First line chemotherapy with planned sequential administration of gemcitabine followed by docetaxel in elderly advanced non-small-cell lung cancer patients: a multicenter phase II study

This multicenter phase II study evaluated, in chemonaive patients with stage IIIB–IV NSCLC, age ⩾70 and with a performance status 0–2, the activity, efficacy and tolerability of planned sequential administration of gemcitabine 1200 mg m−2 on days 1 and 8 every 3 weeks for three courses followed by three cycles of docetaxel 37.5 mg m−2 on days 1 and 8 every 3 weeks, provided there was no evidence of disease progression. A total of 56 patients entered the study. According to intention-to-treat analysis, the objective response rate was 16.0% (95% CI 7.6–28.3%); 23 patients (41.0%) had stable disease and 24 patients (43%) had progressive disease. Five patients who had a stable disease after three courses of gemcitabine obtained a conversion to partial response by docetaxel. Median time to progression was 4.8 months (95% CI 3.6–6.0 months) and median duration of survival was 8.0 months (95% CI 5.6–10.5 months). The 1-year survival rate was 34%. No grade 4 haematological toxicity was observed and grade 3 neutropenia and thrombocytopenia were reported in 5.4 and 3.6% of the patients, respectively. Grade 3/4 mucositis and grade 3 diarrhoea, both occurred in 3.6% of the patients and grade 3 asthenia was observed in 9% of patients. One patient reported a grade 4 skin toxicity. No treatment-related deaths occurred. Sequential gemcitabine and docetaxel is a well-tolerated and effective regimen in elderly advanced NSCLC patients

Phase I study of IMGN901, a CD56-targeting antibody-drug conjugate, in patients with CD56-positive solid tumors.

Background IMGN901 is a CD56-targeting antibody-drug conjugate designed for tumor-selective delivery of the cytotoxic maytansinoid DM1. This phase 1 study investigated the safety, tolerability, pharmacokinetics, and preliminary activity of IMGN901 in patients with CD56-expressing solid tumors. Methods Patients were enrolled in cohorts of escalating IMGN901 doses, administered intravenously, on 3 consecutive days every 21 days. A dose-expansion phase accrued patients with small cell lung cancer (SCLC), Merkel cell carcinoma (MCC), or ovarian cancer. Results Fifty-two patients were treated at doses escalating from 4 to 94 mg/m(2)/day. The maximum tolerated dose (MTD) was determined to be 75 mg/m(2). Dose-limiting toxicities included fatigue, neuropathy, headache or meningitis-like symptoms, chest pain, dyspnea, and myalgias. In the dose-expansion phase (n = 45), seven patients received 75 mg/m(2) and 38 received 60 mg/m(2) for up to 21 cycles. The recommended phase 2 dose (RP2D) was established at 60 mg/m(2) during dose expansion. Overall, treatment-emergent adverse events (TEAEs) were experienced by 96.9 % of all patients, the majority of which were Grade 1 or 2. The most commonly reported Grade 3 or 4 TEAEs were hyponatremia and dyspnea (each 8.2 %). Responses included 1 complete response (CR), 1 clinical CR, and 1 unconfirmed partial response (PR) in MCC; and 1 unconfirmed PR in SCLC. Stable disease was seen for 25 % of all evaluable patients who received doses ≥60 mg/m(2). Conclusions The RP2D for IMGN901 of 60 mg/m(2) administered for 3 consecutive days every 3 weeks was associated with an acceptable tolerability profile. Objective responses were observed in patients with advanced CD56+ cancers

A randomised phase II trial of preoperative chemotherapy of cisplatin–docetaxel or docetaxel alone for clinical stage IB/II non-small-cell lung cancer: results of a Japan Clinical Oncology Group trial (JCOG 0204)

