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Osimertinib is the standard of care in the initial treatment for advanced epidermal growth factor receptor (EGFR) mutation-positive lung cancer. However, clinical data and reliable prognostic biomarkers are insufficient.We performed a retrospective multicentre cohort study for 538 EGFR mutation-positive patients, who received osimertinib as the initial treatment between August 2018 and December 2019. The main outcome was progression-free survival (PFS).The median observation period was 14.7 months (interquartile range 11.4-20.0). The median PFS was 20.5 months (95% confidence interval [CI] 18.6-not reached). Multivariate analysis showed that sex (male) (hazard ratio [HR] 1.99, 95% CI 1.35-2.93, P = 0.001), malignant effusions (HR 1.51, 95% CI 1.11-2.04, P = 0.008), liver metastasis (HR 1.55, 95% CI 1.03-2.33, P = 0.037), advanced unresectable cases (HR 1.71, 95% CI, 1.04-2.82, P = 0.036), mutation type and programmed cell death-ligand 1 (PD-L1) expression were associated with PFS. The L858R (HR 1.55, 95% CI 1.01-2.38, P = 0.043) and uncommon mutations (HR 3.15, 95% CI 1.70-5.83, P 0.001) were associated with PFS. PD-L1 expression of 1-49% (HR 1.66, 95% CI 1.05-2.63, P = 0.029), ≥50% (HR 2.24, 95% CI 1.17-4.30, P = 0.015) and unknown (HR 1.53, 95% CI 1.05-2.22, P = 0.026) was associated with PFS. The main reasons for treatment discontinuation among 219 patients were disease progression (44.3%), pneumonitis (25.5%) and other adverse events (16.0%).During initial treatment with osimertinib, PD-L1 expression is significantly related to PFS. Adverse events are a noteworthy reason for discontinuation.

Fenbendazole is a benzimidazole anthelmintic agent, with a broad antiparasitic range in animals such as dogs and pigs. The agent is also reported to exert antitumor effects and inhibit microtubule-associated tubulin polymerization, but its safety and tolerability profile in humans remains unclear. An 80-year-old female patient with advanced nonsmall cell lung cancer (NSCLC) was started on pembrolizumab monotherapy. The patient experienced severe liver injury 9 months later. An interview with her and her family revealed that she had been taking fenbendazole for a month, solely based on social media reports suggesting its effectiveness against cancer. After discontinuation of the self-administration of fenbendazole, the patient’s liver dysfunction spontaneously resolved. The antitumor inhibitory effects of fenbendazole have been reported; however, she did not experience tumor shrinkage. This is the first case report of a patient with advanced NSCLC who self-administered the anthelmintic, fenbendazole. Twitter and Facebook are online social media platforms which have been constructively used to exchange information among cancer patients. However, sources of medical information on these platforms are often unproven, and it is difficult for nonmedical professionals to accurately select and filter complex medical information. Physicians should enquire patients about self-administration of orally ingested products, including dietary supplements, herbs, or bioactive compounds, in cases of unexpected adverse reactions.

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

Background The data of sequential therapy of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in clinical practice have been limited. Methods We reviewed the clinical data of patients with ALK-rearranged non-small cell lung cancer who received crizotinib (CRZ) or alectinib (ALEC) between May 2012 and December 2016. Patients were divided into two groups based on the first-administered ALK-TKI, the CRZ or ALEC group. The combined time-to-treatment failure (TTF) was defined as the sum of the ‘TTF of CRZ’ plus the ‘TTF of ALEC’ if patients were treated with CRZ followed by ALEC in the CRZ group. The primary end-point is the comparison between the combined TTF and the TTF of ALEC in the ALEC group. Results Of 864 patients enrolled from 61 institutions, 840 patients were analysed. There were 535 of 305 patients in the CRZ/ALEC groups. The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group (median, 34.4 versus 27.2 months; hazard ratio [HR], 0.709; P = 0.0044). However, there was no significant difference in overall survival (OS) between the patients who received ALEC after CRZ in the CRZ group and the patients in the ALEC group (median, 88.4 months versus. not reached; HR, 1.048; P = 0.7770). In the whole population, the CRZ group had a significantly shorter OS than the ALEC group (median, 53.6 months versus not reached; HR, 1.821, P Conclusion The combined TTF in the CRZ group was significantly longer than the TTF in the ALEC group; however, OS benefit of sequential therapy against ALEC as the first ALK-TKI was not shown.

