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Non-small cell lung cancer (NSCLC) inevitably develops resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment. In 5-20% of cases, this can be attributed to aberrant c-Met activity, providing a clear rationale for the use of c-Met inhibitors in these patients. EGFR TKI-resistant tumors often remain sensitive to EGFR signaling, such that c-Met inhibitors are likely to be most effective when combined with continued EGFR TKI therapy. The phase III trials of the c-Met inhibitors onartuzumab and tivantinib, which failed to demonstrate significant benefit in patients with NSCLC but excluded patients with EGFR TKI-resistant disease, do not allow c-Met to be dismissed as a rational target in EGFR TKI-resistant NSCLC. Selective c-Met TKIs exhibit more favorable properties, targeting both hepatocyte growth factor (HGF)-dependent and -independent c-Met activity, with a reduced risk of toxicity compared to non-selective c-Met TKIs. Phase Ib/II trials of the selective c-Met TKIs capmatinib and tepotinib have shown encouraging signs of efficacy. Factors affecting the success of ongoing and future trials of c-Met inhibitors in patients with EGFR TKI-resistant, c-Met-positive NSCLC are considered., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Ceritinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor, which has shown robust anti-tumour efficacy, along with intracranial activity, in patients with ALK-rearranged non-small-cell lung cancer. In phase 1 and 2 studies, ceritinib has been shown to be highly active in both ALK inhibitor-naive and ALK inhibitor-pretreated patients who had progressed after chemotherapy (mostly multiple lines). In this study, we compared the efficacy and safety of ceritinib versus single-agent chemotherapy in patients with advanced ALK-rearranged non-small-cell lung cancer who had previously progressed following crizotinib and platinum-based doublet chemotherapy., Methods: In this randomised, controlled, open-label, phase 3 trial, we recruited patients aged at least 18 years with ALK-rearranged stage IIIB or IV non-small-cell lung cancer (with at least one measurable lesion) who had received previous chemotherapy (one or two lines, including a platinum doublet) and crizotinib and had subsequent disease progression, from 99 centres across 20 countries. Other inclusion criteria were a WHO performance status of 0-2, adequate organ function and laboratory test results, a life expectancy of at least 12 weeks, and having recovered from previous anticancer treatment-related toxicities. We randomly allocated patients (1:1; with blocking [block size of four]; stratified by WHO performance status [0 vs 1-2] and presence or absence of brain metastases) to oral ceritinib 750 mg per day fasted (in 21 day treatment cycles) or chemotherapy (intravenous pemetrexed 500 mg/m 2 or docetaxel 75 mg/m 2 [investigator choice], every 21 days). Patients who discontinued chemotherapy because of progressive disease could cross over to the ceritinib group. The primary endpoint was progression-free survival, assessed by a masked independent review committee using Response Evaluation Criteria in Solid Tumors 1.1 in the intention-to-treat population, assessed every 6 weeks until month 18 and every 9 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01828112, and is ongoing but no longer recruiting patients., Findings: Between June 28, 2013, and Nov 2, 2015, we randomly allocated 231 patients; 115 (50%) to ceritinib and 116 (50%) to chemotherapy (40 [34%] to pemetrexed, 73 [63%] to docetaxel, and three [3%] discontinued before receiving treatment). Median follow-up was 16·5 months (IQR 11·5-21·4). Ceritinib showed a significant improvement in median progression-free survival compared with chemotherapy (5·4 months [95% CI 4·1-6·9] for ceritinib vs 1·6 months [1·4-2·8] for chemotherapy; hazard ratio 0·49 [0·36-0·67]; p<0·0001). Serious adverse events were reported in 49 (43%) of 115 patients in the ceritinib group and 36 (32%) of 113 in the chemotherapy group. Treatment-related serious adverse events were similar between groups (13 [11%] in the ceritinib group vs 12 [11%] in the chemotherapy group). The most frequent grade 3-4 adverse events in the ceritinib group were increased alanine aminotransferase concentration (24 [21%] of 115 vs two [2%] of 113 in the chemotherapy group), increased γ glutamyltransferase concentration (24 [21%] vs one [1%]), and increased aspartate aminotransferase concentration (16 [14%] vs one [1%] in the chemotherapy group). Six (5%) of 115 patients in the ceritinib group discontinued because of adverse events compared with eight (7%) of 116 in the chemotherapy group. 15 (13%) of 115 patients in the ceritinib group and five (4%) of 113 in the chemotherapy group died during the treatment period (from the day of the first dose of study treatment to 30 days after the final dose). 13 (87%) of the 15 patients who died in the ceritinib group died because of disease progression and two (13%) died because of an adverse event (one [7%] cerebrovascular accident and one [7%] respiratory failure); neither of these deaths were considered by the investigator to be treatment related. The five (4%) deaths in the chemotherapy group were all due to disease progression., Interpretation: These findings show that patients derive significant clinical benefit from a more potent ALK inhibitor after failure of crizotinib, and establish ceritinib as a more efficacious treatment option compared with chemotherapy in this patient population., Funding: Novartis Pharmaceuticals Corporation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: Type 1 insulin-like growth factor receptor is deregulated in solid tumors. Cixutumumab, a monoclonal antibody that inhibits the activity of type 1 insulin-like growth factor receptor, was investigated in combination with pemetrexed/cisplatin in the frontline setting., Methods: In this open-label, phase II study, patients with stage IV nonsquamous NSCLC and a performance status of 0 to 1 were randomized (1:1) to receive 20 mg/kg cixutumumab, 500 mg/m 2 pemetrexed, and 75 mg/m 2 cisplatin (cixutumumab [n = 87]) or pemetrexed and cisplatin (control [n = 85]). Eligible patients received pemetrexed-based maintenance therapy with cixutumumab (cixutumumab arm) or without it (control arm). The primary end point was progression-free survival. Secondary end points assessed overall survival, objective response rate, and safety. Survival was analyzed by the Kaplan-Meier method and Cox proportional hazard model. Exploratory correlative analyses were also performed., Results: The mean age of the intent-to-treat population (n = 172) was 59 years (range 32-83). Median progression-free survival was 5.45 months with cixutumumab versus 5.22 months in the control (hazard ratio = 1.15, 95% confidence interval: 0.81-1.61; p = 0.44). Median overall survival was 11.33 months with cixutumumab versus 10.38 months in the control (hazard ratio = 0.93, 95% confidence interval: 0.64-1.36). Objective response rate did not differ between treatments (p = 0.338). Grade 3 or 4 hyperglycemia occurred at a higher rate with cixutumumab than in the control (9.4% versus 1.2%). One death possibly related to cixutumumab occurred., Conclusions: Efficacy was not improved in patients with nonsquamous NSCLC when cixutumumab was added to pemetrexed/cisplatin. Combination therapy was well tolerated and no new safety concerns were reported., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction LY2603618 is a selective inhibitor of checkpoint kinase 1 (CHK1) protein kinase, a key regulator of the DNA damage checkpoint, and is predicted to enhance the effects of antimetabolites, such as pemetrexed. This phase II trial assessed the overall response rate, safety, and pharmacokinetics (PK) of LY2603618 and pemetrexed in patients with non-small cell lung cancer (NSCLC). Methods In this open-label, single-arm trial, patients with advanced or metastatic NSCLC progressing after a prior first-line treatment regimen (not containing pemetrexed) and Eastern Cooperative Oncology Group performance status ≤2 received pemetrexed (500 mg/m(2), day 1) and LY2603618 (150 mg/m(2), day 2) every 21 days until disease progression. Safety was assessed using Common Terminology Criteria for Adverse Events v3.0. Serial blood samples were collected for PK analysis after LY2603618 and pemetrexed administration. Expression of p53, as measured by immunohistochemistry and genetic variant analysis, was assessed as a predictive biomarker of response. Results Fifty-five patients were enrolled in the study. No patients experienced a complete response; a partial response was observed in 5 patients (9.1 %; 90 % CI, 3.7-18.2) and stable disease in 20 patients (36.4 %). The median progression-free survival was 2.3 months (range, 0-27.1). Safety and PK of LY2603618 in combination with pemetrexed were favorable. No association between p53 status and response was observed. Conclusions There was no significant clinical activity of LY2603618 and pemetrexed combination therapy in patients with advanced NSCLC. The results were comparable with historical pemetrexed single-agent data, with similar safety and PK profiles being observed.

