[show abstract][hide abstract] ABSTRACT: Epidermal growth factor receptor (EGFR) mutation testing is standard practice after lung adenocarcinoma diagnosis, and provision of high-quality tumor tissue is ideal. However, there are knowledge gaps regarding the utility of cytology or low tumor content histology samples to establish EGFR mutation status, particularly with regard to the proportion of testing performed using these sample types, and the lack of an established link with efficacy of treatment.
The randomized phase III Iressa Pan-ASia Study (IPASS; ClinicalTrials.gov identifier NCT00322452) of first-line gefitinib versus chemotherapy analyzed samples meeting preplanned specifications (n=437 evaluable for EGFR mutation; n=261 mutation-positive). This supplementary analysis assessed tumor content and mutation status of histology (n=99) and cytology samples (n=116) which were previously unanalyzed due to sample quality, type, and tumor content (<100 cells). Objective response rate (ORR) and change in tumor size with gefitinib treatment were assessed.
EGFR mutation testing was successful in 80% and 19% of previously unanalyzed histology and cytology samples, respectively. Mutations were detected in 54 tumors previously described as mutation-unknown (histology, n=45; cytology, n=9). ORRs in mutation-positive cytology (83%) and histology (74%) subgroups were consistent with previous analyses (71%). Tumor size decrease was consistent across previously analyzed and unanalyzed samples (all mutation subgroups), with less consistency across ORRs in mutation-negative cytology (16%) and histology (25%) subgroups versus the previous analysis (1%).
Histology samples with low tumor content and cytology samples can be used for EGFR mutation testing; patients whose mutation status was confirmed using these sample types achieved a response to treatment consistent with those confirmed using high-quality histology samples. Better sample quantity/quality can potentially reduce false-negative results.
Lung cancer (Amsterdam, Netherlands) 12/2013; · 3.14 Impact Factor
[show abstract][hide abstract] ABSTRACT: Nimotuzumab is a humanized IgG1 monoclonal antibody to the epidermal growth factor receptor (EGFR) and has demonstrated the absence of severe dermatological toxicity commonly caused by other EGFR-targeting antibodies. We conducted a phase I study to assess toxicities, pharmacokinetics, pharmacodynamics, and predictive biomarkers of nimotuzumab administered in Japanese patients with advanced solid tumors.
Three dose levels, 100, 200, and 400 mg, of weekly i.v. nimotuzumab were given until disease progression or drug intolerability. Four patients with solid tumors were enrolled in each dose level. The expression and gene copy number of EGFR or its downstream transducers were investigated using skin biopsy samples and tumor specimens.
Planned dose escalation was completed without dose-limiting toxicity, and maximum tolerated dose was not reached. No allergic reaction and hypomagnesaemia were observed, and grade 3 or 4 toxicity did not occur. The common toxicity was skin rash (58 %); however, all of them were grade 1 or 2. In skin biopsies, no correlation was shown between doses and the phosphorylation of EGFR or its downstream signal transducers. Of 11 evaluable patients, no objective response was obtained, while 8 patients had stable disease (73 %). Patients with a higher-EGFR gene copy number level measured by FISH showed a longer time to progression.
Nimotuzumab administered weekly was feasible and well tolerated up to 400 mg in Japanese patients. A low dermatological toxicity could be a notable advantage as anti-EGFR mAb, and further evaluation is warranted.
Cancer Chemotherapy and Pharmacology 09/2013; · 2.80 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
Investigational New Drugs 08/2013; · 3.50 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Early palliative intervention in advanced cancer patients with metastatic non-small-cell-lung cancer has been shown to improve survival time. Possibly, palliative intervention at the time of outpatient care further improves patient survival time. OBJECTIVE: We performed a comparative study of late and early referrals of patients with advanced cancer to clarify the appropriate time for palliative intervention and the improvement in survival time. METHODS: Two hundred and one cancer patients, all since deceased, who were treated in our department over a period of 4 years were divided into two groups: patients who experienced outpatient services for <7 days (late referral group, 64 patients) and those who experienced outpatient services for ≥7 days (early referral group, 137 patients). Survival time, duration of chemotherapy and post-progression survival were retrospectively analyzed through examination of medical records. RESULTS: Survival time of the early referral group was longer than that of the late referral group in all the cases (19.0 vs. 6.5 months, P < 0.001). Survival time in advanced non-small-cell lung cancer was 3.5 and 14.0 months (P = 0.010) and 16.5 and 20.9 months (P = 0.039) in advanced colorectal cancer, respectively. There was no significant difference in gastric cancer (P = 0.310). Post-progression survival in each group was 0.7 and 2.7 months (P = 0.018) in non-small-cell lung cancer. CONCLUSIONS: The results of this study suggested that early outpatient referral and palliative intervention leads to improvement of the outcome in patients with advanced non-small-cell lung cancer and colorectal cancer. A prospective comparative study is warranted.
