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Purpose: Targeting oncogenic driver mutations, such as sensitizing mutations in the epidermal growth factor receptor gene (EGFR), significantly improves the prognosis of patients with advanced non-squamous non-small-cell lung cancer (NS-NSCLC). As the number of genetic mutations that must be tested increases, the Oncomine Dx Target Test (ODxTT), which can simultaneously detect multiple cancer-related genes, is becoming the main test used, in preference to single-molecule testing. In this study, we evaluated the performance of ODxTT and cobas® EGFR Mutation Test v2 (cobas® EGFR), one of the single-molecule tests, in detecting EGFR mutations.Materials and methods: Samples from 211 patients who had been diagnosed with NS-NSCLC were tested simultaneously or sequentially with the cobas® EGFR Mutation Test and ODxTT. We compared the success rates and detection rates of both tests and evaluated their equivalence by determining the concordance rate and k-coefficient of the two tests.Results: The success rate in detecting EGFR mutations was 95.7% for ODxTT and 100% for cobas® EGFR. EGFR mutations were detected in 26.5% of samples with ODxTT and in 28.0% with cobas® EGFR. For the 200 samples successfully analyzed with both tests, the concordance rate and k-coefficient were 97.5% and 0.938, respectively. ODxTT failed to detect two exon 19 deletion mutations (p.E746_P753delinsVS and p.E746_P753delinsLS), and cobas® EGR failed to detect three instances of an exon 19 deletion (p.L747_P753delinsS), L861R, and an exon 20 insertion (p.P772_H733insV).Discussion: The success rate of ODxTT is slightly inferior to that of cobas® EGFR. ODxTT shared a high concordance rate and k-coefficient with cobas® EGFR in detecting EGFR mutations, but discordant results between the two tests were observed in a few cases, mainly due to the difference of detectable EGFR variants. Therefore, the advantages and limitations of each test must be clarified to ensure that genomic testing methods are used properly.

The ideal management of patients with unresectable non-small-cell lung cancer (NSCLC) is still developing. Unresectable NSCLC has a high mortality rate and poor prognosis. The development of immune checkpoint inhibitors (ICIs) and molecular-targeted therapies has been a breakthrough in the treatment. The correct treatment of this patient population is crucial to maximize the clinical benefits without compromising quality of life (QOL).We review the chemoradiotherapies, cytotoxic chemotherapies, immunotherapies, and molecular-targeted therapies available for unresectable NSCLC, focusing on their effects on overall survival, progression-free survival, and QOL.Although cure is the ultimate goal of cancer treatment, it is often difficult to achieve in advanced NSCLC. Biomarker surveillance techniques, such as next-generation sequencing, have made it possible to provide the most appropriate treatment for each patient. This has led to clinically-meaningful improvements in therapies for unresectable NSCLC. The development of new molecular-targeted therapies and the establishment of treatment for patients who acquired drug resistance after initial treatment have a positive impact on patients' long-term survival. ICIs lead the long-term survival that can be considered a cure of some patients with advanced NSCLC, but such curative survival is difficult to achieve with cytotoxic chemotherapies and molecular-targeted therapies.

Introduction Immune checkpoint inhibitors (ICI) have significantly improved the prognosis of non-small cell lung cancer (NSCLC). However, only a limited proportion of patients can benefit from this therapy, and clinically useful predictive biomarkers remain to be elucidated. Methods Blood was collected from 189 patients with NSCLC before and six weeks after the initiation of the ICI treatment (anti-PD-1 or anti-PD-L1 antibody). Soluble PD-1 (sPD-1) and PD-L1 (sPD-L1) in plasma before and after treatment were analyzed for evaluation of their clinical significance. Results The Cox regression analysis demonstrated that higher sPD-L1 levels before treatment significantly predicted unfavorable progression-free survival (PFS; HR 15.4, 95%CI 1.10–86.7, P = 0.009) and overall survival (OS; HR 11.4, 95%CI 1.19–52.3, P = 0.007) in NSCLC patients treated with ICI monotherapy (n = 122), but not in those treated with ICI combined with chemotherapy (n = 67: P = 0.729 and P = 0.155, respectively). In addition, higher sPD-1 levels after treatment were significantly associated with better OS (HR 0.24, 95%CI 0.06–0.91, P = 0.037) in patients treated with anti-PD-1 monotherapy, whereas higher sPD-L1 levels after treatment were significantly associated with worse PFS (HR 6.09, 95%CI 1.42–21.0, P = 0.008) and OS (HR 42.6, 95%CI 6.83–226, P

