[Clinical Efficacy of Monotherapy with Immune Checkpoint Inhibitors for Advanced Non-Small Cell Lung Cancer].

OBJECTIVE: To retrospectively assess data on immune checkpoint inhibitors(ICIs)in an actual clinical setting, examine the factors that contribute to response and survival using real-world data, and compare the effectiveness of the 3 types of ICIs for patients with non-small cell lung cancer(NSCLC). METHODS: A retrospective analysis of 127 patients with NSCLC treated with ICIs at our hospital was conducted. RESULTS: Nivolumab(56 patients)showed a 3-year survival rate of 21.6% and a disease control rate of 57.1%. These results are consistent with the clinical trials of Nivolumab. Pembrolizumab(36 patients) showed a 2-year survival rate of 60.3%, a response rate of 50.0%, and a disease control rate of 63.9%. Atezolizumab(35 patients)displayed a particularly low response rate with a 1-year survival rate of 58.4%, response rate of 8.6%, and disease control rate of 25.7%. The treatment results for recurrence after surgery for lung cancer were comparable to those for unresectable lung cancer. CONCLUSION: Anti-PD-1 antibody displayed better therapeutic results than anti-PD-L1 antibody. The efficacy of ICI administration for postoperative recurrent lung cancer was also shown in this study.

Phase I/II study of intermitted erlotinib in combination with docetaxel in patients with recurrent non-small cell lung cancer (WJOG4708L).

BACKGROUND: Preclinical data suggest sequential administration of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) following chemotherapy may improve efficacy. We hypothesized that intermittent delivery of EGFR-TKI following chemotherapy may increase efficacy. METHODS: This was a multicenter, single-arm phase I/II study to evaluate the efficacy of intermitted erlotinib in combination with docetaxel in patients with EGFR-negative NSCLC who failed one prior chemotherapy. The phase I primary objectives were to determine the maximum tolerated dose (MTD) and recommended dose (RD) of erlotinib. Erlotinib was administered orally once per day on days 2-16 in combination with 60 mg/m2 docetaxel on day1 for 21 days. A standard 3 + 3 dose escalation design was employed for erlotinib from 100 to 150 mg/dose. The phase II primary endpoint was the objective response rate (ORR). The ORR and 95% confidence interval (CI) were calculated using a binomial distribution. This study required 45 patients. RESULTS: In the phase I part, the planned dose escalation was completed without reaching MTD. The RD of erlotinib was determined as 150 mg/dose. In the phase II part, the ORR and disease control rate were 17.1% (95%CI: 7.2-32.1%) and 53.7% (95%CI: 37.4-69.3%), respectively. Median progression-free survival and overall survival were 3.5 (95%CI: 3.1-4.5) and 11.3 (95%CI: 8.6-16.6) months, respectively. The common non-hematological adverse event was febrile neutropenia (grade 3-4:19.6%). Two treatment-related deaths were occurred because of interstitial lung disease and pleural infection. CONCLUSIONS: Intermittent dosing of erlotinib plus docetaxel is clinically feasible in phase I part but did not significantly improve ORR in phase II part.

A randomised phase II trial of S-1 plus cisplatin versus vinorelbine plus cisplatin with concurrent thoracic radiotherapy for unresectable, locally advanced non-small cell lung cancer: WJOG5008L.

BACKGROUND: Cisplatin-based chemoradiotherapy is the standard treatment for unresectable, locally advanced non-small-cell lung cancer (NSCLC). This trial evaluated two experimental regimens that combine chemotherapy with concurrent radiotherapy. METHODS: Eligible patients with unresectable stage III NSCLC were randomised to either the SP arm (S-1 and cisplatin) or VP arm (vinorelbine and cisplatin), with early concurrent thoracic radiotherapy of 60 Gy, comprising 2 Gy per daily fraction. The primary endpoint was the overall survival rate at 2 years (2-year overall survival (OS)) (Study ID: UMIN000002420). RESULTS: From September 2009 to September 2012, 112 patients were enroled. Of the 108 eligible patients, the 2-year OS was 75.6% (80% confidence interval (CI), 67-82%) in the SP arm and 68.5% (80% CI: 60-76%) in the VP arm. The hazard ratio (HR) for death between the two arms was 0.85 (0.48-1.49). The median progression-free survival was 14.8 months for the SP arm and 12.3 months for the VP arm with an HR of 0.92 (0.58-1.44). There were four treatment-related deaths in the SP arm and five in the VP arm. CONCLUSIONS: The null hypotheses for 2-year OS were rejected in both arms. The West Japan Oncology Group will employ the SP arm as the investigational arm in a future phase III study.