Japanese Journal of Clinical Oncology 06/2013; · 1.90 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND: In IPASS (NCT00322452), progression-free survival (PFS, primary endpoint) was significantly longer with first-line gefitinib versus carboplatin/paclitaxel in never/light ex-smokers with advanced pulmonary adenocarcinoma in Asia, both in the overall intent-to-treat (ITT) population and in the EGFR mutation-positive subgroup. To further characterize the clinical relevance of these data, we investigated objective response rate (ORR) and health-related quality of life (HRQoL) in patients treated with gefitinib. METHODS: Objective response was assessed (RECIST) 6-weekly (previously reported). Post hoc assessments included median time to response, median duration of response and change in tumor size. The analysis of response population included those patients treated with gefitinib who responded (n=262 from ITT; n=94 from EGFR mutation-positive subgroup). The percentage of patients with deterioration in HRQoL (Functional Assessment of Cancer Therapy-Lung [FACT-L], Trial Outcome Index [TOI]) and symptoms (Lung Cancer Subscale [LCS]) at 4 months post-randomization was analyzed according to progression status (EFQ population grouped by progressors/non-progressors in both treatment arms). The ORR (ITT) and incidence of skin rash/acne (evaluable-for-safety) were summarized. RESULTS: In patients whose tumors responded to gefitinib, median time to response was 6.1 weeks in the ITT population (n=262) and 6.0 weeks in the EGFR mutation-positive subgroup (n=94); median duration of response was 9.7 and 8.7 months in these groups, respectively. There was significant tumor shrinkage with gefitinib. A greater percentage of patients in the EFQ population whose tumors progressed experienced deterioration in HRQoL and symptoms at 4 months versus patients whose tumors did not progress (FACT-L 33.7% vs 16.3%; TOI 33.7% vs 13.2%; LCS 31.7% vs 15.5%). In the gefitinib arm of the EFS population, incidence of rash was 75.8% and 68.1% in EGFR mutation-positive and -negative subgroups, respectively (with ORR for the gefitinib arm of the ITT 71.2% vs 1.1%, respectively). CONCLUSIONS: Patients whose tumors responded to first-line gefitinib experienced significant tumor shrinkage and a rapid, durable response. Deterioration in HRQoL and lung cancer symptoms at 4 months post-randomization was found to be associated with tumor progression, highlighting the role of patient-reported outcomes in the evaluation of advanced NSCLC disease. Rash was not supported as a predictive marker of response to gefitinib.
Lung cancer (Amsterdam, Netherlands) 03/2013; · 3.14 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Interstitial lung disease (ILD) is a serious adverse drug reaction associated with epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR TKIs). Its risk factors are yet to be fully elucidated. We sought to identify proteomic biomarkers associated with ILD development in erlotinib-treated Japanese patients with non-small-cell lung cancer (NSCLC) to build predictive models. PATIENTS AND METHODS: We conducted a nested case-control study. The participants were patients with NSCLC enrolled in a phase IV study of erlotinib in whom ILD developed within 120 days after erlotinib administration. The controls were randomly selected patients without ILD from the overall study cohort who were also treated with erlotinib. Serum samples were obtained before the first administration of erlotinib and were assayed by liquid chromatography-mass spectroscopy/mass spectroscopy (LC-MS/MS). Logistic regression analysis was performed to identify the peptide and proteins associated with ILD. RESULTS: A total of 645 patients were enrolled in the cohort; 15 case patients and 64 controls were analyzed. When multiplicity was taken into account, we were unable to statistically verify any genuine association between individual markers and ILD. Investigation of the predictive power based on leave-one-out cross-validation (LOOCV) showed that the area under the receiver operating characteristic curve was 0.73 at a maximum. Additional analysis suggested that 3 proteins (C3, C4A/C4B, and APOA1) have a stronger association with ILD than do the other proteins tested. CONCLUSION: We were unable to demonstrate predictive serum protein markers for ILD development. However, C3, C4A/C4B, and APOA1 are worthy of further investigation.
