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Comprehensive genomic profiling has been approved for use in patients with advanced solid tumours; however, it is only indicated in advanced solid tumour patients without available standard chemotherapeutic treatment or those who have completed standard treatments in Japan, and there are no available data on the clinical feasibility and utility of comprehensive genomic profiling in treatment-naive patients. This multicentre, single-arm, prospective study aims to evaluate the feasibility and utility of the OncoGuide NCC Oncopanel System in treatment-naive patients with six advanced major malignancies: non-small cell lung cancer, breast cancer, gastric cancer, colon cancer, pancreatic cancer and biliary tract cancer (NCCH1908). This study (study cohort) will be compared with the other prospective observational study (control cohort), which enrols patients not receiving comprehensive genomic profiling prior to initial systemic treatment. A total of 200 patients will be enrolled in the study over 21 months. This study has been registered in the UMIN Clinical Trials Registry (www.umin.ac.jp/ctr/) (UMIN000040743). Clinical trial registration This study, initiated in June 2020, has been registered in the UMIN Clinical Trials Registry (www.umin.ac.jp/ctr/) (registration number: UMIN000040743). We plan to enrol a total of 200 patients over a period of 21 months.

Comprehensive genomic profiling (CGP) is being increasingly used for the routine clinical management of solid cancers. In July 2018, the use of tumor tissue‐based CGP assays became available for all solid cancers under the universal health insurance system in Japan. Several restrictions presently exist, such as patient eligibility and limitations on the opportunities to perform such assays. The clinical implementation of CGP based on plasma circulating tumor DNA (ctDNA) is also expected to raise issues regarding the selection and use of tissue DNA and ctDNA CGP. A Joint Task Force for the Promotion of Cancer Genome Medicine comprised of three Japanese cancer‐related societies has formulated a policy proposal for the appropriate use of plasma CGP (in Japanese), available at https://www.jca.gr.jp/researcher/topics/2021/files/20210120.pdf, http://www.jsco.or.jp/jpn/user_data/upload/File/20210120.pdf, and https://www.jsmo.or.jp/file/dl/newsj/2765.pdf. Based on these recommendations, the working group has summarized the respective advantages and cautions regarding the use of tissue DNA CGP and ctDNA CGP with reference to the advice of a multidisciplinary expert panel, the preferred use of plasma specimens over tissue, and multiple ctDNA testing. These recommendations have been prepared to maximize the benefits of performing CGP assays and might be applicable in other countries and regions.

Somatic genetic alteration analysis was performed for post-hysterectomy high-risk early-stage uterine cervical cancer patients who underwent post-operative radiation therapy. Post-operative radiation therapy was performed for patients with pathological features of pelvic lymph node metastasis, parametrium invasion, or positive vaginal margin, which corresponded to the post-operative high-risk category. DNA was extracted from paraffin-embedded surgical specimens, and 50 somatic hotspot genetic alternations were detected using Ion AmpliSeq Cancer Hotspot Panel. The existence of actionable mutation was assessed based on OncoKB evidence level > 3A. Between January 2008 and November 2019, 89 patients who underwent abdominal radical hysterectomy followed by post-operative radiation therapy were identified. The follow-up period for living patients was 82.3 months (range 9.3–153.9), and the 5-year relapse-free survival and overall survival rates were 72.6% and 85.9%, respectively. The most frequently detected somatic mutation was PIK3CA (26 [29.2%] patients); however, no prognostic somatic genetic alterations were identified. Actionable mutations were detected in 30 (33.7%) patients. Actionable mutations were detected in approximately one-third of patients, suggesting that precision medicine can be offered to patients with post-operative high-risk uterine cervical cancer in the near future.

Two cases of pediatric lung cancer (in 23-month-old and 6-year-old boys) resulting from mother-to-infant transmission of uterine cervical tumors were incidentally detected during routine next-generation sequencing of paired samples of tumor and normal tissue. Spontaneous regression of some lesions in the first child and slow growth of the tumor mass in the second child suggested the existence of alloimmune responses against the transmitted tumors. Immune checkpoint inhibitor therapy with nivolumab led to a strong regression of all remaining tumors in the first child. (Funded by the Japan Agency for Medical Research and Development and others; TOP-GEAR UMIN Clinical Trials Registry number, UMIN000011141.).

