Adjuvant Avastin Does Not Improve Survival in NSCLC

The addition of Avastin (bevacizumab) to chemotherapy after initial therapy 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 3 E1505 trial. Results from this trial were reported during a press conference at the 2015 World Conference on Lung Cancer, a meeting of 7,000 oncology professionals.

The phase 3 trial randomized 1,501 patients with NSCLC in a 1:1 ratio to chemotherapy with Avastin (752 patients) or without (749 patients). Data showed that OS did not differ between the two arms. 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.

“The study highlights the importance of randomized trials to prove — or disprove — the utility of drugs in different stages of disease,” Heather A. Wakelee, 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 six to 12 weeks of surgery and were stratified based on the type of chemotherapy they received, histology, stage, and sex. Overall, 28.2 percent of patients were diagnosed with squamous NSCLC. Patients were diagnosed with stage 1B (greater than 4 centimeters; 26.2 percent), stage 2 (43.8 percent), and stage 3A (30 percent).

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

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

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

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 percent of patients remained alive at seven years. In the SEER database, the five-year OS in 2007 was noted as 49 percent for those with stage 1A disease and 14 percent for those with stage 3A. 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 Avastin 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.