Non-small Cell Lung Cancer In Japan Research Articles

Cost-Utility Analysis of Stereotactic Body Radiation Therapy Versus Surgery for Patients With Stage I Non-small Cell Lung Cancer in Japan.

Stereotactic body radiation therapy (SBRT) for patients with operable stage I non-small cell lung cancer (NSCLC) is less invasive than surgery. However, differences in lifetime costs and patient outcomes remain unclear. In this study, a cost-utility analysis of SBRT compared with surgery for Japanese patients with operable stage I NSCLC was conducted. A partitioned survival model was constructed using each treatment arm's overall survival (OS) and progression-free survival (PFS) data. The data for the SBRT arm were extracted from the Japanese multicenter cohort study, which enrolled 678 medically operable patients with stage I NSCLC, and patient registry data were used for the surgery arm. The 5-year OS rate was 78.2% for SBRT and 74.8% for surgery from both studies. The 5-year PFS rate was 57.0% for SBRT and 63.4% for surgery. The quality of life values of PFS and progressive disease were obtained from domestic and overseas literature (PFS: 0.74, progressive disease: 0.65). The time horizon was set to 10 years. The expected costs and quality-adjusted life years for each treatment group were calculated. All costs are expressed in Japanese yen converted to US dollars (USD). SBRT was the dominant strategy, reducing treatment costs by 4,443.8 USD and increasing quality-adjusted life years by 0.131 compared with surgery. According to probabilistic sensitivity analysis, the probability of SBRT being dominant and cost-effective was 50.6% and 72.4%, respectively. Under the budget impact analysis, the total savings for the patients with stage I NSCLC in Japan was 6,252,870.0 USD (n = 1,407). SBRT is a more cost-effective option than surgery in patients with medically operable stage I NSCLC in Japan. Large-scale epidemiologic studies that reflect the latest clinical realities, such as OS/PFS, will be needed to validate this study's robustness.

Biomarker Testing in Patients With Unresectable Advanced or Recurrent Non–Small Cell Lung Cancer

Biomarker testing for driver mutations is essential for selecting appropriate non-small cell lung cancer (NSCLC) treatment but is insufficient. To investigate the status of biomarker testing and drug therapy for NSCLC in Japan for identifying problems in treatment. The REVEAL cohort study included retrospective data collection and prospective follow-up from 29 institutions across Japan. Of 1500 patients diagnosed with advanced or recurrent NSCLC between January 1 and March 18, 2021, 1479 were eligible. Cases recognized at the wrong clinical stage (n = 12), diagnosed outside the study period (n = 6), not treated according to eligibility criteria before recurrence (n = 2), and with deficient consent acquisition procedure (n = 1) were excluded. The primary end point was the biomarker testing status. Treatment-related factors were examined. Among the 1479 patients included in the analysis, the median age was 72 (range, 30-95) years; 1013 (68.5%) were men; 1161 (78.5%) had an Eastern Cooperative Oncology Group performance status 0 or 1; 1097 (74.2%) were current or past smokers; and 947 (64.0%) had adenocarcinoma. Biomarker status was confirmed in 1273 patients (86.1%). Multigene testing was performed in 705 cases (47.7%); single-gene testing, in 847 (57.3%); and both, in 279 (18.9%). Biomarker testing was performed for EGFR in 1245 cases (84.2%); ALK, in 1165 (78.8%); ROS1, in 1077 (72.8%); BRAF, in 803 (54.3%); and MET, in 805 (54.4%). Positivity rates among 898 adenocarcinoma cases included 305 (34.0%) for EGFR, 29 (3.2%) for ALK, 19 (2.1%) for ROS1, 11 (1.2%) for BRAF, and 14 (1.6%) for MET. Positivity rates among 375 nonadenocarcinoma cases were 14 (3.7%) for EGFR, 6 (1.6%) for ALK, 1 (0.3%) for ROS1, 3 (0.8%) for BRAF, and 8 (2.1%) for MET. Poor physical status, squamous cell carcinoma, and other comorbidities were associated with hampered multigene testing. Targeted therapy was received as first-line treatment by 263 of 278 cases (94.6%) positive for EGFR, 25 of 32 (78.1%) positive for ALK, 15 of 24 (62.5%) positive for ROS1, 9 of 12 (75.0%) positive for BRAF, and 12 of 19 (63.2%) positive for MET. Median overall survival of patients with positive findings for driver gene alteration and who received targeted therapy was 24.3 (95% CI, not reported) months; with positive findings for driver gene alteration and who did not receive targeted therapy, 15.2 (95% CI, 7.7 to not reported) months; and with negative findings for driver gene alteration, 11.0 (95% CI, 10.0-12.5) months. Multigene testing for nonadenocarcinomas and adenocarcinomas accounted for 705 (47.7%) of all NSCLC cases. These findings suggest that multigene testing has not been sufficiently implemented in Japan and should be considered prospectively, even in nonadenocarcinomas, to avoid missing rare driver gene alterations.

