Immunotherapy can become a crucial therapeutic option to improve the prognosis of patients with non-small-cell lung cancer (NSCLC). Here, we evaluated the impact of programmed cell death ligand-1 ...(PD-L1) expression in surgically resected NSCLCs.
We estimated PD-L1 expression in 229 consecutive NSCLC specimens using rabbit polyclonal antibodies to human PD-L1 in a SP263 immunohistochemical assay and evaluated PD-L1 expression for potential associations with clinicopathological parameters and survival time.
PD-L1 expression was significantly higher in tumors from men or current smokers. Squamous cell carcinoma histology was independently associated with high PD-L1 expression according to multivariate analysis (p = 0.015). The 5-year survival rate of patients was 70%, and the difference in the 5-year survival rate according to PD-L1 expression was not statistically significant (high expression group 67% vs. low expression group 68%); however, the squamous cell carcinoma group exhibited significantly lower 5-year survival rates as compared to the non-squamous cell carcinoma group (53 and 71%, respectively; p = 0.026).
Here, we revealed high PD-L1 expression and poor prognosis observed in patients with surgically resected squamous NSCLC as compared with non-squamous NSCLC. Our results support the identification of patient subsets that most likely respond to anti-PD-1 therapy as the first step in precision medicine.
Gefitinib treatment has come to be recognized as the standard therapy for patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. However, ...resistance to gefitinib has been observed in certain subpopulations of these patients. The purpose of this study was to evaluate the impact of smoking status on the efficacy of gefitinib in patients with NSCLC harboring EGFR mutations.
The records of NSCLC patients harboring EGFR mutations who were treated with gefitinib at Kitasato University Hospital were retrospectively reviewed, and the treatment outcomes were evaluated.
In 153 patients with NSCLC harboring EGFR mutations, the overall response rate and progression-free survival (PFS) were 66.7% and 9.0 months, respectively. PFS differed significantly among the current smokers and never-smokers/former light smokers (10.7 vs. 5.4 months, p=0.0002), and the response rate was significantly higher in the never-smokers/former light smokers than in the current smokers (72.3 vs. 55.8%, p=0.04). Multivariate analysis identified smoking status as an independent predictor of PFS.
The clinical data obtained in this study provide a valuable rationale for considering smoking status as a predictor of the efficacy of gefitinib in patients with NSCLC harboring activating EGFR mutations.
Background/Aim: Epigenetic abnormalities in microRNAs (miRNAs) have not been analyzed in samples other than pancreaticobiliary tissues in patients with pancreaticobiliary cancer (PBC). To identify ...miRNAs specific for PBC, the present study analyzed the methylation of tumor-suppressive miRNAs in bile from patients with pancreaticobiliary diseases. Materials and Methods: Bile was collected endoscopically or percutaneously from 52 patients with pancreatic cancer, 26 with biliary tract cancer, and 20 with benign pancreaticobiliary diseases. Sequences encoding 16 tumor-suppressive miRNAs were amplified by polymerase chain reaction and sequenced, and their methylation rates were determined. Results: The methylation rates of miR-1247 and miR-200a were significantly higher in patients with pancreatic cancer, and biliary tract cancer than in those with benign diseases, and the methylation rate of miR-200b was significantly higher in patients with pancreatic cancer than in those with benign diseases. Conclusion: Methylation of miR-1247, miR-200a, and miR-200b in bile may be useful for distinguishing PBC from benign diseases.