Preoperative chemotherapy is a promising strategy in patients with early-stage resectable non-small-cell lung cancer (NSCLC); optimal chemotherapy remains unclear. Clinical (c-) stage IB/II NSCLC patients were randomised to receive either two cycles of docetaxel (D)–cisplatin (P) combination chemotherapy (D 60 mg m−2 and P 80 mg m−2 on day 1) every 3–4 weeks or three cycles of D monotherapy (70 mg m−2) every 3weeks. Thoracotomy was performed 4–5 weeks (DP) or 3–4 weeks (D) after chemotherapy. The primary end point was 1-year disease-free survival (DFS). From October 2002 to November 2003, 80 patients were randomised. Chemotherapy toxicities were mainly haematologic and well tolerated. There were two early postoperative deaths with DP (one intraoperative bleeding and one empyema). Pathologic complete response was observed in two DP patients. Docetaxel–cisplatin was superior to D in terms of response rate (45 vs 15%) and complete resection rate (95 vs 87%). Both DFS and overall survival were better in DP. Disease-free survival at 1, 2 and 4 years were 78, 65 and 57% with DP, and were 62, 44 and 36% with D, respectively. Preoperative DP was associated with encouraging resection rate and DFS data, and phase III trials for c-stage IB/II NSCLC are warranted

A randomized phase III study of the docetaxel/carboplatin combination versus docetaxel single-agent as second line treatment for patients with advanced/metastatic Non-Small Cell Lung Cancer

<p>Abstract</p> <p>Background</p> <p>To compare the activity and toxicity of docetaxel/carboplatin (DC) doublet vs single agent docetaxel (D) as second-line treatment in patients with advanced non-small cell lung cancer (NSCLC).</p> <p>Methods</p> <p>Patients pre-treated with front-line platinum-free regimens, were randomized to receive either docetaxel/carboplatin (DC), (docetaxel 50 mg/m²; carboplatin AUC4; both drugs administered on days 1 and 15) or docetaxel single-agent (D), (docetaxel 50 mg/m²on days 1 and 15).</p> <p>Results</p> <p>Response rate was similar between the two arms (DC vs D: 10.4% vs 7.7%; p = 0.764). After a median follow-up time of 28.0 months for DC arm and 34.5 months for D arm, progression free survival (PFS) was significantly higher in the DC arm (DC vs D:3.33 months vs 2.60 months; p-value = 0.012), while no significant difference was observed in terms of overall survival (OS) (DC vs D: 10.3 months vs 7.70 months; p-value = 0.550). Chemotherapy was well-tolerated and grade III/IV toxicities were relatively infrequent. No toxic deaths were observed.</p> <p>Conclusions</p> <p>This study has not achieved its primary objective of significant OS prolongation with docetaxel/carboplatin combination over single-agent docetaxel in patients who had not received front-line docetaxel; however, the docetaxel/carboplatin combination was associated with a significant clinical benefit in terms of PFS.</p

Vinorelbine/carboplatin vs gemcitabine/carboplatin in advanced NSCLC shows similar efficacy, but different impact of toxicity

This randomised phase III study in advanced non-small cell lung cancer (NSCLC) patients was conducted to compare vinorelbine/carboplatin (VC) and gemcitabine/carboplatin (GC) regarding efficacy, health-related quality of life (HRQOL) and toxicity. Chemonaive patients with NSCLC stage IIIB/IV and WHO performance status 0–2 were eligible. No upper age limit was defined. Patients received vinorelbine 25 mg m−2 or gemcitabine 1000 mg m−2 on days 1 and 8 and carboplatin AUC4 on day 1 and three courses with 3-week cycles. HRQOL questionnaires were completed at baseline, before chemotherapy and every 8 weeks until 49 weeks. During 14 months, 432 patients were included (VC, n=218; GC, n=214). Median survival was 7.3 vs 6.4 months, 1-year survival 28 vs 30% and 2-year survival 7 vs 7% in the VC and GC arm, respectively (P=0.89). HRQOL, represented by global QOL, nausea/vomiting, dyspnoea and pain, showed no significant differences. More grade 3–4 anaemia (P<0.01), thrombocytopenia (P<0.01) and transfusions of blood (P<0.01) or platelets (P<0.01) were observed in the GC arm. There was more grade 3–4 leucopoenia (P<0.01) in the VC arm, but the rate of neutropenic infections was the same (P=0.87). In conclusion, overall survival and HRQOL are similar, while grade 3–4 toxicity requiring interventions are less frequent when VC is compared to GC in advanced NSCLC

