Hidehito Horinouchi

Immunohistochemical status of PD-L1 in thymoma and thymic carcinoma

PURPOSE The immune checkpoint ligand programmed cell death 1 ligand 1 (PD-L1) is expressed in various tumors and is associated with the response to anti programmed cell death 1 (PD-1)/PD-L1 drugs. We evaluated PD-L1 expression in thymomas and thymic carcinomas to determine whether PD-L1 represents a therapeutic target in unresectable thymomas or thymic carcinomas that could be amenable to antibody-based immunotherapy. METHOD A tissue microarray (TMA) comprised of 101 thymomas and 38 thymic carcinomas samples was evaluated. After validation of the rabbit monoclonal PD-L1 antibody (clone E1L3N), the TMA was stained and the tumor PD-L1 expression score was calculated using a semiquantitive method (by multiplying the intensity [0-3] by the staining area [0-100%]). RESULTS Seventy percent of thymic carcinoma (type C) and 23% of thymoma (types A, AB, and B) samples stained positive for PD-L1 (P<.001). A WHO classification (type C vs types A, AB, and B) was significantly associated with positive PD-L1 expression (P=0.006), though multivariate analysis did not show PD-L1 positive was a significant negative factor of overall survival (hazard ratio=0.99, 95% confidence interval=0.35-2.73; P=0.987). CONCLUSIONS To the best of our knowledge, this is the largest-scale study to evaluate PD-L1 expression in thymomas and thymic carcinomas. The data suggest that the anti PD-1/PD-L1 drug could be of potential use in immunotherapy for unresectable or relapsed thymomas and thymic carcinomas.

Safety and efficacy of nivolumab and standard chemotherapy drug combination in patients with advanced non-small-cell lung cancer: a four arms phase Ib study

In this phase Ib study, four combination therapies of nivolumab 10 mg/kg and standard chemotherapy (cisplatin/gemcitabine, cisplatin/pemetrexed, carboplatin/paclitaxel/bevacizumab, or docetaxel) showed acceptable toxicity profiles in patients with advanced non-small-cell lung cancer. Furthermore, these combination therapies presented encouraging antitumor activities.

Combination Chemotherapy with Carboplatin and Paclitaxel for Advanced Thymic Cancer

OBJECTIVE Thymic carcinoma is a rare cancer of the thymus, different from thymoma in respect of its malignant nature, and no standard chemotherapy for this cancer has been established yet. METHODS We conducted a retrospective review of the efficacy of combination chemotherapy with carboplatin (an area under the curve of 6) and paclitaxel (200 mg/m(2)) in 16 patients with histologically or cytologically proven thymic carcinoma, Masaoka Stage IVa/IVb or post-operative recurrent disease. RESULTS There were 13 males and 3 females, with a median (range) age of 56 (38-73) years. Squamous cell carcinoma was the most common (n= 12), followed by undifferentiated carcinoma (n= 2) and others (n= 2). Four, nine and three patients had Stage IVa, IVb and post-operative recurrent disease, respectively. Two and four patients showed complete and partial responses, respectively, representing a response rate (95% confidence interval) of 37.5 (15.2-64.6)%. The median (95% confidence interval) progression-free and overall survivals in the 16 patients were 8.6 (1.8-15.3) and 49.4 (30.1-68.8) months, respectively. CONCLUSIONS Combination therapy with carboplatin and paclitaxel yielded an objective response in about one-third of the patients with advanced thymic carcinoma.

Long‐term results of concurrent chemoradiotherapy using cisplatin and vinorelbine for stage III non‐small‐cell lung cancer

