Novel Therapies and Side-Effect Management

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1 TREATING THE PATIENT WITH METASTATIC NON SMALL- CELL LUNG CANCER Novel Therapies and Side-Effect Management Provided through an unrestricted educational grant by Genentech BioOncology and OSI Oncology Lead Authors WILLIAM N. WILLIAM JR, MD EDWARD S. KIM, MD

2 TREATING THE PATIENT WITH METASTATIC NON SMALL- CELL LUNG CANCER Novel Therapies and Side-Effect Management Table of Contents Cytotoxic Therapy for Metastatic NSCLC Frontline Treatment Salvage Treatment Integrating Biologic Agents in the Treatment of Metastatic NSCLC Targeting the EGFR SKIN RASH Targeting the VEGF/VEGFR BLEEDING AND THROMBOSIS HYPERTENSION FATIGUE Conclusion WILLIAM N. WILLIAM JR, MD MAKALA PACE, PHARMD DENISE KUDVA, PHARMD SHEETAL SHETH, PHARMD KAREN OISHI, ANP, APRN, RN EDWARD S. KIM, MD Department of Thoracic/Head and Neck Medical Oncology The University of Texas M. D. Anderson Cancer Center Houston, Texas DANIEL LENIHAN, MD JEAN-BERNARD DURAND, MD Department of Cardiology The University of Texas M. D. Anderson Cancer Center Houston, Texas Table 1. Table 2. Table 3. Table 4. List of Tables and Figures Selected Trials of Single Agents Versus Platinum-Based Doublets in the Frontline Treatment of NSCLC Selected Trials of Platinum-Based Doublets in the Frontline Treatment of NSCLC Positive Trials of Molecular-Targeted Therapies in NSCLC Management of Skin Toxicity Induced by EGFR-Targeted Drugs DISCLAIMER This pocket guide is designed to be a summary of information. While it is detailed, it is not an exhaustive clinical review. McMahon Publishing, Genentech BioOncology, OSI Oncology, and the authors neither affirm nor deny the accuracy of the information contained herein. No liability will be assumed for the use of this pocket guide, and the absence of typographical errors is not guaranteed. Readers are strongly urged to consult any relevant primary literature. 2007, McMahon Publishing, 545 West 45th St., New York, NY Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form. Table 5. Figure 1. Warnings and Common Adverse Effects of Targeted Agents Approved or Under Investigation for the Treatment of NSCLC Algorithm for the evidence-based management of NSCLC Figure 2. Algorithm for the management of hypertension induced by VEGF/VEGFR-targeted agents

3 Lung cancer is a major health problem worldwide. In the United States alone, it is estimated that 213,380 new cases of lung cancer will be diagnosed during the year 2007, second only to prostate cancer (in men) and breast cancer (in women). Lung cancer is anticipated to account for 160,390 deaths this year, therefore representing the leading cause of cancer-related mortality for both sexes. During the past decade, the incidence of lung cancer has been declining in men and leveling off in women, largely reflecting a change in cigarette-smoking habits. Yet, 1 in every 12 people in the United States will ultimately develop this disease during their lifetime. 1 Approximately 85% of patients with lung cancer present a non small-cell histology. Of these, 55% are diagnosed, at initial presentation, with stage IIIB or IV disease that is not amenable to curative treatment. More than half of the remaining 45% of patients treated with curative intent will develop distant metastases and will eventually be considered for palliative systemic treatment as well. 2,3 In recent years, new chemotherapeutic compounds and biologic agents have been developed and approved by the FDA for the first-, second-, and/or third-line treatment of metastatic non small-cell lung cancer (NSCLC). The latter class of drugs has generated particular interest because it allows insight into the biology of the disease, including the significance of molecular targets eg, the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) and its receptor (VEGFR). These agents provide proof that molecular-targeted treatment is a feasible and effective strategy in the management of advanced NSCLC. Although still not in use in the curative setting, biologic compounds have been shown to prolong survival and increase quality of life, with a favorable toxicity profile. The objective of this review is to summarize the current systemic therapeutic options for patients with metastatic NSCLC, with a focus on the newer molecular-targeted agents and the management of their common and most serious side effects. Cytotoxic Therapy for Metastatic NSCLC Frontline Treatment The role of cytotoxic treatment for NSCLC versus that of best supportive care has been established by at least 12 randomized trials involving more than 2,000 patients. A metaanalysis prepared by the Non Small-Cell Lung Cancer Collaborative Group comprehensively analyzed the results of 11 of these studies, indicating a statistically significant relative risk reduction of death of 27% at 1 year (absolute improvement in survival, 10%) and an increase in median survival of 6 weeks for cisplatin-based chemotherapy. 4 Several trials have addressed the question of whether, in addition to the modest increase in survival, chemotherapy also enhanced quality of life in patients with metastatic NSCLC. In this regard, randomized studies have consistently demonstrated that in addition to increasing median survival, chemotherapy with cisplatinbased regimens, 5 single-agent vinorelbine (Navelbine, Glaxo- SmithKline), 6 or single-agent gemcitabine (Gemzar, Lilly) 7 lead to a decrease in hospitalization rates, better quality-of-life scores, and/or a reduction in lung cancer related symptoms compared with best supportive care alone. Taken together, these studies provide compelling evidence for the use of palliative chemotherapy in patients with incurable NSCLC, especially if they present a good performance status (PS). The choice of cytotoxic agent(s) to be used in the first-line treatment of NSCLC has been evaluated in randomized trials and meta-analyses. In a 1998 meta-analysis of studies that evaluated the role of doublets versus singlets, investigators found a 2-fold increase in response rate (RR) (relative risk, 1.93; 95% confidence interval, ) and a modest but statistically significant increase in 1-year survival favoring combination chemotherapy, albeit accompanied by a higher incidence of adverse events. 8 Table 1 outlines select trials of single agents versus platinum-based doublets in the treatment of metastatic NSCLC The Eastern Cooperative Oncology Group (ECOG) trial 1594 randomized 1,155 chemotherapy-naïve patients to 1 of 4 arms of platinum-containing treatments: cisplatin plus paclitaxel, carboplatin plus paclitaxel, cisplatin plus docetaxel (Taxotere, Sanofi-Aventis), or cisplatin plus gemcitabine. The overall RR was 19%, the median overall survival (OS) was 7.9 months, and the 1- and 2-year OS rates were 33% and 11%, respectively, with no statistically significant differences between the arms. 15 The largest trial in metastatic NSCLC performed to date (TAX 326) randomized 1,218 patients to receive one of the following regimens: cisplatin plus docetaxel, 4 5

