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Background Regimens combining pemetrexed (PEM) and immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) or programmed death-ligand 1 (PD-L1) are widely used for the treatment of advanced non-squamous non-small-cell lung cancer (NSq-NSCLC). Recently, PEM was shown to induce immunogenic cell death (ICD) and to enhance immune-regulatory genes. Some patients demonstrate an extremely long-term response to PEM. It is possible that the continued response in these patients is dependent on not only the pharmacological induction of cytotoxic cell death but also antitumor immunity. However, factors that can predict outcomes associated with long-term PEM administration using blood test results have not yet been elucidated. We investigated the clinical characteristics and predictive factors in patients with advanced NSq-NSCLC who underwent long-term PEM maintenance therapy. Methods In total, 504 patients with advanced NSq-NSCLC who received PEM combination therapy/monotherapy (n = 414) or paclitaxel (PTX) combination therapy (n = 90) between January 2010 and November 2019 were recruited; 381 patients were retained for the final analysis. Patients treated with PEM (n = 301) were divided into subgroups according to the total cycles of PEM (≥ 17 [n = 25] for the long-term administration group and ≤ 16 [n = 276] for the intermediate/short-term group) and compared with another population (n = 80) treated with PTX combination regimen. We investigated clinical features and predictive biomarkers, focusing on immune-regulatory factors, absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), and PD-1 and PD-L1 expression, to predict long-term response to PEM. Results The long-term PEM administration group exhibited a higher ALC and a lower NLR than the shorter-term group did. Both these markers displayed greater association with progression-free survival and overall survival in the PEM combination therapy group than in the PTX combination therapy group. Increased PD-1 lymphocytes were associated with the long-term PEM response group, as PD-L1 expression in tumors was associated with a high incidence of immune-related adverse effects following ICI administration. Conclusions ALC, NLR, and PD-1 expression are PEM-mediated predictive biomarkers that are indirectly related to tumor immunity and can provide useful predictive information on the long-term response to PEM in patients with NSq-NSCLC.

Background There are few studies that directly compare the effects of osimertinib on patients with non‐small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) T790M mutation between the generation of prior EGFR tyrosine kinase inhibitors (TKIs). Methods We retrospectively reviewed clinical data from the medical records of consecutive patients with advanced NSCLC who had developed resistance to first‐ or second‐generation EGFR‐TKIs due to EGFR T790M mutation and were subsequently treated with osimertinib at Juntendo University Hospital. In patients with available tumor samples, target amplicon sequencing analyses were performed to explore the genetic biomarkers. Results A total of 38 patients with NSCLC harboring EGFR T790M mutation were treated with osimertinib. Eight patients were classified into group A (afatinib followed by osimertinib) and 30 patients were classified into group B (first‐generation EGFR‐TKI followed by osimertinib). Progression‐free survival (PFS) was significantly longer in group A than in group B (median PFS; not reached vs. 11.0 months, P = 0.018). Fourteen patients had available tissue samples collected before osimertinib treatment for target sequencing. In group A we found no additional mutations, other than EGFR T790M mutation. On the other hand, there were three samples in which other mutations emerged, in addition to EGFR T790M mutation, in group B. Conclusions PFS of osimertinib was significantly longer in patients with NSCLC harboring EGFR T790M mutation after treatment with afatinib than in patients after treatment with first generation EGFR‐TKIs. Additional mutations other than EGFR T790M may affect the efficacy of osimertinib treatment. Key points Significant findings of the study: PFS of osimertinib was significantly longer in patients with NSCLC harboring EGFR T790M mutation after treatment with afatinib than in patients after treatment with first generation EGFR‐TKIs. What this study adds: Additional mutations other than EGFR T790M may affect the efficacy of osimertinib treatment., There are few studies that directly compare the difference between the generation of prior EGFR tyrosine kinase inhibitors (TKIs) before osimertinib treatment in patients with non‐small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) T790M mutation. In our retrospective study, progression‐free survival of osimertinib was significantly longer in patients with NSCLC harboring EGFR T790M mutation after treatment with afatinib than in patients after treatment with first generation EGFR‐TKIs.

