Multi-Institutional Randomized Phase II Trial of Gefitinib for Previously Treated Patients With Advanced Non-Small-Cell Lung Cancer.

PURPOSE: To evaluate the efficacy and tolerability of two doses of gefitinib (Iressa [ZD1839]; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with pretreated advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: This was a randomized, double-blind, parallel-group, multicenter phase II trial. Two hundred ten patients with advanced NSCLC who were previously treated with one or two chemotherapy regimens (at least one containing platinum) were randomized to receive either 250-mg or 500-mg oral doses of gefitinib once daily. RESULTS: Efficacy was similar for the 250- and 500-mg/d groups. Objective tumor response rates were 18.4% (95% confidence interval [CI], 11.5 to 27.3) and 19.0% (95% CI, 12.1 to 27.9); among evaluable patients, symptom improvement rates were 40.3% (95% CI, 28.5 to 53.0) and 37.0% (95% CI, 26.0 to 49.1); median progression-free survival times were 2.7 and 2.8 months; and median overall survival times were 7.6 and 8.0 months, respectively. Symptom improvements were recorded for 69.2% (250 mg/d) and 85.7% (500 mg/d) of patients with a tumor response. Adverse events (AEs) at both dose levels were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent in the higher-dose group. Withdrawal due to drug-related AEs was 1.9% and 9.4% for patients receiving gefitinib 250 and 500 mg/d, respectively. CONCLUSION: Gefitinib showed clinically meaningful antitumor activity and provided symptom relief as second- and third-line treatment in these patients. At 250 mg/d, gefitinib had a favorable AE profile. Gefitinib 250 mg/d is an important, novel treatment option for patients with pretreated advanced NSCLC.

Machine learning-based gene alteration prediction model for primary lung cancer using cytologic images.

BACKGROUND: Understanding the gene alteration status of primary lung cancers is important for determining treatment strategies, but gene testing is both time-consuming and costly, limiting its application in clinical practice. Here, potential therapeutic targets were selected by predicting gene alterations in cytologic specimens before conventional gene testing. METHODS: This was a retrospective study to develop a cytologic image-based gene alteration prediction model for primary lung cancer. Photomicroscopic images of cytology samples were collected and image patches were generated for analyses. Cancer-positive (n = 106) and cancer-negative (n = 32) samples were used to develop a neural network model for selecting cancer-positive images. Cancer-positive cases were randomly assigned to training (n = 77) and validation (n = 26) data sets. Another neural network model was developed to classify cancer images of the training data set into 4 groups: anaplastic lymphoma kinase (ALK)-fusion, epidermal growth factor receptor (EGFR), or Kirsten rat sarcoma viral oncogene homologue (KRAS) mutated groups, and other (None group), and images of the validation data set were classified. A decision algorithm to predict gene alteration for cases with 3 probability ranks was developed. RESULTS: The accuracy and precision for selecting cancer-positive patches were 0.945 and 0.991, respectively. Predictive accuracy for the EGFR and KRAS groups in the validation data set was ~0.95, whereas that for the ALK and None groups was ~0.75 and ~ 0.80, respectively. Gene status was correctly predicted in the probability rank A cases. The model extracted characteristic conventional cytologic findings in images and a novel specific feature was discovered for the EGFR group. CONCLUSIONS: A gene alteration prediction model for lung cancers by machine learning based on cytologic images was successfully developed.

Poor efficacy of anti-programmed cell death-1/ligand 1 monotherapy for non-small cell lung cancer patients with active brain metastases.

