Stepwise prolongation of overall survival from first to third generation EGFR-TKIs for EGFR mutation-positive non-small-cell lung cancer: the Tokushukai REAl-world Data project (TREAD 01).

OBJECTIVE: The introduction of new-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has afforded promising overall survival outcomes in clinical trials for non-small-cell lung cancer. We aim to investigate the current adoption rate of these agents and the real-world impact on overall survival among institutions. METHODS: In a nationwide retrospective cohort study of 46 Tokushukai Medical Group hospitals in Japan, we analyzed clinical data of consecutive patients with non-small-cell lung cancer receiving EGFR-TKIs between April 2010 and March 2020. Univariate and multivariate Cox regression analyses examined the associations between overall survival and patient/tumor-related factors and first-line EGFR-TKIs. RESULTS: A total of 758 patients (58.5% females; median age, 73 years) were included. Of 40 patients diagnosed in 2010, 72.5% received gefitinib, whereas 81.3% of 107 patients diagnosed in 2019 received osimertinib as the first-line EGFR-TKI. With a median follow-up of 15.8 months, the median overall survival was 28.4 months (95% confidence interval, 15.3-31.0). In a multivariate Cox regression analysis, age, body mass index, disease status, EGFR mutational status and first-line epidermal growth factor receptor tyrosine kinase inhibitor were identified as significant prognostic factors after adjusting for background factors including study period, hospital volume and hospital type. The estimated 2-year overall survival rates for gefitinib, erlotinib, afatinib and osimertinib were 70.1% (95% confidence interval 59.7-82.4), 67.8% (95% confidence interval 55.3-83.2), 75.5% (95% confidence interval 64.7-88.0) and 90.8% (95% confidence interval 84.8-97.3), respectively. The median time to treatment failure of gefitinib, erlotinib, afatinib and osimertinib were 12.8, 8.8, 12.0 and 16.9 months or more, respectively. CONCLUSIONS: Our real-world data revealed that the swift and widespread utilization of newer-generation EGFR-TKIs in patients with EGFR mutation-positive non-small-cell lung cancer, and that these newer-generation EGFR-TKIs can prolong overall survival regardless of hospital volume or type. Therefore, osimertinib could be a reasonable first choice treatment for these patients across various clinical practice settings.

The efficacy of amrubicin on central nervous system metastases originating from small-cell lung cancer: a case series of eight patients.

BACKGROUND: Central nervous system (CNS) metastases caused by small-cell lung cancer (SCLC) are incurable and therefore fatal. Although such metastases are usually treated with chemotherapy or radiotherapy, their sensitivity to these treatment measures is unclear. Amrubicin appears to be a promising agent for relapsed SCLC, but its effectiveness in CNS metastases originating from SCLC is unknown. METHODS: Between April 2002 and December 2009, 110 SCLC patients with CNS metastasis were treated at Shizuoka Cancer Center. Of these, we retrospectively reviewed 8 consecutive cases with CNS metastases originating from relapsed SCLC that were treated with amrubicin as a second-line therapy. RESULTS: We recorded three sensitive relapses and five refractory cases. Amrubicin yielded a CNS response rate of 50 % (2 partial responses and 2 complete response; 95 % CI, 21.5-78.5\ %) and the disease control rate for CNS lesions was 87.5 % (95 % CI, 52.9-97.8 %). All of the sensitive relapse patients achieved a partial response. The median time to progression for CNS metastases was 150.5 days (95 % CI, 9-171 days), and the median survival time from the start of amrubicin administration was 230.5 days (95 % CI, 89-619 days). We also report a dramatic improvement in one patient's radiological result of intramedullary spinal cord metastasis and alleviation of her symptoms following amrubicin monotherapy including this case series. CONCLUSIONS: The results of this study suggest that amrubicin is active in patients with CNS metastases originating from SCLC.

A case report of epithelioid inflammatory myofibroblastic sarcoma with RANBP2-ALK fusion gene treated with the ALK inhibitor, crizotinib.

