Original Article
Phase 2 Trial of Maintenance Bevacizumab Alone After Bevacizumab Plus Pemetrexed and Carboplatin in Advanced, Nonsquamous Nonsmall Cell Lung Cancer James P. Stevenson, MD1; Corey J. Langer, MD1; Robert A. Somer, MD2; Tracey L. Evans, MD1; Kumar Rajagopalan, MD2; Kimberly Krieger, CCRP2; Mona Jacobs-Small, CCRC1; Nikolas Dyanick1; Barry Milcarek, PhD2; Susan Coakley, CCRP2; Suzanne Walker, CRNP1; Beth Eaby-Sandy, CRNP1; and Alexandre Hageboutros, MD2
BACKGROUND: The authors performed a phase 2 study of bevacizumab plus pemetrexed and carboplatin followed by maintenance bevacizumab in patients with advanced, nonsquamous nonsmall cell lung cancer. METHODS: Previously untreated patients with advanced, nonsquamous nonsmall cell lung cancer and an Eastern Cooperative Oncology Group performance status of 0 or 1 received bevacizumab 15 mg/kg, pemetrexed 500 mg/m2 and carboplatin at an area under the concentration-time curve of 6 intravenously on day 1 every 21 days. Responding or stable patients who completed 6 cycles then received bevacizumab maintenance every 21 days until disease progression. RESULTS: In total, 43 patients (40 who were evaluable for response) were entered on the study. Treatment-related grade 3/4 toxicities were low and included febrile neutropenia (2%), neutropenia (28%), anemia (18%), thrombocytopenia (11%), hypertension (7%), epistaxis (5%), venous thrombosis (8%), dyspnea (7%), rectovaginal fistula (2.3%), infusion reaction (2%), and cerebrovascular event (2%). One patient died from complications of venous thromboembolism and cerebrovascular accident after Cycle 2. Minimal clinically significant toxicity occurred during maintenance bevacizumab. Two complete responses (5%) were observed, and 17 patients (42%) had a partial response. Fifteen patients (38%) displayed disease stability. The overall disease control rate was 85%. At a median follow-up of 15.8 months, the median progression-free survival was 7.1 months (95% confidence interval, 5.9-8.3 months), and the median overall survival was 17.1 months (95% confidence interval, 8.8-25.5 months). CONCLUSIONS: Combined bevacizumab, pemetrexed, and carboplatin followed by maintenance bevacizumab was well tolerated and displayed remarkable activity in patients with previously untreated, advanced, nonsquamous nonsmall cell lung cancer. Cancer 2012;118:5580-7. C 2012 American Cancer Society. V KEYWORDS: nonsmall cell lung cancer, antiangiogenic therapy, maintenance therapy, phase 2trial, pemetrexed, bevacizumab.
INTRODUCTION Lung cancer remains a therapeutic challenge. It is the leading cause of cancer death worldwide, and approximately 85% of patients who are diagnosed with this neoplasm will die from their disease. There are more than 1.6 million new cases of lung cancer worldwide annually, and approximately 75% to 80% are nonsmall cell lung cancer (NSCLC).1-3 The majority of patients present with advanced disease, and 40% to 70% of those with stage I through III NSCLC develop distant metastatic disease after initial therapy. Treatment options for patients advanced NSCLC previously were limited, because most clinical trials of cytotoxic agents produced 800 previously chemotherapy-naive patients with stage IIIB or IV nonsquamous NSCLC were randomized to receive either bevacizumab plus paclitaxel and carboplatin for 6 cycles followed by maintenance bevacizumab or paclitaxel and carboplatin alone for up to 6 cycles. A median survival of 12.3 months was achieved in the group assigned to chemotherapy plus bevacizumab compared with 10.3 months in the chemotherapy-alone group; and the median
Corresponding author: James P. Stevenson, MD, 51 North 39th Street, Medical Arts Building, Suite 103A, Philadelphia, PA 19104; Fax: (215) 243-3249; james.