Combined chemotherapy with cisplatin, etoposide, and irinotecan versus topotecan alone as second-line treatment for patients with sensitive relapsed small-cell lung cancer (JCOG0605): a multicentre, open-label, randomised phase 3 trial.

BACKGROUND: Etoposide and irinotecan are key drugs in the treatment of small-cell lung cancer. We did this study to investigate whether combined chemotherapy with cisplatin, etoposide, and irinotecan was superior to topotecan monotherapy as second-line chemotherapy in patients with sensitive relapsed small-cell lung cancer. METHODS: We did this open-label, multicentre, randomised phase 3 trial at 29 institutions in Japan. Patients with small-cell lung cancer that responded to first-line treatment but showed evidence of disease relapse or progression at least 90 days after completion of the first-line treatment were eligible to participate. Enrolled patients were randomly assigned (1:1) to receive combination chemotherapy with cisplatin plus etoposide plus irinotecan or topotecan alone. Randomisation was done via the minimisation method with biased-coin balancing for Eastern Cooperative Oncology Group performance status, disease stage at enrolment, and institution. Combination chemotherapy consisted of five 2-week courses of intravenous cisplatin 25 mg/m(2) on days 1 and 8, intravenous etoposide 60 mg/m(2) on days 1-3, and intravenous irinotecan 90 mg/m(2) on day 8, with granulocyte colony-stimulating factor given by hypodermic injection every day starting from day 9 of the first course (except on the days anticancer drugs were given). Topotecan therapy consisted of four courses of intravenous topotecan 1·0 mg/m(2) on days 1-5, every 3 weeks. The primary endpoint was overall survival in the intention-to-treat population, which was analysed with a one-sided α of 5%, and safety was assessed in all patients who received at least one dose of study drug. The trial is registered with University Hospital Medical Information Network Clinical Trials Registry, number UMIN000000828. FINDINGS: Between Sept 20, 2007, and Nov 30, 2012, 180 patients were enrolled, with 90 assigned to each treatment group. The median follow-up for censored patients was 22·7 months (IQR 20·0-35·3). Overall survival was significantly longer in the combination chemotherapy group (median 18·2 months, 95% CI 15·7-20·6) than in the topotecan group (12·5 months, 10·8-14·9; hazard ratio 0·67, 90% CI 0·51-0·88; p=0·0079). The most common grade 3 or 4 adverse events were neutropenia (75 [83%] patients in the combination chemotherapy group vs 77 [86%] patients in the topotecan group), anaemia (76 [84%] vs 25 [28%]), and leucopenia (72 [80%] vs 46 [51%]). Grade 3 or 4 febrile neutropenia was more common in the combination chemotherapy group than in the topotecan group (28 [31%] vs six [7%]), as was grade 3 or 4 thrombocytopenia (37 [41%] vs 25 [28%]). Serious adverse events were reported in four (4%) patients in the topotecan group and nine (10%) in the combination chemotherapy group. Two treatment-related deaths (one each of pneumonitis and pulmonary infection) occurred in the topotecan group and one (febrile neutropenia with sepsis) occurred in the combination chemotherapy group. INTERPRETATION: Combination chemotherapy with cisplatin plus etoposide plus irinotecan could be considered the standard second-line chemotherapy for selected patients with sensitive relapsed small-cell lung cancer. FUNDING: National Cancer Center and the Ministry of Health, Labour and Welfare of Japan.

The Macroscopic Appearance of Computed Tomography-guided Needle Biopsy Specimens Correlates with Tumor Metastasis in Non-small Cell Lung Cancer.