We constructed a data set of EGFR‐mutant non–small‐cell lung carcinoma (NSCLC) patients, and compared the overall survival of first‐generation (1G), and second‐generation (2G) EGFR‐tyrosine kinase inhibitors (TKIs) in clinical practice using a propensity score. We reviewed the clinical data of consecutive EGFR‐mutated NSCLC patients who received EGFR‐TKI therapy between January 2008 and August 2017 at 11 institutions in Japan. The primary endpoint was overall survival (OS). When comparing OS between 1G and 2G EGFR‐TKIs, propensity score analyses were performed using 2 methods: matching and inverse probability of treatment weighting (IPTW). (Clinical Trial information: UMIN000030121) In total, 1400 patients from 11 institutions were enrolled in this study, and the data from the 1366 patients who received only EGFR‐TKI therapy were analyzed (gefitinib [GEF], N = 732; erlotinib [ERL], N = 416; afatinib, N = 218). Median OS times (months [95%CI]) were 29.7 [27.5‐33.5] in the 1G group (gefitinib, 32.0 [28.1‐35.8]; erlotinib, 27.5 [23.9‐31.7]), and 38.6 [32.2‐NR] in the 2G group (afatinib), respectively. The trend of longer OS for afatinib against 1G EGFR‐TKIs remained, even after adjusted by propensity score. (unadjusted, hazard ratio [HR] 0.676, P = .0023; adjusted by IPTW, HR 0.685 P

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/aim Pulmonary pleomorphic carcinoma (PPC) is rare, and few studies have reported its features. We assessed the clinicopathological features, surgical outcomes, oncogenic status and programmed death-ligand 1 (PD-L1) expression of PPC. Patients and methods We retrospectively reviewed data from 22 consecutive patients who underwent resection of PPC between 2007 and 2017. Results The predominant tissue type of the epithelial component was adenocarcinoma in 15 patients (68%) and the others in 7 patients (32%), and the 3-year disease-free survival rate tended to be better in patients with an adenocarcinoma component compared to patients with another component (40.0% vs. 17.1%, p=0.059). PD-L1 expression was observed in all eight tumors whose PD-L1 status could be examined and high PD-L1 expression (≥50%) was frequent (5/8, 63%). Conclusion A predominant adenocarcinoma epithelial component in PPC might be associated with better survival outcomes and high PD-L1 expression might be frequent in PPC.

BACKGROUND: Sarcopenia characterized by skeletal muscle loss may influence postoperative outcomes through physical decline and weakened immunity. We aimed to investigate clinical significance of sarcopenia in resected early-stage non-small cell lung cancer (NSCLC). METHODS: We retrospectively reviewed 315 consecutive patients with pathologic stage I NSCLC who had undergone lobectomy with systematic nodal dissection. Sarcopenia was defined as the lowest quartile of psoas muscle area on the 3rd vertebra on the high-resolution computed tomography (HRCT) image. Clinicopathological variables were used to investigate the correlation to postoperative complications as well as overall and recurrence-free survival. RESULTS: Upon multivariable analysis, male sex [odds ratio (OR) =5.780, 95% confidence interval (CI): 2.681–12.500, P

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.

Programmed death-ligand 1 (PD-L1) expression is a predictor of immune checkpoint inhibitor (ICI) treatment efficacy. The clinical efficacy of ICIs for non-small-cell lung cancer (NSCLC) patients harboring major mutations, such as EGFR or ALK mutations, is limited. We genotyped 190 patients with advanced lung adenocarcinomas who received nivolumab or pembrolizumab monotherapy, and examined the efficacy in NSCLC patients with or without major mutations. Among the patients enrolled in the genotyping study, 47 patients harbored EGFR mutations, 25 patients had KRAS mutations, 5 patients had a HER2 mutation, 6 patients had a BRAF mutation, and 7 patients had ALK rearrangement. The status of PD-L1 expression was evaluated in 151 patients, and the rate of high PD-L1 expression (&ge, 50%) was significantly higher in patients with ALK mutations. The progression-free survival was 0.6 (95% CI: 0.2&ndash, 2.1) months for ALK-positive patients and 1.8 (95% CI: 1.2&ndash, 2.1) months for EGFR-positive patients. All patients with ALK rearrangement showed disease progression within three months from the initiation of anti-PD-1 treatment. Our data suggested that ICI treatment was significantly less efficacious in patients with ALK rearrangement than in patients with EGFR mutations, and PD-L1 expression was not a critical biomarker for ICI treatment for patients with one of these mutations.