4 carboplatin plus docetaxel, or cisplatin plus vinorelbine. The cisplatin docetaxel arm outperformed cisplatin vinorelbine, with a median OS of 11.3 months versus 10.1 months (P=0.044) and better quality of life. 16 These results support the use of a platinum agent paired with either gemcitabine, a taxane, or (less preferably) vinorelbine for the first-line treatment of metastatic NSCLC. ECOG 1594, TAX 326, and other selected trials comparing platinum-based frontline regimens are described in Table In 2005, another meta-analysis examined the role of non platinum-based combination regimens for frontline therapy of metastatic NSCLC. This study demonstrated general superiority in response and survival for platinumcontaining regimens versus non platinum-based chemotherapy, although the incidence of side effects was higher with the former strategy. Furthermore, when platinum-based doublets were compared with third-generation nonplatinum combinations only (ie, combinations of gemcitabine, vinorelbine, Table 1. Selected Trials of Single Agents Versus Platinum-Based Doublets in the Frontline Treatment of NSCLC Clinical Trial n RR, % Median Survival, mo 1-Year Survival, % Median PFS/TTP, mo Hoosier Oncology Group 9 Gemcitabine + cisplatin Cisplatin * * * * 3.7 Southwest Oncology Group 10 Vinorelbine + cisplatin Cisplatin * 12 8* 6 36* 20 4* 2 European 11 Paclitaxel + cisplatin Cisplatin * * 2.7 Cancer and Leukemia Group B Paclitaxel + carboplatin Paclitaxel * * 2.5 Greek Cooperative Group 13 Docetaxel + cisplatin Docetaxel * Swedish Lung Cancer Study Group 14 Gemcitabine + carboplatin Gemcitabine * 11 10* * * 3.4 *Statistically significant difference. NSCLC, non small-cell lung cancer; PFS, progression-free survival; RR, response rate; TTP, time to progression 6 7

5 taxanes, or camptothecins), survival was similar among the 2 groups. 20 In summary, platinum-based doublets are the cornerstone of frontline treatment of metastatic NSCLC, yielding a median OS in the range of 8 to 11 months in the latest trials. However, third-generation nonplatinum combinations may achieve similar outcomes with fewer side effects, and therefore they also are reasonable choices. Single-agent chemotherapy should be reserved for elderly patients; gemcitabine, 7,21 vinorelbine, 6,21,22 and docetaxel 22 have been the most widely studied and utilized regimens in this setting. For patients with poor PS, either single-agent chemotherapy or best supportive care alone should be considered (Figure 1). Salvage Treatment In 2000, Shepherd et al published a seminal study that established the role of salvage treatment for NSCLC after failure of platinum-based chemotherapy. The trial included 103 patients who were randomized to docetaxel or best supportive care alone. There was a statistically significant increase in median OS (7 vs 4.6 months) favoring the chemotherapy arm, 23 accompanied by a trend toward less FRONTLINE TREATMENT PS 0-2 Elderly PS 0-2 PS 3 OR OR Bevacizumab-eligible (nonsquamous histology, no contraindications) Bevacizumab-ineligible (squamous histology or contraindications) Third-generation nonplatinum doublet Single agent: docetaxel or vinorelbine or gemcitabine Best supportive care Figure 1. Algorithm for the evidence-based management of NSCLC. Carboplatin + paclitaxel + bevacizumab OR Cisplatin + gemcitabine + bevacizumab Carboplatin or cisplatin WITH paclitaxel or docetaxel or gemcitabine or vinorelbine SALVAGE TREATMENT PS 0-2 PS 3 PS 4 OR Docetaxel or pemetrexed or erlotinib Erlotinib Best supportive care NSCLC, non small-cell lung cancer; PS, performance status 8 9