BACKGROUND: Computed tomography (CT)-guided needle biopsy is a well-established and dependable procedure for the diagnosis of pulmonary lesions. Some tissue biopsy samples have loose cohesion and disintegrate into tiny pieces before formalin fixation. The purpose of this study was to assess the association between the fresh macroscopic appearance of samples obtained using CT-guided needle biopsy and the clinicopathological features of non-small cell lung cancer (NSCLC). METHODS: A total of 111 patients who underwent CT-guided lung needle biopsy at Osaka City University Hospital between May 2009 and May 2013 were enrolled. Macroscopic appearance was categorized as either loose or tight cohesion. Samples were evaluated using Azan staining to detect collagen fibers. The staining intensity was multiplied by the percentage of positive cells, and the specimen was categorized as having either low (<100) or high expression ( ≥100). Univariate and multivariate logistic regression models were used to evaluate significant covariates for tumor metastasis. RESULTS: In the cohort of 111 patients, the diagnostic rates in loose and tight cohesions were 82.6% and 87.5%, respectively (p=0.509). In 60 patients diagnosed with NSCLC, Azan staining of collagen fibers was positive in 93.5% of the samples with tight cohesion and 28.6% of the samples with loose cohesion (p<0.001). In the multivariate logistic regression models, distant metastasis was significantly associated with loose cohesion (p=0.026). CONCLUSIONS: These results suggest that the macroscopic appearance of CT-guided biopsy samples correlates with tumor metastasis in NSCLC.

Comparing the Effectiveness of Afatinib and Osimertinib for Patients With PD-L1-positive EGFR-mutant Non-small Cell Carcinoma.

Background/Aim: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective for treating non-small cell lung cancer (NSCLC) harboring EGFR mutations. However, higher tumor programmed death ligand-1 (PD-L1) expression is associated with a poor response to EGFR-TKIs, and information on the comparison between afatinib and osimertinib in PD-L1-positive EGFR-mutant NSCLC is scarce. Patients and Methods: We retrospectively analyzed data of patients with PD-L1-positive EGFR-mutant NSCLC to compare the effectiveness of afatinib and osimertinib. Results: A total of 177 patients were included in the study. The Cox proportion hazard model was adjusted for age, sex, performance status, EGFR mutation status, PD-L1 expression level, and brain metastasis, revealing that there was no significant difference in risk for progression [hazard ratio (HR)=0.99, 95% confidence interval (CI)=0.64-1.53] or death (HR=0.96, 95% CI=0.54-1.73) between afatinib and osimertinib. Conclusion: In conclusion, the EGFR-TKI treatment duration and overall survival after the treatment with afatinib or osimertinib were similar in patients with PD-L1-positive EGFR-mutant NSCLC in the present study.

Reaction of plasma adiponectin level in non-small cell lung cancer patients treated with EGFR-TKIs.

BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are routinely used to treat advanced non-small cell lung cancer (NSCLC) patients with activated EGFR mutations, and are associated with excellent response and improvement of performance status. Adipose tissue produces and releases substances called adipokines, which include adiponectin, leptin, resistin, and hepatocyte growth factor (HGF), etc. Previously, we reported that high levels of plasma HGF at diagnosis indicated intrinsic resistance to EGFR-TKIs. EGFR-TKIs have been hypothesized to affect these adipokines. METHODS: This prospective study, to evaluate the correlation between plasma adiponectin and insulin levels and non-hematological adverse effects in advanced NSCLC following EGFR-TKIs administration, was conducted at the Osaka City University Hospital. Plasma adiponectin and insulin levels were determined at diagnosis and on treatment day 30. RESULTS: Overall 33 patients were enrolled. We obtained plasma samples for analyses from all patients at diagnosis and from 26 patients on day 30. Increased adiponectin (13.69 to 14.42 microg/mL, p = 0.0092), and decreased insulin (404.0 to 351.2 pg/mL, p = 0.022) were observed after EGFR-TKI treatments. High levels of adiponectin at diagnosis were associated with severities of skin rash (p = 0.035). CONCLUSIONS: The adiponectin was affected by EGFR-TKI treatments for NSCLC. Besides, the adverse events by EGFR-TKIs were influenced by the plasma adipokines at diagnosis. Our study may provide useful information regarding patient outcomes to EGFR-TKI treatments. A prospective large clinical trial is warranted to clarify these results.

Skeletal-related events in advanced lung adenocarcinoma patients evaluated EGFR mutations.