// Yuko Oya 1 , Tatsuya Yoshida 1 , Hiroaki Kuroda 2 , Masashi Mikubo 3 , Chiaki Kondo 1 , Junichi Shimizu 1 , Yoshitsugu Horio 1 , Yukinori Sakao 2 , Toyoaki Hida 1 and Yasushi Yatabe 3 1 Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan 2 Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya, Japan 3 Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan Correspondence to: Tatsuya Yoshida, email: t.yoshida@aichi-cc.jp Keywords: nivolumab, non-small cell lung cancer, programmed cell death-1(PD-1), programmed cell death-ligand 1 (PD-L1) Received: June 27, 2017 Accepted: September 21, 2017 Published: October 07, 2017 ABSTRACT Background: Nivolumab offers a superior survival benefit over docetaxel in patients with advanced, previously treated non-small-cell lung cancer (NSCLC). An association between programmed cell death ligand-1 (PD-L1) expression and the efficacy of nivolumab has been reported in many studies. However, the association between the clinical parameters and efficacy of nivolumab remains unclear in advanced NSCLC patients. Results: Among 124 patients, 108 (88%) were performance status (PS) 0 to 1. PD-L1 expression was assessed in 89 patients, with 51 (57%) patients having PD-L1 positive expression. In all patients, the objective response rate (ORR) in patients with elevated CRP levels (≥ 1 mg/dl) was significantly worse than those without elevated CRP levels (< 1 mg/dl) (8.3 vs 23.4%, p = 0.0180). The PS (≥ 2), smoking index (< 400), CRP levels (≥ 1 mg/dl) and LDH (≥ 245 IU/L) were significantly associated with a shorter PFS and OS in patients treated with nivolumab. Multivariate analyses showed that the PS (≥ 2), smoking index (< 400), CRP levels (≥ 1 mg/dl) and LDH (≥ 245 IU/L) and PD-L1 expression were significant factors associated with a longer PFS of nivolumab. Materials and Methods: We retrospectively analyzed 124 patients who received nivolumab as a subsequent treatment. The patient characteristics, laboratory data at baseline (C-reactive protein [CRP] and lactate dehydrogenase [LDH]), PD-L1 expression, nivolumab response, progression-free survival (PFS), and overall survival (OS) were evaluated. Conclusions: Clinical parameters, such as PS, serum CRP, serum LDH, and smoking status, were significantly associated with the response duration and survival in patients treated with nivolumab.

Objectives: Acute exacerbation of interstitial lung disease (AEILD) is a severe complication after pulmonary resection. This study investigates whether 2-[18]-fluoro-2-deoxy-D-glucose (18F-FDG) uptake on positron emission tomography (PET) in ILD areas is a predictor of AEILD. Methods: We enrolled 200 non-small cell lung cancer (NSCLC) patients with smoke exposures. Ten (5.0%) developed AEILD of whom seven were diagnosed as severe AEILD requiring medication. Patients were classified into either heterogeneity (HET, presence of ILD and non-ILD areas) or homogeneity (HOM, only non-ILD) according to the 18F-FDG uptake at diaphragm level. Results: The average maximum 18F-FDG uptake by NSCLC and in non-ILD was in HOM comparable to that in HET (p = 0.86 and p = 0.14, respectively); however; it was 2.8-fold higher in ILD than in non-ILD within HET (p < 0.01). Multivariate analyses revealed that only HET was independent factors for AEILD and severe AEILD (p < 0.01, and p = 0.03, respectively). Among HET, honeycombing or a triad of reticulation, consolidation, and ground-glass attenuation on high-resolution computed tomography (n = 21) associated with higher complication rate regarding AEILD and worse prognosis (both p < 0.01). Conclusions: Presurgical 18F-FDG uptake on normal lung areas may predict AEILD in smoke exposures. Synopsis: Heterogeneity consisted of normal lung area and interstitial lung disease area according to 18FFDG uptake. The average maximum 18F-FDG uptake was 2.8-fold higher in interstitial lung area than in normal area within heterogeneity. honeycombing or plenty of distinctive findings of interstitial lung disease on high-resolution computed tomography associated with higher complication rate regarding acute exacerbation of interstitial lung disease and worse prognosis.

