Topics:

First-Line Treatment for Advanced Non–Small-Cell Lung Cancer

First-Line Treatment for Advanced Non–Small-Cell Lung Cancer

ABSTRACT: With best supportive care alone, patients with metastatic non–smallcell lung cancer (NSCLC) have a median survival of 4 to 5 months and a 1-year survival rate of approximately 10%. Trials carried out in the 1980s and 1990s comparing chemotherapy to best supportive care reported variable efficacy results; however, a pivotal meta-analysis of these data indicated that cisplatin-based chemotherapy provided a survival benefit in advanced NSCLC. In the past decade newer agents such as gemcitabine (Gemzar), vinorelbine, paclitaxel, and docetaxel (Taxotere) have all demonstrated activity in NSCLC as single agents; consequently these agents have been combined with cisplatin or carboplatin. Randomized phase III trials comparing these “newer” platin-based doublets have failed to identify an optimal platinum-based doublet therapy regimen. Though it is clear that chemotherapy is an appropriate treatment for many patients with lung cancer, there a sense in which the use of traditional chemotherapeutic agents has reached a therapeutic plateau. Increased understanding of cancer biology has revealed numerous potential therapeutic strategies, including targeting the epidermal growth factor receptor, protein kinase C, rexinoid receptors, and the angiogenesis pathway. The Eastern Cooperative Oncology Group study E4599 comparing paclitaxel/carboplatin with/without bevacizumab is the first phase III randomized trial to show a survival advantage with the addition of a molecularly targeted agent to chemotherapy in the chemotherapy-naive patient population. Future studies will involve the evaluation of additional targeted agents plus chemotherapy as well as looking at combinations of these targeted agents alone or with chemotherapy.

With best supportive care alone, patients with metastatic non-small-cell lung cancer (NSCLC) have a median survival of 4 to 5 months and 1-year survival rates of approximately 10%.[1] Metastatic NSCLC: Chemotherapy Trials carried out in the 1980s and 1990s comparing chemotherapy to best supportive care reported variable efficacy results; however, a pivotal meta-analysis of these data indicated that cisplatin-based chemotherapy provided a survival benefit in advanced NSCLC.[2] The meta-analysis included eight trials involving 778 patients who received cisplatin-based chemotherapy vs best supportive care. The hazard ratio for death was 0.73 in favor of chemotherapy (P < .0001). This equated to a 1.5-month increase in median survival and a 10% increase in survival at 1 year. Chemotherapy for patients with advanced disease has also demonstrated that it can improve a patient's quality of life and be costeffective.[ 3,4] In the past decade newer agents such as gemcitabine (Gemzar), vinorelbine, paclitaxel, and docetaxel(Taxotere) have all demonstrated activity in NSCLC as single agents; consequently, these agents have been combined with cisplatin or carboplatin. Randomized phase III trials have endeavored to identify an optimal platinum- based doublet therapy regimen. Phase III Trials
The largest of these trials are summarized in Table 1. For example, Southwest Oncology Group (SWOG) investigators compared the reference regimen of vinorelbine/cisplatin to paclitaxel/carboplatin in SWOG9509.[5] With over 200 patients per arm, this trial showed no difference in quality of life, objective response rates, median survival, or 1-year survival between the arms. However, grade 3/4 hematologic toxicities were significantly higher on the vinorelbine/ cisplatin arm and more of these patients discontinued therapy because of toxicity (P =.001). The Eastern Cooperative Oncology Group (ECOG) undertook a similar trial (E1594) in which 1,207 chemotherapy-naive patients with advanced NSCLC were randomized to receive cisplatin/paclitaxel as the reference standard (based on earlier work from E5592) or one of three experimental arms: cisplatin/gemcitabine, cisplatin/docetaxel, or carboplatin/paclitaxel.[ 6,7] The gemcitabine/cisplatin arm was associated with a statisticallysignificant longer time to progression but a higher rate of grade 3/4 thrombocytopenia, although this was not clinically significant. Overall response rates and survival did not differ significantly between the reference regimen of cisplatin/paclitaxel and the three investigational arms. Based on toxicity differences, both the SWOG and ECOG chose carboplatin/paclitaxel as their reference regimen for future studies. The European Organisation for Research and Treatment of Cancer (EORTC) compared cisplatin/paclitaxel to gemcitabine/cisplatin or gemcitabine/paclitaxel. Although not statistically significant, the non- platinum-containing regimen gemcitabine/ paclitaxel appeared to be somewhat less efficacious. Overall, there were no significant differences in responserates, time to progression, or survival between the three regimens.