BACKGROUND: The efficacy of anti-programmed cell death-1/ligand 1 antibody monotherapy (anti-PD-1/PD-L1 monotherapy) in patients with active brain metastases (BMs) is not established. Here, we aimed to evaluate the efficacy of anti-PD-1/PD-L1 monotherapy in non-small cell lung cancer (NSCLC) patients with active BMs. METHODS: This retrospective study included NSCLC patients treated with second-line or later-line anti-PD-1/PD-L1 monotherapy between December 2015 and August 2019. Patients were classified into those with or without active BMs, including symptomatic BMs requiring systemic steroids and untreated BMs. The progression-free survival (PFS) and overall survival (OS) of the patients with and without active BMs were compared. Intracranial and extracranial tumor responses were evaluated in patients with active BMs. RESULTS: We analyzed 197 patients who had received anti-PD-1/PD-L1 monotherapy. Among them, 24 had active BMs. Among those without active BMs, 145 had no BMs and 28 had treated asymptomatic BMs. The PFS and OS of patients with active BMs were significantly shorter than those of patients without active BMs (1.3 vs. 2.7 months; P < 0.001, and 4.5 vs. 16.3 months; P = 0.001 respectively). For patients with active BMs, the intracranial and extracranial response rates were 13.3% and 26.7%, respectively. On multivariate analysis, active BMs, poor performance status (PS), and EGFR/ALK positivity were significant factors associated with shorter PFS. Active BMs and poor PS were significant factors associated with shorter OS. CONCLUSIONS: This study suggested that anti-PD-1/PD-L1 monotherapy was not effective for NSCLC patients with active BMs. Further studies on immunotherapy are needed for patients with active BMs. KEY POINTS: Significant findings of the study: The present study showed that anti-PD-1/PD-L1 antibody monotherapy was not effective for non-small cell lung cancer patients with active brain metastases. Intracranial and extracranial response rates were 13.3% and 26.7%, respectively. WHAT THIS STUDY ADDS: Further studies on immunotherapy are needed for patients with active BMs.

Addition of ramucirumab enhances docetaxel efficacy in patients who had received anti-PD-1/PD-L1 treatment.

OBJECTIVES: Docetaxel (DTX) efficacy increases in patients with non-small cell lung cancer (NSCLC) who had received anti-programmed cell death-1/ligand 1 (anti-PD-1/L1) therapy. However, the effect of ramucirumab (Ram) on DTX efficacy following anti-PD-1/L1 therapy is unknown. Here, we aimed to evaluate the effect of Ram on DTX efficacy following anti-PD-1/L1 therapy. MATERIALS AND METHODS: This retrospective study included 99 patients with NSCLC, who were divided into those who had (pre-ICI group) or had not (no-ICI group) received anti-PD-1/L1 antibody before DTX. Both groups were then treated with DTX or DTX plus Ram (DTX/Ram). Patient characteristics were compared between the DTX and DTX/Ram groups and adjusted with inverse probability of treatment weighting using propensity scores and the following confounding variables: age, sex, performance status, smoking status, histology, driver mutation, and line of treatment. We compared DTX/Ram and DTX in terms of efficacy in both the pre-ICI and no-ICI groups. RESULTS: In the pre-ICI group, 18 and 21 patients received DTX and DTX/Ram, respectively. In the no-ICI group, 35 and 25 patients received DTX and DTX/Ram. In the no-ICI group, progression-free survival (PFS) and overall survival (OS) were not significantly different between DTX/Ram- and DTX-treated patients (median PFS, 2.6 versus 1.6 months; p = 0.30, median OS; 8.2 versus 8.0 months; p = 0.30). In the pre-ICI group, PFS was significantly longer in DTX/Ram-treated than in DTX-treated patients (median, 5.9 versus 2.8 months; p = 0.03). Hazard ratio for disease progression or death was 0.75 (95% confidence interval, 0.20-0.96). The OS of DTX/Ram-treated patients tended to be longer than that of DTX-treated patients (median, 19.8 versus 8.6 months; p = 0.10). CONCLUSIONS: DTX efficacy following anti-PD-1/L1 therapy may be enhanced by Ram. Further studies are needed to validate the efficacy of inhibiting the vascular endothelial growth factor pathway following anti-PD-1/L1 therapy.

Dissociated responses at initial computed tomography evaluation is a good prognostic factor in non-small cell lung cancer patients treated with anti-programmed cell death-1/ligand 1 inhibitors.

