Optimizing First-Line Treatment Options for Patients with Advanced NSCLC

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1 This material is protected by U.S. Copyright law. Unauthorized reproduction is prohibited. For reprints contact: Optimizing First-Line Treatment Options for Patients with Advanced NSCLC Heather Wakelee, a Chandra P. Belani b a Stanford University, Stanford, California, USA; b University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA Key Words. Non-small cell lung cancer Chemotherapy Docetaxel Taxanes Bevacizumab Gemcitabine Learning Objectives After completing this course, the reader will be able to: 1. Explain the clinical implications of large randomized trials evaluating chemotherapy combinations for patients with advanced NSCLC. 2. Summarize the activity and toxicity of current chemotherapy regimens for the first-line treatment of advanced NSCLC. 3. Describe regimens that have quality-of-life benefits in the treatment of NSCLC. 4. Identify potential future standards of care for advanced disease based on recent research findings evaluating novel targeted agents. CME Access and take the CME test online and receive 1 AMA PRA category 1 credit at CME.TheOncologist.com Abstract The median survival time for advanced non-small cell lung cancer (NSCLC) remains poor, despite years of research into new chemotherapy combinations. Platinum-based chemotherapy has long been the standard of care for the initial treatment of advanced NSCLC. While no one particular platinum-based chemotherapy regimen is definitely superior to the others (as demonstrated in the Eastern Cooperative Oncology Group s E1594 trial), three randomized phase III trials (the Southwest Oncology Group 9509, Italian Lung Cancer Project, and TAX326 trials) have recently demonstrated that taxane platinum doublets are better tolerated than a combination of vinorelbine and cisplatin(vc). Moreover, a combination of docetaxel and cisplatin produced superior survival and quality of life than VC in the TAX326 study. Nonplatinum combinations, such as a taxane gemcitabine doublet, appear promising and better tolerated than their platinum-based comparators in other studies. Efforts to evaluate chemotherapy specifically in elderly patients and in those with poor performance status (PS) have increased. Single-agent chemotherapy has been safely administered to these populations, but platinum-based doublet therapy may also be feasible in both elderly patients and patients with PS scores of 2. The addition of the monoclonal antibody against vascular endothelial growth factor, bevacizumab, to standard chemotherapy for patients with non-squamous cell advanced NSCLC significantly extended median survival in the E4599 randomized trial. Each incremental advance demonstrates that progress can be made in first-line treatment of advanced NSCLC. The Oncologist 2005;10(suppl 3):1 10 Correspondence: Chandra P. Belani, UPMC Cancer Pavilion, 5150 Centre Avenue, Pittsburgh, Pennsylvania 15232, USA. Telephone: ; Fax: ; belanicp@upmc.edu Received October 4, 2005; accepted for publication October 6, AlphaMed Press /2005/$12.00/0 The Oncologist 2005;10(suppl 3):1 10

2 2 First-Line Treatment for Advanced NSCLC Introduction Lung cancer continues to be the leading cause of cancerrelated mortality in the U.S. With an estimated 172,000 new cases in 2005, lung cancer is expected to kill more than 163,000 Americans this year [1]. The late stage at diagnosis in many patients, and the high rate of relapse for those initially diagnosed in earlier stages, contributes to its lethality. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for approximately 80% of cases. Chemotherapy is generally indicated for patients with advanced NSCLC because the results of many large, randomized phase III clinical trials have established that modern chemotherapies offer superior survival and symptom palliation than best supportive care [2]. Specifically, platinum-based chemotherapy has been the worldwide standard based on the single-agent activity of platinum agents as well as meta-analyses suggesting superiority over nonplatinum-based therapy [3, 4]. For patients with unresectable stage III disease, a combination of platinum-based chemotherapy and radiotherapy is recommended, whereas in stage IV disease, chemotherapy alone is warranted [3]. The most recent treatment guidelines from the American Society of Clinical Oncology (ASCO) reflect the growing evidence that nonplatinum doublets may provide some advantages for some patients, and ASCO currently recommends either a platinum-based or nonplatinum-based chemotherapy regimen for the initial treatment of patients with stage IV disease and good performance status (PS) [3]. This position is supported by a recent meta-analysis demonstrating that, while platinum-containing regimens demonstrate higher response rates than nonplatinum doublets, the 1-year survival rates are similar and toxicity is lower with the nonplatinum doublets [5]. Importantly, there is currently no role for threedrug cytotoxic combination regimens in the management of advanced NSCLC; clinical trials have demonstrated that combination regimens consisting of three cytotoxic drugs produce greater toxicity without improving outcomes in this setting. Recently, however, the Eastern Cooperative Oncology Group (ECOG) E4599 trial demonstrated that a threedrug regimen including the targeted agent bevacizumab (Avastin ; Genentech, Inc., South San Francisco, CA, improves survival relative to a two-drug combination without bevacizumab [6]. The average age for patients diagnosed with lung cancer is 70 years [7]. Age alone is not a predictor of survival or response in advanced NSCLC; however, poor PS, generally defined as a PS score of 2 on the ECOG rating scale, is a prognostic factor [3, 8]. Patients with PS scores of 2 have some restrictions in their physical activity, are unable to work, and spend up to half their waking hours resting or in bed [8]. There is no