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BIBF 1120 is an oral multitargeted tyrosine kinase inhibitor that blocks the activity of vascular endothelial growth factor (VEGF) and other growth factor receptors. We have done a phase I study to evaluate the safety, pharmacokinetics, and pharmacodynamic biomarkers of BIBF 1120. Patients with advanced refractory solid tumors were treated with BIBF 1120 at oral doses of 150 to 250 mg twice daily. Drug safety and pharmacokinetics were evaluated, as were baseline and post-treatment levels of circulating CD117-positive bone marrow–derived progenitor cells and plasma soluble VEGF receptor 2 as potential biomarkers for BIBF 1120. Twenty-one patients were treated at BIBF 1120 doses of 150 (n = 3), 200 (n = 12), or 250 mg twice daily (n = 6). Dose-limiting toxicities of reversible grade 3 or 4 elevations of liver enzymes occurred in 3 of 12 patients at 200 mg twice daily and 3 of 6 patients at 250 mg twice daily. Stable disease was achieved in 16 (76.2%) patients, and median progression-free survival was 113 days (95% confidence interval, 77-119 d). Pharmacokinetic analysis indicated that the maximum plasma concentration and area under the curve for BIBF 1120 increased with the dose within the dose range tested. Levels of CD117-positive bone marrow–derived progenitors and soluble VEGF receptor 2 decreased significantly during treatment over all BIBF 1120 dose cohorts. In conclusion, the maximum tolerated dose of BIBF 1120 in the current study was determined to be 200 mg twice daily, and our biomarker analysis indicated that this angiokinase inhibitor is biologically active. Mol Cancer Ther; 9(10); 2825–33. ©2010 AACR.

Supplementary Figure 1 from Phase I Safety, Pharmacokinetic, and Biomarker Study of BIBF 1120, an Oral Triple Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors

Few clinical studies have been designed for elderly patients with locally advanced non-small cell lung cancer (NSCLC). We conducted a phase I study to evaluate the tolerability of carboplatin/nab-paclitaxel and concurrent thoracic radiotherapy in elderly patients with locally advanced NSCLC. The eligibility criteria were: unresectable stage III NSCLC, performance status 0 or 1, and age ≥ 75 years. Eligible patients received 6 weeks of weekly carboplatin/nab-paclitaxel and concurrent thoracic radiotherapy with a total dose of 64 Gy in 32 fractions. Carboplatin was fixed to an area under the plasma concentration time curve (AUC) of 2 mg/mL/min, and the recommended dose of nab-paclitaxel was evaluated using a dose-escalation study (30 or 40 mg/m2). Tolerability at the recommended dose was evaluated in an expansion study. Nineteen patients were enrolled at four institutions, all of whom were eligible and assessable. The recommended nab-paclitaxel dose was set at 30 mg/m2 because two patients experienced dose-limiting toxicity at 40 mg/m2. The treatment completion rate of the 17 patients analyzed at the recommended dose was 100% (80% confidence interval (CI), 83.8–100%). The overall response rate was 76.5%, and the median progression free survival was 13.4 months (95% CI, 4.2–21.4 months). Common grade 3 and 4 toxicities included leukopenia (23.5%), neutropenia (17.6%), anemia (5.9%), and infection (5.9%). One treatment-related death due to pneumonitis was observed six months after the end of the study. In conclusion, carboplatin/nab-paclitaxel and concurrent thoracic radiotherapy show good tolerability and exhibit promising efficacy in elderly patients with locally advanced NSCLC. This trial was registered with the Japan Registry of Clinical Trials on March 11, 2019 (trial no. jRCTs042180077).

This study aimed to determine the incidence and clinical course of epidermal growth factor receptor (EGFR)-mutated lung cancer with histologic transformation (HT).We conducted a multicentre, retrospective, cohort study of patients with advanced EGFR-mutated lung cancer who received EGFR-tyrosine kinase inhibitors (TKIs) between 2012 and 2019. The primary outcome was the incidence of HT. The secondary outcome was treatment efficacy in patients with HT.In total, 6356 patients were enrolled. In 2624 patients, the histological type was proven by rebiopsy after acquiring resistance to EGFR-TKIs. Among them, 74 patients had HT (incidence rate: 2.8% [95% confidence interval: 2.3%-3.5%]). The median progression-free survival after EGFR-TKIs and first-line therapy after confirming HT was 10.4 and 4.4 months, respectively, which was not significantly different between patients with transformation to high-grade neuroendocrine carcinoma and those with transformation to another subtype of non-small cell lung cancer. Overall survival after confirming HT was 12.2 months. Twenty-seven patients received immune checkpoint inhibitors: 6 and 21 received immune checkpoint inhibitors before and after confirming HT, respectively. No patients achieved 1-year progression-free survival. The median progression-free survival after immune checkpoint inhibitor therapy after confirming HT was 1.6 months.HT occurred in approximately 3% of EGFR-mutated patients who developed resistance to EGFR-TKIs. Cytotoxic agents are likely to be effective in patients with HT. However, the therapeutic effectiveness of immune checkpoint inhibitors was limited in these patients. Given the rarity of HT and absence of prospective trials, our findings are important to inform the treatment of these patients.