Real-World Study of Overall Survival in Patients with Stage III Non-Small Cell Lung Cancer Treated with Chemoradiotherapy with or without Durvalumab and an Exploratory Analysis of Effective Radiation Dose to the Immune Cells

To investigate the real-world data on overall survival (OS) in patients with stage III non-small cell lung cancer (NSCLC) treated with concurrent chemoradiotherapy (CCRT) with or without consolidation durvalumab, and to perform an exploratory analysis on effective radiation dose to the immune cells (EDIC). In our multi-institutional retrospective study, patients who received CCRT between July 2018 and July 2019 for stage III NSCLC in Japan were investigated. EDIC was estimated using mean lung dose, mean heart dose, body volume, body mean dose, and body weight, as reported in the secondary analysis of RTOG 0617. The cut-off value of EDIC was calculated using the maximally selected log-rank statistics. One hundred and seventy-eight patients were eligible for the analysis (136 patients, CCRT with consolidation durvalumab [CCRT+D] cohort; 42 patients, CCRT cohort). The median follow-up period was 42.5 months. Three-year OS rates were 59.8% in the overall cohort: 60.5% in the CCRT+D cohort, and 58.0% in the CCRT cohort with no significant difference (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.45-1.27; P = 0.29). Univariate analysis showed that ECOG-PS, smoking history, histology, EGFR mutational status, gross tumor volume and EDIC were significantly associated with OS. Multivariate analysis showed that ECOG-PS 2, gross tumor volume ≥ 57 cm3 and EDIC ≥ 4.4 Gy were associated with poor OS. Among 21 EGFR-mutated patients, 3 year-OS rates were 64.7% in the CCRT+D cohort and 100% in the CCRT cohort, while 3 year-OS rates were 68.8% and 58.7% among 90 EGFR wild-type patients. Three-year OS rates were 64.6% and 47.6% for EDIC < 4.4 Gy and EDIC ≥ 4.4 Gy in the overall cohort (HR, 1.82; 95% CI, 1.14-2.90; P = 0.015). In the subgroup analysis, 66.3% vs. 44.4% in the CCRT+D cohort (HR, 2.01; 95% CI, 1.17-3.47; P = 0.016), and 59.0% vs. 56.1% in the CCRT cohort (HR, 1.20; 95% CI, 0.48-3.01; P = 0.70), respectively. Our real-world data in Japan showed that there was no significant difference in OS between the CCRT+D cohort and the CCRT cohort. High EDIC could be a risk for poor OS in patients treated with CCRT and consolidation durvalumab compared with those treated with CCRT.

Clinical results of carbon ion radiotherapy for inoperable stage I non-small cell lung cancer: A Japanese national registry study (J-CROS-LUNG)

Background and purposeRadiotherapy is a standard treatment for inoperable stage I non-small cell lung cancer (NSCLC), and carbon-ion radiation therapy (CIRT) may be used for such treatment. Although CIRT for stage I NSCLC has demonstrated favorable outcomes in previous reports, the reports covered only single-institution studies. We conducted a prospective nationwide registry study including all CIRT institutions in Japan. Materials and methodsNinety-five patients with inoperable stage I NSCLC were treated by CIRT between May 2016 and June 2018. The dose fractionations for CIRT were selected from several options approved by the Japanese Society for Radiation Oncology. ResultsThe median patient age was 77 years. Comorbidity rates for chronic obstructive pulmonary disease and interstitial pneumonia were 43% and 26%, respectively. The most common schedule for CIRT was 60 Gy (relative biological effectiveness (RBE)) in four fractions, and the second most common was 50 Gy (RBE) in one fraction. The 3-year overall survival, cause-specific survival, and local control rates were 59.3%, 77.1%, and 87.3%, respectively. Female sex and ECOG performance status of 0–1 were favorable prognostic factors for overall survival in a multivariate analysis. No grade 4 or higher adverse event was observed. The 3-year cumulative incidence of grade 2 or higher radiation pneumonitis was 3.2%. The risk factors for grade 2 or higher radiation pneumonitis were a force expiratory volume in 1 second (FEV1) of <0.9 L and a total does of ≥ 67 Gy(RBE). ConclusionThis study provides real-world treatment outcomes of CIRT for inoperable.stage I NSCLC in Japan.

