response group among them, and the extraction of such patients is an urgent issue. Methods: This is a post hoc analysis of prospective biomarker study, which enrolled 106 patients with advanced non-small cell lung cancer (NSCLC) who were treated with ICI monotherapy between December 2015 and September 2018. We investigated in 68 patients with preserved evaluable tissue samples taken before start of ICI treatment. cGAS, STING, and PD-L1 expression in tumors were stained by immunohistochemistry. cGAS and STING were evaluated by H-score. Using peripheral blood which was collected by the observational study, 41 serum proteins at the time of PD-1/L1 inhibitors initiation and in 4 – 6 weeks later were quantified. Results: The median cGAS and STING H-SCORE were 220 (5 – 300) and 190 (0 – 300), respectively. There were no differences in cGAS or STING H-SCORE between PD-L1 high (TPS ≥50) and low (TPS < 50) groups ( p= 0.990 and 0.283). Cases were divided into two groups according to median of the H-SCORE, respectively, and compared. Unexpectedly, cGAS high (H-SCORE ≥220) patients showed significantly shorter progression free survival of ICI when PD-L1 TPS ≥50 (median progression free survival (PFS); 143 days vs. not reached, p = 0.028) and progression free rate at 18 months was 7 and 53%, while no association was observed when PD-L1 TPS < 50 (median PFS; 47 vs. 61 days, p= 0.798). STING tumor expression was not associated with PFS regardless of PD-L1 TPS. In cytokine analysis, cGAS high was associated with significantly higher serum concentrations of TGF-β1 and β2 before ICI initiation (47.5 vs. 22.3hg/l, p= 0.023; 2118 vs. 882rg/ml, p= 0.037), and H-SCORE of cGAS, not STING, were significantly correlated with TGF-β1 and β2 basal levels (r = 0.447, p= 0.009; r = 0.373, p= 0.033). Analysis about fold change from baseline to 4 – 6 weeks later of 41 cytokines revealed that leptin significantly increased in cGAS high tumor while no difference was seen in all of cytokines between STING high and low tumor. Conclusions: Tumor expression (H-Score) of cGAS, not STING, is a candidate for predictor of poor response to ICI monotherapy in NSCLC with PD-L1 high (TPS ≥50). cGAS tumor expression may be associated with TGF-β producing, immune-suppressive tumor microenvironment in NSCLC. Clinical trial information: UMIN000024414.