Few clinical studies have been designed for elderly patients with locally advanced non-small cell lung cancer (NSCLC). We conducted a phase I study to evaluate the tolerability of carboplatin/nab-paclitaxel and concurrent thoracic radiotherapy in elderly patients with locally advanced NSCLC. The eligibility criteria were: unresectable stage III NSCLC, performance status 0 or 1, and age ≥75 years. Eligible patients received 6 weeks of weekly carboplatin/nab-paclitaxel and concurrent thoracic radiotherapy with a total dose of 64 Gy in 32 fractions. Carboplatin was fixed to an area under the plasma concentration time curve (AUC) of 2 mg/mL/min, and the recommended dose of nab-paclitaxel was evaluated using a dose-escalation study (30 or 40 mg/m2). Tolerability at the recommended dose was evaluated in an expansion study. Nineteen patients were enrolled at four institutions, all of whom were eligible and assessable. The recommended nab-paclitaxel dose was set at 30 mg/m2 because two patients experienced dose-limiting toxicity at 40 mg/m2. The treatment completion rate of the 17 patients analyzed at the recommended dose was 100% (80% confidence interval (CI), 83.8–100%). The overall response rate was 76.5%, and the median progression free survival was 13.4 months (95% CI, 4.2–21.4 months). Common grade 3 and 4 toxicities included leukopenia (23.5%), neutropenia (17.6%), anemia (5.9%), and infection (5.9%). One treatment-related death due to pneumonitis was observed six months after the end of the study. In conclusion, carboplatin/nab-paclitaxel and concurrent thoracic radiotherapy show good tolerability and exhibit promising efficacy in elderly patients with locally advanced NSCLC. This trial was registered with the Japan Registry of Clinical Trials on March 11, 2019 (trial no. jRCTs042180077).

Background: Based on the results of the PACIFIC study, chemoradiotherapy followed by 1-year consolidation therapy with durvalumab was established as the standard of care for unresectable, locally advanced non-small-cell lung cancer (LA-NSCLC). However, some topics not foreseen in that design can be explored, including progression-free survival (PFS) and overall survival (OS) after the start of chemoradiotherapy, the proportion of patients who proceeded to consolidation therapy with durvalumab, and the optimal chemotherapeutic regimens. In Japan, the combination regimen of S-1 + cisplatin (SP), for which the results of multiple clinical studies have suggested a good balance of efficacy and tolerability, is frequently selected in clinical settings. However, the efficacy and safety of consolidation therapy with durvalumab following this SP regimen have not been evaluated. We therefore planned a multicenter, prospective, single-arm, phase II study. Methods: In treatment-naïve LA-NSCLC, two cycles of combination chemotherapy with S-1 (80–120 mg/body, Days 1–14) + cisplatin (60 mg/m2, Day 1) will be administered at an interval of 4 weeks, with concurrent thoracic radiotherapy (60 Gy). Responders will then receive durvalumab every 2 weeks for up to 1 year. The primary endpoint is 1-year PFS rate. Discussion: Compared with the conventional standard regimen in Japan, the SP regimen is expected to be associated with lower incidences of pneumonitis, esophagitis, and febrile neutropenia, which complicate the initiation of consolidation therapy with durvalumab, and have higher antitumor efficacy during chemoradiotherapy. Therefore, SP-based chemoradiotherapy is expected to be successfully followed by consolidation therapy with durvalumab in more patients, resulting in prolonged PFS and OS. Toxicity and efficacy results of the SP regimen in this study will also provide information important to the future establishment of the concurrent combination of chemoradiotherapy and durvalumab. Trial registration: Japan Registry of Clinical Trials, jRCTs031190127, registered 1 November 2019, https://jrct.niph.go.jp/latest-detail/jRCTs031190127

Alectinib has shown marked efficacy and safety in patients with anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangement-positive NSCLC and a good performance status (PS). It has remained unclear whether alectinib might also be beneficial for such patients with a poor PS.Eligible patients with advanced ALK rearrangement-positive NSCLC and a PS of 2 to 4 received alectinib orally at 300 mg twice daily. The primary end point of the study was objective response rate (ORR), and the most informative secondary end point was rate of PS improvement.Between September 2014 and December 2015, 18 patients were enrolled in this phase II study. Of those patients, 12, five, and one had a PS of 2, 3, or 4, respectively, whereas four patients had received prior crizotinib treatment. The ORR was 72.2% (90% confidence interval: 52.9-85.8%). The ORR did not differ significantly between patients with a PS of 2 and those with a PS of 3 or higher (58.3% and 100%, respectively [p = 0.114]). The PS improvement rate was 83.3% (90% confidence interval: 64.8-93.1%, p0.0001), with the frequency of improvement to a PS of 0 or 1 being 72.2%. The median progression-free survival was 10.1 months. Toxicity was mild, with the frequency of adverse events of grade 3 or higher being low. Neither dose reduction nor withdrawal of alectinib because of toxicity was necessary.Alectinib is a treatment option for patients with ALK rearrangement-positive NSCLC and a poor PS.

Lessons Learned Alectinib confers a pronounced survival benefit in patients with ALK rearrangement-positive non-small cell lung cancer and a poor performance status. Survival benefit of alectinib for patients with a poor performance status was consistent regardless of the presence of central nervous system metastases. Background We previously reported a marked objective response rate (ORR) and safety for alectinib treatment in patients with ALK rearrangement-positive non-small cell lung cancer (NSCLC) and a poor performance status (PS) in the Lung Oncology Group in Kyushu (LOGiK) 1401 study. It remained unclear, however, whether alectinib might also confer a long-term survival benefit in such patients. Methods Eighteen patients with ALK rearrangement-positive advanced NSCLC and a PS of 2, 3, or 4 (n = 12, 5, and 1, respectively) were enrolled in LOGiK1401 between September 2014 and December 2015 and received alectinib. We have now updated the survival data for the study. Results The median follow-up time for all patients was 27.3 months. The median progression-free survival (PFS) was 16.2 months (95% confidence interval [CI], 7.1–30.8 months), and the median survival time (MST) and the 3-year overall survival rate were 30.3 months (95% CI, 11.5 months to not reached) and 43.8% (95% CI, 20.8–64.7%), respectively. This survival benefit was similarly manifest in patients with a PS of 2 (MST, 20.5 months) and those with a PS of ≥3 (MST, not reached). PFS did not differ between patients with or without central nervous system (CNS) metastases at baseline (median of 17.5 and 16.2 months, respectively, p = .886). Conclusion Alectinib showed a pronounced survival benefit for patients with ALK rearrangement-positive NSCLC and a poor PS regardless of the presence of CNS metastases, a patient population for which chemotherapy is not indicated.