BACKGROUND: The rate of lung cancer metastasis to the bone is high and skeletal-related events (SREs) decrease the quality of life in many patients. Recently, it was found that a subgroup of patients with non-small cell lung cancer (NSCLC) have specific mutations in the EGFR (epidermal growth factor receptor) gene. We assessed the SREs in advanced lung adenocarcinoma patients that evaluated EGFR mutations in whom bone metastasis was present. METHODS: We retrospectively investigated the clinical records of 377 patients with advanced NSCLC. Patients were evaluated for the presence of EGFR mutations, bone metastases, the incidence of SREs, and treatment history before the first SRE. RESULTS: A total of 78 patients who were evaluated for EGFR mutations had bone metastasis from lung adenocarcinoma. The most frequent site of bone metastasis was the spine (36.2%). SREs occurred in 37 patients (47.4%), the most common of which was bone radiotherapy (41.0%). Significant differences were not observed in the sites of bone metastases or the patterns of SREs between patients with and without EGFR mutations. The median time from bone metastasis to the first SRE was 5.8 months in all of the subjects, history of EGFR-tyrosine kinase inhibitor (TKI) treatment was significantly associated with longer median time to first SRE (14.2 months vs 1.3 months, p < 0.0001), and the median time to first SRE of patients with PS 0-1 was longer (8.5 months vs 0.9 months, p = 0.0023). CONCLUSIONS: We found that SRE patterns have no difference between EGFR mutation positive and negative, and that the time from bone metastasis to the first SRE was longer in advanced lung adenocarcinoma patients with good PS and history of EGFR-TKI treatment.

Study of the clinicopathological features of soluble PD-L1 in lung cancer patients.

Objective: In recent years, an association between serum soluble immune checkpoint molecules (sICMs) and malignant tumors has been reported, which may become important biomarkers in the future. Although several reports have suggested a correlation between sICMs and prognosis, their origin is unclear. In this study, changes in serum soluble PD-L1 (sPD-L1) during the perioperative period and its origin were analyzed in patients with lung cancer. Patients and Methods: Patients with lung tumors (n=39) were included. Samples for sPD-L1 measurements were collected at five time points before and after surgery, and their changes over time were analyzed. ELISA was used to measure sPD-L1 levels. Results: Thirty-nine patients with lung tumors (31, males; 8, females; age, 74 (years) ± 7.7 (range: 51-89) years; malignancy/benign, 33/6) were enrolled. Eight cases of driver gene mutation-positive tumors were included. Twenty-eight (72%) patients were smokers, and their performance status was 0-1 in all 39 patients. PD-L1 TPS was ≥50%/1-49%/<1% in 8/10/14 patients. Stage I/II/III/IV/postoperative recurrence of lung cancer was observed in 21/0/6/5/1 patients, respectively. There were no significant correlations between sPD-L1 levels and clinicopathological features and no correlation with PD-L1 TPS. Comparing localized lesions (stages I-III) with advanced lesions (stage IV and postoperative recurrence), the distribution of sPD-L1 was slightly higher in advanced lesions, although the difference was not significant. No obvious changes in sPD-L1 expression were observed before and after surgery. Conclusion: sPD-L1 levels tended to be high in stage III and above lung cancer. There was no change in sPD-L1 levels before and after surgery. sPD-L1 levels did not correlate with the PD-L1 TPS.

A retrospective study of the efficacy of combined EGFR­TKI plus VEGF inhibitor/cytotoxic therapy vs. EGFR­TKI monotherapy for PD­L1­positive EGFR­mutant non­small cell lung cancer: North Japan Lung Cancer Study Group 2202.

The present multicenter study was performed to compare the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) monotherapy with that of combined EGFR-TKI plus vascular endothelial growth factor receptor (VEGF) inhibitor/cytotoxic therapy in patients with programmed death-ligand 1 (PD-L1)-positive EGFR-mutant non-small cell lung cancer (NSCLC). Data from patients with PD-L1-positive EGFR-mutant NSCLC were collected from 12 institutes. Survival in patients treated with first- and second-generation EGFR-TKIs, osimertinib (third-generation EGFR-TKI), and combined EGFR-TKI plus VEGF inhibitor/cytotoxic therapy was analyzed by multiple regression analysis with adjustments for sex, performance status, EGFR mutation status, PD-L1 expression level, and the presence or absence of brain metastasis using a Cox proportional hazards model. Data from a total of 263 patients were analyzed, including 111 (42.2%) patients who had received monotherapy with a first- or second-generation EGFR-TKI, 132 (50.2%) patients who had received osimertinib monotherapy, and 20 (7.6%) patients who had received combined EGFR-TKI plus VEGF inhibitor/cytotoxic therapy (hereafter referred to as combined therapy). Multiple regression analysis using the Cox proportional hazards model showed that the hazard ratio (95% confidence interval) for progression-free survival was 0.73 (0.54-1.00) in the patients who had received osimertinib monotherapy and 0.47 (0.25-0.90) in patients who had received combined therapy. The hazard ratio for overall survival was 0.98 (0.65-1.48) in the patients who had received osimertinib monotherapy and 0.52 (0.21-1.31) in patients who had received combined therapy. In conclusion, combined therapy was associated with a significant reduction in the risk of progression compared with first- and second-generation EGFR-TKI monotherapy, and therefore, may be promising for the treatment of patients of NSCLC.