consensus on the best treatment approach for patients with advanced NSCLC and poor PS. ASCO recommends initial treatment with single-agent chemotherapy for both elderly patients and those with poor PS [3]. A European Experts Panel recommends single-agent (e.g., gemcitabine [Gemzar ; Eli Lilly and Company, Indianapolis, IN, vinorelbine [Navelbine ; Glaxo- SmithKline, Philadelphia, docetaxel [Taxotere ; Aventis Pharmaceuticals Inc., Bridgewater, NJ, or paclitaxel [Taxol ; Bristol-Myers Squibb, Princeton, NJ, therapy or platinum-based (carboplatin [Paraplatin ; Bristol-Myers Squibb] or low-dose cisplatin [Platinol ; Bristol- Myers Squibb]) doublets for patients with poor PS [8]. Clinical trials are being conducted specifically for the elderly and those with poor PS, and it is hoped that the results from those trials will provide the data necessary to make definitive treatment recommendations. Despite the known benefits of chemotherapy for advanced NSCLC, it appears that many eligible patients remain untreated. Potosky and colleagues evaluated firstline NSCLC treatment patterns using a population-based random sample of patients newly diagnosed with NSCLC in 1996 from 10 geographic areas of the U.S. [9]. Only 52% of all lung cancer patients received the recommended therapy at that time, and rates of received treatment declined further with increasing disease stage. Only 48% and 41% of patients with stage III and stage IV disease, respectively, received the recommended therapy (including chemotherapy), and rates continued to decline with advancing age, even after adjusting for factors such as comorbidities and socioeconomic status. These data suggest that substantial numbers of patients with advanced NSCLC are not afforded the opportunity to benefit from the survival and palliative gains associated with current chemotherapy regimens. The goal of this review is to summarize the results of contemporary clinical trials conducted in advanced NSCLC to demonstrate the benefits of chemotherapy, aid comparative evaluation of numerous regimens, and identify emerging therapies. Phase III Trials of Newer Chemotherapy Doublets Versus Standard Regimens as First-Line Treatment of Advanced NSCLC The availability of a number of newer active agents with perceived better tolerability over their older counterparts led to the development of many trials aimed at identifying the most effective regimen for advanced NSCLC. Agents such as docetaxel, gemcitabine, paclitaxel, and

3 Wakelee, Belani 3 vinorelbine were incorporated into platinum-based therapy as part of this effort; other trials have explored the comparative efficacy of nonplatinum doublets. Table 1 summarizes the design and major outcomes of the randomized phase III trials that have evaluated platinumbased doublets that incorporated gemcitabine, docetaxel, paclitaxel, or vinorelbine into the first-line treatment of advanced disease [10 16]. Table 2 summarizes the trials that have compared nonplatinum doublets with platinumbased doublets in this setting [17 21]. Comparisons of Platinum-Based Therapies Trial E1594 was developed by ECOG to compare four platinum-based regimens in more than 1,000 patients with stage IIIB/IV NSCLC and PS scores of 0 2 [10]. A standard regimen of paclitaxel plus cisplatin (PC, consisting of paclitaxel, 135 mg/m 2 over 24 hours on day 1, and cisplatin, 75 mg/m 2 on day 2, every 21 days) was compared with gemcitabine plus cisplatin (GC, consisting of gemcitabine, 1,000 mg/m 2 on days 1, 8, and 15, and cisplatin, 100 mg/m 2 on day 1, every 28 days), docetaxel plus cisplatin (DC, consisting of cisplatin, 75 mg/m 2, and docetaxel, 75 mg/m 2, every 21 days), and paclitaxel plus carboplatin (PCb, consisting of paclitaxel, 225 mg/m 2 over 3 hours on day 1, and carboplatin, to an area under the concentration time curve [AUC] of 6 on day 1, every 21 days). The primary analysis revealed no significant differences among the regimens with respect to overall survival (OS). Median survival times (MSTs) ranged from 17% with DC and PCb to 21% 22% with PC and GC. The overall response rate (ORR) did not differ among groups. There Table 1. Overview of randomized phase III trials evaluating first-line platinum-based doublets in advanced non-small cell lung cancer platinum-based therapy in all groups Study Regimens Population Outcomes ECOG E1594 [10] PC vs. GC vs. DC vs. PCb n = 1,155, PS score 0 2 No differences among groups in ORR or MST. For all patients: ORR, 19%; MST, 7.9 mos SWOG 9509 [11] PCb vs. VC n = 408, PS score 0 1 Outcome measure PC VC MST (mos) yr survival rate 36% 38% 2-yr suvival rate 16% 15% ILCP [12] GC vs. PCb vs. VC n = 612, PS score 0 2 Outcome measure GC PCb VC MST (mos) yr survival rate 37% 43% 37% TAX326 [13] DC vs. DCb vs. VC n = 1,218, Outcome measure DC VC KPS score MST (mos) a 1-yr survival rate 46% 41% 2-yr survival rate 21% 14% Outcome measure DCb VC MST (mos) yr survival rate 38% 40% 2-yr survival rate 18% 14% JTLCSG [14] DC vs. VdsC n = 302, stage IV only, Outcome measure DC VdsC PS score 0 2 MST (mos) a 1-yr survival rate 48% 41% 2-yr survival rate 24% 12% SLCG [15] GC vs. EP n = 135, KPS Outcome measure GC EP score MST (mos) ORR 41% 22% a FACS [16] IP vs. PCb vs. GC n = 602, PS score 0 1 Outcome measure IP PCb GC VC vs. VC MST (mos) yr survival rate 59% 51% 60% 48% a p <.05. Abbreviations: DC, docetaxel and cisplatin; DCb, docetaxel and carboplatin; ECOG, Eastern Cooperative Oncology Group; EP, etoposide and cisplatin; FACS, Four-Arm Cooperative Study; GC, gemcitabine and cisplatin; GCb, gemcitabine and carboplatin; ILCP, Italian Lung Cancer Project; IP, irinotecan and cisplatin; JTLCSG, Japanese Taxotere Lung Cancer Study Group; KPS, Karnofsky performance status; MST, median survival time; ORR, overall response rate; PC, paclitaxel and cisplatin; PCb, paclitaxel and carboplatin; PS, ECOG performance status; SLCG, Spanish Lung Cancer Group; SWOG, Southwest Oncology Group; VC, vinorelbine and cisplatin; VdsC, vindesine and cisplatin.

