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

Roy S. Herbst From The M.D. Anderson Cancer Center,
Journal of Clinical Oncology, Vol 25, No 30 (October 20), 2007: pp. 4743-4750

Purpose: Bevacizumab (Avastin) a humanized anti–vascular endothelial growth factor monoclonal antibody, and erlotinib (Tarceva) a reversible, orally available epidermal growth factor receptor tyrosine kinase inhibitor, have demonstrated evidence of a survival benefit in the treatment of non–small-cell lung cancer (NSCLC). A single-arm phase I and II study of bevacizumab plus erlotinib demonstrated encouraging efficacy, with a favorable safety profile.

Patients and Methods: A multicenter, randomized phase II trial evaluated the safety of combining bevacizumab with either chemotherapy (docetaxel or pemetrexed) or erlotinib and preliminarily assessed these combinations versus chemotherapy alone, as measured by progression-free survival (PFS). All patients had histologically confirmed nonsquamous NSCLC that had progressed during or after one platinum-based regimen.

Results: One hundred twenty patients were randomly assigned and treated. No unexpected adverse events were noted. Fewer patients (13%) in the bevacizumab-erlotinib arm discontinued treatment as a result of adverse events than in the chemotherapy alone (24%) or bevacizumab-chemotherapy (28%) arms. The incidence of grade 5 hemorrhage in patients receiving bevacizumab was 5.1%. Although not statistically significant, relative to chemotherapy alone, the risk of disease progression or death was 0.66 among patients treated with bevacizumab-chemotherapy and 0.72 among patients treated with bevacizumab-erlotinib. One-year survival rate was 57.4% for bevacizumab-erlotinib and 53.8% for bevacizumab-chemotherapy compared with 33.1% for chemotherapy alone.

Conclusion: Results for PFS and overall survival favor combination of bevacizumab with either chemotherapy or erlotinib over chemotherapy alone in the second-line setting. No unexpected safety signals were noted. The rate of fatal pulmonary hemorrhage was consistent with previous bevacizumab trials. The toxicity profile of the bevacizumab-erlotinib combination is favorable compared with either chemotherapy-containing group.

Approximately 40% of patients diagnosed with lung cancer present with advanced non–small-cell lung cancer (NSCLC).Although 30% to 40% of patients respond initially to cytotoxics, these treatments seemingly reach a therapeutic plateau, and all patients eventually experience progression on or after treatment. Median survival time for these patients is only 8 to 10 months. However, as observed in the Eastern Cooperative Oncology Group (ECOG) E4599 pivotal study, the addition of bevacizumab to chemotherapy increased median survival time beyond the 12-month threshold.

The vascular endothelial growth factor (VEGF) and human epidermal growth factor receptor (HER-1/EGFR) have been identified as key molecular targets for therapy in NSCLC. Bevacizumab (Avastin; Genentech, South San Francisco, CA) is a recombinant, humanized, anti-VEGF monoclonal antibody that received recent US Food and Drug Administration approval for use in combination with carboplatin and paclitaxel chemotherapy, followed by bevacizumab alone until disease progression, for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic nonsquamous NSCLC. Erlotinib (Tarceva; Genentech) is an oral HER-1/EGFR tyrosine kinase inhibitor that is indicated for the treatment of locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen.

Several lines of evidence lent support to the notion that combining erlotinib and bevacizumab for the treatment of recurrent NSCLC might confer additional clinical benefit. First, preclinical data in colon cancer cell lines had demonstrated that the activity of erlotinib and bevacizumab is at least additive and may be synergistic (Genentech, unpublished data). Second, it had been proposed that a dual approach that targeted both the tumor (by inhibiting EGFR signaling) and the endothelial cells that would ultimately support growth of the tumor (by inhibiting VEGF) could be more effective.Finally, the use of two targeted agents would potentially have the added benefit of having fewer nonspecific toxicities than chemotherapy.

A phase I and II trial (n = 40) of erlotinib plus bevacizumab in patients with advanced, nonsquamous NSCLC who had experienced progression after at least one cycle of systemic chemotherapy previously established an effective dose for this combination, which was erlotinib 150 mg/d orally plus bevacizumab 15 mg/kg intravenous on day 1 of every 21-day cycle. This dosage resulted in a response rate of 14.3%, progression-free survival (PFS) time of 6.2 months, and median survival time of 12.6 months. This study was designed to further evaluate the efficacy and safety of bevacizumab in combination with chemotherapy or erlotinib, compared with chemotherapy alone, in patients with refractory, locally advanced or metastatic nonsquamous NSCLC.

Efficacy
The risk of disease progression or death among patients treated with bevacizumab-chemotherapy or bevacizumab-erlotinib compared with chemotherapy alone was 0.66 (95% CI, 0.38 to 1.16) and 0.72 (95% CI, 0.42 to 1.23), respectively. The median PFS times for chemotherapy alone, bevacizumab-chemotherapy, and bevacizumab-erlotinib were 3.0, 4.8, and 4.4 months, respectively. Median overall survival (OS) times were 8.6, 12.6, and 13.7 months for the chemotherapy alone, bevacizumab-chemotherapy, and bevacizumab-erlotinib arms, whereas the 1-year survival rates were 33.1%, 53.8%, and 57.4%, respectively. However, there was no clinically meaningful difference in PFS or OS observed between the bevacizumab-chemotherapy and bevacizumab-erlotinib arms. The PFS and OS observed for the chemotherapy-alone arm in this study are consistent with published data.

Exploratory analyses to compare the combined bevacizumab-containing arms with the chemotherapy only arm demonstrate that the adjusted HR for the combined arms is 0.67, with a 10.3% increase in 6-month PFS rate (31.8% v 21.5%, respectively. The 1-year survival rate was 22.4% higher (55.5% for combined bevacizumab-containing arms v 33.1% for chemotherapy only arm), with an adjusted HR of 0.73.

In this study, chemotherapy in arms 1 and 2 was either pemetrexed or docetaxel based on the discretion of the investigator. In total, 46 patients received docetaxel, and 35 patients received pemetrexed. OS in patients who received pemetrexed alone was not as long as previously observed (data not shown). However, the number of patients was small.

The one known EGFR mutation, which was in a patient randomly assigned to the bevacizumab-erlotinib arm, was detected and confirmed by two independent polymerase chain reaction/sequencing reactions for direct Sanger sequencing and also by the Surveyor platform. This patient had a complete response (duration, 9.7 months; OS, 13.8 months; PFS, 11.1 months). FISH-positive patients in the three arms exhibited similar PFS. For the FISH-negative patients, patients in the bevacizumab-erlotinib arm seemed to exhibit prolonged PFS (data not shown); however, the numbers were small (n = 11). Of the three patients in the bevacizumab-erlotinib arm who had a KRAS mutation, one had partial response (PFS, 149 days), one had stable disease (PFS, 93+ days, as a result of patient's decision to withdraw), and one had progressive disease (PFS, 121 days).