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Immune checkpoint inhibitor (ICI) monotherapy is more effective than cytotoxic chemotherapy in improving overall survival (OS) among patients with advanced-stage non-small cell lung cancer (NSCLC). Recently, chemotherapy combined with ICI has been found to yield good outcomes. However, ICI monotherapy is still considered an important treatment option. Data on long-term progression-free survival (PFS) and OS in real-world settings are limited.This was a multicenter retrospective observational study. A total of 435 consecutive patients histologically diagnosed with advanced, metastatic, or recurrent NSCLC treated with ICI monotherapy were enrolled in this study from December 2015 to December 2018. Clinical data were collected from electronic medical records and pharmacy databases.The PFS and OS of the patients were 3.4 and 13.0 months, respectively. The objective response and disease control rates were 22.8% and 54.9%, respectively, and the 4-year survival rate was 17.9%. Multivariate analyses revealed that elder patients (70 years), good Eastern Cooperative Oncology Group Performance Status (ECOG PS) score, programmed death-ligand 1 tumor proportion score (PD-L1 TPS) of ≥ 50%, absence of bone metastasis, and presence of immune-related skin toxicity, which is an immune-related adverse event, were correlated with good PFS. Moreover, good ECOG PS score, PD-L1 TPS of ≥ 50%, absence of bone metastasis, and presence of skin toxicity were correlated with good OS.The 4-year survival rate was 17.9%. Good ECOG PS score, PD-L1 TPS of ≥ 50%, absence of bone metastasis, and presence of skin toxicity were correlated with good PFS and OS.

In clinical trials, first-line treatment with pembrolizumab improved overall survival (OS) in patients with advanced non-small-cell lung cancer (NSCLC) with a programmed death ligand 1 (PD-L1) tumor proportion score of ≥ 50%. However, data on the efficacy of this treatment between clinical trials and actual clinical practice are inconsistent.Ninety-five patients with histologically diagnosed advanced or recurrent NSCLC and a PD-L1 tumor proportion score of ≥ 50% who received pembrolizumab as first-line treatment were consecutively enrolled onto this multicenter retrospective study from February 2017 to December 2018. Clinical data were collected from electronic medical records. We assessed the objective response rate, progression-free survival (PFS), OS, and immune-related adverse events (irAE), and determined their associations with clinical characteristics.The objective response rate was 40.0%. The median PFS was 6.1 months, and OS did not reach the median. Multivariate analyses revealed that nonadenocarcinoma histology (hazard ratio, 1.78; 95% confidence interval, 1.05-3.03; P = .015) and ≥ 3 metastatic sites (hazard ratio, 3.97; 95% confidence interval, 1.97-8.01; P .001) were independently correlated with poor PFS. Patients with irAE and patients without interstitial lung disease had significantly longer PFS (14.0 and 4.9 months, respectively; P = .011) than patients without irAE or patients with interstitial lung disease.The outcome of patients receiving first-line pembrolizumab treatment was worse in those with nonadenocarcinoma and with a large number of metastatic sites. Patients with irAE and without interstitial lung disease had a more favorable outcome.

Background: Based on the results of the PACIFIC study, chemoradiotherapy followed by 1-year consolidation therapy with durvalumab was established as the standard of care for unresectable, locally advanced non-small-cell lung cancer (LA-NSCLC). However, some topics not foreseen in that design can be explored, including progression-free survival (PFS) and overall survival (OS) after the start of chemoradiotherapy, the proportion of patients who proceeded to consolidation therapy with durvalumab, and the optimal chemotherapeutic regimens. In Japan, the combination regimen of S-1 + cisplatin (SP), for which the results of multiple clinical studies have suggested a good balance of efficacy and tolerability, is frequently selected in clinical settings. However, the efficacy and safety of consolidation therapy with durvalumab following this SP regimen have not been evaluated. We therefore planned a multicenter, prospective, single-arm, phase II study. Methods: In treatment-naïve LA-NSCLC, two cycles of combination chemotherapy with S-1 (80–120 mg/body, Days 1–14) + cisplatin (60 mg/m2, Day 1) will be administered at an interval of 4 weeks, with concurrent thoracic radiotherapy (60 Gy). Responders will then receive durvalumab every 2 weeks for up to 1 year. The primary endpoint is 1-year PFS rate. Discussion: Compared with the conventional standard regimen in Japan, the SP regimen is expected to be associated with lower incidences of pneumonitis, esophagitis, and febrile neutropenia, which complicate the initiation of consolidation therapy with durvalumab, and have higher antitumor efficacy during chemoradiotherapy. Therefore, SP-based chemoradiotherapy is expected to be successfully followed by consolidation therapy with durvalumab in more patients, resulting in prolonged PFS and OS. Toxicity and efficacy results of the SP regimen in this study will also provide information important to the future establishment of the concurrent combination of chemoradiotherapy and durvalumab. Trial registration: Japan Registry of Clinical Trials, jRCTs031190127, registered 1 November 2019, https://jrct.niph.go.jp/latest-detail/jRCTs031190127