BACKGROUND: Dissociated responses (DR) are phenomena in which some tumors shrink, whereas others progress during treatment of patients with cancer. The purpose of the present study was to evaluate the frequency and prognosis of DR in non-small cell lung cancer (NSCLC) patients treated with anti-programmed cell death-1/ligand 1 (anti-PD-1/L1) inhibitors. METHODS: This retrospective study included NSCLC patients who received anti-PD-1/L1 inhibitor as second- or later-line treatment. We excluded patients without radiological evaluation. In patients who showed progressive disease (PD) according to the RECIST 1.1 at the initial CT evaluation, we evaluated all measurable lesions in each organ to identify DR independently of RECIST 1.1. We defined DR as a disease with some shrinking lesions as well as growing or emerging new lesions. Cases not classified as DR were defined as 'true PD'. Overall survival was compared between patients with DR and those with true PD using Cox proportional hazards models. RESULTS: The present study included 62 NSCLC patients aged 27-82 years (median: 65 years). DR and true PD were observed in 11 and 51 patients, respectively. The frequency of DR in NSCLC patients who showed PD to anti-PD-1/L1 was 17.7%. Median overall survival was significantly longer in patients with DR versus true PD (14.0 vs. 6.6 months, respectively; hazard ratio for death: 0.40; 95% confidence interval: 0.17-0.94). CONCLUSIONS: Patients with DR exhibited a relatively favorable prognosis.

Efficacy of anti-PD-1 therapy for recurrence after chemoradiotherapy in locally advanced NSC LC.

PURPOSE: Chemoradiotherapy (CRT) is the standard treatment for locally advanced non-small cell lung cancer (NSCLC). Recently, anti-PD-1 antibody therapy became a key treatment for stage IV NSCLC as the combination of immune checkpoint inhibitors (ICIs) and platinum doublet chemotherapy. However, the efficacy and toxicity of anti-PD-1 therapy for recurrence after CRT in stage III NSCLC are not well examined. METHODS: Patients who received anti-PD-1 therapy for recurrence after CRT were identified in our clinical database. The safety and efficacy of anti-PD-1 therapy were retrospectively analyzed. RESULTS: From March 1, 2013 to April 30, 2018, there were 20 patients who received anti-PD-1 therapy for recurrence after CRT. The median duration from CRT to initial anti-PD-1 therapy was 9.3 months. 12 patients (60%) were alive and 7 patients (35%) were still receiving anti-PD-1 therapy at the data cutoff point (median follow-up, 13.5 months). The ORR for anti-PD-1 therapy was 45.0%. Median progression-free survival (PFS) and overall survival (OS) from initiation of anti-PD-1 therapy was 8.4 months and 26.2 months, respectively. PFS in patients who had a short interval from last CRT to initial anti-PD-1 therapy seemed to have better outcomes (duration from last CRT to initial anti-PD-1 therapy < 9.3 months vs. ≥ 9.3 months; median PFS, 17.0 months vs. 4.9 months). Grade 3 or 4 immune-related adverse events occurred in 5% of patients. Only grade 1 pneumonitis was observed. CONCLUSION: The efficacy of anti-PD-1 therapy for recurrence after CRT in stage III NSCLC might better than in stage IV NSCLC. The duration from CRT to initial anti-PD-1 therapy might be related to efficacy.

Association of High Neutrophil-to-Lymphocyte Ratio With Poor Outcomes of Pembrolizumab Therapy in High-PD-L1-expressing Non-small Cell Lung Cancer.

BACKGROUND: This study aimed to determine whether the neutrophil-to-lymphocyte ratio (NLR) reflected poor treatment benefits in patients with tumor proportion score (TPS) ≥50% and who under went first-line pembrolizumab monotherapy. PATIENTS AND METHODS: This study retrospectively analyzed patients with untreated stage III/IV or recurrent non-small cell lung cancer (NSCLC) with TPS ≥50% and who received pembrolizumab monotherapy at two hospitals between February 2017 and April 2019. The NLR was calculated from pre-treatment complete blood counts. RESULTS: A total of 51 previously untreated patients with NSCLC who had TPS ≥50% and who underwent pembrolizumab monotherapy were evaluated. Multivariate analysis revealed that high NLR, Eastern Cooperative Oncology Group performance status (PS) ≥2, stage IV or recurrent cancer, and TPS=50-74% were significantly and independently associated with poor progression-free survival. Moreover, high NLR and PS ≥2 were significantly associated with short overall survival. CONCLUSION: A high pre-treatment NLR was associated with significantly short progression-free and overall survival in previously untreated patients with NSCLC with high expression of programmed cell-death ligand 1 treated with pembrolizumab monotherapy.

Sorafenib treatment for patients with RET fusion-positive non-small cell lung cancer.

