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Objectives We conducted a Phase I/II study of carboplatin, S-1 and concurrent thoracic radiotherapy (TRT) for elderly patients (71 years or older) with unresectable stage III non-small cell lung cancer (NSCLC). Materials and methods Patients received carboplatin (AUC 3-5) on Day 1 and S-1 (30–40 mg/m2 two times daily) on Days 1–14, every 2 weeks, for up to four cycles, plus concurrent TRT at a total dose of 60 Gy. The primary endpoint for the Phase II study was the 1-year progression-free survival (PFS) rate. Results Eighteen patients were enrolled in the Phase I study. Febrile neutropenia, a decreased platelet count and esophagitis were dose-limiting toxicities. The recommended doses for the Phase II study were determined to be an AUC of 3 for carboplatin, 40 mg/m2 twice daily for S-1. Twenty-eight patients were evaluated in the Phase II study. The 1-year PFS rate was 57.1% (90% CI 41.6–71.4%), and the median PFS was 16.8 months (95% CI 7.8–not assessable [NA]). The lower limit of the 90% CI for 1-year PFS exceeded the prespecified threshold value of 30%; therefore, the primary endpoint was met. Grades 3–4 toxicities included thrombocytopenia (21%) and hyponatremia (11%). Grade 3 radiation pneumonitis was observed in 18% of patients. No treatment-related deaths were observed. Conclusion Combination chemotherapy consisting of carboplatin plus S-1 and concurrent TRT had a promising efficacy in elderly patients with locally advanced NSCLC; however, radiation pneumonitis was frequently observed.

Background Two phase II studies in Japan examined the efficacy and safety of nivolumab, a programmed cell death 1 receptor inhibitor, in patients with advanced squamous and non-squamous non-small cell lung cancer (ONO-4538-05 and ONO-4538-06). We examined the long-term efficacy and safety of nivolumab in these patients treated for up to 5 years. Methods Patients with squamous (N = 35) or non-squamous (N = 76) non-small cell lung cancer received nivolumab (3 mg/kg every 2 weeks) until disease progression/death. Overall survival and progression-free survival were assessed at 5 years after starting treatment in separate and pooled analyses. Safety was evaluated in terms of treatment-related adverse events. Results A total of 17 patients were alive at the database lock (26 July 2019). The median overall survival (95% confidence interval) and 5-year survival rate were 16.3 (12.4–25.2) months and 14.3% in squamous patients, 17.1 (13.3–23.0) months and 19.4% in non-squamous patients and 17.1 (14.2–20.6) months and 17.8% in the pooled analysis, respectively. Programmed death ligand-1 expression tended to be greater among 5-year survivors than in non-survivors (P = 0.0703). Overall survival prolonged with increasing programmed death ligand-1 expression, with 5-year survival rates of 11.8, 21.8 and 41.7% in patients with programmed death ligand-1 expression of, This long-term follow-up demonstrated ongoing efficacy and safety of nivolumab over ≥5 years in patients with squamous or non-squamous non-small cell lung cancer in Japan.

Background The combination use of the vascular disrupting agent ombrabulin with chemotherapeutic agents was previously shown to be highly synergistic in preclinical models. Methods In this dose-escalation study of ombrabulin (15.5-35 mg/m2) in combination with docetaxel (60 or 75 mg/m2) and cisplatin (75 mg/m2), agents were administered 24 h apart every 3 weeks to Japanese patients with advanced solid tumors. The study was designed and conducted in a 3 + 3 manner. Safety, tumor response and pharmacokinetics were evaluated. Results Eleven patients with non small cell lung cancer as the primary tumor were treated. Two patients out of five had dose limiting toxicities (DLTs) in Cycle 1 at the starting doses of ombrabulin 15.5 mg/m2, docetaxel 60 mg/m2 and cisplatin 75 mg/m2. Thus, dose escalation was terminated. The first dose level was re-evaluated in six patients who received prophylactic granulocyte-colony stimulating factor (G-CSF). However, because of the occurrence of DLTs in Cycle 1 in two patients out of six, the study was led to the premature termination without pursued upper dose level. Partial response was observed in four patients out of 11. Pharmacokinetic parameters of ombrabulin and cisplatin were not altered in this combination treatment, while docetaxel clearance decreased by ~40% compared to that observed with docetaxel monotherapy at the same dose (60 mg/m2). Conclusion A combination regimen of ombrabulin with cisplatin and docetaxel was not feasible for Japanese patients owing to the occurrence of hematological and non-hematological DLTs at the initial dose level. Clinical trial registration ID ClinicalTrials.gov number, NCT01095302.