Objectives We performed an open-label, multicenter, single-arm phase II study (UMIN ID 000010532) to prospectively evaluate the efficacy and safety of nab-paclitaxel for previously treated patients with advanced non–small cell lung cancer (NSCLC). Methods Patients with advanced NSCLC who experienced failure of prior platinum-doublet chemotherapy received weekly nab-paclitaxel (100mg/m 2 ) on days 1, 8, and 15 of a 21-day cycle until disease progression or the development of unacceptable toxicity. The primary end point of the study was objective response rate (ORR). Results Forty-one patients were enrolled between September 2013 and April 2015. The ORR was 31.7% (90% confidence interval, 19.3%–44.1%), which met the primary objective of the study. Median progression-free survival was 4.9 months (95% confidence interval, 2.4–7.4 months) and median overall survival was 13.0 (95% confidence interval, 8.0–18.0 months) months. The median number of treatment cycles was four (range, 1–17) over the entire study period, and the median dose intensity was 89.1mg/m 2 per week. Hematologic toxicities of grade 3 or 4 included neutropenia (19.5%) and leukopenia (17.1%), with no cases of febrile neutropenia being observed. Individual nonhematologic toxicities of grade 3 or higher occurred with a frequency of Conclusion Weekly nab-paclitaxel was associated with acceptable toxicity and a favorable ORR in previously treated patients with advanced NSCLC. Our results justify the undertaking of a phase III trial comparing nab-paclitaxel with docetaxel in this patient population.

Binimetinib is a potent, selective MEK1/2 inhibitor with demonstrated efficacy against BRAF- and RAS-mutant tumors. Retinal adverse events associated with MEK inhibitors have been reported in some cases. The aim of this study was to assess single-agent binimetinib, with detailed ophthalmologic monitoring, in Japanese patients with advanced solid tumors.This was an open-label phase I dose-escalation and dose-expansion study (NCT01469130). Adult patients with histologically confirmed, evaluable, advanced solid tumors were enrolled and treated with binimetinib 30 or 45 mg twice daily (BID). The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of single-agent binimetinib in Japanese patients.Twenty-one patients were enrolled; 3 and 8 patients had documented BRAF and KRAS mutations, respectively. Two of 6 patients (33 %) receiving binimetinib 45 mg BID in dose-escalation experienced recurrent grade 2 retinal adverse events (AEs) which were reversible, and this dose was declared the MTD and RP2D. All patients experienced ≥1 AE suspected to be treatment related; the most common (50 %) were blood creatine phosphokinase increase (76 %), retinal detachment and aspartate aminotransferase increase (62 % each), and diarrhea (52 %). There were no complete or partial responses; 14 patients (67 %) had stable disease, which lasted180 days in 5 patients. Expression of phospho-ERK decreased in the skin following binimetinib treatment at both dose levels, indicating target inhibition.Binimetinib demonstrated efficacy and acceptable safety in Japanese patients with solid tumors, supporting the 45 mg BID dose of binimetinib as the RP2D.

Patient: Male, 57-year-old Final Diagnosis: Febrile neutropenia Symptoms: Fever Medication: Nivolumab Clinical Procedure: Chemotherapy Specialty: Oncology Objective: Adverse events of drug therapy Background: Nivolumab is a human IgG4 monoclonal antibody against human programmed cell death 1 (PD-1). It has demonstrated efficacy against metastatic non-small cell lung cancer (NSCLC). Treatment with nivolumab is sometimes associated with immune-related adverse events (ir AEs) in patients. These specific ir AEs include pneumonitis, hypothyroidism, dermatitis, enterocolitis, hepatitis, and neuropathy. However, hematological toxicity is rare. Case Report: A 57-year-old man with lung adenocarcinoma, with brain and adrenal gland metastases, was therefore started on nivolumab therapy as third-line treatment. After administration of the second dose with nivolumab, grade 3 febrile neutropenia (FN) and grade 2 liver dysfunction developed in the patient. The patient was started to on intravenous antibiotics, granulocyte colony-stimulating factor (G-CSF), and corticosteroids. Neutrophil counts and liver function gradually improved, and corticosteroids were tapered over 6 weeks. However, the patient was re-treated with G-CSF because the neutrophil counts decreased again. Conclusions: Care needs to be taken with such patients because neutropenia due to treatment with nivolumab can recur, as well as other ir AEs.

Background: As docetaxel plus S-1 may be feasible for cancer treatment, we conducted a phase I/II trial to determine the recommended docetaxel dose and the fixed S-1 dose (phase I), as well as confirm the regimen&rsquo, s efficacy and safety (phase II) for previously-treated patients with advanced non-small cell lung cancer. Methods: Patients &le, 75 years with performance status &le, 1 and adequate organ function were treated at three-week intervals with docetaxel on day 1 and 80 mg/m2 oral S-1 from days 1&ndash, 14. The starting docetaxel dose was 45 mg/m2 and this was escalated to a maximum of 70 mg/m2. In phase II, response rate, progression-free survival (PFS), overall survival (OS), and safety were assessed. Results: The recommended doses were 50 mg/m2 docetaxel (day 1) and 80 mg/m2 S-1 (days 1&ndash, 14). Grades 3 and 4 leukocytopenia and neutropenia occurred in 44% and 67% of patients, respectively. Nonhematologic toxicities were generally mild. Overall response to chemotherapy was 7.7% (95% confidence interval (CI), 1.6&ndash, 20.9%), and median PFS and OS were 18.0 weeks (95% CI, 11.3&ndash, 22.9 weeks) and 53.0 weeks, respectively. Conclusion: Fifty mg/m2 docetaxel plus 80 mg/m2 oral S-1 had a lower response rate than anticipated, however, the survival data were encouraging. A further investigation is warranted to select the optimal patient population.