BACKGROUND: RET fusions were recently identified in non-small cell lung cancer (NSCLC) and are considered as a potential therapeutic target of NSCLC. Sorafenib, a multi-kinase inhibitor, has potent anti-RET activity. We conducted a study to evaluate the efficacy of sorafenib in a small number of patients with RET fusion-positive NSCLC. MATERIALS AND METHODS: Eligible patients had advanced or recurrent NSCLC, were more than 20 years old, had undergone treatment with one or more previous chemotherapy regimens, had an Eastern Cooperative Oncology Group performance status 0-2, had adequate organ function, and provided informed consent. The presence of the RET fusion gene was confirmed by a split FISH assay. The patients were treated twice daily with 400mg of sorafenib taken orally. The treatment was continued until either disease progression or unacceptable toxicity. RESULTS: From March 2012 to April 2013, three patients were enrolled. The responses to sorafenib included one patient with stable disease (SD) and two patients with progressive disease (PD). One patient took sorafenib for twelve months. The most common toxicities were palmar-plantar erythrodysesthesia syndrome, hypertension, and diarrhea. CONCLUSION: Since sorafenib did not show dramatic responses, we suggest testing other RET inhibitors for the treatment of RET fusion-positive NSCLC. This study was registered at UMIN as trial number 000007515.

Plasma homocysteine levels and hematological toxicity in NSCLC patients after the first cycle of pemetrexed under folate supplementation.

Although baseline plasma homocysteine levels are related to pemetrexed toxicities in patients treated without folate supplementation, the relationship between these parameters in patients treated with folate supplementation is not well understood. The pretreatment plasma homocysteine levels were measured in non-small-cell lung cancer patients treated with pemetrexed alone under folate supplementation. Pemetrexed (500 mg/m) was administered every 3 weeks. As folate supplementation, folic acid (0.5 mg) was orally administered daily and vitamin B12 (1 mg) was injected intramuscularly every 9 weeks starting at least 1 week before treatment. The rate of toxicities during the first cycle of pemetrexed treatment with folate supplementations was evaluated and the relationship between the plasma homocysteine levels and toxicities was examined. Between June 2009 and November 2010, 58 patients were enrolled in this study. The median pretreatment plasma homocysteine level was 7.7 µmol/ml (3.5-34.6 µmol/ml). The pretreatment plasma homocysteine levels were above 11.5 µmol/ml in nine patients (15.5%). The pretreatment plasma homocysteine level correlated significantly with the nadir of the absolute counts of leukocytes, neutrophils, and thrombocytes (r = -0.374, P = 0.004; r = -0.286, P = 0.028; r = -0.324, P = 0.012, respectively). In addition, the rates of decrease in leukocytes, neutrophils, and thrombocytes correlated significantly with the pretreatment plasma homocysteine level (r = +0.378, P = 0.003; r = +0.335, P = 0.009; r = +0.363, P = 0.005, respectively). The plasma homocysteine level is associated with hematological toxicities in patients receiving pemetrexed with folate supplementation.

Phase II study of docetaxel-plus-bevacizumab combination therapy in patients previously treated for advanced non-squamous non-small cell lung cancer.

AIM: This phase II study was conducted to evaluate the efficacy and safety of docetaxel and bevacizumab combination therapy in patients with previously-treated non-squamous non-small cell lung cancer (Nsq NSCLC). PATIENTS AND METHODS: Patients with histologically- or cytologically-confirmed Nsq NSCLC, 20-74 years of age, who had performance status 0-2, and had undergone at least one prior chemotherapy course were eligible for the study. Patients were treated with docetaxel (60 mg/m(2)) and bevacizumab (15 mg/kg) on day 1, which was repeated every three weeks until progressive disease or unacceptable toxicity occurred. The primary end-point was the response rate (RR) and the planned sample size was 28 patients. RESULTS: Between May 2010 and July 2011, 28 patients were enrolled (16 males, 12 females; median age=65 years; performance status 0/1: 19/9; adenocarcinoma/other: 22/6; number of prior chemotherapy courses 1/2/3 or more: 16/5/7). Twenty-eight patients were included in the toxicity analysis, out of whom 27 were evaluable for response. Objective response was observed in 18 patients (partial response in 18, stable disease in 8, progressive disease in 1); the RR and disease control rates were 66.7% and 96.0%, respectively. The median follow-up was 23.9 months, median progression-free survival was 7.2 months, and median overall survival was 21.6 months. The main toxicity associated with this regimen was myelosuppression (grade 3/4 neutropenia: 82.1%; febrile neutropenia: 21%). Mild non-hematological toxicity was observed but there was no severe bleeding. CONCLUSION: The combination regimen of docetaxel-plus-bevacizumab is very active in patients with previously-treated Nsq NSCLC and warrants further research.