Epithelioid inflammatory myofibroblastic sarcoma is a variant of inflammatory myofibroblastic tumor with aggressive clinical course associated with RANBP2-ALK fusion. The present report describes a case of a 22-year-old Japanese man with a pelvic mesenchymal neoplasm. The feature of the neoplasms, including epithelioid morphology, anaplastic lymphoma kinase staining on the nuclear membrane, and results from the reverse transcriptase-polymerase chain reaction, led to diagnosis of epithelioid inflammatory myofibroblastic sarcoma with RANBP2-ALK fusion. Despite two surgical excision procedures, local recurrence rapidly occurred, and the tumor developed resistance to conventional chemotherapy with doxorubicin. Subsequent administration of crizotinib, an oral anaplastic lymphoma kinase inhibitor, resulted in tumor shrinkage. Distinguishing epithelioid inflammatory myofibroblastic sarcoma from conventional inflammatory myofibroblastic tumor is important, and crizotinib is a promising treatment for this aggressive tumor.

Comparison of chemotherapeutic efficacy between LCNEC diagnosed using large specimens and possible LCNEC diagnosed using small biopsy specimens.

BACKGROUND: It is often difficult to diagnose large cell neuroendocrine carcinomas (LCNEC) of the lung using small biopsy specimens. Some recent studies attempted to diagnose LCNEC using biopsy specimens; in 2011, the International Association for the Study of Lung Cancer pathological panels suggested possible LCNEC as a diagnosis for LCNEC by using biopsy specimens. Here, we compared the chemotherapeutic efficacy in possible LCNEC and LCNEC diagnosed using surgically resected specimens. METHODS: We retrospectively reviewed patients who received platinum-based chemotherapy as first-line chemotherapy at our institution during September 2002-September 2011. Further, we compared the clinical characteristics, chemotherapeutic responses, and survival outcomes of patients diagnosed as having "LCNEC definite" with those diagnosed as having "possible LCNEC." RESULTS: We selected 34 patients of whom 10 were diagnosed with LCNEC using surgically resected specimens and 24 patients with possible LCNEC were diagnosed using small biopsy specimens. In both groups, almost all patients were men and were smokers. Small-cell carcinoma-based chemotherapy, such as platinum plus irinotecan or platinum plus etoposide, was used for treating 60 % LCNEC patients (6/10) and 67 % possible LCNEC patients. In the LCNEC and possible LCNEC groups, respectively, the response rate was 70 and 54 % (p = 0.39), median progression-free survival was 2.9 and 4.4 months (p = 0.20), and median survival time was 12.8 and 9.1 months (p = 0.50). CONCLUSION: No statistically significant differences were found in chemotherapeutic responses and survival outcomes between the 2 groups, which suggests that chemotherapeutic efficacy is similar in both possible LCNEC and LCNEC.

[Evaluation of recurrence rates on change in hormone receptor and human epidermal growth factor receptor 2 status after neo-adjuvant chemotherapy in breast cancer patients].

BACKGROUND: Neo-adjuvant chemotherapy(NAC)may affect hormone receptor(HR)and human epidermal growth factor receptor 2(HER2)status in breast cancer patients. However, the correlation between recurrence rates and this status change remains unclear. METHODS: We evaluated 70 consecutive breast cancer patients receiving NAC with anthracyclines and taxanes, with or without trastuzumab, between January 2005 and May 2012. Pre-treatment core needle biopsy samples and specimens obtained after surgery were tested to determine HR and HER2 status. The relationship between HR and HER2 status changes and recurrence rates was then assessed. RESULTS: Pathological complete response(pCR)was observed in 13 cases and non-pCR was observed in 57 cases. Of the non-pCR cases, HR-positive status changed to HR-negative status in 6.3% of patients, but a change from negativity to positivity was not observed. HER2-positive status changed to HER2-negative status in 48.0% of patients, and a change from negativity to positivity was observed in 12.5% of cases. The recurrence rate among patients with conversion to a HR-negative status was 0%and that among patients with conversion to a HER2-negative status was 25.0%. CONCLUSION: Recurrence rates were not significantly associated with HR and HER2 status conversion after NAC. Future research is warranted to confirm out results.

Effectiveness and Safety of Immune Checkpoint Inhibitors Alone or in Combination With Chemotherapy in Pulmonary Sarcomatoid Carcinoma.

