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Originally published as JCO Early Release 10.1200/JCO.2007.12.3026 on October 1 2007 © 2007 American Society of Clinical Oncology. Phase II Study of Efficacy and Safety of Bevacizumab in Combination With Chemotherapy or Erlotinib Compared With Chemotherapy Alone for Treatment of Recurrent or Refractory Non–Small-Cell Lung Cancer
From The M.D. Anderson Cancer Center, Houston, TX; Genentech Inc, South San Francisco; Kaiser Permanente Northern California, Vallejo; Bay Area Cancer Research Group, Concord, CA; University of Pittsburgh Cancer Institute, Pittsburgh, PA; Rush University Medical Center, Chicago, IL; Florida Cancer Specialists, Ft Meyers, FL; and Vanderbilt University, Nashville, TN Address reprint requests to Roy S. Herbst, MD, PhD, The M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 432, Houston, TX 77030; e-mail: rherbst{at}mdanderson.org
Purpose Bevacizumab, a humanized anti–vascular endothelial growth factor monoclonal antibody, and erlotinib, a reversible, orally available epidermal growth factor receptor tyrosine kinase inhibitor, have demonstrated evidence of a survival benefit in the treatment of non–small-cell lung cancer (NSCLC). A single-arm phase I and II study of bevacizumab plus erlotinib demonstrated encouraging efficacy, with a favorable safety profile. Patients and Methods A multicenter, randomized phase II trial evaluated the safety of combining bevacizumab with either chemotherapy (docetaxel or pemetrexed) or erlotinib and preliminarily assessed these combinations versus chemotherapy alone, as measured by progression-free survival (PFS). All patients had histologically confirmed nonsquamous NSCLC that had progressed during or after one platinum-based regimen. Results One hundred twenty patients were randomly assigned and treated. No unexpected adverse events were noted. Fewer patients (13%) in the bevacizumab-erlotinib arm discontinued treatment as a result of adverse events than in the chemotherapy alone (24%) or bevacizumab-chemotherapy (28%) arms. The incidence of grade 5 hemorrhage in patients receiving bevacizumab was 5.1%. Although not statistically significant, relative to chemotherapy alone, the risk of disease progression or death was 0.66 (95% CI, 0.38 to 1.16) among patients treated with bevacizumab-chemotherapy and 0.72 (95% CI, 0.42 to 1.23) among patients treated with bevacizumab-erlotinib. One-year survival rate was 57.4% for bevacizumab-erlotinib and 53.8% for bevacizumab-chemotherapy compared with 33.1% for chemotherapy alone. Conclusion Results for PFS and overall survival favor combination of bevacizumab with either chemotherapy or erlotinib over chemotherapy alone in the second-line setting. No unexpected safety signals were noted. The rate of fatal pulmonary hemorrhage was consistent with previous bevacizumab trials. The toxicity profile of the bevacizumab-erlotinib combination is favorable compared with either chemotherapy-containing group.
Lung cancer remains the leading cause of cancer-related death in the world. The overall prognosis remains poor; fewer than 15% of patients are alive after 5 years.1 Approximately 40% of patients diagnosed with lung cancer present with advanced non–small-cell lung cancer (NSCLC).1 Although 30% to 40% of patients respond initially to cytotoxics, these treatments seemingly reach a therapeutic plateau,2,3 and all patients eventually experience progression on or after treatment.4 Median survival time for these patients is only 8 to 10 months. However, as observed in the Eastern Cooperative Oncology Group (ECOG) E4599 pivotal study, the addition of bevacizumab to chemotherapy increased median survival time beyond the 12-month threshold.5 The vascular endothelial growth factor (VEGF) and human epidermal growth factor receptor (HER-1/EGFR) have been identified as key molecular targets for therapy in NSCLC.5,6 Bevacizumab (Avastin; Genentech, South San Francisco, CA) is a recombinant, humanized, anti-VEGF monoclonal antibody that received recent US Food and Drug Administration approval for use in combination with carboplatin and paclitaxel chemotherapy, followed by bevacizumab alone until disease progression, for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic nonsquamous NSCLC.7 Erlotinib (Tarceva; Genentech) is an oral HER-1/EGFR tyrosine kinase inhibitor that is indicated for the treatment of locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen.8 Several lines of evidence lent support to the notion that combining erlotinib and bevacizumab for the treatment of recurrent NSCLC might confer additional clinical benefit. First, preclinical data in colon cancer cell lines had demonstrated that the activity of erlotinib and bevacizumab is at least additive and may be synergistic (Genentech, unpublished data). Second, it had been proposed that a dual approach that targeted both the tumor (by inhibiting EGFR signaling) and the endothelial cells that would ultimately support growth of the tumor (by inhibiting VEGF) could be more effective.9 Finally, the use of two targeted agents would potentially have the added benefit of having fewer nonspecific toxicities than chemotherapy.10 A phase I and II trial (n = 40) of erlotinib plus bevacizumab in patients with advanced, nonsquamous NSCLC who had experienced progression after at least one cycle of systemic chemotherapy previously established an effective dose for this combination, which was erlotinib 150 mg/d orally plus bevacizumab 15 mg/kg intravenous on day 1 of every 21-day cycle. This dosage resulted in a response rate of 14.3%, progression-free survival (PFS) time of 6.2 months, and median survival time of 12.6 months.11 This study was designed to further evaluate the efficacy and safety of bevacizumab in combination with chemotherapy or erlotinib, compared with chemotherapy alone, in patients with refractory, locally advanced or metastatic nonsquamous NSCLC.