Background Chemotherapy is a standard treatment for patients with advanced non-small cell lung cancer (NSCLC); however, it occasionally causes adverse events. Serious adverse events (SAEs) are defined as any untoward medical occurrence that is related to drug use and results in life-threatening experiences, prolonged or initial hospitalization, or significant or persistent disability. However, as few studies have reported on the risk factors for SAEs, we aimed to identify the factors that could predict SAEs in NSCLC. Patients and methods We retrospectively reviewed the medical records of patients treated with pemetrexed plus cisplatin (PC), paclitaxel plus carboplatin plus bevacizumab (BVCP), docetaxel monotherapy (DTX), or pemetrexed monotherapy (PEM) at Juntendo University Hospital between January 2010 and March 2012. Two investigators reviewed the clinical records and judged SAEs. Multivariate analyses were performed to identify independent risk factors for SAEs among the following factors: gender, age, performance status, line of chemotherapy, preexisting interstitial lung disease (ILD), smoking status, and chemotherapeutic regimen. Results A total of 252 patients received chemotherapy (male/female, 162/90; median age [range], 66 years [36–92 years]; stage III/stage IV/postoperative recurrence, 53/145/54; adenocarcinoma/squamous cell carcinoma/not otherwise specified, 211/24/17; PC/BVCP/PEM/DTX, 50/ 51/ 67/ 84). Of these, 30 (11.9%) patients experienced SAEs. The SAEs were anorexia/nausea in 10 patients, febrile neutropenia (FN) in eight, drug-induced ILD in six, infection (sepsis, pleural infection, soft tissue infection) in three, elevated creatinine level in one, pneumothorax in one, and gastric hemorrhage in one. Treatment-related death was noted in four patients, two with drug-induced ILD, one with FN, and one with infection. Multivariate analysis revealed that preexisting ILD (odds ratio=5.06; p=0.0012) and the chemotherapeutic regimen (p=0.00-0.03) were significantly associated with SAEs. Conclusions Preexisting ILD and the chemotherapeutic regimen were risk factors for the prediction of SAEs in the treatment of NSCLC in clinical practice.

Background Interstitial lung diseases induced by anticancer agents (ILD-AA) are rare adverse effects of anticancer therapy. However, prognostic biomarkers for ILD-AA have not been identified in patients with advanced lung cancer. Our aim was to analyze the association between serum biomarkers sialylated carbohydrate antigen Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D), and clinical characteristics in patients diagnosed with ILD-AA. Methods Between April 2011 and March 2016, 1224 advanced lung cancer patients received cytotoxic agents and epidermal growth factor receptor tyrosine kinase inhibitors at Juntendo University Hospital and Juntendo University Urayasu Hospital. Of these patients, those diagnosed with ILD-AA were enrolled in this case control study. ΔKL-6 and ΔSP-D were defined as the difference between the levels at the onset of ILD-AA and their respective levels prior to development of ILD-AA. We evaluated KL-6 and SP-D at the onset of ILD-AA, ΔKL-6 and ΔSP-D, the risk factors for death related to ILD-AA, the chest high resolution computed tomography (HRCT) findings, and survival time in patients diagnosed with ILD-AA. Results Thirty-six patients diagnosed with ILD-AA were enrolled in this study. Among them, 14 patients died of ILD-AA. ΔSP-D in the patients who died was significantly higher than that in the patients who survived. However, ΔKL-6 did not differ significantly between the two groups. Moreover, ΔSP-D in patients who exhibited diffuse alveolar damage was significantly higher than that in the other patterns on HRCT. Receiver operating characteristic curve analysis was used to set the optimal cut off value for ΔSP-D at 398 ng/mL. Survival time for patients with high ΔSP-D (≥ 398 ng/mL) was significantly shorter than that for patients with low ΔSP-D. Multivariate analysis revealed that ΔSP-D was a significant prognostic factor of ILD-AA. Conclusions This is the first research to evaluate high ΔSP-D (≥ 398 ng/mL) in patients with ILD-AA and to determine the risk factors for ILD-AA in advanced lung cancer patients. ΔSP-D might be a serum prognostic biomarker of ILD-AA. Clinicians should evaluate serum SP-D during chemotherapy and should carefully monitor the clinical course in patients with high ΔSP-D.