Introduction: EGFR-mutant lung cancers are genomically heterogeneous in terms of compound EGFR mutations and mutations in other genes. The purpose of this study was to explore gene mutations in circulating cell-free DNA that are related to resistance to afatinib. Patients and methods: Patients with EGFR-mutant non-small cell lung cancer who received afatinib monotherapy were enrolled in this trial. Plasma samples were longitudinally collected before afatinib treatment, during treatment, and at the time of development of afatinib resistance. Written informed consent was obtained from all patients. Cell-free DNA was extracted from plasma using the QIAamp Circulating Nucleic Acid Kit (QIAGEN). Mutation profiles were determined by next-generation sequencing and analyzed using a human lung cancer panel (QIAGEN). Results: A total of 71 patients were enrolled in this study. Plasma samples both before treatment and at the time of resistance to afatinib were collected from 21 patients. Although currently under analysis, the mutation profiles determined by next-generation sequencing revealed the following changes. 1) The number of gene mutations per patient that newly appeared at resistance development ranged from 0 to 7. 2) The allele frequency of the T790M EGFR mutation, a mutation responsible for resistance to EGFR tyrosine kinase inhibitors, was increased after development of afatinib resistance in approximately half of the patients. Conclusions: The T790M allele frequency tended to increase after the development of resistance to afatinib. Some mutations were detected after resistance to afatinib. The role of this mutation needs to be investigated in a further study. Citation Format: Nanao Terada, Hideharu Kimura, Mako Miyakawa, Hayato Koba, Taro Yoneda, Takayuki Takeda, Hiroki Shirasaki, Kazuhiko Shibata, Koichi Nishi, Koichi Takayama, Kazuo Kasahara. Mutation analysis in cell-free DNA upon development of resistance to afatinib [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 1986.

Birt-Hogg-Dube syndrome (BHD) is an inherited disorder caused by genetic mutations in the folliculin (FLCN) gene. Individuals with BHD have multiple pulmonary cysts and are at a high risk for developing renal cell carcinomas (RCCs). Currently, little information is available about whether pulmonary cysts are absolutely benign or if the lungs are at an increased risk for developing neoplasms. Herein, we describe 14 pulmonary neoplastic lesions in 7 patients with BHD. All patients were confirmed to have germline FLCN mutations. Neoplasm histologies included adenocarcinoma in situ (n = 2), minimally invasive adenocarcinoma (n = 1), papillary adenocarcinoma (n = 1), micropapillary adenocarcinoma (n = 1), atypical adenomatous hyperplasia (n = 8), and micronodular pneumocyte hyperplasia (MPH)-like lesion (n = 1). Five of the six adenocarcinoma/MPH-like lesions (83.3%) demonstrated a loss of heterozygosity (LOH) of FLCN. All of these lesions lacked mutant alleles and preserved wild-type alleles. Three invasive adenocarcinomas possessed additional somatic events: 2 had a somatic mutation in the epidermal growth factor receptor gene (EGFR) and another had a somatic mutation in KRAS. Immunohistochemical analysis revealed that most of the lesions were immunostained for phospho-mammalian target of rapamycin (p-mTOR) and phospho-S6. Collective data indicated that pulmonary neoplasms of peripheral adenocarcinomatous lineage in BHD patients frequently exhibit LOH of FLCN with mTOR pathway signaling. Additional driver gene mutations were detected only in invasive cases, suggesting that FLCN LOH may be an underlying abnormality that cooperates with major driver gene mutations in the progression of pulmonary adenocarcinomas in BHD patients.

e21042Background: In clinical practice of advanced NSCLC pts, a control of CNS metastasis is important issue. Several clinical trials of ICIs have demonstrated the survival benefit in advanced NSCL...