Background: Although treatment with osimertinib confers survival benefits in the second-line treatment of epidermal growth factor receptor (EGFR)-mutated lung cancer with the EGFR T790M mutation, the mechanism of acquired resistance to osimertinib has not been well understood. Here, we planned a multicenter, prospective observational study in order to clarify the possible acquired resistance mechanisms to second-line treatment using osimertinib in Japanese non-small cell lung cancer patients. Methods: EGFR T790M positive advanced non-small cell lung cancer patients were included in this study. We excluded EGFR tyrosine kinase inhibitor naïve patients, patients whose EGFR T790M proved only by liquid biopsy, and patients whose tumor specimens were not adequate for targeted resequencing analysis. Re-biopsy was planned after the patient developed acquired resistance to osimertinib under written informed consent. Nucleic acids were extracted from formalin-fixed paraffin embedded tumor sections and targeted resequencing was performed using a panel consisting of 143 genes (Oncomine Comprehensive Assay, OCA, ThermoFisher Scientific, USA) in a CLIA-certified laboratory (SRL Inc., Japan), and then analyzed using IonReporter software (ThermoFisher Scientific, USA). Results: Between November 2016 and February 2019, 86 patients from 25 institutions were screened. Among 71 patients who were eligible, 31 patients were still on osimertinib and 33 patients developed acquired resistance. Among the 33 patients who developed acquired resistance, 16 patients proceeded to re-biopsy (4 males, 8 Del19 and 7 L858R EGFR mutations). 15/16 samples from re-biopsies and 9/16 samples from pre-osimertinib biopsies proceeded to OCA analyses. Others were excluded because of low quality of extracted nucleic acids. The acquired resistance mechanisms were as follows: T790M maintained in 10 patients with EGFR G796S being found in 1 patient. T790M loss observed in 5 patients with 1 patient having copy number gain in growth-arrest specific gene 6 (GAS6). Another patient possibly had copy number alterations in cell cycle genes. All patients had equal or reduced mutation counts during the therapeutic course, suggesting clonal selections by the therapies. Conclusions: EGFR C797S mutation was not observed in this series. Copy number alteration in GAS6-AXL pathway and cell cycle pathway could be targets of therapy. Citation Format: Atsushi Osoegawa, Masafumi Yamaguchi, Tomomi Nakamura, Ryotaro Morinaga, Kentaro Tanaka, Kosuke Kashiwabara, Kenichi Taguchi, Kazuki Nabeshima, Junji Kishimoto, Kenji Sugio. Revealing the mechanisms of acquired resistance to osimertinib from re-biopsy specimens in advanced non-small cell lung cancer with EGFR T790M mutation (LOGIK1607) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B004. doi:10.1158/1535-7163.TARG-19-B004

Objectives Chemoradiation regimens of greater efficacy are needed for patients with locally advanced non–small cell lung cancer (NSCLC). Patients and methods In a phase I study, escalating doses of weekly nab-paclitaxel (40 or 50 mg/m2) were administered along with weekly carboplatin at an area under the curve (AUC) of 2 mg mL–1 min and concurrent radiotherapy with 60 Gy in 30 fractions to patients with locally advanced NSCLC. This concurrent phase was followed by a consolidation phase consisting of two 3-week cycles of nab-paclitaxel plus carboplatin. In a phase II study, nab-paclitaxel was administered at the recommended dose (RD) together with carboplatin and radiation. Results In the phase I study, one of six patients experienced dose-limiting toxicity (leukopenia of grade 3 requiring a second consecutive skip in the administration of weekly chemotherapy) with nab-paclitaxel at 50 mg/m2, which was therefore determined to be the RD. Fifty-six patients treated at the RD were evaluable for safety and efficacy. Common toxicities of grade 3 or 4 in the concurrent phase included leukopenia (60.7%) and neutropenia (28.6%). No treatment-related deaths occurred during the study period. The objective response rate was 76.8% (95% confidence interval [CI], 64.2–85.9%), median progression-free survival was 11.8 months (60% CI, 10.6–16.2 months; 95% CI, 8.2–20.8 months), and median overall survival was not reached. Conclusion Our results reveal encouraging feasibility and activity for concurrent chemoradiation with nab-paclitaxel at 50 mg/m2 and carboplatin at an AUC of 2 in patients with locally advanced NSCLC.

Lessons Learned Updated survival data for a phase I/II study of carboplatin plus nab-paclitaxel and concurrent radiotherapy were collected. In the group of 58 patients who were enrolled at 14 institutions in Japan, the median overall survival was not reached and the 2-year overall survival rate was 66.1% (95% confidence interval, 52.1%–76.8%). Results reveal encouraging feasibility and activity for this regimen. Background We report the updated survival data for a phase I/II study of carboplatin plus nab-paclitaxel (nab-P/C) and concurrent radiotherapy (CRT) in patients with locally advanced non-small cell lung cancer (NSCLC). Methods Individuals between 20 and 74 years of age with unresectable NSCLC of stage IIIA or IIIB and a performance status of 0 or 1 were eligible for the study. Patients received weekly nab-paclitaxel at 50 mg/m2 for 6 weeks together with weekly carboplatin at an area under the curve (AUC) of 2 mg/ml/min and concurrent radiotherapy with 60 Gy in 30 fractions. This concurrent phase was followed by a consolidation phase consisting of two 3-week cycles of nab-paclitaxel (100 mg/m2 on days 1, 8, and 15) plus carboplatin (AUC of 6 on day 1). After the treatment, patients were observed off therapy. The primary endpoint of the phase II part of the study was progression-free survival (PFS). Results Between October 2014 and November 2016, 58 patients were enrolled at 14 institutions in Japan, with 56 of these individuals being evaluable for treatment efficacy and safety. At the median follow-up time of 26.0 months (range, 4.0–49.6 months), the median overall survival (OS) was not reached (95% confidence interval [CI], 25.3 months to not reached) and the 2-year OS rate was 66.1% (95% CI, 52.1%–76.8%). The median PFS was 11.8 months (95% CI, 8.2–21.0 months), and the 2-year PFS rate was 35.9% (95% CI, 23.1%–48.9%). Subgroup analysis according to tumor histology or patient age revealed no differences in median PFS or OS. Long-term follow-up of toxicities did not identify new safety signals, and no treatment-related deaths occurred during the study period. Conclusion Concurrent chemoradiation with nab-P/C was safe and provided a long-term survival benefit for patients with locally advanced NSCLC.