Eligibility Key inclusion criteria were as follows: adequate hematologic, hepatic, and renal function; progression after one platinum-based chemotherapy regimen for unresectable locally advanced or metastatic nonsquamous NSCLC; and written, informed consent. Key exclusion criteria included the following: prior anti-VEGF and/or anti-EGFR therapy, chemotherapy, major surgery, or radiation therapy within 28 days before random assignment; presence of serious infection; history of clinically significant hematemesis, coagulopathy, or thrombosis; history of hemoptysis (> 1 teaspoon) or presence of cavitation; a central lesion or lesion abutting major blood vessels; CNS metastases; serious uncontrolled medical conditions, including uncontrolled heart disease or hypertension; or a history of myocardial infarction or stroke within 6 months before random assignment. Concomitant full-dose anticoagulants were not permitted.
Study Design and Treatments
The dose of bevacizumab in this study was 15 mg/kg administered by intravenous infusion on the first day of each 3-week cycle (± 5 days). The bevacizumab dose was based on the patient's weight at screening and remained unchanged throughout the study. The bevacizumab/placebo infusion was administered first, followed by the chemotherapy infusion or erlotinib administration. Erlotinib was administered orally at 150 mg/d for up to 52 weeks. The first dose was administered to patients in the clinic on day 0 after the bevacizumab/placebo infusion. Thereafter, tablets were taken at home, preferably in the morning, with up to 200 mL of water, at least 1 hour before or 2 hours after a meal. Toxicity as a result of erlotinib administration was managed by symptomatic treatment, dose interruptions, and/or adjustment of the erlotinib dose. Dose reductions were performed according to the label.8 Dose escalations for erlotinib were not allowed after a dose reduction. No dose reductions were allowed for bevacizumab. For patients randomly assigned to arms 1 and 2, docetaxel (Taxotere; Sanofi-Aventis, Bridgewater, NJ) or pemetrexed (Alimta; Eli Lilly, Indianapolis, IN) was delivered intravenously. Docetaxel was administered over 60 minutes (± 10 minutes) at a dose of 75 mg/m2 on the first day of each 3-week cycle (± 5 days). Pemetrexed was administered intravenously over 10 minutes (± 5 minutes) at a dose of 500 mg/m2 on the first day of each 3-week cycle. Premedication regimens for docetaxel and pemetrexed were administered as described in the respective prescribing information for each drug.12,13 Patients received full supportive care as needed, including hematopoietic growth factors, transfusions of blood and blood products, antibiotics, and so on. Patients with indwelling venous catheters could receive prophylaxis against catheter thrombosis as needed.
Study Assessments
Predictive Marker Assessments
Statistical Methods The emphasis of the efficacy analyses was on estimating the magnitude of the treatment effect difference between arm 2 (chemotherapy-bevacizumab) and arm 1 (chemotherapy-placebo) and between arm 3 (bevacizumab-erlotinib) and arm 1 (chemotherapy-placebo). This phase II trial was not sized to have adequate power to detect minimum clinically meaningful differences between treatment arms. The primary efficacy end point was PFS, which was defined as the time from random assignment until disease progression or death on study, whichever occurred earlier. Death on study was defined as death from any cause within 30 days of the last dose of study treatment. Kaplan-Meier methods were used to estimate median PFS for each arm. The hazard ratios (HRs) and 95% CI were estimated using the Cox proportional hazards regression model with stratification by random assignment factors (ECOG performance status and smoking history). For PFS, patients who had not experienced progression or death on study were censored on the date of the last tumor assessment. Patients without a postbaseline tumor assessment were considered nonresponders. Patients lost to follow-up were censored on the date of last contact.