Background Advanced non-small cell lung cancer (NSCLC) patients often develop thromboembolic events, including cerebral infarction (CI). However, the relationship between advanced NSCLC and CI has not been thoroughly investigated. We examined the association between advanced NSCLC and CI and risk factors for CI in advanced or post-operative recurrent NSCLC patients. Methods We retrospectively investigated 515 patients diagnosed with advanced or post-operative recurrent NSCLC at Juntendo University Hospital between April 2009 and March 2014. Results Among the 515 patients evaluated, 15 patients (2.9 %) developed CI after diagnosis of advanced or post-operative recurrent NSCLC. Univariate and multivariate analyses were conducted, and brain metastasis was the only significant independent risk factor for CI (odds ratio 5.24, 95 % confidence interval 1.72–16.10, p = 0.004). The incidence was 6.3 % in these patients. The median survival time was 36 days, and 1-year survival rate was 6.7 % after development of CI. Overall survival from diagnosis of advanced NSCLC or post-operative recurrence was significantly shorter in patients with CI than in patients without CI (223 days versus 895 days; HR, 3.46; 95 % confidence interval, 2.04–6.02; p = 0.001). Conclusions The incidence of CI is high in advanced or post-operative recurrent NSCLC, and is especially higher in patients with brain metastasis than in those without brain metastasis. Moreover, CI may affect patient’s prognosis. Careful monitoring for the development of CI in patients with advanced or post-operative recurrent NSCLC is needed, especially for patients with brain metastasis.

Docetaxel or pemetrexed monotherapy is recommended either as a second-line treatment for non-small cell lung cancer (NSCLC) patients without EGFR mutation or ALK fusion genes or as a third-line treatment for patients with EGFR mutation or ALK fusion. However, efficacy and survival for these two settings have not been compared, leaving it unclear whether these two populations can be included in the same clinical trials. Moreover, prognostic factors for patients who are recommended to receive docetaxel/pemetrexed monotherapy are largely unknown. Docetaxel or pemetrexed was administered to 67 EGFR wild-type patients as a second-line treatment following one platinum-based combination chemotherapy and to 17 EGFR mutant patients as a third-line treatment following EGFR tyrosine kinase inhibitors and one platinum-based combination chemotherapy. Docetaxel and pemetrexed were administered at 60 and 500 mg/m2, respectively, every 3 weeks until disease progression, intolerable toxicity, or patient refusal. Overall survivals (OSs) between the two groups were compared using the log-rank test, and prognostic factors were evaluated via Cox’s proportional hazards models. The median OS was 345.5 days in the EGFR wild-type second-line group and 616 days in the EGFR mutant third-line group. Multivariate analyses revealed that the stage before first-line treatment, performance status, and EGFR status were significant prognostic factors. When planning clinical studies of NSCLC patients recommended to receive docetaxel or pemetrexed as single-agent chemotherapy, the EGFR status and stage before first-line treatment should be considered as stratification factors of randomized clinical studies.

e18527 Background: As the efficacy of chemotherapy for advanced lung cancer patients has been increased, some advanced lung cancer patients may benefit from combined modality therapy including surg...

e19129 Background: Serious adverse events, which cause immediate hospitalization, prolonged hospitalization, permanent damage, or death, are clinically defined as severe adverse events (SAEs). Few ...