[ 8] Similarly, the Italian Lung Cancer Project compared two new agent- platinum regimens (cisplatin/gemcitabine and carboplatin/paclitaxel) with a reference regimen of cisplatin/vinorelbine in 612 chemotherapy-naive patients.[9] Patients on the cisplatin/ vinorelbine arm had the highest percentages of dose reductions and omissions, mainly because of hematologic toxicities, while peripheral neuropathy and alopecia were significantly more common with carboplatin/paclitaxel. The results again revealed no significant difference in response rates, time to progression, or overall survival. The largest trial to date is TAX- 326.[10] In this multicenter randomized phase III study involving 1,220 patients, cisplatin/docetaxel and carboplatin/ docetaxel were compared with cisplatin/vinorelbine in chemotherapy- naive patients with advanced and metastatic NSCLC. The incidence of grade 3/4 neutropenia was substantial (74% to 79%), but the incidence of febrile neutropenia was low (4%) across all arms of the study. The cisplatin/docetaxel arm had a significantly higher response rate (32% vs 25%) and median survival (11.3 vs 10.1 months, P = .044) compared with cisplatin/vinorelbine. The 1- and 2-year survival rates were significantly different at 47% and 21% for docetaxel/cisplatin compared to 41% and 14% for cisplatin/vinorelbine. The carboplatin/docetaxel arm performed similarly to the control arm of cisplatin/vinorelbine, suggesting that cisplatin may provide a slight response and survival advantage over carboplatin in this disease; however, this trial was not designed to compare the two docetaxel arms. On the basis of these data, the combination of cisplatin/ docetaxel has recently been added to the list of platinum-based doublets approved by the US Food and Drug Administration for first-line treatment of advanced NSCLC. Although there are minor differences in response rates and survival times between these five trials, it should be noted that the ratio of stageIII to stage IV disease differed in many of them. For example, in the TAX- 326 study only about two-thirds (67%) of the patients in TAX-326 had stage IV disease, compared with 80% to 90% in the other large trials. As patients with stage IIIB disease tend to live longer, this difference potentially introduces some bias and makes it difficult to compare across trials. In summary, numerous studies have been conducted comparing the platinumbased doublets amongst themselves and no clinically significant differences have been identified. Other Aspects of the Chemotherapy Approach
Other approaches to improving chemotherapy in metastatic NSCLC have included the manipulation of chemotherapy duration and the addition of a third chemotherapy agent. In general, regimens containing three chemotherapy agents have failed to demonstrate any superiority over two-drug regimens in advanced NSCLC.[11,12] Typically three-drug combinations cause increased toxicity and financial cost without an improvement in survival. Triplet therapy cannot be recommended outside the confines of a clinical trial.[13] The duration of first-line chemotherapy in patients with advanced disease has been somewhat controversial and recommendations have ranged from 3 to 12 months of chemotherapy. Prospective trials investigating this issue include a phase III trial in which 230 patients with stage IIIB/IV NSCLC were randomized to receive carboplatin and paclitaxel every 21 days for four cycles or continuous treatment until progression.[14] At progression, patients on both arms were to receive weekly paclitaxel. The majority of patients (57%) were able to receive the four planned cycles ofchemotherapy, and on the continuous treatment arm the median number of cycles delivered was also 4 (42% received ≥ 5 cycles and 18% received ≥ 8 cycles). Objective response rates did not differ between arms (22% vs 24%, P = .80). Importantly, all responses in both arms occurred within the first four cycles of treatment. This trial and others like it, failed to show a benefit for continuing therapy in advanced NSCLC beyond four cycles.[ 14,15] In addition to response and survival rates, the palliative benefits of chemotherapy appear to plateau after the first few cycles.[16,17] For example, Ellis and colleagues administered mitomycin/ vinblastine/cisplatin to 110 symptomatic patients with advanced or metastatic NSCLC.[17] A total of 69% of patients had complete or significant resolution of symptoms, with 61% of those achieving symptomatic improvement after one course of therapy and 96% experiencing this benefit after two courses. In conclusion, in the past decade it has become clear that doublet platinum- based regimens are the standard of care for most patients with metastatic NSCLC. Doublet regimens are superior to single agents with respect to efficacy as well as economic and quality-of-life data.[18-20] Randomized phase II studies have demonstrated that all of the new agent-platinum doublet combinations appear roughly equivalent with regard to objective responses rate and survival. Subtle differences between them allow a clinician some flexibility to choose among toxicity profiles, convenience, and cost. Metastatic NSCLC: Molecularly Targeted Therapy With the use of chemotherapy, median survivals of 8 to 10 months and 1-year survival rates of 30% to 40% are routinely reported for large cooperative group studies (Table 1). Though it is clear that chemotherapy is an appropriate treatment for many patients with lung cancer, there is a sense that the use of traditional chemotherapeutic agents has reached a therapeutic plateau. Increased understandingof cancer biology has revealed numerous potential therapeutic strategies. EGFR Inhibitors