Purpose: Phase I data (ASCEND-1) showed ceritinib efficacy in patients with ALK-rearranged non-small-cell lung cancer (NSCLC), regardless of brain metastases status and with or without prior therapy with an inhibitor of the ALK protein. Data are presented from a phase II trial (ASCEND-2) in which ceritinib efficacy and safety were evaluated in patients who had ALK-rearranged NSCLC previously treated with at least one platinum-based chemotherapy and who had experienced progression during crizotinib treatment as their last prior therapy., Patients and Methods: Patients with advanced ALK-rearranged NSCLC, including those with asymptomatic or neurologically stable baseline brain metastases, received oral ceritinib 750 mg/d. Whole-body and intracranial responses were investigator assessed (according to RECIST version 1.1). Patient-reported outcomes were evaluated with the Lung Cancer Symptom Scale and European Organisation for Research and Treatment of Cancer surveys (the core-30 and the 13-item lung cancer-specific quality-of-life questionnaires)., Results: All 140 patients enrolled had received two or more previous treatment regimens, and all patients had received crizotinib. The median duration of exposure and the follow-up time with ceritinib were 8.8 months (range, 0.1 to 19.4 months) and 11.3 months (range, 0.1 to 18.9 months), respectively. Investigator-assessed overall response rate was 38.6% (95% CI, 30.5% to 47.2%). Secondary end points, all investigator assessed, included disease control rate (77.1%; 95% CI, 69.3% to 83.8%), time to response (median, 1.8 months; range, 1.6 to 5.6 months), duration of response (median, 9.7 months; 95% CI, 7.1 to 11.1 months), and progression-free survival (median, 5.7 months; 95% CI, 5.4 to 7.6 months). Of 100 patients with baseline brain metastases, 20 had active target lesions at baseline; investigator-assessed intracranial overall response rate was 45.0% (95% CI, 23.1% to 68.5%). The most common adverse events (majority, grade 1 or 2) for all treated patients were nausea (81.4%), diarrhea (80.0%), and vomiting (62.9%). Patient-reported outcomes showed a trend toward improved symptom burden. The global quality-of-life score was maintained during treatment., Conclusion: Consistent with its activity in ASCEND-1, ceritinib treatment provided clinically meaningful and durable responses with manageable tolerability in chemotherapy- and crizotinib-pretreated patients, including those with brain metastases., (© 2016 by American Society of Clinical Oncology.)

Background: Unintentional weight loss occurs among advanced non-small-cell lung cancer (NSCLC) patients and is associated with worse survival. Small studies have suggested that weight gain during treatment is associated with superior survival., Patients and Methods: A retrospective analysis analyzed data from three international phase III studies comprising 2301 advanced, non-squamous NSCLC patients who received a platinum-based, first-line doublet, with or without bevacizumab and maintenance therapy. Body weight was recorded before and after treatment by each study's schedule. The relationship between weight gain and overall survival (OS) and progression-free survival (PFS) was assessed using log-rank test and adjusted Cox modeling. Logistic regression assessed the association between baseline covariates and post-baseline weight gain., Results: Four hundred and twenty-one (18.3%) patients had >5% weight gain after baseline. More than half of the weight gain cohort exhibited initial weight gain by 3 weeks. The median OS was 16.7 months versus 10.7 months for the >5% versus ≤5% weight gain subgroup (n = 1880) (P < 0.001). PFS was 6.9 versus 4.8 months, respectively (P < 0.001). Differences in overall tumor response rate (50.8% versus 25.4%, respectively) and disease control rate (tumor response or stable disease) (91.5% versus 63.6%, respectively) were also significant (P < 0.001). The Cox modeling revealed the >5% subgroup had longer survival [hazard ratio (HR) = 0.54, 95% confidence interval (CI) 0.47-0.62; P < 0.001] than the ≤5% subgroup after adjusting for baseline factors. Similar significant results were found for PFS (HR = 0.59, 95% CI 0.52-0.67; P < 0.001). Unadjusted logistic regression indicated a significant association between weight gain (>5% versus ≤5%) and age, and BMI., Conclusions: Weight gain during treatment may be an early indicator of clinical benefit. If confirmed in prospective studies, monitoring weight change may provide important information regarding survival outcomes in NSCLC and may provide ideas for new therapeutic strategies., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Tivantinib, a MET receptor tyrosine kinase inhibitor, demonstrated increased anticancer activity in preclinical and early clinical studies when combined with erlotinib. Our study aimed to confirm efficacy and safety of the combination in previously treated patients with non-small-cell lung cancer (NSCLC)., Patients and Methods: Patients with advanced nonsquamous NSCLC previously treated with one to two systemic regimens, including a platinum doublet, were randomly assigned at a 1:1 ratio to receive erlotinib 150 mg daily plus oral tivantinib 360 mg twice daily (E + T) or erlotinib plus placebo (E + P) until disease progression. Tumor specimens were evaluated for EGFR and KRAS mutations, MET expression, and MET gene amplification. The primary end point was overall survival (OS). Secondary and exploratory objectives included progression-free survival (PFS), OS in molecular subgroups, and safety., Results: The study enrolled 1,048 patients and was discontinued for futility at the interim analysis. OS did not improve with E + T versus E + P (median OS, 8.5 v 7.8 months, respectively; hazard ratio [HR], 0.98; 95% CI, 0.84 to 1.15; P = .81), even though PFS increased (median PFS, 3.6 v 1.9 months; HR, 0.74; 95% CI, 0.62 to 0.89; P < .001). Exploratory subgroup analyses suggested OS improvement in patients with high MET expression (HR, 0.70; 95% CI, 0.49 to 1.01). Most common adverse events occurring with E + T versus E + P were rash (33.1% v 37.3%, respectively), diarrhea (34.6% v 41.0%), asthenia or fatigue (43.5% v 38.1%), and neutropenia (grade 3 to 4; 8.5% v 0.8%)., Conclusion: E + T was well tolerated and increased PFS but did not improve OS in the overall nonsquamous NSCLC population., (© 2015 by American Society of Clinical Oncology.)

Background: To evaluate the effects of administering chemotherapy following surgery, or following surgery plus radiotherapy (known as adjuvant chemotherapy) in patients with early stage non-small cell lung cancer (NSCLC),we performed two systematic reviews and meta-analyses of all randomised controlled trials using individual participant data. Results were first published in The Lancet in 2010., Objectives: To compare, in terms of overall survival, time to locoregional recurrence, time to distant recurrence and recurrence-free survival:A. Surgery versus surgery plus adjuvant chemotherapyB. Surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapyin patients with histologically diagnosed early stage NSCLC.(2)To investigate whether or not predefined patient subgroups benefit more or less from cisplatin-based chemotherapy in terms of survival., Search Methods: We supplemented MEDLINE and CANCERLIT searches (1995 to December 2013) with information from trial registers, handsearching relevant meeting proceedings and by discussion with trialists and organisations., Selection Criteria: We included trials of a) surgery versus surgery plus adjuvant chemotherapy; and b) surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapy, provided that they randomised NSCLC patients using a method which precluded prior knowledge of treatment assignment., Data Collection and Analysis: We carried out a quantitative meta-analysis using updated information from individual participants from all randomised trials. Data from all patients were sought from those responsible for the trial. We obtained updated individual participant data (IPD) on survival, and date of last follow-up, as well as details of treatment allocated, date of randomisation, age, sex, histological cell type, stage, and performance status. To avoid potential bias, we requested information for all randomised patients, including those excluded from the investigators' original analyses. We conducted all analyses on intention-to-treat on the endpoint of survival. For trials using cisplatin-based regimens, we carried out subgroup analyses by age, sex, histological cell type, tumour stage, and performance status., Main Results: We identified 35 trials evaluating surgery plus adjuvant chemotherapy versus surgery alone. IPD were available for 26 of these trials and our analyses are based on 8447 participants (3323 deaths) in 34 trial comparisons. There was clear evidence of a benefit of adding chemotherapy after surgery (hazard ratio (HR)= 0.86, 95% confidence interval (CI)= 0.81 to 0.92, p< 0.0001), with an absolute increase in survival of 4% at five years.We identified 15 trials evaluating surgery plus radiotherapy plus chemotherapy versus surgery plus radiotherapy alone. IPD were available for 12 of these trials and our analyses are based on 2660 participants (1909 deaths) in 13 trial comparisons. There was also evidence of a benefit of adding chemotherapy to surgery plus radiotherapy (HR= 0.88, 95% CI= 0.81 to 0.97, p= 0.009). This represents an absolute improvement in survival of 4% at five years.For both meta-analyses, we found similar benefits for recurrence outcomes and there was little variation in effect according to the type of chemotherapy, other trial characteristics or patient subgroup.We did not undertake analysis of the effects of adjuvant chemotherapy on quality of life and adverse events. Quality of life information was not routinely collected during the trials, but where toxicity was assessed and mentioned in the publications, it was thought to be manageable. We considered the risk of bias in the included trials to be low., Authors' Conclusions: Results from 47 trial comparisons and 11,107 patients demonstrate the clear benefit of adjuvant chemotherapy for these patients, irrespective of whether chemotherapy was given in addition to surgery or surgery plus radiotherapy. This is the most up-to-date and complete systematic review and individual participant data (IPD) meta-analysis that has been carried out.

