Search

Established treatment options for rare cancers are limited by the small number of patients. The current comprehensive genomic profiling (CGP) testing might not fully exploit opportunities for precision oncology in patients with rare cancers. Therefore, we aimed to explore the factors associated with CGP testing utility in rare cancers and identify barriers to implementing precision oncology. Patients who underwent CGP testing at our institution between September 2019 and June 2021 were enrolled in this retrospective study. Based on their results, the patients received molecularly targeted drugs or immune checkpoint inhibitors. Univariate and multivariate analyses evaluated the association between patient characteristics and the proportion of patients receiving molecularly targeted drugs. Overall, 790 patients underwent CGP testing. Among them, 333 patients with rare cancers were identified, of whom 278 (83.5%) had actionable genomic alterations, 127 (38.1%) had druggable genomic alterations, and 25 (7.5%) received genomically matched therapy. The proportion of patients receiving molecularly targeted drugs was significantly higher among those with treatment options with evidence levels A-D (8.7%) than those without treatment options with evidence levels A-D (2.9%). A potential barrier to CGP testing utility in rare cancers is the limited number of molecularly targeted drugs with clinical evidence. We propose that CGP testing be performed in patients with rare cancers who have treatment options with evidence levels A-D to maximize CGP testing utility in real-world practice., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The phase 2, single-arm, multicenter, open-label J-ALTA study evaluated the efficacy and safety of brigatinib in Japanese patients with advanced ALK+ non-small-cell lung cancer (NSCLC). One expansion cohort of J-ALTA enrolled patients previously treated with ALK tyrosine kinase inhibitors (TKIs); the main cohort included patients with prior alectinib ± crizotinib. The second expansion cohort enrolled patients with TKI-naive ALK+ NSCLC. All patients received brigatinib 180 mg once daily (7-day lead-in at 90 mg daily). Among 47 patients in the main cohort, 5 (11%) remained on brigatinib at the study end (median follow-up: 23 months). In this cohort, the independent review committee (IRC)-assessed objective response rate (ORR) was 34% (95% CI, 21%-49%); median duration of response was 14.8 months (95% CI, 5.5-19.4); median IRC-assessed progression-free survival (PFS) was 7.3 months (95% CI, 3.7-12.9). Among 32 patients in the TKI-naive cohort, 25 (78%) remained on brigatinib (median follow-up: 22 months); 2-year IRC-assessed PFS was 73% (90% CI, 55%-85%); IRC-assessed ORR was 97% (95% CI, 84%-100%); the median duration of response was not reached (95% CI, 19.4-not reached); 2-year duration of response was 70%. Grade ≥3 adverse events occurred in 68% and 91% of TKI-pretreated and TKI-naive patients, respectively. Exploratory analyses of baseline circulating tumor DNA in ALK TKI-pretreated NSCLC showed associations between poor PFS and EML4-ALK fusion variant 3 and TP53. Brigatinib is an important treatment option for Japanese patients with ALK+ NSCLC, including patients previously treated with alectinib., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The role of previous thoracic radiation therapy as a risk factor of immune-related pneumonitis is unclear. Furthermore, some patients develop radiation recall pneumonitis, which is characterized by a radiation pneumonitis-like imaging pattern with consolidation progressing within a previous radiation field. In this multicenter retrospective study, we analyzed the relationship of previous thoracic radiation therapy with immune-related pneumonitis and the characteristics of radiation recall pneumonitis. The medical records of patients with non-small-cell lung cancer who had received nivolumab between December 2015 and March 2017 at five institutions were retrospectively reviewed. Incidence, imaging patterns, clinical course, and risk factors of immune-related pneumonitis and radiation recall pneumonitis were evaluated. A total of 669 patients were evaluated, and the incidences of all-grade and grade 3 or higher immune-related pneumonitis were 8.8% and 2.6%, respectively. The incidences of immune-related pneumonitis were 13.2% (34/257) and 6.1% (25/412) in patients with and those without previous thoracic radiation therapy, respectively. A history of previous thoracic radiation therapy was associated with immune-related pneumonitis (odds ratio, 2.11; 95% confidence interval, 1.21-3.69 in multivariate analysis). Among the patients with previous thoracic radiation therapy, 6.2% (16/257) showed radiation recall pattern. This study found an increased risk of nivolumab-induced immune-related pneumonitis associated with a history of thoracic radiation therapy. Radiation recall pattern was one of the major patterns of immune-related pneumonitis among the patients with previous thoracic radiation therapy. Incidence, risk factors, and clinical outcome of radiation recall pneumonitis were elucidated., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The global phase 3 IMpower010 study evaluated adjuvant atezolizumab versus best supportive care (BSC) following platinum-based chemotherapy in patients with resected stage IB-IIIA non-small cell lung cancer (NSCLC). Here, we report a subgroup analysis in patients enrolled in Japan. Eligible patients had complete resection of histologically or cytologically confirmed stage IB (tumors ≥4 cm)-IIIA NSCLC. Upon completing 1-4 cycles of adjuvant cisplatin-based chemotherapy, patients were randomized 1:1 to receive atezolizumab (fixed dose of 1200 mg every 21 days; 16 cycles or 1 year) or BSC. The primary endpoint of the global IMpower010 study was investigator-assessed disease-free survival, tested hierarchically first in patients with stage II-IIIA NSCLC whose tumors expressed programmed death-ligand 1 (PD-L1) on ≥1% of tumor cells, then in all randomized patients with stage II-IIIA NSCLC, and finally in the intention-to-treat (ITT) population (stage IB-IIIA NSCLC). Safety was evaluated in all patients who received atezolizumab or BSC. The study comprised 149 enrolled patients in three populations: ITT (n = 117; atezolizumab, n = 59; BSC, n = 58), all-randomized stage II-IIIA (n = 113; atezolizumab, n = 56; BSC, n = 57), and PD-L1 tumor cells ≥1% stage II-IIIA (n = 74; atezolizumab, n = 41; BSC, n = 33). At the data cutoff date (January 21, 2021), a trend toward disease-free survival improvement with atezolizumab vs BSC was observed in the PD-L1 tumor cells ≥1% stage II-IIIA (unstratified hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.25-1.08), all-randomized stage II-IIIA (unstratified HR, 0.62; 95% CI, 0.35-1.11), and ITT (unstratified HR, 0.61; 95% CI, 0.34-1.10) populations. Atezolizumab-related grade 3/4 adverse events occurred in 16% of patients; no treatment-related grade 5 events occurred. Adjuvant atezolizumab showed disease-free survival improvement and a tolerable toxicity profile in Japanese patients in IMpower010, consistent with the global study results., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Previous clinical trials indicate that 10%-25% of patients received genomically matched therapy after comprehensive genomic profiling (CGP) tests. However, the clinical utility of CGP tests has not been assessed in clinical practice. We assessed the clinical utility of CGP tests for advanced or metastatic solid tumor and determined the proportion of patients receiving genomically matched therapy among those with common and non-common cancers. From August 2019 to July 2020, a total of 418 patients had undergone CGP tests, and the results were discussed through the molecular tumor board at our site. The median age of patients was 57 (range: 3-86) years. Colorectal cancer was the most common, with 47 (11%) patients. Actionable genomic alterations (median 3, range: 1-17) were identified in 368 (88.0%) of 418 patients. Druggable genomic alterations were determined in 196 (46.9%) of 418 patients through the molecular tumor board. Genomically matched therapy was administered as the subsequent line of therapy in 51 (12.2%) patients, which is comparable to the proportion we previously reported in a clinical trial (13.4%) (p = 0.6919). The proportion of patients receiving genomically matched therapy was significantly higher among those with common cancers (16.2%) than non-common cancers (9.4%) (p = 0.0365). Genomically matched therapy after the CGP tests was administered to 12.2% of patients, which is similar to the proportion reported in the previous clinical trials. The clinical utility of CGP tests in patients with common cancers greatly exceeded that in patients with non-common cancers., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Postmarketing surveillance of Japanese patients with unresectable, previously treated, advanced or recurrent non-small-cell