Clinical Lung Cancer 03/2013; · 2.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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 ED-SCLC.
Patients and Methods
Eligibility included histologically or cytologically proven SCLC, no previous systemic chemotherapy, performance status of 0-2, and age ≥70 years old. Patients received amrubicin (70-74 years old: 40-45 mg/m2, ≥75 years: 40 mg/m2) intravenously on days 1-3 every 3 weeks for 4-6 cycles or carboplatin (area under the curve of 5 intravenously on day 1) and etoposide (80 mg/m2 intravenously on days 1-3) every 3 weeks for 4-6 cycles.
The target number of patients was 130, with 65 in each arm. However, the study was terminated early due to three treatment-related deaths in the amrubicin arm and only 62 patients (median age: 76, range: 70-88) 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=0.7353), 4.7 vs. 4.4 months and 74.2% (23/31) vs. 60.0% (18/30), respectively, and quality of life showed no significant difference between the two 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).
These results show that amrubicin monotherapy at 40-45 mg/m2 is toxic and intolerable in elderly Japanese patients with extensive-disease SCLC.
Clinical Lung Cancer 01/2013; · 2.04 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background
Previous studies have demonstrated the efficacy and safety of bevacizumab in the treatment of non-small-cell lung cancer (NSCLC).Methods
Summary data from randomised trials comparing first-line bevacizumab plus platinum-based chemotherapy with chemotherapy alone for inoperable locally advanced, recurrent or metastatic NSCLC were meta-analysed. Pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and pooled odds ratio (OR) for adverse events were calculated. The chi-squared tests evaluated interactions between treatment effects, and prognostic factors and patient characteristics.ResultsData of 2194 patients (1313 bevacizumab; 881 controls) from four phase II and III trials: AVF-0757g, JO19907, ECOG 4599 and AVAiL, were analysed. Compared with chemotherapy alone, bevacizumab significantly prolonged OS (HR 0.90; 95% confidence interval [CI] 0.81, 0.99; P = 0.03), and PFS (0.72; 95% CI 0.66, 0.79; P < 0.001). Bevacizumab showed a significantly greater effect on OS in patients with adenocarcinoma versus other histologies (P = 0.02), and patients with body weight loss ≤5% versus >5% (P = 0.03). Bevacizumab significantly increased the risk of grade ≥3 proteinuria, hypertension, haemorrhagic events, neutropenia, and febrile neutropenia.Conclusions
Bevacizumab significantly prolonged OS and PFS when added to first-line platinum-based chemotherapy in patients with advanced NSCLC; no unexpected toxicity was evident.
[show abstract][hide abstract] ABSTRACT: 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.
Investigational New Drugs 05/2012; · 3.50 Impact Factor
[show abstract][hide abstract] ABSTRACT: Interstitial lung disease (ILD) is an adverse drug reaction (ADR) of concern in Japanese patients with non-small-cell lung cancer (NSCLC) receiving erlotinib. To investigate erlotinib safety and efficacy in Japanese patients, a large-scale surveillance study was implemented.
All patients with recurrent/advanced NSCLC receiving erlotinib in Japan were enrolled (December 2007-October 2009). During the 12-month observation period, adverse-event data were collected; any adverse event where erlotinib could not be excluded as a causative factor was termed an ADR. An independent review committee assessed ILD-like events. Overall survival and progression-free survival were also assessed. Interim data were analyzed for patients registered before June 30, 2008.
In total, 10,708 patients were enrolled, 3743 by June 30, 2008, with data available for 3488 patients. Overall ADR incidence was 81.8% (mostly grade 1/2); skin disorders (68.5%) including rash (63.0%) were most common. However, 81.8% of patients who experienced rash recovered or improved. ILD-like events, diagnosed by local physicians, were reported in 189 patients. The independent review committee confirmed ILD (all grades) in 158 patients (4.5% of interim population) with a mortality rate of 1.6% (55 patients). Significant ILD risk factors included concomitant or previous ILD, smoking history, concomitant or previous lung infection, and Eastern Cooperative Oncology Group performance status 2 to 4. Median overall survival and progression-free survival were 260 and 64 days, respectively.
These interim data support the clinical benefits of erlotinib in Japanese NSCLC patients with no new safety signals. The risk/benefit balance for erlotinib in recurrent/advanced NSCLC remains favorable.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 05/2012; 7(8):1296-303. · 4.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: In the IRESSA Pan-Asia Study (IPASS), 1217 patients in East Asia with pulmonary adenocarcinoma who were never-smokers or ex/light-smokers received first-line gefitinib (250 mg/day) or carboplatin/paclitaxel (area under the curve 5/6; 200 mg/m(2) ). Efficacy analyses were pre-planned in patients in China.
