Lung cancer is the leading cause of cancer deaths in the United

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1 ORIGINAL ARTICLE Randomized, Double-Blinded, Multicenter, Phase II Study of Pemetrexed, Carboplatin, and Bevacizumab with Enzastaurin or Placebo in Chemonaïve Patients with Stage IIIB/IV Non-small Cell Lung Cancer Hoosier Oncology Group LUN Erin M. Casey, MD,* Wael Harb, MD, Daniel Bradford, MD, Jose Bufill, MD, FACP, Sreenivasa Nattam, MD, Jyoti Patel, MD, # William Fisher, MD, ** Jane E. Latz, MS, Xiaochun Li, PhD,* Jingwei Wu, MS,* and Nasser Hanna, MD* Introduction: Bevacizumab is approved in combination with chemotherapy as first-line treatment for non-small cell lung cancer (NSCLC). Preclinical data suggest that enzastaurin and bevacizumab may have complementary effects in inhibiting angiogenesis. Methods: Eligibility criteria: 18 years of age, chemonaïve, stage IIIB/IV nonsquamous NSCLC, and Eastern Cooperative Oncology Group performance status 0 to 1. Patients were randomized to placebo or enzastaurin 500 mg orally daily (after a loading dose), plus pemetrexed 500 mg/m 2, carboplatin area under the curve 6, and bevacizumab 15 mg/kg, intravenously, every 21 days for four cycles. Patients without progression received maintenance therapy with bevacizumab and placebo or enzastaurin. The primary objective was progression-free survival (PFS). Planned sample size was 90 patients, one-sided alpha of 0.20, with two interim analyses: one for safety and the second for futility, with a PFS hazard ratio of Results: Forty patients were randomized. No unique safety concerns were noted at the first interim analysis. The early stopping rule for futility was met at the second interim analysis. Median PFS was 3.5 months and 4.3 months (hazard ratio: 1.04, 95% confidence interval: ), and response rates were 20% and 30% (p 0.462) for enzastaurin and placebo, respectively. Grade 3 or 4 toxicity was similar between the two arms. Two patients died on study because of respiratory arrest and pulmonary embolism. An additional patient *Indiana University, Indianapolis; Horizon Oncology Center, Lafayette; Hoosier Oncology Group, Indianapolis, Indiana; Highlands Oncology Group, Fayetteville, Arkansas; Northern Indiana Cancer Research Consortium, CCOP, South Bend; Fort Wayne Medical Oncology/Hematology, Inc., Fort Wayne, Indiana; #Northwestern University, Chicago, Illinois; **Medical Consultants, Muncie; and Eli Lilly and Company, Indianapolis, Indiana. Disclosure: Jane E. Latz, MS, is a full-time employee of Eli Lilly and Company and a stockholder via the company s 401K plan. Address for correspondence: Nasser Hanna, MD, 535 Barnhill Dr RT 473, Indianapolis, IN nhanna@iupui.edu Trial data were reported in part at the 2009 Annual Meeting of the American Society of Clinical Oncology. Copyright 2010 by the International Association for the Study of Lung Cancer ISSN: /10/ died of sepsis secondary to a gastrointestinal perforation 30 days after study treatment discontinuation. Conclusions: Enzastaurin does not improve efficacy when combined with pemetrexed, carboplatin, and bevacizumab. This combination does not warrant further study in NSCLC. Key Words: Non-small cell lung cancer, Enzastaurin, Bevacizumab. (J Thorac Oncol. 2010;5: ) Lung cancer is the leading cause of cancer deaths in the United States with more than 150,000 deaths projected. 1 Approximately 85% of patients with lung cancer have non-small cell lung cancer (NSCLC), the majority of who present with advanced disease. Platinum-based chemotherapy has demonstrated a survival advantage over best supportive care. 2 4 Studies with the antimetabolite, pemetrexed, combined with carboplatin in chemonaïve patients with advanced NSCLC have yielded similar efficacy results as other platinum doublets with less toxicity. 5 7 Pemetrexed has been approved in combination with cisplatin in the first-line setting of nonsquamous NSCLC. 8 The role of angiogenesis in the progression of lung cancer has been well described, and inhibition of angiogenesis is a therapeutic strategy in many tumor types, including lung cancer. 