Background: The prognosis of peritoneal carcinomatosis in patients with lung cancer is poor. However, some cases of peritoneal carcinomatosis from lung cancer harboring specific gene alterations have ...responded to molecular targeted drugs. B-Raf protooncogene (BRAF) mutations occur in about 2-4% of NSCLCs, with about half of these cases having the BRAF V600E mutation. Concomitant inhibition of BRAF with dabrafenib and inhibition of the downstream mitogen-activated protein kinase with trametinib showed efficacy in NSCLC patients with the BRAF V600E mutation. Herein, we report a patient with peritoneal carcinomatosis from lung cancer with the BRAF V600E mutation who responded to dabrafenib plus trametinib. Case Presentation: A 67-year-old Japanese male never-smoker was diagnosed with stage IA3 lung adenocarcinoma. He underwent thoracoscopic left lower lobectomy but developed recurrence of the cancer with peritoneal carcinomatosis 33 months after the operation. An Oncomine Dx target test of the resected specimen was positive for the BRAF V600E mutation. He was started on dabrafenib 150 mg twice per day and trametinib 2 mg once per day. He had a good clinical response to dabrafenib/trametinib therapy with resolution of abdominal distention. He continued dabrafenib/trametinib treatment without disease progression for 7 months, with no severe adverse effects. Conclusion: This case highlights the importance of assessing genetic alterations in lung cancer patients with peritoneal carcinomatosis and treating them with appropriate molecular targeted drugs. Keywords: BRAF V600E mutation, dabrafenib, lung cancer, peritoneal carcinomatosis, trametinib
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The detection of circulating tumor cells (CTCs) in peripheral blood is currently an important field of study. Detection of CTCs by the OBP-401 assay (TelomeScan®) has previously been reported to be ...useful in the diagnosis, prognosis and evaluation of therapeutic efficacy in breast and gastric cancer. The aim of the present study was to evaluate the OBP-401 assay as a novel method of detecting CTCs of small cell lung cancer (SCLC) patients and to evaluate whether CTC count is associated with prognosis. Prospectively, 30 consecutively diagnosed SCLC patients who had commenced chemotherapy or chemoradiotherapy were enrolled as subjects of the current study. Peripheral blood specimens were collected from the SCLC patients prior to and following the initiation of treatment and the viable CTCs were detected in the specimens following incubation with a telomerase-specific, replication-selective, oncolytic adenoviral agent, which was carrying the green fluorescent protein gene. CTCs were detected in 29 patients (96%). The group of 21 patients with a CTC count of <2 cells/7.5 ml prior to treatment (baseline) had a significantly longer median survival time than the group of eight patients with a CTC count of ≥2 cells/7.5 ml prior to treatment (14.8 and 3.9 months, respectively; P=0.007). The results of a multivariate analysis showed that the baseline CTC count was an independent prognostic factor for survival time (hazard ratio, 3.91; P=0.026). Among the patients that achieved a partial response to treatment, patients who had a CTC count of <2 cells/7.5 ml following two cycles of chemotherapy tended to have a longer median progression-free survival compared with patients who had a CTC count of ≥2 cell/7.5 ml (8.3 and 3.8 months, respectively; P=0.07). Therefore, CTCs may be detected via OBP-401 assay in SCLC patients and the CTC count prior to treatment appears to be a strong prognostic factor.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract only
e20677
Background: Amrubicin (AMR) is a totally synthetic 9-aminoanthracycline and clinically active against non-small cell lung cancer (NSCLC). We found that the combination of AMR and ...erlotinib (ERL) had significant synergistic effect on NSCLC cell line with wild-type EGFR in vitro. We conducted a phase I study of AMR and ERL combination therapy in previously treated patients with advanced NSCLC, and have already reported the safety and the effectiveness. Furthermore we observed a high response rate of 33% in EGFR wild-type NSCLC. Methods: We conducted a multi-center, single-arm phase II trial to evaluate the efficacy of AMR and ERL combination therapy in patients with previously treated, advanced NSCLC, PS 0-1, and aged < 75 years, EGFR wild type. Patients were treated at 3weeks intervals with AMR(35mg/m
2
, intravenous injection on days 1-3) plus ERL(100mg/day, once daily on days 1-21). The primary endpoint is progression free survival (PFS). Secondary endpoints are response rate (RR), disease control rate (DCR), time to treatment failure (TTF), overall survival (OS), and toxicity. The concentration of trough ERL was measured after first cycle of treatment as additional investigation. Results: From June 2013 to July 2016, 25 patients were enrolled in this trial. The PFS according to the central test was 3.6 months (95%CI 2.1 - 5.1). The RR and the DCR were 24.0% and 64.0%, respectively. We observed grade 3 or 4 hematological toxicities such as leukopenia (68%), neutropenia (72%), anemia (8%) and febrile neutropenia (12%). The grade 3 or 4 non-hematological toxicities were anorexia (12%), oral mucositis (12%) and rash (8%). We had no treatment related death in this study. Conclusions: The PFS of AMR and ERL combination therapy in this study was superior to that of AMR monotherapy in historical setting. This combination therapy might be an option for previously treated NSCLC patients without a driver oncogene mutation. Clinical trial information: UMIN 000010582. Clinical trial information: UMIN 000010582.