4 4 First-Line Treatment for Advanced NSCLC Table 2. Overview of randomized phase III trials evaluating first-line nonplatinum- vs. platinum-based therapy in advanced nonsmall cell lung cancer Study Regimen Population Outcomes HORG [17] DG vs. VC n = 413, PS score 0 2 Outcome measure DG VC ORR 30% 39.2% a MST (mos) yr survival rate 34% 41% 2-yr survival rate 14% 11% Pujol et al. [18] DG vs. VC n = 311, KPS score Outcome measure DG VC MST (mos) yr survival rate 46% 42% HeCOG [19] GP vs. GCb n = 445, PS score 0 1 Outcome measure GP GCb MST (mos) yr survival rate 44% 42% 2-yr survival rate 16% 14% Alpha Oncology GCb vs. GP vs. PCb n = 982, PS score 0 1 Outcome measure GCb GP PCb [20] MST (wks) yr survival rate 32% 33% 33% 1-yr survival rate 11% 10% 11% GEMVIN [21] GV vs. (GC or VC) n = 501, PS score 0 2 Outcome measure GV GC/VC MST (wks) PFS (wks) b a p =.053. b p =.004 (one-sided). Abbreviations: DG, docetaxel and gemcitabine; GC, gemcitabine and cisplatin; GCb, gemcitabine and carboplatin; GEMVIN, Italian Gemcitabine Vinorelbine group trial; GP, gemcitabine and paclitaxel; GV, gemcitabine and vinorelbine; HeCOG, Hellenic Cooperative Oncology Group; HORG, Hellenic Oncology Research Group; KPS, Karnofsky performance status; MST, median survival time; ORR, overall response rate; PCb, paclitaxel and carboplatin; PFS, progression-free survival; PS, Eastern Cooperative Oncology Group performance status; VC, vinorelbine and cisplatin. was a significantly longer median time to progression (TTP) with GC than with PC (4.2 vs. 3.4 months, respectively; p =.001); however, this result is complicated by a significantly higher rate of withdrawal in the GC arm because of treatment-related complications (27% vs. 15%, respectively; p <.001). Ultimately, the E1594 trial demonstrated no significant advantage of one regimen over the others. The Southwest Oncology Group (SWOG) conducted the 9509 trial to compare a taxane platinum doublet with its reference regimen, vinorelbine plus cisplatin (VC), in advanced NSCLC patients with good PS [11]. A total of 408 eligible patients received either PCb (consisting of paclitaxel, 225 mg/m 2 over 3 hours, and carboplatin, AUC 6, every 21 days) or VC (consisting of vinorelbine, 25 mg/m 2 per week, and cisplatin, 100 mg/m 2 on day 1, every 28 days). The MST did not differ between the groups, nor did the 1-year or 2-year survival rates. The rates of grade 3 4 leukopenia and neutropenia and grade 3 nausea/vomiting were significantly higher with VC, while there was significantly more grade 3 peripheral neuropathy with the PCb regimen. Twice as many patients in the VC arm refused treatment secondary to toxicity (28% vs. 14%), and as a result, dose intensity was lower in the VC arm. An effort to evaluate quality of life (QoL) was begun in the middle of the trial. In the small subgroup of patients completing the Functional Assessment of Cancer Therapy Lung (FACT-L) questionnaire at baseline and at 13 and 25 weeks, no differences were seen at the latter time points with respect to the percent of patients with improved, stable, or deteriorated QoL. These results are limited by the small sample size and may reflect the bias associated with only healthy survivors completing the questionnaires. The SWOG concluded from this trial that PCb is as effective as, but better tolerated than, VC for the initial treatment of advanced NSCLC. The Italian Lung Cancer Project (ILCP) compared a VC regimen with GC and with PCb in their randomized trial [12]. A total of 612 patients was randomized to either VC (consisting of vinorelbine, 25 mg/m 2 per week 12, then every other week, and cisplatin, 100 mg/m 2, on day 1 every 28 days), GC (consisting of gemcitabine, 1,250 mg/ m 2 on days 1 and 8, and cisplatin, 75 mg/m 2 on day 2, every 21 days), or PCb (consisting of paclitaxel, 225 mg/m 2 over 3 hours on day 1, and carboplatin, AUC 6, on day 1, every 21 days). There were no statistically significant differences among the treatment groups in objective response rates, which were 30%, 32%, and 30% for patients treated with

5 Wakelee, Belani 5 VC, PCb, and GC, respectively, or in MSTs (9.5 months, 9.9 months, and 9.8 months, respectively) or 1-year survival rates (37%, 43%, and 37%, respectively). The rates of febrile neutropenia (FN) were low in all arms. The rate of grade 3 4 neutropenia was significantly higher with VC than with GC or PCb (43% vs. 17% and 35%, respectively; p <.001), whereas severe thrombocytopenia was significantly more frequent in the GC and PCb arms than in the VC arm (16% and 3% vs. 0.1%; p <.001 for each comparison with VC). Peripheral neuropathy was significantly more common in the PCb arm, although most cases were grade 1 in severity. QoL was assessed with the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30- LC13 tool. There were no differences in QoL between the GC and VC arms. PCb was associated with better results for role functioning, fatigue, nausea, vomiting, and anorexia, while VC produced better results for peripheral neuropathy and alopecia after two cycles of therapy. However, after 4 weeks of therapy, these differences faded, which may reflect the lessening impact of acute toxicity on QoL at later time points or the impact of healthy survivor bias on the results, since discontinuation before the completion of four cycles was greatest in the VC arm. The conclusion was that all three arms were equivalent. The TAX326 trial was a three-arm trial designed to compare a taxane platinum doublet with a VC reference regimen [13]. A total of 1,218 patients was randomized to receive either DC (consisting of 75 mg/m 2 of each, every 21 days), docetaxel plus carboplatin (DCb, consisting of docetaxel, 75 mg/m 2, and carboplatin, AUC 6, every 21 days), or VC (consisting of vinorelbine, 25 mg/m 2 per week, and cisplatin, 100 mg/m 2 on day 1, every 28 days). Unlike other trials reported to date, a survival benefit was seen with one of the treatment arms. The MST was 1 month longer in the DC arm than in the VC arm (11.3 months vs months, respectively; p =.044). However, the MST did not differ between the