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Treatment of Metastatic Renal Cell Carcinoma With a Combination of Bevacizumab and Erlotinib
http://www.100md.com 《临床肿瘤学》
     the Sarah Cannon Research Institute

    Vanderbilt-Ingram Cancer Center, Nashville, TN

    ABSTRACT

    PURPOSE: To evaluate the efficacy and toxicity of combined treatment with two targeted agents, an antibody against vascular endothelial growth factor (bevacizumab) and an epidermal growth factor receptor tyrosine kinase inhibitor (erlotinib), in the treatment of patients with metastatic clear-cell renal carcinoma.

    PATIENTS AND METHODS: Sixty-three patients with metastatic clear-cell renal carcinoma were treated with bevacizumab 10 mg/kg intravenously every 2 weeks and erlotinib 150 mg orally daily. Patients were reevaluated after 8 weeks of treatment; patients who responded continued treatment until they experienced tumor progression.

    RESULTS: Fifteen (25%) of 59 assessable patients (95% CI, 16% to 37%) had objective responses to treatment, and an additional 36 patients (61%) had stable disease after 8 weeks of treatment. Only eight patients' (14%) disease had progressed at this time point. The median and 1-year progression-free survivals were 11 months and 43%, respectively. After a median follow-up of 15 months, median survival has not been reached; survival at 18 months was 60%. Treatment was generally well tolerated; only two patients discontinued treatment because of toxicity (skin rash). Grade 1/2 skin rash and diarrhea were the most frequent treatment-related toxicities.

    CONCLUSION: The combination of bevacizumab and erlotinib is an effective and well-tolerated treatment for patients with advanced renal cell carcinoma. The efficacy of these two drugs in combination suggests that targeting of separate pathways critical to tumor growth and dissemination may achieve results superior to either drug as a single agent. Additional development of this and other combinations of targeted agents is warranted.

    INTRODUCTION

    Renal cell carcinoma accounts for approximately 32,000 cases yearly in the United States and is the tenth most common cancer. Many patients with renal cell carcinoma are cured with surgical resection; however, up to 50% of patients either have metastatic disease at the time of diagnosis or have recurrence after surgical resection. To date, systemic treatment in patients with advanced disease has been largely ineffective. Standard cytotoxic agents have generally produced response rates of less than 10% in this disease.1-5 Although immunotherapy with interleukin-2 or interferon has shown activity in this disease, these treatments can be associated with substantial toxicity and produce major clinical benefit in less than 10% of patients with metastatic renal carcinoma.6-9 Therefore, active and well-tolerated new agents are urgently needed in the treatment of advanced renal carcinoma.

    Recent advances in understanding the biology of renal cancer have suggested possible roles for several of the newer, targeted antineoplastic agents. It is now known that the majority of sporadic clear-cell renal cancers (which account for approximately 80% of all renal cancers) have silencing or hypermethylation of the von Hippel-Lindau (VHL) gene.10-12 When functioning normally, the VHL gene regulates cellular levels of hypoxia-induced factor-1 through regulation of ubiquitination and subsequent protein breakdown by the proteasome.13 However, with loss of VHL function, hypoxia-induced factor-1 levels increase, and a large set of genes sensitive to hypoxia are activated. As a result, expression of vascular endothelial growth factor (VEGF), transforming growth factor alpha (TGF-), platelet-derived growth factor beta (PDGF-?), and numerous other genes is increased.14,15 Because the dysregulated production of these growth factors seems to be integral to the transformation, growth, and dissemination of clear-cell renal cancer, inhibition of their activity may provide effective treatment.

    The recent demonstration of single-agent activity of bevacizumab, a monoclonal antibody targeting VEGF, further strengthens this hypothesis. In a randomized trial, Yang et al16 demonstrated prolonged progression-free survival in patients with refractory, metastatic renal cancer when treated with single-agent bevacizumab versus placebo (4.8 v 2.5 months, respectively; P < .001). At a dose of 10 mg/kg every 2 weeks, bevacizumab produced a 10% partial response rate in these patients and resulted in disease stability or minor responses in an additional group of patients. However, the duration of benefit from bevacizumab was limited in most patients; thus, the overall impact of this single-agent treatment was modest.

