Tetsu Shinkai

Phase III Study, V-15-32, of Gefitinib Versus Docetaxel in Previously Treated Japanese Patients With Non–Small-Cell Lung Cancer

PURPOSE This phase III study (V-15-32) compared gefitinib (250 mg/d) with docetaxel (60 mg/m(2)) in patients (N = 489) with advanced/metastatic non-small-cell lung cancer (NSCLC) who had failed one or two chemotherapy regimens. METHODS The primary objective was to compare overall survival to demonstrate noninferiority for gefitinib relative to docetaxel. An unadjusted Cox regression model was used for the primary analysis. RESULTS Noninferiority in overall survival was not achieved (hazard ratio [HR], 1.12; 95.24% CI, 0.89 to 1.40) according to the predefined criterion (upper CI limit for HR <or= 1.25); however, no significant difference in overall survival (P = .330) was apparent between treatments. Poststudy, 36% of gefitinib-treated patients received subsequent docetaxel, and 53% of docetaxel-treated patients received subsequent gefitinib. Gefitinib significantly improved objective response rate and quality of life versus docetaxel; progression-free survival, disease control rates, and symptom improvement were similar for the two treatments. Grades 3 to 4 adverse events occurred in 40.6% (gefitinib) and 81.6% (docetaxel) of patients. Incidence of interstitial lung disease was 5.7% (gefitinib) and 2.9% (docetaxel). Four deaths occurred due to adverse events in the gefitinib arm (three deaths as a result of interstitial lung disease, judged to be treatment related; one as a result of pneumonia, not treatment related), and none occurred in the docetaxel arm. CONCLUSION Noninferiority in overall survival between gefitinib and docetaxel was not demonstrated according to predefined criteria; however, there was no statistically significant difference in overall survival. Secondary end points showed similar or superior efficacy for gefitinib compared with docetaxel. Gefitinib remains an effective treatment option for previously treated Japanese patients with NSCLC.

Phase III Study of Docetaxel Compared With Vinorelbine in Elderly Patients With Advanced Non–Small-Cell Lung Cancer: Results of the West Japan Thoracic Oncology Group Trial (WJTOG 9904)

PURPOSE Docetaxel has shown activity in elderly patients with advanced non-small-cell lung cancer (NSCLC). This randomized phase III trial evaluated the efficacy and safety of docetaxel versus vinorelbine (the current standard treatment) in elderly patients. PATIENTS AND METHODS Chemotherapy-naïve patients age 70 years or older with stage IIIB/IV NSCLC and performance status 2 or lower were eligible. Patients randomly received docetaxel 60 mg/m2 (day 1) or vinorelbine 25 mg/m2 (days 1 and 8) every 21 days for four cycles. The primary end point was overall survival. Overall disease-related symptom improvement was assessed using an eight-item questionnaire. RESULTS In total, 182 patients were enrolled. Median age was 76 years (range, 70 years to 86 years). There was no statistical difference in median overall survival with docetaxel versus vinorelbine (14.3 months v 9.9 months; hazard ratio, 0.780; 95% CI, 0.561 to 1.085; P = .138). There was a significant difference in median progression-free survival (5.5 months v 3.1 months; P < .001). Response rates were also significantly improved with docetaxel versus vinorelbine (22.7% v 9.9%; P = .019). The most common grade 3 to 4 toxicities were neutropenia (82.9% for docetaxel; 69.2% for vinorelbine; P = .031) and leukopenia (58.0% for docetaxel; 51.7% for vinorelbine). Other toxicities were mild and generally well tolerated. Docetaxel improved overall disease-related symptoms over vinorelbine (odds ratio, 1.86; 95% CI, 1.09 to 3.20). CONCLUSION Docetaxel improved progression-free survival, response rate, and disease-related symptoms versus vinorelbine. Overall survival was not statistically significantly improved at this time. Docetaxel monotherapy may be considered as an option in the standard treatment of elderly patients with advanced NSCLC.