In China, 372 patients (30.6% of the overall group) were randomized. The primary end-point was progression-free survival (PFS). Secondary end-points were overall survival (OS), objective response rate (ORR), health-related quality of life (HRQoL), symptom improvement, safety and tolerability.
For patients in China, PFS did not significantly differ from the overall IPASS population (interaction test P= 0.427). PFS was numerically longer (hazard ratio [HR] 0.79; 95% CI 0.62-1.01; P= 0.065; median PFS 6.8 months for both treatments) and ORR significantly higher (ORR 44.6 vs 29.8%; odds ratio 1.88; 95% CI 1.22-2.89; P= 0.004) for gefitinib than carboplatin/paclitaxel. OS (mature data) was similar for both treatments (HR 0.92; 95% CI 0.73-1.17; P= 0.511; median OS gefitinib 18.1 months vs 18.3 months carboplatin/paclitaxel). HRQoL improvement rates favored gefitinib; symptom improvement rates were similar for both treatments. Gefitinib had a more favorable tolerability profile than carboplatin/paclitaxel. Efficacy by epidermal growth factor receptor biomarker status (exploratory analyses) was difficult to interpret due to low patient numbers with known biomarker status.
For the Chinese subgroup of IPASS, gefitinib demonstrated improved PFS and ORR, similar OS, higher HRQoL, similar symptom improvement rates and a more favorable tolerability profile than carboplatin/paclitaxel, generally consistent with the overall IPASS population.
[show abstract][hide abstract] ABSTRACT: We conducted a feasibility study of induction chemotherapy followed by gefitinib and thoracic radiotherapy (TRT) for unresectable locally advanced adenocarcinoma of the lung.
Patients received induction chemotherapy with cisplatin (80 mg/m(2), days 1 and 22) and vinorelbine (25 mg/m(2), days 1, 8, 22, and 29) followed by gefitinib (250 mg daily, beginning on day 43, for 1 year) and TRT (60 Gy/30 fractions, days 57-98). The primary end point was feasibility, which was defined as the proportion of patients who completed 60 Gy of TRT and received >75% of the planned dose of gefitinib without developing grade 2 or worse pneumonitis.
Of the 38 enrolled patients, 23 patients [60.5% ; 80% confidence interval (CI) 48.8-71.3] completed treatment without experiencing grade 2 or worse pneumonitis. During the chemoradiation phase, grade 3-4 alanine aminotransferase elevations were observed in 37.1% of the patients. The overall response rate was 73.0% . The median survival time was 28.5 months (95% CI 22.5-38.2), and the 2-year survival rate was 65.4% .
Although the results did not meet our criterion for feasibility, the toxicity was acceptable. This treatment warrants further evaluation among patients with locally advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutations.
Annals of Oncology 02/2012; 23(9):2253-8. · 7.38 Impact Factor
[show abstract][hide abstract] ABSTRACT: Monotherapy with a third generation anticancer agent has been regarded as the standard therapy for elderly patients with advanced non-small-cell lung cancer (NSCLC). However, it is unclear whether elderly patients with a good performance status can tolerate platinum-doublet chemotherapy like younger patients.
A combination phase I/II study was conducted in chemo-naive elderly patients with NSCLC to establish the toxicity and maximum tolerated dose (MTD) and to investigate the antitumor activity of carboplatin (CBDCA) plus gemcitabine (GEM). GEM was infused on days 1 and 8, and CBDCA on day 1 every 3 weeks.
Seventy-five patients were enrolled. The most frequent toxicities were hematological, especially thrombocytopenia. Three of three patients experienced a dose-limiting toxicity at dose level 3: 1000 mg/m(2) GEM with AUC 5 CBDCA (MTD), and one of seven patients at level 2a: 1000 mg/m(2) GEM with AUC 4 CBDCA (recommended dose). In the phase II study, the overall response rate was 22.2% and the median overall survival time was 14.2 months.
Although the recommended dosage is restricted to a lower level compared to younger patients, combination therapy using CBDCA with GEM is tolerable and promising for elderly patients with advanced NSCLC.
Lung cancer (Amsterdam, Netherlands) 02/2012; 77(1):110-5. · 3.14 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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).
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).
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.
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).