Introduction: Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of lung cancer associated with poor prognosis and resistance to conventional chemotherapy. Immune checkpoint inhibitors (ICIs), alone or in combination with chemotherapy, were found to have clinical benefits in PSC in recent studies. Nevertheless, because these studies included a small number of patients owing to disease rarity, larger studies are needed to evaluate the effectiveness and safety of ICI-based therapy for PSC. Methods: This multicenter retrospective study evaluated patients with ICI-naive advanced or metastatic PSC who were treated with ICI-based therapy at 25 hospitals in Japan. Results: A total of 124 patients were evaluated. The overall response rate, median progression-free survival (PFS), and median overall survival (OS) were 59.0%, 10.5 months, and 32.8 months, respectively. The PFS and OS rates at 24 months were 35.3% and 51.5%, respectively. Programmed death-ligand 1 expression, concomitant chemotherapy, and the treatment line were not significantly associated with PFS or OS. Immune-related adverse events (irAEs) were observed in 70 patients (56.5%), including 30 (24.2%) with grade 3 to 5 events. Patients with mild irAEs (grades 1-2) had longer PFS and OS than did those with severe (grades 3-5) or no irAEs. In a multivariate analysis, any-grade irAEs and the absence of liver metastases were independently associated with PFS, whereas any-grade irAEs and Eastern Cooperative Oncology Group performance status less than or equal to 1 were independently associated with OS. Conclusions: ICI-based therapy was found to have promising effectiveness in patients with advanced or metastatic PSC, regardless of programmed death-ligand 1 expression, concomitant chemotherapy, or treatment line.

Prognostic impact of concomitant pH-regulating drugs in patients with non-small cell lung cancer receiving epidermal growth factor receptor tyrosine kinase inhibitors: the Tokushukai REAl-world Data project 01-S1.

PURPOSE: This study aimed to examine the prognostic impact of concomitant pH-regulating drug use in patients with epidermal growth factor receptor (EGFR)-mutation-positive non-small-cell lung cancer (NSCLC) receiving EGFR-tyrosine kinase inhibitors (TKIs). METHODS: We conducted a nationwide retrospective cohort study and reviewed clinical data of consecutive patients with NSCLC treated with the first-line EGFR-TKIs in 46 hospitals between April 2010 and March 2020. Cox regression analyses were conducted to examine the differences in overall survival (OS) between patients treated with and without concomitant pH-regulating drugs, including potassium-competitive acid blockers (P-CABs), proton pump inhibitors (PPIs), and H2-receptor antagonists (H2RAs). RESULTS: A total of 758 patients were included in the final dataset, of which 307 (40%) were administered concomitant pH-regulating drugs while receiving frontline EGFR-TKIs. After adjusting for basic patient characteristics, patients administered gefitinib, erlotinib, afatinib, and osimertinib with concomitant pH-regulating drugs had lower OS than those without concomitant pH-regulating drugs, with hazard ratios of 1.74 (with a 95% confidence interval of 1.34-2.27), 1.33 (0.80-2.22), 1.73 (0.89-3.36), and 5.04 (1.38-18.44), respectively. The 2-year OS rates of patients receiving gefitinib with or without concomitant pH-regulating drugs were 65.4 and 77.5%, those for erlotinib were 55.8 and 66.6%, and those for afatinib were 63.2 and 76.9%, respectively. The 1-year OS rates of patients receiving osimertinib with or without concomitant pH-regulating drugs were 88.1% and 96.9%, respectively. CONCLUSION: In addition to the first-generation EGFR-TKIs, the second- and third-generation EGFR-TKIs also resulted in OS deterioration in patients with EGFR mutation-positive NSCLC when used concurrently with pH-regulating drugs.

Atezolizumab and Platinum Plus Pemetrexed With or Without Bevacizumab for Metastatic Nonsquamous Non-Small Cell Lung Cancer: A Phase 3 Randomized Clinical Trial.