A Phase I Dose-Escalation Study of ZD6474 in Japanese Patients with Solid, Malignant Tumors

Introduction: ZD6474 (vandetanib) is an orally available inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor, and RET receptor tyrosine kinase activity. This study assessed the safety and tolerability of escalating doses of ZD6474 in Japanese patients with solid, malignant tumors. Methods: Adult patients with solid tumors refractory to standard therapy received a once-daily oral dose of ZD6474 (100–400 mg) in 28-day cycles, until disease progression or unacceptable toxicity was observed. Results: Eighteen patients were treated at doses of 100 mg (n = 3), 200 mg (n = 6), 300 mg (n = 6), and 400 mg (n = 3). Dose-limiting toxicities at the completion of cycle 2 were hypertension (n = 3), diarrhea (n = 1), headache (n = 1), toxic skin eruption (n = 1), and alanine aminotransferase increase (n = 1). A dose of 400 mg/day was considered to exceed the maximum tolerated dose (MTD). Toxicities were manageable with dose interruption and/or reduction. Objective tumor response was observed in four of nine patients with non-small cell lung cancer (NSCLC) at doses of either 200 or 300 mg. Terminal half-life was about 90–115 hours. Plasma trough concentrations achieved steady-state conditions after approximately 1 month of daily dosing. Conclusions: It was concluded that a dose of 400 mg/day was considered to exceed the MTD, and doses for phase II study were thought to be not more than 300 mg/day. The objective response observed in some NSCLC patients is encouraging for further studies in this tumor type.

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).

A Randomized, Double-Blind, Phase IIa Dose-Finding Study of Vandetanib (ZD6474) in Japanese Patients With Non-Small Cell Lung Cancer

Introduction: Vandetanib (ZACTIMATM) is a once-daily, oral anticancer drug that selectively inhibits vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) signaling. Vandetanib was evaluated as a monotherapy in a randomized, double-blind, dose-finding study in Japan. Patients and Methods: Eligible patients with locally advanced or metastatic (stage IIIB/IV) or recurrent non-small cell lung cancer, previously treated with chemotherapy, were randomized to receive once-daily oral vandetanib 100, 200, or 300 mg (1:1:1). The primary objective was to determine the objective response rate for each vandetanib dose. Results: Fifty-three patients received vandetanib (100 mg, n = 17; 200 mg, n = 18; 300 mg, n = 18). The objective response rate in each dose arm was 17.6% (3 of 17; 100 mg), 5.6% (1 of 18; 200 mg), and 16.7% (3 of 18; 300 mg). Common adverse events included rash, diarrhea, hypertension, and asymptomatic QTc prolongation. The adverse event profile was generally consistent with that reported previously for agents that inhibit the VEGFR or EGFR signaling pathways. Among the three responders evaluated for EGFR mutation, two had no mutation, and in one case, the EGFR mutation status could not be determined by direct DNA sequencing and amplification refractory mutation system assay of EGFR exons 19–21. Baseline plasma VEGF levels appeared to be lower in patients who experienced clinical benefit after vandetanib treatment. Conclusion: In Japanese patients with advanced non-small cell lung cancer, vandetanib monotherapy (100–300 mg/d) demonstrated antitumor activity with an acceptable safety and tolerability profile.

Phase I study of CPT-11 and etoposide in patients with refractory solid tumors.