DCb and VC arms. The rates of thrombocytopenia, infection, and FN were similar, while there was significantly more grade 3 4 anemia, nausea, and vomiting with VC. Diarrhea, alopecia, edema, and nail disorders were more common in the docetaxel-containing arms, but hospitalizations and discontinuation because of adverse events were less frequent. QoL was assessed in a subgroup (n = 926) of patients for whom native language versions of the Lung Cancer Symptom Scale (LCSS) and EuroQOL tool were available. Both tools demonstrated improvements in QoL with docetaxel-based therapy, while QoL generally deteriorated in the VC arm. Patients receiving DC or DCb experienced significantly less weight loss and deterioration in PS than those treated with VC. These results, in combination with those from the SWOG 9509 and the ILCP trials, undermine the utility of the VC regimen as initial treatment for advanced NSCLC because of poor tolerability. Moreover, in contrast to the other trials, TAX326 demonstrated that improvements in survival are possible in this setting with traditional cytotoxic chemotherapy agents. The Japanese Taxotere Lung Cancer Study Group (JTLCSG) also reported longer survival with a DC regimen in metastatic NSCLC [14]. A total of 311 patients was randomized (302 evaluable)to receive either a combination of docetaxel (60 mg/m 2 ) plus cisplatin (80 mg/m 2 ) every 3 4 weeks or vindesine plus cisplatin (VdsC, consisting of vindesine, 3 mg/m 2 on days 1, 8, and 15, and cisplatin, 80 mg/ m 2 on day 1) every 4 weeks. The trial enrolled only patients with stage IV disease and included patients with poor PS. Treatment was designed to be given until disease progression or unacceptable toxicity. The median number of cycles of DC administered was three, whereas the median number of VdsC cycles was two (p <.01). Despite the longer treatment course in the DC arm, fewer patients experienced severe hematologic toxicity. The incidences of grade 3 anemia and grade 3 4 leukopenia were significantly higher in the VdsC arm. Overall survival was the primary end point of the trial, and MST was significantly longer in the DC arm than in the VdsC arm (11.3 months vs. 9.6 months; p =.014). QoL, measured with the validated, Japanese Questionnaire for Cancer Patients Treated with Anticancer Drugs tool, tended to be superior for the functional, physical, and mental domains in the DC arm, although only the physical domain results were statistically significant (p =.02). The results of this phase III trial led to the replacement of VdsC with DC as standard therapy for patients with stage IV NSCLC in Japan. Comparisons of Nonplatinum-Based and Platinum-Based Therapies Because of the toxicity associated with platinum-based therapy, many groups are evaluating nonplatinum doublets in an effort to improve tolerability (Table 2) [17 21]. The Hellenic Oncology Research Group (HORG) compared docetaxel plus gemcitabine (DG) with VC in a recently reported clinical trial [17]. A total of 413 patients with stage IIIB/IV NSCLC and PS scores of 0 2 were randomized to receive either DG (docetaxel, 100 mg/m 2 on day 8, and gemcitabine, 1,000 mg/m 2 on days 1 and 8, every 21 days) or VC (vinorelbine, 30 mg/m 2 on days 1 and 8, and cisplatin, 80 mg/m 2 on day 8, every 21 days). Both groups received prophylactic G-CSF on days 9 15 of each cycle. There were no differences between treatment arms for MST (9 months with DG vs. 9.7 months with VC), 1- year or 2-year survival rate, or TTP, although there was a trend toward a higher response rate in the VC group. The rates of anemia, neutropenia, nausea, and neurotoxicity

6 6 First-Line Treatment for Advanced NSCLC were significantly higher in the VC arm (55% vs. 34% for grade 2 4 anemia, 37% vs. 16% for grade 3 4 neutropenia, and 15% versus 2% for grade 3 4 nausea, respectively; p =.0001 for each comparison; 26% vs. 15% for grade 2 4 neurotoxicity; p =.004). There were three deaths from FN in the VC group and one in the DG group; the incidence rates were 11% and 6%, respectively (p = 0.086). The LCSS was used to assess QoL at baseline and after the third and final cycles. Compliance was good in each arm, with more than 83% of patients completing all questionnaires. Patients in the DG arm reported a significant improvement in QoL from baseline to the end of therapy for the symptoms of hemoptysis and pain. There were no significant improvements in the VC arm. These results demonstrate that taxane-based therapy is an effective, well-tolerated alternative to platinum-based therapy in advanced NSCLC. Pujol and colleagues also reported that a first-line DG combination was as effective as and better tolerated than VC in patients with stage IIIB/IV NSCLC [18]. A total of 311 patients was randomized to treatment with either DG (consisting of docetaxel, 85 mg/m 2 on day 8, and gemcitabine, 1,000 mg/m 2 on days 1 and 8, every 3 weeks) or VC (consisting of vinorelbine, 30 mg/m 2 on days 1, 8, 15, and 22, and cisplatin, 100 mg/m 2 on day 1, every 4 weeks) in this multicenter study conducted in France. Progression-free survival, the primary end point, did not differ between groups, nor did MST. Compliance with the regimen was greater in the DG arm, and the median number of cycles administered in that arm was five (vs. four in the VC arm; p <.001). Myelosuppression was significantly more common with VC, particularly grade 3 4 anemia (21% vs. 6%; p <.001), grade 3 4 neutropenia (83% versus 52%; p <.001), and FN (22% vs. 8%; p <.001). Grade 3 4 pulmonary events were significantly more common with DG (5% vs. 0.6%; p =.02). Changes in QoL from baseline were assessed with the EORTC QLQ-C30; there were no differences between groups with respect to the time to definite impairment in health-related QoL. Overall, DG was demonstrated to be a safe and effective alternative to platinum-based therapy for patients with advanced NSCLC. Results from two other studies presented at the 2005 ASCO annual meeting further support taxane gemcitabine doublets as initial treatment of advanced NSCLC [19, 20]. The Hellenic Cooperative Oncology Group (HeCOG) compared gemcitabine plus paclitaxel (GP, consisting of gemcitabine, 1,000 mg/m 2 on days 1 and 8, and paclitaxel, 200 mg/m 2 on day 1 every 21 days) with gemcitabine plus carboplatin (GCb, consisting of gemcitabine, 1,000 mg/m 2 on days 1 and 8, and carboplatin, AUC 6, every 21 days) in 445 chemotherapy-naïve patients with good PS. The two regimens were equally active; there were no differences in survival outcomes such as MST, 1-year survival rate, or TTP. Myelotoxicity was worse in the GCb arm, with significantly higher rates of grade 3 4 leukopenia (19% vs. 8%; p =.001), neutropenia (28% vs. 17%; p =.009), thrombocytopenia (25% vs. 2.4%; p <.001), and anemia (13% vs. 5%; p =.001). Grade 3 alopecia and neurotoxicity were significantly more common with GP (61% vs. 6% and 5% vs. 0.5%, respectively; p <.003 for each comparison). Alpha Oncology reported that outcomes were similar for three regimens: GCb (consisting of gemcitabine, 1,000 mg/ m 2 on days 1 and 8, and carboplatin, AUC 5.5 on day 1, every 21 days), GP (consisting of gemcitabine, 1,000 mg/m 2 on days 1 and 8, and paclitaxel, 200 mg/m 2, every 21 days), and PCb (consisting of paclitaxel, 225 mg/m 2 on day 1, and carboplatin, AUC 6 on day 1, every 21 days). Rates of grade 3 4 neutropenia, thrombocytopenia, and anemia were highest in the GCb arm, although most cases were uncomplicated. Neurosensory events, alopecia, and metabolic/laboratory derangements were more common with the paclitaxel-based regimens. The QoL data from that trial were not available at the time of the presentation, but the authors suggested that given equal efficacy, QoL and toxicity profile should determine the optimal regimen for NSCLC. A combination of gemcitabine plus vinorelbine (GV) has also been evaluated as an alternative to platinumbased therapy in advanced NSCLC [21]. The Italian Gemcitabine Vinorelbine (GEMVIN) group and the National Cancer Institute of Canada conducted a randomized phase III trial to compare GV (consisting of gemcitabine, 1,000 mg/m 2, and vinorelbine, 25 mg/m 2 on days 1 and 8) with platinum-based therapy given every 3 weeks. Patients were randomized to either GV or the control arm, and the latter group was then randomized to either GC (consisting of gemcitabine, 1,200 mg/m 2 on days 1 and 8, and cisplatin, 80 mg/m 2 on day 1) or VC (consisting of vinorelbine, 30 mg/m 2 on days 1 and 8, and cisplatin, 80 mg/m 2 on day 1). The two platinum-based arms were combined for the analysis. QoL at the end of the second cycle was the primary end point of the study; the EORTC QLQ-C30 tool was used for data collection. The median time on treatment and the mean number of cycles administered were similar in both the GV and control arms. The completion rate of QoL questionnaires was good, declining from 82% 84% at week 1 to 74% 80% at week 9. Baseline QoL scores were similar, and there were no significant differences between groups in global QoL score after the second cycle. Platinum-based therapy was associated with higher rates of anemia, neutropenia, thrombocytopenia, vomiting, renal toxicity, alopecia, ototoxicity, and fatigue. The GV regimen was associated with more hepatic toxicity. There were no differences in MST or ORR. Progression-

7 Wakelee, Belani 7 free survival was longer with platinum-based therapy (23 weeks vs. 17 weeks; p <.05). Nonetheless, the GV regimen has a favorable risk:benefit profile and is a viable alternative to platinum-based therapy. Overall, these recent trials support ASCO s position that nonplatinum doublets are an option for the first-line therapy of advanced NSCLC. Further support for this position is given by a meta-analysis of 37 trials including 7,633 patients, which demonstrated that, although platinum doublets have a higher response rate, they also have a higher toxicity rate, without providing a significant improvement in survival over nonplatinum doublets [5]. Recent studies continue to indicate that we have reached an efficacy plateau with chemotherapy combinations, with or without a platinum agent, but these treatments do improve survival and QoL for patients. Special Populations: Elderly and Poor PS As many as 40% of patients with advanced NSCLC have poor PS, and these patients are often excluded from clinical trials [8]. They tend to have poorer responses to treatment and shorter survival than their counterparts with PS scores of 0 1. It is also generally believed that they are at greater risk for toxicity [8]. This concern was initially borne out in the E1594 trial, which was amended to exclude patients with PS scores of 2 after 66 had been enrolled. There appeared to be an unacceptably high rate of serious adverse events in this subgroup, and MST was significantly lower in this group (10.8 months for patients with PS scores of 0 vs. 3.9 months for patients with PS scores of 2; p <.001) [10]. However, a later analysis revealed that only two of the five deaths in the PS = 2 subgroup of the E1594 trial could be directly attributed to therapy, and overall toxicity was ultimately found to be generally similar to that reported in the PS = 0 1 population [22]. Currently, patients with PS scores of 2 are recognized as a distinct population of patients with advanced NSCLC, and dedicated trials are being conducted in this group to identify safe and effective regimens for this large cohort of patients routinely seen in clinical practice. As with poor PS patients, elderly patients are also under-represented in clinical trials, and there is little consensus on optimal treatment [8, 23]. Although half of all patients diagnosed with lung cancer are 70 years of age and older, and one third are over 75, only 40% of the lung cancer patients enrolled in clinical trials conducted by SWOG in the 1990s were 65 years of age or older [24, 25]. However, an international expert panel recently concluded that fit elderly patients are as likely to benefit from chemotherapy as their younger counterparts, and they urged for the inclusion of otherwise healthy elderly patients with advanced NSCLC into clinical trials [26]. Several clinical trials have