    Levels of TGF-, a ligand for the endothelial growth factor (EGF) receptor, are usually elevated in renal cell carcinoma; the EGF receptor therefore provides an additional target for therapeutic agents. In laboratory models, inhibition of the EGF receptor also results in suppression of VEGF expression.17,18 Finally, elevated expression of VEGF has been considered a possible mechanism for acquired resistance to EGF receptor blockage.19 Taken together, these findings make a compelling case for combined blockade of both the VEGF and EGF pathways.

    The phase II trial reported here represents the first attempt to inhibit these two pathways in patients with advanced renal cell carcinoma. In this combination regimen, inhibition of VEGF is achieved with bevacizumab, and EGF receptor inhibition is achieved with erlotinib, an EGF tyrosine kinase receptor inhibitor.20 In this report, we detail the efficacy and toxicity of this novel combination regimen.

    PATIENTS AND METHODS

    This multicenter, phase II trial was initiated in January 2003. Participating centers in the trial included the Sarah Cannon Cancer Center, the Vanderbilt-Ingram Cancer Center, and selected sites from the Minnie Pearl Cancer Research Network (Appendix). Before the patients were enrolled, this trial was approved by the institutional review boards of all participating institutions.

    Eligibility

    To be eligible for this trial, patients were required to have progressive, biopsy-proven metastatic or locally recurrent unresectable clear-cell renal carcinoma. If tumors had mixed histology, the clear-cell component was required to comprise more than 75% of the biopsy specimen. Patients were required to have nephrectomy more than 30 days before initiating protocol treatment except in situations in which extensive, symptomatic metastases precluded nephrectomy as a reasonable medical option. Patients with metastatic disease at the time of nephrectomy were not required to have additional tumor progression before initiating treatment with bevacizumab/erlotinib. Patients were allowed to have received a maximum of one previous systemic regimen with immunotherapy and/or chemotherapy for metastatic disease. No previous treatment with other EGF receptor inhibitors or antiangiogenesis agents (including thalidomide) was allowed. Patients with brain metastases were eligible only if they had less than three metastases, had completed surgical treatment or radiation therapy more than 8 weeks before study entry, and had no neurologic symptoms or dexamethasone requirement at the time of study entry. Additional entry criteria included Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1; measurable metastatic lesions; absolute neutrophil count 1,500/mL and platelets 75,000/mL; serum bilirubin 1.6 mg/dL; serum creatinine 2.0 mg/dL; no proteinuria; age 18 years; and no other active, serious medical problems.

    Because of concerns regarding bleeding or clotting problems related to the use of antiangiogenesis agents, patients with prior bleeding disorders, deep vein thromboses, or other thromboembolic disease were excluded. In addition, patients with clinical history of hemoptysis or hematemesis were excluded. Patients could not receive full-dose oral or parenteral anticoagulation or thrombolytic agents; however, the use of low-dose Coumadin (1 mg daily) as prophylaxis for patients with central venous access devices was permitted. Patients with major surgical procedures or open biopsies within 28 days from the start of the study were excluded. Concurrent use of several other medications was not allowed because of potential interactions with erlotinib. These drugs included phenytoin, carbamazepine, barbiturates, rifampin, systemic retinoids, and St John's wort. All patients were required to give written informed consent before participating in this trial.

    Pretreatment Evaluation

    Before beginning therapy, all patients underwent complete history, physical examination, complete blood count, chemistry profile, prothrombin time, partial thromboplastin time, and urinalysis. Radiologic evaluation included computed tomography scanning of the head, chest, and abdomen. A bone scan or positron emission tomography scan was performed if bone metastases were clinically suspected. Tumor measurements were performed in all patients before beginning therapy.

    Treatment

    All patients were treated with bevacizumab 10 mg/kg, administered by intravenous infusion on days 1 and 15 of each 28-day course. The initial dose of bevacizumab was infused over 90 minutes. If well tolerated, the second infusion was infused over 60 minutes, and if tolerated, all subsequent infusions were given by 30-minute intravenous infusion. There were no regularly scheduled premedications administered with bevacizumab.

    Erlotinib was administered orally at a daily dose of 150 mg. Patients took their dose of erlotinib each morning either at least 1 hour before or 2 hours after meals. No routine premedications were taken with erlotinib.

    Before each dose of bevacizumab, patients had complete blood counts, chemistry profile, and urinalysis performed. Patients were seen and examined by their physicians on a monthly basis. After 8 weeks of treatment, patients were evaluated for response. At this time, repeat computed tomography scans of all measurable lesions were performed. Based on this evaluation, all patients were assigned a response category. Patients with objective response to treatment and those with stable disease continued to receive bevacizumab and erlotinib. Patients with tumor progression were removed from the study.