9 Overexpression of vascular endothelial growth factor (VEGF) has been associated with poor prognosis in patients with NSCLC. 10,11 In addition to decreasing formation of new blood vessels, it is also felt that blocking VEGF may improve drug delivery by lowering interstitial pressure to tumors. 12 Bevacizumab is a humanized monoclonal antibody that blocks VEGF and has been studied in thousands of patients in multiple tumor types. A large, randomized, phase III study demonstrated a 2-month improvement in median survival when bevacizumab was combined with carboplatin and paclitaxel in patients with stages IIIB and IV NSCLC. 13 Bevacizumab has subsequently been approved in this setting. The phase III AVAiL study combined cisplatin, gemcitabine, Journal of Thoracic Oncology Volume 5, Number 11, November

2 Casey et al. Journal of Thoracic Oncology Volume 5, Number 11, November 2010 and either bevacizumab or placebo, and the primary endpoint of progression-free survival (PFS) was 6.7 months and 6.1 months, respectively. 14 A recent phase II study combining pemetrexed, carboplatin, and bevacizumab demonstrated a manageable safety profile and promising efficacy in patients with nonsquamous NSCLC. 15 Enzastaurin HCl, an oral serine/threonine kinase inhibitor, targets the protein kinase C (PKC) and phosphoinositide 3-kinase/AKT pathways to inhibit tumor cell proliferation, induce tumor cell apoptosis, and suppress tumor-induced angiogenesis. These pathways are specifically activated in endothelial cells in response to angiogenic stimuli such as VEGF. Prior studies have suggested pharmacological inhibition of PKC as a treatment strategy for multiple tumor types In animal models, oral dosing with enzastaurin suppresses VEGF-induced angiogenesis and the growth of human colon cancer and glioblastoma xenografts. 19 It is hypothesized that further inhibition of VEGF-induced angiogenesis through the PKC pathway with enzastaurin may enhance the antiangiogenic effects of bevacizumab. Additionally, recent preclinical investigation suggests that pemetrexed and enzastaurin can produce additive or even synergistic antitumor activity in freshly explanted primary tumor specimens. 20 We conducted a randomized, double-blinded, phase II study to investigate the addition of enzastaurin to the combination of pemetrexed, carboplatin, and bevacizumab in chemonaïve patients with advanced nonsquamous NSCLC. PATIENTS AND METHODS Eligibility Criteria Patients were enrolled from participating sites of the Hoosier Oncology Group. Patients met the following eligibility criteria: age 18 years; histologic or cytologic evidence of nonsquamous NSCLC (stage IIIB or IV); no prior systemic chemotherapy, immunotherapy, targeted therapy, or biologic therapy for advanced disease; presence of measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.0); Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1; and adequate baseline hematologic, renal, and hepatic function. Prior radiotherapy was allowed to 25% of the bone marrow if completed 2 weeks before randomization. Pregnant or lactating women were excluded, and males and female patients with childbearing potential were required to use contraception during and for 3 months after discontinuation (DC) of the study. Patients were excluded if they had central nervous system disease; major surgery, open biopsy, or trauma 28 days before randomization; history of gastrointestinal fistula, perforation, or abscess, inflammatory bowel disease, or diverticulitis within 6 months; significant vascular disease; evidence of bleeding diathesis or coagulopathy; history of hemoptysis within 3 months before randomization; history of serious cardiac condition within 6 months before randomization or QTc prolongation 450 (men) or 470 (women) msec or family history of congenital long-qtcsyndrome; third-space fluid collections; inability to interrupt aspirin or other nonsteroidal antiinflammatory drugs; anticoagulation with warfarin or an equivalent; inadequately controlled hypertension or history of hypertensive