8529 Background: Chemoradiation regimens of greater efficacy are needed for patients with locally advanced non–small cell lung cancer (NSCLC). Methods: Patients between 20 and 74 years of age with unresectable NSCLC of stage IIIA or IIIB and a performance status of 0 or 1 were eligible for the study. In the phase II part of the study, patients received weekly nab-paclitaxel at 50 mg/m2 together with weekly carboplatin at an area under the curve (AUC) of 2 mg mL–1 min and concurrent radiotherapy with 60 Gy in 30 fractions. This concurrent phase was followed by a consolidation phase consisting of two 3-week cycles of nab-paclitaxel plus carboplatin. The primary end point of the phase II part of the study was progression-free survival (PFS). Results: Between October 2014 and November 2016, 58 patients were enrolled at 14 institutions in Japan, with 56 of these individuals being evaluable for treatment efficacy and safety. At the median follow-up time of 26.0 months (range, 4.0 to 49.6 months), the median overall survival (OS) was not reached (95% confidence interval [CI], 25.3 months to not reached) and the 2-year OS rate was 66.1% (95% CI, 52.1% to 76.8 %). The median PFS was 11.8 months (60% CI, 10.6 to 16.8 months; 95% CI, 8.2 to 21.0 months). The overall response rate was 76.8% (95% CI, 64.2% to 85.9%), and the disease control rate was 94.6% (95% CI, 85.4% to 98.2%). Subgroup analysis according to histology or age revealed no significant differences in median PFS or OS. Common toxicities of grade 3 or 4 in the concurrent phase included leukopenia (60.7%) and neutropenia (28.6%). Pneumonitis of grade 3 was observed in two patients during the study period. No treatment-related deaths occurred. Conclusions: Our results reveal encouraging feasibility and activity for concurrent chemoradiation with nab-paclitaxel at 50 mg/m2 and carboplatin at an AUC of 2 mg mL–1 min in patients with locally advanced NSCLC. Clinical trial information: UMIN000012719.

Summary Objectives Unsatisfactory efficacy of current treatments for advanced lung cancer has prompted the search for new therapies, with sorafenib, a multikinase inhibitor, being one candidate drug. This phase I trial was conducted to evaluate drug safety and pharmacokinetics as well as tumor response of sorafenib in combination with paclitaxel and carboplatin in patients with advanced non-small cell lung cancer (NSCLC). Methods Eligible patients received paclitaxel (200 mg/m2) and carboplatin (area under the curve [AUC]of 6 mg min mL−1) on day 1 and sorafenib (400 mg, twice daily) on days 2 through 19 of a 21-day cycle. Results Four of the initial six patients (cohort 1) experienced dose-limiting toxicities (DLTs), resulting in amendment of the treatment protocol. An additional seven patients (cohort 2) were enrolled, two of whom developed DLTs. DLTs included erythema multiforme, hand-foot skin reaction, and elevated plasma alanine aminotransferase in cohort 1 as well as gastrointestinal perforation at a site of metastasis and pneumonia in cohort 2. Most adverse events were manageable. One complete and six partial responses were observed among the 12 evaluable patients. Coadministration of the three drugs had no impact on their respective pharmacokinetics. Conclusion The present study confirmed that sorafenib at 400 mg once daily in combination with carboplatin AUC 5 mg min mL−1 and paclitaxel 200 mg/m2 is feasible in Japanese patients with advanced NSCLC. The results of this study also showed that this combination therapy had encouraging antitumor activity and was not associated with relevant pharmacokinetic interaction in Japanese NSCLC patients.

Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with the response to EGFR tyrosine kinase inhibitors in patients with non-small cell lung cancer (NSCLC). Increased EGFR copy number has also been associated with sensitivity to these drugs. However, given that it is often difficult to obtain sufficient amounts of tumor tissue for genetic analysis from patients with advanced NSCLC, the relationship between these two types of EGFR alterations has remained unclear. We have now evaluated EGFR mutation status both by direct sequencing and with a high-sensitivity assay, the Scorpion-amplification-refractory mutation system, and have determined EGFR copy number by fluorescence in situ hybridization (FISH) analysis in paired tumor specimens obtained from 100 consecutive patients with advanced NSCLC treated with chemotherapy. EGFR mutations or FISH positivity (EGFR amplification or high polysomy) were apparent in 18% (18/100) and 32% (32/100) of patients, respectively. The Scorpion-amplification-refractory mutation system was more sensitive than direct sequencing for the detection of EGFR mutations. Furthermore, EGFR mutations were associated with EGFR amplification (P = 0.009) but not with FISH positivity (P = 0.266). Our results therefore suggest the existence of a significant association between EGFR mutation and EGFR amplification in patients with advanced NSCLC.

Multidrug-resistant Pseudomonas aeruginosa, especially metallo-beta-lactamase (MBL)-producing P. aeruginosa, is an important pathogen in nosocomial infection and emergence of this pathogen has revived interest in polymyxin B (PMB) and colistin (COL). In this study, we evaluated the efficacies of PMB, COL and other antipseudomonal agents against IMP-type MBL-producing P. aeruginosa both in vitro and in vivo. A total of 75 isolates of bla(IMP)-positive P. aeruginosa obtained from clinical specimens (94.6% of isolates demonstrated resistance to beta-lactam, fluoroquinolone and aminoglycoside agents) were evaluated in the in vitro study. More than 90% of the examined isolates were susceptible to PMB (minimum inhibitory concentration for 50/90% of the isolates (MIC(50)/MIC(90)) 4/4 mg/L), although COL was less potent (MIC(50)/MIC(90) 8/16 mg/L). Cyclophosphamide-treated mice were intraperitoneally inoculated with bla(IMP)-positive P. aeruginosa. Treatment with PMB, but not COL, imipenem/cilastatin or aztreonam, significantly improved the survival rate and decreased the number of bacteria in the blood in a dose-dependent manner. Our results indicate that, among the agents studied, PMB is the most effective agent against bla(IMP)-positive P. aeruginosa.