lung cancer treated with nivolumab was undertaken during the conditional approval period. The study aim was to evaluate the occurrence of treatment-related adverse events of nivolumab in the real world. Patients were registered between December 2015 and March 2016 at 536 sites. Nivolumab was given intravenously (3 mg/kg every 2 weeks); the observation period was 12 months after the first dose of nivolumab. Patients were evaluated for safety (n = 3601; 18.2% ≥75 years, 22.4% ECOG performance status ≥2) and effectiveness (n = 3570). The frequencies of any grade and grade 3 or higher treatment-related adverse events were 47.1% and 15.9%, respectively. The most frequent treatment-related adverse events (any grade) were interstitial lung disease (6.4%), hypothyroidism (5.7%), and diarrhea (4.4%). Treatment-related adverse events of special interest (priority items) occurring at a frequency of 5% or more were adverse events related to interstitial lung disease, thyroid dysfunction, liver dysfunction, colitis/severe diarrhea, infusion reaction, and infusion reaction within 24 hours. Significant risk factors for these priority items were identified by competing risk analysis: interstitial lung disease (previous/comorbid interstitial lung disease, abnormal findings on chest imaging, and smoking history); liver dysfunction (previous/comorbid liver disease, smoking history, and metastasis); thyroid dysfunction (previous/comorbid thyroid disease and performance status); and colitis/severe diarrhea (treatment line 2 vs ≥3). The 12-month survival rate was 40.7%. In conclusion, the safety profile of nivolumab in this postmarketing surveillance was similar to that in clinical trials, and no new safety signals were identified. The study was registered with the Japan Pharmaceutical Information Center (clinicaltrials.jp: Japic-163271)., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Nivolumab, a human monoclonal antibody against programmed death-1, is approved for the treatment of non-small cell lung cancer (NSCLC). Although nivolumab is generally well tolerated, it can cause interstitial lung disease (ILD), a rare but potentially fatal immune-related adverse event. Currently, there are limited data available on the treatment of nivolumab-induced ILD and its outcome. This retrospective cohort study based on a post-marketing study described the treatment of nivolumab-induced ILD and its outcome in NSCLC patients in Japan through the assessment of clinical and chest imaging findings by an expert central review committee. Treatment details for patients who experienced a relapse of ILD were also analyzed. Of the 238 patients identified as having nivolumab-induced ILD, 37 patients died of ILD. Corticosteroids were used in 207 (87.0%) patients. Of those, 172 (83.1%) patients responded well and survived and 35 (16.9%) died (most died during corticosteroid treatment). A total of nine patients experienced a relapse; at the time of relapse, four patients were taking nivolumab. Of those who were receiving corticosteroids at the time of relapse, three of four patients were taking low doses or had nearly completed dose tapering. All patients (except one, whose treatment was unknown) received corticosteroids for the treatment of relapse, but one patient died. Patients with NSCLC who experience nivolumab-induced ILD are treated effectively with corticosteroids, and providing extra care when ceasing or reducing the corticosteroid dose may prevent relapse of ILD., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Nivolumab can cause interstitial lung disease (ILD), which may be fatal; however, mortality risk factors have not been identified. This postmarketing study evaluated the poor prognostic factors of ILD in nivolumab-treated patients with non-small cell lung cancer (NSCLC) in Japan. Clinical and chest imaging findings for each ILD case were assessed by an expert central review committee, and prognosis was evaluated by radiographic findings, including the presence/absence of peritumoral ground-glass opacity (peritumoral-GGO). Poor prognostic factors were identified by univariate and multivariate Cox regression analysis. Of the 238 patients with nivolumab-induced ILD, 37 died. The main radiographic patterns of ILD were cryptogenic organizing pneumonia/chronic eosinophilic pneumonia-like (53.4%), faint infiltration pattern/acute hypersensitivity pneumonia-like (20.2%), diffuse alveolar damage (DAD)-like (10.9%), and nonspecific interstitial pneumonia-like (6.3%). The main poor prognostic factors identified were DAD-like pattern (highest hazard ratio: 10.72), ≤60 days from the start of nivolumab treatment to the onset of ILD, pleural effusion before treatment, lesion distribution contralateral or bilateral to the tumor, and abnormal change in C-reactive protein (CRP) levels. Of the 37 deaths due to ILD, 17 had DAD-like radiographic pattern, three had peritumoral-GGO, and five had a change in radiographic pattern from non-DAD at the onset to DAD-like. Patients with NSCLC who develop ILD during nivolumab treatment should be managed carefully if they have poor prognostic factors such as DAD-like radiographic pattern, onset of ILD ≤60 days from nivolumab initiation, pleural effusion before nivolumab treatment, lesion distribution contralateral or bilateral to the tumor, and abnormal changes in CRP levels., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Combination antiprogrammed death 1/programmed death-ligand 1 Ab and platinum-based chemotherapy is standard first-line treatment for advanced non-small-cell lung cancer without targetable oncogene alterations. We describe the long-term safety and efficacy data from a previously reported phase Ib study of nivolumab and chemotherapy. Japanese patients with non-small-cell lung cancer were assigned to a treatment arm based on histology and treatment history. Nivolumab (10 mg/kg, i.v.) and chemotherapy (4 arms) were given every 3 weeks: arm A, 4 cycles of cisplatin and gemcitabine (first-line); arm B, 4 cycles of cisplatin and pemetrexed followed by pemetrexed maintenance therapy (first-line); arm C, 4-6 cycles of carboplatin, paclitaxel, and bevacizumab followed by bevacizumab (first-line); and arm D, docetaxel (second- or third-line). Study treatments were continued every 3 weeks as maintenance therapy until disease progression. Minimum follow-up period was 57.9 months. Median progression-free survival (median [range, plus sign indicates censored data]) was 6.3 (0.7+-47.8), 11.8 (1.4-65.1+), 40.7 (5.3-60.8+), and 3.2 (1.9-10.9) months, and 5-year progression-free survival was observed in 0/6, 1/6, 1/6, and 0/6 patients in arms A, B, C, and D, respectively. Median overall survival was 13.2 (11.0-55.4), 28.5 (14.6-66.2+), not reached (24.2-67.4+), and 12.5 (9.8-16.9) months; the number of patients surviving 5 years were 0/6, 1/6, 4/6, and 0/6 in arms A, B, C, and D, respectively. No unexpected severe adverse events or treatment-related deaths occurred. Nivolumab and platinum-based chemotherapy combinations showed long-term tolerability. A moderate proportion of patients in arm C showed 5-year progression-free and overall survival., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Thymic carcinoma is a rare malignant disease with no standard systemic chemotherapy. The purpose of the present study was to investigate tumor-infiltrating immune cells (TIIC) in the tumor microenvironment (TME), focusing on the impact of TIIC and program death-ligand 1 (PD-L1) expression on clinical outcomes in thymic cancer. Patients with thymic carcinoma resected between 1973 and 2017 were investigated. The tissue specimens were analyzed through immunohistochemical staining to elucidate the prognostic effects of TIIC, their ratios and PD-L1 in a preliminary cohort (n = 10). The density of TIIC as well as PD-L1 expression was evaluated in intraepithelial and tumor-stromal areas on the representative whole section of tumors. The immune factors showing significant association with disease-free survival (DFS) were evaluated in the total cohort (n = 42). TIIC in the preliminary population showed no significant difference between the two groups. However, CD8, CD20, CD204, FOXP3 and CD20/CD204 ratio demonstrated a tendency to act as predictive markers for recurrence. In the total cohort, significant differences were observed for CD8 + , CD20 + and CD204 + cells in tumor islets, and for CD8 + , CD20 + and FOXP3 + cells as well as the CD8/CD204 and CD20/CD204 ratios in the stroma, indicating their prognostic effect. The prognostic effect of the PD-L1 expression in tumor cells could not be established, possibly because of intratumoral heterogeneity. CD8, CD20 and CD204 positive TIIC in stroma were identified as possible better prognostic biomarkers, considering the heterogeneity of other biomarkers. The present study paves the way for exploring strategies of combination immunotherapy targeting B cell immunity in thymic carcinoma., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

