Combination chemotherapy with bevacizumab or cetuximab
Evidence (combination chemotherapy with bevacizumab or cetuximab):
Two randomized trials have evaluated the addition of bevacizumab, an antibody targeting vascular endothelial growth factor, to standard first-line combination chemotherapy.
In a randomized study of 878 patients with recurrent or advanced stage IIIB or stage IV NSCLC, 444 patients received paclitaxel and carboplatin alone, and 434 patients received paclitaxel and carboplatin plus bevacizumab. Chemotherapy was administered every 3 weeks for six cycles, and bevacizumab was administered every 3 weeks until disease progression was evident or toxic effects were intolerable. Patients with squamous cell tumors, brain metastases, clinically significant hemoptysis, or inadequate organ function or PS (ECOG PS >1) were excluded.
The median survival was 12.3 months in the group assigned to chemotherapy plus bevacizumab, as compared with 10.3 months in the chemotherapy-alone group (HR for death, 0.79; P = .003).
The median PFS in the two groups was 6.2 months and 4.5 months, respectively (HR for disease progression, 0.66; P < .001), with corresponding response rates of 35% and 15%, respectively (P < .001).
Rates of clinically significant bleeding were 4.4% and 0.7%, respectively (P < .001). There were 15 treatment-related deaths in the chemotherapy-plus-bevacizumab group, including five from pulmonary hemorrhage.
For this subgroup of patients with NSCLC, the addition of bevacizumab to paclitaxel and carboplatin may provide survival benefit.[Level of evidence: 1iiA]
Another randomized phase III trial investigated the efficacy and safety of cisplatin/gemcitabine plus bevacizumab. Patients were randomly assigned to receive cisplatin (80 mg/m2) and gemcitabine (1,250 mg/m2) for up to six cycles, plus low-dose bevacizumab (7.5 mg/kg), high-dose bevacizumab (15 mg/kg), or placebo every 3 weeks until disease progression. The primary endpoint was amended from OS to PFS during the course of the study. A total of 1,043 patients were accrued (placebo group, n = 347; low-dose group, n = 345; high-dose group, n = 351).
PFS was significantly prolonged; the HRs for PFS were 0.75 (median PFS, 6.7 mo vs. 6.1 mo for placebo group; P = .03) in the low-dose group and 0.82 (median PFS, 6.5 mo vs. 6.1 mo for placebo group; P = .03) in the high-dose group compared with the placebo group.[Level of evidence: 1iiB]
Objective response rates were also improved with the addition of bevacizumab, and they were 20.1%, 34.1%, and 30.4% for placebo, low-dose bevacizumab, and high-dose bevacizumab plus cisplatin/gemcitabine, respectively.
Incidence of grade 3 or greater adverse events was similar across arms.
Grade 3 or greater pulmonary hemorrhage rates were 1.5% or less for all arms, despite 9% of patients receiving therapeutic anticoagulation.
These results support the addition of bevacizumab to platinum-containing chemotherapy, but the results are far less impressive than when the carboplatin-paclitaxel combination was used.
Furthermore, no significant difference in survival was shown in this study, as reported in abstract form.
Altogether, these findings may suggest that the backbone of chemotherapy may be important when bevacizumab is added.
Two trials have evaluated the addition of cetuximab to first-line combination chemotherapy.[33,34]
In the first trial, 676 chemotherapy-naïve patients with stage IIIB (pleural effusion) or stage IV NSCLC, without restrictions by histology or EGFR expression, received cetuximab with taxane (paclitaxel or docetaxel with carboplatin) or combination chemotherapy.
The addition of cetuximab did not result in a statistically significant improvement in PFS, the primary study endpoint, or OS.
Median PFS was 4.40 months with cetuximab/chemotherapy versus 4.24 months with taxane/carboplatin (HR, 0.902; 95% CI, 0.761–1.069; P = .236).
Median OS was 9.69 months with cetuximab/chemotherapy versus 8.38 months with chemotherapy (HR, 0.890; 95% CI, 0.754–1.051; P = .169).
No significant associations were found between EGFR expression, EGFR mutation, EGFR copy number, or KRAS mutations and PFS, OS, and response in the treatment-specific analyses.
The second trial was composed of 1,125 chemotherapy-naïve patients with advanced EGFR-expressing stage IIIB or stage IV NSCLC treated with cisplatin/vinorelbine chemotherapy plus cetuximab or chemotherapy alone.
The primary study endpoint, OS, was longer for patients treated with cetuximab and chemotherapy (median 11.3 months vs. 10.1 months; HR for death, 0.871; 95% CI, 0.762–0.996; P = .044).
A survival benefit was seen in all histological subgroups; however, survival benefit was not seen in non-white or Asian patients. Only the interaction between the treatment and the ethnic origin was significant (P = .011).
The main cetuximab-related adverse event was acne-like rash (10%, grade 3).
It is not clear whether the differences in outcome in these two studies are the result of differences in the study populations, tumor characterization for EGFR expression, or chemotherapy regimens.