Tyrosine kinase inhibitors are used as first-line treatment for non-small cell lung cancer (NSCLC) patients harboring driver mutations in EGFR, ALK, ROS1, and BRAF. Currently, standard molecular testing approaches help identify single genes for such targetable driver mutations in NSCLC; however, next-generation sequencing (NGS)-based genetic profiling provides a more comprehensive approach and is hence strongly recommended. This case study aimed to highlight the benefits of NGS-based tests for the diagnosis of complex EGFR L858R mutations. A patient was diagnosed with stage IVB NSCLC using a government-approved in vitro diagnostic test and was noted to have a high programmed death-ligand 1 tumor proportion score. This patient was treated with pembrolizumab monotherapy followed by cisplatin and pemetrexed owing to the lack of actionable driver gene mutations, including EGFR mutations. After treatment failure, a sample harvested from the same transbronchial lung biopsy specimen (formalin-fixed and paraffin-embedded) used for the initial EGFR test was subjected to NGS-based broad genetic profiling. The NGS-based test identified an EGFR L858R-K860I cis doublet mutation; however, neither of these mutations was identified upon initial molecular testing. The patient was then successfully treated with a third-generation EGFR-tyrosine kinase inhibitor, osimertinib. In this study, we delved deeper into the realm of L858R and K860I mutations in NSCLC and discuss the potential causes underlying our initial negative diagnosis. Furthermore, this study highlighted the additional benefits of replacing typical molecular tests with NGS-based broad profiling approaches. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: The EGFR L858R-K860I cis doublet mutation was not detected by a PCR-based EGFR test. A next generation sequencing (NGS)-based test was able to identify the L858R-K860I cis doublet mutation. WHAT THIS STUDY ADDS: Osimertinib was effective in an NSCLC patient with EGFR L858R and K860I mutations.

Next-generation sequencing (NGS) of tumor tissue (ie, clinical sequencing) can guide clinical management by providing information about actionable gene aberrations that have diagnostic and therapeutic significance. Here, we undertook a hospital-based prospective study (TOP-GEAR project, 2nd stage) to investigate the feasibility and utility of NGS-based analysis of 114 cancer-associated genes (the NCC Oncopanel test). We examined 230 cases (comprising more than 30 tumor types) of advanced solid tumors, all of which were matched with nontumor samples. Gene profiling data were obtained for 187 cases (81.3%), 111 (59.4%) of which harbored actionable gene aberrations according to the Clinical Practice Guidelines for Next Generation Sequencing in Cancer Diagnosis and Treatment (Edition 1.0) issued by 3 major Japanese cancer-related societies. Twenty-five (13.3%) cases have since received molecular-targeted therapy according to their gene aberrations. These results indicate the utility of tumor-profiling multiplex gene panel testing in a clinical setting in Japan. This study is registered with UMIN Clinical Trials Registry (UMIN 000011141).

The year 2019 was considered to be the first year of cancer genome medicine in Japan, with three gene-panel tests using next-generation sequencing (NGS) techniques being introduced into clinical practice. Among the three tests, the Oncomine CDx Target test was approved under the category of regular molecular testing for lung cancer, which meant that this test could be used to select patients for molecularly targeted drugs. Conversely, the other two tests, NCC OncoPanel and FoundationOne CDx, were assigned to be used under the National Cancer Genome Medicine Network, and implementation was restricted to patients for whom standard treatment was completed or expected to be completed. These NGS tests can detect a series of genetic alterations in individual tumors, which further promotes the development of therapeutic agents and elucidates molecular pathways. The NGS tests require appropriate tissue size and tumor cell content, which can be accessed only by pathologists. In this report, we review the current reimbursement schema in our national healthcare policy and the requirements of the specimens for NGS testing based on the recently published 'Guidance of Gene-panel Testing Using Next-Generation Sequencers for Lung Cancer', by the Japanese Society of Lung Cancer.