Health Care Resource Use Among Patients with Advanced Non–Small Cell Lung Cancer in Japan, 2017–2019

First-line immune checkpoint inhibitor (ICI) monotherapy for advanced non-small cell lung cancer (NSCLC) was introduced in Japan in February 2017. Limited information is available since that time regarding health care resource use for NSCLC in Japan, where the hospitalization burden is high. We evaluated health care resource use from first- through third-line systemic anticancer therapy for patients with advanced NSCLC included in a multicenter, retrospective chart review study. Eligible patients were aged 20 years or older with unresectable locally advanced/metastatic NSCLC with no known actionable genomic alteration who initiated first-line systemic anticancer therapy from July 1, 2017, to December 20, 2018, at 23 Japanese hospitals. We calculated the percentage of patients with a record of each resource used, the total number of each resource, and the resource use per 100 patient-weeks of follow-up from initiation of first-, second-, and third-line therapy, overall and by the 3 most common regimen categories, namely, ICI monotherapy, platinum-doublet chemotherapy (without concomitant ICI), and nonplatinum cytotoxic regimens (nonplatinum). Study follow-up ended September 30, 2019. Among 1208 patients (median age = 70 years; 975 [81%] men), 463 patients (38%) received ICI monotherapy, 647 (54%) received platinum-doublet chemotherapy, and 98 (8%) received nonplatinum regimens as first-line therapy. During the study, 621 (51%) patients initiated second-line, and 281 (23%) initiated third-line therapy. The majority of patients experienced ≥1 hospitalization (76%-94%) and ≥1 outpatient visit (85%-90%) during each therapy line. The number of hospitalizations increased from 6.5 per 100 patient-weeks in first-line to 8.0 per 100 patient-weeks in third-line. During first-line therapy, the number of hospitalizations per 100 patient-weeks were 4.8, 8.4, and 6.5 for patients receiving ICI monotherapy, platinum-doublet chemotherapy, and nonplatinum regimens, respectively, and the percentages of hospitalizations categorized as attributable to NSCLC treatment administration (no surgery, procedure, treatment of metastasis, or palliative lung radiation) were 64%, 77%, and 73%, respectively. The number of outpatient visits increased from 43.0 per 100 patient-weeks in first-line to 51.4 per 100 patient-weeks in third-line therapy. During first-line therapy, outpatient visits per 100 patient-weeks were 41.0, 46.7, and 33.0 for patients receiving ICI monotherapy, platinum-doublet chemotherapy, and nonplatinum regimens, respectively, and the percentages of outpatient visits for infusion therapy were 48%, 34%, and 36%, respectively. The results of this study, although solely descriptive, showed differing patterns of health care resource use during first-line therapy among the 3 common systemic anticancer therapy regimens for advanced NSCLC in Japan and suggest that further research is needed to investigate these apparent differences by treatment regimen.

Emerging PD-1/PD-L1 targeting immunotherapy in non-small cell lung cancer: Current status and future perspective in Japan, US, EU, and China.

Non-small cell lung cancer (NSCLC), one of the deadliest types of cancers worldwide, has been the target of immunotherapy due to its high immune antigenicity. With the addition of immune-checkpoint inhibitors (ICIs), including anti-PD-1/PD-L1 antibodies, as an indispensable and powerful regimen for the treatment of this lethal disease, the median survival time for patients with stage IV NSCLC is approximately 2 years. In contrast, the response rate to ICIs remains less than 50%, even if the patients are selected using biomarkers such as PD-L1. Pharmaceutical companies have begun to develop additional anti-PD-1/PD-L1 antibodies to overcome resistance and are devising further immunotherapy combinations. More than 20 anti-PD-1/PD-L1antibodies have been approved or are currently in development. Numerous combination therapies are under development, and several combination therapies have provided positive results in randomized controlled trials. This review aimed to examine the current status of approved and investigational anti-PD-1/PD-L1antibodies for NSCLC in Japan, the United States, the European Union, and China. Further, this review discusses the challenges and future perspectives for developing new ICIs in alignment with the global developments in Japan.