Reduced CYP2D6 function is associated with gefitinib-induced rash in patients with non-small cell lung cancer.

BACKGROUND: Rash, liver dysfunction, and diarrhea are known major adverse events associated with erlotinib and gefitinib. However, clinical trials with gefitinib have reported different proportions of adverse events compared to trials with erlotinib. In an in vitro study, cytochrome P450 (CYP) 2D6 was shown to be involved in the metabolism of gefitinib but not erlotinib. It has been hypothesized that CYP2D6 phenotypes may be implicated in different adverse events associated with gefitinib and erlotinib therapies. METHODS: The frequency of each adverse event was evaluated during the period in which the patients received gefitinib or erlotinib therapy. CYP2D6 phenotypes were determined by analysis of CYP2D6 genotypes using real-time polymerase chain reaction techniques, which can detect single-nucleotide polymorphisms. The CYP2D6 phenotypes were categorized into 2 groups according to functional or reduced metabolic levels. In addition, we evaluated the odds ratio (OR) of the adverse events associated with each factor, including CYP2D6 activities and treatment types. RESULTS: A total of 232 patients received gefitinib therapy, and 86 received erlotinib therapy. Reduced function of CYP2D6 was associated with an increased risk of rash of grade 2 or more (OR, 0.44; 95% confidence interval [CI], 0.21-0.94; *p = 0.03), but not diarrhea ≥ grade 2 (OR, 0.49; 95% CI, 0.17-1.51; *p = 0.20) or liver dysfunction ≥ grade 2 (OR, 1.08; 95% CI, 0.52-2.34; *p = 0.84) in the gefitinib cohort. No associations were observed between any adverse events in the erlotinib cohort and CYP2D6 phenotypes (rash: OR, 1.77; 95% CI, 0.54-6.41; *p = 0.35/diarrhea: OR, 1.08; 95% CI, 0.21-7.43; *p = 0.93/liver dysfunction: OR, 0.93; 95% CI, 0.20-5.07; *p = 0.93). CONCLUSIONS: The frequency of rash was significantly higher in patients with reduced CYP2D6 activity who treated with gefitinib compared to patients with functional CYP2D6. CYP2D6 phenotypes are a risk factor for the development of rash in response to gefitinib therapy.

Comparison of adverse events of erlotinib with those of gefitinib in patients with non-small cell lung cancer: a case-control study in a Japanese population.

BACKGROUND: Rash, liver dysfunction, and diarrhea are known as adverse events of erlotinib and gefitinib. However, clinical trials with gefitinib have reported different adverse events compared to those with erlotinib. In an in vitro study, cytochrome P450 (CYP) 2D6 was shown to be involved in the metabolism of gefitinib and not of erlotinib. It has been hypothesized that gefitinib therapy results in different adverse events compared to erlotinib therapy. METHODS: The frequency of each adverse event was evaluated in a case-control study on Japanese patients who were treated with gefitinib or erlotinib. The CYP2D6 phenotype was categorized into 2 groups according to functional or reduced metabolic levels. In addition, we evaluated the odds ratio (OR) of adverse events with each factor, including CYP2D6 activities as well as treatment types. RESULTS: A total of 112 patients received gefitinib therapy, 74 patients received erlotinib therapy, and 17 patients received erlotinib and gefitinib sequentially. The OR of developing rash with gefitinib versus erlotinib treatment was 0.38 (95% confidence interval [CI], 0.15-0.86). The OR of developing diarrhea with gefitinib versus erlotinib treatment was 0.46 (95% CI, 0.22-0.94). The OR of developing liver dysfunction with gefitinib versus erlotinib treatment was 3.30 (95% CI, 1.59-7.22). Reduced function of CYP2D6 was not associated with an increased risk of any adverse events in both gefitinib and erlotinib cohorts. CONCLUSIONS: Erlotinib had higher rate of rash and diarrhea than gefitinib. Liver dysfunction occurred significantly more often in the gefitinib group than in the erlotinib group.