Background Concurrent chemoradiation therapy (CRT) is the current standard of care for patients with locally advanced lung adenocarcinoma; however, little has been reported about the impact of epidermal growth factor receptor ( EGFR ) mutation on CRT efficacy. Methods From 2006 to 2013, we retrospectively screened 104 unresectable stage III adenocarcinoma patients who were examined for EGFR mutation status and received definitive concurrent CRT consisting of platinum doublet chemotherapy in first-line setting and compared the clinical outcomes and recurrence patterns according to mutation status. Results Among 104 patients, EGFR mutation was detected in 29 (28%). The overall response rate did not differ between EGFR -mutant and wild-type patients (72.4% versus 72.0%, p = 0.607). The median progression-free survival in concurrent CRT was significantly shorter in EGFR-mutant patients than in wild-type patients (9.8 [95% confidence interval, CI: 7.6–19.0] versus 16.5 [95% CI: 11.8–19.9] months, p = 0.041). The 2-year recurrence-free survival rate was 7.7% and 28.1% in EGFR -mutant and wild-type patients, respectively ( p = 0.028). Distant metastases were more frequently identified as the first recurrence site in EGFR-mutant patients than in wild-type patients (76% versus 40%, p = 0.001). The brain was the most often affected site in EGFR -mutant patients (35%). However, locoregional recurrence was less common in EGFR -mutant patients than in the wild-type population (14% versus 35%, p = 0.027). Overall survival was similar between EGFR -mutant and wild-type patients (51.1 [95% CI: 28.2–70.2] versus 42.9 [95% CI: 35.3 to not available] months, p = 0.637). Among the EGFR wild-type population who were examined for Kras mutation, Kras -mutant patients had significantly worse overall survival than Kras wild-type patients (21.6 versus 49.8 months, p = 0.024). Conclusion Concurrent CRT resulted in shorter progression-free survival in EGFR -mutant stage III adenocarcinoma patients than in wild-type patients, mainly because of distant metastasis relapse, regardless of better local control. Because of these distinct biological features, a different strategy, including EGFR-tyrosine kinase inhibitors for EGFR -mutant locally advanced adenocarcinoma patients receiving definitive CRT may be needed.

Anti-PD-1 therapy has been the standard treatment for advanced NSCLC patients. Some patients show durable response, while there are cases that show rapid progression after initiation of ICI treatment, which leads to early death. Therefore, we need a clear biomarker that identifies for early death after initiation of ICI treatment. We reported that CRP is a predictive marker for the efficacy of nivolumab for advanced NSCLC. Among pro-inflammatory cytokines, IL 6 and IL-1β are reported as a poor prognostic factor of cancer patients, and TNFα and INF-γ are reported to be one of the predictors of ICI efficacy.The aim of this study is to investigate the relationship between serum pro-inflammatory cytokines levels and the efficacy of ICI treatment and early death after ICI treatment. Methods: We retrospectively reviewed the predictive factors of efficacy and early death (death within 3 months after initiation of treatment) in anti-PD-1 monotherapy in all cohort (N=307). Based on the results in all cohort, we investigated the relationship of proinflammatory cytokines (IL-1β, IL6, IL10, INFγ) level in serum before pre-anti PD-1 therapy by Luminex® system and the clinical outcome of anti-PD-1 treatment in cytokine cohort (N=67). Patients with advanced or postoperative recurrence NSCLC who received 1≤ dose of ICI from December 2015 to September 2018 in our institute were included. Results: Among 307 patients, 45 patients (14.6%) died within 3 months after the initiation of anti-PD-1 therapy in all cohort. The median PFS of ICI treatment was 3.1months (95%CI: 2.5-4.1). EGFR or ALK mutation, poor PS (2≤), PD-L1 negative, high CRP(1.0 mg/dl≤) were identified as predictive factors for shorter PFS using Cox proportional model. Poor PS, high lung immune prognostic index (2≤), low albumin ( Conclusions:This analysis demonstrated that serum high IL6 level at baseline associated with the early death after initiation anti-PD-1 treatment and shorter PFS in advanced NSCLC. Citation Format: Yuko Oya, Tatsuya Yoshida, Teppei Yamaguchi, Hiroaki Kuroda, Junichi Shimizu, Yoshitsugu Horio, Hirokazu Matsushita, Toyoaki Hida. High serum interleukin 6 level associates with early death after initiation of treatment with PD-1 inhibitor in advanced NSCLC [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 5390.