Importance: The combination of an antibody to programmed cell death-1 (PD-1) or to its ligand (PD-L1) with chemotherapy is the standard first-line treatment for metastatic non-small cell lung cancer (NSCLC). Bevacizumab is expected to enhance the efficacy not only of chemotherapy but also of PD-1/PD-L1 antibodies through blockade of vascular endothelial growth factor-mediated immunosuppression, but further data are needed to support this. Objective: To evaluate the efficacy and safety of bevacizumab administered with platinum combination therapy and atezolizumab in patients with advanced nonsquamous NSCLC. Design, Setting, and Participants: An open-label phase 3 randomized clinical trial was conducted at 37 hospitals in Japan. Patients with advanced nonsquamous NSCLC without genetic driver alterations or those with genetic driver alterations who had received treatment with at least 1 approved tyrosine kinase inhibitor were enrolled between January 20, 2019, and August 12, 2020. Interventions: Patients were randomly assigned to receive either atezolizumab plus carboplatin with pemetrexed (APP) or atezolizumab, carboplatin plus pemetrexed, and bevacizumab (APPB). After 4 cycles of induction therapy, maintenance therapy with atezolizumab plus pemetrexed or with atezolizumab, pemetrexed, and bevacizumab was administered until evidence of disease progression, development of unacceptable toxic effects, or the elapse of 2 years from the initiation of protocol treatment. Main Outcomes and Measures: The primary end point was progression-free survival (PFS) as assessed by blinded independent central review (BICR) in the intention-to-treat (ITT) population. Results: A total of 412 patients were enrolled (273 men [66%]; median age, 67.0 [range, 24-89] years) and randomly assigned, with 205 in the APPB group and 206 in the APP group of the ITT population after exclusion of 1 patient for good clinical practice violation. The median BICR-assessed PFS was 9.6 months with APPB vs 7.7 months with APP (stratified hazard ratio [HR], 0.86; 95% CI, 0.70-1.07; 1-sided stratified log-rank test; P = .92). According to prespecified subgroup analysis of BICR-assessed PFS, an improved PFS with APPB vs APP was apparent specifically in driver oncogene-positive patients (median, 9.7 vs 5.8 months; stratified HR, 0.67; 95% CI, 0.46-0.98). Toxic effects related to bevacizumab were increased in the APPB group. Conclusions and Relevance: The findings of this trial did not show superiority of APPB over APP for patients with nonsquamous NSCLC; however, this regimen showed a similar tolerability and improved survival relative to APP in patients with driver oncogenes. Trial Registration: Japan Registry of Clinical Trials Identifier: jRCT2080224500.

A phase II study of cisplatin /S-1 in patients with carcinomas of unknown primary site.

BACKGROUND: Carcinomas of unknown primary site (CUPs) are heterogeneous tumors associated with a poor prognosis. This phase II trial was designed to evaluate the efficacy and safety of a novel combination chemotherapy of S-1 and cisplatin (CDDP) in patients with CUP. PATIENTS AND METHODS: Patients with previously untreated CUPs were eligible for this trial. The treatment schedule consisted of oral S-1 (40 mg/m(2)) twice a day on days 1-21, and intravenous CDDP (60 mg/m(2)) on day 8. This schedule was repeated every 5 weeks. RESULTS: A total of 46 patients were enrolled. The overall response rate and the disease control rate were 41.3% and 80.4%, respectively. The median overall survival time was 17.4 months. Grade 3/4 neutropenia, thrombocytopenia, and febrile neutropenia occurred in 28.3%, 13.0%, and 2.2% of the patients, respectively. CONCLUSION: CDDP plus S-1 combination chemotherapy is well tolerated and active first-line empiric therapies for patients with CUP.

A phase I study of S-1 with concurrent radiotherapy in elderly patients with locally advanced non-small cell lung cancer.

BACKGROUND: A phase I study was performed to evaluate dose-limiting toxicity and the recommended dose for the oral fluoropyrimidine S-1 administered concurrently with thoracic radiotherapy (TRT) in elderly (≥ 70 years of age) patients with locally advanced non-small cell lung cancer. METHODS: S-1 was administered on days 1 to 14 and 22 to 35 at oral doses of 65 or 80 mg m(-2) day(-1). TRT was administered in 2-Gy fractions five times weekly for a total dose of 60 Gy. Twelve previously untreated patients were treated with S-1 at 65 (n=6) or 80 (n=6) mg m(-2) day(-1). RESULTS: All patients completed the planned 60 Gy of TRT. Dose-limiting toxicity included pneumonitis (n=2), infection (n=1), and stomatitis (n=1), each of grade 3, but each event was reversible. The recommended dose for S-1 was determined to be 80 mg m(-2) day(-1). No patient experienced toxicity of grade 4. The dose intensity of S-1 was well maintained and the combination of S-1 plus TRT was well tolerated overall. The overall response rate was 83.3 %, with a median survival time of 34.0 months. CONCLUSIONS: Administration of S-1 at 80 mg m(-2) day(-1) on days 1 to 14 and 22 to 35 can be safely combined with concurrent TRT in elderly patients with locally advanced non-small cell lung cancer.