crisis; or baseline proteinuria. All patients gave written informed consent, and the local institutional review boards at each site approved the protocol before enrollment. The trial was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. Study Design and Treatment Plan The primary objective of this randomized, multicenter, double-blinded phase II study was to compare PFS between pemetrexed, carboplatin, bevacizumab, and enzastaurin followed by maintenance bevacizumab and enzastaurin (enzastaurin arm) with pemetrexed, carboplatin, bevacizumab, and placebo followed by maintenance bevacizumab and placebo (placebo arm). Secondary objectives included evaluation of response rates, overall survival (OS), and toxicity. Random assignment to treatment groups was determined by a computer-generated random sequence using an interactive voice response system and was stratified for ECOG PS (0 or 1), disease stage (IIIB or IV), and investigative site. Patients were balanced between treatment arms in each stratum for each prognostic factor by using the algorithm of Pocock and Simon. A loading dose of enzastaurin, 375 mg, or placebo was given three times on day 1, followed by 500 mg enzastaurin or placebo orally once daily until progressive disease (PD) or DC. Up to four cycles of pemetrexed carboplatin bevacizumab administered once every 21 days (q21d) beginning on day 7: pemetrexed 500 mg/m 2 intravenously over 10 minutes, carboplatin area under the curve of 6 intravenously over 30 minutes, and bevacizumab 15 mg/kg intravenously over 90 minutes. If no PD after four cycles of pemetrexed carboplatin bevacizumab, additional cycles of bevacizumab were administered q21d until PD or DC. All patients also received folic acid, vitamin B12, and dexamethasone as stated in the pemetrexed label. Enzastaurin or placebo was held for drug-related febrile neutropenia, absolute neutrophil count 500/liter for more than 7 days, platelet count 25,000, and grade 3 or 4 transaminase elevations or other grade 3 or 4 nonhematologic toxicity. If the event resolved to grade 1 or better, patients were allowed to continue with enzastaurin or placebo at a dose reduction of 250 mg orally daily. If, after restarting enzastaurin or placebo, the patient did not have recurrence of the event after 14 days of therapy, the dose could be reescalated to the full dose (500 mg) at the discretion of the investigator. If the event did not resolve after 21 days or another event occurred during therapy with the 250 mg dose, patients were discontinued from enzastaurin or placebo. Before treatment with carboplatin and pemetrexed, patients were required to have absolute neutrophil count 1500/liter, platelets 75,000/liter, and a creatinine clearance of 45 ml/min. Treatment was delayed to allow sufficient time to recover and then carboplatin and pemetrexed were dose reduced based on the nadir of blood counts from the previous cycle. Dose reductions were also allowed for any grade 3 or 4 nonhematologic toxicity. Patients who required a dose reduction continued to receive a reduced dose for the remain Copyright 2010 by the International Association for the Study of Lung Cancer

3 Journal of Thoracic Oncology Volume 5, Number 11, November 2010 Pemetrexed, Carboplatin, and Bevacizumab der of the study with the exception of enzastaurin, which could be reescalated. If there was a recurrence of grade 3 or 4 toxicities, either hematologic or nonhematologic, after two dose reductions or if there was a delay of longer than 42 days, carboplatin and pemetrexed were discontinued. No dose reductions were allowed for bevacizumab. Bevacizumabrelated adverse events that required treatment DC or interruption for up to 2 months included hypertension, hemorrhage, venous thrombosis, arterial thromboembolic events, congestive heart failure, proteinuria, gastrointestinal perforation, bowel obstruction, and wound dehiscence. Patients requiring DC of any of the study medications were allowed to continue with the other medications provided those medications were not believed to contribute to the reason for DC. Baseline