Background: Iniparib is a novel anticancer agent initially considered a poly (ADP-ribose) polymerase (PARP) inhibitor, but subsequently shown to act via non-selective protein modification through cysteine adducts. This randomized phase II study investigated the addition of iniparib to gemcitabine-cisplatin in metastatic non-small-cell lung cancer (NSCLC) patients., Patients and Methods: Patients with histologically confirmed stage IV NSCLC were randomized 2 : 1 to receive gemcitabine (1250 mg/m(2), days 1/8) and cisplatin (75 mg/m(2), day 1) with [gemcitabine/cisplatin/iniparib (GCI)] or without [gemcitabine/cisplatin (GC)] iniparib (5.6 mg/kg, days 1/4/8/11) every 3 weeks for six cycles. The primary end point was the overall response rate (ORR). Secondary objectives included progression-free survival (PFS), overall survival (OS), and safety. The study was not designed for formal efficacy comparison, the control arm being to benchmark results against the literature., Results: One hundred and nineteen patients were randomized (39 GC and 80 GCI). More GCI patients were male (80% GCI and 67% GC) and had PS 0 (61% GCI and 49% GC). The ORR was 25.6% [95% confidence interval (CI) 13.0%-42.1%] with GC versus 20.0% (95% CI 11.9%-30.4%) with GCI, which did not allow rejection of the null hypothesis (ORR with GCI ≤20%; P = 0.545). Median PFS was 4.3 (95% CI 2.8-5.6) months with GC and 5.7 (95% CI 4.6-6.6) months with GCI (hazard ratio 0.89, 95% CI 0.56-1.40). Median OS was 8.5 (95% CI 5.5 to not reached) months with GC, and 12.0 (95% CI 8.9-17.1) months with GCI (hazard ratio 0.78, 95% CI 0.48-1.27). More GCI patients received second-line treatment (51% GC and 68% GCI). Toxicity was similar in the two arms. Grade 3-4 toxicities included asthenia (28% GC and 8% GCI), nausea (3% GC and 14% GCI), and decreased appetite (10% in each)., Conclusions: Addition of iniparib to GC did not improve ORR over GC alone. The GCI safety profile was comparable to GC alone. Imbalances in PS and gender distribution may have impacted study results regarding PFS and OS., Trial Registration: ClinicalTrial.gov Identifier NCT01086254., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: The Italian Association of Medical Oncology and the Italian Society of Anatomic Pathology and Diagnostic Cytopathology organized an external quality assessment (EQA) scheme for anaplastic lymphoma kinase (ALK) rearrangement by florescence in situ hybridization (FISH) analysis in non-small-cell lung cancer (NSCLC)., Methods: Sections from tissue microarrays, each including 10 NSCLC samples with known ALK status, were first validated in five referral laboratories and then provided to 37 participating centers. The laboratories were requested to perform the FISH test, using their usual protocols, and to complete the analysis within 3 weeks. By using a predefined scoring system, two points were assigned in case of correct genotype and zero points to false-negative or false-positive results. The threshold value to pass the EQA scheme was set at 18 points. Two rounds were planned., Results: Thirty-four centers submitted the results within the established deadline. Several errors in the evaluation of genotype (n = 18) were reported, with both false-positive (n = 7) and false-negative (n = 11) results. Test failure occurred in seven cases. Two samples were found to be critical by two referral laboratories and seven participating centers. Twenty-six (70%) laboratories passed the first round and six the second round. Overall, 32 (86%) laboratories passed the ALK EQA scheme., Conclusions: The results of this first EQA scheme for ALK testing in NSCLC cancer patients indicate that ALK analysis is performed with adequate quality in most Italian laboratories and highlight the importance of EQA in revealing methodological problems that need to be addressed to further increase the reproducibility of molecular tests.

Background: This preplanned subset analysis of the phase III MONET1 study aimed to determine whether motesanib combined with carboplatin/paclitaxel (C/P) would result in improved overall survival (OS) versus chemotherapy alone, in a subset of Asian patients with nonsquamous nonsmall-cell lung cancer (NSCLC)., Patients and Methods: Patients with nonsquamous NSCLC (stage IIIB/IV or recurrent) and no prior systemic therapy for advanced disease were randomized to IV carboplatin (AUC, 6 mg/ml min) and paclitaxel (200 mg/m2) for up to six 3-week cycles, plus either oral motesanib 125 mg q.d. or placebo. Primary end point was OS; secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety., Results: Two hundred twenty-seven Asian patients from MONET1 were included in this descriptive analysis. Median OS was 20.9 months in the motesanib plus C/P arm and 14.5 months in the placebo plus C/P arm (P=0.0223); median PFS was 7.0 and 5.3 months, respectively, (P=0.0004); and ORR was 62% and 27%, respectively, (P<0.0001). Grade≥3 adverse events were more common in the motesanib plus C/P arm versus placebo plus C/P (79% versus 61%)., Conclusion: In this preplanned subset analysis of Asian patients with nonsquamous NSCLC, motesanib plus C/P significantly improved OS, PFS, and ORR versus placebo plus C/P., Clinical Trial Number: NCT00460317.

Although the interpretation of the data reported in meta-analyses may hide several issues, it is undoubtable that this methodological approach may significantly contribute to implement the results of clinical trials, and represent a useful and practical tool for the evidence-based medicine process. Indeed, level-one recommendations should consider well-conducted meta-analyses as well as large and adequately powered randomized trials as the main contributors for the definition of guidelines for clinical practice. In addition, the role of meta-analyses for issues whereas conflicting data (and/or unpowered results) are provided, is well established. In the field of lung cancer, meta-analyses already participated to change the current standard, and are now facing the challenging issues of predictive biomarkers of prognosis and/or efficacy of targeted agents. With this aim, the meta-analytic approach helped in the recent years to implement the quantification of the magnitude of the benefit of targeted agents, and added new insights by interpreting the data coming from clinical trials by integrating them with biomarkers. The treatment-interaction analyses according to putative predictive factors of efficacy may clarify unknown issues and generate new hypotheses for future perspectives. The current review attempts to put in the context of the clinical data of targeted agents for lung cancer all the pros and cons of the meta-analytic process published to date, and critically analyze all the potential perspectives which this methodology may add for both current practice and forthcoming research.

Introduction: Recent clinical trials led to the approval of crizotinib (PF-02341066; Pfizer) by the U.S. Food and Drug Administration for the treatment of locally advanced or metastatic non-small-cell lung cancer (NSCLC) patients whose tumors are positive for anaplastic lymphoma kinase (ALK) alterations. The European Medicines Agency accepted the regulatory submission of crizotinib for the treatment of these patients. Therefore, ALK gene testing has become mandatory to choose the most appropriate therapy., Methods: To help physicians, involved in the management of NSCLC patients to be treated with ALK inhibitors in Italy, the Italian Association of Medical Oncology and the Italian Society of Pathology and Cytopathology identified a large panel of Italian medical oncologists and pathologists that outlined recommendations for ALK testing in NSCLC patients., Results: The guidelines produced include specific information on the target patient population, the biological material for molecular analysis, a section dedicated to the histocytopathologic diagnosis of NSCLC, and the methods for the assessment of ALK alterations that are summarized in this article., Conclusions: Clinicopathologic recommendations were produced to guide the management of NSCLC patients who need to be tested for ALK rearrangements before treatment with ALK inhibitors.

Purpose: To compare the efficacy of aflibercept (ziv-aflibercept), a recombinant human fusion protein targeting the vascular endothelial growth factor (VEGF) pathway, with or without docetaxel in platinum-pretreated patients with advanced or metastatic nonsquamous non-small-cell lung cancer., Patients and Methods: In this international, double-blind, placebo-controlled phase III trial, 913 patients were randomly assigned to (ziv-)aflibercept 6 mg/kg intravenous (IV; n = 456) or IV placebo (n = 457), both administered every 3 weeks and in combination with docetaxel 75 mg/m(2). The primary end point was overall survival (OS). Other efficacy outcomes, safety, and immunogenicity were also assessed., Results: Patient characteristics were balanced between arms; 12.3% of patients had received prior bevacizumab. (Ziv-)Aflibercept did not improve OS (hazard ratio [HR], 1.01; 95% CI, 0.87 to 1.17; stratified log-rank P = .90). The median OS was 10.1 months (95% CI, 9.2 to 11.6 months) for (ziv-)aflibercept and 10.4 months (95% CI, 9.2 to 11.9 months) for placebo. In exploratory analyses, median progression-free survival was 5.2 months (95% CI, 4.4 to 5.6 months) for (ziv-)aflibercept versus 4.1 months (95% CI, 3.5 to 4.3 months) for placebo (HR, 0.82; 95% CI, 0.72 to 0.94; P = .0035); overall response rate was 23.3% of evaluable patients (95% CI, 19.1% to 27.4%) in the (ziv-)aflibercept arm versus 8.9% (95% CI, 6.1% to 11.6%; P < .001) in the placebo arm. Grade ≥ 3 adverse events occurring more frequently in the (ziv-)aflibercept arm versus the placebo arm were neutropenia (28.0% v 21.1%, respectively), fatigue (11.1% v 4.2%, respectively), stomatitis (8.8% v 0.7%, respectively), and hypertension (7.3% v 0.9%, respectively)., Conclusion: The addition of (ziv-)aflibercept to standard docetaxel therapy did not improve OS. In exploratory analyses, secondary efficacy end points did seem to be improved in the (ziv-)aflibercept arm. The study regimen was associated with increased toxicities, consistent with known anti-VEGF and chemotherapy-induced events.