The role of ßIII-tubulin in non-small cell lung cancer patients treated by taxane-based chemotherapy.

BACKGROUND: The aim of this study is to evaluate whether class III ß-tubulin (TUBB3) expression could predict progression-free survival or overall survival in relapsed non-small cell lung cancer (NSCLC) patients treated with taxene-based chemotherapy. METHODS: Immunohistochemistal staining was used to examine the expression of TUBB3 in resected lung tumor specimens obtained from 56 patients treated with platinum-based chemotherapy against recurrent tumors after curative resections. Excision repair cross-complementation group 1, breast cancer susceptibility gene 1, vascular endothelial growth factor, Ki-67, CD34, and p53 were also correlated with clinical features and outcome after treatment. RESULTS: Of the 56 patients enrolled in the study, 29 were treated by carboplatin plus paclitaxel as first-line treatment, and 24 patients received docetaxel monotherapy as second- or third-line treatment. A positive TUBB3 expression is closely associated with a poor response to taxane-based chemotherapy. TUBB3 expression was an independent prognostic factor for predicting poor progression-free survival after docetaxel administration. However, TUBB3 expression could not predict outcome after carboplatin plus paclitaxel treatment. The other biomarkers tested were not independent prognostic factors for predicting outcome after taxane-based chemotherapy. CONCLUSION: TUBB3 expression is associated with resistance to taxane-based chemotherapy and is an independent prognostic factor for predicting poor progression-free survival after docetaxel treatment alone. TUBB3 expression may be a predictive marker for chemoresistance to docetaxel in NSCLC with postoperative recurrent disease.

Phase I and pharmacokinetic study of dacomitinib (PF-00299804), an oral irreversible, small molecule inhibitor of human epidermal growth factor receptor-1, -2, and -4 tyrosine kinases, in Japanese patients with advanced solid tumors.

BACKGROUND: Dacomitinib (PF-00299804) is an oral, irreversible, small molecule inhibitor of human epidermal growth factor receptor-1, -2, and -4 tyrosine kinases. METHODS: This phase I, open-label, dose-escalation study (clinicaltrials.gov: NCT00783328) primarily evaluated the safety and tolerability of dacomitinib by dose-limiting toxicity (DLT), and determined the clinically recommended phase II dose (RP2D) in Japanese patients with advanced solid tumors. Dacomitinib was administered orally at three dose levels (15, 30, or 45 mg once daily [QD]). Patients initially received a single dose, and after 9 days of follow-up, continuously QD in 21-day cycles. Endpoints included pharmacokinetics (PK) and antitumor activity. RESULTS: Thirteen patients were assigned to the three dose levels (15 mg cohort: n = 3; 30 mg cohort: n = 3; 45 mg cohort: n = 7) according to a traditional '3 + 3' design. None of the treated patients experienced a DLT. Toxicities were manageable and similar in type to those observed in other studies. PK concentration parameters increased with dose over the range evaluated, with no evidence of accumulation over time. Of 13 evaluable patients, one with NSCLC (adenocarcinoma) had a partial response and nine patients had stable disease. CONCLUSIONS: Dacomitinib 45 mg QD was defined as the RP2D and demonstrated preliminary activity in Japanese patients with advanced solid tumors.

HER3 Augmentation via Blockade of EGFR/AKT Signaling Enhances Anticancer Activity of HER3-Targeting Patritumab Deruxtecan in EGFR-Mutated Non-Small Cell Lung Cancer.