and Treatment Assessments The baseline assessment included a history and physical examination, complete blood count, comprehensive blood chemistry, calculated creatinine clearance, and assessment of disease with computerized tomography, magnetic resonance imaging, or chest radiograph. Physical examinations, ECOG PS, and toxicity evaluations (graded using Common Terminology Criteria for Adverse Events version 3.0) were completed before each cycle, hematology was done weekly, and disease assessment occurred every other cycle (every 6 weeks 1 week). Twelve-lead electrocardiograms were done at baseline, in cycles 2 and 4, and at post-dc follow-up. Response was measured using RECIST, and all responses were confirmed a minimum of 4 weeks after the initial response was recorded. PFS was defined as the time from randomization to the first date of objectively determined PD or death from any cause. Patients who were alive at the time of data cutoff and did not have objective PD were censored at the date of the last objective progression-free assessment. After DC from all study treatment, patients who received subsequent anticancer therapy before objective PD or death were censored at the date of the last objective progression-free assessment before initiation of post-dc anticancer therapy. OS was defined as the time from date of randomization to the date of death from any cause. Statistical Analyses Statistical analyses were performed using SAS version 9.1 (SAS Institute Inc., Cary, NC). Unless otherwise noted, all tests of treatment effects were conducted at a two-sided alpha level of 0.05, with 95% confidence intervals (CIs). All patients who were randomized were included in the time-toevent analyses, and all patients who received at least one dose of study drug were included in the safety analyses. Kaplan- Meier estimates were used to assess PFS and OS, and the 2 or Fisher s exact test was used to assess response rates. The initial study plan was to enroll 90 patients (45/arm) with the final analysis of PFS after a minimum of 57 events (PD or death) using a log-rank test with one-sided alpha of This provided approximately 70% statistical power to detect superiority of the enzastaurin arm over the placebo arm assuming a hazard ratio (HR) of 0.7, based on a 6.2-month median PFS for the placebo arm 13 and a 9-month median PFS for the enzastaurin arm. There were two planned interim analyses, the first (safety only) after 20 patients had been treated for one cycle and the second (efficacy and safety) after 45 patients had been treated for one cycle. A PFS HR of the enzastaurin arm versus the placebo arm of greater than was the efficacy criterion for futility. RESULTS The first planned interim analysis occurred on June 5, 2008, and the study was continued without modification. Subsequently, two patients experienced gastrointestinal perforations that required emergency surgery. The principal investigator and sponsor suspended patient accrual on July 3, 2008, to allow for further review of the safety data for these patients. The protocol was then amended to include the second interim analysis after 40 patients had been treated. The second analysis was to determine whether there was sufficient evidence of lack of efficacy or excessive toxicity. The study was terminated early on November 7, 2008, because of futility as prespecified HR of for the comparison of enzastaurin versus placebo with no evidence of excess toxicity. Patient Characteristics Between October 2007 and July 2008, 40 patients were randomly assigned to receive either enzastaurin or placebo. Baseline demographics and disease characteristics were well balanced between the two treatment arms and are presented in Table 1. The mean age was 61.6 years, 85.0% of patients had stage IV disease, and 52.5% had a baseline ECOG PS of 0. Treatment Administered All 40 patients enrolled received at least one dose of treatment. The mean number of cycles for the enzastaurin arm was 4.8, whereas the placebo arm averaged 6.4 cycles. The actual mean dose for enzastaurin was mg compared with the