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.

Several second-generation inhibitors of anaplastic lymphoma kinase (ALK) have demonstrated potent activity in ALK rearrangement-positive non-small cell lung cancer (NSCLC). Two of these agents, ceritinib, and alectinib, recently received approval for the treatment of ALK-rearranged NSCLC in Japan. The efficacy of treatment with a second-generation ALK inhibitor after failure with a different second-generation ALK inhibitor remains unclear. We present a series of eight patients with ALK-rearranged NSCLC treated with alectinib who experienced disease progression after ceritinib. Both crizotinib and ceritinib were administered to six patients, with four (29%) patients receiving crizotinib followed by ceritinib. Among the eight study patients, two (25%) had partial response, one (12%) stable disease, and five (63%) had progressive disease. The median progression-free survival was 3.6 months (95% confidence interval=0-7.1 months). The results of this study suggest that the second-generation ALK inhibitor alectinib has limited efficacy after initial treatment with the second-generation ALK inhibitor ceritinib.

Background Emergence of the T790M point mutation in exon 20 of epidermal growth factor receptor (EGFR) is the most common mechanism of resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). It remains unclear whether the efficacy of platinum-doublet chemotherapy is impacted by the presence of the T790M mutation. The aim of this study is to evaluate the efficacy of platinum-doublet chemotherapy after initial EGFR-TKI failure according to the EGFR T790M in patients with advanced EGFR-mutation-positive non-small cell lung cancer (NSCLC). Patients and methods We retrospectively reviewed 50 patients with advanced NSCLC harboring EGFR mutations who underwent rebiopsy to evaluate their T790M mutation status after development of resistance to first-line EGFR-TKIs (gefitinib, erlotinib, or afatinib) and were subsequently treated with second-line platinum-based chemotherapy. Results The median age of patients was 63 years (range, 35–77 years), and 15 (30%) patients were male. Histological examination revealed that all patients had adenocarcinoma, 39 (78%) had stage IV disease, and 11 (22%) patients had postoperative recurrence. Of all, 17 patients (34%) had the T790M mutation by rebiopsy after initial EGFR-TKI failure. The overall response rate (ORR) of platinum-doublet chemotherapy was 24% for both T790M-positive and T790M-negative patients. There was no significant difference in the progression-free survival (PFS) in T790M-positive and T790M-negative patients (median PFS, 6.0 months vs. 5.1 months; 95% confidence interval [CI], 0.1–11.9 vs. 4.4–5.8; hazard ratio [HR], 0.90 [95%CI, 0.49–1.66]; P = 0.7210). None of the factors were predictive of platinum-doublet chemotherapy efficacy by the multivariate analysis. Conclusion There were no differences in clinical outcomes of platinum-based chemotherapy according to the T790M status of NSCLC patients.