Aprepitant is used with dexamethasone and 5-HTUrinary 11β-hydroxytestosterone (11β-OHT)/testosterone concentration ratio and plasma 4β-hydroxycholesterol (4β-OHC) concentrations were measured before and after cisplatin treatment (days 1, 4, and 8). CYP3A5 was genotyped, and plasma aprepitant concentrations were measured on day 4 to examine its influence on CYP3A endogenous markers.The urinary 11β-OHT/testosterone concentration ratio in the 35 patients included in this study increased by 2.65-fold and 1.21-fold on days 4 and 8 compared with day 1, respectively. Their plasma 4β-OHC concentration increased by 1.46-fold and 1.66-fold, respectively. The mean plasma aprepitant concentration on day 4 was 1,451 ng/mL, which is far lower than its inhibitory constant. The allele frequencies of CYP3A5*1 and CYP3A5*3 were 0.229 and 0.771, respectively. In patients with the CYP3A5*1 allele, the plasma 4β-OHC concentration was significantly lower at baseline but more potently increased with chemotherapy.CYP3A activity was significantly induced from day 4 to day 8 in patients receiving cisplatin and three antiemetic drugs.

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

Increasing the T-cell immune response to Mycobacterium tuberculosis with an anti-programmed cell death 1 (anti-PD-1) antibody may ultimately have detrimental effects. We present the case of a patient with advanced non-small cell lung cancer who developed active tuberculosis (TB) after initial treatment with pembrolizumab, an anti-PD-1 antibody. Pembrolizumab was resumed after completing anti-TB treatment, and no relapse of TB was observed clinically or radiologically. Checkpoint inhibitor-related pneumonitis (CIP) is first suspected when a pulmonary shadow presents during treatment with an anti-PD-1 antibody. It is sometimes difficult to diagnose CIP using computed tomographic images alone. Careful testing, including bacterial examinations and bronchoscopic biopsy, should be performed.

Purpose Immune checkpoint blockade therapy is the standard treatment for metastatic or refractory non-small cell lung cancer (NSCLC). However, it is associated with immune-related adverse events (irAEs). irAEs are sometimes fatal; however, an efficient method for early irAEs detection has not been developed because their onset timing varies. We examined the significance of non-specific symptoms as a prodrome of irAEs in patients with NSCLC. Methods We reviewed consecutive patients who received nivolumab at a dosage of 3 mg/kg every 2 weeks for metastatic NSCLC between December 2015 and August 2017. Patient demographics, irAEs and signal symptoms were recorded. Non-specific symptoms (fever and fatigue) occurred 7 days or earlier before the onset of irAEs were considered signal symptoms. For statistical analyses, the association between irAEs and clinical information, including signal symptoms, was evaluated using Fisher’s exact test and logistic regression. Results A total of 200 patients received nivolumab; 131 (65.5%) were male, their median age was 63 years (range 30–83), 174 (87.0%) had performance status of 0–1. Signal symptoms occurred in 38 (19.0%) of the 77 patients (38.5%) who experienced irAEs, and were positively associated with the occurrence of irAEs (P Conclusion The occurrence of signal symptoms could be used in the early detection and management of irAEs in patients during immune checkpoint blockade therapy.