This study determined individual optimal amrubicin doses for Japanese patients with lung cancer after platinum-based treatment. We carried out population pharmacokinetic and pharmacodynamic modeling incorporating gene polymorphisms of metabolizing enzymes and transporters. Fifty patients with lung cancer, who were given 35-40 mg/m 2 amrubicin on days 1-3 every 3-4 weeks, were enrolled. Mechanism-based modeling described relationships between the pharmacokinetics of amrubicin and absolute neutrophil counts. A population pharmacokinetic and pharmacodynamic model was developed for amrubicin and amrubicinol (active metabolite), connected by a delay compartment. The final model incorporated body surface area as a covariate of amrubicin and amrubicinol clearance and distribution volume. SLC28A3 single nucleotide polymorphism (rs7853758) was also incorporated as a constant covariate of the delay compartment of amrubicinol. Performance status was considered a covariate of pharmacokinetic (amrubicinol clearance) and pharmacodynamic (mean maturation time) parameters. Twenty-nine patients with grade 4 neutropenia showed higher amrubicinol area under the plasma concentration-time curve from 0 to 72 hours (AUC 0-72 , P = .01) and shorter overall survival periods than other patients did (P = .01). Using the final population pharmacokinetic and pharmacodynamic model, median optimal dose to prevent grade 4 neutropenia aggravation was estimated at 22 (range, 8-40) mg/m 2 for these 29 patients. We clarified correlations between area under the plasma concentration-time curve from 0 to 72 hours of amrubicinol and severity of neutropenia and survival of patients given amrubicin after platinum chemotherapy. This analysis revealed important amrubicin pharmacokinetic-pharmacodynamic covariates and provided useful information to predict patients who would require prophylactic granulocyte colony stimulating factor., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