There are few reports on the use of salvage surgery for small cell lung cancer (SCLC). Five patients who underwent resection of post-chemoradiotherapy residual lesion/local reprogression of SCLC between 2005 and 2017 were included in the study. We retrospectively reviewed their surgical outcomes and prognosis to assess the feasibility and potential efficacy of salvage surgery. Indications for salvage surgery were local reprogression (four patients) and residual lesion (one patient) with ycN0 disease. Complete pathological resection was achieved in four patients; however, malignant pleural effusion was diagnosed in one patient after the surgery. Morbidity and mortality rates were 0%. Estimated 5-year survival rate was 67%. Recurrence and death after surgery occurred only in the patient with malignant pleural effusion. We demonstrate the feasibility of salvage surgery in SCLC. In carefully-selected patients, especially those without lymph node involvement, salvage surgery may provide effective local control and favorable survival outcomes.

This subgroup analysis of ASCEND-5 study demonstrated better efficacy of ceritinib compared with the standard second-line chemotherapy in chemotherapy- and crizotinib-pretreated Japanese patients with ALK-rearranged NSCLC., Background In the global, Phase 3, ASCEND-5 study, ceritinib improved progression-free survival (PFS) vs chemotherapy in patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) who had previously progressed on crizotinib and platinum-based chemotherapy. Here, we report efficacy and safety in a subset of Japanese patients from the ASCEND-5 study. Methods Patients with advanced ALK-rearranged NSCLC received oral ceritinib 750 mg/day or chemotherapy (intravenous pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 [investigator’s choice], every 21 days). Results Among the 231 patients, 29 were Japanese, of which, 11 were treated with ceritinib and 18 were treated with chemotherapy (5 with pemetrexed and 13 with docetaxel). All the patients received prior crizotinib and one or two lines of prior chemotherapy for advanced disease. Median follow-up time was 16.6 months for ceritinib arm and 16.4 months for chemotherapy arm in the overall population. The median PFS by blinded independent review committee was 9.8 months (95% CI, 4.3–14.0) in ceritinib arm vs 1.6 months (95% CI, 1.4–3.0) in chemotherapy arm. Grade 3 or 4 adverse events, suspected to be study drug related, were reported in 36.4% of ceritinib arm and 72.2% of chemotherapy arm, respectively. No Grade 3 or 4 events of diarrhea, nausea and vomiting were reported in both the treatment arms. Adverse events leading to study drug discontinuation were reported in one patient in each arm: Grade 3 central-nervous system metastases in ceritinib-treated patient and Grade 3 febrile neutropenia in chemotherapy-treated patient. Conclusions Consistent with overall population, ceritinib demonstrated better efficacy compared with the standard second-line chemotherapy in Japanese patients with crizotinib-resistant ALK+ NSCLC. ClinicalTrials.gov identifier NCT01828112

Introduction Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer is sensitive to tyrosine kinase inhibitors; however, resistance can develop. Data are presented from the phase II trial (ASCEND-2) evaluating efficacy and safety in a subset of Japanese patients with ALK-rearranged non-small cell lung cancer previously treated with platinum-based chemotherapy, who experienced disease progression on crizotinib. Methods Patients with advanced ALK-rearranged non-small cell lung cancer, including those with asymptomatic or neurologically stable baseline brain metastases, received oral ceritinib 750 mg/day. Whole-body and intracranial responses were assessed by investigator and Blinded Independent Review Committee (RECIST v1.1). Safety and tolerability were also investigated. Results All 24 Japanese patients had received ≥2 previous treatment regimens, with crizotinib the last therapy received prior to ceritinib. Median duration of ceritinib exposure was 8.1 (range: 0.2-12.5) months. Overall response rate was 45.8% (95% confidence interval: 25.6-67.2). Other efficacy endpoints included disease control rate (79.2% [95% confidence interval: 57.8-92.9]), time to response (median 1.9 months [range: 1.7-3.5]), duration of response (median 9.2 months [95% confidence interval: 4.0-not estimable]) and progression-free survival (median 6.6 months [95% confidence interval: 3.7-9.3]). Of the four patients with active baseline target brain lesions, two achieved an intracranial partial response (50%). The most commonly reported adverse events (majority grade 1/2) were nausea (91.7%), diarrhea (83.3%) and vomiting (83.3%). Conclusions This study demonstrates the clinical activity and manageable tolerability of ceritinib in a Japanese subset of chemotherapy- and crizotinib-pretreated patients with ALK-rearranged non-small cell lung cancer who progressed on crizotinib, as was shown in the whole ASCEND-2 study population. ClinicalTrials.gov identifier: NCT01685060.