INTRODUCTION: Immune-mediated adverse events (imAEs), including all-cause immune-mediated pneumonitis, were reported in approximately 25% of patients in the placebo-controlled, phase III PACIFIC trial of durvalumab monotherapy (for up to 12 months) in patients with unresectable, stage III NSCLC and no disease progression after concurrent chemoradiotherapy; only 3.4% of patients experienced grade 3/4 imAEs. With broad application of the PACIFIC regimen (consolidation durvalumab after chemoradiotherapy), now standard-of-care in this setting, there is a need to better characterize the occurrence of imAEs with this regimen. METHODS: We performed descriptive, post-hoc, exploratory analyses to characterize the occurrence of imAEs (pneumonitis and non-pneumonitis) in PACIFIC in terms of: incidence, severity, and timing; clinical management and outcomes; and associations between the occurrence of imAEs and (1) all-cause AEs and (2) baseline patient, disease, and treatment characteristics. RESULTS: Any-grade immune-mediated pneumonitis (9.4%) and non-pneumonitis imAEs (10.7%) occurred infrequently and were more common with durvalumab versus placebo. Grade 3/4 immune-mediated pneumonitis (1.9%) and non-pneumonitis imAEs (1.7%) were uncommon with durvalumab, as were fatal imAEs (0.8%; all pneumonitis). The most common non-pneumonitis imAEs with durvalumab were thyroid disorders, dermatitis/rash, and diarrhea/colitis. Dermatitis/rash had the shortest time to onset (from durvalumab initiation), followed by pneumonitis; dermatitis/rash had the longest time to resolution, followed by thyroid disorders. Most patients with immune-mediated pneumonitis (78.4%) and non-pneumonitis imAEs (56.3%) had these events occur ≤ 3 months after initiating durvalumab. ImAEs were well managed with administration of systemic corticosteroids, administration of endocrine replacement therapy, and interruption/discontinuation of durvalumab. Time elapsed from completion of prior radiotherapy to trial randomization (

Background Programmed cell death ligand 1 (PD‐L1) is known to have soluble forms aside from its membrane‐bound forms. The aim of this study was to evaluate the predictive and prognostic values of serum soluble PD‐L1 (sPD‐L1) in patients with non‐small cell lung cancer (NSCLC) who were treated with anti‐PD‐1 antibody. Methods A total of 233 patients were enrolled in this study. We assessed the level of serum sPD‐L1 before anti‐PD‐1 antibody treatment (pembrolizumab or nivolumab) and evaluated the correlation with PD‐L1 expression on tumor cells, the response to anti‐PD‐1 antibody treatment, and patient outcome. Results The median serum sPD‐L1 concentration was 67.7 (range, 25 to 223) pg/mL. A weak correlation between serum sPD‐L1 and tumor PD‐L1 expression was observed. The disease control rate in the high sPD‐L1 group (≥90 pg/mL) was significantly lower than that in the low sPD‐L1 group (, The PFS and OS of the high sPD‐L1 group were significantly shorter than those of the low sPD‐L1 group. The high level of serum sPD‐L1 was independently associated with a shorter PFS and OS.

The development of immune checkpoint inhibitors (ICIs), such as anti-programmed death 1/programmed death ligand 1 (PD-1/PD-L1) inhibitors, has been a breakthrough in the treatment of non-small-cell lung cancer (NSCLC). Durvalumab, a PD-L1 inhibitor, has shown survival benefit as a maintenance therapy for patients with unresectable stage III NSCLC following definitive chemoradiotherapy, and is approved by the U.S. Food and Drug Administration and the European Medicines Agency.In this article, we review the development of durvalumab, its pharmacology, and its safety profile as a monotherapy and in combination with other agents, including epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), ICIs such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) blockers, and cytotoxic chemotherapy.ICIs, including durvalumab, cause unique side effects, known as immune-mediated adverse events, which are commonly manageable with standard treatment algorithms. The safety profile of durvalumab monotherapy is similar to those of other PD-1/PD-L1 inhibitors. In the PACIFIC trial, durvalumab after radiotherapy resulted in a slight increase in pulmonary toxicity, but most cases were mild. The enhanced effect of ICIs when used in combination therapies is accompanied by an increased risk of side effects. Therefore, the authors evaluated the safety profile and risk-benefit balance of durvalumab combined with various agents.

