Improved Progression-Free but Not Overall Survival With Addition of Maintenance Erlotinib to Bevacizumab After Chemotherapy Plus Bevacizumab in NSCLC
In the phase IIIB ATLAS trial reported in the Journal of Clinical Oncology, Bruce E. Johnson, MD, of Dana-Farber Cancer Institute, and colleagues assessed the addition of maintenance erlotinib (Tarceva) to bevacizumab (Avastin) following chemotherapy plus bevacizumab in first-line treatment of advanced non–small cell lung cancer (NSCLC). The addition of erlotinib improved progression-free survival but not overall survival and was associated with additional toxicity.
Study Details
In the double-blind trial, 1,145 patients with histologically or cytologically confirmed NSCLC (stage IIIB with malignant pleural effusion, stage IV, or recurrent) received four cycles of chemotherapy plus bevacizumab. A total of 743 patients without disease progression or significant toxicity were then randomly assigned to bevacizumab 15 mg/kg on day 1 of 21-day cycles plus either placebo (n = 373) or erlotinib 150 mg/d (n = 370). The primary endpoint was progression-free survival. Patients were stratified by sex, smoking history (never vs former/current), Eastern Cooperative Oncology Group (ECOG) performance status (0 vs ≥ 1), and initial chemotherapy regimen.
The bevacizumab and bevacizumab/erlotinib groups were generally well balanced for age (median, 64 years in both), sex (53% and 52%), ECOG performance status (0 in 47% and 49%, 1 in 53% and 51%), clinical stage (IIIB in 10% and 9%, stage IV in 83% and 86%), histology (adenocarcinoma in 83% and 81%), smoking status (former or current in 83% and 84%), and chemotherapy (carboplatin/paclitaxel in 47% and 48%, carboplatin/gemcitabine in 28% in both).
Survival Outcomes
Median progression-free survival from time of random assignment was 3.7 months in the bevacizumab group vs 4.8 months in the bevacizumab/erlotinib group (hazard ratio [HR] = 0.71, P < .001 on stratified analysis; HR = 0.683, P < .001 on unstratified analysis). Median overall survival from random assignment was 13.3 months in the bevacizumab group vs 14.4 months in the bevacizumab/erlotinib group (HR = 0.92, P = .5341 on stratified analysis; HR = 0.941, P = .6473 on unstratified analysis) at the primary data cutoff. The 1-year survival rates were 58.6% vs 60.1%. On an updated analysis, median overall survival was 13.6 vs 14.4 months (HR = 0.904, P = .3534)
Effect of EGFR Mutation
Patients with an activating EGFR mutation (n = 52) had a greater improvement in progression-free survival with bevacizumab/erlotinib (HR = 0.44, 95% confidence interval [CI] = 0.22–0.86) compared with those (n = 295) with wild-type EGFR (HR = 0.85, 95% CI = 0.64–1.13). Updated overall survival results showed a similar difference in outcome by EGFR mutation status (HR = 0.46, 95% CI = 0.21–1.02 among EGFR mutation–positive patients; HR = 0.86, 95% CI = 0.65–1.15 among EGFR wild-type patients).
Toxicity
During the postchemotherapy phase, there were more adverse events of any grade (96% vs 87%), more grade 3 or 4 adverse events (46% vs 33%; mainly rash, 6.8% vs 0.5%, and diarrhea, 9.8% vs 1.9%), more serious adverse events, and more adverse events of special interest leading to erlotinib/placebo discontinuation (9.0% vs 5.7%) in the bevacizumab/erlotinib group.
Adverse events of special interest led to bevacizumab discontinuation in 7.6% of patients in both groups. Among the prespecified adverse events of special interest (hemorrhage, proteinuria, hypertension, cardiovascular events, rash, diarrhea, and infection), the incidences of any-grade rash (63% vs 22%), diarrhea (52% vs 20%), and infection (30% vs 25%) were greater in the bevacizumab/erlotinib group.
No grade 3 or 4 interstitial lung disease–like events were reported in the bevacizumab group, and three patients (0.8%) in the bevacizumab/erlotinib group experienced a grade 3 interstitial lung disease-like event. Six grade 5 adverse events of special interest were reported, consisting of two in the bevacizumab group (congestive heart failure and lobar pneumonia) and four in the bevacizumab/erlotinib group (cardiac arrest in two, cerebellar infarction in one, and deep-vein thrombosis in one). An additional grade 5 event (gastrointestinal perforation) occurred in a patient in the bevacizumab/erlotinib group after the primary data cutoff.
The investigators concluded, “The addition of erlotinib to bevacizumab significantly improved [progression-free survival] but not [overall survival]. Although generally well tolerated, the modest impact on survival and increased toxicity associated with the addition of erlotinib to bevacizumab maintenance mean that this two-drug maintenance regimen will not lead to a new postchemotherapy standard of care.”
Dr. Johnson and Fairooz Kabbinavar, MD, of University of California Los Angeles, are both primary authors, and Dr. Johnson is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by Genentech.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