6 deterioration of quality of life. 24 A subsequent randomized, Phase III, noninferiority trial with 571 patients examined the role of pemetrexed (Alimta, Lilly) as second-line treatment of NSCLC. Overall survival was not different between the pemetrexed and docetaxel arms. However, pemetrexedtreated patients exhibited fewer side effects, mostly attributable to a reduction in the incidence of febrile neutropenia. 25 Hence, both pemetrexed and docetaxel are currently considered standard-of-care options for salvage treatment of NSCLC (Figure 1). Integrating Biologic Agents in the Treatment of Metastatic NSCLC Targeting the EGFR Oral tyrosine kinase inhibitors (TKIs) are small molecules that competitively block adenosine triphosphate binding in the intracellular domain of the EGFR, thereby inhibiting EGFR autophosphorylation. 26 This leads to further inhibition of intracellular signaling propagation 26 and in turn produces antineoplastic effects. The first agent in this class of drugs to show Table 2. Selected Trials of Platinum-Based Doublets in the Frontline Treatment of NSCLC Clinical Trial n RR, % Median Survival, mo 1-Year Survival, % Median PFS/TTP, mo ECOG Paclitaxel + carboplatin Paclitaxel + cisplatin Docetaxel + cisplatin Gemcitabine + cisplatin * TAX Docetaxel + cisplatin Docetaxel + carboplatin Vinorelbine + cisplatin Rosell et al 17 Paclitaxel + carboplatin Paclitaxel + cisplatin Italian Lung Cancer Project 18 Paclitaxel + carboplatin Vinorelbine + cisplatin Gemcitabine + cisplatin Southwest Oncology Group 19 Paclitaxel + carboplatin Vinorelbine + cisplatin *Statistically significant difference compared with paclitaxel + cisplatin. Statistically significant difference. NSCLC, non small-cell lung cancer; PFS, progression-free survival; RR, response rate; TTP, time to progression 10 11

7 clinical activity in NSCLC was gefitinib (Iressa, AstraZeneca), which was evaluated in the randomized Phase II trials IDEAL 1 27 and IDEAL Although this drug did not demonstrate a survival benefit in a following randomized, placebo-controlled, Phase III study, 29 it was clearly shown to interfere with the biology of some subtypes of NSCLC (ie, in women, never-smokers, Asians, and adenocarcinoma histologies), at least to some extent. Gefitinib is now available through a limited-access program for patients with locally advanced or metastatic NSCLC who have failed platinum-based and docetaxel therapies and who are benefiting or have benefited from the drug. 30 Subsequently, another oral EGFR TKI, erlotinib (Tarceva, Genentech/OSI Oncology), was evaluated in a large randomized, double-blind, placebo-controlled, Phase III trial (BR.21). 31 The trial included patients with stage IIIB or IV NSCLC, with a PS between 0 and 3, who had received 1 or 2 previous regimens of combination chemotherapy and were not eligible for further chemotherapy (patients older than 70 years of age could have received 1 or 2 single agents). In this study, 731 patients were randomized in a 2:1 ratio to receive erlotinib 150 mg per day or placebo. Response rates were 8.9% for erlotinib and less than 1% for placebo (P<0.001), and there was a significant difference in median OS favoring the targeted agent (6.7 vs 4.7 months; P<0.001) (Table 3). More patients in the erlotinib group had symptomatic improvement of cough, pain, dyspnea, and domain of overall physical function. The most frequent grade 3-5 adverse events associated with the drug were rash (9%) and diarrhea (6%). Infection of any grade was more common in the erlotinib group compared with the placebo group (34% vs 21%; P<0.001); however, grade 3-5 infection was more common in the placebo group compared with the erlotinib group (5% vs 2%; P=0.03). The importance of the BR.21 trial is heightened as a result of the following: (1) it is the only randomized trial to prove a survival advantage of systemic treatment in the third-line setting (50% of the patients) versus best supportive care; (2) it Table 3. Positive Trials of Molecular-Targeted Therapies in NSCLC Clinical Trial n RR, % Median Survival, mo 1-Year Survival, % Median PFS/TTP, mo BR.21 (salvage) 31 Erlotinib Best supportive care * <1 6.7* 4.7 n/a n/a 2.2* 1.8 ECOG 4599 (frontline) 32 Paclitaxel + carboplatin + bevacizumab Paclitaxel + carboplatin * * * * 4.5 BO (frontline) 33 Gemcitabine + cisplatin + bevacizumab (15 mg/kg) Gemcitabine + cisplatin + bevacizumab (7.5 mg/kg) Gemcitabine + cisplatin * 34* 20 n/a n/a n/a n/a n/a n/a 6.5* 6.7* 6.1 *Statistically significant difference. Overall survival has not been reported. However, the difference in median PFS was statistically significant for the bevacizumab 15 mg/kg and 7.5 mg/kg arms compared with the control arm. n/a, not available; NSCLC, non small-cell lung cancer; PFS, progression-free survival; RR, response rate; TTP, time to progression 12 13