Background Several studies have previously demonstrated the survival benefit of both EGFR‐TKI treatment and chemotherapy in patients with non‐small cell lung cancer (NSCLC) harboring EGFR mutations. The aim of the present study was to clarify the factors influencing the treatment sequence after failure of EGFR‐TKI therapy, focusing on the number of organs with metastasis (hereafter, metastatic organs). Methods Between January 2010 and December 2016, consecutive patients with EGFR‐mutated NSCLC who were started on first‐line EGFR‐TKI were reviewed. The factors influencing withholding systemic chemotherapy and the post‐progression survival (PPS) after failure of EGFR‐TKI were investigated. Results A total of 393 patients were started on first‐line EGFR‐TKI during the study period. After excluding patients maintained on EGFR‐TKI or who received osimertinib targeting secondary EGFR T790M, 297 patients were included in the analysis. Among these, 180 (60.6%) received chemotherapy after failure of EGFR‐TKI (TKI‐Ct group), while the remaining 117 (39.4%) received no chemotherapy (TKI‐only group). Multivariate analysis identified older age (≥75 years: odds ratio [OR] = 0.25, 95% confidence interval [CI]: 0.11–0.43, P

Patients with uncommonLay abstract Tyrosine kinase inhibitor (TKI) medications are targeting EGFR work on the first-line treatment for patients with common

Introduction: The prognosis of patients with advanced non-small cell lung cancer (NSCLC) remains poor, with a 5-year overall survival rate of around 15%. Immune checkpoint inhibitors, such as programmed cell death protein 1 and programmed death-ligand 1 (PD-L1) inhibitors, have opened a new era in the management of NSCLC. Three checkpoint inhibitors (nivolumab, pembrolizumab, and atezolizumab) are currently approved by the US Food and Drug Administration (FDA) for advanced NSCLC. Durvalumab, an anti-PD-L1 antibody, is under investigation in several trials.Areas covered: This article reviews the pharmacological properties, clinical efficacy, and safety of durvalumab as monotherapy and in combination with other drugs for the treatment of locally advanced and advanced NSCLC.Expert opinion: Durvalumab as monotherapy or in combination with tremelimumab was effective with well-tolerated safety profiles for advanced NSCLC in several phase I or II studies. The PACIFIC study assessed the effectiveness of durvalumab as maintenance therapy following definitive chemoradiotherapy for unresectable stage III NSCLC, and met its primary endpoints of progression-free survival and overall survival. These results led to FDA approval for this NSCLC population. It will be exciting to follow ongoing phase III studies assessing how durvalumab fits into the rapidly evolving therapeutic landscape for advanced NSCLC.

Summary Background In the ongoing, phase 3 PACIFIC trial, durvalumab improved the primary endpoints of progression-free survival and overall survival compared with that for placebo, with similar safety, in patients with unresectable, stage III non-small-cell lung cancer. In this analysis, we aimed to evaluate one of the secondary endpoints, patient-reported outcomes (PROs). Methods PACIFIC is an ongoing, international, multicentre, double-blind, randomised, controlled, phase 3 trial. Eligible patients were aged at least 18 years, had a WHO performance status of 0 or 1, with histologically or cytologically documented stage III, unresectable non-small-cell lung cancer, for which they had received at least two cycles of platinum-based chemoradiotherapy, with no disease progression after this treatment. We randomly assigned patients (2:1) using an interactive voice response system and a blocked design (block size=3) stratified by age, sex, and smoking history to receive 10 mg/kg intravenous durvalumab or matching placebo 1–42 days after concurrent chemoradiotherapy, then every 2 weeks up to 12 months. The primary endpoints of progression-free survival and overall survival have been reported previously. PROs were a prespecified secondary outcome. We assessed PRO symptoms, functioning, and global health status or quality of life in the intention-to-treat population with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) version 3 and its lung cancer module, the Quality of Life Questionnaire-Lung Cancer 13 (QLQ-LC13) at the time of random allocation to groups, at weeks 4 and 8, every 8 weeks until week 48, and then every 12 weeks until progression. Changes from baseline to 12 month in key symptoms were analysed with mixed model for repeated measures (MMRM) and time-to-event analyses. A 10-point or greater change from baseline (deterioration or improvement) was deemed clinically relevant. This study is registered with ClinicalTrials.gov , NCT02125461 , and EudraCT, 2014-000336-42. Findings Between May 9, 2014, and April 22, 2016, 476 patients were assigned to receive durvalumab, and 237 patients were assigned to receive placebo. As of March 22, 2018, the median follow-up was 25·2 months (IQR 14·1–29·5). More than 79% of patients given durvalumab and more than 82% of patients given placebo completed questionnaires up to week 48. Between baseline and 12 months, the prespecified longitudinal PROs of interest, cough (MMRM-adjusted mean change 1·8 [95% CI 0·06 to 3·54] in the durvalumab group vs 0·7 [–1·91 to 3·30] in the placebo group), dyspnoea (3·1 [1·75 to 4·36] vs 1·4 [–0·51 to 3·34]), chest pain (−3·1 [–4·57 to −1·60] vs −3·5 [–5·68 to −1·29]), fatigue (−3·0 [–4·53 to −1·50] vs −5·2 [–7·45 to −2·98]), appetite loss (−5·8 [–7·28 to −4·36] vs −7·0 [–9·17 to −4·87]), physical functioning (0·1 [–1·10 to 1·28] vs 2·0 [0·22 to 3·73]), and global health status or quality of life (2·6 [1·21 to 3·94] vs 1·8 [–0·25 to 3·81]) remained stable with both treatments, with no clinically relevant changes from baseline. The between-group differences in changes from baseline to 12 months in cough (difference in adjusted mean changes 1·1, 95% CI −1·89 to 4·11), dyspnoea (1·6, −0·58 to 3·87), chest pain (0·4, −2·13 to 2·93), fatigue (2·2, −0·38 to 4·78), appetite loss (1·2, −1·27 to 3·67), physical functioning (−1·9, −3·91 to 0·15), or global health status or quality of life (0·8, −1·55 to 3·14) were not clinically relevant. Generally, there were no clinically important between-group differences in time to deterioration of prespecified key PRO endpoints. Interpretation Our findings suggest that a clinical benefit with durvalumab can be attained without compromising PROs. This result is of note because the previous standard of care was observation alone, with no presumed detriment to PROs. Funding AstraZeneca.