[Carcinomatous meningitis in a post-operative patient with lung adenocarcinoma for which erlotinib was effective - a case report].

A 53-year-old female was admitted to our hospital complaining of disturbance of consciousness and hallucinations. About one year and 5 months ago she had adenocarcinoma of the lung, which was treated with surgery and chemotherapy. Computed tomography and magnetic resonance imaging revealed that her lung cancer had relapsed as caricinomatous meningitis and multiple lung metastases. She was treated with erlotinib, which rapidly resulted in disappearance of her symptoms. She still continues to receive erlotinib therapy without suffering from evident relapse 7 months after the initiation of the treatment.

Clinical outcome of amrubicin therapy according to the prior chemotherapy sensitivities of extensive small cell lung cancer.

BACKGROUND: Amrubicin (AMR) is an active agent for relapsed small cell lung cancer (SCLC). However, the activity of AMR in refractory relapsed patients is controversial. The objective of this retrospective analysis was to evaluate the efficacy and safety of AMR as second-line chemotherapy in SCLC, especially refractory relapsed SCLC. METHODS: Between July 2003 and February 2009, a total of 27 patients were treated with AMR at a dosage of 40 mg x m(-2) x day(-1) on days 1-3 every 3 weeks. Safety was assessable for all patients. Efficacy was evaluated in 26 patients (one patient was not assessable for response), in 12 patients with chemotherapy-sensitive relapse and 14 patients with chemotherapy-refractory relapse. Sensitive relapse means that a first-line response lasted more than 90 days. Refractory relapse means that either did not respond to first-line chemotherapy or responded initially but relapsed within 90 days. RESULTS: Thirteen patients (50%, 95% CI, 31% to 69%) had partial response, including 6 (50%) of the 12 patients with chemotherapy-sensitive relapse and 7 (50%) of 14 patients with chemotherapy-refractory relapse. Median survival times of patients with chemotherapy-sensitive and -refractory relapse were 9.7 months and 8.4 months, respectively, showing significant difference (p = 0.0337). Adverse events were observed in all 27 patients. Grade 3 and 4 neutropenia was seen in 8 patients (29.6%) and 15 patients (55.5%), respectively. Grade 3 and 4 thrombocytopenia occurred in 10 patients (37.0%) and 2 patients (7.4%). Non-hematologic toxicities were generally mild, except for febrile neutropenia. Febrile neutropenia was seen in 6 patients (22.2%). No treatment-related deaths occurred. CONCLUSIONS: AMR is an active agent for the treatment of relapsed SCLC, especially chemotherapy-refractory relapse SCLC, with predictable and manageable toxicities.

For which lung cancer patients is re-administration of immune checkpoint inhibitors effective?

Objective: Currently, immune checkpoint inhibitors (ICIs) play a central role in the treatment of lung cancer. However, ICI re-administration is still uncommon, and its utility should be evaluated as early as possible. Patients and Methods: Twenty-five patients who received ICIs twice or more in any of the drug treatment lines for advanced/relapsed non-small cell lung cancer were included. OS, PFS, ORR, and DCR were examined, and factors such as age, sex, histopathological type, PD-L1 expression, whether radical surgery was performed, driver gene mutations, and immune-related adverse events (irAEs), were evaluated for their relevance and as prognostic factors. Results: Of the 25 patients, 17 were men and 8 were women, with an average age of 68 ± 8.4 (range, 48-85 years), and histology was non-squamous cell carcinoma/squamous cell carcinoma in 19/6 cases. One driver gene mutation positive case was included. PD-L1 TPS was ≥50%/1-49%/0-1%/ unknown in 7/8/5/5 cases. The first ICI administered was pembrolizumab/nivolumab/atezolizumab in 5/13/7 cases. The median number of courses was 9 (range, 1-52) months, and the median PFS was 9 (95% CI, 6.0-12.0) months. Cytotoxic chemotherapy or radiation therapy was administered to 6 patients during the interval up to re-administration. The second ICI administered was pembrolizumab/nivolumab/atezolizumab in 5/8/12 cases, and all patients received antibody drugs different from those given as the first ICI. The median number of courses was 5 (range, 1-24), and the median PFS was 3 months (95% CI, 1.0-5.0) months. In 5 of the 6 patients (24%) who achieved PFS of 6 months or longer after re-administration, the order of administration was anti-PD-1 antibody to anti-PD-L1 antibody. Conclusion: The effect of re-administration is limited, but it may be effective depending on the type of cases and the order of ICI administration. Further studies are required to verify its effectiveness.