8 is the only randomized trial with an oral TKI to date to show a survival advantage in the overall study population irrespective of possible prespecified response-predictive factors; (3) it included patients with a PS of 2 (25% of the patients) and 3 (9%) and still demonstrated tolerability and symptomatic control in this setting. 31 Thus, erlotinib received FDA approval in November 2004 as monotherapy for the treatment of patients with locally advanced or metastatic NSCLC after failure of at least 1 prior chemotherapy regimen. 34 SKIN RASH Although generally well tolerated, gefitinib and erlotinib induce grade 1-2 skin rash in approximately 35% to 67% of patients and grade 3-5 skin rash in roughly 2% to 9%. 29,31 This is the most frequent adverse event associated with these drugs and could constitute limiting factors for their administration in a subset of patients. Although there have been no prospective studies assessing the effectiveness of certain treatments, recommendations for the management of dermatologic toxicities induced by EGFR inhibitors have been published. 35 These are summarized in Table 4. Skin rash, along with other adverse effects, is also described in Table 5. Targeting the VEGF/VEGFR Bevacizumab (Avastin, Genentech) is a recombinant humanized monoclonal antibody directed to circulating VEGF. The first Phase II trial to evaluate its role (in combination with paclitaxel and carboplatin) in the treatment of patients with chemotherapy-naïve, metastatic NSCLC was published in In this trial, 99 patients were randomized to receive Table 4. Management of Skin Toxicity Induced by EGFR-Targeted Drugs 35 Toxicity Grade Macular Rash Pustular Rash Dry Skin Pruritus 1 (Mild) Hydrocortisone topical cream/lotion Clindamycin gel (for isolated lesions)/lotion (for scattered lesions) Ulcerative Lesions 2 (Moderate) Oral methylprednisolone (if >2 body regions) Topical hydrocortisone (if <2 body regions) Minocycline or doxycycline 100 mg PO bid for d Emollient applied bid Topical antihistamine or diphenhydramine mg PO q6h prn 3 (Severe) Oral methylprednisolone Minocycline or doxycycline 100 mg PO bid for d Emollient applied bid Diphenhydramine mg PO q6h or hydroxyzine mg PO q6h prn Silver sulfadiazine ointment Dermatology consult 4 (Severe) Consider discontinuing therapy Reprinted with permission from reference 35: Chou LS, et al. Clin Lung Cancer. 2006;8 Suppl 1:S15-S

9 Table 5. Warnings and Common Adverse Effects of Targeted Agents Approved or Under Investigation for the Treatment of NSCLC* Agent Warnings/Adverse Effects Incidence, % Recommendations Bevacizumab 36 Gastrointestinal perforations Permanently discontinue. Wound healing complications 0.8 Permanently discontinue in patients with wound dehiscence requiring medical intervention. Arterial thrombotic events 4.4 Permanently discontinue. RPLS <0.1 Discontinue and manage hypertension, if present. Safety of reinitiating therapy is not known. Neutropenia, infection 26.2, 4.5 Treat accordingly. Proteinuria Up to 1.8 Discontinue in patients with nephrotic syndrome; monitor and consider interrupting therapy for less severe proteinuria ( 2 g/24 h). CHF 1.7 Safety regarding treatment continuation or resumption has not been studied. HTN 8-18 Monitor blood pressure every 2 to 3 wk. Permanently discontinue if hypertensive crisis or encephalopathy develops. Temporarily suspend for severe HTN not controlled with medical management. See Figure 2. Hemorrhage 2.3 Avoid in patients with recent hemoptysis. Discontinue in patients with serious hemorrhage and initiate aggressive management. Pregnancy category C NA Consider accordingly. *The information in this Table is PI-based, with the exception of certain recommendations not specified in the PI. CBC, complete blood cell; CHF, congestive heart failure; HTN, hypertension; ILD, interstitial lung disease; LVD, left ventricular dysfunction; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NA, not applicable; PI, prescribing information; RPLS, reversible posterior leukoencephalopathy syndrome Continued on next page bevacizumab 7.5 or 15 mg/kg plus carboplatin and paclitaxel, or carboplatin and paclitaxel alone. It found an encouraging RR of 31.5%, progression-free survival (PFS) of 7.4 months, and median survival of 17.7 months in the high-dose bevacizumab arm (compared with 18.8%, 4.2 months, and 14.9 months, respectively, among patients treated with paclitaxel and carboplatin alone). Subsequently, the ECOG conducted a multicenter, randomized, Phase III trial of first-line 16 17