We report a case of small cell lung cancer (SCLC) developing after prolonged treatment (more than 2 years) for primary adenocarcinoma of the lung, and we show that both the SCLC and non-small cell lung cancer (NSCLC) tissues obtained from the same site share the same deletion in exon 19 of EGFR. This case suggests that the activating EGFR mutations may confer the pathogenesis of a subset of SCLC.

A trial was conducted to evaluate the feasibility, efficacy, and safety of biweekly administration of irinotecan, a novel topoisomerase I inhibitor, for patients with metastatic breast cancer (MBC) previously treated with either anthracycline-based or taxane-based chemotherapy.Eligible patients were HER2-negative, had a performance status of 0 to 2, and had been treated previously with either anthracyclines or taxanes for MBC. Patients received irinotecan intravenously at 150 mg/m(2) on days 1 and 15 every 4 weeks. The primary end-point was feasibility, and the treatment was considered feasible if a patient was able to receive three administrations of irinotecan within the first 8 weeks, as pre-specified in the protocol.Eighteen patients (median age 60 years) were enrolled. Fifteen patients received irinotecan more than 3 times within the first 8 weeks, with resulting feasibility of 83.3%. The median number of treatment cycles was 2 (range 1-16) during this period, and the relative dose intensity was 91.2%. Partial response was observed for one patient, so overall response rate was 5.6%. Nine patients (50.0%) had stable disease, and overall disease control was 50.0%. Median progression-free survival and overall survival periods were 3.2 and 9.6 months, respectively. The only grade 3/4 hematological toxicity was neutropenia (22.2%). Grade 3/4 non-hematological toxicities were anorexia (11.2%), diarrhea (11.2%), and fatigue (5.6%). No treatment-related death occurred.This study demonstrated that biweekly administration of 150 mg/m(2) irinotecan was feasible for patients with MBC treated previously with anthracyclines or taxanes.

Background The oral multi-kinase inhibitor sunitinib malate improves the survival of patients with gastrointestinal stromal tumors (GIST) after the disease progresses or intolerance to imatinib mesylate develops. Urinary fistulae arising during treatment with sunitinib for GIST have not been described. Case presentation We describe a 62-year-old female patient diagnosed with unresectable GIST that involved the abdominal wall, urinary bladder wall, bowel, mesentery and peritoneum in the pelvic cavity. Intestinocutaneous fistulae developed on a surgical lesion after orally administered imatinib was supplemented by an arterial infusion of 5-flurouracil. Sunitinib was started after the patient developed resistance to imatinib. On day 4 of the fourth course of sunitinib, a widely dilated cutaneous fistula discharged large amounts of fluid accompanied by severe abdominal pain. Urinary communication was indicated based on the results of an intravenous injection of indigo carmine. Computed tomography findings suggested a small opening on the anterior urinary bladder wall and fistulous communication between the bladder and abdominal walls bridged by a subcutaneous cavity. The fistula closed and the amount of discharge decreased when sunitinib was discontinued. Therefore, sunitinib might have been associated with the development of the vesicocutaneous fistula in our patient. Conclusion This is the first description of a vesicocutaneous fistula forming while under sunitinib treatment. Clinicians should be aware of the possible complication of vesicocutaneous fistula formation during treatment with molecular targeting agents in patients with extravesical invasion and peritoneal dissemination of GIST.

A 53-year-old man was admitted to our department because of interstitial pneumonia found on chest computed tomography when he was given a diagnosis of amyopathic dermatomyositis. Bronchoalveolar lavage (BAL) fluid showed an increased total cell count and lymphocytosis. An acute exacerbation of interstitial pneumonia occurred just after the BAL. Although the administration of corticosteroid and immunosuppressant for the progressive interstitial pneumonia produced temporary improvement, left hemothorax suddenly occurred soon after initiating treatment. The hemothorax was improved by thoracic drainage alone, but the patient died due to progressive worsening of interstitial pneumonia. In this case, we could not clarify the etiological mechanism of the hemothorax, however, there was a possible link with amyopathic dermatomyositis-associated interstitial pneumonia.

A 30-year-old man, who had kept a dog for nine years and often ate raw beef liver, visited a hospital because of a chest nodular shadow in the left lung field found on a checkup examination. Chest computed tomography obtained 8 days after the checkup showed no abnormal shadow in the left lung but two nodular shadows with halos in the right upper and lower lobes. Peripheral blood eosinophil counts and serum IgE values were elevated. Immunological examination including microplate ELISA showed a high titer of specific antibody against Toxocara canis in the serum. He was successfully treated with albentazole. Parasitic disease, especially toxocariasis, is an important consideration in the differential diagnosis of migratory nodular shadow with a halo on chest computed tomography, and serology is useful in diagnosis screening.

A 72-year-old man, a Shiitake mushroom grower over fifty years, was admitted to our hospital because of bilateral chest interstitial shadow with chronic cough and breathlessness. Chest computed tomography showed traction bronchiectasis, subpleural micro-cystic changes and partial ground-glass opacities in both lungs, and mild mediastinal lymphadenopathy. A diagnosis of chronic hypersensitivity pneumonitis induced by Shiitake mushrooms was comprehensively confirmed by occupational history, radiological findings, and positive findings of an incidental environmental provocation test and lymphocyte stimulation test for Shiitake mushroom extracts. We reviewed the clinical features in five patients with chronic hypersensitivity pneumonitis induced by Shiitake mushrooms reported in Japan. There was a tendency toward increasing lymphocytes and high CD4/CD8 ratio in bronchoalveolar lavage fluids. Treatment with steroids seems to have a limited effect, while avoidance of the antigen is important.