Background: Though PD-ligand 1 (PD-L1) expression on tumor tissue has been established as companion diagnostics in non-small-cell lung cancer (NSCLC) for anti-PD-1 treatment, additional biomarkers are critically needed. While immune related adverse events (irAEs) have been reported to be associated with efficacy, there are no established biomarkers to predict irAEs onset. Here, we measured multiple serum proteins in NSCLC patients treated with immune checkpoint inhibitors (ICIs) and explored the potential of predicting clinical response and irAE onset. Patients and Methods: Advanced NSCLC patients received nivolumab, pembrolizumab or atezolizumab until progressive disease (PD) or unacceptable toxicity. Serum samples were collected at baseline and after the treatment (at week 4 or week 6). Durable clinical benefit (DCB) was defined as patients whose response was lasting over 6 months. Using Luminex technology, serum levels of 41 proteins consisting of cytokines, chemokines, growth factors, and angiogenesis factors were measured. All statistical analyses were carried out using JMP Pro software (ver. 14.0). Cut-off value of serum protein levels were estimated with receiver operating characteristic curve. Results: Ninety-eight patients were registered in the study between January 2016 and May 2019 at Wakayama Medical University Hospital and 97 were included in the final analysis. Demographics of the patients were as follows: median age 70 (range, 49 to 91); male 78%; stage III/IV 31/69%; squamous/non-squamous/unknown 29/69/2%; previous treatment: 0/≥1 22/78%; ICI: nivolumab/pembrolizumab/atezolizumab 46/41/13%. Objective response rate was 24.7% (24/97), and disease control rate was 46.4% (45/97). Among 41 serum proteins measured serially, IL-8 levels at baseline were significantly lower in DCB patients than non-DCB patients in entire cohort (p < 0.05). Among those, Kaplan-Meier analysis revealed lower levels of IL-8 were significantly associated with longer PFS (cut-off, 11.9217 pg/ml; median PFS, 293 vs 59 days; p < 0.01). In second or later line subset, GRO-α, IL-8, IP-10, PLGF and VEGF-D were significantly lower in DCB patients than non-DCB-patients at baseline (p < 0.05). Lower levels of those proteins except for VEGF-D were significantly associated with longer PFS ((cut-off, 1.073 ng/ml, 11.9217 pg/ml, 480.8 pg/ml, and 14.83 pg/ml; median PFS, 183 vs 49, 293 vs 49, 133 vs 42, and 153 vs 49 days; 95% CI, 56-322 days, 69 days-not reached, 58-211 days and 52-293 days; p < 0.05, 0.01, 0.05, 0.01). Follistatin which we previously reported to be associated with DCB upon novolumab treatment, also showed significant association with longer PFS both in entire cohort (cut-off, 572.5; median PFS, 160 vs 59 days; 95% CI, 68-322 days, p < 0.05) and 2nd or later line subset (cut-off, 572.5; median PFS, 100 vs 49 days; 95% CI, 39-322 days, p < 0.05), though it was not significantly different between DCB and non-DCB. Regarding irAEs, GRO-α levels were significantly increased between baseline and the second sampling point in patients who acquired irAEs both in entire cohort and 2nd or later line subset (p < 0.01). Conclusions: We identified potential serum protein markers associated with clinical benefit and irAEs in advanced NSCLC treated with ICIs by multiplex protein-based assay. Citation Format: Jun Oyanagi, Yasuhiro Koh, Koichi Sato, Shunsuke Teraoka, Atsushi Hayata, Nahomi Tokudome, Hiroaki Akamatsu, Yuichi Ozawa, Keiichiro Akamatsu, Masanori Nakanishi, Hiroki Ueda, Nobuyuki Yamamoto. Predictive significance of serum proteins on clinical outcome in advanced non-small-cell lung cancer patients treated with immune checkpoint inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4305.

e21076 Background: PD-L1 inhibitor, durvalumab has been approved since the PACIFIC study showed its efficacy as consolidation therapy after CCRT for locally advanced NSCLC. But predictive factor for the efficacy of CCRT on this post PACIFIC era have not been known. LIPI has been proposed as a new biomarker for the anti-PD-1 therapy of advanced NSCLC. In this study, we investigated the usefulness of LIPI as a predictive marker in multicenter cohort of patients with locally advanced NSCLC who received CCRT as initial treatment. Methods: 219 patients with available baseline LIPI were reviewed. The progression free survival (PFS) was estimated by the Kaplan-Meier method, and LIPI were calculated at baseline. Kaplan-Meier estimates of PFS and recurrence were compared using the log-rank test for trend. Multivariable analysis was conducted using the Cox and logistic regression models, respectively, adjusted for age, sex, ECOG-PS, smoking, histology, TNM stage, chemotherapy regimens, Body mass index (BMI), PD-L1 status, EGFR or ALK mutation, and baseline LIPI. Results: 62.5% (n = 137) of the patients had a good (0 factors) LIPI, while 37.5% (n = 82) had intermediate (1 factor) and poor (2 factors) LIPI respectively. In multivariable analysis, good LIPI (0 factors) were significantly associated with longer PFS (HR = 0.46, 95% CI 0.28-0.75; P < 0.01) as did ECOG-PS0 (P < 0.01), ≤stageIIIA (P < 0.01), being treated with durvalumab after CRT (P = 0.04). There were no difference in the patient characteristics between good LIPI and intermediate/poor LIPI, significantly. Higher LIPI (1 or 2 factors) were strongly prognostic factor for recurrence after CCRT in multivariate analysis (P = 0.04), along with ECOG-PS1≤ (P < 0.01), stage IIIB≤ (P < 0.01). Conclusions: The good LIPI predictive value for PFS and disease control in patients treated with CCRT was confirmed. Although a strong statistical significance, we needs to be confirmed further with longer follow-up and prospective study.