Introduction: A widely held misperception contends that all elderly patients, even those with good performance status (PS 0-1), are unable to tolerate aggressive chemotherapy. The objective of these analyses was to evaluate the survival and safety of treatment with pemetrexed in elderly patients with nonsquamous non-small-cell lung cancer (NSCLC) and PS 0-1., Patients and Methods: Two randomized studies, 1 reporting the activity of pemetrexed in combination with cisplatin vs. cisplatin and gemcitabine in chemotherapy-naive patients (N = 1725) and another comparing single-agent pemetrexed with placebo in the maintenance setting (N = 663) were retrospectively considered. Data from patients with nonsquamous advanced NSCLC with PS 0-1 in these studies were evaluated in 2 separate dichotomous analyses (< 65 years and ≥ 65 years and < 70 years and ≥ 70). Cox proportional hazard models were used to estimate covariate-adjusted between-arm hazard ratios (HRs) with 95% confidence intervals for each age group., Results: In the first-line study, 32.7% of the 1252 patients with nonsquamous NSCLC were ≥ 65 years and 12.8% were ≥ 70 years old. In the maintenance study, 33.1% of the 481 patients with nonsquamous NSCLC were ≥ 65 years and 16.0% were ≥ 70 years old. In both studies, the adjusted HRs for overall survival (range, 0.62-0.89) favored pemetrexed and were similar between the older and younger age groups. Dose intensity delivered and toxicities observed for patients treated with pemetrexed were manageable and similar between the older and younger age groups., Conclusions: For elderly patients with nonsquamous advanced NSCLC and PS 0-1, pemetrexed therapy, with its favorable toxicity profile, is a viable option, either in combination with cisplatin in the first-line setting or as maintenance therapy after initial chemotherapy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Advances in our understanding of tumour biology have encouraged reassessment of tumour classification by the site of origin in favour of molecular characteristics and/or oncogenic drivers amenable to treatment. The identification of EML4-anaplastic lymphoma kinase (ALK) as an oncogenic driver in non-small cell lung cancer (NSCLC) early in the clinical development of crizotinib and the observation of promising clinical responses in patients with NSCLC harbouring ALK translocations accelerated its clinical development in ALK-positive NSCLC. Phase I and II trials of crizotinib in patients with ALK-positive advanced NSCLC reported notably high response rates that tended to be rapid and of prolonged duration. Crizotinib was well tolerated; treatment-related adverse events were typically gastrointestinal (grade 1/2) and visual disorders (almost exclusively grade 1). Crizotinib provided NSCLC symptom relief and maintained quality of life. Based on the phase I and II trial data, the US Food and Drug Administration granted approval of crizotinib in August 2011. The consistency of the crizotinib data to date suggests accurate selection of the target population for crizotinib treatment. The ability to molecularly select patients likely to respond to an investigational agent argues that future clinical development of targeted agents should be re-evaluated. Updated trial designs incorporating molecular testing, early use of enrichment biomarkers and intermediary endpoints may accelerate and optimise clinical evaluation of targeted agents. Such trial designs should allow rapid clinical evaluation, minimise exposure of patients to therapies unlikely to be of benefit and, potentially, allow accelerated drug approval in molecularly specified populations., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Symptomatic brain metastases (BM) frequently occurs after initial treatment of non-small-cell lung cancer (NSCLC). Therefore, 2 large randomized trials that involved pemetrexed were retrospectively analyzed to determine the pattern of symptomatic relapse in the brain and to gauge if pemetrexed could influence the incidence., Methods: Two large phase III studies of pemetrexed in advanced NSCLC were included. One study compared pemetrexed with docetaxel in previously treated patients (n = 571); the other study tested cisplatin plus pemetrexed vs. cisplatin plus gemcitabine in chemotherapy-naive patients with advanced NSCLC (n = 1725). Patients with known BM at study entry were excluded from this analysis. Each study was analyzed separately, then jointly to determine the rate of BM reported as the only site of progressive disease by treatment group and histology. Logistic regression was used to obtain an odds ratio for the treatment effect on the overall occurrence of BM while controlling for potential confounding factors., Results: Overall, 71.5% of patients in pemetrexed-containing arms (819 of 1145), and 68.2% of patients in non-pemetrexed-containing arms (785 of 1151) experienced progressive disease. BM recurrence rates were 3.2% (95% confidence interval [CI], 2.1%-4.6%) in the pemetrexed-containing arms vs. 6.6% (95% CI, 5.0%-8.6%) in the non-pemetrexed-containing arms (P = .002). The odds ratio for BM recurrence associated with exposure to pemetrexed was 0.49 (95% CI, 0.32-0.76; P = .001). The beneficial effect of pemetrexed on BM was confined to patients with nonsquamous NSCLC., Conclusions: Patients with advanced nonsquamous NSCLC treated with pemetrexed either in first-line or second-line therapy may reduce the risk of developing BM as the first site of progressive disease. This retrospective analysis is limited due to the lack of baseline and periodic brain scans, and it reflects symptomatic BM only. Regardless, these findings suggest a potential beneficial effect of pemetrexed-based treatments on the control of BM., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: This phase III trial was conducted to test whether the novel vascular disrupting agent ASA404 (vadimezan), when combined with first-line platinum-based chemotherapy, improves survival in patients with advanced non-small-cell lung cancer (NSCLC) versus chemotherapy alone., Patients and Methods: Patients with advanced stage IIIB or IV NSCLC, stratified by sex and tumor histology, were randomly assigned 1:1 to paclitaxel (200 mg/m(2)) and carboplatin (area under the curve, 6.0) with or without ASA404 (1,800 mg m(2)), given intravenously once every 3 weeks for six cycles followed by maintenance ASA404 or placebo. Primary end point was overall survival (OS); secondary end points included overall response rate (ORR) and progression-free survival (PFS)., Results: One thousand two hundred ninety-nine patients were randomly assigned. The trial was stopped for futility at interim analysis. At final analysis, there was no difference in OS seen between ASA404 (n = 649) and placebo (n = 650) arms: median OS was 13.4 and 12.7 months respectively (hazard ratio [HR], 1.01; 95% CI, 0.85 to 1.19; P = .535). Similarly, no OS difference was seen in the histologic (squamous or nonsquamous) and sex (male or female) strata. Median PFS was 5.5 months in both arms (HR, 1.04; P = .727), while ORR was 25% in both arms (P = 1.0). Overall rate of adverse events (AEs) was comparable between the ASA404 and placebo arms. Grade 4 neutropenia (27% v 19%) and infusion site pain (10% v 0.5%) were reported more frequently in the ASA404 arm., Conclusion: The addition of ASA404 to carboplatin and paclitaxel, although generally well tolerated, failed to improve frontline efficacy in advanced NSCLC.

Introduction: Brain metastases frequently cause significant morbidity in patients with non-small cell lung cancer (NSCLC). Sunitinib is a multitargeted inhibitor of tyrosine kinase receptors, including vascular endothelial growth factor receptors and platelet-derived growth factor receptors, which has single-agent antitumor activity in refractory NSCLC. This phase II study evaluated the antitumor activity and safety of sunitinib in patients with pretreated NSCLC and irradiated brain metastases., Methods: Patients received sunitinib 37.5 mg on a continuous daily dosing schedule. The primary end point was progression-free survival. Secondary end points included overall survival, patient-reported outcomes, and safety, including risk of intracranial hemorrhage (ICH) associated with focal neurological deficit., Results: Sixty-four patients received sunitinib (median age 61 years), most (83%) had received prior systemic therapy, 63% had adenocarcinoma, and 19% had squamous cell carcinoma; most (55%) were never-smokers. Median progression-free survival was 9.4 weeks (90% confidence interval [CI]: 7.5-13.1), and median overall survival was 25.1 weeks (95% CI: 13.4-35.5). The most common treatment-emergent (all-causality) nonhematologic toxicities (any grade) were fatigue (38%) and decreased appetite and constipation (both 25%). The most common grade 3/4 nonhematologic toxicities were dyspnea (9%) and fatigue (8%). Lymphopenia (20%) and neutropenia (13%) were the most common grade 3/4 hematologic abnormalities. Serious neurologic adverse events occurred in six patients (9%), and none were treatment-related. No cases of ICH were reported., Conclusions: Sunitinib administration on a continuous daily dosing schedule in patients with NSCLC and brain metastases was safe and manageable, with no increased risk of ICH.

Introduction: Recently, histology has emerged as a predictive factor for pemetrexed efficacy in non-small cell lung cancer (NSCLC). These analyses evaluate whether the differential efficacy of pemetrexed by NSCLC histology is reproducible and consistent across three registration studies of different lines of therapy (first-line/second-line and maintenance settings)., Methods: The reported studies for patients with advanced NSCLC were pemetrexed versus docetaxel in previously treated patients (N = 571), cisplatin plus pemetrexed versus cisplatin plus gemcitabine in chemotherapy-naive patients (N = 1725), and maintenance pemetrexed plus best supportive care versus placebo plus best supportive care (N = 663). Cox models of overall survival (OS) and progression-free survival (PFS) were used to test for a significant treatment-by-histology interaction (THI). A significant THI indicates that the efficacy benefit for pemetrexed relative to the control arm is greater in patients with nonsquamous histology than in those with squamous histology. Subsequent Cox models were used to estimate hazard ratios for OS and PFS according to histology., Results: Histology was well balanced between treatment arms in each study. Across all three studies, no clinically relevant differences were observed for the safety profile of pemetrexed among histologic groups. THIs were statistically significant in all three studies for OS (p = 0.001, 0.002, and 0.033, respectively) and PFS (p = 0.004, 0.002, and 0.036, respectively)., Conclusions: These analyses demonstrate a statistically significant interaction between treatment effect and NSCLC histology, indicating superior efficacy of pemetrexed in nonsquamous patients compared with other standard treatment options. Thus, histology is consistently predictive of the improved efficacy of pemetrexed in patients with nonsquamous NSCLC.