ZD6474 – clinical experience to date

ZD6474 selectively targets two key pathways in tumour growth by inhibiting vascular endothelial growth factor (VEGF)-dependent tumour angiogenesis and epidermal growth factor (EGF)-dependent tumour cell proliferation and survival. Phase I clinical evaluation has shown ZD6474 to be generally well tolerated, with a pharmacokinetic profile appropriate for once-daily oral dosing. Phase II evaluation of ZD6474 at doses of 100−300 mg is ongoing in a range of patient types in single and combination regimens. These include three randomised studies of patients with non-small-cell lung cancer. In one of these trials, the efficacy of ZD6474 monotherapy is being compared with that of the EGF receptor tyrosine kinase inhibitor gefitinib (Iressa™) in previously treated patients. In the other two trials, the efficacy of ZD6474 in combination with certain standard chemotherapy regimens is being compared with that of standard chemotherapy alone: one with carboplatin and paclitaxel in previously untreated patients, and the second with docetaxel in patients who progressed after platinum-containing therapy. The advent of novel molecular-targeted agents such as ZD6474 has necessitated a re-evaluation of conventional cancer study design in order to optimise appraisal of this new generation of anticancer agents. The specific considerations of the ZD6474 clinical programme are discussed

Gemcitabine and vinorelbine followed by docetaxel in patients with advanced non-small-cell lung cancer: a multi-institutional phase II trial of nonplatinum sequential triplet combination chemotherapy (JMTO LC00-02)

To evaluate the efficacy and toxicity of the sequential nonplatinum combination chemotherapy consisting of gemcitabine (GEM) and vinorelbine (VNR) followed by docetaxel (DOC) in patients with advanced non-small-cell lung cancer (NSCLC), we conducted the multiinstitutional phase II study. A total of 44 chemotherapy-naive patients with advanced NSCLC were treated with GEM 1000 mg m−2 and VNR 25 mg m−2 intravenously on days 1 and 8 every 3 weeks for three cycles. DOC 60 mg m−2 was then administrated intravenously at 3-week intervals for three cycles. Patients were evaluated for response and toxicity with each cycle of the treatment. The major objective response rate was 47.7% (95% confidence interval (CI), 33.8–62.1%). Median survival time (MST) was 15.7 months and 1-year survival rate was 59%. In the GEM/VNR cycle, grade 3/4 neutropenia occurred in 36.3%, grade 3/4 anaemia in two patients (4.5%) and grade 3 thrombocytopenia in one patient (2.3%). Grade 3 pneumonitis occurred in two patients (4.5%) in GEM/VNR cycles. In the DOC cycles, grade 3/4 neutropenia occurred in 39.4% but no patient experienced grade 3/4 anaemia or thrombocytopenia. Of the 44 eligible patients, 33 patients completed three cycles of GEM/VNR and 22 patients completed six cycles of planned chemotherapy (three cycles of GEM/VNR followed by three cycles of DOC). The sequential triplet nonplatinum chemotherapy consisted of GEM/VNR followed by DOC, and was very active and well tolerated. This study forms the basis for an ongoing phase III trial that compares this nonplatinum triplet and standard platinum doublet combination (carboplatin/paclitaxel)

Second-line paclitaxel in non-small cell lung cancer initially treated with cisplatin: a study by the European Lung Cancer Working Party

In the context of a phase III trial comparing in advanced non-small cell lung cancer (NSCLC) sequential to conventional administration of cisplatin-based chemotherapy and paclitaxel, we evaluated the activity of paclitaxel as second-line chemotherapy and investigated any relation of its efficacy with the type of failure after cisplatin. Patients received three courses of induction GIP (gemcitabine, ifosfamide, cisplatin). Non-progressing patients were randomised between three further courses of GIP or three courses of paclitaxel. Second-line paclitaxel was given to patients with primary failure (PF) to GIP and to those progressing after randomisation to further GIP (secondary failure or SF). One hundred sixty patients received second-line paclitaxel. Response rates were 7.7% for PF and 11.6% for SF (P=0.42). Median survival times (calculated from paclitaxel start) were 4.1 and 7.1 months for PF and SF (P=0.002). In multivariate analysis, three variables were independently associated with better survival: SF (hazard ratio (HR)=1.55, 95% confidence interval (CI) 1.08–2.22; P=0.02), normal haemoglobin level (HR=1.56, 95% CI 1.08–2.26; P=0.02) and minimal weight loss (HR=1.79, 95% CI 1.26–2.55; P=0.001). Paclitaxel in NSCLC patients, whether given for primary or for SF after cisplatin-based chemotherapy, demonstrates activity similar to other drugs considered active as second-line therapy