9039 Background: Durvalumab was approved as a consolidation therapy after chemoradiotherapy (CRT) for locally advanced non-small cell lung cancer (NSCLC) and established as the standard of care. However, since the approval of durvalumab, little has been reported on the frequency, severity, or clinical course of pneumonitis/radiation pneumonitis throughout the course of CRT. Methods: We conducted a 17-center, retrospective cohort study of consecutive patients with locally advanced NSCLC who received concurrent chemoradiotherapy (CCRT) with platinum-based chemotherapy between May 2018 and May 2019. Results: A total of 275 patients were included; their median age was 69.9 (range, 40.3-87.5), mean V20 was 19.4% (range, 1.4-37.9), and mean "mean lung dose" was 10.9 Gy (range, 1.5-31.3). Of these, 204 patients received durvalumab consolidation therapy (74.2%). Median follow-up time from the initiation of CCRT was 8.4 months (range, 1.5-15.7). During follow-up, 225 patients (81.8%) developed any-grade pneumonitis/radiation pneumonitis. Of these, more than half (134 of 225) were asymptomatic (grade 1), 18 (6.5%) were ≥grade 3, and 4 patients (1.5%) had fatal pneumonitis/radiation pneumonitis. By the time of initial assessment of response to CCRT, 64 (23.3%) patients had developed radiation pneumonitis. Logistic regression revealed that only V20 ≥25 % was an independent risk factor of symptomatic (≥grade 2) pneumonitis/radiation pneumonitis (OR: 2.74, 95% CI: 1.35-5.53, p = 0.0045). Of the 275 patients, 67 were treated with corticosteroids for pneumonitis/radiation pneumonitis (24.7%), and 14 (5.1%) needed home oxygen therapy after the treatment of pneumonitis/radiation pneumonitis. Among patients treated with corticosteroids, 21 patients received durvalumab rechallenge. Of the 21 patients, 6 (29%) showed pneumonitis/radiation pneumonitis relapse, of which 3 (14%) resulted in suspension of durvalumab rechallenge, but none were fatal. Conclusions: Although over four-fifths of the patients treated with CCRT after the approval of durvalumab developed pneumonitis/radiation pneumonitis, more than half of them were asymptomatic, and ≥grade 3 events accounted for 6.5%. Sometimes patients needed corticosteroid therapy, which was in many occasions effective, and some also underwent durvalumab rechallenge. V20 was an independent risk factor of symptomatic pneumonitis/radiation pneumonitis.

Osimertinib is a standard treatment for epidermal growth factor receptor (EGFR)-mutated, T790M-positive patients with progression during EGFR-tyrosine kinase inhibitor (TKI) therapy. Osimertinib, a third-generation EGFR-TKI, allows progression-free survival of around 10 months, but its toxicity is well-tolerated compared with other EGFR-TKIs. Preclinical and clinical evidence suggests that EGFR-TKI may work synergistically with vascular endothelial growth factor inhibitors. We therefore plan a phase I/II study to investigate this possibility. In phase I, the primary endpoint is assessment of the tolerability of osimertinib and bevacizumab in 6 patients. Phase II then explores the efficacy of combined treatment compared with osimertinib monotherapy with progression-free survival as the primary endpoint. Secondary endpoints are overall response rate, time to treatment failure, overall survival, and safety. Eighty patients will be enrolled in phase II.