We conducted a large-scale surveillance study as a post-marketing commitment to investigate the safety and effectiveness of alectinib in patients with ALK-positive non-small-cell lung cancer (NSCLC) in Japan. Patients receiving 300 mg twice-daily alectinib (September 2014 to June 2015) were monitored until termination of alectinib or completion of 18 months of treatment at 519 Japanese study sites. The primary endpoint was the incidence of adverse drug reactions (ADR), which are important identified risks for alectinib in Japanese patients. Overall survival (OS), a key secondary endpoint, was assessed according to information on outcome. Overall, 1251 patients were enrolled. The median patient age was 62.0 years; 12.9% of patients were aged ≥75 years. At baseline, 63.0% of patients had received crizotinib and 40.6% had brain metastases. Altogether, 1512 ADR occurred in 654 patients (53.6%), with 164 grade ≥3 ADR in 123 patients (10.1%). Commonly occurring ADR were hepatic disorders (all grades, 19.8%; grade ≥3, 2.0%), decreased neutrophil and/or white blood cell count (all grades, 7.6%; grade ≥3, 1.1%), and interstitial lung disease (all grades, 3.8%; grade ≥3, .7%). Median OS was not estimable. The 18-month cumulative OS rate was longer in patients with ECOG performance status ≤1 (vs 2 or ≥3; 83.7% vs 44.5% or 27.2%), without prior crizotinib (vs with; 81.1% vs 73.4%), receiving first-line alectinib (vs second and third or later line; 83.0% vs 79.2% or 71.9%), without brain metastases (vs with; 79.5% vs 71.5%). These data confirm the favorable safety and effectiveness of alectinib in patients with ALK-positive NSCLC in Japan., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Thyroid dysfunction (TD) induced by immune checkpoint inhibitors is not sufficiently understood. The purpose of this retrospective observational study was to identify risk factors and the clinical course of TD induced by nivolumab. Patients with advanced solid tumors who were treated with nivolumab from March 2009 through to March 2016 at the National Cancer Center Hospital (Tokyo, Japan) were included. Thyroid function and antithyroid Abs from serum samples among all patients were evaluated at baseline and during nivolumab treatment. Overt hypothyroidism was defined as low serum-free T4 together with elevated thyroid-stimulating hormone (TSH) >10 μIU/mL. Thyrotoxicosis was defined as low TSH with elevated free T4 and/or free T3. We defined thyroid autoimmunity as the presence of antithyroid Abs at baseline, including antithyroid peroxidase Abs and antithyroglobulin Abs (TgAb). Twenty-three (14%) of a total of 168 patients developed TD, including 17 cases of hypothyroidism and 20 of thyrotoxicosis. Thyrotoxicosis followed by hypothyroidism occurred in 14 cases. Fourteen of 35 patients (40%) with thyroid autoimmunity developed TD vs 9 of 133 (7%) without (odds ratio 9.19; 95% confidence interval [CI], 3.53-23.9). In multivariate analysis, elevated TSH and TgAb at baseline were significantly associated with the development of TD, with odds ratio of 7.36 (95% CI, 1.66-32.7) and 26.5 (95% CI, 8.18-85.8), respectively. Association between TD and elevated antithyroid peroxidase Abs at baseline was not significant. These results suggest that patients with pre-existing TgAb and elevated TSH at baseline are at high risk of TD., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Limited treatment options are available for stage IIIB/IV non-small cell lung cancer (NSCLC). Nivolumab, a programmed cell death-1 immune checkpoint inhibitor antibody, has been shown to be effective for the treatment of NSCLC. The present study investigated the effectiveness and safety of nivolumab in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum-containing chemotherapy. In this multicenter phase II study, patients were treated with nivolumab (3 mg/kg, i.v.) every 2 weeks until progressive disease or unacceptable toxicity was seen. Primary endpoint was overall response rate (ORR) assessed by independent radiology review committee (IRC) and secondary endpoints included a study site-assessed ORR, overall survival (OS), progression-free survival (PFS), duration of response, time to response, best overall response (BOR), and safety. The study included 35 patients from 17 sites in Japan. Patients had IRC-assessed ORR of 25.7% (95% CI 14.2, 42.1) and the study site-assessed ORR was 20.0% (95% CI 10.0, 35.9). Median OS, median time to response and median PFS were 16.3 (95% CI 12.4-25.4), 2.7 (range 1.2-5.5) and 4.2 (95% CI 1.4-7.1) months, respectively. The IRC-assessed BOR was partial response, stable disease, and progressive disease for 25.7%, 28.6%, and 45.7% of patients, respectively. Treatment-related adverse events were reported in 24 patients (68.6%), most of which resolved with appropriate treatment including steroid therapy or ‎discontinuation of nivolumab. Nivolumab was effective and well tolerated in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum-containing chemotherapy., Clinical Trial Registration Number: JapicCTI-132072., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Potentially life-threatening, serious hemoptysis is an adverse event associated with bevacizumab in non-squamous non-small-cell lung cancer (NSCLC) trials. Suggested risk factors include central tumor location and cavitation; however, the profile of hemoptysis occurrence in clinical practice is still unclear. A nested case-control study was conducted to assess the onset profile and risk factors for hemoptysis in bevacizumab-treated patients in a real-world setting in Japan. After bevacizumab was approved for NSCLC, physicians registered all NSCLC patients scheduled for bevacizumab therapy, from November 2009 to August 2011. Patients developing grade 2 hemoptysis requiring an injectable hemostatic agent or grade ≥3 hemoptysis were selected as case subjects, matched with four control subjects each. Case report forms were collected after an observation period of 24 weeks. Radiologists assessed blinded thoracic images. Risk factors for hemoptysis were assessed by univariate and stepwise multivariate analysis. Of 6774 patients registered, 23 (0.3%) experienced grade ≥2 drug-related hemoptysis. A total of 104 patients (21 cases, 83 controls) were analyzed by central reviewers for risk factors of hemoptysis occurrence. In the univariate analysis seven factors were associated with hemoptysis. In the step-wise multivariate analysis, prior thoracic radiotherapy (P = 0.1844), presence of tumor exposure in the central airway (P = 0.0256) and concomitant radiotherapy (P = 0.1169) were identified as risk factors for hemoptysis. While the incidence of hemoptysis was low in the real-world setting in Japan, the three risk factors identified, prior thoracic radiotherapy, presence of tumor exposure in the central airway and concomitant radiotherapy, should be considered when selecting patients for bevacizumab treatment. Although technically classed as a clinical trial, a nested case-control study was a non-interventional surveillance study analyzing all NSCLC patients receiving bevacizumab in Japan, therefore it was not registered as a phase II/III clinical trial would be., (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