Pemetrexed monotherapy has come to be recognized as the standard of care for second-line therapy of non-squamous non-small cell lung cancer (NSCLC). Thymidylate synthase (TS) expression is recognized ...as a potential predictor of the response to pemetrexed-based chemotherapy in patients with advanced NSCLC. The purpose of this study was to identify useful predictors of the response to pemetrexed other than TS expression.
The records of non-squamous NSCLC patients without driver mutations who received pemetrexed monotherapy as a second or later line of chemotherapy at Kitasato University Hospital between March 2009 and October 2015 were retrospectively reviewed, and the treatment outcomes were evaluated.
In the 116 patients with non-squamous NSCLC, the overall response rate and progression-free survival (PFS) were 10.3% and 2.1 months, respectively. The disease control rate and PFS differed significantly among current smokers and never-smokers/former light smokers (44.9 vs. 65.8%, and 1.8 vs. 4.0 months, respectively). Furthermore, multivariate analysis identified Eastern Cooperative Oncology Group Performance Status and smoking status as independent predictors of the PFS.
The clinical data obtained in this study may provide a valuable basis for the use of smoking status as a predictor of pemetrexed monotherapy in wild-type NSCLC patients.
Currently, only a few treatment options exist for performance status (PS) 2 patients with advanced non-small cell lung cancer (NSCLC), whereas the carboplatin/nab-paclitaxel (CBDCA/nab-PTX) regimen ...is attracting attention as a standard of care for PS 0-1 patients because of its wide suitability and modest risk of peripheral neuropathy. However, the treatment dose and schedule should be optimized for PS 2 patients. Therefore, we planned a single-arm phase II study to characterize the efficacy and tolerability of our modified CBDCA/nab-PTX regimen for untreated PS 2 patients with advanced NSCLC.
Enrolled patients were treated with CBDCA (area under the curve 5 on day 1) plus nab-PTX (70 mg/m
on days 1, 8, and 15) every 4 weeks for up to six cycles. The primary endpoint was the progression-free survival (PFS) rate at 6 months. As exploratory analyses, the reasons for PS 2 (disease burden versus comorbidities/indeterminant) and the Charlson Comorbidity Index (CCI) were evaluated as efficacy indicators.
This study was terminated early because of slow accrual. Seventeen patients median age, 68 years (range, 50-73 years) received a median of three cycles. The 6-month PFS rate, median PFS, and median overall survival were 20.8% 95% confidence interval (CI): 0-41.6, 3.0 months (95% CI: 1.7-4.3), and 9.5 months (95% CI: 5.0-14.0), respectively. Exploratory analyses suggested better overall survival in patients whose PS was not attributable to the disease burden (median, 9.5
7.2 months) or whose CCI was ≤3 (median, 15.5
7.2 months). Grade 3-4 adverse events occurred in 12 (71%) patients, and grade 5 pleural infection occurred in one (6%) patient. Meanwhile, only one (6%) patient each experienced grade 1 peripheral neuropathy and grade 2 interstitial pneumonitis.