    For patients continuing treatment, reevaluations were performed at 2-month intervals. Initially, the duration of treatment with bevacizumab and erlotinib was to be 12 months. However, this study was subsequently amended to allow patients who were benefiting from treatment to continue for as long as benefit persisted.

    Dose Modifications

    On the basis of previous clinical experience with bevacizumab, the expected toxicities with this agent were proteinuria, hemorrhagic events, and hypertension. Before each dose of bevacizumab, patients were tested for proteinuria by using dipstick analysis. If the dipstick showed 2+ proteinuria, bevacizumab was held and a 24-hour urine collection was obtained. Bevacizumab was continued as long as the 24-hour urine protein remained less than 2,000 mg/24 hours. If proteinuria was 2,000 mg/24 hours, bevacizumab was held for 2 weeks, and 24-hour urine protein was remeasured. Bevacizumab was restarted when proteinuria decreased to less than 2,000 mg/24 hours. Bevacizumab was held for patients who had evidence of grade 3 or 4 bleeding and was discontinued if any life-threatening hemorrhagic events occurred. For bleeding events of grade 3 or less, bevacizumab could be restarted at the discretion of the treating physician after the bleeding episode had resolved. Patients who developed grade 3 hypertension on bevacizumab were treated by using standard antihypertensives. If patients developed grade 4 hypertension, bevacizumab was interrupted, antihypertensive treatment was initiated, and bevacizumab was restarted at the discretion of the treating physician only after satisfactory control of blood pressure was achieved.

    Expected toxicities with erlotinib included skin rash and diarrhea. Patients experiencing grade 1 or 2 toxicities were continued on the same dose of erlotinib, and symptomatic treatment was administered. Patients developing grade 3 or 4 skin toxicity had erlotinib stopped for 1 week or until the skin toxicity improved to grade 2 or less. Erlotinib was then restarted at full dose. If grade 3 or 4 skin toxicity recurred, erlotinib was reduced to 100 mg daily. For grade 3 or 4 diarrhea not controlled by using standard schedules of loperamide, erlotinib was interrupted for 1 week or until diarrhea improved to grade 2 or less. Erlotinib was then reinstituted at full dose. If grade 3 or 4 diarrhea occurred, the dose of erlotinib was decreased to 100 mg daily.

    For other unexpected grade 3 or 4 toxicities caused by either of these agents or their combination, administration of the offending agent or agents was discontinued for 2 weeks or until the toxicity had decreased to less than grade 2. Treatment then was reinstituted at full dose at the discretion of the treating physician. Patients who developed grade 3 or 4 toxicities that failed to resolve after holding treatment for 2 weeks were removed from the study.

    Definition of Response

    All patients were reevaluated for response after completion of 8 weeks of treatment, and response categories were assigned by using Response Evaluation Criteria in Solid Tumors (RECIST) criteria.21 All patients with major responses had confirmation of response on repeat scans performed at 8-week intervals. Patients with stable disease or minor responses at 8 weeks were reevaluated at 2-month intervals as treatment continued. The final response category assigned to these patients represented the best response obtained during their treatment course.

    Statistical Considerations

    This nonrandomized phase II study was designed to assess the efficacy and toxicity of the combination of bevacizumab and erlotinib. In a previous clinical trial, treatment with single-agent bevacizumab (10 mg/kg every 2 weeks) resulted in a 10% objective response rate and a median progression-free survival of 4.8 months in patients with metastatic renal cancer refractory to high-dose interleukin-2.13 Therefore, we considered the achievement of a 20% objective response rate to be a level of efficacy worthy of additional development of this combination regimen. Using a Simon two-stage design, we looked for four objective responses among the first 28 patients treated. When more than four responses were observed, we continued accrual to a total of 63 patients. Achievement of 16 responses among the 63 patients indicated a true response rate of more than 20%. The level of this design was .05 and the power was 0.9.

    Progression-free survival was defined as the date of study entry until the date that tumor progression was documented. Overall survival was measured from the date of study entry until the date of death. Survival curves were constructed by using the method of Kaplan and Meier.22 Comparisons of survival for various subsets of patients were accomplished by using two-sided log-rank analysis.23 Toxicity was evaluated in all patients who received at least 1 dose of therapy. Toxicity was graded according to National Cancer Institute Common Toxicity Criteria, version 3.0.