Safety and effectiveness of ramucirumab and docetaxel: a single-arm, prospective, multicenter, non-interventional, observational, post-marketing safety study of NSCLC in Japan

ABSTRACT Background This study evaluated the safety and effectiveness of ramucirumab and docetaxel for non-small cell lung cancer (NSCLC) in real-world settings. Research Design and Methods This single-arm, prospective, multicenter, non-interventional, post-marketing study was conducted in Japan between August 2016 and January 2020. Patients diagnosed with unresectable advanced/recurrent NSCLC were eligible for study inclusion. Data on adverse events (AEs) and survival were collected electronically. Results Of 401 enrolled patients, 398 were eligible for study inclusion. Most patients were male (68.6%) with a median age of 67.0 years. Patients were predominantly diagnosed with adenocarcinoma (78.1%) or squamous cell carcinoma (16.6%); 46.2% received prior treatment with bevacizumab and 38.7% with immune-checkpoint inhibitors. AEs (any grade) were observed in 323 patients (81.2%; grade ≥ 3: n = 174, 43.7%). The most common AEs (any grade) were malaise (14.3%), decreased appetite (13.0%), and neutrophil count decrease (11.6%). At 12 months from treatment commencement, 93.2% of patients had discontinued, mostly due to progressive disease (53.4%) or AEs (28.3%). The 12-month survival rate was 56.7% (95% confidence interval: 51.5–61.8). Conclusions Data from real-world settings demonstrate ramucirumab and docetaxel treatment appears to be tolerable and effective in Japanese patients regardless of patient baseline characteristics and prior treatment.

Treatment Sequencing in Patients with Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer in Japan: A Real-World Observational Study.

The anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) alectinib was approved in Japan in 2014 for the treatment of ALK fusion gene-positive advanced non-small cell lung cancer (NSCLC). With the approvals of crizotinib in 2012 and ceritinib in 2017, Japan became the first country with multiple ALK TKIs available for first-line or later use in patients with ALK-positive advanced NSCLC. Here, we collected and evaluated real-world data on ALK TKI clinical usage patterns and sequencing in patients with ALK-positive NSCLC in Japan. This retrospective observational study used the Japanese Medical Data Vision database to analyze data from patients with a confirmed diagnosis of lung cancer who visited a healthcare facility in the database between April 2010 and March 2017, underwent an ALK test, received a prescription for an ALK TKI, and were at least 18years old as of the date of the first ALK TKI prescription. There were no exclusion criteria. Descriptive analyses of demographics, baseline characteristics, ALK TKI treatment patterns and sequences, non-ALK TKI treatments received before, during, and after ALK TKI treatment, and treatment durations were reported. A total of 378 patients met the inclusion criteria and were evaluated in mutually exclusive groups of patients receiving one, two, or three ALK TKIs. The initial ALK TKI prescribed was crizotinib for 52.1% of patients and alectinib for 47.9% of patients; however, the proportion of patients receiving alectinib as the initial ALK TKI increased over time following the Japanese approval of alectinib in 2014. Of the 117 patients who received two or three ALK TKIs, 106 received crizotinib as the first ALK TKI and 11 received alectinib. Before the date of the patient's first ALK TKI prescription, 153 of 378 patients (40.5%) had received chemotherapy. Of 104 patients who discontinued ALK therapy, 46.2% received chemotherapy and 5.8% received immunotherapy as their next treatment. At the time of this analysis, most patients who received more than one ALK TKI received crizotinib as the initial ALK TKI. Additional ALK TKIs have since been approved in Japan as first-line or later therapeutic options for patients with ALK-positive NSCLC, but the optimal sequence of ALK TKI usage remains undetermined. As new data continue to emerge, additional research will be warranted to evaluate ALK TKI sequences that do not include crizotinib as the first therapy in this patient population.

Safety and effectiveness of alectinib in a real-world surveillance study in patients with ALK-positive non-small-cell lung cancer in Japan.

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.

Phase I study of cemiplimab, a human monoclonal antibody to programmed death (PD)-1, in Japanese patients (pts) with advanced malignancies: Results from the dose exploration.

33 Background: Cemiplimab (REGN2810), a high-affinity, highly potent, human monoclonal antibody to PD-1, has demonstrated a safety profile comparable with that of other anti-PD-1 antibodies and antitumor activity in various solid tumors including cutaneous squamous cell carcinoma and non-small-cell lung cancer (NSCLC) in pts outside of Japan. We present analysis of Part 1 of a two-part, multicenter, open-label, Phase 1 study of cemiplimab in Japanese pts with advanced malignancies. Methods: Part 1 dose exploration pts received either cemiplimab 250 mg (n=6) or 350 mg (n=7) Q3W IV for up to 108 weeks. Tumor measurements were performed every 9 weeks according to RECIST 1.1. Data cut-off date was July 13, 2018. Results: Thirteen pts were enrolled: median age, 62 years (range: 33–75); 8 F. Twelve (92.3%) and 7 (53.8%) pts had received prior cancer-related systemic therapy and radiotherapy, respectively. Median duration of cemiplimab exposure was 13.1 weeks (range: 3.0–54.6). At the data cut-off date Part 1 was fully enrolled and 9 pts (69.2%) had discontinued treatment, primarily due to disease progression (n=7, 53.8%). The most common treatment-emergent adverse events (TEAEs) of any grade were contact dermatitis, rash, and viral upper respiratory tract infection, each occurring in 3 pts (23.1%). The following grade ≥3 TEAEs occurred in 1 pt (7.7%): hypophosphatemia, hyponatremia, autoimmune colitis, and dehydration; the last two events occurred in the same pt. No dose-limiting toxicities were reported. Cemiplimab serum concentrations were as expected from the reported PK characteristics of cemiplimab. Objective response rate (ORR; complete response + partial response [PR]) and disease control rate (ORR + stable disease [SD]) were 23.1% (3 PR) and 53.8% (7/13; 4 SD), respectively. Conclusions: Cemiplimab exhibited substantial antitumor activity in Japanese pts with advanced malignancies. Cemiplimab 350 mg Q3W dosing regimen was selected for the expansion studies. The safety profile was comparable with those previously reported for cemiplimab and other anti-PD-1 agents. Part 2 is open and enrolling pts with NSCLC in Japan. Clinical trial information: NCT02760498.