Patient Characteristics Between October 2004 and November 2005, 122 patients at 51 sites were randomly assigned; 120 patients were treated. The two untreated patients (one in arm 2 and one in arm 3) were eligibility violators and were excluded from all analyses. There was one patient who was randomly assigned to the bevacizumab-chemotherapy arm but did not receive bevacizumab. As of September 2006, five patients remained on treatment (one in arm 1, two in arm 2, and two in arm 3), and the median follow-up time for all patients was 15.8 months. Baseline demographics across the three arms were comparable (Table 1). Although there were more female patients and more patients with bronchioloalveolar carcinoma (BAC) in arm 3, these differences were not statistically significant. The majority of patients were white (78.3%) and were former or current smokers (86.7%). Most patients (99.2%) had an ECOG performance status of 0 or 1. The most common cancer histology was adenocarcinoma (79.2%), of which 7.5% were BAC or BAC-like (Table 1). Seven tested patients (20%) had KRAS mutations (Table 1). Fifty-one (78.5%) of 65 patients with assessable tissue specimens scored positive for EGFR expression by immunohistochemistry (IHC), and 26.8% were positive by FISH analysis (Table 1). Fifty-three patients had both valid IHC and FISH results; 12 were IHC positive/FISH positive, 13 were IHC negative/FISH negative, 27 were IHC positive/FISH negative, and one was IHC negative/FISH positive (data not shown). One patient had an EGFR mutation out of 30 studied (Table 1).
Safety and Tolerability Drug discontinuation as a result of AE was greater in the chemotherapy-containing arms (24% in the chemotherapy-alone arm and 28% in the bevacizumab-chemotherapy arm compared with 13% in the bevacizumab-erlotinib arm; Table 2). Consistent with this, the incidence of severe AEs was higher in the chemotherapy-containing arms (55% in the chemotherapy arm and 41% in the bevacizumab-chemotherapy arm compared with 33% in the bevacizumab-erlotinib arm). There were six treatment-related deaths; two occurred in the chemotherapy-alone arm (one venous thrombosis and one unexplained), three occurred in the bevacizumab-chemotherapy arm (two pulmonary hemorrhages and one wound dehiscence), and one occurred in the bevacizumab-erlotinib arm (pulmonary hemorrhage).
Across all arms, the most common nonhematologic AE was fatigue (79 of 120 patients, 65.8%) followed by nausea (52 of 120 patients, 43.3%; Table 3). As expected, there was a greater incidence of rash and diarrhea in the bevacizumab-erlotinib arm (66.7% and 74.3%, respectively) compared with the other two arms (26.2% and 16.7% for arm 1, respectively, and 12.8% and 43.6%, respectively, for arm 2), whereas vomiting and alopecia were more common in the chemotherapy-containing arms.
Among the hematologic AEs (Table 3), the incidence of neutropenia was 24.3% in the chemotherapy-alone arm and 30.8% in the chemotherapy-bevacizumab arm and were higher than the incidence observed for the bevacizumab-erlotinib arm (10.3%). In addition, proportionally more AEs were grade 3 or 4 for the chemotherapy-containing arms than for arm 3. No grade 5 neutropenia was reported. There were two reported instances of febrile neutropenia, both in the bevacizumab-chemotherapy arm (Table 4). Anemia was observed with higher frequency in the two chemotherapy-containing arms (21% in the chemotherapy-alone arm and 33% in the bevacizumab-chemotherapy arm, a rate 2 to 3 times greater than for the bevacizumab-erlotinib arm, in which anemia was observed in approximately 10.3% of patients; Table 3). The incidence of thrombocytopenia was significantly higher in the bevacizumab-chemotherapy arm (seven of 39 patients, 17.9%) than in arms 1 or 3 (approximately 2.5% for both arms). There was one GI perforation (nonfatal) in the bevacizumab-chemotherapy arm (Table 4). The overall incidence of grade 3 to 5 hemorrhage was 4.2% (five of 120 patients). In patients who had received bevacizumab (arms 2 and 3), the incidence of grade 3 to 5 hemorrhage was 5.1% (four of 78 patients; Table 4). One patient in the bevacizumab-chemotherapy arm required surgery for GI hemorrhage and subsequently died of wound dehiscence (Table 4). The other three events (3.8%) were grade 5 pulmonary hemorrhages (Table 4). Two of these events (one in each bevacizumab-containing arm) occurred in patients who had cavitation at enrollment and were, therefore, protocol violations that were not discovered until retrospective review.