A phase 1 study of linifanib in combination with carboplatin/paclitaxel as first-line treatment of Japanese patients with advanced or metastatic non-small cell lung cancer (NSCLC).

INTRODUCTION: Linifanib is a potent, orally active, and selective inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor kinase activities with clinical efficacy in non-small cell lung cancer (NSCLC). This phase 1 dose-escalation study evaluated the pharmacokinetics, safety, and efficacy of linifanib in combination with carboplatin/paclitaxel in Japanese patients with advanced NSCLC. METHODS: Carboplatin (AUC = 6 mg/mL/min) and paclitaxel (200 mg/m²) were administered on day 1 of each 21-day cycle up to a maximum of six cycles. Oral linifanib (7.5 mg) was given to six patients once daily throughout all cycles and escalated to 12.5 mg/day in a second cohort of six patients. RESULTS: Twelve patients received at least one dose of linifanib. The most common adverse events were hematologic and consistent with expected toxicities with carboplatin/paclitaxel. With 12.5 mg linifanib, grade 3/4 neutropenia, leukopenia, and thrombocytopenia occurred in 100, 83, and 83 % of patients, respectively. Dose-limiting grade 4 thrombocytopenia occurred in one patient at each dose level. Linifanib pharmacokinetics was similar to that in non-Japanese patients. At 12.5 mg, linifanib Cmax was 0.32 µg/mL and AUC24 was 4.29 µg h/mL. Linifanib Cmax occurred at 2-3 h with both doses and when given alone or in combination with carboplatin/paclitaxel. Exposure to linifanib appeared to be increased by carboplatin/paclitaxel, and exposure to paclitaxel appeared to be increased by linifanib. Partial responses were observed in nine patients. CONCLUSIONS: Linifanib added to carboplatin/paclitaxel is well tolerated in Japanese patients with advanced/metastatic NSCLC. The recommended dose of linifanib with carboplatin/paclitaxel is 12.5 mg, same as for US patients.

A subset of small cell lung cancer with low neuroendocrine expression and good prognosis: a comparison study of surgical and inoperable cases with biopsy.

Patients with small cell lung carcinoma (SCLC) rarely demonstrate long-term survival. We previously reported that gene expression profiling identified a subset of SCLC with good prognosis in surgical cases. To find an easier way to routinely identify SCLC belonging to this subset, we conducted the present study with a hypothesis that neuroendocrine (NE) or basaloid (BA) phenotypes may influence prognosis. To confirm the subset, we used an array platform to analyze fresh samples. Because inoperable cases may differ from surgical cases, we enrolled 51 biopsy cases and 43 resected samples. To evaluate NE and BA phenotypes, we used NE (synaptophysin, chromogranin A, and CD56) and BA (p63 and CK34ßE12) markers. To varying extents, expression profiling based on the array platform duplicated the subsets. For NE phenotypes, 77% of surgical cases and 100% of biopsy cases were positive for at least 1 marker. For BA phenotypes, only 19% of surgical cases were positive for at least 1 marker, whereas there were no positive biopsy cases. Cases undergoing surgery were categorized based on NE and BA immunoreactivity; 58% into NE+BA-, 19% into NE+BA+, 23% into NE-BA-, and 0 into NE-BA+ groups. NE- patients (n = 10) demonstrated a significantly better prognosis (P = .0306) than their NE+ counterparts (n = 33), whereas no survival difference was evident between the BA+ and BA- groups. Multivariate analyses showed that NE positivity was an independent prognostic factor. In conclusion, the SCLC subset with good prognosis is identified by low NE marker expression, which was found only in surgical cases.

Phase II study of erlotinib for acquired resistance to gefitinib in patients with advanced non-small cell lung cancer.