A 63-year-old man had undergone excision of a growing mass with a wide margin in the left supraclavicular fossa. A diagnosis of fibrosarcomatous variant of dermatofibrosarcoma protuberans (DFSP-FS) was made. Three years later, an abnormal chest shadow was detected on a medical checkup. Chest computed tomography showed a heterogeneously-enhanced 2-cm coin lesion with a distinct border in the right lower lobe and a 3-mm nodule in the left lower lobe. Transbronchial lung biopsy specimens from the right lung revealed a DFSP pattern. We then performed right basal segmentectomy and partial resection of the left lower lobe. DFSP is a relatively rare skin tumor that is considered to be intermediate malignancy. It frequently recurs locally but rarely has systemic metastasis. However, DFSP-FS, a subtype of DFSP, has an increased likelihood of systemic metastasis. The lung is the most common site of metastasis of DFSP-FS. DFSP-FS sometimes recurs even a long time after excision. Therefore, long-term follow-up, including chest X-ray and CT are important in DFSP-FS patients.

A 61-year-old woman who had been followed up after resection of lung cancer (adenosquamous cell carcinoma), was admitted to our hospital because of recurrence. She received systemic anticancer chemotherapy and the chief adverse event was leukopenia (Grade 3). Nineteen days after initiating chemotherapy, she suffered painful vesicular eruption on the right upper limb and the right upper hemithorax which was diagnosed as herpes zoster. After treatment with anti-viral drugs the vesicular eruption disappeared, but chest X-ray film revealed a right diaphragmatic relaxation. Although herpes zoster virus usually affects sensory nerves and causes painful vesicular eruption, it can also damage motor nerves. Herpes zoster virus almost affects cranial nerves, but it should be considered as the cause of diaphragmatic paralysis in this case.

544 Background: Neurotoxicity is the most frequent dose-limiting toxicity of oxaliplatin. Cumulative sensory peripheral neurotoxicity results in discontinuation of chemotherapy for cancer and impairs neurological function irreversibly. To develop new strategies to continue chemotherapy according to the treatment plan without more severe neurotoxicity, objective assessment tools for oxaliplatin-induced peripheral neuropathy (OIPN) are needed. The clanging tuning fork test (CTFT) and the nerve conduction velocity test (NCVT) are widely used forbenign neuropathies. However, little is known about their clinical usefulness for OIPN. Methods: Colorectal cancer patients were prospectively monitored at baseline and during chemotherapy with modified FOLFOX6. The incidence and severity of OIPN were recorded using NCI-CTC grading (ver. 4.0). CTFT was conducted every 2 weeks and NCVT every 8 weeks. A generalized estimating equation model was used to examine the correlations between NCI-CTC grade and CTFT/NCVT. The accuracy of the assessment was evaluated using receiver operating characteristic (ROC) curve analysis. Results: Twenty-one patients without peripheral sensory neuropathy (PSN) were enrolled. Mean CTFT values were 13.4 ± 0.7 sec at baseline, 14.1 ± 0.4 sec with grade 0 PSN, 14.0 ± 0.4 sec with grade 1 PSN, 12.5 ± 0.7 sec with grade 2 PSN, and 7.5 ± 0.9 sec with grade 3 PSN. The mean CTFT value with grade 3 PSN was significantly shorter than with the other grades (p

This study was conducted to investigate the toxicity and efficacy of modified FOLFOX6 plus bevacizumab in patients with metastatic colorectal cancer with particular regard to oxaliplatin-induced neuropathy. Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) (version 3.0). The evaluation was especially focused on grade 2 oxaliplatin-induced neuropathy. The estimated median treatment time to occurrence of grade 2 sensory neuropathy was 7.3 months. The estimated median cumulative dose to occurrence of grade 2 sensory neuropathy was 931 mg/m2. This study clarified the treatment time from first dose as well as the cumulative dose of oxaliplatin leading to grade 2 neuropathy. It may be important to institute some clinical countermeasures when grade 2 neuropathy occurs so as to reduce the chance of progression to irreversible grade 3 neuropathy.

