A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PHASE IIIB TRIAL (ATLAS) COMPARING BEVACIZUMAB THERAPY WITH OR WITHOUT ERLOTINIB AFTER COMPLETION OF CHEMOTHERAPY WITH B FOR FIRST-LINE TREATMENT OF LOCALLY ADVANCED, RECURRENT, OR METASTATIC NSCLC

Miller VA, O’Connor P, Soh C, Kabbinavar F, for the ATLAS Investigators; Memorial Sloan-Kettering Cancer Center, New York, NY; Genentech, Inc, South San Francisco, CA; University of California, Los Angeles, Los Angeles, CA

Affecting over 219 000 Americans this year, lung cancer is the leading cause of cancer-related deaths.1 The majority of these patients have non–small-cell lung cancer (NSCLC), and despite recent advances in chemotherapy, additional treatment options are necessary. Recent studies indicate that the supplementation of traditional platinum-based chemotherapy with bevacizumab may prolong survival of patients with recurrent or advanced NSCLC by approximately 2 months (ie, 12.3 months with bevacizumab vs 10.3 months with chemotherapy alone)2; similarly, the use of erlotinib following failure of first- or second-line chemotherapy for NSCLC has been shown to increase survival time by 2 months (ie, 6.7 months with erlotinib vs 4.7 months with placebo).3 Furthermore, subsequent findings suggest that combination therapy with bevacizumab and erlotinib may enhance treatment efficacy. Specifically, data have shown that patients who received second-line therapy with bevacizumab and erlotinib had an increased 1-year survival rate compared with those who were treated with chemotherapy alone (57.4% vs 33.1%).4 Additionally, a study comparing bevacizumab plus erlotinib with erlotinib alone for the treatment of advanced NSCLC in patients who failed first-line therapy found that combination treatment doubled both progression-free survival (PFS) and objective response rate, compared with erlotinib alone.5

The ATLAS study, which took place from May 2005 to May 2008, was conducted to compare the efficacy of bevacizumab plus erlotinib with that of bevacizumab alone, following the completion of platinum-based doublet chemotherapy with bevacizumab in patients with stage IIIb/IV NSCLC. Although bevacizumab should generally be used with caution in patients with squamous cell carcinomas, central nervous system (CNS) metastases, and/or those with an increased risk of bleeding, such patients were eligible for study participation if they had peripheral and/or extra-thoracic squamous tumors, if brain metastases had been treated, or they were undergoing anticoagulation with a low–molecular-weight heparin. All patients were initially treated with 4 cycles of bevacizumab (15 mg/kg every 3 weeks) along with chemotherapy. Subsequently, patients who did not experience disease progression or significant toxicity were randomized to receive bevacizumab and erlotinib (150 mg daily) or bevacizumab and placebo; investigators compared PFS (primary end point), overall survival, and safety (secondary end points) between the 2 treatment regimens.

Of the 1160 patients enrolled in the ATLAS study, 768 were randomized to receive treatment. Results indicated that the median PFS following randomization was 4.8 months for bevacizumab and erlotinib versus 3.7 months for bevacizumab and placebo (hazard ratio = 0.722; 95% confidence interval, 0.592–0.881; P = .0012); the safety profiles of these medications were consistent with expectations. Because the primary end point was satisfied early, the trial was discontinued at the second planned interim efficacy analysis. Investigators concluded that the combination of bevacizumab and erlotinib following chemotherapy with bevacizumab significantly improves PFS in patients with locally advanced, recurrent, or metastatic NSCLC.6

Although this study revealed significant findings, baseline demographics for the 2 treatment arms were not provided, thus it is difficult to determine whether the 2 groups were similar in nature. Investigators also did not report overall survival rates, although this was listed as a study end point. Additionally, medication safety data were not specified; however, because it was stated that adverse drug events were consistent with known safety profiles, it can be inferred that bevacizumab was commonly associated with epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis,7 whereas erlotinib was associated with rash, diarrhea, anorexia, and fatigue.8 The study was appropriately conducted to provide an extension to current knowledge regarding the use of bevacizumab and erlotinib for the treatment of recurrent or advanced NSCLC. Based on these findings, further research may be performed to determine how this regimen may best be used to treat patients with NSCLC.

References
1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2009. CA Cancer J Clin. 2009;59:225-249.
2. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542-2550.
3. Shepherd FA, Pereira JR, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353:123-132.
4. Herbst RS, O’neill VJ, Fehrenbacher L, et al. 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. J Clin Oncol. 2007;25:4743-4750.
5. Hainsworth RH. A phase III, multicenter, placebo-controlled, double-blind, randomized clinical trial to evaluate the efficacy of bevacizumab (Avastin) in combination with erlotinib (Tarceva) compared with erlotinib alone for treatment of advanced non-small cell lung cancer after failure of standard first-line chemotherapy (BETA). Thoracic Oncol. 2008;3(11)suppl4:S302.
6. Miller VA, O’Connor P, Soh C, Kabbinavar F. A randomized, double-blind, placebo-controlled, phase IIIb trial (ATLAS) comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemotherapy with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol 27:18s, 2009 (suppl; abstr LBA8002).
7. Bevacizumab [package insert]. South San Francisco, CA: Genentech, Inc.; 2009.
8. Erlotinib [package insert]. Melville, NY: OSI Pharmaceuticals, Inc.; 2009.
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