Lactic acidosis is a rare complication in lung cancer. We report a case of lung cancer accompanied by both syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and lactic acidosis. A 70-year-old man was referred to our hospital for examination of a left hilar mass shadow on a chest X-ray film. Small cell lung cancer (SCLC) was demonstrated by brushing the bronchial mucosa of the left lower lobe bronchus. His laboratory data showed SIADH and lactic acidosis that were probably due to SCLC. Fluid restriction improved SIADH, and combination chemotherapy for SCLC improved the lactic acidosis although the tumor size did not change.

We examined the effect of selective thromboxane A2 (TXA2) receptor antagonists, calcium 5(Z)-1R, 2S, 3S, 4S-7-[3-phenylsulphonylaminobicyclo [2.2.1] hept-2-yl]-5-heptonoate hydrate (S-1452) and +/- -7-(3,5,6,-trimethyl-1,4-benzoquinon-2-yl)-7-phenylhaptanoic acid (AA-2414), on sensitivity to cis-diamminedichloroplatinum (II) (CDDP) in non-small-cell lung cancer cell lines. IC50 values to CDDP using MTT assay were decreased 2.1- and 4.6-fold respectively by treatment with 250 or 500 microM S-1452, for a 2 h simultaneous drug exposure, and those of PC-9/CDDP, a CDDP-resistant cell line, were decreased 3.1- and 6.1-fold. Sensitivity to carboplatin was also enhanced by the treatment with S-1452. IC50 values to CDDP and carboplatin were decreased by treatment with AA-2414 in a dose-dependent manner. Isobologram analysis showed that the combination of CDDP with S-1452 or AA-2414 produced supra-additive or additive effects in each cell line. Neither glutathione content nor glutathione S-transferase activity was changed in either cell line by treatment with 500 microM S-1452. Accumulation of platinum into PC-9 and PC-9/CDDP was increased by the treatment in a dose-dependent manner. Na+, K+-ATPase activity of PC-9 and PC-9/CDDP was enhanced by the treatment of S-1452 in a dose-dependent manner. These data show that the TXA2 receptor antagonists may enhance the sensitivity of non-small-cell lung cancer cell lines to platinum agents. Increase in Na+, K+-ATPase activity induced by S-1452 may be the mechanism of its sensitising effect through increase in platinum accumulation.

Cisplatin is a key drug in chemotherapy for lung cancer. It has been reported that intracellular accumulation of cisplatin is an important step as a determinant for resistance to cisplatin, which may be modulated by Na+, K+-ATPase activity. And it has been reported that beta-adrenoceptor agonists modulate the Na+, K+-ATPase in some organs. In this study, the effects of a beta-adrenoceptor agonist and an antagonist on membrane Na+, K+-ATPase activity were evaluated using human non-small cell (NSCLC) lung cancer cell lines. In the NSCLC cell lines, sensitivity to cisplatin was improved by treatment with isoproterenol. Na+, K+-ATPase was activated and intracellular accumulation of cisplatin increased with the treatment. But the antagonist, propranolol, did not modulate sensitivity to cisplatin or Na+, K+-ATPase activity. These results suggest that beta-adrenoceptors may be one of the determinant for sensitivity to cisplatin in NSCLC, but endogenous catecholamine dose not play a role in the intracellular accumulation of cisplatin in these cell lines. Exogenous beta-adrenoceptor agonists may improve the antitumor effect of chemotherapy involving cisplatin.

We report a case of broncholithiasis with bronchoesophageal fistula that was successfully managed endoscopically using endoscopic laser therapy and a covered self-expandable metallic stent.

e19028 Background: Erlotinib is one of the standard therapies for previously treated patients (pts) of advanced non-small-cell lung cancer (NSCLC) without EGFR mutations. However, response rate of ...