We report pharmacokinetics, efficacy and safety data for a new 150-mg alectinib capsule in ALK+ non-small-cell lung cancer in a multicenter, open-label pharmacologic study (JP28927). Eligible patients (≥20 years, locally advanced/metastatic ALK+ disease, ALK inhibitor-naïve and -pretreated [including crizotinib refractory]) were randomized 1:1 to receive one of two sequences of alectinib 300 mg twice daily (comprising different schedules of 20/40-mg and 150-mg capsules) until investigator-determined lack of clinical benefit. Co-primary endpoints were: bioequivalence of alectinib 20/40 mg vs 150 mg; food effect with 150 mg; and safety. Thirty-five patients were enrolled; median treatment duration was 13.1 months (range 1.1-15.0). Under fasting conditions, exposure of the two formulations was similar; mean AUC last  ± standard deviation 3230 ± 914 h·ng/mL vs 3710 ± 1040 h·ng/mL, respectively, for 150-mg vs 20/40-mg capsules. Food effect with 150 mg alectinib was negligible. Treatment-related adverse events in >20% of patients were constipation (31.4%), dysgeusia (25.7%), and decreased white blood cell and neutrophil count (22.9% each). No treatment-related grade 4/5 events occurred. Median time to response was 1.2 months (95% CI 1.1-2.1). For the full analysis set (n = 35) and crizotinib-failure subpopulations (n = 23), the overall response rate was 70.0% (95% CI 50.6-85.3) and 65.0% (95% CI 40.8-84.6), and median progression-free survival was 13.9 months (95% CI 11.1-not reached) and 12.9 months (95% CI 3.9-not reached), respectively. The 150-mg capsule had a similar exposure profile to 20/40-mg capsules. Alectinib demonstrated promising efficacy and was well tolerated., (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Crizotinib is a standard treatment for advanced ALK-positive non-small-cell lung cancer (NSCLC). We undertook this study to investigate the pharmacokinetics of crizotinib and clinical and pharmacogenomic factors that may increase the risk of adverse events (AEs). We defined clinically significant AEs as grade 4 hematological toxicity, grade ≥3 non-hematological toxicity, and any grade of interstitial lung disease. Eight subjects with ALK-positive NSCLC scheduled to receive crizotinib 250 mg twice daily were studied. Six patients were female and two were male, and most of the patients had low body weight with a median body weight of 46.8 kg (range, 42.4-61.0 kg). All patients developed AEs, five developing six clinically significant AEs. Six patients required dose reduction. In pharmacokinetic analysis, blood samples were obtained on days 1 and 15. The mean area under the plasma concentration-time curve from 0-12 h (AUC0-12 ) on day 15 was significantly increased in patients with clinically significant AEs (n = 5) compared with those without (n = 3) (P = 0.04). Genetic polymorphisms of ABCB1 were analyzed. One patient with the ABCB1 1236TT-2677TT-3435TT genotype was an outlier, with an AUC0-12 and peak concentrations on day 15 of 2.84× and 2.61× the mean, respectively, compared with those with other genotypes. Our results suggest that some Japanese NSCLC patients treated with crizotinib developed clinically significant toxicities that were related to altered pharmacokinetics parameters due to genotype and body weight factors., (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The frequency and clinical profile of patients with stage III non-small cell lung cancer harboring KRAS mutations have not yet been well documented. Here, we analyzed hotspot KRAS mutations using high-resolution melting analyses in tumor specimens from patients who received chemoradiotherapy between January 2001 and December 2010 at the National Cancer Center Hospital. The associations between the presence of KRAS mutations and the response rate, relapse-free survival, first relapse sites, survival post-progression and overall survival were investigated. A total of 274 non-squamous non-small cell lung cancer patients received chemoradiotherapy at our hospital. After excluding 121 patients for whom tumor specimens were not available and 34 patients with EGFR mutations, the remaining 119 patients were included in the analysis. KRAS mutations were found at a frequency of 13%. Patients with KRAS mutations had a shorter median relapse-free survival (6.1 vs 10.9 months) and a lower response rate (63% vs 81%). As for the first relapse site, patients with KRAS mutations had fewer local relapses (8% vs 23%) and more brain metastases (46% vs 12%). After disease progression, patients with KRAS mutations had a significantly shorter median survival post-progression (2.5 vs 7.3 months, P = 0.028) and median overall survival (15.1 vs 29.1 months, P = 0.022). Our results suggested that KRAS mutation could be associated with a reduced efficacy of chemoradiotherapy and a shortened survival time., (© 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)