Introduction: We conducted an exploratory, post hoc, subgroup analysis of the East Asian (EA) patients in a multinational phase III trial to determine whether the efficacy results for this subgroup were consistent with those observed for the entire study population., Methods: Thousand seven hundred twenty-five patients with advanced non-small cell lung cancer (NSCLC), including 126 EA patients (7.3%) from Taiwan and Korea, were enrolled in the trial and randomly assigned first-line chemotherapy with cisplatin and pemetrexed (CP; n = 862) or cisplatin and gemcitabine (CG; n = 863). Adjusted Cox proportional hazards models were used to compare overall survival and progression-free survival between the treatment arms in the EA subgroup. Median time-to-event data were estimated with the Kaplan-Meier method., Results: Consistent with the results for the entire study population, survival in the EA subgroup trended in favor of CP over CG in patients with non-squamous histology, despite the more frequent use of post discontinuation targeted therapy in the CG arm. The opposite trend was noted for patients with squamous tumors. A higher proportion of patients in the EA subgroup were never smokers compared with the entire study population. A trend toward improved survival with CP compared with CG was seen regardless of smoking status, particularly in non-squamous patients., Conclusions: The key finding of this subgroup analysis was that the NSCLC histology effect on treatment outcomes for pemetrexed-treated patients seen in the entire study population was also apparent in the EA subgroup. The potential prognostic influence of race, histology subtype, and smoking status should be assessed in future NSCLC studies.

PURPOSE This phase III, multicenter, randomized, placebo-controlled trial assessed the efficacy and safety of sorafenib, an oral multikinase inhibitor, in combination with carboplatin and paclitaxel in chemotherapy-naïve patients with unresectable stage IIIB or IV non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Nine hundred twenty-six patients were randomly assigned to receive up to six 21-day cycles of carboplatin area under the curve 6 and paclitaxel 200 mg/m(2) (CP) on day 1, followed by either sorafenib 400 mg twice a day (n = 464, arm A) or placebo (n = 462, arm B) on days 2 to 19. The maintenance phase after CP consisted of sorafenib 400 mg or placebo twice a day. The primary end point was overall survival (OS); secondary end points included progression-free survival and tumor response. RESULTS Overall demographics were balanced between arms; 223 patients (24%) had squamous cell histology. On the basis of a planned interim analysis, median OS was 10.7 months in arm A and 10.6 months in arm B (hazard ratio [HR] = 1.15; 95% CI, 0.94 to 1.41; P = .915). The study was terminated after the interim analysis concluded that the study was highly unlikely to meet its primary end point. A prespecified exploratory analysis revealed that patients with squamous cell histology had greater mortality in arm A than in arm B (HR = 1.85; 95% CI, 1.22 to 2.81). Main grade 3 or 4 sorafenib-related toxicities included rash (8.4%), hand-foot skin reaction (7.8%), and diarrhea (3.5%). CONCLUSION No clinical benefit was observed from adding sorafenib to CP chemotherapy as first-line treatment for NSCLC.

Introduction: Recent phase III studies in advanced non-small-cell lung cancer (NSCLC) have demonstrated differential efficacy for pemetrexed according to NSCLC histology. The results of 2 phase II studies of pemetrexed and a platinum agent (carboplatin or oxaliplatin) were pooled to determine whether outcomes in the studies differed by tumor histology., Patients and Methods: Chemotherapy-naive patients with stage IIIB/IV NSCLC received pemetrexed 500 mg/m2 plus carboplatin area under the curve of 6 (n = 89) or pemetrexed 500 mg/m2 plus oxaliplatin 120 mg/m2 (n = 41); both regimens were administered every 21 days. The primary endpoint of both trials was response rate. Treatment arms were pooled, and Cox models with main effects for squamous histology were used to assess overall survival and progression-free survival. Cofactor adjustments incorporated terms for performance status, disease stage, and sex., Results: More than three quarters of enrolled patients had a nonsquamous histology. Mean age was 59.9 years for patients with nonsquamous histology and 63.7 years for patients with squamous histology. Response rates were 30% for patients with nonsquamous histology and 17.2% for patients with squamous histology. Overall survival was 10.5 months for patients with nonsquamous histology and 9.8 months for patients with squamous histology (hazard ratio [HR], 0.95; 95% CI, 0.52-1.74). Progression-free survival was 5.6 months for patients with nonsquamous histology and 4.7 months for patients with squamous histology (HR, 0.72; 95% CI, 0.43-1.19)., Conclusion: In patients treated with pemetrexed/ platinum doublets, nonsquamous histology was associated with better outcomes. The benefit of pemetrexed treatment among patients with nonsquamous histology is consistent with the results reported from previous studies.

Introduction: We examined the efficacy of enzastaurin plus pemetrexed as second-line therapy in patients with advanced (stage IIIA/B or IV) non-small cell lung cancer in a double-blinded, randomized, phase II study., Methods: Patients received pemetrexed 500 mg/m intravenously on day 1 of 21-day cycles (day 8 in cycle 1) plus oral enzastaurin (250 mg two times per day; combination arm) or placebo (pemetrexed arm). Both arms received supplementation with vitamin B12, folic acid, and dexamethasone. An interim analysis was conducted to determine whether efficacy would warrant a phase III study., Results: The interim analysis showed no evidence of improved progression-free survival with enzastaurin. At final analysis (N = 160, 80 in each arm), baseline characteristics were well balanced. There was no significant difference in progression-free survival (3.0 months, p = 0.544) or overall survival (9.6 months in combination arm and 7.4 months in pemetrexed arm, p = 0.171). Drug-related serious adverse events included cerebrovascular accident, palpitations, and renal failure (n = 1, each) in combination arm and neutropenic sepsis, thrombocytopenia, and panniculitis (n = 1, each) in pemetrexed arm. Nonhematologic drug-related grade 3/4 toxicities were similar in both arms. Grade 3/4 hematologic toxicities were higher with the combination, specifically leukopenia (6.3% versus 0%), neutropenia (15.2% versus 5.0%), and thrombocytopenia (8.9% versus 1.3%). Of the 26 deaths reported on-study or within 30 days of discontinuation (10 in combination arm and 16 in pemetrexed arm), none were drug related., Conclusion: The combination regimen of enzastaurin and pemetrexed is well tolerated but does not improve efficacy over pemetrexed and placebo as second-line treatment of unselected patients with advanced non-small cell lung cancer.

It has been >35 years since the link between angiogenesis and the growth of tumors was first reported. Targeting angiogenesis became feasible with the availability of bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody. Initial studies revealed that the combination of bevacizumab and chemotherapy led to longer overall survival times than with chemotherapy alone in patients with advanced colorectal cancer. Since then, drug development strategies have added small molecule tyrosine kinase inhibitors to the panel of antiangiogenic agents under evaluation; data from numerous trials are now available. The challenge now is to identify the optimal antiangiogenic agent for specific patient groups and to understand not only the mechanistic differences between agents, but also the variability in their antitumor activity across different tumor types and their differing side-effect profiles. As in other solid tumors, angiogenesis contributes to the development of non-small cell lung cancer (NSCLC), and this review summarizes the role of angiogenesis in this disease. We review the current developmental status of antiangiogenic tyrosine kinase inhibitors (including vandetanib, sunitinib, axitinib, sorafenib, vatalanib, and pazopanib) in NSCLC and conclude by briefly discussing the need for optimal patient selection and potential future directions.

The evaluation of gene and protein expression profiles is a promising strategy to drive the therapeutical decision-making in non-small cell lung cancer (NSCLC). Among the several candidate genes that have been proposed, many retrospective studies have indicated excision repair cross-complementing 1 (ERCC1), an endonuclease responsible for the repair of DNA damages, as a reliable biomarker of tumor sensitivity to platinum-based agents. Moreover, the recent evidences showing the clinical efficacy of next-generation multitargeted antifolate drugs, in NSCLC, have highlighted the role of the determination of thymidylate synthase (TS) expression levels. Here is presented a brief overview of the literature regarding these two genes that are currently under prospective investigation as predictive markers of treatment efficacy in NSCLC.

Background: Recent studies of pemetrexed have identified a predictive role for non-small cell lung cancer (NSCLC) histology. We further reviewed the differential efficacy of pemetrexed according to histology in two large, phase III NSCLC trials., Methods: One study tested pemetrexed versus docetaxel in previously treated patients (n = 571) and the other tested cisplatin plus pemetrexed versus cisplatin plus gemcitabine in chemotherapy-naive patients (n = 1,725) with advanced NSCLC. Cox proportional hazard models were used to test for covariate-adjusted treatment-by-histology interactions (THIs) for overall survival (OS) and progression-free survival (PFS). For each histologic subgroup, the Kaplan-Meier method was used to estimate unadjusted within-arm medians, and Cox models were used to estimate covariate-adjusted between-arm hazard ratios (HRs)., Results: In both studies, treatment arms were well balanced for histology. THIs were statistically significant (p < .005) for both OS and PFS. Nonsquamous patients treated with pemetrexed-based therapy experienced longer survival than the comparators (HR, 0.78 and 0.84, respectively), whereas squamous patients had shorter survival (HR, 1.56 and 1.23, respectively). Whereas the efficacy of pemetrexed regimens differed according to histology, it did not differ for docetaxel or for cisplatin plus gemcitabine. Pemetrexed was well tolerated across histologic groups., Conclusions: The consistency of these results across studies confirms the predictive effect of histology for pemetrexed and the survival advantage for pemetrexed in patients with nonsquamous histology. These analyses suggest pemetrexed should not be recommended for the treatment of squamous cell carcinoma, but, because of efficacy and safety advantages, pemetrexed may be preferable to other agents for treatment of patients with nonsquamous NSCLC.