BACKGROUND: Gefitinib and erlotinib are used to treat advanced non-small cell lung cancer (NSCLC). Gefitinib is a common first-line treatment, but most patients develop resistance. This phase II study evaluated the efficacy of erlotinib after acquired resistance to gefitinib. PATIENTS AND METHODS: Between January 2008 and September 2009, we enrolled 50 patients with advanced NSCLC who had received one or more chemotherapy regimens, including gefitinib monotherapy to which they had partial responses (PR) or stable disease (SD). Erlotinib (150 mg) was administered until disease progression or unacceptable toxicity. Patients were 11 males, 39 females; median age 65 years (range=36-81 years); 46 with adenocarcinoma; performance status 0/1/2: 24/19/7; and smoking status, never/former/current: 33/15/2. Prior gefitinib response, PR/SD: 36/14. Median duration of prior gefitinib therapy was 419 days (range=63-1,540 days). Median interval after gefitinib therapy was 29 days (range=13-1,198 days). RESULTS: Of 47 patients on erlotinib, four showed PR and 29 showed SD [response rate, 8.5%; disease control rate (DCR), 70.2%]. DCR for patients who continued gefitinib treatment for more than one year was significantly higher (81.5%) than for patients who could not continue (57.1%; p=0.018); but was not affected by prior gefitinib response or treatment interval. Median tiMETo treatment failure: 100 days (95% confidence interval=90-110 days); median overall survival: 342 days (95% confidence interval=242-442 days). Rash (78%) and diarrhea (68%) were the most common adverse reactions; grade 5 pneumonitis occurred in one patient (2%). CONCLUSION: Erlotinib treatment after gefitinib failure may prolong the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors treatment.

A randomized phase III study of single-agent amrubicin vs. carboplatin/etoposide in elderly patients with extensive-disease small-cell lung cancer.

INTRODUCTION: The efficacy and safety of amrubicin, a third-generation synthetic anthracycline, were evaluated by comparison with carboplatin/etoposide combination therapy in elderly Japanese patients with extensive-disease small-cell lung cancer (ED-SCLC). PATIENTS AND METHODS: Eligibility included histologically or cytologically proven SCLC, no previous systemic chemotherapy, performance status of 0 to 2, and age ≥ 70 years. Patients received amrubicin (70-74 years old, 40-45 mg/m(2); ≥ 75 years old, 40 mg/m(2)) intravenously on days 1 to 3 every 3 weeks for 4 to 6 cycles or carboplatin (area under the curve of 5 intravenously on day 1) and etoposide (80 mg/m(2) intravenously on days 1 to 3) every 3 weeks for 4 to 6 cycles. RESULTS: The target number of patients was 130 with 65 in each arm. However, the study was terminated early owing to 3 treatment-related deaths in the amrubicin arm, and only 62 patients (median age, 76 years; range, 70-88 years) were enrolled. The characteristics of the patients in the amrubicin and carboplatin/etoposide arms did not differ significantly. Overall survival, time to progression, and objective response rate were 10.9 vs. 11.3 months (P = .7353), 4.7 vs. 4.4 months, and 74.2% (23 of 31) vs. 60.0% (18 of 30), respectively, and quality of life showed no significant difference between the 2 arms. Higher incidences of febrile neutropenia and interstitial lung disease of grade 3 or worse occurred with amrubicin (34.4% vs. 3.3% and 12.5% vs. 0%, respectively). CONCLUSION: These results indicate that amrubicin monotherapy at 40 to 45 mg/m(2) is toxic and intolerable in elderly Japanese patients with ED-SCLC.

LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both.

PURPOSE: New molecular targeted agents are needed for patients with non-small-cell lung cancer (NSCLC) who progress while receiving erlotinib, gefitinib, or both. Afatinib, an oral irreversible ErbB family blocker, has preclinical activity in epidermal growth factor receptor (EGFR [ErbB1]) mutant models with EGFR-activating mutations, including T790M. PATIENTS AND METHODS: This was a Japanese single-arm phase II trial conducted in patients with stage IIIB to IV pulmonary adenocarcinoma who progressed after ≥ 12 weeks of prior erlotinib and/or gefitinib. Patients received afatinib 50 mg per day. The primary end point was objective response rate (complete response or partial response) by independent review. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Of 62 treated patients, 45 (72.6%) were EGFR mutation positive in their primary tumor according to local and/or central laboratory analyses. Fifty-one patients (82.3%) fulfilled the criteria of acquired resistance to erlotinib and/or gefitinib. Of 61 evaluable patients, five (8.2%; 95% CI, 2.7% to 18.1%) had a confirmed objective response rate (partial response). Median PFS was 4.4 months (95% CI, 2.8 to 4.6 months), and median OS was 19.0 months (95% CI, 14.9 months to not achieved). Two patients had acquired T790M mutations: L858R + T790M, and deletion in exon 19 + T790M; they had stable disease for 9 months and 1 month, respectively. The most common afatinib-related adverse events (AEs) were diarrhea (100%) and rash/acne (91.9%). Treatment-related AEs leading to afatinib discontinuation were experienced by 18 patients (29%), of whom four also had progressive disease. CONCLUSION: Afatinib demonstrated modest but noteworthy efficacy in patients with NSCLC who had received third- or fourth-line treatment and who progressed while receiving erlotinib and/or gefitinib, including those with acquired resistance to erlotinib, gefitinib, or both.