    RESULTS

    Patient Characteristics

    Between January 2003 and January 2004, 63 patients were enrolled onto this clinical trial. Patient characteristics are listed in Table 1. The median age of 61 years was typical of the renal carcinoma population; all patients had good performance status (ECOG, 0 or 1). The spectrum of metastatic sites in these patients was typical of metastatic renal carcinoma. All patients in this trial had previously undergone radical nephrectomy. The majority of patients (68%) had received no previous systemic treatment for metastatic disease.

    Patients were retrospectively categorized into prognostic groups as described by Motzer et al.24 In this prognostic index, patients were divided into groups on the basis of the presence of five clinical features: Karnofsky performance status less than 80%, anemia (hemoglobin less than the lower limit of normal), high serum lactate dehydrogenase (> 1.5 times the upper limit of normal), high "corrected" serum calcium (> 10 mg/dL), and absence of previous nephrectomy. Three distinct prognostic groups are comprised of patients with zero factors (favorable), one to two factors (intermediate), and three to five factors (poor). Because our patients are routinely categorized according to the ECOG performance status system rather than the Karnofsky scale, we substituted an ECOG performance status of 1 or 2 for a Karnofsky score of less than 80% in determining risk category. In this study, 42% of patients were categorized as low risk, whereas 29% had high risk (Table 1).

    Treatment Received

    Fifty-eight (92%) of 63 patients received at least 2 months of treatment and were reevaluated for response. Five patients discontinued treatment during the first 8 weeks. One patient discontinued treatment because of rapid tumor progression and is categorized as a nonresponder. The other four patients discontinued treatment because of toxicity (one patient) or patient decision (usually because of the inconvenience of long-distance travel to obtain treatment; three patients) and were not reevaluated for response.

    The median duration of treatment was 8 months (range, 1 to 19+ months). At present, 16 patients are continuing treatment after treatment durations of 13 to 19 months.

    Efficacy

    Fifty-eight (92%) of 63 patients were evaluated for response, and the one patient who had rapid tumor progression before 8 weeks is also included as a nonresponder. The responses to treatment are summarized in Table 2. Fifteen (25%) of 59 assessable patients (95% CI, 16% to 37%) had objective responses (one complete response, 14 partial responses). An additional 36 patients (61%; 95% CI, 48% to 72%) had stable disease. Of the patients with stable disease, 13 patients (22%) had measurable reduction in tumor size but did not meet RECIST criteria for partial response. Only eight patients (14%) had progressive renal cancer at the time of first reevaluation. Of the 15 objective responses, 14 were evident at the time of first reevaluation (8 weeks). One patient had stable disease for the first 12 months of treatment and then achieved partial response at 12 months and complete response at 14 months. At the time of this writing, nine of 15 responders had progression-free disease after 13 to 20 months of treatment; five patients continue to receive bevacizumab/erlotinib, whereas four stopped treatment after 12 to 18 months of treatment either at their request or at the discretion of their physicians. Six responders have experienced relapse after response durations of 5 to 18 months.

    The progression-free survival for all 63 patients is shown in Figure 1. After a median follow-up of 15 months, the median progression-free survival was 11 months, and the progression-free survivals at 12 and 18 months were 43% and 26%, respectively. Figure 2 shows the overall survival for this group of patients. The median survival has not been reached; 12- and 18-month survival rates were 78% and 60%, respectively.

    The objective response rate for the 39 assessable patients who were previously untreated was 31%, versus 15% in the 20 patients who had received previous cytokine therapy. The progression-free survival rates of these two subgroups are shown in Figure 3. Patients without previous treatment had longer progression-free survival when compared to previously treated patients (12.9 v 8.9 months; P = .038).

    Objective responses to treatment with erlotinib/bevacizumab were observed in patients in all Motzer risk categories. Patients in low-, intermediate-, and high-risk categories had major response rates of 18%, 33%, and 22%, respectively. Progression-free survival was similar in these three patient subgroups (Fig 4). The overall survival rates in the low-, intermediate-, and high-risk groups were 88%, 71%, and 67%, respectively (Fig 5). Patients in the low-risk group seemed to have improved survival versus the group of intermediate- and high-risk patients (P = .02).

