Survival Not Improved by Adjuvant Bevacizumab in NSCLC

Heather A. Wakelee, MD

The addition of bevacizumab (Avastin) to adjuvant chemotherapy did not improve overall survival (OS) in patients with surgically resected early-stage non—small cell lung cancer (NSCLC), according to results of the phase III E1505 trial reported during a press conference at the 2015 World Conference on Lung Cancer.

The phase III trial randomized 1501 patients with NSCLC in a 1:1 ratio to chemotherapy with bevacizumab (n = 752) or without (n = 749). Data showed that OS did not differ between the two arms (hazard ratio [HR], 0.99; 95% CI, 0.81-1.21; P = .93). Median OS was more than 72 months in both cohorts. Similar data was reported with disease-free survival, a secondary endpoint, between the two arms (HR, 0.98; 95% CI, 0.84-1.14; P = .75).

“The study highlights the importance of randomized trials to prove—or disprove–the utility of drugs in different stages of disease,” Heather A. Wakelee, MD, associate professor of Medicine (Oncology), at Stanford University Medical Center, said in a statement. “With the development of other active agents in metastatic lung cancer, it will be important to investigate them fully in earlier stages and not assume the benefit seen in advanced stage will also be proven in earlier stages, though we can remain hopeful.”

The study enrolled patients between 2007 and 2013, and was conducted by the ECOG-ACRIN Cancer Research Group. Patients were enrolled within 6 to 12 weeks of surgery and were stratified based on the type of chemotherapy they received, histology, stage, and sex. Overall, 28.2% of patients were diagnosed with squamous NSCLC. Patients were diagnosed with stage IB (>4 centimeters; 26.2%), stage II (43.8%), and stage IIIA (30%).

Chemotherapy regimens involved a planned four cycles of cisplatin at 75 mg/m² every 3 weeks for approximately 3 months with vinorelbine (25%), docetaxel (22.9%), gemcitabine (18.9%), or pemetrexed (33.2%). Patients in the bevacizumab arm received the angiogenesis inhibitor at 15 mg/kg every 3 weeks for 1 year. Post-operative radiation therapy was not permitted.

No unexpected toxicities were found with the addition of bevacizumab; however, there was a significant increase in neutropenia and hypertension. There was no significant difference in treatment-related deaths (2% vs 3%, with chemotherapy and bevacizumab, respectively).

Serious adverse events (AEs) related to bevacizumab included gastrointestinal perforation, neutropenic sepsis, myocardial infarction, gastrointestinal hemorrhage CNS infarction, and pulmonary hemorrhage. The most common AEs associated with bevacizumab include asthenia, constipation, pain, abdominal pain, upper respiratory infection, headache, hypertension, epistaxis, diarrhea, nausea, dyspnea, vomiting, anorexia, exfoliative dermatitis, proteinuria, and stomatitis.

The study had an 85% power to detect a 21% reduction in the OS HR with a one-sided P value of .025. At an interim analysis, a Data Safety Monitoring Committee recommended that the study should be unblinded. At the time of interim analysis, with a median follow-up time of 41 months.

At 84 months from the time of registration, the Kaplan-Meier curves showed nearly a 0.5 overall survival probability, suggesting that approximately 50% of patients remained alive at 7 years. In the SEER database, the 5-year OS in 2007 was noted as 49% for those with stage IA disease and 14% for those with stage IIIA. However, the findings from E1505 suggested a higher figure in both arms of the study.

“I think there are a lot of advancements in what we are able to do to support patients over that time,” Wakelee said regarding the better than expected data. “Part of it could have been selection, as well. The [eligibility requirements] were not any stricter than a lot of the prior trials’. I think it is just showing improvements in what we are able to offer patients who get extra treatments.”

Though bevacizumab was shown to not have benefit in the adjuvant setting when combined with chemotherapy, Wakelee said additional steps would be taken following these results, including biomarker analyses.

“This is not the end of the story,” Wakelee said. “We have a significant number of correlates planned. Tissue, blood, and serum were collected from these patients, so analyses will be done. We also have a lot of subsets of interest looking at the patients across the board.”

Wakelee HA, Dahlberg SE, Keller SM, et al. Randomized phase III trial of adjuvant chemotherapy with or without bevacizumab in resected non-small cell lung cancer (NSCLC): Results of E1505. Presented at: 16th World Conference on Lung Cancer; September 6-9; Denver, CO. Abstract 1608.

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