One such approach is to interfere with the epidermal growth factor receptor (EGFR) on the cell surface in order to disrupt intracellular signaling. EGFR is overexpressed in a variety of solid tumors and is particularly common in NSCLC, with 40% to 80% of tumors expressing EGFR.[21-24] When stimulated, the transmembrane receptors trigger a cascade of intracellular signaling that affects cellular proliferation and apoptosis. Strategies to target the EGFR receptor include the use of tyrosine kinase inhibitors, monoclonal antibodies, antisense oligonucleotides, and ligand-toxins or immunoconjugates. There are many compounds at various stages of clinical testing; however, gefitinib (Iressa) and erlotinib (Tarceva) are furthest along in clinical trials. These agents will be discussed in greater detail in this issue in the paperby Dr. Buter and Dr. Giaccone, but suffice it to say that both of these agents have shown activity in certain subsets of patients with previously treated NSCLC, with erlotinib currently the only EGFR-TKI that has been shown to prolong survival when compared to placebo in patients with one or two prior chemotherapies.[25] Largely because of the tolerability of these drugs in phase I combination trials and the promise demonstrated in the single-agent phase II studies, randomized phase III trials of chemotherapy with or without EGFR tyrosine kinase inhibitors (TKIs) were initiated. The INTACT (Iressa in NSCLC Trial Assessing CombinationTherapy) 1 and 2 trials were large randomized phase III studies in chemotherapy- naive patients with advanced stage III or IV NSCLC.[26,27] The trials were similar in design and both randomized patients to receive chemotherapy with gefitinib or placebo (INTACT 1 used cisplatin/gemcitabine and INTACT 2 used carboplatin/ paclitaxel). Together, INTACT 1 and 2 enrolled over 2,000 patients, twothirds of whom received gefitinib in addition to standard chemotherapy. Unfortunately, the results of these trials did not confirm that the addition of gefitinib resulted in an improvement in overall survival. The results of a parallel set of trials conducted using the small molecule EGFR tyrosine kinase inhibitor erlotinib instead of gefitinib demonstrated similar results. The TRIBUTE (carboplatin/paclitaxel with or without erlotinib) and TALENT (cisplatin/ gemcitabine with or without erlotinib) studies together enrolledover 2,200 patients and again failed to demonstrate any difference in survival associated with the addition of erlotinib to chemotherapy.[28,29] The reason for this apparent lack of benefit remains undefined. Some experts have proposed that despite sound preclinical data, the concurrent use of chemotherapy and the EGFR TKIs might have been antagonistic, and have suggested that a sequential use of these drugs might be more successful. Others feel that it is related to our inability to discriminate between subgroups of patients who are biologically more likely to respond to TKIs, and that the true benefit was diluted in an unselected population.[30] Prediction of Response
There is an accumulation of evidence suggesting that there may be a subgroup of patients with NSCLC who do respond preferentially to the EGFR TKIs. It was noted from the phase I trials and anecdotal evidence that women, nonsmokers, and patients with adenocarcinoma and bronchioloalveolar carcinoma (BAC) seem to respond better to the TKIs. Important evidence to support this observation has come from single-institution retrospective analyses of patients treated with single-agent TKIs. For example, a multivariate analysis identified the presence of any BAC features and being a never-smoker was significantly correlated with response to gefitinib in a retrospective review of 139 patients treated at Memorial-Sloan- Kettering Cancer Center.[31] Because of these observations, two prospective phase II trials were undertaken specifically in patients with BAC or adenocarcinoma with BAC features. In a SWOG study 138 such patients received single-agent gefitinib (102 chemo-naive, 36 previously treated).[32] Using standard criteria to assess tumor response the chemonaive group had a response rate of 21% whereas the previously treated group had a response rate of 10%. The rates of stable disease were 30% and 36%, and the median survival was 12 and 10 months for the previously untreated and treated groups, respectively. In subgroup analyses female gender, never-smokers, and thedevelopment of a rash from the gefitinib all predicted for improved survival. A similar study of erlotinib in 69 patients with BAC treated with erlotinib also found that smoking status and the presence of a rash predicted for response.