PURPOSE: EGFR-tyrosine kinase inhibitor (TKI) is a standard first-line therapy for activated EGFR-mutated non-small cell lung cancer (NSCLC). Treatment options for patients with acquired EGFR-TKI resistance are limited. HER3 mediates EGFR-TKI resistance. Clinical trials of the HER3-targeting antibody-drug conjugate patritumab deruxtecan (HER3-DXd) demonstrated its anticancer activity in EGFR-mutated NSCLC; however, the mechanisms that regulate HER3 expression are unknown. This study was conducted with the aim to clarify the mechanisms underlying HER3 regulation in EGFR-mutated NSCLC tumors and explored the strategy for enhancing the anticancer activity of HER3-DXd in EGFR-mutated NSCLC. EXPERIMENTAL DESIGN: Paired tumor samples were obtained from 48 patients with EGFR-mutated NSCLC treated with EGFR-TKI(s). HER3 expression was immunohistochemically quantified with H-score, and genomic alteration and transcriptomic signature were tested in tumors from pretreatment to post-EGFR-TKI resistance acquisition. The anticancer efficacy of HER3-DXd and osimertinib was evaluated in EGFR-mutated NSCLC cells. RESULTS: We showed augmented HER3 expression in EGFR-mutated tumors with acquired EGFR-TKI resistance compared with paired pretreatment samples. RNA sequencing revealed that repressed PI3K/AKT/mTOR signaling was associated with HER3 augmentation, especially in tumors from patients who received continuous EGFR-TKI therapy. An in vitro study also showed that EGFR-TKI increased HER3 expression, repressed AKT phosphorylation in multiple EGFR-mutated cancers, and enhanced the anticancer activity of HER3-DXd. CONCLUSIONS: Our findings help clarify the mechanisms of HER3 regulation in EGFR-mutated NSCLC tumors and highlight a rationale for combination therapy with HER3-DXd and EGFR-TKI in EGFR-mutated NSCLC.

The Tumor Immune Microenvironment and Frameshift Neoantigen Load Determine Response to PD-L1 Blockade in Extensive-Stage SCLC.

Introduction: Despite a considerable benefit of adding immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy for patients with extensive-stage SCLC (ES-SCLC), a durable response to ICIs occurs in only a small minority of such patients. Methods: A total of 135 patients with ES-SCLC treated with chemotherapy either alone (chemo-cohort, n = 71) or together with an ICI (ICI combo-cohort, n = 64) was included in this retrospective study. Tumors were classified pathologically as inflamed or noninflamed on the basis of programmed death-ligand 1 expression and CD8+ tumor-infiltrating lymphocyte density. Immune-related gene expression profiling was performed, and predicted neoantigen load was determined by whole-exome sequencing. Results: Among patients in the ICI combo-cohort, median progression-free survival was 10.8 and 5.1 months for those with inflamed (n = 7) or noninflamed (n = 56) tumors, respectively (log-rank test p = 0.002; hazard ratio of 0.26). Among the 89 patients with immune-related gene expression profiling data available, inflamed tumors had a higher T cell-inflamed GEP score than did noninflamed tumors (-0.18 versus -0.58, p < 0.001). The 12-month progression-free survival rate was 16.1% and 0% for patients in the ICI combo-cohort harboring tumors with a high (n = 26) or low (n = 18) frameshift neoantigen load, respectively. A high-frameshift neoantigen load was associated with up-regulation of gene signatures related to antigen presentation and costimulatory signaling. A durable clinical benefit of ICI therapy was observed only in patients with inflamed tumors and a high-frameshift neoantigen load. Conclusions: Expression of programmed death-ligand 1, CD8+ T cell infiltration, and a high-frameshift neoantigen load are associated with clinical benefit of ICI therapy in ES-SCLC. Clinical trial registration: UMIN000041056.

Efficacy of gefitinib for non-adenocarcinoma non-small-cell lung cancer patients harboring epidermal growth factor receptor mutations: a pooled analysis of published reports.