Thymic carcinoma (TC) is a rare cancer with minimal evidence of survival following palliative‐intent chemotherapy. Sunitinib, everolimus, and pembrolizumab have been proposed as active agents based on previous phase II trials. In this phase II study, TC patients previously treated with platinum‐based chemotherapy were enrolled. The patients received S‐1 orally twice daily at a dose of 40‐60 mg/m2 for 4 weeks, followed by 2 weeks off until the progression of the disease or the presence of unacceptable toxicities. The primary endpoint was the objective response rate (ORR), and secondary endpoints were progression‐free survival (PFS), overall survival (OS), and safety. The sample size of 26 patients was planned to reject the ORR of 10% under the expectation of 30% with a power of 0.80 and a type I error of 0.05 (one‐sided). Twenty‐six patients were recruited between 2013 and 2016; 23 patients had squamous cell carcinoma and 10 had an ECOG performance status of 0. One patient showed complete response and seven patients showed partial responses, resulting in a 30.8% response rate (90% confidence interval [CI], 18.3‐46.9) and an 80.8% disease control rate (90% CI, 65.4‐90.3). The median PFS was 4.3 months (95% CI, 2.3‐10.3 months) and median OS was 27.4 months (95% CI, 16.6‐34.3). Adverse events of grade ≥ 3 included neutropenia (12%), skin rash (8%), elevated alanine aminotransferase, and fatigue (4%). No treatment‐related death was observed. S‐1 confirmed clinical activity with tolerability in patients with previously treated TC. (UMIN000010736)., Not a few patients of TC can be treated with S‐1 in a longer period. The toxicity of S‐1 was also acceptable. S‐1 is a promising drug for TC with easy accessibility and low cost.

In this phase Ib study, four combination therapies of nivolumab 10 mg/kg and standard chemotherapy (cisplatin/gemcitabine, cisplatin/pemetrexed, carboplatin/paclitaxel/bevacizumab, or docetaxel) showed acceptable toxicity profiles in patients with advanced non-small-cell lung cancer. Furthermore, these combination therapies presented encouraging antitumor activities., Background The human IgG4 monoclonal antibody nivolumab targets programmed cell death-1 (PD-1) and promotes antitumor response by blocking the interaction of PD-1 with its ligands. This single-center phase Ib study investigated the tolerability, safety, and pharmacokinetics of nivolumab combined with standard chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods Patients who had stage IIIB without indication for definitive radiotherapy, stage IV, or recurrent NSCLC were eligible. Regimens were nivolumab 10 mg/kg + gemcitabine/cisplatin (arm A), pemetrexed/cisplatin (arm B), paclitaxel/carboplatin/bevacizumab (arm C), or docetaxel (arm D). Regimens A, B, and D were repeated every 3 weeks for up to four cycles and regimen C was repeated for up to six cycles; nivolumab alone (arm A), with pemetrexed (arm B), bevacizumab (arm C), or docetaxel (arm D) was continued every 3 weeks as maintenance therapy until disease progression or unacceptable toxicity. Dose-limiting toxicity (DLT) was evaluated during the first treatment cycle. Results As of March 2014, six patients were enrolled in each arm. The combination of nivolumab 10 mg/kg and chemotherapy was well tolerated. DLT was observed in only one patient in arm A (alanine aminotransferase increased). Select adverse events (those with a potential immunologic cause) of any grade were observed in six, four, six, and five patients in arms A, B, C, and D, respectively. Three, three, six, and one patient achieved partial response while median progression-free survival was 6.28, 9.63 months, not reached, and 3.15 months in arms A, B, C, and D, respectively. Conclusions Combination of nivolumab 10 mg/kg and chemotherapy showed an acceptable toxicity profile and encouraging antitumor activity in patients with advanced NSCLC. Clinical trials number Japanese Pharmaceutical Information Center Clinical Trials Information (JapicCTI)-132071.

Objective Cervical cancer is the fourth most common cause of cancer-related deaths in Asian women, due to its poor prognosis. This study aimed to decipher genomic alteration profiles of a cohort of Japanese cervical cancer patients to understand why certain patients benefited from molecular targeted therapies and their prognostic significance. Methods During 2008–2018, 154 cervical cancer patients underwent a potentially curative resection procedure at the National Cancer Center Hospital. Genomic DNA samples were analyzed using Ion AmpliSeq™ Cancer Hotspot Panel v2. Alterations in the copy number of PIK3CA, ERBB2, PTEN, and STK11 were detected using the TaqMan assay. HPV-positive results were confirmed by genomic testing and in situ hybridization assay. Results The frequency of genomic alterations in PIK3CA (36%), STK11 (16%), PTEN (11%), TP53 (11%), and KRAS (8%) was >5%. KRAS mutations were preferentially detected in patients with adenocarcinomas, and the frequency of PIK3CA mutations in patients with squamous cell carcinomas was higher than that in patients with other histological cancer types. HPV-positive results were observed in 139/154 (90.3%) patients, and TP53 mutants were detected in HPV-negative specimens. In this study, the overall survival of patients with genomic alterations in STK11 was worse than in patients with wild–type STK11 (hazard ratio = 10.6, P = 0.0079) and TCGA dataset (hazard ratio = 2.46, P = 0.029). Conclusions More than one-third of Japanese cervical cancer patients exhibit mutations targeted by molecular targeted therapies. We have proposed the prognostic value of STK11 genomic alterations.

