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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.

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 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 ...

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

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.