Purpose: The effect of translesion DNA synthesis system in conferring cellular tolerance to DNA-damaging agents has been recently described. DNA polymerase eta (Pol eta) is part of this machinery and in vitro models showed that it can overcome DNA damages caused by cisplatin and UV rays. The aim of the present study was to investigate the role of Pol eta mRNA expression levels in non-small cell lung cancer (NSCLC)., Experimental Design: Pol eta mRNA expression levels were evaluated by real-time PCR in (a) formalin-fixed paraffin-embedded biopsies of 72 NSCLC patients treated with platinum-based chemotherapy, (b) fresh snap-frozen surgical specimens of tumor and corresponding normal lung tissue from 50 consecutive patients not treated with perioperative or postoperative chemotherapy, and (c) five NSCLC cell lines., Results: High Pol eta expression levels were strongly associated with shorter survival at both univariate (6.9 versus 21.1 months; P = 0.003) and multivariate (hazard ratio, 3.18; 95% confidence interval, 1.73-5.84; P = 0.008) analysis in the group of platinum-treated patients. By contrast, Pol eta expression was not significantly correlated with the prognosis in surgically resected patients (P = 0.54) and mRNA levels did not significantly differ in tumor versus normal lung (P = 0.82). Moreover, endogenous Pol eta mRNA expression was found to be inducible by cisplatin in three of five cell lines and significantly associated with in vitro sensitivity (P = 0.01)., Conclusions: Taken together, these data indicate Pol eta as a predictive rather than prognostic marker worth of further investigation in NSCLC patients candidate to platinum-based chemotherapy.

The results of large randomised studies have clearly demonstrated that adjuvant chemotherapy prolongs overall survival by approximately 5% at 5 years in patients with early-stage non-small cell lung cancer (NSCLC). The benefit appears to be largely confined to patients with stage II/III disease, although approximately 25% of patients with stage I disease are at high risk of relapse within 5 years of surgery and therefore could benefit from adjuvant chemotherapy. There is an urgent need to predict more accurately which patients are likely to relapse after surgery and who, therefore, might benefit from further therapy. Preliminary studies indicate that molecular tumour markers may be able to identify tumours that are more likely to respond to chemotherapy and patients who are more likely to achieve improved survival from those who do not benefit at all from adjuvant chemotherapy. A pivotal study has shown that analysis of tumour gene expression can be used to predict the risk of relapse with greater accuracy than that which is achievable using clinical factors. In the future, pharmacogenomics may be used in this approach to identify patients for adjuvant chemotherapy, thus increasing the efficacy of treatment and reducing the burden of therapy in patients who are unlikely to benefit from further therapy.

Platinum-based therapy remains the standard of care for the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). When combined with a third-generation agent, platinum-based doublets improve survival compared with the third-generation agent given alone. Controversy remains, however, regarding the relative risks and benefits of the third-generation agents. Four large phase III trials have addressed this question, with only one trial finding a survival benefit in one of the treatment arms. TAX 326 compared docetaxel-based therapy with vinorelbine/cisplatin, and found that survival, response, and quality of life outcomes all favoured the docetaxel/cisplatin regimen. Consistent benefits have been reported with this regimen in other studies. The non-platinum-based docetaxel/gemcitabine combination is an alternative for patients who are not suitable candidates for platinum-based therapy. Other results have shown that single-agent docetaxel is an appropriate option for elderly patients and those with poor performance status. Overall, the wealth of data with docetaxel in advanced NSCLC suggests that it plays an important role in first-line treatment and, as a single agent, can be considered a reasonable approach in elderly and frail patients.

Proteasome inhibition is a novel therapeutic approach that is being investigated in non-small cell and small cell lung cancer (NSCLC and SCLC). Proteasome inhibition affects a range of intracellular signals and disrupts the levels of numerous proteins, causing apoptosis via multiple pathways. Importantly, malignant cells are more sensitive to proteasome inhibition than normal cells. A number of proteasome inhibitors have demonstrated activity in preclinical studies, both as single agents and in combination with conventional and novel antineoplastic agents. However, only bortezomib, a dipeptide boronic acid analog, has been investigated in lung cancer clinical trials, in which it has shown activity as a single agent and in combination regimens. Numerous preclinical and clinical studies are ongoing in both NSCLC and SCLC. Proteasome inhibition could potentially play a significant role in the future management of these conditions.

Pemetrexed is a novel antifolate antimetabolite that targets multiple folate-dependent enzymatic pathways and inhibits multiple enzymes involved in purine and pyrimidine synthesis. Its targets include pathways that, when amplified, are associated with reduced efficacy in conventional cytotoxic agents. As second-line treatment for advanced non-small cell lung cancer, (NSCLC) pemetrexed, when administered with folic acid and vitamin B12, has demonstrated comparable efficacy and a superior toxicity profile relative to docetaxel. A retrospective analysis of the Phase III trial of pemetrexed versus docetaxel shows a statistically significant longer toxicity-free survival time for pemetrexed compared with docetaxel. Newer targeted therapies, especially the epidermal growth factor receptor inhibitors gefitinib and erlotinib, have produced conflicting results and have only been compared with best supportive care and placebo. They should be compared directly to pemetrexed as second-line therapy in large, randomised studies of patients with advanced NSCLC. For patients with advanced recurrent NSCLC and good performance status who progress after first-line chemotherapy, pemetrexed should be considered as a new standard of care.

Purpose: To study the prognostic value for overall survival of baseline assessment of functional status, comorbidity, and quality of life (QoL) in elderly patients with advanced non-small-cell lung cancer treated with chemotherapy., Patients and Methods: Data from 566 patients enrolled onto the phase III randomized Multicenter Italian Lung Cancer in the Elderly Study (MILES) study were analyzed. Functional status was measured as activities of daily living (ADL) and instrumental ADL (IADL). The presence of comorbidity was assessed with a checklist of 33 items; items 29 and 30 of the European Organisation for Research and Treatment of Cancer (EORTC) core questionnaire QLQ-C30 (EORTC QLQ-C30) were used to estimate QoL. ADL was dichotomized as none versus one or more dependency. For IADL and QoL, three categories were defined using first and third quartiles as cut points. Comorbidity was summarized using the Charlson scale. Analysis was performed by Cox model, and stratified by treatment arm., Results: Better values of baseline QoL (P = .0003) and IADL (P = .04) were significantly associated with better prognosis, whereas ADL (P = .44) and Charlson score (P = .66) had no prognostic value. Performance status 2 (P = .006) and a higher number of metastatic sites (P = .02) also predicted shorter overall survival., Conclusions: Pretreatment global QoL and IADL scores, but not ADL and comorbidity, have significant prognostic value for survival of elderly patients with advanced non-small-cell lung cancer who were treated with chemotherapy. Using these scores in clinical practice might improve prognostic prediction for treatment planning.

Purpose: Gemcitabine-platinum combination activity has been clearly established in a number of phase II studies. It has also been compared against other combinations in many phase III trials. It is generally believed that all such regimens have an equivalent impact on survival. This meta-analysis aims to quantify the treatment effect of gemcitabine plus a platinum agent in the treatment of advanced NSCLC and compare the combination to other regimens used globally., Design: Data from a total of 4556 patients from 13 randomized trials investigating gemcitabine in combination with a platinum agent versus any other platinum-containing regimen were included in a meta-analysis of time-to-event outcomes., Results: A significant reduction in overall mortality in favor of gemcitabine-platinum regimens was observed, hazard ratio (HR) 0.90 (95% CI: 0.84-0.96) with an absolute benefit at 1 year of 3.9%. Median survival was 9.0 months for the gemcitabine-platinum regimens and 8.2 months for the comparator regimens. Sub-group analysis of the first- and second-generation platinum-based comparator regimens also indicated a significant benefit for gemcitabine-platinum regimens, HR 0.84 (CI: 0.71-0.9985). Analysis of third-generation agent plus platinum regimens showed a non-significant trend favoring gemcitabine-platinum regimens, HR 0.93 (CI: 0.86-1.01). There was a significant decrease in the risk of disease progression in favor of gemcitabine-platinum regimens, HR 0.88 (CI: 0.82-0.93). An absolute benefit of 4.2% at 1 year was estimated. Median progression-free survival was 5.1 months for gemcitabine-platinum regimens compared with 4.4 months for the comparator regimens. Sub-group analysis indicated a statistically significant progression-free survival benefit for patients assigned to gemcitabine-platinum treatment compared to first- and second-generation platinum regimens, HR 0.85 (CI: 0.77-0.94), and third-generation agent plus platinum regimens, HR 0.89 (CI: 0.82-0.96).