Interstitial lung disease (ILD) occurrence and risk factors were investigated in the Japanese non-small-cell lung cancer, post-marketing, large-scale surveillance study, POLARSTAR. All patients with unresectable, recurrent/advanced non-small-cell lung cancer who were treated with erlotinib in Japan between December 2007 and October 2009 were enrolled. Primary endpoints were patterns of ILD and risk factors for onset of ILD and ILD-related death. Overall survival, progression-free survival, and occurrence of adverse drug reactions were secondary endpoints. Interstitial lung disease was confirmed in 429 (4.3%) patients. Concurrent/previous ILD (hazard ratio, 3.19), emphysema or chronic obstructive pulmonary disease (hazard ratio, 1.86), lung infection (hazard ratio, 1.55), smoking history (hazard ratio, 2.23), and period from initial cancer diagnosis to the start of treatment (<360 days; hazard ratio, 0.58) were identified as significant risk factors for developing ILD by Cox multivariate analysis. Logistic regression analysis identified Eastern Cooperative Oncology Group performance status 2-4 (odds ratio, 2.45 [95% confidence interval, 1.41-4.27]; P = 0.0016), ≤50% remaining normal lung area (odds ratio, 3.12 [1.48-6.58]; P = 0.0029), and concomitant honeycombing with interstitial pneumonia (odds ratio, 6.67 [1.35-32.94]; P = 0.02) as poor prognostic factors for ILD death. Median overall survival was 277 days; median progression-free survival was 67 days. These data confirm the well-characterized safety profile of erlotinib. Interstitial lung disease is still an adverse drug reaction of interest in this population, and these results, including ILD risk factors, give helpful information for treatment selection and monitoring. Erlotinib efficacy was additionally confirmed in this population. (POLARSTAR trial ML21590.)., (© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)

The predictive factors for the development of brain metastases in patients with stage III non-small-cell lung cancer receiving concurrent chemoradiotherapy remain unclear. Several studies have suggested adenocarcinoma as a predictive factor of brain relapses. In the current analysis, we tried to identify the factors associated with brain metastases in stage III lung adenocarcinoma. The demographic and clinical characteristics, site and date of recurrence, and date of death were reviewed in patients with unresectable stage III lung adenocarcinoma who underwent concurrent platinum-based chemoradiotherapy. In total, 116 patients were identified with a median (range) age of 57 (35-74) years. Of these, 86 (74%) were men, all patients had platinum-based chemotherapy, and 100 (86%) received a total dose of 60 Gy in 30 fractions as definitive thoracic radiotherapy. Of the 95 patients with disease progression or recurrence, 19 (16%) developed brain metastases as the sole site of initial recurrence. A total of 43 (37%) patients developed brain metastases at some time during follow-up. Time to brain metastases was significantly associated with the pretreatment carcinoembryonic antigen (CEA) value, with a hazard ratio (95% confidence interval) of 2.64 (1.39-5.02, P = 0.003). Patients who developed brain metastases as the first recurrent site had marginally better survival (log-rank test, P = 0.066) than those with metastases other than brain. In conclusion, stage III lung adenocarcinoma patients with an elevated CEA value before treatment had a higher risk of developing brain metastases after chemoradiotherapy. Further effort is mandatory to control brain metastases in this patient population by a therapeutic strategy based on the tumor histology and pretreatment CEA value., (© 2012 Japanese Cancer Association.)

This phase I, open-label study investigated the Toll-like receptor 9 agonist, PF-3512676, in combination with carboplatin and paclitaxel in Japanese patients with advanced, non-small-cell lung cancer (NSCLC). Patients (n = 12) with treatment-naive stage IIIB or IV NSCLC received single-agent PF-3512676 subcutaneously once during the first 7 days (monotherapy phase) in three escalating dose levels (0.1, 0.2, and 0.4 mg/kg) followed by a combination phase during which patients received 0.1 or 0.2 mg/kg PF-3512676 subcutaneously on days 8 and 15 of each 3-week cycle of carboplatin (area under the curve, 6 mg x min/mL) and paclitaxel (200 mg/m(2)). Safety and pharmacokinetics of PF-3512676 were assessed during monotherapy and combination therapy phases. PF-3512676 was tolerable as monotherapy or in combination with chemotherapy in patients with NSCLC. Most common treatment-related, non-hematologic adverse events (AEs) throughout the study were injection-site reactions (n = 12, 100%) and flu-like symptoms (n = 11, 91.7%) that were each grade 1 or 2 in all but one patient. All patients experienced neutropenia and leukopenia (>or=grade 3 in 11 [91.7%] and seven [58.3%] patients, respectively). One patient in dose level 2 had a dose-limiting toxicity: grade 3 rash and grade 3 increase in gamma-glutamyltransferase during combination therapy. Mean PF-3512676 half-life ranged from 4.8 to 21.6 h (longer with higher doses). Four (33%) patients had objective responses (one complete response, three partial responses), and seven (58%) patients achieved stable disease. PF-3512676 as monotherapy and in combination with chemotherapy had an acceptable safety profile in Japanese patients with treatment-naive NSCLC.