Background: BEZ235 is an oral, ATP-competitive inhibitor that targets class l PI3K and downstream effectors mTORC1/2. In previous phase I studies in mainly Western patients, the maximum tolerated dose (MTD) of single-agent BEZ235 solid dispersion system (SDS) sachet once daily (QD) was declared as 1200 mg and the recommended dose (RD) as 1000 mg; the MTD of the same formulation of BEZ235 twice daily (BID) was declared as 400 mg (Rodon EORTC-NCI-AACR 2012, Arkenau ASCO 2012). Here we present the results of a phase I, multicenter, open-label, dose escalation study of single-agent BEZ235 SDS sachet, administered QD or BID, in adult Japanese patients with advanced solid tumors (NCT01195376). Methods: Patients with histologically confirmed, unresectable advanced solid tumors not amenable to standard therapy, received continuous oral BEZ235, QD or BID in 28-day cycles. The primary objective was to determine the MTD/RD of single-agent BEZ235 in adult Japanese patients, based on dose-limiting toxicity (DLT) using a standard 3+3 method for dose escalation. MTD was defined as the highest dose causing DLT in no more than 1/6 patients in Cycle 1. Secondary objectives included preliminary antitumor activity (RECIST v1), safety profiles (CTCAE v3), and pharmacokinetics (PK). Results: As of Feb 10, 2013, 32 patients (mean age 58 yrs) were treated with BEZ235 at 2 dosing schedules; 27 patients received BEZ235 QD at 5 dose levels: 400, 800, 1000, 1200, or 1400 mg; and 5 patients received BEZ235 BID at 400 mg. 2 DLTs were reported with QD dosing: Grade 2 allergic reaction (1200 mg) and Grade 4 thrombocytopenia (1400 mg). Although equivalent DLT ratios were recorded at 1200 mg and 1400 mg (1/6 evaluable patients each), clinical observation led to 1200 mg being declared as the maximum, clinically tolerable dose and 1000 mg being declared as the RD of single-agent BEZ235 QD. The primary reason for discontinuation was disease progression (63%). Common suspected BEZ235-related AEs (≥40%) were diarrhea, decreased appetite, nausea, stomatitis, fatigue, vomiting, and rash; no difference in AE profile was observed between QD and BID schedules. Three patients experienced serious suspected BEZ235-related AEs: infectious enterocolitis, pneumonia, and diarrhea. No death related to treatment was reported. Best overall response was stable disease in 15/27 evaluable patients (56% disease control rate). After Feb 10, 2013, 3 additional patients were enrolled at 400 mg BID (8 in total) and 1 DLT (Grade 2 liver dysfunction) out of 6 evaluable patients was observed. PK data revealed a slow rate of absorption, less than dose-proportional exposure, and large interpatient variability for single-agent BEZ235 SDS sachet. Conclusions: The maximum, clinically tolerable dose of BEZ235 QD was declared as 1200 mg and the RD was declared as 1000 mg, in agreement with previous studies in Western populations. In addition, the tolerability of 400 mg BEZ235 BID was confirmed. The findings of this first-in-Japanese study suggest no major difference in BEZ235 tolerability and PK profile between Japanese and Western populations. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A167. Citation Format: Koichiro Watanabe, Hironobu Minami, Satoshi Otsu, Yoshinori Hirashima, Ryotaro Morinaga, Kazuo Nishikawa, Yasushi Hisamatsu, Toru Mukohara, Naomi Kiyota, Naoko Chayahara, Masanori Toyoda, Yoshinori Imamura, Yutaka Fujiwara, Cornelia Quadt, Matthew Robson, Kazuto Natsume, Takuji Aoki, Kuniaki Shirao. A phase I study of single-agent BEZ235 (SDS sachet), once- or twice-daily, in Japanese patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A167.

Purpose Chemotherapy-induced nausea and vomiting (CINV) is one of the major adverse events in patients receiving cancer chemotherapy. Preventing CINV is the key to maintaining a patient's quality of life. At Oita University Hospital, the antiemetic regimen was standardized based on the antiemetic guidelines for CINV published by the Japanese of Society Clinical Oncology (JSCO) in May 2010. In the present study, we retrospectively evaluated the clinical and economic effects of standardizing the antiemetic regimen. Methods Palonosetoron, dexamethasone aprepitant, was administered as antiemetics according to the newly standardized regime. The efficacy and costs of antiemetic treatment of chemotherapy before and after standardization of the antiemetic regimen between July 2010 and December 2010 were compared between patients receiving high-grade emetogenic chemotherapy (HEC) and those receiving moderate-grade emetogenic chemotherapy (MEC). The efficacy was evaluated by the proportion of patients without nausea ( Results A total of 50 and 38 patients were treated by the HEC and MEC regimens, respectively. In the HEC group, the proportion of patients without nausea (90.0% versus 92.0%) and complete response (89.0% versus 92.0%) were not significantly different between before and after the standardization. In the MEC group, the proportion of patients without nausea after the standardization was significantly higher than that before the standardization (94.7% and 76.7%, respectively, P Conclusion Using the standardized antiemetic treatment may help reduce the nausea or vomiting suffered by patients receiving cancer chemotherapy and will be less of a financial burden to these patients.

Background Erlotinib has been reported to be useful for treating EGFR mutation-positive (EGFR-mt) non-small cell lung cancer (NSCLC) (OPTIMAL ESMO 2010, EURTAC Lancet Oncol. 2012). However, its usefulness had not been investigated in Japanese patients. Hence, we conducted a multicenter phase II study to investigate the efficacy and safety of erlotinib in Japanese patients with pretreated EGFR-mt NSCLC. Methods Erlotinib, 150 mg/day, was orally administered daily to patients with pretreated EGFR-mt (exon 19/21) NSCLC who had not been treated with EGFR-TKIs. The primary endpoint was objective response rate (ORR), and the secondary endpoints were disease control rate (DCR), progression-free survival (PFS), and safety. Results Between April 2009 and January 2011, 26 patients were enrolled from 15 participating centers. The patient characteristics were as follows: median age, 68 years (51 to 79); men/women, 11/15; adenocarcinoma/others, 24/2; nonsmoking/smoking, 20/6; ECOG PS 0/1/2, 16/8/2; exon 19/21, 19/7; and 2nd/3rd line therapy, 25/1. The antitumor effect was as follows: PR, 14 patients; SD, 7 patients; PD, 4 patients; NE, 1 patient; ORR, 54%; and DCR, 81%. The ORR and DCR according to the EGFR status were 47.4%/71.4% (exon 19/21, p = 0.3913) and 73.7%/100% (p = 0.2782), respectively. The PFS was 9.3 months (range, 0.9 to 19.2 mo). Major adverse drug reactions were rash (96%) and hepatic function disorder (40%); most episodes were grade 2 or less, and all were tolerable. No patients developed interstitial lung disease, and there were no treatment-related deaths. Conclusion In this study, the usefulness of erlotinib was investigated prospectively in Japanese patients with pretreated EGFR-mt NSCLC for the first time, and this drug was shown to be effective and tolerable. At this congress, we will report the study results including the ORR and PFS according to the patient characteristics. Disclosure Y. Nakanishi: From Chugai Pharmaceutical, I received 7500 Euro as honoraria on 2011, and 22000 Euro on 2010 and 70000 Euro on 2011 as research grant. Y. Ichinose: I have research funding with Chugai Pharmaceutical company. All other authors have declared no conflicts of interest.