Purpose: The purpose of this study was to determine whether the addition of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (Iressa, ZD1839; AstraZeneca, Wilmington, DE) to standard first-line gemcitabine and cisplatin provides clinical benefit over gemcitabine and cisplatin alone in patients with advanced or metastatic non-small-cell lung cancer (NSCLC). Gefitinib has demonstrated encouraging efficacy in advanced NSCLC in phase II trials in pretreated patients, and a phase I trial of gefitinib in combination with gemcitabine and cisplatin showed favorable tolerability., Patients and Methods: This was a phase III randomized, double-blind, placebo-controlled, multicenter trial in chemotherapy-naive patients with unresectable stage III or IV NSCLC. All patients received up to six cycles of chemotherapy (cisplatin 80 mg/m(2) on day 1 and gemcitabine 1,250 mg/m(2) on days 1 and 8 of the 3-week cycle) plus either gefitinib 500 mg/d, gefitinib 250 mg/d, or placebo. Daily gefitinib or placebo was continued until disease progression. End points included overall survival (primary), time to progression, response rates, and safety evaluation., Results: A total of 1,093 patients were enrolled. There was no difference in efficacy end points between the treatment groups: for the gefitinib 500 mg/d, gefitinib 250 mg/d, and placebo groups, respectively, median survival times were 9.9, 9.9, and 10.9 months (global ordered log-rank [GOLrank] P =.4560), median times to progression were 5.5, 5.8, and 6.0 months (GOLrank; P =.7633), and response rates were 49.7%, 50.3%, and 44.8%. No significant unexpected adverse events were seen., Conclusion: Gefitinib in combination with gemcitabine and cisplatin in chemotherapy-naive patients with advanced NSCLC did not have improved efficacy over gemcitabine and cisplatin alone. The reasons for this remain obscure and require further preclinical testing.

Purpose: Preclinical studies indicate that gefitinib (Iressa, ZD1839; AstraZeneca, Wilmington, DE), an orally active epidermal growth factor receptor tyrosine kinase inhibitor, may enhance antitumor efficacy of cytotoxics, and combination with paclitaxel and carboplatin had acceptable tolerability in a phase I trial. Gefitinib monotherapy demonstrated unparalleled antitumor activity for a biologic agent, with less toxicity than docetaxel, in phase II trials in refractory, advanced non-small-cell lung cancer (NSCLC). This phase III, randomized, placebo-controlled, double-blind trial evaluated gefitinib plus paclitaxel and carboplatin in chemotherapy-naive patients with advanced NSCLC., Patients and Methods: Patients received paclitaxel 225 mg/m(2) and carboplatin area under concentration/time curve of 6 mg/min/mL (day 1 every 3 weeks) plus gefitinib 500 mg/d, gefitinib 250 mg/d, or placebo. After a maximum of six cycles, daily gefitinib or placebo continued until disease progression. End points included overall survival, time to progression (TTP), response rate (RR), and safety evaluation. Results A total of 1,037 patients were recruited. Baseline demographic characteristics were well balanced. There was no difference in overall survival (median, 8.7, 9.8, and 9.9 months for gefitinib 500 mg/d, 250 mg/d, and placebo, respectively; P =.64), TTP, or RR between arms. Expected dose-related diarrhea and skin toxicity were observed in gefitinib-treated patients, with no new significant/unexpected safety findings from combination with chemotherapy. Subset analysis of patients with adenocarcinoma who received > or = 90 days' chemotherapy demonstrated statistically significant prolonged survival, suggesting a gefitinib maintenance effect., Conclusion: Gefitinib showed no added benefit in survival, TTP, or RR compared with standard chemotherapy alone. This large, placebo-controlled trial confirmed the favorable gefitinib safety profile observed in phase I and II monotherapy trials.

Less than 20-25% of non-small cell lung cancer (NSCLC) patients present with stage I or II disease are best treated by surgical resection. Long-term survival in NSCLC remains poor also in these early stages: the 5-year survival rate of patients who undergo complete surgical resection is only 40 to 50%. The majority of post-surgical relapses are distant metastases with the risk of a local recurrence after complete resection being less than 10%. Postoperative treatments, including chemotherapy, radiotherapy or both, have been widely evaluated during the last decades and, unfortunately, none has demonstrated any significant impact on survival. Data regarding large-scale adjuvant chemotherapy trials, closed for the accrual almost four to five years ago, will be fully available soon and, hopefully, a specific meta-analysis will be performed.

The present study describes supportive care (SC) in patients with advanced non-small-cell lung cancer (NSCLC), evaluating whether it is affected by concomitant chemotherapy, patient's performance status (PS) and age. Data of patients enrolled in three randomised trials of first-line chemotherapy, conducted between 1996 and 2001, were pooled. The analysis was limited to the first three cycles of treatment. Supportive care data were available for 1185 out of 1312 (90%) enrolled patients. Gastrointestinal drugs (45.7%), corticosteroids (33.4%) and analgesics (23.8%) were the most frequently observed categories. The mean number of drugs per patient was 2.43; 538 patients (45.4%) assumed three or more supportive drugs. Vinorelbine does not produce substantial variations in the SC pattern, while cisplatin-based treatment requires an overall higher number of supportive drugs, with higher use of antiemetics (41 vs 27%) and antianaemics (10 vs 4%). Patients with worse PS are more exposed to corticosteroids (42 vs 30%). Elderly patients require drugs against concomitant diseases significantly more than adults (20 vs 7%) and are less frequently exposed to antiemetics (12 vs 27%). In conclusion, polypharmacotherapy is a relevant issue in patients with advanced NSCLC. Chemotherapy does not remarkably affect the pattern of SC, except for some drugs against side effects. Elderly patients assume more drugs for concomitant diseases and receive less antiemetics than adults.

Gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) and cisplatin are commonly used in the treatment of many solid tumors, although the impact of chemotherapy is limited in metastatic non-small cell lung cancer. However, in clinical practice, there is a minority of patients who can attain long-term survival. Upregulation of mRNA transcripts has been linked to chemoresistance, and in some instances, mRNA expression has been correlated with polymorphisms. Cisplatin resistance is directly linked to the nucleotide excision repair system, specifically to the transcription-coupled nucleotide excision repair pathway that involves genes that are deficient in rare inborn disorders such as Cockayne syndrome and xeroderma pigmentosum. Overexpression of ERCC1 correlates with poor survival in gemcitabine/cisplatin-treated non-small cell lung cancer patients. At the preclinical level, ERCC1 and XPD mRNA expression correlate with each other, and overexpression of XPD causes selective cisplatin resistance in human tumor cell lines. XPD polymorphisms have been associated with lower DNA repair capacity. In our experience, time to progression is significantly higher in gemcitabine/cisplatin-treated patients with the Lys751Gln genotype (9.6 months) than in those with the Lys751Lys genotype (4.2 months; P =.03). Other polymorphisms involved in parallel DNA repair systems may well provide the same information, indicating a high degree of biologic redundancy. The overexpression of the subunit M1 of ribonucleotide reductase (RRM1) has been linked to gemcitabine resistance in our retrospective assessment. Preliminary findings that a subset of gemcitabine/cisplatin-treated patients with low ERCC1 and RRM1 mRNA levels show a significantly longer survival and highlight the possibilities of individually tailored chemotherapy.

Background: In spite of the growing list of genetic abnormalities identified as being involved in DNA repair pathways that alter chemosensitivity in non-small-cell lung cancer (NSCLC) patients, translational assays have not yet been developed for use in individualized chemotherapy., Methods: In metastatic NSCLC, no single cisplatin-based chemotherapy regimen has been shown to be superior to any other. Although these studies show a small survival tail at 3 years, the majority of patients had a median survival of 8 to 10 months. We review the principal mechanisms of cisplatin resistance, particularly those involved in the nucleotide excision repair (NER) pathways (transcription-coupled repair and global genomic repair)., Results: ERCC1 is a single-stranded DNA endonuclease that forms a tight heterodimer with xeroderma pigmentosum complementation group F. It incises DNA on the 5' side of a lesion such as cisplatin-DNA adduct. Therefore, overexpression of ERCC1 and other NER enzymes during ovarian cancer chemotherapy with cisplatin appears to be implicated in the formation of cellular and clinical drug resistance. Recently, baseline ERCC1 mRNA overexpression has been related to poor response and survival in cisplatin-treated NSCLC patients., Conclusions: The level of evidence for many assays is limited, and only ERCC1 mRNA levels have been analyzed extensively. The impact of ERCC1 should be fully validated in prospective clinical trials.

Non-small-cell lung cancer patients with locally advanced or metastatic disease at the time of diagnosis show marginal response to chemotherapy in terms of tumor shrinkage, time to progression and median survival. The identification and implementation of predictive genetic markers of response-specific cytotoxic drugs is a priority of current research and future trials. In this study, we have used quantitative PCR to analyse expression of beta-tubulin III, stathmin, RRM1, COX-2 and GSTP1 in mRNA isolated from paraffin-embedded tumor biopsies of 75 nonsmall-cell lung cancer patients treated as part of a large randomized trial. In total, 22 patients were treated with gemcitabine/cisplatin, 25 with vinorelbine/cisplatin and 28 with paclitaxel/carboplatin. There were no differences in clinical characteristics and transcript levels in the pretreatment biopsies according to treatment arm. Patients with low beta-tubulin III levels had better response in the paclitaxel/carboplatin arm (P=0.05), and those with low RRM1 levels showed a tendency to better response in the gemcitabine/cisplatin arm. Time to progression was influenced by beta-tubulin III (P=0.03) and stathmin (P=0.05) levels in the vinorelbine/cisplatin arm, and there was a tendency toward correlation between beta-tubulin III levels and time to progression in the paclitaxel/carboplatin arm. RRM1 levels influenced time to progression (P=0.05) and even more so, survival (P=0.0028) in the gemcitabine/cisplatin arm. The predictive value of beta-tubulin III, stathmin and RRM1 should be tested in prospective customized chemotherapy trials, the results of which will help tailor chemotherapy to improve patient survival.