[email protected] 1
Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania; 2Cooper Cancer Institute, Voorhees, New Jersey
DOI: 10.1002/cncr.27576, Received: February 8, 2012; Revised: March 1, 2012; Accepted: March 6, 2012, Published online April 27, 2012 in Wiley Online Library (wileyonlinelibrary.com)
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progression-free survival (PFS) for the 2 groups was 6.2 months and 4.5 months, respectively, with corresponding response rates of 35% and 15% (P < .001). The results from that trial established a new standard of care in this patient population. The mode of action of bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF), and its lack of cumulative toxicity made it particularly compelling for use as maintenance therapy in patients with nonsquamous NSCLC. Shortly after the publication of ECOG 4599, a randomized trial of the novel antifolate pemetrexed proved that it was not inferior to docetaxel as second-line treatment for NSCLC.8 A subsequent study revealed that combination pemetrexed and cisplatin was superior to gemcitabine and cisplatin in the front-line setting for patients with nonsquamous histology,9 and pemetrexed is now used routinely in combination with a platinum agent for previously untreated patients with nonsquamous NSCLC. The finding of superior activity of pemetrexed in patients with nonsquamous NSCLC and its overall favorable toxicity profile suggest that it potentially may build on the results of ECOG 4599 when combined with bevacizumab and carboplatin in a similar fashion. Here, we present the results from our phase 2 study of this combination followed by maintenance bevacizumab in patients with advanced, nonsquamous NSCLC. MATERIALS AND METHODS Eligibility
Eligible patients were aged 18 years and had cytologically or histologically confirmed, nonsquamous NSCLC that was stage IIIB (malignant pleural effusion) or IV and had received no prior chemotherapy, immunotherapy, biologic therapy, or antiangiogenic drugs. Patients also were required to have measurable disease; an ECOG performance status of 0 or 1; and adequate hematologic, hepatic, and renal function as defined by the following required laboratory values: serum creatinine 60% of patients per arm). Since the initiation of our study and the reports of ECOG 4599 and AVAiL, we have learned much about the role of pemetrexed in the treatment of NSCLC. We now know that pemetrexed has superior activity in nonsquamous versus squamous NSCLC when received alone or in combination with a platinum agent, and now it is used exclusively in nonsquamous subtypes. Most recently, Ciuleanu et al reported improved PFS (4.5 months vs 2.6 months) and OS (15.5 months vs 10.3 months) in patients with nonsquamous NSCLC when they received Cancer
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Figure 1. Kaplan-Meier estimate of progression-free survival.
pemetrexed as maintenance therapy until progression developed after 4 cycles of a platinum-containing doublet versus placebo plus best supportive care.12 That study led to the approval of ‘‘switch’’ maintenance therapy with pemetrexed. Given the relatively short infusion times and similar schedule of administration, the prospect of the combination of 2 maintenance therapies (bevacizumab and pemetrexed) in nonsquamous NSCLC has become attractive. Patel et al conducted a phase 2 study of bevacizumab, pemetrexed, and carboplatin followed by maintenance bevacizumab and pemetrexed in a total of 51 patients with nonsquamous NSCLC.13 Those authors reported a response rate of 55%, a median PFS of 7.8 months, and a median OS of 14.1 months, not dissimilar to our results. The adverse event profile for the regimen also was fairly similar to that in our study, although grade 3/4 diverticulitis was observed in 8% of their patients, and Cancer
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their study subsequently was amended to exclude patients who had a history of diverticulitis or significant diverticulosis. The development of a rectovaginal fistula in 1 patient on our study who had underlying diverticular disease raises the possibility that this toxicity may be unique to this regimen, although bowel perforation is a known adverse event associated with bevacizumab (with an overall incidence of 2.4% per prescribing information).14 Spigel et al recently reported their results with maintenance bevacizumab alone after 6 cycles of pemetrexed, carboplatin, and bevacizumab in a randomized phase 2 trial comparing that regimen to pemetrexed, gemcitabine, and bevacizumab in elderly patients (aged >70 years) with advanced, nonsquamous NSCLC.15 Improved TTP and OS were observed in the pemetrexed, carboplatin, and bevacizumab arm at 10.2 months and 14.8 months, respectively, and the response rate was 35%. These 5585
Original Article
Figure 2. Kaplan-Meier estimate of overall survival.