10 Table 5. Warnings and Common Adverse Effects of Targeted Agents Approved or Under Investigation for the Treatment of NSCLC* (cont d) Agent Warnings/Adverse Effects Incidence, % Recommendations Eriotinib 34 Pulmonary toxicity, ILD 0.7 Interrupt pending evaluation. If ILD, discontinue. MI/ischemia 2.3 Manage condition. Cerebrovascular accident 2.3 Manage condition. Microangiopathic hemolytic anemia with thrombocytopenia 0.8 Manage condition. Rash 75 Severe rash may require dose reduction/temporary interruption of therapy. See Table 4. Diarrhea 54 Manage with loperamide. Severe diarrhea unresponsive to loperamide may require dose reduction/temporary interruption of therapy. Pregnancy category D NA Not recommended. Gefitinib 30 Pulmonary toxicity, ILD ~1 Interrupt pending evaluation. If ILD, discontinue. Rash 43 Severe rash may require dose reduction/temporary interruption of therapy. See Table 4. Diarrhea 48 Severe diarrhea may require dose reduction/temporary interruption of therapy. Pregnancy category D NA Not recommended. *The information in this Table is PI-based, with the exception of certain recommendations not specified in the PI. CBC, complete blood cell; CHF, congestive heart failure; HTN, hypertension; ILD, interstitial lung disease; LVD, left ventricular dysfunction; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NA, not applicable; PI, prescribing information; RPLS, reversible posterior leukoencephalopathy syndrome Continued on next page carboplatin paclitaxel with or without bevacizumab in 878 patients with stage IIIB (pleural effusion), stage IV, or recurrent NSCLC with no squamous-cell histology predominance (ECOG 4599). 32 The RR in the bevacizumab arm was 35% compared with 15% in the chemotherapy-only group (P<0.001). There were statistically significant improvements in median OS (12.3 vs 10.3 months; P=0.003) and PFS (6.2 vs 4.5 months; P<0.001) among the bevacizumab-treated patients (Table 3). The results of this trial led to the approval, in October 2006, of the combination of bevacizumab, paclitaxel, and carboplatin for the frontline treatment of unresectable, locally advanced, recurrent, or metastatic nonsquamous NSCLC. 36 Of note, for the first 18 19

11 Table 5. Warnings and Common Adverse Effects of Targeted Agents Approved or Under Investigation for the Treatment of NSCLC* (cont d) Agent Warnings/Adverse Effects Incidence, % Recommendations Sorafenib 37 HTN 17 Monitor and treat accordingly. Temporarily suspend if severe. See Figure 2. Hemorrhage 15 Discontinue in patients with serious hemorrhage and initiate aggressive management. Rash 40 Severe rash may require dose reduction/temporary interruption of therapy. See Table 4 and PI. Diarrhea 43 Severe diarrhea may require dose reduction/temporary interruption of therapy. Pregnancy category D NA Not recommended. Sunitinib 38 LVD 1 (decreased LVEF, 11-21) If CHF, discontinue. Interrupt or reduce if ejection fraction <50% and >20% below baseline. Monitor patients with prior cardiac events. QT interval prolongation, torsades de pointes Torsades de pointes, <0.1 Monitor and use with caution in at-risk patients and patients taking CYP3A4 inhibitors. Hypothyroidism 3-4 Measure baseline thyroid function. Monitor for signs/ symptoms. Treat as needed. Adrenal function NA Monitor for adrenal insufficiency in patients subjected to stress such as surgery, trauma, or severe infection. *The information in this Table is PI-based, with the exception of certain recommendations not specified in the PI. CBC, complete blood cell; CHF, congestive heart failure; HTN, hypertension; ILD, interstitial lung disease; LVD, left ventricular dysfunction; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NA, not applicable; PI, prescribing information; RPLS, reversible posterior leukoencephalopathy syndrome Continued on next page time, the survival mark of 12 months was exceeded in a randomized Phase III trial of metastatic NSCLC. Important safety information was obtained from these studies. In the initial Phase II trial, the most prominent drug-related adverse event was bleeding; 6 out of 67 bevacizumab-treated patients (9%) presented with major hemoptysis or hematemesis, which resulted in 4 deaths. All 6 patients had centrally located tumors close to major blood vessels, 5 had cavitation or necrosis, and 4 had squamouscell histology. In a subset analysis of patients with nonsquamous histology, bevacizumab treatment was just as efficacious, yet the rate of serious bleeding was lower (4%). 39 These results led the investigators to exclude patients with predominantly squamous-cell carcinomas from the 20 21