    Toxicity

    Treatment-related toxicities are listed in Table 3. This treatment regimen was well tolerated by most patients. Only two patients discontinued treatment because of toxicity. One of these patients developed severe skin toxicity, which did not resolve after 2 weeks of discontinuation of erlotinib; therefore, the patient was removed according to study parameters. The second patient requested that treatment be stopped because of a bothersome skin toxicity and pruritus, although the severity of these adverse effects did not meet protocol specifications for discontinuation of treatment.

    Only one episode of grade 4 toxicity (gastrointestinal bleeding) occurred among the 63 patients on this treatment. Thirty-five patients (56%) had episodes of grade 3 toxicity of types described previously with these agents. However, in most cases the toxicities were managed successfully while allowing the patient to continue treatment. Grade 3 hypertension was successfully managed medically in all cases and did not require interruption of treatment. Patients with erlotinib-related skin toxicity and diarrhea were generally managed successfully with symptomatic measures. Three patients required a decrease in the daily erlotinib dose from 150 to 100 mg because of these toxicities. Four patients (6%) had grade 3 bleeding episodes, possibly related to bevacizumab (hemorrhoidal bleeding, two patients; gastrointestinal bleeding of undetermined source, one patient; surgical incision, one patient). In all these patients, bleeding was self-limited, and treatment was subsequently resumed.

    Grade 1/2 toxicities were relatively common, particularly skin rash and diarrhea. Again, these toxicities were managed successfully with symptomatic measures. Because of the concern regarding bevacizumab-related bleeding, all episodes of minor bleeding were recorded in these patients. Although 24 patients (39%) had some minor bleeding, it is likely that some of these episodes were not bevacizumab related. The most common types of bleeding in this group included hemorrhoidal bleeding, epistaxis, and microscopic hematuria. No toxicity differences were observed in previously untreated patients when compared to patients who had received previous cytokine therapy.

    DISCUSSION

    In this multicenter phase II trial, treatment with the combination of bevacizumab and erlotinib was effective and well tolerated in patients with metastatic clear-cell renal cancer. Twenty-five percent of patients had major objective responses by RECIST criteria, and an additional 61% of patients had stable disease at initial reevaluation. Thirteen patients (22%) with stable disease actually had objective tumor regression but not of the magnitude necessary to meet RECIST criteria for partial response. Patients with stable disease often had substantial clinical benefit; 24 (67%) of these 36 patients remained on treatment for more than 6 months, and 13 (36%) received treatment for more than 12 months. The median progression-free and overall survival produced by this treatment (11 and > 20 months, respectively) compare favorably with reports of other treatments. Specifically, interferon alfa as first-line therapy produced median progression-free and overall survival of 4.7 and 13 months, respectively, in a group of 463 patients pooled from several clinical trials.25

    Unlike some of the other treatment options for advanced renal carcinoma, the bevacizumab/erlotinib combination was well tolerated; only 2 (3%) of 63 patients stopped treatment because of toxicity. Acneiform skin rash and diarrhea were common adverse effects of treatment but were managed easily and subsided with time in most patients. Other adverse effects associated with bevacizumab, including proteinuria and hypertension, were frequent but usually mild and easily managed. Only one patient had a gastrointestinal bleed that required hospitalization; complete endoscopy did not reveal a bleeding source, and the patient was able to continue treatment. No unexpected toxicities unique to this combination were observed.

    After a long history of futility in the treatment of patients with metastatic renal cell carcinoma, several agents inhibiting VEGF, its receptor, and other signaling pathways have emerged as active and potentially useful agents. The therapeutic potential of these agents is predictable based on current understanding of the molecular biology of sporadic clear-cell renal cancer. The loss of VHL gene function, a feature common to most clear-cell renal carcinomas, results in the overproduction of multiple growth factors for tumor cells, endothelial cells, and cells supporting neovascularization. Overproduced growth factors included VEGF, TGF-, and PDGF-?; these growth factors and their signaling pathways seem to be important drivers of the malignant process and provide obvious potential therapeutic targets.

    Inhibition of VEGF alone using single-agent bevacizumab produced a 10% major objective response rate by World Health Organization criteria and led to prolonged progression-free survival versus placebo (4.8 v 2.5 months, respectively) in a randomized trial.16 More recently, preliminary results from clinical trials with two multitargeted agents, SU011248 and BAY 43-9006, have demonstrated substantial activity against advanced renal carcinoma.26,27 Both of these agents inhibit the VEGF receptor in addition to other targets of potential significance. The most obvious of these other targets are PDGF-? (SU011248 and BAY43-9006) and RAF kinase (BAY 43 to 9006).