Surgery remains the mainstay of treatment for early non-small cell lung cancer (NSCLC) but more than 80% of recurrences occur within 2 years from radical surgery. The pattern of recurrence may differ by histology with more local recurrences seen for patients with squamous cell carcinoma and more distant metastases seen in patients with adenocarcinoma. A number of studies demonstrate that dissemination of cancer cells at levels much below those detected by any current available imaging techniques, including PET scanning also, affect prognosis of patients with clinical early-stage NSCLC. The current clinical evidence does not recommend adjuvant chemotherapy and/or radiotherapy in completely resected stage I-II-IIIA for N1. There are few randomised trials available for analysis of neo-adjuvant chemotherapy involving patients with resectable stage III disease; overall these trials suggest that induction chemotherapy (with or without radiation) improves survival, particularly in those patients who undergo significant downstaging. Heterogeneous study populations limit the ability to define the optimal patient population who would most benefit from this approach. There is no conclusive evidence that neo-adjuvant chemotherapy in early NSCLC is associated with an increased post surgical morbility and mortality. Additional trials are needed. More recently neo-adjuvant chemotherapy has been tested in resectable stage I-II NSCLC and proved to be feasible and better tolerated than adjuvant chemotherapy. Several randomised trials are currently ongoing. In the next future the role of targeted biological therapies as agents acting on minimal residual disease should be explored., (Copyright 2002 Elsevier Science Ireland Ltd.)

In this review, we deal with six groups of cytotoxic drugs commonly used in the treatment of non-small cell lung cancer (NSCLC). Although there are many reviews of thymidylate synthase (TS) and antifolate inhibitors, in this article, we have tried to highlight aspects that are more important for medical oncologists to consider when treating NSCLC patients. There is compelling evidence that TS gene transcripts and TS polymorphisms could be used to decide which patients can best benefit from adjuvant chemotherapy approaches, especially in colorectal cancer, and not less importantly, to tailor chemotherapy in metastatic NSCLC when using drugs akin to fluorouracil, such as pemetrexed. Secondly, cisplatin is central to chemotherapy combinations and evidence indicates that DNA repair capacity influences response to cisplatin-based regimens. ERCC1 gene transcript stands out as a predictive marker of cisplatin sensitivity. Thirdly, preliminary studies indicate that upregulation of beta-tubulin III correlates with response to paclitaxel and vinorelbine. Fourthly, overexpression of ribonucleotide reductase can influence response to gemcitabine. Fifthly, we describe mechanisms of resistance to topoisomerase I inhibitors, although this subject has not yet been completely elucidated. Finally, to understand the mechanisms of resistance to EGF-R inhibitors, which have been shown to be useful in many different types of cancer, the Src-STAT signaling pathways are described here in detail. Hopefully, the assessment of Src and of STAT-3 can be implemented as predictive markers.

The limited single-agent activity of cisplatin, its toxicity profile, and the inconvenience involved in hydrating patients has compelled researchers to investigate other treatments as possible alternative therapies in non-small cell lung cancer. More recently, interest has focused on the potential of nonplatinum combinations. Phase II studies show that the combination of docetaxel (Taxotere; Aventis, Antony, France) and gemcitabine is active in stage IIIB/IV non-small cell lung cancer not previously treated by chemotherapy. Response rates of up to 54% and a median survival time of 13 months have been reported. These data are comparable with the achievements of cisplatin-based combinations. A randomized phase II trial of docetaxel plus gemcitabine versus docetaxel plus cisplatin found that the two regimens were equally active in terms of response rate, median, and 1-year survival. However, the combination of docetaxel with gemcitabine produced significantly less neutropenia and nonhematologic toxicities. In combination, from 80% to 100% of the full single-agent gemcitabine and docetaxel doses can safely be administered once every 3 weeks. The combination of docetaxel plus vinorelbine is also active in non-small cell lung cancer and preliminary data suggest that this schedule with prophylactic filgrastim may optimize tolerability and dose intensity. In a phase II study using this approach, a confirmed response rate of 51% was obtained in 35 patients. At 12 months, the predicted median survival is 14 months and the predicted 1-year survival rate is 60%. Excessive lacrimation, fatigue, and onycholysis were cumulative toxicities. However, the incidence of mucositis and neuropathy was low with the combination of docetaxel and vinorelbine. Docetaxel combined with other new agents, particularly gemcitabine, may offer another useful alternative to cisplatin-based chemotherapy in patients with good performance status.

Purpose: To investigate the activity and toxicity of gemcitabine as a single agent in patients with advanced non-small-cell lung cancer (NSCLC) after recurrence or failure of previous treatment with a platinum-containing regimen., Patients and Methods: From November 1995 to October 1997, 83 patients with stage IIIB or IV NSCLC received gemcitabine 1,000 mg/m(2) once a week for 3 weeks every 28 days. Responses were assessed every two treatment courses. The median age of the patients was 63 years; Eastern Cooperative Oncology Group performance status was 0 to 1 in 62 patients and 2 in 21 patients. The predominant histology was squamous (39 patients); 49 patients had stage IV disease and 34 patients had stage III disease (33 stage IIIB and one stage IIIA)., Results: Sixteen patients (19%) achieved a partial response to treatment; the median duration of response was 29 weeks (range, 6 to 50 weeks). Treatment was well tolerated: grade 2 to 3 (World Health Organization standardized response criteria) leukopenia and thrombocytopenia occurred in 23% and 20% of patients, respectively. Mild asthenia was observed in 16% of patients, and peripheral edema in 5% of patients. Nausea and vomiting were present in 16% of patients., Conclusion: In this experience, gemcitabine showed significant activity without relevant toxicity, mainly in patients who were previously responsive to chemotherapy. This suggests a possible role for gemcitabine as a second-line treatment in patients who had a previous response or achieved stable disease with a platinum-containing regimen.

Purpose: To compare two cisplatin based chemotherapy schedules in patients with advanced non-small-cell lung cancer (NSCLC)., Patients and Methods: A total of 332 patients with advanced NSCLC were randomized to receive cisplatin 80 mg/m2 on day 1 either in combination with teniposide 100 mg/m2 on days 1, 3, and 5 (arm A) or paclitaxel 175 mg/m2 by 3-hour infusion on day 1 (arm B); cycles were repeated every 3 weeks., Results: Fifteen patients were ineligible; patient characteristics were well balanced between the two arms: 71% were male, 71% had less than 5% weight loss, 89% had a World Health Organization (WHO) performance status of 0 to 1, 51% had adenocarcinoma, and 61% had stage IV disease. Hematologic toxicity was significantly more severe in arm A (leukopenia, neutropenia, and thrombocytopenia grade 3 or 4: 66% v 19%, 83% v 55%, 36% v 2% in arms A and B, respectively), which resulted in more febrile neutropenia (27% v 3% in arms A and B, respectively), dose reductions, and treatment delays. There were a total of nine toxic deaths, six due to neutropenic sepsis: five in arm A and one in arm B. In contrast, arthralgia/myalgia (grade 2 or 3, 4% v 17%), peripheral neurotoxicity (grade 2 or 3, 6% v 29%), and hypersensitivity reactions (1% v 7%, all grades) were significantly more frequent in arm B. The frequency and severity of other toxicities were comparable between the two arms. Responses were one complete and 44 partial on arm A (28%) and two complete and 61 partial (41%) on arm B (P = .018). There was no significant difference in survival, with median and 1-year survivals 9.9 versus 9.7 months and 41% versus 43%, respectively in arm A and B. Progression-free survival was 4.9 and 5.4 months in arm A and B, respectively. Selected centers participated in a quality-of-life (QoL) assessment, which was performed by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and LC-13 administered at baseline and every 6 weeks thereafter. Arm B achieved a better score at week 6 for emotional, cognitive and social functioning, global health status, fatigue, and appetite loss, which was lost at 12 weeks. In conclusion, arm B appears superior to arm A with regard to response rate, side effects, and QoL., Conclusion: Although survival was not improved, arm B offers a better palliation for advanced NSCLC patients than arm A.

A total of 332 patients with advanced non-small-cell lung cancer were randomized by the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group (EORTC) to receive one of two cisplatin (Platinol)-based chemotherapy regimens: Paclitaxel (Taxol) 175 mg/m2 given by 3-hour infusion followed by cisplatin 80 mg/m2 on day 1; Or cisplatin 80 mg/m2 on day 1, followed by teniposide (Vumon) 100 mg/m2 given on days 1, 3, and 5. Cycles were repeated every 3 weeks. Preliminary analysis of the results of this phase III trial shows that hematologic toxicity was decidedly more severe in the group treated with cisplatin/teniposide than in those given paclitaxel/cisplatin. Of 264 patients evaluable so far, responses have been observed in 47% of those given paclitaxel and in 29% of those treated with teniposide. However, extramural radiologic response evaluation is still under way, so these figures are expected to change somewhat. It appears clear that the paclitaxel-based therapy affords a benefit in terms of response and toxicity, but survival results are premature and any definite conclusions await final analysis.