Concurrent chemoradiotherapy is the standard treatment for unresectable stage III non‐small cell lung cancer (NSCLC). The long‐term feasibility and efficacy of vinorelbine and cisplatin with concurrent thoracic radiotherapy were investigated. Eighteen patients received cisplatin (80 mg/m2) on day 1 and vinorelbine (20 mg/m2 in level 1, and 25 mg/m2 in level 2) on days 1 and 8 every 4 weeks for four cycles in a phase I trial. Ninety‐three patients received the same chemotherapy regimen except for the fixed vinorelbine (20 mg/m2) dosage and consolidation therapy with docetaxel (60 mg/m2, every 3 weeks). The thoracic radiotherapy consisted of a single dose of 2 Gy once daily to a total dose of 60 Gy. A total of 111 patients were analyzed in the present study: male/female, 91/20; median age, 60 years; stage IIIA/IIIB, 50/61; and squamous/non‐squamous histology, 26/85. The 3‐, 5‐, and 7‐year overall survival rates (95% CI) were 43.2% (33.9–52.2), 25.2% (17.6–33.5), and 23.2% (15.8–31.4), respectively. The median progression‐free survival and median survival time (95% CI) were 13.5 (10.1–16.7) months and 30.0 (24.3–38.8) months, respectively. Four patients (4%) experienced Grade 5 pulmonary toxicities from 4.4 to 9.4 months after the start of treatment. In conclusion, approximately 15% of patients with unresectable stage III NSCLC could be cured with chemoradiotherapy without severe late toxicities after 10 months of follow‐up. Although based on the data from highly selected population participated in phase I and phase II trial, this analysis would strengthen and confirm the previous reports concerning concurrent chemoradiotherapy with third generation cytotoxic agents. (Cancer Sci 2013; 104: 93–97)

Risk Factors for Treatment-Related Death Associated with Chemotherapy and Thoracic Radiotherapy for Lung Cancer

Introduction: The aim of the study is to evaluate the current status of treatment-related death (TRD) in lung cancer patients. Methods: We retrospectively analyzed the incidence and risk factors of TRD in lung cancer patients who received chemotherapy and/or thoracic radiotherapy using logistic regression analyses. Results: Between January 2001 and December 2005, 1225 (222 small cell and 1003 non-small cell lung cancers) patients received chemotherapy and/or thoracic radiotherapy as the initial treatment. Of these, 43 patients receiving chemotherapy followed by thoracic radiotherapy were included into both the chemotherapy-alone and radiotherapy-alone groups. There were a total of 23 (1.9%) TRDs. Chemotherapy-related deaths occurred in 7 of 927 (0.8%) patients, including 4 from drug-induced lung injury, 2 from pneumonia, and 1 from unknown cause. Concurrent chemoradiotherapy-related deaths occurred in 12 of 245 (4.9%) patients, including 11 from radiation pneumonitis and 1 from pneumonia. Thoracic radiotherapy-related deaths occurred in 4 of 96 (4.2%) patients. The incidence of chemotherapy-related death was correlated with poor performance status (odds ratio [OR]: 11.4, 95% confidence interval [CI]: 3.53–37.1), the presence of hypoxia (OR: 19.3, CI: 6.06–61.7), hyponatremia (OR: 45.5, CI: 13.4–154), and treatment with epidermal growth factor receptor-tyrosine kinase inhibitors (OR: 8.56, CI: 2.48–29.5), whereas the incidence of concurrent chemoradiotherapy-related death was correlated with pulmonary fibrosis (OR: 22.2, CI: 5.61–87.8). Radiotherapy results were not analyzed because there were too few patients. Conclusions: TRD occurred in 1.9% of the patients as a result of treatment-related lung injury in the majority of the cases.

Short Hydration in Chemotherapy Containing Cisplatin (≥75 mg/m2) for Patients with Lung Cancer: A Prospective Study

OBJECTIVE We previously reported that 22% of lung cancer patients experienced a Grade 2 or 3 elevation in creatinine after chemotherapy containing cisplatin. We conducted a Phase II trial to evaluate the safety and efficacy of short hydration. METHODS The major eligibility criteria included patients with lung cancer for whom a ≥75 mg/m(2) cisplatin-based regimen was indicated and adequate organ function. Cisplatin was administered with pre- and post-hydration containing 10 mEq of potassium chloride in 500 ml of fluid over a 60-min period. Immediately before the administration of cisplatin, mannitol (20%, 200 ml) was administered as forced diuresis over 30 min. And magnesium sulfate (8 mEq) was added to pre-hydration. RESULTS Forty-four patients were enrolled between April and December 2011. The patients included 29 men and 15 women with a median (range) age of 64 (42-74) years. Twenty patients received cisplatin and pemetrexed as their most frequent regimen and 38 patients received three to four cycles of chemotherapy. The median (range) duration and volume of the chemotherapies were 4.0 (3.3-6.8) h and 1600 (1550-2050) ml, respectively. Of the 44 patients, 43 (97.8%) completed the cisplatin-based chemotherapy without Grade 2 or higher renal dysfunction. The only patient who had Grade 2 elevation in creatinine (maximum value 1.7 mg/dl) had prompt improvement in creatinine levels and completed four cycles of chemotherapy. CONCLUSIONS The short hydration is safe without severe renal toxicities in regimens containing cisplatin (≥75 mg/m(2)) for patients with lung cancer.