    The inhibition of the EGF receptor is also of potential therapeutic value in the treatment of advanced renal carcinoma. Levels of TGF- are consistently elevated, and EGF receptors are consistently overexpressed in clear-cell renal carcinomas. However, clinical experience with antibodies blocking the EGF receptor (cetuximab, ABX-ECF) and other EGF receptor tyrosine kinase inhibitors (gefitinib) has failed to demonstrate activity in nearly 200 patients with advanced renal carcinoma.28-31 In limited experience with erlotinib, one of 19 patients treated as part of a phase I trial had a partial response.32

    Despite poor results with single-agent treatment, preclinical data suggest that treatment with an EGF receptor tyrosine kinase inhibitor in the presence of VEGF blockade may result in a different outcome. VEGF blockade may be critical in preventing resistance to EGF receptor inhibition.19 Furthermore, EGF receptor blockade may limit the levels of VEGF and thereby allow more complete VEGF blockade by an agent such as bevacizumab.17,18 The use of agents such as erlotinib and bevacizumab that target different signaling pathways and affect different cell types (tumor cell and endothelial cell) may abide by different rules than standard cytotoxic chemotherapy because of the significant cross talk between the pathways in numerous cell types.

    As increasing numbers of intracellular targets are identified and become amenable to manipulation with new agents, the feasibility of simultaneous inhibition of multiple targets increases. Unlike chronic myelogenous leukemia, in which a single bcr/abl mutation is responsible for the malignant process, most cancers have multiple points at which dysregulation may play a role in determining malignancy. Therefore, combined blockade of critical targets is strongly supported by current understanding of the biology of human tumors.

    The results of this first attempt at combination targeted therapy in advanced clear-cell renal carcinoma are encouraging. Concurrent administration of full doses of both agents was feasible and well tolerated by a relatively unselected group of patients with advanced renal cell carcinoma. Although the efficacy of this combination treatment seems superior when compared retrospectively to results with either agent used alone, the phase II design of this trial does not permit a definitive conclusion. Our results may have been favorably influenced by several features of our patient population, including limited previous treatment (68% untreated), and the requirements that patients have previous nephrectomy and clear-cell histology. Similarly, comparisons of the bevacizumab/erlotinib combination with recently reported results with the multitargeted agents SU011248 and BAY 43-9006 are difficult because of the variations in trial design and patient selection. However, preliminary results suggest comparable response rates and progression-free intervals for all of these treatments.26,27

    On the basis of these phase II study results, the combination of bevacizumab and erlotinib is an active and well-tolerated treatment for patients with advanced renal cell carcinoma. Additional investigation of this regimen is indicated; a randomized phase II trial comparing this regimen with single-agent bevacizumab recently completed patient accrual. The feasibility of improving overall and complete response rates by adding these agents to "standard" treatments such as interleukin-2 or interferon alfa should be investigated also, and evaluation of other combinations of targeted agents on the basis of known molecular mechanisms in clear-cell renal carcinoma is warranted. PDGF-? is another factor that is present in increased amounts in clear-cell renal cancers with loss of VHL gene function. Pericyte proliferation is stimulated by PDGF-?; preclinical studies have shown synergistic antitumor activity when endothelial and pericyte proliferation are blocked simultaneously.33 For these reasons, we have initiated a follow-up phase I/II trial to evaluate the benefit of imatinib, a PDGF-? inhibitor, added to the bevacizumab/erlotinib combination.

    In a broader sense, the results of this clinical trial engender optimism and provide strong rationale for additional development of rational combinations of targeted agents. Preliminary results with the bevacizumab/erlotinib combination in patients with refractory non–small-cell lung cancer also have demonstrated remarkable activity.34 Inhibition of critical pathways of malignancy, on the basis of improved understanding of molecular mechanisms, will likely play a major role in the future of cancer treatment.

    Appendix

    Minnie Pearl Cancer Research Network Participating Sites

    Tennessee Oncology, PLLC, Nashville, TN; Grand Rapids CCOP, Grand Rapids, MI; and Medical Oncology, LLC, Baton Rouge, LA.

    Authors' Disclosures of Potential Conflicts of Interest

    The authors indicated no potential conflicts of interest.

    NOTES

    Supported by grants from Genentech, Inc, and the Minnie Pearl Cancer Foundation.

    Authors' disclosures of potential conflicts of interest are found at the end of this article.

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