[33] Such trials have raised the question of whether patients who fit these specific criteria should be considered for first-line therapy with an EGFR TKI, but this issue is highly controversial. Another focus of intensive research is the use of molecular biology to predict responders to targeted therapy such as the EGFR TKIs. Exciting reports from two institutions have identified mutations in the tyrosine binding domain of the EGFR that appear to correlate with patients who have dramatic responses to gefitinib.[34,35] These studies had a limited number of patients but the results are intriguing and demand serious attention. A massive worldwide effort is under way to replicate and expand on these results and to better define EGFR gene mutations. Other Promising Agents
Despite some controversial results molecularly targeted therapy is an important paradigm shift and represents the future of lung cancer treatment. There are many other agents that have demonstrated great potential activity in phase II studies that are currently being tested in the phase III setting. The rexinoid bexarotene (Targretin) selectively activates RXR receptors which modulate functions associated with differentiation, inhibition of cell growth, apoptosis, and metastasis. Two randomized phase III trials were performed to determine the survival benefit of adding bexarotene to either carboplatin/paclitaxel or cisplatin/ vinorelbine chemotherapy in patients with chemotherapy-naive advanced or metastatic NSCLC. In each of these trials over 600 patients were randomized to chemotherapy consisting of either carboplatin at an AUC of 6 and paclitaxel 200 mg/m2 IV every 3 weeks or cisplatin (100 mg/m2 every 4 weeks) and vinorelbine (25 mg/m2 every week) IV with or without bexarotene (400 mg/m2/d). There wereno differences with respect to the primary end point, overall survival in either study (P = .19). An initial trend analysis suggests a relationship between bexarotene dose intensity and biomarker response (triglyceride elevation) with survival is being further evaluated in parallel with other risk factor analyses to better identify determinants of benefit and risk to bexarotene in a firstline setting.[36,37] Bevacizumab (Avastin) is a recombinant humanized monoclonal antibody to the vascular endothelial growth factor (VEGF) and has shown great promise in phase II NSCLC trials and in phase III studies in colorectal cancer.[38,39] One concern in the phase II NSCLC trial was a high incidence of life-threatening pulmonary hemorrhage in patients with squamous cell histology. The ECOG reported on the results of their large randomized phase III study of carboplatin/paclitaxel with or without bevacizumab in patients with advanced nonsquamous NSCLC.[40] The primary end point of this randomized, multicenter trial was to compare the effects of the addition of bevacizumab to paclitaxel/carboplatin (PC) on overall survival in patients with previously untreated nonsquamous NSCLC. Secondary end points included response rate, time to progression, and tolerability. Eligibility criteria included ECOG performance status 0 or 1 and adequate hematologic, renal, and hepatic function. Patients with brain metastases and squamous cell histology were excluded. Patients were randomized to receive paclitaxel at 200 mg/m2 plus carboplatin at an area under the concentration- time curve of 6 on day 1 every 3 weeks or PC plus bevacizumab at 15 mg/kg day 1 (PCB) every 3 weeks (Figure 1). Patients on PCB continued single-agent bevacizumab after six cycles until progressive disease or intolerable toxicity. The study opened in July 2001, was suspended for a planned toxicity evaluation from February 2002 through August 2002, and accrual was completed in April 2004 with 444 patients assigned to PC and 434 to PCB. The results presented were based on a second planned interim analysisthat was conducted with 469 of a planned 650 deaths (72.2%) for full analysis. The response rate (10% vs 27%, P < .0001, Fisher's exact test), progression-free survival (4.5 vs 6.4 months, P < .0001 [two-sided]), and median survival (10.2 vs 12.5 months, P = .0075, two-sided Wald test) all favored the PCB arm. Both regimens were well tolerated with selected toxicities as follows (PC vs PCB): grade 4/5 neutropenia (16.4% vs 24%) and thrombocytopenia (0% vs 1.6%), grade 3/4 thrombosis/embolism (3% vs 3.8%), grade 3-5 neuropathy (11.9% vs 9.5%) and hemorrhage (1.0% vs 4.1%). There were 10 treatment- related deaths (PC arm: 2; PCB arm: 8); 5 were due to hemoptysis, all on the PCB arm .[40] Summary Advances in chemotherapy have improved progression-free and median survival for patients with advanced NSCLC from 4 to 6 months with best supportive care to 8 to 10 months. Biologically targeted therapies have demonstrated activity and excellent tolerability in early trials, and the optimal way to integrate these exciting new agents is an area of active investigation.