Picoliter-Droplet Digital Polymerase Chain Reaction-Based Analysis of Cell-Free Plasma DNA to Assess EGFR Mutations in Lung Adenocarcinoma That Confer Resistance to Tyrosine-Kinase Inhibitors

PURPOSE The objective of this study was to evaluate the utility of analyzing cell-free plasma DNA (cfDNA) by picoliter-droplet digital polymerase chain reaction (ddPCR) to detect EGFR mutations that confer resistance to tyrosine-kinase inhibitors (TKIs) used for treatment of lung adenocarcinoma (LADC). EXPERIMENTAL DESIGN Thirty-five LADC patients who received epidermal growth factor receptor (EGFR)-TKI therapy, including ten who received tumor rebiopsy after development of resistance, were subjected to picoliter-ddPCR-cfDNA analysis to determine the fraction of cfDNA with TKI-sensitive (L858R and inflame exon 19 deletions) and -resistant (i.e., T790M) mutations, as well as their concordance with mutation status in rebiopsied tumor tissues. RESULTS cfDNA samples from 15 (94%) of 16 patients who acquired resistance were positive for TKI-sensitive mutations. Also, 7 (44%) were positive for the T790M mutation, with fractions of T790M (+) cfDNA ranging from 7.4% to 97%. T790M positivity in cfDNA was consistent in eight of ten patients for whom rebiopsied tumor tissues were analyzed, whereas the remaining cases were negative in cfDNA and positive in rebiopsied tumors. Prior to EGFR-TKI therapy, cfDNAs from 9 (38%) and 0 of 24 patients were positive for TKI-sensitive and T790M mutations, respectively. Next-generation sequencing of cfDNA from one patient who exhibited innate resistance to TKI despite a high fraction of TKI-sensitive mutations and the absence of the T790M mutation in his cfDNA revealed the presence of the L747P mutation, a known driver of TKI resistance. CONCLUSION Picoliter-ddPCR examination of cfDNA, supported by next-generation sequencing analysis, enables noninvasive assessment of EGFR mutations that confer resistance to TKIs. IMPLICATIONS FOR PRACTICE Noninvasive monitoring of the predominance of tumors harboring the secondary T790M mutation in the activating mutation in EGFR gene is necessary for precise and effective treatment of lung adenocarcinoma. Because cells harboring the T790M mutation are resistant to epidermal growth factor receptor-tyrosine-kinase inhibitors (TKIs), the predominance of tumor cells harboring the T790M mutations influences the choice of whether to use conventional or next-generation TKIs. Digital polymerase chain reaction-based examination of cfDNA is a promising method; however, its feasibility, including its consistency with examination of rebiopsied tumor tissue, has not been fully proven. Here, picoliter-droplet digital polymerase chain reaction technology is presented as a candidate method for testing cfDNA and assessing the predominance of T790M-mutant tumors.

Cytotoxic chemotherapy may overcome the development of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) therapy

OBJECTIVES In the first-line treatment of non-small cell lung cancer (NSCLC) harboring EGFR mutations, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) has been shown to yield a longer progression-free survival (PFS) rate than platinum-doublet chemotherapy; however, after the initial response, most patients develop resistance to the EGFR-TKIs. We hypothesized that the insertion of platinum-doublet chemotherapy after the initial response to EGFR-TKIs might prevent the emergence of acquired resistance to EGFR-TKIs and prolong survival. METHODS We carried out a phase II study of the following first-line treatment for patients with advanced NSCLC harboring EGFR mutations. Gefitinib (250 mg) was administered on days 1-56. Then, after a two-week drug-free period, three cycles of cisplatin (80 mg/m2) and docetaxel (60 mg/m2) were administered on days 71, 92, and 113. Thereafter, gefitinib was re-started on day 134 and continued until disease progression. The primary endpoint was the two-year PFS rate. RESULTS A total of 34 patients were enrolled. Of the 33 eligible patients and 12 achieved a two-year PFS. Thus, this therapeutic strategy met the criterion for usefulness. The 1-, 2-, 3-, and 5-year PFS rates were 67.0%, 40.2%, 36.9%, and 22.0%, respectively, and the median PFS was 19.5 months. The 1-, 2-, 3- and 5-year survival rates were 90.6%, 71.9%, 64.8%, and 36.5% respectively, and the median survival time was 48.0 months. CONCLUSION These results indicate that the insertion of platinum-doublet chemotherapy might prevent the development of acquired resistance to EGFR-TKIs in patients with advanced NSCLC harboring EGFR mutations.