Emergence of the T790M point mutation in exon 20 of the epidermal growth factor receptor (EGFR) is the most common mechanism of resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). The aim of this study was to investigate the association between T790M mutation status and the progression patterns during EGFR-TKI treatment.We reviewed 181 patients with advanced non-small-cell lung cancer harboring EGFR mutation, who were evaluated for T790M mutation status after initial EGFR-TKI failure (gefitinib, erlotinib, or afatinib). We retrospectively investigated the patient characteristics, initial EGFR-TKI response, T790M mutation status, subsequent treatment after initial EGFR-TKIs, timing of re-biopsy, and progression patterns during the EGFR-TKI treatment.After the resistance to the EGFR-TKIs, the T790M mutation was identified in 87 (48%) of 181 patients. Seventy-three (40%) patients had solitary lesion progression, and 108 (60%) had multiple lesion progression during the initial EGFR-TKI treatment. The prevalence of the T790M mutation was significantly greater in patients with solitary lesion progression than those with multiple lesion progression (58% vs. 24%; P .0001). The overall response rate and progression-free survival on initial EGFR-TKIs were significantly better in patients who acquired T790M after failure of EGFR-TKIs than those without T790M (overall response rate, 80% vs. 60%; P = .0033 and progression-free survival, 11.4 vs. 9.3 months; P = .0050). The multivariate analysis showed that gender, initial EGFR-TKI response, and progression patterns were significantly associated with T790M mutation status.The progression patterns during initial EGFR-TKIs and initial EGFR-TKI response are associated with the T790M mutation.

9038 Background: Previous clinical trials demonstrated that alectinib (ALEC) had a longer time-to-progression than crizotinib (CRZ) in 1st-line settings. Information on long-term overall survival (OS), however, is still limited with a few studies having reported that the sequential strategy of “CRZ followed by other ALK-inhibitor” can provide extended OS. In Japan, ALEC was approved for a 1st-line setting earlier than in other countries. Methods: We reviewed the clinical data of ALK-rearranged NSCLC patients who received CRZ or ALEC between May 2012 and Dec 2016. Patients were divided into two groups according to the first-administered ALK inhibitor, the CRZ or ALEC group. In order to evaluate the efficacy of the sequential strategy of “CRZ followed by ALEC”, the combined time to treatment failure (TTF) was calculated in the CRZ group as defined by the sum of the “TTF of CRZ” plus the “TTF of ALEC” if patients were treated with ALEC followed by CRZ. In the ALEC group, the “TTF of ALEC” was calculated. The primary endpoint is the comparison between the combined TTF in the CRZ group with the TTF in the ALEC group. Results: Of 864 patients enrolled from 61 institutions, 840 patients were analyzed. Median age was 61 (range, 20-94); 56% were female; and 95% had adenocarcinoma. There were 535/305 patients in the CRZ/ALEC group. In the CRZ group, 282 patients received ALEC after CRZ failure. The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group; median, 34.4 vs 27.2 months (mo); hazard ratio (HR), 0.709 [95%CI;0.559- 0.899]; P= 0.0044. However, there was no significant difference in OS between the patients who received ALEC after CRZ in the CRZ group and the patients in the ALEC group; median, 88.4 months vs. not reached; HR 1.048 [95%CI;0.758-1.451]; P= 0.7770. In the whole population, the CRZ group had a significantly shorter OS than the ALEC group; median, 53.6 mo vs not reached HR, 1.821 [95%CI;1.372-2.415]; P< 0.0001. Conclusions: The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group, however, OS benefit of sequential therapy of CRZ followed by ALEC was not shown. Clinical trial information: UMIN000028605.

BACKGROUND Lung adenocarcinoma in the young is a rare entity, and the oncogenic genetic alterations (GAs) and clinical characteristics associated with this disease are poorly understood. Conversely, it has been demonstrated that young age at diagnosis defines unique biology in other cancers. For this report, the effects of young age on lung adenocarcinoma are reported. METHODS The authors retrospectively screened 1746 consecutive patients who were diagnosed with stage I through IV adenocarcinoma between 2009 and 2015 and identified 81 who were aged 40 years or younger at diagnosis. The clinical and genetic characteristics of this younger population were analyzed. RESULTS Of the 81 younger patients identified, 36 (44%) were men, 36 (44%) were never smokers, and the median age was 36 years (range, 26-40 years). Thirty-three patients (41%) harbored anaplastic lymphoma kinase (ALK) translocations, 24 (30%) had epidermal growth factor receptor (EGFR) mutations, and 2 (2%) had v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. Rare oncogenic GAs also were studied in patients who had wild-type ALK/EGFR/KRAS adenocarcinoma, including 4 patients with HER2 mutations, 2 with Ret proto-oncogene (RET) translocations, and 2 with ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) translocations. Notably, oncogenic GAs (P < .001), ALK (P < .001) and ROS1 (P = .033) translocations, and HER2 mutations (P < .001) were associated with young age, and a similar trend was observed for RET translocations (P = .108). Younger patients who had adenocarcinoma without GAs had a significantly worse prognosis compared with older patients without GAs (overall survival, 8.9 vs 16.4 months; P < .001) and patients with GAs (24.9 months; P < .001). CONCLUSIONS Younger patients with adenocarcinoma have a distinctly unique prevalence of oncogenic GAs. Comprehensive oncogenic GA screening is especially recommended for personalized medicine strategies in this population. Cancer 2017;123:1731–1740. © 2017 American Cancer Society.