recently been reported that focus on these special populations. One key research question is whether single-agent or doublet therapy is most appropriate for elderly or poor PS patients. The largest phase III trial conducted in elderly patients with advanced NSCLC, known as the Multicenter Italian Lung Cancer in the Elderly Study (MILES), demonstrated that single-agent vinorelbine or gemcitabine is preferable to the combination of both in this population [27]. ASCO currently recommends single-agent therapy for elderly patients [3]. Retrospective analyses of large cooperative group trials, however, indicate that elderly patients (>70 years old) with good PS do just as well as their younger counterparts. In an analysis of the E1594 trial, the response rate in those over 70 (25%) was similar to that in the younger cohort (22%), as was the MST (8.3 months in those 70 vs. 8.2 months in those <70), and grade 4 toxicity was no higher (71% for those 70 and 66% for those <70) [28]. A more recent study asking the question of one vs. two drugs was presented by The Minnie Pearl Cancer Research Network, which compared single-agent weekly docetaxel with a DG combination in elderly and/or poor PS patients with chemotherapy-naïve advanced NSCLC [29]. Docetaxel (36 mg/m 2 ) was given on days 1, 8, and 15 every 4 weeks for six cycles, and the combination consisted of docetaxel at a dose of 30 mg/m 2 and gemcitabine at a dose of 800 mg/m 2 on the same schedule. Survival was the primary end point of the trial. The interim safety analysis revealed that the DG combination was more toxic than single-agent docetaxel, but to date, the incidence rates of grade 3 4 myelotoxicity, fatigue, and diarrhea have not reached 20% in either group, allowing for the continuation of the trial. The West Japan Thoracic Oncology Group recently reported the results of a phase III randomized trial comparing docetaxel with vinorelbine for the first-line treatment of elderly patients with PS scores of 0 2 (n = 179) [30]. Either docetaxel (60 mg/m 2 ) was given every 3 weeks or vinorelbine (25 mg/m 2 ) was given on days 1 and 8 of a 3-week cycle. Each group received a maximum of four cycles. The overall response rate was significantly higher in the docetaxel group (23% vs. 10%; p =.019). The MST and 1-year survival rates were numerically (but not significantly) higher with docetaxel (14.3 vs. 9.9 months and 59% vs. 37%, respectively). Rates of FN were similar in both groups (12.5% with docetaxel, 11.0% with vinorelbine), but the rates of grade 3 4 neutropenia were significantly higher with docetaxel (83% vs. 69.3%; p =.031). Nonetheless, QoL results (measured using a visual face scale) favored docetaxel. Overall, symptoms were significantly better with docetaxel than with vinorelbine. The STELLAR3 (Selected Target Efficacy in Lung Cancer Lower Adverse Reactions) trial is the first phase III

8 8 First-Line Treatment for Advanced NSCLC trial to evaluate first-line doublet therapy in patients with PS scores of 2 [28]. A combination of carboplatin with a novel paclitaxel conjugate was compared with standard PCb. Paclitaxel poliglumex (PPX) is a macromolecular polymer-drug conjugate hypothesized to improve the efficacy of paclitaxel while reducing toxicity. A total of 400 patients was treated in the STELLAR3 trial with either PPX (210 mg/m 2 ) or standard paclitaxel (225 mg/m 2 ) in combination with carboplatin (AUC 6) given every 3 weeks. There were no differences in the MST (7.8 vs. 7.9 months, respectively), 1-year survival rate (31% in each group), or TTP (3.9 vs. 4.6 months) between the PPX/Cb and PCb arms. The rates of many expected adverse events were lower in the PPX/Cb group, including significantly lower rates of alopecia, cardiac events, and musculoskeletal events. Grade 3 4 thrombocytopenia was more common in the PPX/Cb arm (16% vs. 4%; p <.001), although the rates of platelet transfusion were similar (5% vs. 3%). The incidences of grade 3 4 neutropenia (7% and 8%, respectively) and FN (6% and 3%, respectively) were similar in the PPX/Cb and PCb arms. There were no differences in the incidence of grade 3 4 nausea, vomiting, or neuropathy. Overall, the trial demonstrates that combination chemotherapy can be safely administered to patients with poor PS, and that these patients can achieve meaningful survival outcomes with such treatment. Future Directions Although numerous phase III trials have been conducted to evaluate new drugs and new combinations for the initial treatment of advanced NSCLC, many researchers note that the efficacy of chemotherapy appears to have plateaued in this setting. New approaches to treatment include using pharmacogenomics to identify patients likely to respond to specific therapies and combining standard chemotherapy with targeted therapies. Translational research has yielded a potential marker predictive of response to cisplatin-based therapy. The excision repair cross-complementing 1 (ERCC1) protein is a critical component of the nucleotide excision repair (NER) system responsible for repairing cisplatin-induced damage. Overexpression of ERCC1 is associated with platinum resistance in vitro and with poor response and shorter survival time in cisplatin-treated patients [31, 32]. The hypothesis behind a recent phase III trial was that patients whose tumors expressed high levels of ERCC1 would respond better to a nonplatinum-based chemotherapy regimen than to a standard taxane platinum combination [33]. A total of 264 patients was randomized to a control arm or to an arm in which treatment was administered according to genotype. Patients in the control arm received docetaxel (75 mg/m 2 ) with cisplatin (75 mg/m 2 ) every 3 weeks for six cycles. In the genotype arm, patients with low tumor ERCC1 expression also received this DC regimen. Patients with high tumor ERCC1 expression received DG, consisting of docetaxel (40 mg/m 2 ) on days 1 and 8 and gemcitabine (1,000 mg/m 2 ) on days 1 and 8 every 3 weeks for six cycles. Patients in the low-ercc1 genotype arm had a significantly higher response rate than did patients in the other two