The safety of anti-programmed cell death 1 (PD-1) antibody for patients with preexisting interstitial lung disease (ILD) remains unknown. The aim of this study was to evaluate the dependence of preexisting ILD on anti-PD-1 antibody-induced pneumonitis in non-small cell lung cancer (NSCLC) patients. We retrospectively reviewed the association of preexisting ILD with the incidence, radiographic pattern, and outcome of pneumonitis in NSCLC patients receiving anti-PD-1 antibody. A total of 331 patients were included in this study. Of these patients, 17 had preexisting ILD. The incidence of pneumonitis was higher among the patients with preexisting ILD than among those without preexisting ILD (29% vs. 10%, P = 0.027). The distributions of the CT appearances at the onset of anti-PD-1 antibody-induced pneumonitis were as follows: for the patients with preexisting ILD, two patients (40%) had diffuse alveolar damage (DAD), one patient each with organizing pneumonia-like (OP), hypersensitivity pneumonitis (HP), and other patterns (20% each); for the patients without preexisting ILD, 19 patients (61%) had OP, 8 (26%) had HP, 3 (10%) had DAD, and 1 (3.2%) had other patterns. The median onset time from the initiation of anti-PD-1 antibody treatment until the development of pneumonitis was 1.3 months (range 0.3-2.1 months) for the patients with preexisting ILD and 2.3 months (range 0.2-14.6 months) for the patients without preexisting ILD. Careful attention to the development of pneumonitis is needed, especially within the first 3 months after the start of anti-PD-1 antibody treatment, when using anti-PD-1 antibody to treat patients with preexisting ILD.