Objective This Phase I study was carried out to assess the safety, tolerability, pharmacokinetics and preliminary efficacy of the flavonoid tumor-vascular disrupting agent ASA404 (vadimezan) in combination with docetaxel in Japanese patients with advanced or recurrent solid tumors. Methods Nine Japanese patients were given ASA404 (1800 mg/m(2)) plus two doses of docetaxel, 60 or 75 mg/m(2), administered every 3 weeks. Results Dose-limiting toxicity of Grade 3 febrile neutropenia was observed in one patient during Cycle 1 at Level 2 of ASA404 (1800 mg/m(2)) and docetaxel (75 mg/m(2)) treatment. The most frequently reported adverse events were neutropenia, fatigue, alopecia, decreased appetite, constipation and injection site pain. These adverse events were mainly Grade 1 or 2 in severity and, with the exception of injection site pain, were typically associated with docetaxel therapy. A partial response was observed in one patient, and five patients (55.6%) exhibited stable disease. Overall, the study demonstrated that ASA404 has an acceptable tolerability profile when combined with docetaxel at doses up to 75 mg/m(2) in Japanese patients with advanced solid tumors. Conclusions The study supports the enrollment of Japanese patients in the Phase III study (ATTRACT-2) of ASA404 in combination with docetaxel for the second-line treatment of advanced non-small cell lung cancer. Clinicaltrials.gov identifier: NCT01285453.

This Phase I study was carried out to assess the safety, tolerability, pharmacokinetics and preliminary efficacy of the flavonoid tumor-vascular disrupting agent ASA404 (vadimezan) in combination with docetaxel in Japanese patients with advanced or recurrent solid tumors.Nine Japanese patients were given ASA404 (1800 mg/m(2)) plus two doses of docetaxel, 60 or 75 mg/m(2), administered every 3 weeks.Dose-limiting toxicity of Grade 3 febrile neutropenia was observed in one patient during Cycle 1 at Level 2 of ASA404 (1800 mg/m(2)) and docetaxel (75 mg/m(2)) treatment. The most frequently reported adverse events were neutropenia, fatigue, alopecia, decreased appetite, constipation and injection site pain. These adverse events were mainly Grade 1 or 2 in severity and, with the exception of injection site pain, were typically associated with docetaxel therapy. A partial response was observed in one patient, and five patients (55.6%) exhibited stable disease. Overall, the study demonstrated that ASA404 has an acceptable tolerability profile when combined with docetaxel at doses up to 75 mg/m(2) in Japanese patients with advanced solid tumors.The study supports the enrollment of Japanese patients in the Phase III study (ATTRACT-2) of ASA404 in combination with docetaxel for the second-line treatment of advanced non-small cell lung cancer. Clinicaltrials.gov identifier: NCT01285453.

Background: Pemetrexed in combination with cisplatin (Pem/Cis) is used globally for the treatment of malignant pleural mesothelioma (MPM). This Phase I/II study was conducted to determine the recommended dose (RD) (Phase I) of Pem/Cis, and evaluate the efficacy and safety (Phase II) in Japanese MPM patients. Methods: Key eligibility criteria were histologic diagnosis of MPM incurable by surgery, no prior chemotherapy, and a performance status 0‐1. Under full vitamin supplementation, pemetrexed was intravenously administered on Day 1 of a 21-day cycle, followed by cisplatin. A cohort of six patients, starting from pemetrexed 500 mg/m 2 and cisplatin 75 mg/m 2 (Level 1), were studied in the dose-escalation Phase I( Step 1). The RD determined in Step 1w as carried forward into Phase II (Step 2). Planned number of patients treated with Pem/Cis was 18‐38. Results: In Step 1, 13 patients were enrolled: seven in Level 1 and six in Level 21 (pemetrexed 500 mg/m 2 , cisplatin 60 mg/m 2 ). Two of six evaluable patients had dose-limiting toxicities (pneumonitis and neutropenia) in Level 1, establishing Level 1 as the RD. In Step 2, 12 patients were enrolled, for a total of 19 patients treated at the RD. Seven patients achieved a partial response among these patients, for a response rate of 36.8% (95% confidence interval: 16.3‐ 61.6); overall survival was 7.3 months. One drug-related death occurred due to worsening of a pre-existing pneumonia. Common grade 3/4 toxicities were neutropenia and decreased-hemoglobin. Conclusion: The Pem/Cis combination provides promising activity and an acceptable safety profile for chemonaive Japanese MPM patients with the same recommend dosage and schedule used in rest of the world.

The human placental form of glutathione S-transferase pi (GST-pi) was measured by a sandwich enzyme-linked immunosorbent assay in lung cancer cell lines established in our laboratories. In classic-type small cell lung cancer (SCLC), variant-type SCLC and non-small cell lung cancer (NSCLC), the respective mean GST-pi values were 0.83 +/- 0.88, 3.27 +/- 2.85 and 2.40 +/- 0.76 micrograms/mg protein. Cell lines with high GST-pi content had low levels of neuron specific enolase, which is known as a representative tumor marker for SCLC. This suggests that GST-pi may also be used as a potential marker for NSCLC. The lines with low GST-pi content were more sensitive to radiation than those with high GST-pi content. Cell lines not subjected to prior therapy also showed a good correlation between GST-pi levels and chemosensitivity to cisplatin. The findings suggest that GST-pi can be used as an adjunctive marker for lung cancer.