12 Table 5. Warnings and Common Adverse Effects of Targeted Agents Approved or Under Investigation for the Treatment of NSCLC* (cont d) Agent Warnings/Adverse Effects Incidence, % Recommendations Sunitinib 38 (cont d) Laboratory tests NA Perform CBC count at beginning of each treatment cycle. HTN Monitor and treat accordingly. Temporarily suspend if severe. See Figure 2. Hemorrhage Discontinue in patients with serious hemorrhage and initiate aggressive management. Rash Severe rash may require dose reduction/temporary interruption of therapy. See Table 4. Diarrhea Severe diarrhea may require dose reduction/temporary interruption of therapy. Pregnancy category D NA Not recommended. *The information in this Table is PI-based, with the exception of certain recommendations not specified in the PI. CBC, complete blood cell; CHF, congestive heart failure; HTN, hypertension; ILD, interstitial lung disease; LVD, left ventricular dysfunction; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NA, not applicable; PI, prescribing information; RPLS, reversible posterior leukoencephalopathy syndrome subsequent randomized, Phase III ECOG 4599 trial. 32 In the ECOG 4599 trial, the rates of grade 3-5 neutropenia (25.5%), hypertension (7%), febrile neutropenia (5.2%), bleeding (4.4%), hyponatremia (3.5%), proteinuria (3.1%), headache (3%), rash (2.3%), and thrombocytopenia (1.6%) were significantly higher in the paclitaxel carboplatin bevacizumab arm compared with the chemotherapy-only arm. There were more treatment-related deaths in the bevacizumab group (15 vs 2 deaths), 5 of which were due to pulmonary hemorrhage, 5 to febrile neutropenia, 2 to cerebrovascular events, 2 to gastrointestinal hemorrhage, and 1 to pulmonary embolism. Overall, there were more deaths in the chemotherapy-only arm compared with the bevacizumab arm (344 vs 305 deaths). 32 Partial results of the 3-arm trial BO17704, which compares cisplatin gemcitabine ± bevacizumab (7.5 mg/kg or 15 mg/kg every 3 weeks) in the frontline treatment of nonsquamous NSCLC, were presented at the 2007 annual meeting of the American Society of Clinical Oncology. 33 In this randomized, double-blind, multicenter, Phase III trial, the RRs in the bevacizumab arms were higher than in the control group (30%, 34%, and 20%, respectively, for the bevacizumab 15 mg/kg, bevacizumab 7.5 mg/kg, and control arms), as was PFS (6.5, 6.7, and 6.1 months, respectively) (Table 3). Data on OS have not been presented, but these results suggest that bevacizumab can be safely combined with other cytotoxic agents in the frontline treatment of NSCLC and that lower doses (eg, 7.5 mg/kg every 3 weeks) might be as effective as the original doses studied in the pivotal ECOG Phase III trial (15 mg/kg every 3 weeks). Promising anti-angiogenic agents that target the VEGFR (as opposed to directly targeting VEGF, as bevacizumab does) are currently under study for the treatment of metastatic NSCLC. These include the dual EGFR/VEGFR TKI vandetanib (Zactima, AstraZeneca) 40 and the multi-tkis sorafenib (Nexavar, Bayer) 22 23