planned mean dose of 500 mg. In addition, compliance rates for enzastaurin and placebo ranged from 97 to 100% throughout the study. Three patients required dose adjustment of enzastaurin or placebo because of adverse events. The most common reason for DC was disease progression, reported in 12 patients (60%) on the enzastaurin arm and 13 (65%) on the placebo arm. Efficacy The median PFS for enzastaurin (n 20) was 3.5 months compared with placebo (n 20), which was 4.3 months (Figure 1, Table 2). The HR at the time of the second interim analysis was 0.94 (p 0.774) and at the time of the final analysis was 1.04 (95% CI: ; p 0.925). Four (20%) partial responses (PRs) were reported on the enzastaurin arm and 6 (30%) on the placebo arm (Table 2). The disease control rate (CR PR stable disease [SD]) for the enzastaurin arm was 55% compared with 75% for the placebo arm (p 0.175). Median OS was 9.1 months for enzastaurin and 7.6 months for placebo with a HR of 0.83 (95% CI: ; p 0.492). The number of patients censored at the time of the final analysis was 60% and 45% for enzastaurin and placebo, respectively. Copyright 2010 by the International Association for the Study of Lung Cancer 1817

4 Casey et al. Journal of Thoracic Oncology Volume 5, Number 11, November 2010 TABLE 1. Patient Demographics and Baseline Characteristics Parameters Enzastaurin (N 20) Placebo (N 20) Total (N 40) Age, mean (SD) 62.1 (9.3) 61.2 (9.0) 61.6 (9.1) Gender, n (%) Male 11 (55.0) 10 (50.0) 21 (52.5) Female 9 (45.0) 10 (50.0) 19 (47.5) Smoking status, n (%) Never smoked 0 (0.0) 1 (5.0) 1 (2.5) Has not smoked in 3 (15.0) 3 (15.0) 6 (15.0) 30 years Quit 3 months ago 7 (35.0) 8 (40.0) 15 (37.5) but 30 years ago Current smoker or quit 10 (50.0) 8 (40.0) 18 (45.0) 3 months ago ECOG performance status, n (%) 0 10 (50.0) 11 (55.0) 21 (52.5) 1 10 (50.0) 9 (45.0) 19 (47.5) Prior therapy, n (%) Yes 3 (15.0) 3 (15.0) 6 (15.0) No 17 (85.0) 17 (85.0) 34 (85.0) Disease stage, n (%) IIIB 3 (15.0) 3 (15.0) 6 (15.0) IV 17 (85.0) 17 (85.0) 34 (85.0) Site of metastasis, n (%) Lung 8 (40.0) 7 (35.0) 15 (37.5) Pleural fluid 5 (25.0) 3 (15.0) 8 (20.0) Adrenal 4 (20.0) 7 (35.0) 11 (27.5) Liver 5 (25.0) 2 (10.0) 7 (17.5) Bone 8 (40.0) 7 (35.0) 15 (37.5) Other 5 (25.0) 8 (40.0) 13 (32.5) None 2 (10.0) 0 (0.0) 2 (5.0) Percentage is calculated based on N. N, total randomized treated patients; n, number of patients; SD, standard deviation; ECOG, Eastern Cooperative Oncology Group. TABLE 2. (N 40) Parameters Progression-Free Survival and Response Rates Enzastaurin (N 20) Placebo (N 20) p Median PFS (months)* * Patients censored (%) 5 (25) 2 (10) Responses (%) Complete response 0 0 Partial response 4 (20) 6 (30) Stable disease 7 (35) 9 (45) Progressive disease 5 (25) 4 (20) Unassessable 4 (20) 1 (5) Response rate (CR PR) 4 (20) 6 (30) Disease control rate (CR PR SD) 11 (55) 15 (75) PFS, progression-free survival; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease. * Unstratified log-rank test. Because of lack of disease evaluation. Comparison was based on an unadjusted, normal-distribution approximation for the difference in rates. Toxicity All 40 patients were evaluable for toxicity. Fifty percent of enzastaurin patients and 70% of placebo patients experienced at least one grade 3 or 4 adverse event possibly related to treatment (Table 3). The most commonly reported adverse events on both arms included nausea, vomiting, diarrhea, fatigue, and epistaxis. The most common hematological adverse events on both arms were thrombocytopenia and anemia. One patient on each treatment arm experienced a gastrointestinal perforation. Both patients had a history of diverticulosis. One of the patients on the enzastaurin arm had a history of a gastrointestinal fistula within 6 months of study entry and was subsequently determined to have been ineligible for the study. Four patients on the enzastaurin arm discontinued treatment because of adverse events including diverticulitis, in- ee Survival Distribution Fu unction Pr rogression-fr Enzastaurin Placebo 0.0 FIGURE Kaplan-Meier curves Time (months) Copyright 2010 by the International Association for the Study of Lung Cancer