Concurrent chemoradiation therapy (CCRT) is the treatment of choice for locally advanced non-small cell lung cancer (LA-NSCLC). Several clinical trials that combine programmed cell death 1 (PD-1) axis inhibitors with radiotherapy are in development for patients with LA-NSCLC. However, the effect of CCRT on programmed cell death ligand-1 (PD-L1) expression on tumor cells is unknown. In this study, we analysed paired NSCLC specimens that had been obtained pre- and post-CCRT. PD-L1 expression on tumor cells was studied by immunohistochemistry. A total of 45 patients with LA-NSCLC were included, among which there were sufficient pre- and post-CCRT specimens in 35 patients. Overall, the percentage of tumor cells with PD-L1 expression significantly decreased between pre- and post-CCRT specimens (P = 0.024). Sixteen, 15, and 4 patients had decreased, unchanged, or increased PD-L1 expression after CCRT, respectively. Median OS of patients with decreased, unchanged, or increased PD-L1 expression was 85.1, 92.8, and 14.6 months, respectively (P

The patient was a 70-year-old woman with lymphoplasmacytic lymphoma which showed a predominantly diffuse involvement of the bone marrow and kidney. Because atypical lymphocytes appeared in the cerebrospinal fluid, the intrathecal administration of methotrexate (MTX) and cytosine arabinoside (Ara-C) was repeated several times. The patient developed flaccid paraplegia 8 months after the beginning of intrathecal administration, and died 4 months later. Autopsy demonstrated extensive transverse necrosis involving the lower thoracic cord and marked vacuolar degeneration of the white matter of the cervical, upper thoracic and lumbo-sacral cord. Focal vacuolar degeneration of the white matter was also noted in the left parietal lobe. Although vacuolar degeneration of the white matter is a common feature in MTX myelopathy, extensive transverse necrosis is rare. In the present case, an overlapping of two mechanisms, that is, injury of vascular endothelial cells and the direct toxic effect of MTX and Ara-C on the white matter, probably played a crucial role in the pathogenesis of severe myelopathy. Because severe myelopathy occurs infrequently, considering the large number of patients receiving the intrathecal administration of MTX, it is possible that a constitutional predisposition or abnormal sensitivity to MTX was involved in the pathogenesis in the present patient.