A vitamin B12 supplement is required in pemetrexed single agent therapy. Intramuscular administration is the method of choice; however, oral administration is simpler and easier and may be sufficiently effective. We conducted a Phase II study to evaluate the safety of oral administration of vitamin B12 in patients with advanced non-small cell lung cancer who received pemetrexed single agent therapy. Folic acid and vitamin B12 were given orally for ˃1 week before pemetrexed administration. The primary end-point was onset of a grade ≥3 neutropenia ratio (50 % of threshold expression ratios; an expectation expression ratio of 21 %; α, 0.05; β, 0.1). Blood concentration of folic acid and homocysteine which are markers of vitamin B12 deficiency were also examined (UMIN000003180). A total of 25 cases were registered from February 2010 to July 2014. The ratio of grade ≥3 neutropenia was 36 % (95 % CI 22–52 %). Grade ≥3 non-hematologic toxicity and hematologic toxicity were seen in 20 % (5 cases) and 44 % (11 cases) of patients, respectively. In addition, the homocysteine blood concentration just before the first cycle dosage of pemetrexed was significantly elevated relative to the 2–3 cycle. This study failed to meet its primary endpoint. We could not demonstrate the safety and efficacy of the 1-week vitamin B12 oral administration protocol as compared with intramuscular administration.

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

The recommended dose of erlotinib is 150 mg daily either 1 h before a meal (complete fasting) or 2 h after a meal (2 h post-meal), because of the food effect. We conducted a cross-over pharmacokinetic study to compare the fed bioequivalence in the two conditions. Twenty-three patients with non-small cell lung cancer were included in the analysis. AUC0–24 and C max in the 2-h post-meal status were significantly higher than in the complete fasting status (GMR = 1.33, P

Background. Prior supplementation with folic acid and vitamin B12 is required to reduce pemetrexed therapy toxicity; the recommended lead-in time is at least 7 days. On the basis of previous pharmacokinetic and clinical studies, we hypothesized that the lead-in time could be shortened to 24 hours, enabling earlier commencement of standard chemotherapy; thus, we planned the first prospective trial of this regimen. Methods. Patients with advanced nonsquamous non-small cell lung cancer who had not previously received cytotoxic chemotherapy were enrolled. After measurement of homocysteine concentrations, the patients received 1,000 μg of vitamin B12 by intramuscular injection and began taking 350–500 μg of oral folic acid daily. Starting 24–48 hours after the vitamin B12 injection, the patients received intravenous 500 mg/m2 pemetrexed and 75 mg/m2 cisplatin for 4 cycles at 3 weekly intervals. The primary endpoint was the proportion of patients who developed neutropenia grade ≥3. Results. Thirty patients received chemotherapy starting within 48 hours of the vitamin B12 injection. No treatment-related deaths or grade 4 toxicity occurred. Neutropenia grade ≥3, other laboratory toxicities grade ≥3, and nonlaboratory toxicities grade ≥3 occurred in 6.7%, 13%, and 13% of patients, respectively. The baseline homocysteine concentrations were not higher in patients with grade ≥3 toxicities than in the remainder of the cohort (mean values, 8.6 and 10.7 μmol/L, respectively). The response rate to chemotherapy was 43%. Conclusion. The shortened vitamin supplementation was well tolerated and retained antitumor efficacy. Analysis of baseline homocysteine concentrations confirmed the efficacy of short-term vitamin supplementation.