Pemetrexed and cisplatin for advanced non-squamous non-small cell lung cancer in Japanese patients: phase II study.

BACKGROUND: Although pemetrexed/cisplatin (P-C) is a standard treatment for advanced non-squamous non-small cell lung cancer (Nsq-NSCLC), neither its efficacy nor the effects of potential differences between driver mutations, such as the anaplastic lymphoma kinase (ALK) translocation and epidermal growth factor receptor (EGFR) mutations, have been thoroughly examined. PATIENTS AND METHODS: A single-arm phase II study of P-C was conducted in Japanese patients with chemo-naïve advanced Nsq-NSCLC. Patients received four cycles of pemetrexed (500 mg/m(2)) combined with cisplatin (75 mg/m(2)) on day 1 every three weeks. The primary end-point was the response rate (RR) and the secondary end-points were toxicity, progression-free survival (PFS), and overall survival (OS). RESULTS: A total of 50 patients were analyzed (males, 68%; adenocarcinoma, 80%). The RR was 44.0%. The median PFS and OS were 4.3 months and 22.2 months, respectively. Toxicities were mild, and no new toxicity profiles were identified. Among the 39 out of 50 samples, six (15.4%) presented ALK translocation and nine (23.1%) presented EGFR mutations; of the remaining patients, 24 (61.5%) were wild-type for both ALK and EGFR. Objective response was observed in two out of six patients with ALK translocations, six out of nine with EGFR mutations, and in 11 (45.8%) wild-type patients. CONCLUSION: The combination of pemetrexed and cisplatin was effective and safe in Japanese patients with Nsq-NSCLC. We did not observe obvious differences in the efficacy of P-C between patients with ALK translocation or EGFR mutation and those with wild-type genotype.

A phase II study of S-1 in relapsed small cell lung cancer.

S-1 is a new oral fluoropyrimidine derivative designed to enhance anticancer activity and reduce gastrointestinal toxicity. This phase II trial aimed to evaluate S-1 in patients with relapsed small cell lung cancer (SCLC). SCLC patients who had experienced treatment failure with ≥1 prior chemotherapies were eligible. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2 and adequate organ function. Treatment consisted of oral S-1 at 40 mg/m2 twice/day for 28 days every 6 weeks. Twenty-six patients were enrolled, 85% of whom were males. The median age was 68 years (range, 33-79) and 81% of the patients had a performance status of 0-1, and 46% of the patients had relapse-sensitive SCLC. An objective response was obtained in only 1 patient (3.8%), and the median progression-free survival (PFS) was 1.1 months. The median overall survival was 5.3 months, and the 1-year survival rate was 23%. The most common grade 3/4 toxicities included neutropenia (7.7%), leukopenia (7.7%), anemia (7.7%), hyponatremia (7.7%), rash (7.7%), infection (7.7%) and diarrhoea (3.8%). None of the patients developed febrile neutropenia and no deaths were attributed to treatment. In conclusion, S-1 has minimal single-agent activity in relapsed SCLC.

Randomized phase II study of first-line carboplatin-paclitaxel with or without bevacizumab in Japanese patients with advanced non-squamous non-small-cell lung cancer.