Clinical Efficacy of Alectinib in Patients with ALK-Rearranged Non-small Cell Lung Cancer After Ceritinib Failure.

Several second-generation inhibitors of anaplastic lymphoma kinase (ALK) have demonstrated potent activity in ALK rearrangement-positive non-small cell lung cancer (NSCLC). Two of these agents, ceritinib, and alectinib, recently received approval for the treatment of ALK-rearranged NSCLC in Japan. The efficacy of treatment with a second-generation ALK inhibitor after failure with a different second-generation ALK inhibitor remains unclear. We present a series of eight patients with ALK-rearranged NSCLC treated with alectinib who experienced disease progression after ceritinib. Both crizotinib and ceritinib were administered to six patients, with four (29%) patients receiving crizotinib followed by ceritinib. Among the eight study patients, two (25%) had partial response, one (12%) stable disease, and five (63%) had progressive disease. The median progression-free survival was 3.6 months (95% confidence interval=0-7.1 months). The results of this study suggest that the second-generation ALK inhibitor alectinib has limited efficacy after initial treatment with the second-generation ALK inhibitor ceritinib.

Systemic Treatment Patterns With Advanced or Recurrent Non–small Cell Lung Cancer in Japan: A Retrospective Hospital Administrative Database Study

PurposeData on the treatment of non–small cell lung cancer (NSCLC) in real-world clinical practice in Japan are limited. This large-scale, retrospective cohort study examined data on patients’ characteristics and systemic therapies for advanced or recurrent NSCLC in routine practice in Japan. MethodsThis study used an electronic health records–based database of health claims and Diagnosis Procedure Combination data from 215 consenting hospitals in Japan. Records from April 2008 to September 2015 were analyzed. Regimens were examined by histology, age, sex, and therapeutic line. Logistic regression analysis was performed to predict which clinical and demographic factors affected patients’ probability of receiving first- or second-line therapy or completing first-line platinum-based chemotherapy. FindingsAmong 16,413 patients, 67.9%, 39.2%, and 22.3% received first-, second-, and third-line systemic treatment, respectively. Treatment was more common in patients aged <75 versus ≥75 years (76.0% vs 51.6%), in female versus male patients (71.6% vs 65.4%), and in patients with nonsquamous versus squamous disease (75.6% vs 61.9%). More than 30 systemic regimens were administered. The most common first-line therapy was platinum-based chemotherapy (nonsquamous, 53.6%; squamous, 73.7%). Non–platinum-based chemotherapy use increased in the second-line setting, but platinum-based chemotherapy use remained high (nonsquamous, 33.9%; squamous, 38.6%). Tyrosine kinase inhibitors were used in 32.0% and 29.4% of patients with nonsquamous NSCLC in the first- and second-line settings, respectively. Switches from first- to second-line platinum-based chemotherapy and from first- to second-line tyrosine kinase inhibitors occurred. Forty-two percent of the patients died during hospitalization. In the logistic regression analysis, factors associated with a decreased likelihood of receiving first-line therapy were male sex, squamous histology, age >75 years, treatment at a general (vs cancer-specific) hospital, worse scores on certain activities of daily living, presence of chronic pulmonary disease, worse Hugh–Jones classification, and positive smoking status. The likelihood of completing first-line platinum-based chemotherapy was increased with greater body mass index, better activities of daily living scores, absence of chronic pulmonary disease, and better Hugh-Jones classification. The likelihood of continuing with second-line therapy was decreased with older age and recurrence of NSCLC. ImplicationsSystemic treatment patterns for advanced or recurrent NSCLC in Japan were varied. Nearly 30% of all patients and approximately half of elderly patients did not receive systemic treatment. Treatment rates declined with subsequent therapeutic lines. Generally, guidelines were followed with first-line treatment administration, but not with second-line administration. These results underscore the need for better guideline adherence and more optimal treatment in and elderly patients and in those receiving later-line treatment in Japan.