No conclusion could be drawn from this study because of its early termination. However, our modified CBDCA/nab-PTX regimen might be useful for PS 2 patients who hesitate to use regimens other than nab-PTX, and particularly patients concerned about peripheral neuropathy or interstitial pneumonitis. The potential role of PS 2 and CCI as efficacy predictors for this regimen should be further examined.
Summary
Background
Previous study indicated that an optional anti-cancer drug for the treatment of small-cell lung cancer (SCLC) is amrubicin. However, no prospective studies have evaluated amrubicin ...in chemo-naive elderly or poor-risk patients with SCLC. Therefore, this study aimed to evaluate the efficacy of amrubicin as first-line chemotherapy for elderly or poor-risk patients with extensive-disease SCLC (ES-SCLC).
Methods
Patients with chemotherapy-naive ES-SCLC received multiple cycles of 40 mg/m
2
amrubicin for 3 consecutive days every 21 days. The primary endpoint was the overall response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety.
Results
Between March 2011 and August 2015, 36 patients were enrolled in this study. Each patient received a median of four treatment cycles (range, 1–6 cycles). ORR was 52.8% 95% confidence interval (CI), 37–69%. The median PFS and OS periods were 5.0 months (95% CI, 3.4–6.6 months) and 9.4 months (95% CI, 5.2–13.6 months), respectively. Neutropenia was the most common grade 3 or 4 adverse event (69.4%), with febrile neutropenia developing in 13.9% of patients. No treatment-related death occurred. At the time of starting second-line chemotherapy, 19 of 22 patients (86%) had significantly improved or maintained their performance status (PS) relative to their PS at the time of starting amrubicin monotherapy as first-line chemotherapy (
P
= 0.027).
Conclusions
The results of the present study suggest that amrubicin could be considered as a viable treatment option for chemotherapy-naive elderly or poor-risk patients with ES-SCLC (Clinical trial registration number: UMIN000011055
www.clinicaltrials.gov
).
Abstract
Background: Standard second-line chemotherapy against advanced non-small-cell lung cancer (NSCLC) is a single agent such as docetaxel, pemetrexed, or erlotinib (Erl). We recently reported ...that the combination of amrubicin (AMR) and Erl was clinically safe and effective for previously treated NSCLC patients. The purpose of this research is to confirm the experimental effectiveness of the combination and to investigate mechanism of the action.
Methods: We perform to evaluate the NSCLC cell lines proliferation inhibition by using XTT assay and to make two-dimension isobolograms for assessment of the combination effect. Flowcytemetry analysis (FACS) and Western blot analysis (WB) is also done in vitro. In vivo growth inhibition assay using subcutaneous model on SCID mice is performed. In addition, we measure intracellular concentration of amrubicinol(AMR-OH) which is converted as active metabolite from AMR in both cells treated with AMR alone and the combination.
Results: The combination of AMR and Erl had significant synergistic effect on EGFR wild type NSCLC cell line A549, while additive effect on EGFR mutant cell line PC-9. Sub G0-G1 population on FACS was significantly increased in A549 cells treated with combination. The combination activated apoptosis related proteins in WB. The strong growth inhibition of subcutaneous tumors on SCID mice was observed in the combination cohort. Intracellular concentration of AMR-OH was significantly increased in the combination than in AMR monotherapy.
Conclusion: The combination of AMR and Erl is synergistically induced apoptosis and growth inhibition on A549 cells via increasing intracellular concentration of AMR-OH. This combination may be a promising therapeutic option against advanced NSCLC with wild type EGFR.
Citation Format: Sakiko Otani, Jiichiro Sasaki, Kuniko Masuda, Kazuya Okamoto, Akiko Namubu, Toshihide Matsumoto, Masumi Tanaka, Mikiko Ishihara, Yoshiro Nakahara, Tomoya Fukui, Satoshi Igawa, Noriyuki Masuda. Synergistic anti-tumor effect of the combination of amrubicin and erlotinib in non-small cell lung cancer with wild type EGFR. abstract. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2284.
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