5 Journal of Thoracic Oncology Volume 5, Number 11, November 2010 Pemetrexed, Carboplatin, and Bevacizumab TABLE 3. Select Grade 3 or 4 Toxicity (N 40) Toxicity Enzastaurin, n (%) Placebo, n (%) Neutropenia 3 (15) 6 (30) Febrile neutropenia 0 (0) 1 (5) Anemia 3 (15) 2 (10) Thrombocytopenia 3 (15) 5 (25) Thrombosis 1 (5) 1 (5) Pulmonary hemorrhage 1 (5) 0 (0) GI perforation 1 (5) 1 (5) n, number of patients; GI, gastrointestinal. creased creatinine, and pulmonary hemorrhage. One patient on the placebo arm discontinued treatment because of a gastrointestinal perforation. Two patients died of adverse events while on study or within 30 days of treatment DC. The death on the enzastaurin arm was from sepsis after developing a gastrointestinal perforation. The death on the placebo arm was due to a pulmonary embolus. There was no statistically significant difference in toxicity between the enzastaurin and placebo treatment arms. DISCUSSION This is the first study in NSCLC evaluating chemotherapy in combination with bevacizumab and the serine/threonine kinase inhibitor, enzastaurin. The PFS of 3.5 months for enzastaurin compared with 4.3 months for placebo met the futility parameter to discontinue the study early. In addition, there was no statistical difference in response rates between the enzastaurin and placebo treatment arms. Notably, the PFS was 4.3 months for the placebo group in our study, whereas a PFS of 7.8 months was reported by Patel et al. 15 in a phase II study of pemetrexed, carboplatin, and bevacizumab. This difference may be partly explained by the fact that the study by Patel et al. continued maintenance pemetrexed in addition to maintenance bevacizumab, whereas our study stopped pemetrexed after four cycles of therapy. Data presented by Schuette et al. 21 at the 2009 European Society for Medical Oncology meeting suggest that cisplatin and pemetrexed may be more efficacious than carboplatin and pemetrexed in advanced NSCLC. Consideration should be given to combining pemetrexed with cisplatin in future studies of advanced NSCLC. The number of patients with liver metastases was higher in the enzastaurin arm (25%) compared with the placebo arm (10%). This is another possible explanation as to the failure of enzastaurin to improve PFS when combined with chemotherapy and bevacizumab in our study. There was also difference in the number of cycles administered between the two arms, 4.8 for enzastaurin and 6.4 for placebo. There was no statistical difference in toxicity to explain this and the main reason for DC was progression. It is possible that this difference could represent interference of chemotherapy delivery by enzastaurin but more likely highlights the overall lack of efficacy of enzastaurin in NSCLC. In our study, two patients, one on each arm, had a history of diverticulosis and developed gastrointestinal perforations. Gastrointestinal perforations are a known complication of bevacizumab, and its use is contraindicated in patients with a history of perforation, abscess, or fistula. Patel et al. 15 reported four patients (8%) who developed diverticulitis, including one bowel perforation, while receiving pemetrexed, carboplatin, and bevacizumab. All four patients had a history of diverticulosis or diverticulitis; the study was subsequently amended to exclude those patients. These findings suggest that bevacizumab should be used with caution in patients with a history of diverticulosis or diverticulitis in future studies. Enzastaurin was first studied in advanced NSCLC as a single agent. Oh et al. 22 evaluated 55 patients who were treated with enzastaurin as second- or third-line therapy for stage IIIB or IV NSCLC. All patients had received prior therapy with a platinum-based regimen. No objective responses were observed, the median PFS was 1.8 months, and OS was 8.4 months. Seven patients (13%) had median PFS 6 months, and enzastaurin was well tolerated with very few grade 3 toxicities. In a recent randomized phase II study, 218 patients randomly received pemetrexed, carboplatin, and enzastaurin; pemetrexed and carboplatin; or docetaxel and carboplatin. 