The aim of this phase II study was to evaluate the efficacy of combination chemotherapy consisting of docetaxel and carboplatin in patients with inoperable non-small cell lung cancer (NSCLC).For this multicenter phase II study, the eligibility criteria included histologically or cytologically proven inoperable NSCLC, measurable lesions, Eastern Cooperative Oncology Group performance status (PS) 0-2, adequate organ and bone marrow functions, and written informed consent. Patients received 60 mg/m2 of docetaxel and carboplatin (target AUC 5.5) on day 1 every 3 weeks until disease progression. The primary end-point of this study was response rate and the secondary end-points were toxicities, time to progression and overall survival.A total of 40 patients were enrolled and 39 patients were eligible. A complete response and partial response were observed in 1 and 13 patients, respectively. An objective response rate was 35.9% (95% confidential interval [CI] 20.8-51.0%). The median time to progression was 5.2 months and the median overall survival was 12.0 months. The 1- and 2-year survival rates were 53.8% and 25.1%, respectively. The major toxicities were leukocytopenia and neutropenia. Grade 3 or 4 thrombocytopenia was rare and non-hematological toxicities were generally mild. Grade 3 non-hematological toxicities were observed in 6 patients (2 with nausea and vomiting, 1 with diarrhea, 1 with elevated transaminase levels, 1 with allergic reaction and 1 with edema). No grade 4 non-hematological toxicities were observed.Docetaxel and carboplatin combination chemotherapy was well tolerated and active in Japanese patients with advanced or metastatic NSCLC.

Summary Purpose Gemcitabine (GEM) and vinorelbine (VNR) have demonstrated activity as a first-line treatment in elderly patients with advanced non-small-cell lung cancer (NSCLC). We conducted a multicenter phase II trial to evaluate the efficacy and toxicity of bi-weekly administration of GEM plus VNR in elderly patients with advanced NSCLC. Patients and methods Forty-six chemotherapy-naive elderly (age: ≥70 years) NSCLC patients were enrolled. Patients were eligible if they had histologically or cytologically confirmed unresectable NSCLC with measurable and/or assessable disease. Patients received GEM (1000 mg/m2) and VNR (25 mg/m2) every 2 weeks. Results The objective response rate of this treatment was 22.7% (95% confidence interval (CI), 10.3–35.1%), median survival time was 310 days, and median time to progression was 133 days. The one-year survival rate was 40.9% (95% CI, 26.3–55.4%), and most adverse events were mild. Only three (6.8%) patients needed to omit GEM because of grade 4 neutropenia or due to physician judgment. No patients suffered treatment-related death. Conclusions Bi-weekly administration of GEM plus VNR in elderly patients was an effective, feasible and well-tolerated treatment schedule.

Rhabdomyolysis with myoglobinuria is an uncommon complication of sepsis, whether monomicrobial or polymicrobial, even in its severe form. We describe a middle-aged woman with acute leukemia who developed rhabdomyolysis and myoglobinuria during the fatal course of chemotherapy-induced sepsis due to Bacteroides thetaiotaomicron and Enterococcus faecalis, followed by multiple organ dysfunction syndrome. In addition, autopsy revealed disseminated infections with Aspergillus and Candida. None of these organisms has been reported to be involved in the pathogenesis of rhabdomyolysis. Therefore, the etiology of the rhabdomyolysis in this case was probably multifactorial, with polymicrobial septic processes being possibly important contributing factors.

Purpose: This phase I study was designed to determine the maximum tolerated dose of carboplatin combined with a fixed dose of docetaxel (60 mg/m 2 ) and the safety and efficacy of this combination chemotherapy in unresectable non-small cell lung cancer. Methods: Patients received a 60 min intravenous infusion of docetaxel followed by a 90 min infusion of carboplatin with dose escalation using the continual reassessment method. The starting dose of carboplatin was targeted to an area under the plasma concentration curve of 3 using Calvert's equation and dose escalation was based on course 1 toxicities. Results: From January 1999 to February 2000, 16 patients entered this trial. The major dose-limiting toxicity was neutropenia. Thrombocytopenia was rare and major non-hematological toxicities included fever that was not associated with neutropenia and grade 2 nausea and vomiting. Objective responses were seen in five patients (response rate 31.3%). Conclusions: Based on this phase I clinical trial, the maximum tolerated dose of carboplatin combined with 60 mg/m 2 of docetaxel was a target area under the plasma concentration curve (tAUC) of 6 and the recommended tAUC for further trials is 5.5. This combination appeared to be effective for non-small cell lung cancers. A phase II clinical trial is recommended using 60 mg/m 2 of docetaxel and carboplatin with a tAUC of 5.5.