Background The central nervous system (CNS) is a preferential progression site related to poor penetration of crizotinib into the CNS in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) patients treated with crizotinib. We evaluated the clinical impact of crizotinib on central nervous system progression in ALK-positive NSCLC. Methods Between January 2006 and September 2015, 59 ALK-positive NSCLC patients treated with crizotinib as the initial ALK inhibitor were retrospectively evaluated for baseline characteristics, initial response to crizotinib, brain metastasis (BM) status at baseline, and progression patterns. Results Among 59 patients, 48 (81%) received crizotinib as first-line or second-line treatment for advanced or recurrent disease. Out of the 26 (44%) patients who had BM, 13 had untreated BM, and 13 had previously undergone intracranial radiotherapy or surgery. The overall response rate for crizotinib was 66%, with a median progression-free survival (PFS) of 9.7 months. Disease progression assessed by response evaluation criteria in solid tumors-progressive disease (RECIST-PD) occurred in 48 patients. The CNS was the common initial progression site in 24 patients, which included isolated CNS progression in 18 patients. There was a significantly shorter median PFS in the BM versus the non-BM patients before crizotinib treatment (median PFS: 6.7 months vs. 10.2 months, P =0.0347). Multivariate analysis revealed that poor performance status (PS) (≥2) or untreated BM were associated with the PFS duration (poor PS: hazard ratio (HR) 3.322, 95% CI 1.402–7.353, P =0.0078; untreated BM: HR 2.314, 95% CI 1.153–4.400, P =0.0196). In addition, the time to the occurrence of CNS progression from the start of crizotinib was significantly shorter in the BM versus non-BM patients (11.1 vs. 22.1 months, P =0.0255). Conclusion The common progression site in ALK-positive patients treated with crizotinib was the CNS. BM status was significantly associated with both PFS in crizotinib-treated patients and the occurrence of CNS progression.

e19138 Background: The next generation ALK inhibitor, alectinib, reportedly has potent efficacy after crizotinib failure in ALK-positive NSCLC patients. In the present study, we investigated progre...

e19123 Background: Patients with NSCLC with EGFR-activating mutations initially respond to EGFR-TKIs. However, clinical efficacy is limited by acquired resistance, and the secondary EGFR T790M muta...

Aim: The purpose of this study is to better identify imaging characteristics on computed tomography (CT) in patients with non-small-cell lung carcinoma (NSCLC) with known epidermal growth factor receptor (EGFR) mutations, KRAS mutations, and anaplastic lymphoma kinase (ALK) gene rearrangements. Methods: Two hundred fifty-seven patients with a diagnosis of NSCLC and EGFR mutations, KRAS mutations or ALK gene rearrangements were assessed. We retrospectively analyzed the CT characteristics of each cohort. Results: We evaluated 257 patients with NSCLC. One hundred fifty-three patients (59.5%) had EGFR mutations, 54 patients (21.0%) had KRAS mutations, and 50 (19.5%) had ALK gene rearrangements. All mutations were mutually exclusive. Most patients had stage III or IV disease. One hundred twenty-one cases were male, and 136 were female. The mean age was 62.1 years (range29-89). Patients with EGFR mutations tend to have ground grass opacity (GGO), air bronchograms, and lung metastases (p Conclusions: These findings may help to make a proper diagnosis in the current era of molecular targeted therapies. Disclosure: All authors have declared no conflicts of interest.