Phase II Study of the Modified Weekly Nab-paclitaxel Regimen in Previously Treated Patients With Advanced Non-Small Cell Lung Cancer.

OBJECTIVES: We conducted a clinical phase II study to evaluate the modified weekly nanoparticle albumin-bound paclitaxel (nab-paclitaxel) regimen in pretreated patients with advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: This multicenter single-arm phase II study enrolled patients with advanced NSCLC who had previously received >1 chemotherapy regimen. Patients received nab-paclitaxel at 80 mg/m2 on days 1, 8, and 15 (21-d cycle). The primary endpoint was the investigator-assessed overall response rate (ORR). Secondary endpoints included overall survival, progression-free survival (PFS), disease control rate, and safety. The planned enrollment was 30 patients according to a Simon 2-stage minimax design. RESULTS: Thirty patients were enrolled between November 2015 and August 2017. Seventeen patients (56.7%) had received >2 regimens. The ORR was 23.3% (95% confidence interval [CI], 8.2%-38.4%), meeting the primary objective of the study. Median PFS was 5.7 months (95% CI, 3.4-9.0 mo), and median overall survival was 12.6 months (95% CI, 8.7-20.8 mo). The median number of treatment cycles was 4 (range, 1 to 20) over the entire study period, and median dose intensity was 63.6 mg/m2/wk (range, 45.7 to 100.0 mg/m2/wk). No new safety signals were reported; the most common grade ≥3 adverse events were neutropenia (56.7%), leukopenia (23.3%), and infection (10.0%). No cases of febrile neutropenia were observed. CONCLUSIONS: Nab-paclitaxel monotherapy with a dose and schedule suitable for outpatients showed high ORR, long median PFS, and acceptable toxicity for patients with previously treated NSCLC. This dosage method may be useful for selected patients.

Randomized phase II trial of uracil/tegafur and cisplatin versus pemetrexed and cisplatin with concurrent thoracic radiotherapy for locally advanced unresectable stage III non-squamous non-small cell lung cancer: NJLCG1001.

BACKGROUND: The optimal regimen for concurrent chemoradiotherapy (CCRT) of locally advanced non-squamous non-small cell lung cancer (NSCLC) was not definitive. We conducted randomized phase II study, NJLCG0601, and chemoradiotherapy with uracil/tegafur (UFT) and cisplatin achieved promising efficacy without severe toxicities. Here, we evaluated between this regimen and pemetrexed plus cisplatin in chemoradiotherapy for stage III non-squamous NSCLC. METHODS: Patients with inoperable stage III non-squamous NSCLC were randomly assigned in a 1:1 ratio to UFT 400 mg/m2 on days 1-14 and 29-42, and cisplatin 80 mg/m2 on days 8 and 36 (UP), or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on days 1, 22, and 43 (PP). Involved-field radiotherapy (IFRT) underwent from day 1 to a total dose of 66 Gy in 33 fractions. Consolidation chemotherapy after CCRT was prohibited for this study. The primary endpoint was defined as 2-year overall survival (OS). This trial was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000003948). RESULTS: From November 2010 to June 2017, 86 patients were entered from 11 institutions. Median follow-up was 54 months. Of the 85 eligible patients, the 2-year OS rate was 78.6% (95% CI, 62.8-88.3%) in UP and 85.5% (95% CI, 70.5-93.2%) in PP. Median PFS and OS was 12.3 and 64.2 months in UP, 26.2 months and not reached in PP, respectively. Grade 3/4 febrile neutropenia was more frequent in the UP group (14.0% vs. 2.0%). CONCLUSIONS: Both UP and PP with IFRT achieved the expected 2-year OS. PP engendered more favorable OS and PFS compared to UP in terms.

Plasma concentration of amrubicinol in plateau phase in patients treated for 3 days with amrubicin is correlated with hematological toxicities.