e19103 Background: Prognostic factors in non-small cell lung cancer (NCSLC) with EGFR mutations have not been evaluated in detail. Methods: We retrospectively examined NSCLC pts with EGFR mutations treated with EGFR-TKIs, and evaluated patient characteristics and serum tumor markers from the perspective of prognosis. Survival time was analyzed using Kaplan-Meier methods and Cox regression modeling. Results: Participants comprised 159 pts, among whom 106 were women, 115 were never- or light smokers, and 155 had with adenocarcinoma. Deletions in exon 19 were seen in 76 pts, the L858R mutation in 67, and other EGFRmutations in 16. All pts were treated with EGFR-TKIs (gefitinib, n=110; erlotinib, n=28; both sequentially, n=17; other, n=4). No significant relationship was observed between response rate and patient characteristics; however, progression-free survival (PFS) with EGFR-TKI treatment was significantly associated with ECOG PS at start of treatment with EGFR-TKI (good PS [0,1] vs. poor PS [2-4], MST 1...

e19083 Background: Several retrospective studies have reported that continued treatment with EGFR-TKI after developing progressive disease (PD) by RECIST improved survival compared to TKI-free treatment in NSCLC patients with EGFR mutations. However, it is unclear which patients would benefit from EGFR-TKI after PD. We hypothesized that patients with CNS progression only, without systemic deterioration, would show a good prognosis with EGFR-TKI after PD. Methods: In order to clarify the survival benefits in patients treated by EGFR-TKI after developing PD, particularly patients with CNS metastasis alone, NSCLC patients with EGFR mutations who were treated with EGFR-TKI and showed progression were analyzed retrospectively. The patients were categorized into two groups: patients continuing with EGFR-TKI treatment after progression (continuation group) and patients switched to chemotherapy or BSC (discontinuation group). Patients were also classified into two groups by site of progression: patients who showed deterioration involving only CNS metastasis (CNS group) and patients who showed progression of the primary lesion, lymph nodes, bone, liver, adrenal glands, CNS, or other sites (systemic group). Differences in post-EGFR-TKI progression survival (PPS) and overall survival were compared between the groups. Results: A total of 75 patients, including 54 women, 56 never smokers, 73 patients with adenocarcinomas, and 57 patients with good PS (0, 1), were analyzed. There were 40 patients with deletions in exon 19, 29 patients with L858R, and 6 with minor mutations. The continuation group (n=36) had a significantly longer PPS than the discontinuation group (n=39) (16.2 m vs. 8.5 m, p

We examined the mechanisms involved in the bioactivation of mitomycin C (MMC) and a newly developed MMC analogue: 7-N-(2-([2-(gamma-L-glutamylamino)ethyl]dithio)ethyl)mitomycin C, KW-2149, in non-small-cell lung cancer (NSCLC) cell lines under aerobic and hypoxic conditions. To investigate these mechanisms, we used MMC-resistant non-small-cell lung cancer cell lines (PC-9/MC4) that had been established in our laboratory from the parent PC-9 cell line by continuous exposure to MMC. We previously reported that the MMC-resistant cell line (PC-9/MC4) was poor in NAD(P)H dehydrogenase (quinone) activity and approximately 6-fold more resistant than the parent cells (PC-9) to MMC on 2-h exposure under aerobic conditions. In this study, the subline PC-9/MC4 was 6.7-fold more resistant to MMC than PC-9, the parent cell line, under aerobic conditions, and 5.2-fold more resistant under hypoxic conditions after 2-h exposure to MMC. However, on co-incubation with tempol, an inhibitor of the one-electron reduction pathway, the sensitivity of PC-9/MC4 to MMC was impaired under hypoxic conditions, but the impairment was not evident under aerobic conditions. KW-2149, the newly developed MMC analogue, was cytotoxic for both PC-9/MC4 and PC-9 cells, and the sensitivity of both cell lines to KW-2149 was not changed by exposure to hypoxic conditions or by coincubation with tempol. There were no significant differences in the intracellular uptake of MMC and the activities of cytosolic detoxification enzymes between the PC-9 and PC-9/MC4 cell lines. These results support the hypothesis that the one-electron reduction pathway plays a partial role in the bioactivation of MMC, but not of KW-2149, and that KW-2149 is excellent at circumventing resistance to MMC in NSCLC.