We examined the diagnostic accuracy of the cumulative smoking dose for identifying the epidermal growth factor receptor (EGFR) exon 19 deletion and L858R mutation among Japanese patients with non-small-cell lung cancer (NSCLC). EGFR mutations in exon 19 and exon 21 were determined in 1001 NSCLC patients. A receiver-operating characteristic (ROC) curve methodology was applied to estimate the diagnostic accuracy. EGFR mutations were detected in 314 patients (31.4%). A cumulative smoking dose of less than 13 pack-years (PY) was the optimal cut-off point for predicting a positive EGFR mutation status, producing a balance between the sensitivity (73.5%) and the specificity (77%). The area under the ROC curve was 0.77, indicating that the smoking dose had a moderate diagnostic accuracy. The median survival time or the median progression-free survival time of patients who had smoked less than 13 pack-years (PY) were 18.6 and 6.3 months, respectively, while those of patients with equal to or more than 13 PY were 9.6 and 2.4 months, respectively. The overall survival (OS) and progression-free survival (PFS) rates were significantly different between the two groups (OS: hazard ratio [HR] = 0.64, 95% confidence interval [CI] = 0.51-0.80, P = 0.0001) (PFS: HR = 0.58, 95% CI = 0.47-0.71, P < 0.0001). Our study indicated that the smoking dose predicted EGFR mutations with a moderate diagnostic accuracy. Thus, patients who have smoked less than 13 PY might be candidates for gefitinib treatment when EGFR mutation status cannot be determined.

Epidermal growth factor receptor (EGFR) mutations have been reported as a predictive factor for favorable prognosis of gefitinib-treated patients with lung adenocarcinoma. However, its confounding with sex and smoking makes it unclear whether the EGFR mutation is independently associated with prolonged patient survival. In this study, we analyzed a large-scale database to discriminate the survival impact of EGFR mutations against those of sex and smoking after gefitinib therapy. EGFR mutations in exon19 and exon21 named drug-sensitive EGFR mutations were examined to investigate the impact of EGFR mutation, sex, and smoking status on survival of 362 gefitinib-treated patients with lung adenocarcinoma. Drug-sensitive EGFR mutations were detected in 169 patients (46.7%). The multivariate analysis including EGFR, sex, and smoking status showed that drug-sensitive EGFR mutations were significantly related to longer overall survival (OS) (P < 0.001) and progression-free survival (PFS) (P < 0.001). In addition, we investigated the impact of sex and smoking status according to EGFR mutation status, and the impact of EGFR mutation status according to sex and smoking status on survival. Sex and smoking status were not significantly associated with longer OS and PFS according to EGFR mutation status. Drug-sensitive EGFR mutations were significantly associated with longer OS and PFS according to sex or smoking status. Our results indicated that drug-sensitive EGFR mutations were the only independent factor for longer survival of patients treated with gefitinib, suggesting that patient selection based on EGFR mutation status for gefitinib therapy will lead to a better outcome for patients with lung adenocarcinoma.

In lung cancer, somatic mutations of epidermal growth factor receptor (EGFR) are concentrated in exons 18-21, especially in adenocarcinoma (Ad), but these mutations have rarely been reported in small cell lung carcinoma (SCLC). Combined SCLC is rare, and the EGFR mutation status and its relationship to the clinicopathological features of this tumor type have not yet been elucidated. We retrospectively studied six patients with combined SCLC with Ad components among 64 consecutive patients who underwent resection of SCLC. The clinicopathological features of each patient were reviewed, especially for the distribution pattern of the Ad component and lymph node metastases. EGFR mutations were screened by high-resolution melting analysis in each case, and were confirmed by sequencing of each mutation in the microdissected SCLC or Ad components. Regarding EGFR, no specific mutation was detected in five of the six patients, whereas one female patient who had never smoked had a missense mutation. In this case, both the SCLC and Ad components shared the same mutation in exon 21 (L858R). We identified a patient with combined SCLC with Ad sharing an identical EGFR mutation in both the SCLC and Ad components. In addition to the clinicopathological characteristics of this rare histological type of lung cancer, these findings provide useful information for better understanding the biology, natural history and clinical management of SCLC.

To determine whether bodyweight (BW) loss, daily urine volume (UV) or furosemide use are associated with cisplatin nephrotoxicity, performance status, serum chemistries before treatment, average daily UV, maximum BW loss and use of furosemide on days 1-5 of chemotherapy were evaluated retrospectively in chemotherapy-naive patients with thoracic malignancies who had received 80 mg/m(2) cisplatin. Associations between these parameters and the worst serum creatinine levels (group 1, grade 0-1; and group 2, grade 2-3) during the first cycle were evaluated. Of the 417 patients (327 men and 90 women; median age, 59 years), 390 were categorized into group 1 and 27 were categorized into group 2. More women and older patients were observed in group 2 than in group 1 (11.1 vs 5.2%, P = 0.044, and 65 vs 59 years, P = 0.041, respectively). The median average daily UV was 3902 mL in group 1 and 3600 mL in group 2 (P = 0.021). A maximum BW loss > or 2.1 kg was noted in 4.4% of patients in group 1 and 18.5% of patients in group 2 (P = 0.006). Furosemide was used in 206 (49.4%) patients. The median total dose of furosemide in groups 1 and 2 were 0 mg and 26 mg, respectively (P = 0.024). A multivariate analysis showed that a maximum BW loss > or = 2.1 kg and the total furosemide dose were significantly associated with group category. In conclusion, BW loss and total furosemide dose were associated with cisplatin nephrotoxicity.