Background Thymic carcinoma is a rare neoplasm of the thymus, and information regarding its genetic profile and optimal medical treatment is limited. We sought to characterize the genetic profile of thymic carcinoma and to evaluate the efficacy of various medical treatments, including treatment with tyrosine kinase inhibitors (TKIs), cytotoxic agents, and immune checkpoint inhibitors. Methods We retrospectively reviewed medical records of 64 consecutive patients with thymic carcinoma at the National Cancer Center Hospital between April 1973 and March 2014. We analyzed treatment course of patients who underwent medical treatment involving investigational drugs. For patients with available tissue samples, targeted sequencing of 50 cancer-related genes using next-generation sequencing was performed. Results Thirty-six patients had received chemotherapy. Median progression-free survival in patients receiving first-line chemotherapy was 7.07 months (95% confidence interval, 5.67–8.93). Median survival time was 32.6 months (95% confidence interval, 23.2–43.4). As second- or later-line chemotherapy, a total of 13 patients were treated with 24 investigational drugs, including 8 multi-targeted TKIs, 5 cytotoxic agents, and 2 immune checkpoint inhibitors. Six (24%) of the patients treated with investigational drugs maintained disease control for at least 6 months. Tissue samples of 52 patients (81.3%) were available for targeted sequencing, consisting of 52 formalin-fixed, paraffin-embedded (FFPE) and 16 fresh frozen tissue samples. The genetic alterations of TP53 , KRAS , FBXW7 , and NRAS were detected in 7 patients (13.5%), and no KIT mutations were noted. Conclusions Multi-targeted TKIs exhibited potential clinical efficacy for previously-treated thymic carcinoma. The frequency of genetic alterations in this study was low, with no apparent relationship with the efficacy of chemotherapy.

Inhibition of transforming growth factor-beta receptor I (TGF-beta RI)-mediated signaling pathways blocks tumor growth and metastases in nonclinical studies. Galunisertib (LY2157299), a small molecule inhibitor of TGF-beta RI serine/threonine kinase, had antitumor effects with acceptable safety/tolerability in a first-in-human dose (FHD) study conducted mainly in Caucasian patients with glioma. In this nonrandomized, open-label, dose-escalation study, we assessed safety/tolerability, pharmacokinetics (PK), and tumor response in Japanese patients.Patients with advanced and/or metastatic disease refractory were assigned sequentially to Cohort-1 (80 mg) or Cohort-2 (150 mg) of galunisertib, administered twice daily and treated using 2-week on, 2-week off treatment cycles. Dose escalation was guided by predefined PK criteria and dose-limiting toxicities (DLT). Safety assessments included treatment-emergent adverse events (TEAEs) and cardiac safety (ultrasound cardiography/Doppler imaging, electrocardiogram, chest computed tomography, and cardiotoxicity serum biomarkers).Twelve patients (Cohort-1, n = 3; Cohort-2, n = 9) were enrolled and the most common types of cancer were pancreatic (n = 5) and lung cancer (n = 3). Seven patients (Cohort-1, n = 2; Cohort-2, n = 5) experienced possibly galunisertib-related TEAEs. The most frequent related TEAEs were brain natriuretic peptide increased (n = 2), leukopenia (n = 2), and rash (n = 2). No cardiovascular toxicities or other DLTs were reported. PK profile of galunisertib was consistent with the FHD study. Maximum plasma concentration was reached within 2 h post-dose, and the mean elimination half-life was 9 h.Galunisertib had an acceptable tolerability and safety profile in Japanese patients with advanced cancers. CLINICATRIALS.GOV.NCT01722825.

CD5-positive (CD5+) diffuse large B-cell lymphoma (DLBCL) shows poor prognosis and frequent central nervous system (CNS) relapses under anthracycline-containing chemotherapy. The aim of this study was to determine the prognosis and CNS relapse incidence of CD5+ DLBCL in the rituximab era.We analyzed 337 patients with CD5+ DLBCL who received chemotherapy with (R-chemotherapy group; n = 184) or without (chemotherapy group; n = 153) rituximab.No significant difference was found in clinical background comparisons between the two groups. In the R-chemotherapy group, 60% of the patients were older than 65 years at diagnosis. Both the complete response rate and overall survival (OS) were significantly better in the R-chemotherapy group (P = 0.0003 and P = 0.002, respectively). Multivariate analysis confirmed that chemotherapy without rituximab was associated with unfavorable OS. However, the probability of CNS relapse did not differ between the two groups (P = 0.89). The CNS relapse was strongly associated with short OS (P0.0001). In the R-chemotherapy group, 83% of patients who experienced CNS relapse had parenchymal disease.Our results indicate that rituximab improves the OS of patients with CD5+ DLBCL but does not decrease the CNS relapse rate. More effective treatments with CNS prophylaxis are needed for CD5+ DLBCL patients.