groups (ORR: control arm, 40.4%; low ERCC1 arm, 56.6%; high ERCC1 arm, 37.7%; p =.02). Within the control group, the response rate was significantly higher for patients who were subsequently determined to have low tumor ERCC1 expression than for those with high ERCC1 expression (47.3% vs. 26%, respectively; p =.02). These data provide further evidence that low tumor ERCC1 expression is associated with a better response to platinum-based therapy. It is unclear why more patients with high tumor ERCC1 expression did not respond to DG therapy. There were significant imbalances in baseline demographics; patients in the high-expression arm were significantly older and significantly fewer had adenocarcinoma than in the other arms. Additional research is needed to determine whether there are nonplatinum regimens that can produce an acceptably high response rate for these patients. The final analysis looking at survival data from this trial is expected in The addition of targeted agents to chemotherapy has been very disappointing until this year. Several trials have attempted to improve upon the standard chemotherapy doublet by adding targeted therapy such as epidermal growth factor receptor (EGFR) inhibitors, antisense molecules, immune modulators and others to first-line regimens. Until 2005, all these trials had been negative. The ECOG E4599 trial was the first positive trial to show a survival advantage with the addition of a targeted agent to standard chemotherapy in lung cancer [6]. That trial combined the monoclonal antibody bevacizumab (Avastin ; Genentech, Inc.), which targets vascular endothelial growth factor (VEGF), with PCb chemotherapy and demonstrated significantly longer survival for patients with advanced, nonsquamous NSCLC. Tumor growth is known to be dependent on angiogenesis, which in turn is dependent on the VEGF pathway. VEGF overexpression is frequent in lung cancer patients and associated with a poor prognosis. ECOG trial E4599 compared PCb with PCb plus bevacizumab in 855 patients with advanced or recurrent NSCLC. Patients with hemoptysis at baseline, with brain metastases, on anticoagulation, or with squamous cell histology were excluded from the trial because these characteristics were associated with a higher risk for bleeding in the phase II trial [34]. PCb consisted of paclitaxel (200 mg/m 2 ) and carboplatin (AUC 6) given every 3 weeks for up to six cycles. The PCb bevacizumab arm included bevacizumab at a dose of 15 mg/kg

9 Wakelee, Belani 9 Table 3. Results of the Eastern Cooperative Oncology Group E4599 trial: paclitaxel plus carboplatin (PCb) versus PCb plus bevacizumab for the first-line treatment of advanced, nonsquamous non-small cell lung cancer PCb PCb plus bevacizumab p value ORR 10% (0 CR) 27.2% (1.4% CR) <.0001 HR, p value PFS (mos) , p <.0001 MST (mos) , p =.007 Abbreviations: CR, complete response; HR, hazard ratio; MST, median survival time; ORR, overall response rate; PFS, progression-free survival; PR, partial response. also given every 3 weeks, which was continued as a single agent beyond the six cycles of chemotherapy. Both response and survival parameters were significantly better with the addition of bevacizumab to PCb chemotherapy (Table 3). There was a slightly but significantly higher rate of serious bleeds in the PCb bevacizumab arm. Grade 3 or greater hemorrhage occurred in 4.5% of patients in the PCb bevacizumab arm but in only 0.7% in the PCb arm (p <.001). Deaths attributed to treatment occurred in 2 of 427 patients in the PCb arm (gastrointestinal bleed and neutropenic fever) and 8 of 420 in the PCb bevacizumab arm (five from hemoptysis, two from gastrointestinal bleed, one from neutropenic fever). Hypertension was more common in the experimental treatment arm (6% vs. 0.7%, respectively; p <.001). Grade 4 neutropenia and thrombocytopenia were also significantly greater with the addition of bevacizumab, occurring in 24% and 1.4% of patients in this arm, compared with 16.4% and 0% of the patients in the PCb arm, respectively (p <.01 for each comparison). There were no differences in the rate of FN, and there was one death related to FN in each arm. ECOG has made the PCb bevacizumab combination its new reference standard for future trials in this patient population; other trials are ongoing to evaluate other active doublets in combination with bevacizumab. Conclusions Chemotherapy is the treatment of choice for most patients with metastatic NSCLC. Numerous two-drug chemotherapy regimens have been evaluated in phase III clinical trials and have generally been found to have equal efficacy. In two studies, TAX326 and a JTLCSG trial, a combination of docetaxel and cisplatin was found to produce a significantly longer survival duration than VC and VdsC, respectively, in patients with stage IIIB/IV NSCLC. Gemcitabine platinum combinations are also efficacious and well tolerated. Encouraging data have been reported with nonplatinum doublet regimens in this setting as well, mostly with taxane gemcitabine doublets. Elderly patients and those with poor PS represent special populations. Specific studies addressing these populations indicate that single chemotherapy drugs may be similarly efficacious, with less toxicity, particularly in those with poor PS. More studies to investigate these groups are needed. Finally, the addition of the antivegf monoclonal antibody bevacizumab to PCb chemotherapy is a significant step forward. The results of that trial represent the first time that a targeted therapy has improved survival when added to chemotherapy for advanced NSCLC. Many new agents are in development and it is hoped that we will continue to see steady progress in survival for patients with NSCLC. Disclosure of Potential Conflicts of Interest Dr. Belani has acted as a consultant for sanofi-aventis, Genentech, and Eli Lilly. References 1 Jemal A, Murray T, Ward E et al. Cancer statistics, CA Cancer J Clin 2005;55: Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in nonsmall cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 1995;311: Pfister DG, Johnson DH, Azzoli CG et al. American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: updated J Clin Oncol 2004;22: Barlesi F, Pujol JL, Daures JP. Should chemotherapy (Cx) for advanced non-small cell lung cancer (NSCLC) be platinum-based? A literaturebased meta-analysis of randomized trials. J Clin Oncol 2005:673s. 5 D Addario G, Pintilie M, Leighl NB et al. Platinum-based versus non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a metaanalysis of the published literature. J Clin Oncol 2005;23: Sandler AB, Gray R, Brahmer J et al. Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC#