findings are comparable to our results as well as those of Patel and colleagues with doublet maintenance therapy. The results of our study demonstrated that combination bevacizumab, pemetrexed, and carboplatin followed by ‘‘continuous’’ maintenance therapy with bevacizumab alone for bevacizumab-eligible patients with nonsquamous NSCLC builds on the current US standard of care with bevacizumab, paclitaxel, and carboplatin in terms of efficacy, tolerability, and ease of administration. The question of maintenance monotherapy versus doublet therapy is important with respect not only to efficacy and toxicity but also to cost, because patients who exhibit a continuing benefit may remain on maintenance therapy for durations ranging from months to years. Three ongoing randomized trials will help to answer this question. The POINTBREAK trial of bevacizumab, pemetrexed, and carboplatin followed by maintenance bev5586
acizumab plus pemetrexed versus bevacizumab, paclitaxel, and carboplatin followed by bevacizumab monotherapy has completed planned accrual of approximately 900 patients, and results are expected sometime soon.16 It is noteworthy that the maintenance approach in POINTBREAK after bevacizumab, pemetrexed, and carboplatin did not feature bevacizumab monotherapy but, rather, the bevacizumab and pemetrexed combination as piloted by Patel et al. The AVAPERL1 study (a study of bevacizumab [Avastin] with or without pemetrexed as maintenance therapy after Avastin in first line in patients with nonsquamous NSCLC) comparing maintenance bevacizumab (7.5 mg/kg every 21 days) versus maintenance bevacizumab (7.5 mg/ kg) plus pemetrexed after 4 cycles of front-line bevacizumab (7.5 mg/kg), pemetrexed, and cisplatin has completed accrual.17 Final results are pending; however, preliminary results presented at the 2011 European Multidisciplinary Cancer
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Cancer Congress indicated a 50% reduction in the hazard ratio for PFS with doublet maintenance therapy versus monotherapy.18 The results of that study also may raise the question of using cisplatin versus carboplatin in the frontline setting, because the phase 3 results favoring pemetrexed in patients with nonsquamous disease were observed with cisplatin.9 We chose to use carboplatin in our trial to be consistent with ECOG 4599, because the AVAiL results had not been reported yet, and carboplatin is generally the preferred platinum agent for use in advanced NSCLC in the United States. However, it is noteworthy that results from the cisplatin versus carboplatin (CISCA) meta-analysis reported in 2007 (after the initiation of our trial) indicated that cisplatin-based therapies produced superior response rates and survival compared with carboplatin-based regimens, and the survival effect was most notable in patients with nonsquamous histology who were receiving ‘‘thirdgeneration’’ chemotherapy regimens, although no pemetrexed-containing or bevacizumab-containing studies were included.19 Therefore, the AVAPERL1 overall survival results will be of great interest in this regard. The third trial, ECOG 5508, which is currently in progress, investigates bevacizumab versus pemetrexed given alone versus combination bevacizumab and pemetrexed as maintenance therapy after 4 cycles of bevacizumab, paclitaxel, and carboplatin in patients with advanced, nonsquamous NSCLC.20 The results of these 3 important trials should clarify the preferred maintenance strategy in bevacizumab-eligible patients. FUNDING SOURCES This work was supported by a research grant from Genentech, Inc.
CONFLICT OF INTEREST DISCLOSURES James P. Stevenson received research funding from Genentech Inc and Eli Lilly and Company. Corey J. Langer is a consultant to and is on the advisory boards of Genentech Inc. and Eli Lilly and Company. Suzanne Walker is on the Speaker’s Bureau of Eli Lilly and Company. Beth Eaby-Sandy is on the Speaker’s Bureaus of Eli Lilly and Company and Genentech Inc. Alexandre Hageboutros is on the Speaker’s Bureau of Eli Lilly and Company.
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