[Background] The bioavailability of several oral anticancer drugs changes with food exposure. The recommended dose of erlotinib (E) is 150 mg daily either one hour before a meal (complete fasting) or two hours after a meal (post-meal), because of the food effect. Although the two gastric emptying states have been considered equivalent in clinical practice, no study had in fact demonstrated the fed bioequivalence in the two conditions. [Methods] We conducted a cross-over pharmacokinetic study in Cohort A (post-meal to complete fasting) and Cohort B (complete fasting to post-meal); seven days in each fed condition period. Blood samples were obtained just before administration of E on days 1, 2, 5, 7, 8, 9, 12, and 14, and at 1, 2, 4, 6, 8, 10, and 24 hours after administration on days 7 and 14. Area under the curve from 0 to 24 hours (AUC0-24), mean residence time (MRT) from 0 to 24 hours, peak concentration (Cmax), and time to Cmax (Tmax) were estimated by noncompartment analysis. Statistical analysis in the ln-transformed AUC0-24 and Cmax of E was performed using a two-sample t-test with unequal variance, and the ratios of geometric means (GMR) were calculated for AUC0-24 and Cmax. Time to first skin rash was analyzed with a Kaplan-Meier curve compared with the log-rank test, with P < 0.05 considered significant. [Results] Twenty-five patients were randomly assigned, and 23 patients (12 in Cohort A and 11 in Cohort B) were included in the pharmacokinetic analysis. The geometric mean of AUC0-24 was significantly higher in the post-meal status than in the complete fasting status (41.5 ± 11.2 vs. 31.0 ±13.7 μg*h/mL; P < .001) and GMR was 1.33, and likewise in the geometric mean of Cmax (2.64 ± 0.77 vs. 1.83 ± 0.82 μg/mL; P < .001), and GMR was 1.44. Tmax was also significantly longer in the post-meal status (P = .014) while MRT was significantly longer in the complete fasting status (P < .001). Alteration in AUC0-24, Cmax, Tmax, and MRT on day 7 suggested that the two gastric emptying states might differ in their absorption. However, because the concentration of E did not reach the steady state within seven days in the complete fasting group, we conducted further analyses only on day 14. No significant difference between the complete fasting and post-meal condition was seen in AUC0-24 (P = .815), nor in Cmax (P = .564). GMRs were 1.08 in Cmax, and 1.03 in AUC. In Cohort A, a skin rash appeared in 50% in eight days, and in 83% in 15 days. In Cohort B, a skin rash was seen in 64% in 8 days, and in 82% in 15 days. There was no significant association between time to first skin rash of any grade and the two conditions (P = .974). [Conclusion] Although the AUC0-24 of E increased significantly faster in the post-meal status than in complete fasting status, there was no significant difference in pharmacokinetics in steady state and toxicitiy between the two clinically-used fed conditions of E. Citation Format: Yuki Katsuya, Yutaka Fujiwara, Kuniko Sunami, Hirofumi Utsumi, Yasushi Goto, Shintaro Kanda, Hidehito Horinouchi, Hiroshi Nokihara, Noboru Yamamoto, Yuichiro Ohe, Satoko Osawa, Akinobu Hamada. Comparison of the pharmacokinetics of erlotinib administered in complete fasting and two hours after a meal in non-small cell lung cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4509. doi:10.1158/1538-7445.AM2015-4509

Background: The phase II NEJ001 trial suggested that gefitinib was active against advanced non-small cell lung cancer (NSCLC), even in patients with poor performance status (PS). Because the NEJ001 trial established definitive clinical evidence, and a further phase III trial may not be required, there is little additional information on the clinical outcomes of gefitinib in poor PS patients. Patients and methods: This was a retrospective review of patients with EGFR mutation-positive NSCLC and poor PS (PS ≥2 for patients >75 years or PS 3 or 4 for patients of any age) who were treated with first-line gefitinib between 2004 and 2013 at Tokyo Metropolitan Cancer and Infectious Diseases Center at Komagome Hospital. Results: A total of 52 patients (median age, 75 years; range, 54–87 years) met the inclusion criteria. The overall response rate was 65.4%. The median progression-free survival, median survival time, and one-year survival rate were 6.6 months, 19.6 months, and 62.9%, respectively. Gefitinib was terminated in 17 patients (32.7%) due to toxicity (6 patients due to interstitial lung disease, 3 patients due to inability to continue oral intake, and 3 patients due to elevated transaminase levels). Conclusions: Gefitinib is effective in patients with poor PS, even in the clinical setting. The overall response rate, progression-free survival, and median survival time were similar to those in NEJ001. As in NEJ001, progression-free survival was shorter than reported in clinical trials for patients with EGFR mutation and good PS.