Cost-effectiveness analysis of EGFR mutation testing and gefitinib as first-line therapy for non-small cell lung cancer

The combination use of gefitinib and epidermal growth factor receptor (EGFR) testing is a standard first-line therapy for patients with non-small cell lung cancer (NSCLC). Here, we examined the cost-effectiveness of this approach in Japan. Our analysis compared the 'EGFR testing strategy', in which EGFR mutation testing was performed before treatment and patients with EGFR mutations received gefitinib while those without mutations received standard chemotherapy, to the 'no-testing strategy,' in which genetic testing was not conducted and all patients were treated with standard chemotherapy. A three-state Markov model was constructed to predict expected costs and outcomes for each strategy. We included only direct medical costs from the healthcare payer's perspective. Outcomes in the model were based on those reported in the Iressa Pan-Asia Study (IPASS). The incremental cost-effectiveness ratio (ICER) was calculated using quality-adjusted life-years (QALYs) gained. Sensitivity and scenario analyses were conducted. The incremental cost and effectiveness per patient of the 'EGFR testing strategy' compared to the 'no-testing strategy' was estimated to be approximately JP¥122,000 (US$1180; US$1=JP¥104 as of February 2014) and 0.036 QALYs. The ICER was then calculated to be around JP¥3.38 million (US$32,500) per QALY gained. These results suggest that the 'EGFR testing strategy' is cost-effective compared with the 'no-testing strategy' when JP¥5.0 million to 6.0 million per QALY gained is considered an acceptable threshold. These results were supported by the sensitivity and scenario analyses. The combination use of gefitinib and EGFR testing can be considered a cost-effective first-line therapy compared to chemotherapy such as carboplatin-paclitaxel for the treatment for NSCLC in Japan.

Alectinib for the treatment of ALK-positive stage IV non-small cell lung cancer

Our increased understanding of the molecular subsets of non-small cell lung cancer (NSCLC) has led to the development of highly effective targeted therapies. In particular, the outcomes of patients with advanced NSCLC driven by the EML4-ALK fusion protein, which comprise 3-5% of cases, have remarkably improved with the use of crizotinib, an oral multi-tyrosine kinase inhibitor that targets ALK. However, patients inevitably develop progression while on crizotinib due to various mechanisms of resistance. Alectinib is a novel oral small molecule that inhibits ALK with high potency and selectivity, and demonstrates promising antitumor effects in NSCLC. Preclinical studies have shown that it is also active against several mutant forms of ALK that confer resistance to crizotinib, including the gatekeeper mutation L1196M. Moreover, an objective response rate of over 90% was observed in a phase I trial. Due to the impressive results of early phase studies, alectinib was approved for the treatment of advanced ALK-positive NSCLC in Japan, while it has been granted a breakthrough therapy designation by the FDA. A phase III trial is currently ongoing. This review will describe the biology and significance of ALK rearrangements in NSCLC, ALK inhibition by crizotinib and mechanisms of resistance, as well as the preclinical and clinical evidence for the novel ALK inhibitor alectinib.

Efficacy and safety of erlotinib in elderly patients in the phase IV POLARSTAR surveillance study of Japanese patients with non-small-cell lung cancer

ObjectiveMore tolerable treatment options are needed for the large number of elderly patients with non-small-cell lung cancer (NSCLC). An analysis of the phase IV POLARSTAR surveillance study examined the safety and efficacy of erlotinib in elderly Japanese patients with previously treated NSCLC. Materials and methodsFrom December 2007 to October 2009, all erlotinib-treated patients with unresectable, recurrent/advanced NSCLC in Japan were enrolled. Efficacy and safety data were stratified by age (<75 years, 75–84 years, ≥85 years). Kaplan–Meier methodology was used to estimate median progression-free survival (PFS). Safety data were collected with a focus on interstitial lung disease (ILD). ResultsA total of 9907 patients were eligible for safety assessment (<75 years, n=7848; 75–84 years, n=1911; ≥85 years, n=148) and 9651 for efficacy assessment (<75 years, n=7701; 75–84 years, n=1815; ≥85 years, n=135). Other baseline characteristics were balanced. The incidence of ILD (all grades) was 4.2% (<75 years), 5.1% (75–84 years), and 3.4% (≥85 years). The mortality rate due to ILD was ≤1.7% in all age groups. Other toxicities (including rash) were similar between age groups. The median PFS was 65 days (95% confidence interval [CI], 62–68) for patients aged <75 years, 74 days (95% CI, 69–82) for patients aged 75–84 years, and 72 days (95% CI, 56–93) for patients aged ≥85 years. ConclusionsEfficacy and tolerability of erlotinib for elderly patients was not numerically inferior to that reported in younger patients. Erlotinib could be considered for elderly patients with recurrent/advanced NSCLC.