Phase I study of the HER3-targeted antibody patritumab (U3-1287) combined with erlotinib in Japanese patients with non-small cell lung cancer

OBJECTIVES Human epidermal growth factor receptor 3 (HER3) is a key dimerization partner for HER family members and is associated with resistance to other HER family receptor-targeted therapeutics. This study evaluated the safety, tolerability, pharmacokinetics and efficacy of patritumab (U3-1287), a fully human anti-HER3 monoclonal antibody, in combination with erlotinib, an epidermal growth factor receptor-tyrosine kinase inhibitor in patients with previously treated advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS This study enrolled patients with stage IIIB/IV NSCLC with Eastern Cooperative Oncology Group performance status 0-1, life expectancy >3 months and who had progressed after at least one prior course of chemotherapy (excluding erlotinib). This open-label study included two parts: dose escalation (Part 1) and dose expansion (Part 2). In Part 1, patients received intravenous patritumab 9 or 18 mg/kg every 3 weeks in addition to per-oral erlotinib 150 mg/day daily. In Part 2, patients received the recommended dose of patritumab as determined in Part 1. Adverse event rates, pharmacokinetics and tumor responses were determined. RESULTS Twenty-four Japanese patients received patritumab at 9 mg/kg (n=3) or 18 mg/kg (n=21), and erlotinib. No dose-limiting toxicities were reported, indicating the maximum-tolerated dose was not reached. The most frequent adverse events were gastrointestinal or skin toxicities, which were generally mild and manageable. Patritumab pharmacokinetics were similar to those reported in previous studies. The median progression-free survival (95% confidence interval) was 44.0 (22.0-133.0) days for the EGFR wild-type group (n=9) and 107.0 (74.0-224.0) days for the EGFR-activating mutation group (n=13). Evaluation of biomarkers by immunohistochemical analysis did not indicate a relationship between efficacy and HER3 expression in tumor tissues. CONCLUSION Patritumab in combination with erlotinib was well tolerated and the efficacy of the combination was encouraging, especially in patients where prior gefitinib treatment failed.

Epidermal Growth Factor Receptor Mutation Is Associated With Longer Local Control After Definitive Chemoradiotherapy in Patients With Stage III Nonsquamous Non–Small-Cell Lung Cancer

PURPOSE To determine the frequency and clinical significance of epidermal growth factor receptor (EGFR) mutations in patients with potentially curable stage III non-small-cell lung cancer (NSCLC) who are eligible for definitive chemoradiotherapy (CRT). PATIENTS AND METHODS Between January 2001 and December 2010, we analyzed the EGFR mutational status in consecutive NSCLC patients who were treated by CRT. The response rate, relapse-free survival, 2-year relapse-free rate, initial relapse sites, and overall survival of the patients were investigated. RESULTS A total of 528 patients received CRT at our hospital during the study period. Of these, 274 were diagnosed as having nonsquamous NSCLC. Sufficient specimens for mutational analyses could be obtained from 198 of these patients. The proportion of patients with EGFR activating mutations was 17%. In addition to the well-known characteristics of patients carrying EGFR mutations (female, adenocarcinoma, and never/light smoker), the proportion of cases with smaller primary lesions (T1/2) was found to be higher in patients with EGFR mutations than in those with wild-type EGFR. Patients with EGFR mutations showed similar response rate, relapse-free survival, and 2-year relapse-free rates as compared to patients with wild-type EGFR. Local relapses as the site of initial relapse occurred significantly less frequently in patients with EGFR mutation (4% vs 21%; P=.045). Patients with EGFR mutations showed longer local control (adjusted hazard ratio 0.49; P=.043). After disease progression, a majority of the patients with EGFR mutations received EGFR tyrosine kinase inhibitors (62%), and these patients showed longer postprogression survival than those with wild-type EGFR. CONCLUSIONS Our study is the first to show radiosensitive biology of EGFR-mutated tumors in definitive CRT with curative intent. This finding could serve as a credible baseline estimate of EGFR-mutated population in stage III nonsquamous NSCLC.