Efficacy The risk of disease progression or death among patients treated with bevacizumab-chemotherapy or bevacizumab-erlotinib compared with chemotherapy alone was 0.66 (95% CI, 0.38 to 1.16) and 0.72 (95% CI, 0.42 to 1.23), respectively (Table 5). The median PFS times for chemotherapy alone, bevacizumab-chemotherapy, and bevacizumab-erlotinib were 3.0, 4.8, and 4.4 months, respectively (Table 5). Median overall survival (OS) times were 8.6, 12.6, and 13.7 months for the chemotherapy alone, bevacizumab-chemotherapy, and bevacizumab-erlotinib arms, whereas the 1-year survival rates were 33.1%, 53.8%, and 57.4%, respectively. However, there was no clinically meaningful difference in PFS or OS observed between the bevacizumab-chemotherapy and bevacizumab-erlotinib arms (Fig 2). The PFS and OS observed for the chemotherapy-alone arm in this study are consistent with published data.19
A best response of complete response or partial response was reported for 12.2% of patients in the chemotherapy-alone arm, 12.5% of patients in the bevacizumab-chemotherapy arm, and 17.9% of patients in the bevacizumab-erlotinib arm. There were two complete responses, one each in the bevacizumab-chemotherapy and bevacizumab-erlotinib arms. Stable disease was reported for an additional 26.8%, 40.0%, and 33.3% of patients in arms 1, 2, and 3, respectively (Table 5). Thirteen patients from arm 1 and 15 patients from arm 2 received single-agent erlotinib after discontinuing study drug. Exploratory analyses to compare the combined bevacizumab-containing arms with the chemotherapy only arm demonstrate that the adjusted HR for the combined arms is 0.67, with a 10.3% increase in 6-month PFS rate (31.8% v 21.5%, respectively; Fig 2C). The 1-year survival rate was 22.4% higher (55.5% for combined bevacizumab-containing arms v 33.1% for chemotherapy only arm), with an adjusted HR of 0.73 (Fig 2D). In this study, chemotherapy in arms 1 and 2 was either pemetrexed or docetaxel based on the discretion of the investigator. In total, 46 patients received docetaxel, and 35 patients received pemetrexed (Table 1). OS in patients who received pemetrexed alone was not as long as previously observed (data not shown). However, the number of patients was small (Table 1). The one known EGFR mutation, which was in a patient randomly assigned to the bevacizumab-erlotinib arm, was detected and confirmed by two independent polymerase chain reaction/sequencing reactions for direct Sanger sequencing and also by the Surveyor platform. This patient had a complete response (duration, 9.7 months; OS, 13.8 months; PFS, 11.1 months). FISH-positive patients in the three arms exhibited similar PFS. For the FISH-negative patients, patients in the bevacizumab-erlotinib arm seemed to exhibit prolonged PFS (data not shown); however, the numbers were small (n = 11). Of the three patients in the bevacizumab-erlotinib arm who had a KRAS mutation, one had partial response (PFS, 149 days), one had stable disease (PFS, 93+ days, as a result of patient's decision to withdraw), and one had progressive disease (PFS, 121 days).
The VEGF and EGFR pathways represent two validated targets for NSCLC. There is strong biologic rationale for combining drugs that inhibit these pathways. In addition to the combination of bevacizumab and erlotinib, multitargeted oral agents designed to inhibit both the VEGF and EGFR pathways are currently under evaluation.20 In preclinical studies, small-molecule tyrosine kinase inhibitor agents targeting both EGFR and VEGF receptor have shown activity against NSCLC cell lines and against xenograft models resistant to treatment with tyrosine kinase inhibitors targeting solely EGFR.21 However, targeting the VEGF receptor and EGFR pathways with a single agent carries the potential disadvantage that optimal inhibition of the respective targets may not be achieved. This randomized, phase II, multicenter study suggests that, in the second-line setting, bevacizumab enhances the activity of chemotherapy and, in combination with erlotinib, has efficacy similar to the combination of bevacizumab and chemotherapy. However, because of the planned sample size of the trial, these data do not provide definitive conclusions or reach statistical significance with respect to differences between the arms. Because it avoids the toxicities of standard chemotherapy, the bevacizumab-erlotinib combination compares favorably to bevacizumab-chemotherapy and to chemotherapy alone in terms of safety. Bevacizumab has its own emerging group of class effects, such as hypertension and bleeding, which have been observed with all anti-VEGF agents. However, patient selection has greatly reduced the incidence of pulmonary hemorrhage in patients receiving bevacizumab. In this study, the rate