Clinical development of S-1 for non-small cell lung cancer: a Japanese perspective

For more than a decade, S-1 has been investigated aggressively against non-small cell lung cancer (NSCLC) in Japan. Recently, two randomized phase III trials of S-1 combined with cisplatin (CDDP) or carboplatin (CBDCA) compared with the standard platinum doublet chemotherapy were reported. S-1 and CDDP was noninferior to CDDP and DTX in terms of overall survival (OS) (median survival time [MST] 16.1 versus 17.1 months, respectively; hazard ratio [HR] 1.013; 96.4% confidence interval [CI] 0.837-1.227). Noninferiority of S-1 and CBDCA compared with CBDCA and paclitaxel was also confirmed for OS (MST 15.2 versus 13.3 months, respectively; HR 0.928; 99.2% CI 0.671-1.283). The noninferiority design employed an upper CI limit of HR<1.322 in the former trial and HR<1.33 in the latter. S-1 combined with CDDP or CBDCA was thought to be one of the standard platinum doublet regimens in the first-line setting for patients with advanced NSCLC in Japan. Some additional interesting phase I and II studies have been published in Japan. They include studies of S-1 as first-line chemotherapy when combined with nonplatinum agents; as second-line chemotherapy; within chemoradiotherapy for locally advanced disease; and in the postoperative adjuvant setting. This review will also describe the use of S-1 for the treatment of NSCLC in these settings.

Prospective observational cohort study of second-line chemotherapy administration after first-line platinum-based chemotherapy for patients with advanced NSCLC in Japan (SAPPHIRE study).

8058 Background: Maintenance therapy after first-line platinum-based chemotherapy (first-CT) is reported to be beneficial to patients with advanced non-small cell lung cancer (NSCLC). However, its impact on overall survival appears to be marginal or negligible, if those without maintenance receive active second-line chemotherapy (second-CT), which is initiated at disease progression. The purpose of this study is to investigate the proportion of second-CT administration after first-CT for patients with advanced NSCLC. Methods: From April 2010 to September 2011, 865 patients with advanced NSCLC who were initiated on first-CT at 30 institutions in Japan were enrolled in this prospective observational study. Baseline characteristics, regimens and responses to first-CT, whether or not they received second-CT, and if not, reasons for non-administration were recorded. This report describes from patients with at least 6 months of follow up. This study was supported by the Public Health Research Center Foundation CSPOR. Results: A total of 865 eligible patients with advanced NSCLC provided patient characteristics and details of first-CT. Of all patients, 70% had adenocarcinoma, 20% had squamous cell carcinoma, and 10% were positive for the EGFR mutation. At this data cut off, 225 patients were excluded from the analysis due to disease progression and loss of follow-up during first-CT, and 194 (22%) patients received maintenance therapy after first-CT. Among the 508 patients who were followed up for at least 6 months, 131 patients (26%) could not receive second-CT; the reasons were as follows: declined PS, 79 (60%); patient refusal, 28 (21%); death of any cause, 6 (5%); others, 18 (14%). Conclusions: Preliminary results of this large observational study in Japan suggested that around 20% of patients missed an opportunity to receive appropriate second-CT despite the follow-up of advanced NSCLC patients after first-CT. Further investigation is needed to elucidate the selection criteria of patients that may benefit the most from maintenance therapy, not second-CT at disease progression.