13 and sunitinib (Sutent, Pfizer). 41 Interestingly, these agents present somewhat similar toxicities to VEGF-targeted bevacizumab, indicating a common pathophysiology. However, they also share toxicities, such as rash and diarrhea, with EGFR inhibitors. Some common toxicities associated with the VEGFR inhibitors and with bevacizumab include bleeding and thrombosis, hypertension, and fatigue, which are discussed in more detail below. Important warnings and adverse effects are further described in Table 5, along with recommendations for management. A systematic study of the side effects of angiogenesis inhibitors is warranted because most of them are clinically relevant, may lead to significant morbidity, and could possibly impair the delivery of adequate doses of the drugs. BLEEDING AND THROMBOSIS Both hemorrhagic and thromboembolic complications have been recognized in patients receiving angiogenesis inhibitors. One possible mechanism is related to the decreased ability of endothelial cells to respond to an injury and repair vasculature when the VEGF VEGFR axis is inhibited, thereby leading to a hemorrhagic tendency. Additionally, following a vascular injury, the coagulation cascade is activated by the exposure of tissue factor, and a thrombotic event may occur. 42,43 Hemorrhage is currently listed as a black box warning for bevacizumab when used in the treatment of NSCLC, with an incidence of severe/fatal hemoptysis of 2.3% in nonsquamous NSCLC. 36 In trials evaluating oral TKIs (eg, sorafenib and sunitinib), grade 1 hemorrhage (defined as mild bleeding that does not require medical intervention) was most commonly reported (incidence, 15%-30%), whereas grade 3-4 hemorrhage was described in no more than 3% of patients. 37,38 The package inserts of bevacizumab, sorafenib, and sunitinib recommend considering permanent discontinuation or delaying the doses in patients who experience hemorrhage that requires medical intervention Furthermore, caution is advised with the co-administration of sorafenib and warfarin. Fluctuations in the international normalized ratio have been noted in this setting, and more frequent laboratory monitoring is recommended. 37 Overall rates of thromboembolic events are not higher in patients receiving chemotherapy with bevacizumab versus chemotherapy alone. 44 However, the risk of arterial thromboembolism, although low (3%), is increased by approximately 2-fold when bevacizumab is added to the cytotoxic treatment. 36,45 The use of aspirin appears to promote a protective effect, 46 although this has never been studied in a prospective manner. In the event of a severe arterial thrombotic episode, bevacizumab should be permanently discontinued. Patients with colorectal cancer who develop venous thrombosis during treatment with bevacizumab may continue on the drug, provided that full-dose anticoagulation is instituted. 44 This has yet to be established in NSCLC because of the potential exacerbation of the risk of hemoptysis. Of note, none of the completed bevacizumab Phase III trials (in any cancer type) allowed enrollment of fully anticoagulated patients at baseline. HYPERTENSION Hypertension is considered a class effect of VEGF/VEGFR-targeted drugs. In vivo, VEGF is believed to lower blood pressure, enhance endothelial nitric oxide synthase, and stimulate the construction of new capillaries. These actions can be expected to decrease vascular resistance. 47,48 Drug-induced hypertension associated with VEGF antagonists is reversible upon discontinuation of treatment, which argues against anatomical explanations such as reduced density of microvasculature 47 and may suggest a transient vasoconstrictive effect. Although the exact mechanism behind VEGF inhibitor induced hypertension is not known, and considering the vasodilative effect of VEGF, vasoconstriction is a plausible explanation. Long-term and regular monitoring of blood pressure, including home measurements, is strongly recommended in patients treated with any anti-angiogenic agent. The decision to initiate and/or adjust antihypertensive medications should not be based on a single abnormal blood pressure value, but should take into consideration multiple blood pressure measurements obtained both in the clinic and at home on separate occasions. Therefore, it is strongly advised that patients maintain and bring a blood pressure log to every follow-up visit. Figure 2 provides an algorithm for the treatment of 24 25

14 hypertension induced by VEGF/VEGFR-targeted agents, based on recommendations of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7). 49 Briefly, patients should initiate lifestyle modifications, including a low-salt diet (<6 g NaCl per day) and limited alcohol intake. Exercise and weight loss, although recommended by JNC 7 as long-term goals, are often unrealistic in patients with limited life expectancy and cancer-related clinical complications. If the blood pressure goal is not met, 1 or more pharmacologic agents should be added. The choice of drugs should take into consideration the presence of existing comorbidities (compelling indications), side-effect profile, potential for pharmacologic interaction, and mechanism of action. In patients with NSCLC, who often exhibit tobacco-related cardiovascular disease, angiotensin- converting enzyme inhibitors, angiotensin II receptor blockers, and β-blockers are reasonable choices. Of note, β-blockers should be used with caution in patients with a history of bronchospasm. Calcium channel blockers should not be prescribed to patients with ischemic heart disease, unless used with a β-blocker. Dihydropyridine calcium channel blockers do not inhibit CYP3A4; thus, they are preferred over non-dihydropyridine calcium channel blockers (verapamil and diltiazem), which do interact with CYP3A4 and should be avoided in patients treated with sorafenib, sunitinib, and vandetanib. Diuretics have the potential for inducing hypovolemia and electrolyte imbalances, and this should be taken into consideration when treating patients with reduced food intake and/or patients receiving platinum-based chemotherapy. Antihypertensive agents with vasodilating properties Not at goal blood pressure (<140/90 mm Hg) (<130/80 mm Hg for patients with diabetes or chronic kidney disease) Lifestyle changes + Initial drug With compelling indications for use of a particular drug Therapeutic options: Heart failure: BB, ACEI, ARB, diuretic, ALDO ANT Post MI: BB, ACEI, ALDO ANT CVD risk: thiazide, BB, ACEI, CCB Diabetes: thiazide, BB, ACEI, ARB, CCB Chronic kidney disease: ACEI, ARB Without compelling indications for use of a particular drug Not at goal blood pressure Maximize dosages Add agent from another class Follow up (by phone or visit): Most within 2-3 weeks For SBP >160: within 2-3 days For SBP >170: within 48 hours Therapeutic options: Vasodilator such as ACEI, CCB, hydralazine 3 drugs and not at goal? Consider secondary cause and consult cardiology or hypertensive expert Figure 2. Algorithm for the management of hypertension induced by VEGF/VEGFRtargeted agents. 49 ACEI, angiotensin-converting enzyme inhibitor; ALDO ANT, aldosterone antagonist; ARB, angiotensin II receptor antagonist; BB, β-blocker; CCB, calcium channel blocker; CVD, cardiovascular disease; MI, myocardial infarction; SBP, systolic blood pressure; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor Adapted from reference 49: Chobanian AV, et al. Hypertension. 2003;42:

15 could theoretically overcome the vasoconstrictive activity of the VEGF/VEGFR antagonists, but they have not been formally and specifically evaluated in this setting. Patients who require more than 3 drugs for blood pressure control should be referred to a specialist and evaluated for causes of secondary hypertension. 49 events will improve our understanding of the drugs mechanisms of action and facilitate the development of effective toxicity management strategies. References 1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, CA Cancer J Clin. 2007;57: FATIGUE Fatigue is a common side effect reported in patients using antibody and small-molecule angiogenesis inhibitors. The incidence of fatigue varies among patients receiving either antibodies or TKIs that target EGFR, VEGF, and/or VEGFR. 36,37 Bevacizumab has been associated with a 16% rate of grade 3-5 fatigue in the treatment of NSCLC. 36 Sorafenib and sunitinib have shown rates of grade 3-4 fatigue of 5% and 9%, respectively. 37,38 However, it is important to remember that fatigue is also a common complaint in patients with advanced malignant disease, which is where these targeted biologic agents are primarily used. Therefore, it is difficult to differentiate if the fatigue is caused by the disease or by the targeted biologic therapy. For example, although the rate of fatigue with bevacizumab was 16%, the rate in the placebo group was not much lower (13%). 36 The National Comprehensive Cancer Network has developed clinical practice guidelines for managing cancer-related fatigue. 50 In diagnosing, evaluating, and managing cancer-related fatigue, these guidelines are helpful when concerned about fatigue in patients being treated with angiogenesis inhibitors. Conclusion The palliative treatment of NSCLC has been rapidly evolving over the past few years. Molecular-targeted drugs are now part of the routine management of these patients, providing more therapeutic options associated with improvements in both survival and quality of life. The EGFR inhibitor erlotinib and the VEGF inhibitor bevacizumab are indicated for use in metastatic NSCLC. Other targeted agents, including sorafenib, sunitinib, and vandetanib, are under investigation for the treatment of NSCLC. Despite more favorable side-effect profiles, as compared with conventional cytotoxic chemotherapy, these agents exhibit unique toxicities that have only recently come to appreciation. The systematic evaluation of these adverse 2. Bulzebruck H, Bopp R, Drings P, et al. New aspects in the staging of lung cancer. Prospective validation of the International Union Against Cancer TNM classification. Cancer. 1992;70: Mountain CF. Revisions in the international system for staging lung cancer. Chest. 1997;111: 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. BMJ. 1995;311: Jaakkimainen L, Goodwin PJ, Pater J, Warde P, Murray N, Rapp E. Counting the costs of chemotherapy in a National Cancer Institute of Canada randomized trial in nonsmall-cell lung cancer. J Clin Oncol. 1990;8: Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. The Elderly Lung Cancer Vinorelbine Italian Study Group. J Natl Cancer Inst. 1999;91: Anderson H, Hopwood P, Stephens RJ, et al. Gemcitabine plus best supportive care (BSC) vs BSC in inoperable non-small cell lung cancer a randomized trial with quality of life as the primary outcome. UK NSCLC Gemcitabine Group. Non-Small Cell Lung Cancer. Br J Cancer. 2000;83: Lilenbaum RC, Langenberg P, Dickersin K. Single agent versus combination chemotherapy in patients with advanced nonsmall cell lung carcinoma: a meta-analysis of response, toxicity, and survival. Cancer. 1998;82: 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. J Clin Oncol. 2000;18: Wozniak AJ, Crowley JJ, Balcerzak SP, et al. Randomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of advanced non-small-cell lung cancer: a Southwest Oncology Group study. J Clin Oncol. 1998;16: Gatzemeier U, von Pawel J, Gottfried M, et al. Phase III comparative study of high-dose cisplatin versus a combination of paclitaxel and cisplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol. 2000;18: Lilenbaum RC, Herndon JE 2nd, List MA, et al. Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: the cancer and leukemia group B (study 9730). J Clin Oncol. 2005;23:

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