The efficacy of gefitinib for patients with non-adenocarcinoma non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations is unclear, because only a small percentage of patients enrolled in the clinical trials to evaluate the efficacy of gefitinib for tumors harboring EGFR mutation were non-adenocarcinoma NSCLC. A pooled analysis was conducted to clarify the efficacy of gefitinib for non-adenocarcinoma NSCLC patients harboring EGFR mutations. A systematic search of the PUBMED databases was conducted to identify all clinical reports that contained advanced non-adenocarcinoma NSCLC patients harboring EGFR mutations and treated with gefitinib. The selected patients were advanced non-adenocarcinoma NSCLC patients harboring EGFR mutations who were treated with gefitinib and described in reports containing the data of the histology, status of EGFR mutations and response to gefitinib. This study selected 33 patients from 15 reports. Twenty-seven and three of the 33 patients were squamous cell carcinoma and adenosquamous cell carcinoma, respectively. One patient each had large-cell carcinoma, pleomorphic carcinoma and spindle cell carcinoma. Twenty-one patients (64%) had sensitive EGFR mutations. The response rate (RR), disease control rate (DCR) and median progression-free survival (mPFS) was 27%, 67-70% and 3.0 months, respectively. These factors were statistically significantly inferior in the non-adenocarcinoma NSCLC patients harboring EGFR mutations to adenocarcinoma patients harboring EGFR mutations selected from the same published reports (RR: 27%vs 66%, P = 0.000028; DCR: 67-70%vs 92-93%, P = 0.000014; mPFS: 3.0 vs 9.4 months, P = 0.0001, respectively). Gefitinib is less effective in non-adenocarcinoma NSCLC harboring EGFR mutations than adenocarcinoma harboring EGFR mutations.

Phase I study of YM155, a novel survivin suppressant, in patients with advanced solid tumors.

PURPOSE: YM155, a novel molecular targeted agent, suppresses survivin, a member of the inhibitor of apoptosis protein family that is overexpressed in many tumor types. The aim of this study was to determine the maximum tolerated dose (MTD) and to assess the safety, pharmacokinetics, and antitumor activity of YM155 in patients with advanced refractory solid tumors. EXPERIMENTAL DESIGN: Patients with advanced refractory solid tumors were treated with escalating doses of YM155 administered by continuous i.v. infusion for 168 hours in 21-day cycles. RESULTS: Of the 34 patients enrolled, 33 (median age, 59 years) received at least 1 dose of YM155 (range, 1-19 cycles). The dose levels studied were 1.8, 3.6, 4.8, 6.0, 8.0, and 10.6 mg/m(2)/d. The MTD was determined to be 8.0 mg/m(2)/d, based on a dose-limiting toxicity of increased blood creatinine observed in 2 patients receiving 10.6 mg/m(2)/d. The most common adverse reactions judged to be related to YM155 were urine microalbumin present; fever; injection-site phlebitis; fatigue; and decreased hemoglobin/anemia, blood albumin, and lymphocyte count. The pharmacokinetic profile was almost linear over the dosing range and was similar between cycles 1 and 2. Urinary excretion of YM155 showed no definite difference among doses. Stable disease was achieved in nine patients. CONCLUSIONS: YM155 was safely administered to patients with advanced refractory solid tumors by 168-hour continuous i.v. infusion in 21-day cycles. The MTD was determined to be 8.0 mg/m(2)/d. The safety profile, plasma concentrations achieved, and antitumor activity observed merit further studies with this survivin suppressant, alone and in combination regimens.

Phase I clinical and pharmacokinetic study of RAD001 (everolimus) administered daily to Japanese patients with advanced solid tumors.

OBJECTIVE: To determine the pharmacokinetics and safety of RAD001 (everolimus) in Japanese patients with advanced solid tumors. METHODS: An open-label, non-randomized, dose-escalation Phase I study of RAD001 administered continuously once daily in a 28-day cycle was performed. The study had a '3 + 3' design, with three patients recruited to each of three successive cohorts treated with RAD001 at 2.5, 5.0 or 10.0 mg/day. RESULTS: The pharmacokinetics of RAD001 in Japanese patients were similar to those previously determined in Caucasians. The drug safety profile was consistent with that of a mammalian target of rapamycin inhibitor. No dose-limiting toxicities were observed. One patient with esophageal cancer and one with gastric cancer treated with RAD001 at 10 mg/day showed marked tumor responses. CONCLUSIONS: Treatment of Japanese cancer patients with RAD001 may be undertaken with the expectation that previously determined pharmacokinetic and safety profiles apply. The drug may hold promise for treatment of esophageal and gastric cancer.

N-telopeptide of type I collagen is useful for monitoring therapeutic response in non-small cell lung cancer patients with bone metastases.