Aim: ONO-4538 (BMS-936558, nivolumab) is a fully human monoclonal antibody targeting PD-1 (programmed cell death 1) and enhances antitumor activity by blocking PD-1 / PD-L1·L2 (programmed cell death 1 ligand 1·2) binding that down-regulates T-cell co-stimulatory signal. This phase I study investigated the tolerability, safety and pharmacokinetics of ONO-4538 in combination with chemotherapy in Japanese patients with advanced non-small-cell lung cancer (NSCLC). Methods: Patients who have stage IIIB without indication for definitive radiotherapy, stage IV, or recurrent NSCLC were eligible. ONO-4538 (10 mg/kg, day 1) and chemotherapy [Arm A: cisplatin (80 mg/m2, day 1) / gemcitabine (1250 mg/m2, day 1 and 8), Arm B: cisplatin (75 mg/m2, day 1) / pemetrexed (500 mg/m2, day 1), Arm C: carboplatin (AUC 6, day 1) / paclitaxel (200 mg/m2, day 1) / bevacizumab (15 mg/kg, day 1), Arm D: docetaxel (75 mg/m2, day 1)] were administered every three weeks. Arm A and B were administrated for four cycles and Arm C was for six cycles as first-line chemotherapy. After that, ONO-4538 in Arm A, ONO-4538 / pemetrexed in Arm B, and ONO-4538 / bevacizumab in Arm C were continued every three weeks as maintenance therapy until disease progression. Arm D were administrated until disease progression as second-line chemotherapy. Dose limiting toxicity was evaluated during the first treatment cycle. Results: As of April 10, 2014, six patients each in Arms A to D, total 24 patients [male / female: 17 / 7, PS 0 / 1: 11 / 13), aged 34-73 (median 63) years] were enrolled. Dose limiting toxicity was observed in one patient in Arm A (ALT increased). Severe adverse events were reported in eight patients. Two patients in Arm A, 3 in Arm B, 5 in Arm C, and 1 in Arm D achieved partial response (evaluated by RECIST version 1.1). Conclusions: ONO-4538 10 mg/kg showed acceptable toxicity profile and encouraging antitumor activity in combination with chemotherapy in Japanese patients with advanced NSCLC. Disclosure: T. Tamura: TT has a commercial research grant from Chugai, BMS, Boehringer Ingelheim, Yakult, Abbott, GSK, Eli Lilly, Ono, Kirin, and Quintiles Transnational Japan; and has a honoraria from Taiho, Chigai, and Eli Lilly. All other authors have declared no conflicts of interest.

Aim: KRAS, a member of the RAS oncogene family, is known to be mutated at exon2 or exon3 in approximately 15%–30% of patients with advanced non-small cell lung cancer (NSCLC). The influence of mutated KRAS on the efficacy of chemotherapy or patient prognosis has been reported with some variability in magnitude, depending on the report. Notably, the influence of KRAS mutation in patients with potentially curable stage III NSCLC remains unknown. Methods: We evaluated the presence of KRAS mutations in consecutive non-squamous NSCLC patients who received chemoradiotherapy (CRT) between January 2001 and December 2010 at the National Cancer Center Hospital. The KRAS mutational analysis of exon2 (codon12 and codon13) was performed using a high-resolution melting analysis (HRMA). The response rate (RR), relapse-free survival (RFS), first relapse sites, survival post-progression (SPP), and overall survival (OS) were investigated according to the KRAS mutational status. Results: A total of 274 non-squamous NSCLC patients received CRT during the study period. Of these, sufficient specimens for mutational analysis could be obtained from 119 patients. Patients with KRAS mutations (Mt) were found at a frequency of 13% (16 out of 119). No significant differences in sex, age, smoking-index, clinical stage, or therapeutic regimens were observed between the Mt and wild-type KRAS (Wt) groups. The Mt group had a lower RR (63% vs. 81%) and a shorter median RFS (6.1 months vs. 10.9 months, P = 0.083). Regarding the first relapse sites, the Mt group had fewer local relapses (0% vs. 23%) and more brain metastases (46% vs. 12%). After disease relapse, the Mt group had a significantly shorter median SPP (2.5 months vs. 7.3 months, P = 0.028) and a shorter median OS (15.1 months vs. 29.1 months, P = 0.022). Conclusions: Among the stage III non-squamous NSCLC patients who received definitive CRT, 13% had KRAS mutations. The Mt group experienced more distant relapses (mainly in the brain) as their first relapses and had a significantly shorter survival time. Disclosure: All authors have declared no conflicts of interest.