Disclosures

Dr. Sandler has consulted for and served on speakers bureaus for Genentech, OSI, AstraZeneca, and Sanofi- Aventis. He has consulted for Ligand.

References

1. Johnson DH: Chemotherapy for metastatic non-small-cell lung cancer—Can that dog hunt? [comment]. J Natl Cancer Inst 85(10):766-767, 1993.
2. Anonymous: Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-Small Cell Lung Cancer Collaborative Group. Br Med J 311(7010):899- 909, 1995.
3. Evans WK, Will BP, Berthelot JM, et al: The economics of lung cancer management in Canada [comment]. Lung Cancer 14(1):19-29, 1996.
4. Cullen MH, Billingham LJ, Woodroffe CM, et al: Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: Effects on survival and quality of life [comment]. J Clin Oncol 17(10):3188-3194, 1999.
5. Kelly K, Crowley J, Bunn PA, Jr, et al: Randomized phase III trial of paclitaxel pluscarboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non– small-cell lung cancer: A Southwest Oncology Group trial. J Clin Oncol 19(13):3210-3218, 2001.
6. Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346(2):92-98, 2002.
7. Bonomi P, Kim K, Fairclough D, et al: Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: Results of an Eastern Cooperative Oncology Group trial. J Clin Oncol 18(3):623- 631, 2000.
8. Van Meerbeeck JP, Smit EF, Lianes P, et al: An EORTC randomized phase III trial of three chemotherapy regimens in advanced nonsmall cell lung cancer (NSCLC) (abstract 1228). Proc Am Soc Clin Oncol 20:308a, 2001.
9. 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 20(21):4285-4291, 2002.
10. 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 nonsmall- cell lung cancer: The TAX 326 Study Group. J Clin Oncol 21(16):3016-3024, 2003.
11. Alberola V, Camps C, Provencio M, et al: Cisplatin plus gemcitabine versus a cisplatin-based triplet versus nonplatinum sequential doublets in advanced non-small-cell lung cancer: A Spanish Lung Cancer Group phase III randomized trial. J Clin Oncol 21(17):3207-3213, 2003.
12. Rudd RM, Gower NH, James LE, et al: Phase III randomized comparison of gemcitabine and carboplatin (GC) with mitomycin, ifosfamide and cisplatin (MIP) in advanced non-small cell lung cancer (NSCLC) (abstract 1164). Proc Am Soc Clin Oncol 21:292s, 2002.
13. Sandler A: State-of-the-art treatment for advanced non-small-cell lung cancer. Oncology 17(12 suppl 13):15-22, 2003.
14. Socinski MA, Schell MJ, Peterman A, et al: Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advancedstage IIIB/IV non-small-cell lung cancer. J Clin Oncol 20(5):1335-1343, 2002.
15. Smith IE, O’Brien ME, Talbot DC, et al: Duration of chemotherapy in advanced nonsmall- cell lung cancer: A randomized trial of three versus six courses of mitomycin, vinblastine, and cisplatin. J Clin Oncol 19(5):1336- 1343, 2001.
16. Larsen H, Sorensen JB, Nielsen AL, et al: Evaluation of the optimal duration of chemotherapy in phase II trials for inoperable nonsmall- cell lung cancer (NSCLC). Ann Oncol 6(10):993-997, 1995.
17. Ellis PA, Smith IE, Hardy JR, et al: Symptom relief with MVP (mitomycin C, vinblastine and cisplatin) chemotherapy in advanced non-small-cell lung cancer. Br J Cancer 71(2):366-370, 1995.
18. Sandler AB, Nemunaitis J, Denham C, et al: Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer [comment]. J Clin Oncol 18(1):122-130, 2000.
19. Lilenbaum RC, Herndon J, List M, et al: Single-agent (SA) versus combination chemotherapy (CC) in advanced non-small cell lung cancer (NSCLC): A CALGB randomized trial of efficacy, quality of life (QOL), and costeffectiveness (abstract 2). Proc Am Soc Clin Oncol 21:1a, 2002.
20. Sederholm C: Gemcitabine versus gemcitabine/carboplatin in advanced non-small cell lung cancer: Preliminary findings in a phase III trial of the Swedish Lung Cancer Study Group. Semin Oncol 29(3 suppl 9): 50- 54, 2002.