Background First-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater. Methods This randomised, open-label, phase 3 study was done in 213 medical centres in 32 countries. Eligible patients were adults (≥18 years) with previously untreated locally advanced or metastatic non-small-cell lung cancer without a sensitising EGFR mutation or ALK translocation and with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, life expectancy 3 months or longer, and a PD-L1 TPS of 1% or greater. Randomisation was computer generated, accessed via an interactive voice-response and integrated web-response system, and stratified by region of enrolment (east Asia vs rest of world), ECOG performance status score (0 vs 1), histology (squamous vs non-squamous), and PD-L1 TPS (≥50% vs 1-49%). Enrolled patients were randomly assigned 1:1 in blocks of four per stratum to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles or the investigator's choice of platinum-based chemotherapy for four to six cycles. Primary endpoints were overall survival in patients with a TPS of 50% or greater, 20% or greater, and 1% or greater (one-sided significance thresholds, p=0·0122, p=0·0120, and p=0·0124, respectively) in the intention-to-treat population, assessed sequentially if the previous findings were significant. This study is registered at ClinicalTrials.gov, number NCT02220894. Findings From Dec 19, 2014, to March 6, 2017, 1274 patients (902 men, 372 women, median age 63 years [IQR 57-69]) with a PD-L1 TPS of 1% or greater were allocated to pembrolizumab (n=637) or chemotherapy (n=637) and included in the intention-to-treat population. 599 (47%) had a TPS of 50% or greater and 818 patients (64%) had a TPS of 20% or greater. As of Feb 26, 2018, median follow-up was 12·8 months. Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three TPS populations (≥50% hazard ratio 0·69, 95% CI 0·56-0·85, p=0·0003; ≥20% 0·77, 0·64-0·92, p=0·0020, and ≥1% 0·81, 0·71-0·93, p=0·0018). The median surival values by TPS population were 20·0 months (95% CI 15·4-24·9) for pembrolizumab versus 12·2 months (10·4-14·2) for chemotherapy, 17·7 months (15·3-22·1) versus 13·0 months (11·6-15·3), and 16·7 months (13·9-19·7) versus 12·1 months (11·3-13·3), respectively. Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636 treated patients in the pembrolizumab group and in 252 (41%) of 615 in the chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, respectively. Interpretation The benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non-small-cell lung cancer without sensitising EGFR or ALK alterations and with low PD-L1 TPS. Funding Merck Sharp & Dohme.

Background The aim of this study was to evaluate the usefulness of the presence of malignant pleural effusion (MPE) as a negative predictor of anti-PD-1 antibody efficacy. Methods A retrospective review of patients with advanced or recurrent non-small cell lung cancer treated with an anti-PD-1 antibody between December 2015 and March 2018 at the National Cancer Center Hospital, Japan, was conducted. Progression-free survival (PFS) and overall survival (OS) were compared between patients with and without MPE. Additional survival analysis according to PD-L1 expression status was conducted. Univariate and multivariate analyses were performed. Results A total of 252 patients were identified before the commencement of anti-PD-1 antibody treatment: 33 with MPE and 219 without MPE. PFS and OS were significantly shorter in patients with MPE than in patients without MPE (median PFS 3.0 vs. 5.8 months, hazard ratio [HR] 1.7, P = 0.014; median OS 7.9 vs. 15.8 months, HR 2.1, P = 0.001). In patients with PD-L1 expression in ≥ 1% of their tumor cells, the PFS of patients with MPE was significantly shorter than of patients without MPE (median PFS 3.1 vs. 6.5 months, HR 2.0, 95% confidence interval 1.0-3.5; P = 0.021). The presence of MPE was independently associated with a shorter PFS and OS in multivariate analysis. Conclusion The presence of MPE in patients administered an anti-PD-1 antibody is associated with shorter PFS and OS, regardless of the presence of PD-L1 expression ≥ 1% of tumor cells.

Background Cytotoxic chemotherapy for advanced non-small cell lung cancer (NSCLC) as second-line or subsequent treatment generally results in a poor treatment outcome. Several reports have indicated that subsequent cytotoxic chemotherapy in patients who have received immune checkpoint inhibitors (ICIs) might have relatively better efficacy. Methods The clinical data of advanced NSCLC patients treated with nivolumab during clinical practice at the National Cancer Center Hospital between 17 December 2015 and 31 August 2017 were consecutively reviewed, and the treatment outcomes of docetaxel-based chemotherapy (docetaxel +/- ramucirumab) or S-1 after nivolumab were analyzed. The results were then compared with those of advanced NSCLC patients treated with docetaxel or S-1 but not ICIs during clinical practice between 17 December 2014 and 16 December 2015. Results Thirty patients were administered docetaxel-based chemotherapy and 21 patients were administered S-1 in any line after nivolumab. Twenty-four patients were administered docetaxel-based chemotherapy and 15 patients were administered S-1 immediately after nivolumab. Sixty-six patients were administered docetaxel and 23 patients were administered S-1 without ICIs. The objective response rate, disease control rate, and median progression-free survival duration were 28.6%, 53.6%, and 5.26 months for patients receiving docetaxel-based chemotherapy or S-1 immediately after nivolumab treatment; 24.3%, 51.4%, and 3.88 months for patients receiving docetaxel-based chemotherapy or S-1 in any line after nivolumab; and 16.4%, 56.7%, and 2.74 months, for patients receiving docetaxel or S-1 without ICIs, respectively. Conclusion Subsequent cytotoxic chemotherapy, especially immediately after nivolumab, has better treatment efficacy than that of regimens without ICI pretreatment.