23 The median OS for the three arms was 7.2, 11.8, and 9.4 months, respectively. The addition of enzastaurin did not improve the activity of pemetrexed and carboplatin. Toxicity did not seem to increase with the combination of enzastaurin and chemotherapy. With improved understanding of the molecular biology of cancer, we continue to see the development of new targeted agents. Many clinical trials are now evaluating various targeted agents in combination with bevacizumab. In NSCLC, bevacizumab has been combined with the endothelial growth factor receptor inhibitor, erlotinib. 24,25 A phase III randomized, double-blinded, placebo-controlled trial in patients with advanced NSCLC compared bevacizumab and erlotinib with placebo and erlotinib (Bevacizumab [Avastin] in combination with Erlotinib in the Treatment of Advanced non-small cell lung cancer [BETA] trial). 25 The primary endpoint of OS was not statistically significant at 9.3 and 9.2 months, respectively. There was, however, significant improvement in PFS and overall response rates, and the toxicity was similar to the known toxicities of each agent. The endothelial growth factor receptor inhibitor, cetuximab, has also been combined with bevacizumab in advanced NSCLC. A phase II study by the Southwest Oncology Group combined carboplatin, paclitaxel, bevacizumab, and cetuximab, for up to six cycles, followed by bevacizumab and cetuximab maintenance until disease progression. 26 PFS was 7 months, OS was 14 months, and the conclusion was that this regimen was tolerable and demonstrated promising efficacy. Preclinical studies have suggested that combined anti- VEGF therapy may further inhibit tumor growth, which our study was designed to evaluate. A phase I study by Azad et al. 27 combined sorafenib, a multikinase inhibitor with anti- VEGF activity, and bevacizumab in 39 patients with advanced cancer. PRs or disease stabilization 4 months was seen in 22 of 37 patients (59%). Despite using a lower dose than the approved dose, an increased rate of toxicity occurred with the combination of sorafenib and bevacizumab com- Copyright 2010 by the International Association for the Study of Lung Cancer 1819

6 Casey et al. Journal of Thoracic Oncology Volume 5, Number 11, November 2010 pared with that previously reported with single agent use. In addition, 74% of patients required dose reductions of sorafenib. Sorafenib has also been combined with bevacizumab in renal cell carcinoma. 28 Toxicity, specifically hand-foot syndrome, led to lower median tolerated doses of both agents. The results of these two studies suggest that combined antiangiogenic therapy may have higher rates of toxicity and lead to lower tolerable doses. Efficacy with these lower doses is not fully known. Our study of combined antiangiogenic therapy was well tolerated and did not show increased toxicity when combining enzastaurin with bevacizumab, when compared with placebo. An ongoing phase I trial is investigating the combination of carboplatin, paclitaxel, bevacizumab, and sorafenib in patients with untreated stage IIIB and IV NSCLC, which will also help to address the toxicity profile of combining VEGF inhibitors. 29 In conclusion, enzastaurin in combination with pemetrexed, carboplatin, and bevacizumab failed to demonstrate an improvement in PFS compared with pemetrexed, carboplatin, bevacizumab, and placebo for the first-line treatment of advanced nonsquamous NSCLC. This combination will not be pursued further in NSCLC by the Hoosier Oncology Group. ACKNOWLEDGMENTS Supported by Eli Lilly and Company. The authors thank Noelle Gasco for editorial assistance; study team colleagues at Hoosier Oncology Group and Eli Lilly & Company study personnel at each of the investigator sites; and patients and families for their willingness to participate in studies aiming to advance the standard of care in NSCLC. REFERENCES 1. Jemal A, Siegel R, Ward E, et al. 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