SY12-3 - Targeting ALK Tyrosine Kinase in Lung Cancer

ABSTRACT In order to discover novel transforming genes in cancer specimens, we developed a sensitive retroviral expression library system for full-length cDNAs. By using this technology coupled with a focus formation assay with mouse 3T3 cells, we could discover, from a specimen of non-small cell lung cancer (NSCLC), a novel oncogenic fusion-type tyrosine kinase EML4-ALK. Both of EML4 and ALK genes are mapped closely on the same short arm of human chromosome 2, but a small inversion involving these two loci, inv(2)(p21p23), leads to fuse the 5'-part of EML4 to the 3′ part of ALK encoding the tyrosine kinase domain. Transgenic mice expressing EML4-ALK in lung epithelial cells developed hundreds of adenocarcinoma nodules in both lungs only at a few weeks after birth, and oral administration of a specific inhibitor to ALK successfully cleared such nodules from the mice, proving in vivo that EML4-ALK is the primary genetic event to trigger cancer, and, therefore, specific inhibitors against EML4-ALK could be a novel and effective drug.Currently, a number of clinical trials with ALK inhibitors are ongoing worldwide, and the result of phase I/II studies with one of such compound, crizotinib, was made public, demonstrating the dramatic therapeutic efficacy of the compound against EML4-ALK-positive NSCLC. Further, crizotinib has just been approved as a therapeutic drug by US FDA in a record breaking speed of drug development. To help individuals with EML4-ALK-positive NSCLC in Japan, we started from early 2009 ‘ALK Lung Cancer Study group (ALCAS)’, a nation-wide diagnostic network for such tumors. Through the ALCAS initiative, we also noticed a patient who was once effectively treated with crizotinib, but later underwent abrupt relapse. Molecular analyses of these specimens led to the discovery of secondary mutations C1156Y and L1196M within EML4-ALK accounting for the observed drug tolerance. Our data thus demonstrate that a subset of lung cancer express previously unidentified fusion kinases that are promising candidates for a therapeutic target as well as for a diagnostic molecular marker for this intractable disorder.

1181PD - Randomized Phase II Study of Adjuvant Chemotherapy with S-1 Versus CDDP + S-1 in Resected Stage II-IIIA Non-Small-Cell Lung Cancer (WJOG4107)

ABSTRACT Background Postoperative cisplatin doublet chemotherapy benefits patients with completely resected stage II-IIIA non-small-cell lung cancer (NSCLC). S-1 is an oral fluorinated pyrimidine formulation that combines tegafur (FT), 5-chloro-2, 4-dihydroxypyridine (CDHP), and potassium oxonate in a molar ratio of 1:0.4:1 and widely used by single agent or platinum doublet for advanced NSCLC in Japan. This phase II trial assessed the efficacy and safety of S-1 and cisplatin plus S-1 for adjuvant chemotherapy. Methods From September 2007 to Dec 2009, 200 patients with completely resected stage II and IIIA (exclude multi-station N2 cases) NSCLC were randomized to receive either oral S-1 (40 mg/m2 twice per day) for consecutive 2 weeks repeated every 3 weeks for 1 year or cisplatin (60 mg/m2 day1) plus oral S-1 (40 mg/m2 twice per day) for consecutive 2 weeks repeated every 3 weeks for 4 cycles within 8 weeks after surgery. Main inclusion criteria were no prior chemotherapy or radiotherapy, ECOG PS 0-1, an age of less than 75 years, and an adequate organ function. Stratification factors included histology, stage and institutions. Primary endpoint was relapse free survival rate on 2 years and secondary endpoints were overall survival (OS) and toxicity. Results Patient demographics were well balanced between the arms in terms of sex, age, histologic type and stage. 52.6% of patients in S-1 arm and 76.7% in cisplatin plus S-1 arm were completed planned administration. Relapse free survival rate on 2 years was 65.6% (95% confidence interval, 55.3-74.0%) in the S-1 arm and 58.1% (95% confidence interval, 47.7-67.2%) in the cisplatin plus S-1 arm. OS were not matured in the both arms. Though the rates of leukopenia or neutropenia of grade 3/4, febrile neutropenia, nausea, and vomiting were more frequent in the cisplatin plus S-1 arm, there were no treatment related deaths in the both groups. Conclusion Both S-1 monotherapy and cisplatin plus S-1 are feasible as adjuvant chemotherapy for completed resected NSCLC. Disclosure I. Yoshino: Research Funds from Taiho Pharmaceutical Co. and Chugai Pharmaceutical Co. All other authors have declared no conflicts of interest.

The Role of Epidermal Growth Factor Receptor Mutations and Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors in the Treatment of Lung Cancer

Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small-cell lung cancer (NSCLC) cases comprise approximately 85% of the lung cancer cases. Before the era of target therapy, platinum-based doublet chemotherapy only led to a median survival of 8–9 months and a one-year survival of 30%–40% in patients with advanced NSCLC. In July 2002, gefitinib, a small-molecule epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), was approved for the treatment of patients with advanced NSCLC in Japan. After the widespread use of gefitinib in the treatment of NSCLC, there have been many new studies regarding the association between the clinical anticancer efficacy of gefitinib and the somatic EGFR mutation status in patients with NSCLC. This article summarizes the role of EGFR mutations in lung cancer and the use of EGFR antagonists in the treatment of lung cancer and its associated adverse effects.