21. Fontanini G, De Laurentiis M, Vignati S, et al: Evaluation of epidermal growth factor- related growth factors and receptors and of neoangiogenesis in completely resected stage I-IIIA non-small-cell lung cancer: Amphiregulin and microvessel count are independent prognostic indicators of survival. Clin Cancer Res 4(1):241-249, 1998.
22. Rusch V, Klimstra D, Venkatraman E, et al: Overexpression of the epidermal growth factor receptor and its ligand transforming growth factor alpha is frequent in resectable non-small cell lung cancer but does not predict tumor progression. Clin Cancer Res 3(4):515-522, 1997.
23. Salomon DS, Brandt R, Ciardiello F, et al: Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 19(3):183-232, 1995.
24. Ritter CA, Arteaga CL: The epidermal growth factor receptor-tyrosine kinase: A promising therapeutic target in solid tumors. Semin Oncol 30(1 suppl 1):3-11, 2003.
25. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al: Erlotinib in previously treated non-small cell lung cancer. N Engl J Med 353:123-132, 2005.
26. Herbst RS, Giaccone G, Schiller JH, et al: Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: A phase III trial—INTACT 2. J Clin Oncol 22(5):785-794, 2004.
27. Giaccone G, Herbst RS, Manegold C, et al: Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: A phase III trial—INTACT 1. J Clin Oncol 22(5):777-784, 2004.
28. Herbst RS, Prager D, Hermann R, et al: TRIBUTE—A phase III trial of erlotinib HCL (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small cell lung cancer (abstract 7011). Proc Am Soc Clin Oncol 23:617, 2004.
29. Gatzemeier U, Pluzanska A, Szczesna A, et al: Results of a phase III trial of erlotinib (OSI-774) combined with cisplatin and gemcitabine chemotherapy in advanced nonsmall cell lung cancer (abstract 7010). Proc Am Soc Clin Oncol 23:617, 2004.
30. Johnson DH, Arteaga CL: Gefitinib in Recurrent non-small-cell lung cancer: An IDEAL trial? J Clin Oncol 21(12):2227-2229, 2003.
31. Miller VA, Kris MG, Shah N, et al: Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol 22(6):1103-1109, 2004.
32. West H, Franklin WA, Gumerlock PH, et al: Gefitinib (ZD1839) therapy for advanced bronchioloalveolar lung cancer: Southwest Oncology Group Study S0126 (abstract 7014). Proc Am Soc Clin Oncol 23:618, 2004.
33. Kris MG, Sandler A, Miller V, et al: Cigarette smoking history predicts sensitivity to erlotinib: Results of a phase II trial in patients with bronchioloalveolar carcinoma (abstract 7062) Proc Am Soc Clin Oncol 23:628, 2004.
34. Paez JG, Janne PA, Lee JC, et al: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304(5676):1497-1500, 2004.
35. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350(21):2129-2139, 2004.
36. Blumenschein GR, Khuri F, Gatzemeier U, et al: A randomized phase III trial comparing bexarotene/carboplatin/paclitaxel versus carboplatin/paclitaxel in chemotherapy-naive patients with advanced or metastatic non-small cell lung cancer (NSCLC) (abstract 7001). J Clin Oncol 23(suppl 16S):621s, 2005.
37. Jassem J, Zatloukal P, Ramlau R, et al: A randomized phase III trial comparing bexarotene/cisplatin/vinorelbine versus cisplatin/vinorelbine in chemotherapy-naive patients with advanced or metastatic non-small cell lung cancer (abstract 7024). J Clin Oncol 23(suppl 16S):627s, 2005.
38. 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 22:2184-2191, 2004.
39. Hurwitz H, Fehrenbacher L, Cartwright T, et al: Bevacizumab (a monoclonal antibody to vascular endothelial growth factor) prolongs survival in first-line colorectal cancer: Results of a phase III trial of bevacizumab in combination with bolus IFL (irinotecan, 5-fluorouracil, leucovorin) as first-line therapy in subjects with metastatic colorectal cancer (abstract 3646). American Society of Clinical Oncology 39th annual meeting, Chicago, 2003.
40. Sandler AB, Gray R, Brahmer J, et al: Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC #704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): An Eastern Cooperative Oncology Group (ECOG) Trial—E4599 (abstract 4). J Clin Oncol 23(suppl 16S):2s, 2005.
 
Loading comments...
Please Wait 20 seconds or click here to close