Amrubicinol (AMR-OH) is an active metabolite of amrubicin (AMR), a novel synthetic 9-aminoanthracycline derivative. The time-concentration profile of AMR-OH exhibits a continuous long plateau slope in the terminal phase. To determine the relationships between the steady-state plasma concentration of AMR-OH and treatment effects and toxicities associated with AMR therapy, we carried out a pharmacokinetic/pharmacodynamic study in patients treated with AMR alone or the combination of AMR+cisplatin (CDDP). AMR was given at a dose of 30 or 40 mg/m(2) on days 1-3. Plasma samples were collected 24 h after the third injection (day 4). Plasma concentrations of AMR-OH or total CDDP were determined by a high-performance liquid chromatography or an atomic absorption spectrometry. Percent change in neutrophil count (dANC) and the plasma concentration of AMR-OH were evaluated using a sigmoid E(max) model. A total of 35 patients were enrolled. Significant relationships were observed between AMR-OH on day 4 and the toxicity grades of leukopenia, neutropenia, and anemia (P=0.018, P=0.012, and P=0.025, respectively). Thrombocytopenia grade exhibited a tendency toward relationship with AMR-OH on day 4 (P=0.081). The plasma concentration of AMR-OH on day 4 was positively correlated with dANC in the group of all patients, as well as in patients treated with AMR alone and in patients coadministered with CDDP. In conclusion, the plasma concentration of AMR-OH on day 4 was correlated with hematological toxicities in patients treated with AMR. The assessment of plasma concentration of AMR-OH at one timepoint might enable the prediction of hematological toxicities.

A Phase II Study of Gefitinib With Concurrent Thoracic Radiotherapy in Patients With Unresectable, Stage III Non-small-cell Lung Cancer Harboring EGFR Mutations (WJOG6911L).

Locally advanced non-small-cell lung cancer (NSCLC) is curable. Standard treatment is concurrent chemoradiotherapy, but its efficacy with cytotoxic agents seems to reach a plateau. Among patients with advanced NSCLC who have epidermal growth factor receptor (EGFR) mutation, EGFR-tyrosine kinase inhibitor is the key drug. Thus, a similar strategy should be tested in patients with locally advanced NSCLC who have EGFR mutation. This single arm, phase II study aims to explore the efficacy and tolerability of gefitinib with concurrent thoracic radiotherapy in patients with unresectable stage III NSCLC harboring EGFR mutations. The primary endpoint is progression-free survival rate at 2 years. The secondary endpoints are overall response rate, progression-free survival, overall survival, and safety. A total of 27 patients will be enrolled in this trial.

Dose Escalation Study of Concurrent Chemoradiotherapy With the Use of Involved-field Conformal Radiotherapy and Accelerated Hyperfractionation in Combination With Cisplatin and Vinorelbine Chemotherapy for Stage III Non-small Cell Lung Cancer: The Final Report.

OBJECTIVES: A phase I study to determine a recommended dose of thoracic radiotherapy using accelerated hyperfractionation for unresectable non-small cell lung cancer was conducted. MATERIALS AND METHODS: We used chemotherapy of a cisplatin doublet and 2 dose levels of radiation with accelerated hyperfractionation. The radiation dose levels were: a total dose of 60 Gy in 40 fractions at level 1, and 66 Gy in 44 fractions at level 2. Eligible patients with unresectable stage III non-small cell lung cancer received cisplatin and vinorelbine. Radiation therapy started on day 2 of chemotherapy and was delivered twice daily for 5 days a week. RESULTS: Total 12 patients were enrolled, with 6 patients each at dose levels 1 and 2. Dose-limiting toxicity was noted in 2 patients at level 1; one patient had grade 3 febrile neutropenia and the other patient had grade 3 esophagitis. No dose-limiting toxicity was noted in the 6 patients at level 2. Grade 3 to 4 leukopenia, neutropenia, and anemia were noted in 11 (92%), 9 (75%), and 8 (67%) of the total 12 patients, respectively. Grade 3 anorexia and infection were noted in 2 patients (17%) at each level. Grade 3 nausea, fatigue, esophagitis, and febrile neutropenia were noted in 1 patient (8%) at each level. The response rate in the total 12 patients was 83.3%. The median progression-free survival time and the median overall survival time were 10.7 and 24.2 months, respectively. CONCLUSIONS: Sixty-six gray in 44 fractions is the recommended dose for the following phase II study.