Background Although non-small cell lung cancers (NSCLCs) harboring EGFR mutations initially respond well to EGFR-tyrosine kinase inhibitors (TKIs), they typically progress after approximately one year. The EGFR T790M mutation is the most common resistance mechanism. NSCLCs with T790M respond well to osimertinib; however, the heterogeneity of NSCLCs may limit the efficacy. Some patients exhibit a mixed response (MR), in which some lesions shrink and others progress, but little is known of the incidence and characteristics of such a response. We sought to determine the frequency and clinical course in MR patients. Methods We retrospectively reviewed the records of patients who had received osimertinib for NSCLC with EGFR T790M. Results Between April and December 2016, 48 patients were administered osimertinib. Seven patients (15%) exhibited one of two MR types: (i) progressive lesions that did not include the re-biopsy site (5 patients), and (ii) progressive lesions that included the re-biopsy site (2 patients). The most frequent progressive sites were liver and lung metastases (4 patients). Three patients continued osimertinib following an MR, one of whom had received local therapy for liver metastasis and achieved disease control on osimertinib for an additional four months. Conclusion An MR was detected in 15% of NSCLC patients with T790M. This finding suggests that several different resistance mechanisms are active within a single patient who develops resistance to EGFR-TKIs. Osimertinib is basically effective for tumors that acquire resistance to EGFR-TKIs as a result of T790M mutation. Therefore, additional local therapy may be beneficial for patients who develop an MR to osimertinib.

8536 Background: Concurrent chemoradiotherapy followed by durvalumab maintenance for up to 12 months is the standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC). However, the best timing of starting durvalumab after completion of chemoradiation has not been identified. Progression-free survival (PFS) and overall survival (OS) were better in the subgroup of patients administered durvalumab within 14 days after last radiation to randomization according to the PACIFIC study (Antonia SJ, et al. 2017, 2018 NEJM). Methods: This study was a prospective, single-arm, multicenter, phase II clinical trial. Eligibility criteria included patients with unresectable stage III NSCLC, ECOG PS 0-1, age < 75 years old. Patients who did not have disease progression after definitive concurrent chemoradiotherapy (CCRT) (chemotherapy: 2 cycles of platinum-based doublet chemotherapy, radiotherapy: 60 Gy/30 Fr) received durvalumab (10 mg/kg, every 2 weeks for up to 12 months) from the next day (allowed up to 5 days) after last radiation. The primary endpoint was 1-year PFS rate from registration assessed by an independent review committee. The planned sample size was 47 with a threshold value of 50% based on results of the PACIFIC study, an expected value of 63%, one-sided alpha of 20% and power of 80% in 1-year PFS rate. Results: From January 2020 to August 2020, 50 patients were enrolled from 16 institutions and 47 patients were evaluable for efficacy and safety. Forty-two patients received durvalumab maintenance therapy. Patient characteristics were: male/female 41/6; median age 65 (range 42-75); ECOG PS 0/1 28/19; IIIA/IIIB/IIIC 19/21/7. The 1-year PFS rate from registration was 75.0% (60% CI: 69.0 to 80.0). The 1-year OS rate from registration was 97.7% (95%CI: 84.6 to 99.7). ORR, median PFS and median OS were 78.7%, 14.2 months (95%CI: 13.4 to not reached (NR)) and NR, respectively. Grade 3/4 adverse events were pneumonitis (4.3%), neutropenia (44.7%), febrile neutropenia (4.3%). There was no treatment-related death. Conclusions: Our study met the primary endpoint. Durvalumab can be safely administered immediately after completion of CCRT for patients with unresectable stage III NSCLC, no additional or unexpected toxicity occurred as a reference to the PACIFIC study. Clinical trial information: jRCTs031190117.