Lung cancer (Amsterdam, Netherlands) 01/2012; 76(3):362-7. · 3.14 Impact Factor
[show abstract][hide abstract] ABSTRACT: A Phase I study to determine a recommended dose of thoracic radiotherapy using accelerated hyperfractionation for unresectable non-small-cell lung cancer was conducted.
Patients with unresectable Stage III non-small-cell lung cancer were treated intravenously with carboplatin (area under the concentration curve 2) and paclitaxel (40 mg/m(2)) on Days 1, 8, 15, and 22 with concurrent twice-daily thoracic radiotherapy (1.5 Gy per fraction) beginning on Day 1 followed by two cycles of consolidation chemotherapy using carboplatin (area under the concentration curve 5) and paclitaxel (200 mg/m(2)). Total doses were 54 Gy in 36 fractions, 60 Gy in 40 fractions, 66 Gy in 44 fractions, and 72 Gy in 48 fractions at Levels 1 to 4. The dose-limiting toxicity, defined as Grade ≥4 esophagitis and neutropenic fever and Grade ≥3 other nonhematologic toxicities, was monitored for 90 days.
Of 26 patients enrolled, 22 patients were assessable for response and toxicity. When 4 patients entered Level 4, enrollment was closed to avoid severe late toxicities. Dose-limiting toxicities occurred in 3 patients. They were Grade 3 neuropathy at Level 1 and Level 3 and Grade 3 infection at Level 1. However, the maximum tolerated dose was not reached. The median survival time was 28.6 months for all patients.
The maximum tolerated dose was not reached, although the dose of radiation was escalated to 72 Gy in 48 fractions. However, a dose of 66 Gy in 44 fractions was adopted for this study because late toxicity data were insufficient.
International journal of radiation oncology, biology, physics 11/2011; 83(1):327-31. · 4.59 Impact Factor
[show abstract][hide abstract] ABSTRACT: To evaluate the combination chemotherapy using oral antimetabolite S-1 plus cisplatin (SP) with concurrent thoracic radiotherapy (RT) followed by the consolidation SP for locally advanced non-small cell lung cancer.
Patients with stage III non-small cell lung cancer, 20 to 74 years of age, and Eastern Cooperative Oncology Group performance status 0 to 1 were eligible. The concurrent phase consisted of full dose S-1 (orally at 40 mg/m/dose twice daily, on days 1-14) and cisplatin (60 mg/m on day 1) repeated every 4 weeks for two cycles with RT delivered beginning on day 1 (60 Gy/30 fractions over 6 weeks). After SP-RT, patients received an additional two cycles of SP as the consolidation phase.
Fifty-five patients were registered between November 2006 and December 2007. Of the 50 patients for efficacy analysis, the median age was 64 years; male/female 40/10; Eastern Cooperative Oncology Group performance status 0/1, 21/29; clinical stage IIIA/IIIB 18/32; and adenocarcinoma/others 20/30. There were 42 clinical responses including one complete response with an objective response rate of 84% (95% confidence interval [CI], 71-93%). The 1- and 2-year overall survival rates were 88% (95% CI, 75-94%) and 70% (95% CI, 55-81%), respectively. The median progression-free survival was 20 months. Of the 54 patients for safety analysis, common toxicities in the concurrent phase included grade 3/4 neutropenia (26%), thrombocytopenia (9%), and grade 3 esophagitis (9%) and febrile neutropenia (9%). In one patient, grade 3 pneumonitis was observed in the consolidation phase. There were two treatment-related deaths caused by infection in the concurrent phase.
SP-RT showed a promising efficacy against locally advanced NCSLC with acceptable toxicity.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 11/2011; 6(12):2069-75. · 4.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: Evaluation of health-related quality-of-life (HRQoL) and symptom improvement were preplanned secondary objectives for the overall population and posthoc analyses for epidermal growth factor receptor (EGFR) mutation-positive/negative subgroups in IPASS.
HRQoL was assessed using the Functional Assessment of Cancer Therapy-Lung (FACT-L) and Trial Outcome Index (TOI); symptom improvement by the Lung Cancer Subscale (LCS). Improvements defined as: 6 or more (FACT-L; TOI), 2 or more (LCS) points increase maintained for 21 or more days.