of grade 5 hemorrhage in bevacizumab-treated patients was 5.1% (four of 78 patients). One patient had a severe GI hemorrhage and subsequently died from wound dehiscence, and three deaths were from pulmonary hemorrhage. On retrospective review of computed tomography scans, two of these patients had evidence of cavitation at the time of enrollment and, therefore, were protocol violators. Although the erlotinib-containing arm had higher incidences of grade 3 to 4 rash and diarrhea, the overall safety profile favored the bevacizumab-erlotinib combination. This was evidenced by the fact that fewer patients (13%) in the bevacizumab-erlotinib arm discontinued the study as a result of AE compared with patients in the chemotherapy alone (24%) and bevacizumab-chemotherapy (28%) arms. The 10.3% incidence of neutropenia in the bevacizumab-erlotinib arm was higher than what has been observed in previous studies. The higher rate of severe AEs observed in arm 1 may have been a result of the higher use of docetaxel in that arm. By EGFR gene amplification status, as assessed by FISH, there was no significant difference in patient outcome. However, among FISH-negative patients, those in the bevacizumab-erlotinib arm seemed to exhibit prolonged PFS. Among patients in the bevacizumab-erlotinib arm whose tumors harbored a KRAS mutation, which is a possible resistance marker to erlotinib monotherapy,17 best responses included one partial response, one stable disease, and one progressive disease. If these findings are confirmed in a larger study, it would be important because it would suggest that the combination of erlotinib and bevacizumab may be active in a broader population of patients compared with erlotinib alone. These trial results support examining the combination of bevacizumab and erlotinib in a phase III trial. If confirmed in a phase III setting, this combination may represent an alternative to chemotherapy. Ongoing randomized studies in advanced NSCLC are examining erlotinib-bevacizumab versus erlotinib-placebo and bevacizumab-erlotinib versus bevacizumab-placebo as maintenance therapy. Bevacizumab-erlotinib is also being studied in other tumor types.22 Given such potential for the combination of targeted agents, lung cancer therapy is showing new promise.
Employment or Leadership Position: Vincent J. O'Neill, Genentech (C); David Ramies, Genentech (C); Ming Lin, Genentech (C) Consultant or Advisory Role: Roy S. Herbst, Genentech (C); Chandra P. Belani, Genentech (C); Philip D. Bonomi, Genentech (C), OSI Pharmaceuticals (C); Alan Sandler, Genentech (C) Stock Ownership: Vincent J. O'Neill, Genentech; David Ramies, Genentech; Ming Lin, Genentech Honoraria: Roy S. Herbst, Genentech; Philip D. Bonomi, Genentech, OSI Pharmaceuticals; Alan Sandler, Genentech Research Funding: Roy S. Herbst, Genentech; Louis Fehrenbacher, Genentech; Chandra P. Belani, Genentech; Philip D. Bonomi, Genentech, OSI Pharmaceuticals; Lowell Hart, Genentech; Ostap Melnyk, Genentech; Alan Sandler, Genentech Expert Testimony: None Other Remuneration: None
Conception and design: Roy S. Herbst, Chandra P. Belani, David Ramies Administrative support: Chandra P. Belani Provision of study materials or patients: Louis Fehrenbacher, Lowell Hart, Ostap Melnyk Collection and assembly of data: Roy S. Herbst, Louis Fehrenbacher, Chandra P. Belani, Philip D. Bonomi, Lowell Hart Data analysis and interpretation: Roy S. Herbst, Vincent J. O'Neill, Louis Fehrenbacher, Chandra P. Belani, David Ramies, Ming Lin Manuscript writing: Roy S. Herbst, Vincent J. O'Neill, Louis Fehrenbacher, Chandra P. Belani, Philip D. Bonomi, David Ramies, Ming Lin, Alan Sandler Final approval of manuscript: Roy S. Herbst, Vincent J. O'Neill, Louis Fehrenbacher, Chandra P. Belani, Philip D. Bonomi, Lowell Hart, Ostap Melnyk, David Ramies, Ming Lin, Alan Sandler
We thank OSI Pharmaceuticals for providing erlotinib for use in this study and all investigators in the OSI2950g study group. We also thank Stephanie Kareht and Genentech Inc, for providing editorial assistance for this article.
published online ahead of print at www.jco.org on October 1, 2007. Supported by Genentech Inc, South San Francisco, CA. Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA; the 18th Annual European Organisation for Research and Treatment of Cancer–National Cancer Institute–American Association for Cancer Research Symposium on Molecular Targets and Cancer Therapeutics, November 7-10, 2006, Prague, Czech Republic; and the 4th Annual International Association for the Study of Lung Cancer International Chicago Symposium on Malignancies of the Chest and Head and Neck, October 26-28, 2006, Chicago, IL. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
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