To determine the recommended phase II dose of vinorelbine in combination with cisplatin and thoracic radiotherapy (TRT) in patients with unresectable stage III non-small cell lung cancer (NSCLC), 18 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 4 cycles. TRT consisted of a single dose of 2 Gy once daily for 3 weeks followed by a rest of 4 days, and then the same TRT for 3 weeks to a total dose of 60 Gy. Fifteen (83%) patients received 60 Gy of TRT and 14 (78%) patients received 4 cycles of chemotherapy. Ten (77%) of 13 patients at level 1 and all 5 patients at level 2 developed grade 3-4 neutropenia. Four (31%) patients at level 1 and 3 (60%) patients at level 2 developed grade 3-4 infection. None developed > or = grade 3 esophagitis or lung toxicity. Dose-limiting toxicity was noted in 33% of the patients in level 1 and in 60% of the patients in level 2. The overall response rate (95% confidence interval) was 83% (59-96%) with 15 partial responses. The median survival time was 30.4 months, and the 1-year, 2-year, and 3-year survival rates were 72%, 61%, and 50%, respectively. In conclusion, the recommended dose is the level 1 dose, and this regimen is feasible and promising in patients with stage III NSCLC.

We investigated the validity and inter-criteria reproducibility between RECIST (Response Evaluation Criteria in Solid Tumors) guidelines and WHO (World Health Organization) criteria, considering the decrease in patient numbers resulting from inclusion of the minimum lesion size criterion introduced in RECIST guidelines. RECIST guidelines are based on unidimensional measurement and exclusion of small lesions from measurement. The aims of the study were to examine: (1) the effect of the minimum lesion size criterion, (2) the validity of unidimensional and bidimensional measurements, i.e., their relationship with tumor volume, (3) the inter-criteria reproducibility between current RECIST guidelines and previous WHO criteria. One hundred and twenty patients with non-small cell lung cancer (NSCLC) in clinical trials were evaluated. By applying the minimum lesion size criterion, six cases became ineligible without any influence on precision of tumor volume measurement. In the validity study, actual tumor volume was regarded as the gold standard. Although the unidimensional measurement had a lower correlation with tumor volume value than the bidimensional measurement, both the unidimensional measurement and bidimensional measurement correlated sufficiently well with tumor volume changes and the assessed tumor volume response. In the inter-criteria reproducibility study between RECIST guidelines and WHO criteria, the response rate assessed by RECIST guidelines (19.3%) was almost the same as that assessed by WHO criteria (20.0%). In conclusion, RECIST guidelines are adequate for evaluating tumor response to chemotherapy in terms of both validity in relation to tumor volume and inter-criteria reproducibility with the WHO criteria.

TZT-1027 (Soblidotin), an antimicrotubule agent, has been demonstrated to show potent antitumor effects, though the relationships among antitumor effect, cytotoxicity and anti-vascular effect of TZT-1027 have not been studied. We established in vivo human lung vascular-rich tumor models using a vascular endothelial growth factor-secreting tumor (SBC-3/VEGF). SBC-3/VEGF tumors exhibited a high degree of angiogenesis in comparison with the mock transfectant (SBC-3/Neo) tumors in a dorsal skinfold chamber model and grew much faster and larger than SBC-3/Neo tumors in the tumor growth study. The antitumor activity of antimicrotubule agents, including TZT-1027, was evaluated in both early- and advanced-stage SBC-3/Neo and SBC-3/VEGF tumor models to elucidate the relationship between the antitumor activity and anti-vascular effect of these agents. TZT-1027 exhibited potent antitumor activity against both early- and advanced-stage SBC-3/Neo and SBC-3/VEGF tumors, whereas combretastatin A4 phosphate did not. Vincristine and docetaxel exhibited potent antitumor activity against early-stage SBC-3/Neo and SBC-3/VEGF tumors, and advanced-stage SBC-3/Neo tumors, but did not exhibit activity against advanced-stage SBC-3/VEGF tumors. The difference in antitumor activity between these agents could be ascribed to differences in direct cytotoxicity and anti-vascular effect. Furthermore, a prominent accumulation of erythrocytes in the tumor vasculature, followed by leakage and scattering of these erythrocytes from the tumor vasculature, was observed after TZT-1027 administration to mice bearing advanced-stage SBC-3/VEGF tumors. These findings strongly suggest that TZT-1027 has a potent anti-vascular effect, in addition to direct cytotoxicity.

To clarify the long-term survival data and factors that are correlated with survival outcome of unresectable locally advanced non-small cell lung cancer (NSCLC) following chemoradiotherapy, we analyzed patients who entered the Japan Clinical Oncology Group (JCOG) clinical trials for unresectable locally advanced NSCLC. Between October 1989 and August 1997, 240 patients (male 207, female 33; PS (performance status) 0 58, PS 1 172, PS 2 9, unknown 1; stage IIB 2, IIIA 62, IIIB 175, unknown 1) entered the 6 trials. All patients received chemotherapy and radiotherapy. The associations between survival outcome and treatment-related factors were analyzed using Cox regression analysis. Median survival times and 5-year survival rates in the trials were 11.9-19.7 months and 0-17.6%, respectively. Median survival time was 16.1 months and the 5- and 7-year survival rates of all 240 patients were 14.4% and 12.0%, respectively. No deaths were observed 7 years after initiation of the treatment or later. For stage IIIA and IIIB patients, the 5-year survival rates were 16.3% and 13.4%, respectively. Node status and age were significantly associated with survival, but no factors of the treatment were associated with survival of patients with unresectable locally advanced NSCLC. The present retrospective analysis showed that approximately 12% of patients with unresectable locally advanced NSCLC could be cured by various chemoradiotherapy regimens.