Overall (n = 1151/1217 evaluable), HRQoL improvement rates were significantly greater with gefitinib versus carboplatin/paclitaxel; symptom improvement rates were similar for both treatments. Significantly more patients recorded improvements in HRQoL and symptoms with gefitinib in the EGFR mutation-positive subgroup (n = 259; FACT-L 70.2% versus 44.5%; odds ratio, 3.01 [95% confidence interval, 1.79-5.07]; p < 0.001; TOI 70.2% versus 38.3%; 3.96 [2.33-6.71]; p < 0.001; LCS 75.6% versus 53.9%; 2.70 [1.58-4.62]; p < 0.001), and with carboplatin/paclitaxel in the EGFR mutation-negative subgroup (n = 169; FACT-L 14.6% versus 36.3%; odds ratio, 0.31 [0.15-0.65]; p = 0.002; TOI 12.4% versus 28.8%; 0.35 [0.16-0.79]; p = 0.011; LCS 20.2% versus 47.5%; 0.28 [0.14-0.55]; p < 0.001). Median time-to-worsening (months) FACT-L score was longer with gefitinib versus carboplatin/paclitaxel for the overall population (8.3 versus 2.5) and EGFR mutation-positive subgroup (15.6 versus 3.0), and similar for both treatments in the EGFR mutation-negative subgroup (1.4 versus 1.4). Median time-to-improvement with gefitinib was 8 days in patients with EGFR mutation-positive tumors who improved.
HRQoL and symptom endpoints were consistent with efficacy outcomes in IPASS and favored gefitinib in patients with EGFR mutation-positive tumors and carboplatin/paclitaxel in patients with EGFR mutation-negative tumors.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 11/2011; 6(11):1872-80. · 4.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: Cetuximab, an antibody directed against the epidermal growth factor receptor, is an effective clinical therapy for patients with colorectal, head and neck, and non-small cell lung cancer, particularly for those with KRAS and BRAF wild-type cancers. Treatment in all patients is limited eventually by the development of acquired resistance, but little is known about the underlying mechanism. Here, we show that activation of ERBB2 signaling in cell lines, either through ERBB2 amplification or through heregulin up-regulation, leads to persistent extracellular signal-regulated kinase 1/2 signaling and consequently to cetuximab resistance. Inhibition of ERBB2 or disruption of ERBB2/ERBB3 heterodimerization restores cetuximab sensitivity in vitro and in vivo. A subset of colorectal cancer patients who exhibit either de novo or acquired resistance to cetuximab-based therapy has ERBB2 amplification or high levels of circulating heregulin. Collectively, these findings identify two distinct resistance mechanisms, both of which promote aberrant ERBB2 signaling, that mediate cetuximab resistance. Moreover, these results suggest that ERBB2 inhibitors, in combination with cetuximab, represent a rational therapeutic strategy that should be assessed in patients with cetuximab-resistant cancers.
Science translational medicine 09/2011; 3(99):99ra86. · 10.76 Impact Factor
[show abstract][hide abstract] ABSTRACT: In IPASS (IRESSA Pan-Asia Study), clinically selected patients with pulmonary adenocarcinoma received first-line gefitinib or carboplatin/paclitaxel. This preplanned, exploratory analysis was conducted to increase understanding of the use of surrogate samples, such as serum, versus tumor biopsy samples for determining EGFR mutation status in the Japanese cohort (n = 233).
EGFR mutations were assessed using tumor tissue-derived DNA (n = 91) and circulating free (cf) DNA from pretreatment serum samples (n = 194).
Fewer patients were EGFR mutation positive when assessed using pretreatment cfDNA (23.7%) versus tumor tissue-derived DNA (61.5%). cfDNA results identified no false positives but a high rate of false negatives (56.9%). There was a significant interaction between cfDNA EGFR mutation status and treatment for progression-free survival (PFS) (p = 0.045). PFS was significantly longer and objective response rate (ORR) higher with gefitinib than carboplatin/paclitaxel in the cfDNA EGFR mutation-positive subgroup (PFS: hazard ratio [HR], 0.29; 95% confidence interval [CI], 0.14-0.60; p < 0.001; ORR: odds ratio [OR], 1.71; 95% CI, 0.48-6.09; 75.0% versus 63.6%; p = 0.40). There was a slight numerical advantage in PFS and ORR for gefitinib over carboplatin/paclitaxel in the cfDNA EGFR mutation-negative subgroup, likely due to the high rate of false negatives within this subgroup.
These results merit further investigation to determine whether alternative sources of tumor DNA, such as cfDNA in serum, could be used for determining EGFR mutation status in future; currently, where a sample is available, analysis of tumor material is recommended.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 09/2011; 7(1):115-21. · 4.55 Impact Factor