Background: Though PD-ligand 1 (PD-L1) expression on tumor tissue has been established as companion diagnostics in non-small-cell lung cancer (NSCLC) for anti-PD-1 treatment, additional biomarkers are critically needed. While immune related adverse events (irAEs) have been reported to be associated with efficacy, there are no established biomarkers to predict irAEs onset. Here, we measured multiple serum proteins in NSCLC patients treated with immune checkpoint inhibitors (ICIs) and explored the potential of predicting clinical response and irAE onset. Patients and Methods: Advanced NSCLC patients received nivolumab, pembrolizumab or atezolizumab until progressive disease (PD) or unacceptable toxicity. Serum samples were collected at baseline and after the treatment (at week 4 or week 6). Durable clinical benefit (DCB) was defined as patients whose response was lasting over 6 months. Using Luminex technology, serum levels of 41 proteins consisting of cytokines, chemokines, growth factors, and angiogenesis factors were measured. All statistical analyses were carried out using JMP Pro software (ver. 14.0). Cut-off value of serum protein levels were estimated with receiver operating characteristic curve. Results: Ninety-eight patients were registered in the study between January 2016 and May 2019 at Wakayama Medical University Hospital and 97 were included in the final analysis. Demographics of the patients were as follows: median age 70 (range, 49 to 91); male 78%; stage III/IV 31/69%; squamous/non-squamous/unknown 29/69/2%; previous treatment: 0/≥1 22/78%; ICI: nivolumab/pembrolizumab/atezolizumab 46/41/13%. Objective response rate was 24.7% (24/97), and disease control rate was 46.4% (45/97). Among 41 serum proteins measured serially, IL-8 levels at baseline were significantly lower in DCB patients than non-DCB patients in entire cohort (p < 0.05). Among those, Kaplan-Meier analysis revealed lower levels of IL-8 were significantly associated with longer PFS (cut-off, 11.9217 pg/ml; median PFS, 293 vs 59 days; p < 0.01). In second or later line subset, GRO-α, IL-8, IP-10, PLGF and VEGF-D were significantly lower in DCB patients than non-DCB-patients at baseline (p < 0.05). Lower levels of those proteins except for VEGF-D were significantly associated with longer PFS ((cut-off, 1.073 ng/ml, 11.9217 pg/ml, 480.8 pg/ml, and 14.83 pg/ml; median PFS, 183 vs 49, 293 vs 49, 133 vs 42 , and 153 vs 49 days; 95% CI, 56-322 days, 69 days-not reached, 58-211 days and 52-293 days; p < 0.05, 0.01, 0.05, 0.01). Follistatin which we previously reported to be associated with DCB upon nivolumab treatment, also showed significant association with longer PFS both in entire cohort (cut-off, 572.5; median PFS, 160 vs 59 days; 95% CI, 68-322 days, p < 0.05) and 2nd or later line subset (cut-off, 572.5; median PFS, 100 vs 49 days; 95% CI, 39-322 days, p < 0.05), though it was not significantly different between DCB and non-DCB. Regarding irAEs, GRO-α levels were significantly increased between baseline and the second sampling point in patients who acquired irAEs both in entire cohort and 2nd or later line subset (p < 0.01). Conclusions: We identified potential serum protein markers associated with clinical benefit and irAEs in advanced NSCLC treated with ICIs by multiplex protein-based assay. Citation Format: Jun Oyanagi, Yasuhiro Koh, Hiroaki Akamatsu, Koichi Sato, Shunsuke Teraoka, Kuninobu Kanai, Atsushi Hayata, Nahomi Tokudome, Yuichi Ozawa, Keiichiro Akamatsu, Masanori Nakanishi, Hiroki Ueda, Nobuyuki Yamamoto. Detection of serum protein levels for predicting clinical benefit in advanced non-small-cell lung cancer patients treated with immune checkpoint inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A052. doi:10.1158/1535-7163.TARG-19-A052

Purpose: Circulating tumor cells (CTCs) have a potential for the noninvasive decision-making. AXL, a receptor tyrosine kinase is associated with promoting cell proliferation, migration, epithelial-to-mesenchymal transition and drug resistance. We previously reported that the establishment of the detection method of AXL-expressing CTCs by an automated microcavity array (MCA) system incorporating mesenchymal marker vimentin (VM). Here we analyzed the clinicopathological correlation with VM-positive AXL-expressing CTCs in advanced non-small-cell lung cancer (NSCLC) patients. Methods: For detecting CTCs, 6 mL of peripheral blood collected from patients was divided into two portions and used for CTC identification in parallel incorporating markers cytokeratin (CK) and VM, respectively. An automated MCA system was used for enrichment and staining for CD45, DAPI, CK or VM with the additional staining for AXL. DAPI-positive, CK or VM-positive, and CD45-negative cells were defined as CTCs. All statistical analyses were carried out using GraphPad Prism 6 and Mann-Whitney U test, Fisher’s exact test, and rog-rank test were performed accordingly. A p value Citation Format: Mio Ikeda, Yasuhiro Koh, Shunsuke Teraoka, Koichi Sato, Kuninobu Kanai, Atsushi Hayata, Nahomi Tokudome, Hiroaki Akamatsu, Yuichi Ozawa, Keiichiro Akamatsu, Katsuya Endo, Masayuki Higuchi, Masanori Nakanishi, Hiroki Ueda, Nobuyuki Yamamoto. Clinical significance of vimentin-positive AXL-expressing circulating tumor cells in advanced non-small-cell lung cancer patients [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A032. doi:10.1158/1535-7163.TARG-19-A032