PURPOSE: This multicenter, randomized, open-label, phase II study (JO19907) compared the efficacy and safety of first-line carboplatin-paclitaxel (CP) alone with bevacizumab-CP in Japanese patients with advanced non-squamous non-small-cell lung cancer (NSCLC). METHODS: Chemonaïve patients with stage IIIB, IV or recurrent non-squamous NSCLC were eligible for participation. Patients were randomly assigned in a 2:1 ratio to receive bevacizumab-CP or CP alone. Chemotherapy was repeated for up to 6 cycles or until disease progression or unacceptable toxicity. Bevacizumab recipients who completed ≥3 cycles of chemotherapy could continue bevacizumab as monotherapy until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). RESULTS: After confirming the tolerability of bevacizumab-CP in a small number of patients, 180 patients were recruited, of whom 121 were assigned to bevacizumab-CP and 59 to CP alone. Hazard ratio (HR) for PFS was 0.61 with bevacizumab-CP versus CP alone (p=0.0090; median 6.9 versus 5.9 months). Objective response rate was significantly higher with bevacizumab-CP than with CP alone (60.7% versus 31.0%; p=0.0013). Median overall survival was >22 months in both treatment groups (HR 0.99; p=0.9526). No new safety signals were detected. CONCLUSION: Study JO19907 met its primary endpoint, demonstrating that the addition of bevacizumab to first-line CP significantly improves PFS in Japanese patients with advanced non-squamous NSCLC. This prolonged PFS by bevacizumab did not translate into OS benefit with the extremely longer underlying survival compared to historical data. No new safety signals were identified in this population. (Japan Pharmaceutical Information Center [JAPIC] registration number: CTI-060338).

Factors exacerbating peripheral neuropathy induced by paclitaxel plus carboplatin in non-small cell lung cancer.

No established supportive therapy to prevent and treat chemotherapy-induced peripheral neuropathy (PN) is available. Minimizing the severity of PN is therefore critical in clinical use. We aimed to determine when and how often PN occurs in association with paclitaxel plus carboplatin (PC therapy), a regimen used to treat non-small cell lung cancer, and factors that exacerbate this condition. Patients who received PC therapy for non-small cell lung cancer at the Japanese Foundation for Cancer Research, Cancer Institute Hospital, between May 20, 2009, and November 30, 2010, were included. PN was evaluated by the study pharmacist using specific questions based on the Common Terminology Criteria for Adverse Events Version 3.0. Univariate analysis was used to compare a group with no, Grade 1, or Grade 2 PN (non-serious) and a group with Grade 3 PN (serious). Analyses were conducted using the Cox proportional hazard model with patient characteristics having p < or = 0.20 when assessed as independent variables. Of 50 patients, 38 (76.0%) developed PN by day 6 of the first course of anticancer treatment. Grade 3 PN had an incidence of 25.0% in the fourth course. In multivariate analysis with the Cox proportional hazard model, pack-year [hazard ratio = 1.029; 95% confidence interval (CI): 1.009-1.050, p = 0.005] and creatinine clearance (hazard ratio = 0.957; 95% CI: 0.920-0.996, p = 0.031) were significant factors. A high pack-year and a low creatinine clearance exacerbated PN in patients treated with PC. PN must be carefully evaluated in patients with exacerbating factors.

Randomized phase II study of two schedules of carboplatin and gemcitabine for stage IIIB and IV advanced non-small cell lung cancer (JACCRO LC-01 study).

BACKGROUND: Gemcitabine combined with carboplatin (CG) is one of the regimens used widely for advanced non-small cell lung cancer. Improvement in its toxicity may result in good clinical outcomes. METHODS: A new schedule of gemcitabine and carboplatin (CG8) was compared with the standard one (CG1). Both are 3-weekly regimens, but carboplatin is administered on day 1 in CG1 and on day 8 in CG8. RESULTS: The response rate of CG1 was 29.2%, which was higher than that of CG8 (22.2%). Median survival times in CG1 and CG8 were 348 and 455.5 days, respectively. Grade ≥3 leukopenia, thrombocytopenia and anemia were observed in 56.0, 72.0 and 36.0% of patients with CG1 and in 33.3, 25.9 and 14.8% of patients with CG8, respectively. Whereas grade ≥3 elevation of asparatate aminotransferase, alanine aminotransferase and alkaline phosphatase was seen mainly in CG8, grade ≥3 non-hematologic toxicities such as febrile neutropenia, infection, appetite loss, diarrhea and eruption were observed only in CG1. CONCLUSION: CG1 is superior in response rate, but CG8 shows improved toxicities and a tendency of prolonged survival.