3-Hydroxymethyl-5-aziridinyl-1-methyl-[1H-indole-4,7-dione]-prop-beta-en -alpha-ol (EO9) is a bioreductive anticancer agent active for non-small cell lung cancer (NSCLC) and structurally related to mitomycin C (MMC). DT-diaphorase (DTD) is regarded as a two electron reductase that plays an important role in the biotransformation of MMC to antitumor metabolites. To evaluate the role of DTD as a bioactivator of EO9 in NSCLC cell lines under oxic and hypoxic conditions, we examined the inhibitory effect of dicumarol which was regarded as a selective inhibitor of DTD on the sensitivity to EO9 in vitro. In this study, we used an MMC-resistant NSCLC cell line (PC-9/MC4) which was established from a PC-9 cell line as a parent cell line by continuous exposure to MMC in our laboratory. We reported previously that the subline PC-9/MC4 was 6.7-fold more resistant to MMC than PC-9 with decreased DTD activity. The IC50 value of PC-9 against EO9 was significantly increased by co-incubation with dicumarol under oxic conditions. EO9 was more cytotoxic against PC-9/MC4 than against PC-9 cells and the enhancement was impaired by tempol under hypoxic conditions. These findings suggest a suppressive role of DTD against one-electron reduction pathway in the bioactivation of EO9 under hypoxic conditions and EO9 may be more active against oxygen-deficient solid tumors especially in MMC-resistant NSCLC cells with low levels of DTD activity.

7294 Background: While the prognosis for LA-NSCLC has improved, satisfactory results have not been obtained. Therapeutic outcomes for radiotherapy combined with low-dose of CDDP were significantly ...

7091 Background: Gefitinib (G) is an EGFR-TK inhibitors and G and paclitaxel (P) have synergistic antitumor effect in G-resistant non-small cell lung cancer cell lines in vitro. The purpose of this...

7331 Objective: The purpose of this phase II trial was to evaluate the activity and the toxicity in elderly NSCLC pts of biweekly administration of this combination. Pts and Methods: 45 elderly pts...

We evaluated the effect of thromboxane A2 (TXA2) blockade on cisplatin-induced apoptosis in non-small-cell lung cancer (NSCLC) cell lines. Cisplatin induced apoptosis in PC/9 and PC-9/CDDP in a dose-dependent manner. Treatment with specific TXA2 antagonist, calcium 5(Z)-1R,2S,3S,4S-7-[3-phenylsul‐ fonylaminobicyclo[2.2.1]hept-2-yl]-5-heptonoate hydrate (S-1452) and 5(Z-6-{(1R,2R,3R,4S)-3-(N-4-bromoben‐ zenesulfonyl aminomethyl) bicyclo[2,2,1]heptane-2-yl}hex-5-enoic acid (ONO-NT-126), enhanced the cisplatin-induced apoptosis in each cell line. Acetyl-l-aspartyl-glutamyl-valyl-aspart-1-aldehyde (Ac-DEVD-CHO) inhibited cisplatin-induced apoptosis and enhancement of the apoptosis by TXA2 blockade, but acetyl-l-tyrosyl-valyl-alanyl-aspart-1-aldehyde (Ac-YVAD-CHO) had no effect on the apoptosis. There was no difference in the interleukin-1β-converting enzyme (ICE) protease protein expression in either cell line. Cysteine protease p32(CPP32) protein expression was lower in PC-9/CDDP but was not changed by S-1452, cisplatin, or cotreatment with cisplatin and S-1452. Ice and Ced-3 homolog (ICH-1l) expression was significantly lower in PC-9/CDDP and was up-regulated by S-1452 or ONO-NT-126. These data suggest that ICH-1l might play a critical role in cisplatin-induced apoptosis and that TXA2 blockade up-regulates ICH-1l protein expression. Overexpression of ICH-1l and treatment with cisplatin might result in an increase in apoptosis in NSCLC cell lines.