PURPOSE To determine the maximum-tolerated dose (MTD) and acceptable dose level of a cytotoxic regimen of CPT-11, a new camptothecin derivative, in combination with etoposide (VP-16) and to describe the principal toxicities associated with it. PATIENTS AND METHODS Patients with refractory solid tumors received VP-16 and CPT-11 daily for 3 consecutive days (days 1 through 3) every 3 or 4 weeks. Groups entered the trial at escalating CPT-11/VP-16 dose levels of 40/60, 60/60, 60/80, and 80/60 mg/m2. Thirty-four patients entered this study, of whom 33 were assessable for toxicity and 22 for therapeutic efficacy. RESULTS Granulocytopenia was so severe that this regimen required supportive therapy with recombinant human granulocyte colony-stimulating factor (G-CSF). The majority of the patients experienced a 5% weight loss and diarrhea was the dose-limiting toxicity. The MTDs were 60/80 and 80/60 mg/m2 administered on days 1 through 3. Five of seven previously untreated patients with non-small-cell lung cancer (NSCLC) achieved partial responses (PRs) to this therapy, as did two with NSCLC who had received prior chemotherapy, two with head and neck cancer, and one with an adenocarcinoma (primary tumor unknown). CONCLUSION The recommended dose of CPT-11/VP-16 for this regimen with G-CSF is 60/60 mg/m2 on days 1 through 3 every 3 to 4 weeks. We suggest that the combination of topoisomerase I and II inhibitors is likely to be an effective treatment strategy. The activity of this regimen against NSCLC is particularly encouraging and should be evaluated in a phase II trial.

Etoposide and cisplatin versus irinotecan and cisplatin in patients with limited-stage small-cell lung cancer treated with etoposide and cisplatin plus concurrent accelerated hyperfractionated thoracic radiotherapy (JCOG0202): a randomised phase 3 study.

BACKGROUND Four cycles of etoposide plus cisplatin and accelerated hyperfractionated thoracic radiotherapy (AHTRT) is the standard of care for limited-stage small-cell lung cancer (SCLC). Irinotecan plus cisplatin significantly improved overall survival compared with etoposide plus cisplatin for extensive-stage SCLC. We compared these regimens for overall survival of patients with limited-stage SCLC. METHODS We did this phase 3 study in 36 institutions in Japan. Eligibility criteria included age 20-70 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and adequate organ functions. Eligible patients with previously untreated limited-stage SCLC received one cycle of etoposide plus cisplatin (intravenous etoposide 100 mg/m(2) on days 1-3; intravenous cisplatin 80 mg/m(2) on day 1) plus AHTRT (1.5 Gy twice daily, 5 days a week, total 45 Gy over 3 weeks). Patients without progressive disease following induction therapy were randomised (1:1 ratio, using a minimisation method with biased-coin assignment balancing on ECOG performance status [0 vs 1], response to induction chemoradiotherapy [complete response plus near complete response vs partial response and stable disease], and institution) to receive either three further cycles of consolidation etoposide plus cisplatin or irinotecan plus cisplatin (intravenous irinotecan 60 mg/m(2) on days 1, 8, 15; intravenous cisplatin 60 mg/m(2) on day 1). Patients, physicians, and investigators were aware of allocation. The primary endpoint was overall survival after randomisation; primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00144989, and the UMIN Clinical Trials Registry, number C000000095. FINDINGS 281 patients were enrolled between Sept 1, 2002, and Oct 2, 2006. After induction etoposide plus cisplatin and AHTRT, 258 patients were randomised to consolidation etoposide plus cisplatin (n=129) or irinotecan plus cisplatin (n=129). In the etoposide plus cisplatin group, median overall survival was 3.2 years (95% CI 2.4-4.1). In the irinotecan and cisplatin group, median overall survival was 2.8 years (95% CI 2.4-3.6); overall survival did not differ between the two groups (hazard ratio 1.09 [95% CI 0.80-1.46], one-sided stratified log-rank p=0.70). The most common adverse events of grade 3 or 4 were neutropenia (120 [95%] in the etoposide plus cisplatin group vs 101 [78%] in the irinotecan plus cisplatin group), anaemia (44 [35%] vs 50 [39%]), thrombocytopenia (26 [21%] vs six [5%]), febrile neutropenia (21 [17%] vs 18 [14%]), and diarrhoea (two [2%] vs 13 [10%]). There was one treatment-related adverse event leading to death in each group (radiation pneumonitis in the etoposide plus cisplatin group; brain infarction in the irinotecan plus cisplatin group). INTERPRETATION Four cycles of etoposide plus cisplatin and AHTRT should continue to be the standard of care for limited-stage SCLC. FUNDING National Cancer Center and the Ministry of Health, Labour, and Welfare of Japan.