Background This study aimed to assess the prognostic accuracy of serum CA 19-9 in patients with advanced lung adenocarcinoma. Methods We retrospectively reviewed data of 246 patients who were diagnosed at our institute with advanced (stage IIIB or IV) lung adenocarcinoma between March 2006 and December 2012. We excluded patients who received no chemotherapy, or for whom we had no data on pre-treatment tumor markers. We also evaluated 116 consecutive resected specimens from patients with clinical stage I lung adenocarcinoma pathologically. Results The 76 (31 %) patients who were CA 19-9+ had shorter overall survival (OS) than CA 19-9− group (12.5 vs 26.2 months, P = 0.005). Cox’s multivariate regression analysis identified Eastern Cooperative Oncology Group Performance Status 0 or 1 (P

Background: A severely altered level of consciousness has been considered a possible contraindication to noninvasive positive pressure ventilation (NPPV). We compared the clinical outcome of patients with acute hypoxic respiratory failure and different degrees of conscious levels. Methods: This retrospective study comprised 132 patients who visited our emergency room for acute hypoxic respiratory failure and received NPPV from January 2013 to June 2015. Comparing the patients with and without altered level of consciousness, we investigated their clinical outcomes. Result: Fifty (37%) of the 132 patients who received NPPV had altered level of consciousness. Although patient with higher age, higher APATCHII score, higher IPAP, and pneumonia tended to be unclear conscious level (p= No correlation was either found when using multivariate analysis (p=0.27). Conclusion: This study confirms that NPPV may be safely applied to patients with acute respiratory failure with altered conscious level.

Data on prognosis and predictors of overall survival in advanced lung cancer patients diagnosed following emergency admission (DFEA) are currently lacking.We retrospectively analysed data from 771 patients with advanced nonsmall cell lung cancer between April 2004 and April 2012.Of the 771 patients, 103 (13%) were DFEA. DFEA was not an independent predictor of overall survival by multivariate Cox proportional hazard models, whereas good performance status (PS), epidermal growth factor receptor gene mutation, stage IIIB, adenocarcinoma and chemotherapy were independent predictors of overall survival (hazard ratio (95% CI) 0.36 (0.29–0.44), pDFEA is relatively common. DFEA and PS at emergency admission were not independent predictors of overall survival, but good PS just prior to opting for chemotherapy was an independent predictor of longer overall survival. Efforts to improve patient PS after admission should be considered vital in such circumstances.

Background Data on characteristics, outcomes, and prognosis of advanced non-small-cell lung cancer (NSCLC) patients who develop pneumonitis during systemic anti-cancer therapy (pneumonitis) are currently lacking. Methods We conducted a retrospective cohort study of 910 consecutive patients diagnosed with advanced NSCLC between January 2004 and January 2014. Of these, 140 patients were excluded because they did not receive systemic anti-cancer therapy at this hospital. Results A total of 770 patients were included in the study, of whom 44 (6%) were diagnosed with pneumonitis. The mortality rate of pneumonitis was 36%. The incidence of pneumonitis was independently associated with pre-existing ILD (adjusted odds ratio, 2.99, P = 0.008), and survivors were significantly associated with younger age (P = 0.003) and radiographic non-acute interstitial pneumonia pattern (P = 0.004). In all patients, pneumonitis was identified as an independent predictor of overall survival (OS) (adjusted hazard ratio 1.53, 95% CI, 1.09–2.09, P = 0.015). Performance status was poor in 82% of survivors of pneumonitis; in 62% of survivors, the PS worsened after the pneumonitis improved. Additionally, 54% of survivors received no further systemic anti-cancer therapy after pneumonitis. The median survival time of survivors after pneumonitis was 3.5 months (95% CI, 2.3–7.2 months). Conclusions Our study indicated that 6% of patients with advanced NSCLC developed pneumonitis during systemic anti-cancer therapy. The early mortality rate of pneumonitis is high, and the survival and PS after pneumonitis is extremely poor. Additionally, pneumonitis has an adverse impact on the survival of patients with advanced NSCLC. These data should be considered for the management of pneumonitis, and we recommend that future work focuses on pneumonitis particularly to improve the survival of patients with advanced NSCLC.