BACKGROUND: Elevated levels of N-telopeptide of type I collagen (NTX) are associated with skeletal-related events and death. However, it is unclear whether NTX is useful for monitoring therapeutic response in non-small cell lung cancer (NSCLC) patients with bone metastases. PATIENTS AND METHODS: Urinary NTX levels were assessed at baseline and after one cycle of chemotherapy in 30 NSCLC patients with bone metastases. NTX levels were categorized as normal (NTX <64 nmol/mmol creatinine) or high (NTX ≥64 nmol/mmol creatinine). RESULTS: In 30 patients, the median NTX level at 1 month was significantly lower than that at baseline (P = 0.0016). The NTX levels after treatment were significantly lower than those at baseline in 20 patients with partial response (n = 2) or stable disease (n = 18). However, no significant difference of the NTX levels was observed in 10 patients with progressive disease. Sixteen (53.3%) of 30 patients had high baseline NTX levels. Ten patients had normal NTX levels after one cycle of chemotherapy, whereas 6 patients also had high NTX levels after treatment. The 10 patients with normal NTX levels had significantly better prognosis than the 6 patients with high NTX levels. CONCLUSION: Urinary NTX levels at 1 month after chemotherapy may be useful for predicting therapeutic response in NSCLC patients with bone metastases. Normalization of elevated baseline NTX at 1 month after chemotherapy was associated with survival benefits.

Evaluation of S-1 as third- or further-line chemotherapy in advanced non-small-cell lung cancer.

BACKGROUND: No investigation of S-1 monotherapy in previously treated advanced non-small-cell lung cancer (NSCLC) patients has yet been reported. We conducted a retrospective study to evaluate the efficacy and tolerability of S-1 in patients with failure of second- or further-line chemotherapy. PATIENTS AND METHODS: The records of NSCLC patients who had received S-1 monotherapy between January 2005 and November 2006 with the following eligibility criteria were reviewed: previously treated with at least two regimens including platinum and docetaxel in the case of nonadenocarcinoma patients, and including platinum, docetaxel and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) in the case of adenocarcinoma patients. S-1 was administered for 28 consecutive days, followed by a 14-day drug-free period (42 days in one course). The drug was administered in two divided doses daily at 80 mg/day for patients with a body surface area <1.25 m(2), 100 mg/day for those with a body surface area of 1.25-1.5 m(2), and 120 mg/day for those with a body surface area > or = 1.5 m(2). RESULTS: Thirty-five patients were registered. The median number of courses administered per patient was 2 (range 1-9). The toxicity profile was mild, and grade 3 or more severe toxicity was rare. The overall response and disease control rates were 5.7% and 40%, respectively. The median survival time was 208 days. CONCLUSION: S-1 exhibits modest activity and acceptable toxicity when used as a third or subsequent line of chemotherapy in patients with advanced NSCLC.

[Evaluation of chemotherapy, especially combined therapy with Carboplatin Plus Etoposide(CE), in patients aged > or =80 years old with extensive-disease small-cell lung cancer].

The standard chemotherapy at present for extensive-disease small-cell lung cancer(ED-SCLC)is platinum-based chemotherapy. However, reports concerning the safety and efficacy of this chemotherapy in patients aged> or =80 with ED-SCLC are still scarce. The purpose of our study was to evaluate the treatment for patients aged> or =80 with ED-SCLC, especially the tolerability and efficacy of carboplatin plus etoposide(CE). Between January 2005 and August 2008, 12 patients aged> or =80 years old with ED-SCLC were treated at our hospital. We retrospectively evaluated the safety and efficacy of the treatment in these 12 patients based on clinical imaging and laboratory data. The median age of patients was 82. 5 years(range: 80-89); PS 1/2/3/4, 6/3/1/2; Clinical stageIIIB/IV, 2/9; treatment with BSC/CE/Amurubicin, 5/6/1. All 6 patients treated with CE, could be treated with four courses. Febrile neutropenia of> or = Grade 3 occurred in two patients. In relation to the best efficacy, PR was observed in four and SD in the remaining two. The median survival time was 15 months in the CE treatment group. Although Grade> or =3 severe neutropenia occurred at a high frequency, no Grade> or =3 severe non-hematological toxicities were observed.