Phase I study of sequentially administered topoisomerase I inhibitor (irinotecan) and topoisomerase II inhibitor (etoposide) for metastatic non-small-cell lung cancer

We conducted a phase I study of irinotecan (CPT-11) and etoposide (VP-16) given sequentially to untreated patients with metastatic non-small-cell lung cancer. Arm A: CPT-11 was given over 90 min on days 1-3 and VP-16 was given over 60 min on days 4-6. Arm B: VP-16 was given on days 1-3 and CPT-11 on days 4-6. G-CSF was given to all patients daily on days 7-17. Twenty-seven patients were entered randomly at the two arms. The major dose-limiting toxicities in arms A and B were granulocytopenia and diarrhoea. Transient elevations of transaminases and bilirubin were observed in both arms. The degree of the toxicities did not differ between the two arms. The maximum tolerated doses (MTDs) were 60 mg m-2 CPT-11 and 60 mg m-2 VP-16 in both arms. Of the 13 patients who received more than two cycles, two out of five achieved partial response (PR) at the first level of arm A and one out of four achieved PR at the second level of arm B. We conclude that these schedules of sequential CPT-11 and VP-16 administration were inappropriate because of severe toxicities.

Effect of chemotherapy on natural-killer activity and antibody-dependent cell-mediated cytotoxicity in carcinoma of the lung.

The effect of chemotherapy on natural killer (NK) activity and antibody-dependent cell-mediated cytotoxicity (ADCC) in 15 advanced carcinomas of the lung was examined with regard to the drug, dose, route and timing of administration. The relationship between the effect of chemotherapy on the prognosis for the patients, and the changes in NK activity and ADCC, was also analysed. The NK activity and ADCC in patients with poor prognosis were significantly subnormal, even before treatment. The NK activity and ADCC began to decrease 2 weeks after the initiation of treatment and reached the lowest level during the 3rd or 4th week in all patients. Thereafter, they returned to the pretreatment level in 8 patients with stabilized disease. In contrast, they were not restored in 7 patients with progressive disease and poor prognosis. In 4 patients it was found that the effect of chemotherapy with pepleomycin and carbazilquinone on NK activity and ADCC differed according to the drug used. From this pilot study it is suggested that NK activity and ADCC are valuable prognostic factors in patients with advanced carcinoma of the lung, and that detailed analysis of the effect of each anticancer agent on NK activity and ADCC is desirable for the establishment of better treatment regimens for advanced carcinoma of the lung.

Multi-institutional phase II trial of irinotecan, cisplatin, and etoposide for sensitive relapsed small-cell lung cancer

Irinotecan (CPT-11) has been shown to exhibit excellent antitumour activity against small-cell lung cancer (SCLC). A multi-institutional phase II study was therefore conducted to evaluate the efficacy and toxicity of CPT-11 combined with cisplatin (CDDP) and etoposide (ETOP) (PEI regimen) for the treatment of sensitive relapsed SCLC. Patients who responded to first-line chemotherapy but relapsed more than 8 weeks after the completion of first-line therapy (n=40) were treated using the PEI regimen, which consisted of CDDP (25 mg m−2) weekly for 9 weeks, ETOP (60 mg m−2) for 3 days on weeks 1, 3, 5, 7, and 9, and CPT-11 (90 mg m−2) on weeks 2, 4, 6, and 8 with granulocyte colony-stimulating factor support. Five complete responses and 26 partial responses were observed, and the overall response rate was 78% (95% confidence interval 61.5–89.2%). The median survival time was 11.8 months, and the estimated 1-year survival rate was 49%. Grade 3/4 leucocytopenia, neutropenia, and thrombocytopenia were observed in 55, 73, and 33% of the patients, respectively. Nonhaematological toxicities were mild and transient in all patients. In conclusion, the PEI regimen is considered to be highly active and well tolerated for the treatment of sensitive relapsed SCLC.