Aim: The aim of this trial was to evaluate the safety and efficacy of oral hydration as a substitute for intravenous (IV) hydration after CDDP administration. Methods: The major eligibility criteria included patients with lung cancer, indications for a CDDP-based regimen at a dose of 60 mg/m2 or higher, an age of between 20 and 74 years, and adequate renal function. Antiemetic prophylaxis consisted of an appropriate dose of palonosetron, aprepitant and dexamethasone. CDDP was administered after IV pre-hydration with MgSO4 (8 mEq) and KCL. Five hundred milliliters of commercially available oral hydration solution (OS-1®: Otsuka Pharmaceutical Factory, Inc., Japan) was used as a substitute for IV post-hydration and was administered orally within an hour after CDDP administration. OS-1® contains 50 mEq/L of NaCl, 20 mEq/L of K and 2 mEq/L of MgSO4. The primary endpoint was the proportion of patients without a grade (G) 2 or higher creatinine (Cr) elevation after the first cycle of chemotherapy. The planned sample size was 46 to reject a proportion of 70% under an expectation of 88% with a power of 90% and an alpha error of 5%. Results: Between May and November 2013, 31 men and 15 women with a median (range) age of 64 (33-74) years were enrolled from three institutions. Of these, 5 received adjuvant chemotherapy, 17 received definitive chemoradiotherapy, and 24 received chemotherapy for advanced diseases. All the patients were able to consume OS-1® within 1 hour without requiring IV post-hydration. The median (range) number of chemotherapy cycles was 4 (3-5). Seven patients received additional IV hydration on day 2 or later, with a median duration (range) of 2 (1-19) days, mainly because of chemotherapy-related anorexia. After the first cycle of CDDP administration, none of the patients experienced a Cr elevation of G 2 or higher, thereby meeting the primary endpoint. Of the 46 patients, 45 (97.8%) completed the CDDP-based chemotherapy without G 2 or higher renal dysfunction. The only patient who experienced a G 2 elevation in Cr (maximum value, 1.97 mg/dL) experienced G 3 chemotherapy-induced diarrhea and exhibited a prompt improvement in the Cr level to 1.11 mg/dL after the resolution of the diarrhea. Conclusions: Oral hydration can be used as a safe and convenient substitute for IV post-hydration for CDDP administration at the standard dose. Disclosure: K. Kubota: Honoraria from TAIHO PHARMACEUTICAL CO., LTD.; All other authors have declared no conflicts of interest.

Background Although several agents have been introduced for the treatment of relapsed small-cell lung cancer (SCLC), there is still only limited evidence regarding second- and later-line chemotherapies for these patients. Patients and Methods Consecutive patients with relapsed SCLC treated at the National Cancer Center Hospital between 2000 and 2014 were analyzed. Patients' characteristics and treatments to explore factors associated with the survival outcomes were reviewed. Results A total of 580 patients diagnosed as having SCLC received first-line chemotherapy/chemoradiotherapy, of which 343 (59%) received second-line chemotherapy. Among the 343 patients, 193, 148, and 2 patients were diagnosed sensitive relapse, refractory relapse, and relapse of unknown sensitivity status, respectively. Second-line chemotherapy regimens used were as follows: amrubicin (AMR) in 188 (55%) patients; weekly cisplatin/etoposide/irinotecan (PEI) in 56 (16%) patients; topotecan in 18 (5.2%) patients; others in 81 (24%) patients. In the analysis including all patients, the following outcomes were obtained for the patients treated with AMR and PEI, respectively: objective response rate: 51% and 73%; median progression-free survival: 4.5 and 4.2 months; median overall survival: 10.0 and 10.8 months. Multivariate analysis identified sensitive relapse to first-line treatment (vs. refractory relapse) (P = .007) and AMR as second-line treatment (vs. PEI) (P = .005) as independent favorable prognostic factors for survival. Conclusion AMR showed a favorable trend compared with PEI in terms of the progression-free survival and feasibility in SCLC patients with relapsed disease. Based on our findings, we suggest that a randomized trial comparing AMR and PEI is warranted.