10 10 First-Line Treatment for Advanced NSCLC ) in patients with advanced non-squamous, non-small-cell lung cancer (NSCLC): an Eastern Cooperative Oncology Group (ECOG) Trial E4599. J Clin Oncol 2005;23:2s. (Updated based on presentation.) 7 American Cancer Society. Cancer Facts and Figures Available at Accessed September 7, Gridelli C, Ardizzoni A, Le Chevalier T et al. Treatment of advanced nonsmall-cell lung cancer patients with ECOG performance status 2: results of an European Experts Panel. Ann Oncol 2004;15: Potosky AL, Saxman S, Wallace RB et al. Population variations in the initial treatment of non-small-cell lung cancer. J Clin Oncol 2004;22: Schiller JH, Harrington D, Belani CP et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346: Kelly K, Crowley J, Bunn PA Jr et al. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol 2001;19: Scagliotti GV, De Marinis F, Rinaldi M et al. Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer. J Clin Oncol 2002;20: Fossella F, Pereira JR, von Pawel J et al. Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol 2003;21: Kubota K, Watanabe K, Kunitoh H et al. Phase III randomized trial of docetaxel plus cisplatin versus vindesine plus cisplatin in patients with stage IV non-small-cell lung cancer: the Japanese Taxotere Lung Cancer Study Group. J Clin Oncol 2004;22: Cardenal F, López-Cabrerizo MP, Antón A et al. Randomized phase III study of gemcitabine-cisplatin versus etoposide-cisplatin in the treatment of locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 1999;17: Kubota K, Nishiwaki Y, Ohashi Y et al. The Four-Arm Cooperative Study (FACS) for advanced non-small-cell lung cancer (NSCLC). J Clin Oncol 2004;22(post-meeting ed):14s. 17 Georgoulias V, Ardavanis A, Tsiafaki X et al. Vinorelbine plus cisplatin versus docetaxel plus gemcitabine in advanced non-small-cell lung cancer: a phase III randomized trial. J Clin Oncol 2005;23: Pujol JL, Breton JL, Gervais R et al. Gemcitabine-docetaxel versus cisplatin-vinorelbine in advanced or metastatic non-small-cell lung cancer: a phase III study addressing the case for cisplatin. Ann Oncol 2005;16: Kosmidis PA, Kalofonos C, Syrigos K et al. Paclitaxel and gemcitabine vs. carboplatin and gemcitabine: a multicenter phase III randomized trial in patients with advanced inoperable non-small cell lung cancer (NSCLC). J Clin Oncol 2005;23:621s. (Updated based on presentation.) 20 Treat J, Belani CP, Edelman MJ et al. A randomized phase III trial of gemcitabine (G) in combination with carboplatin (C) or paclitaxel (P) versus paclitaxel plus carboplatin in advanced (stage IIIB, IV) non-small cell lung cancer (NSCLC): update of Alpha Oncology trial (A L). J Clin Oncol 2005;23:627s. (Updated based on presentation.) 21 Gridelli C, Gallo C, Shepherd FA et al. Gemcitabine plus vinorelbine compared with cisplatin plus vinorelbine or cisplatin plus gemcitabine for advanced non-small-cell lung cancer: a phase III trial of the Italian GEM- VIN investigators and the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2003;21: Sweeney CJ, Zhu J, Sandler AB et al. Outcome of patients with a performance status of 2 in Eastern Cooperative Oncology Group Study E1594: a phase II trial in patients with metastatic nonsmall cell lung carcinoma. Cancer 2001;92: Gridelli C, Shepherd FA. Chemotherapy for elderly patients with nonsmall cell lung cancer: a review of the evidence. Chest 2005;128: Hutchins LF, Unger JM, Crowley JJ et al. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 1999;341: Sequist LV, Lynch TJ. Aggressive treatment for the fit elderly with nonsmall-cell lung cancer? Yes! J Clin Oncol 2003;21: Gridelli C, Aapro M, Ardizzoni A et al. Treatment of advanced non-smallcell lung cancer in the elderly: results of an international expert panel. J Clin Oncol 2005;23: Gridelli C, Perrone F, Gallo C et al. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst 2003;95: Langer CJ, Socinski MA, Ross H et al. Paclitaxel poliglumex (PPX)/carboplatin vs. paclitaxel/carboplatin for the treatment of PS2 patients with chemotherapy-naïve advanced non-small cell lung cancer (NSCLC): a phase II study. J Clin Oncol 2005;23:623s. (Updated based on presentation.) 29 Mainwaring MG, Hainsworth JD, Spigel DR et al. Weekly docetaxel versus weekly docetaxel/gemcitabine as first-line therapy for patients who are elderly or with poor performance status (PS) or with serious comorbidities with advanced non-small cell lung cancer (NSCLC): interim safety analysis of a Minnie Pearl Cancer Research Network phase III trial. J Clin Oncol 2005;23:658s. 30 Takeda K, Kudoh S, Nakagawa K et al. Randomized phase III study of docetaxel (D) versus vinorelbine (V) for elderly patients (pts) with advanced non-small cell lung cancer (NSCLC): results of a West Japan Thoracic Oncology Group trial (WJTOG9904). J Clin Oncol 2005;23:623s. (Updated based on presentation.) 31 Altaha R, Liang X, Yu JJ et al. Excision repair cross complementing-group 1: gene expression and platinum resistance. Int J Mol Med 2004;14: Rosell R, Taron M, Ariza A et al. Molecular predictors of response to chemotherapy in lung cancer. Semin Oncol 2004;31(suppl 1): Rosell R, Cobo M, Isla D et al. ERCC! mrna-based randomized phase III trial of docetaxel (doc) doublets with cisplatin (cis) or gemcitabine (gem) in stage IV non-small-cell lung cancer (NSCLC) patients (pts). J Clin Oncol 2005;23:621s. (Updated based on presentation.) 34 Johnson DH, Fehrenbacher L, Novotny WF et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 2004;22: