Eligibility criteria
Patients were required to have nonsquamous NSCLC and have not received any prior systemic chemotherapy, except preoperative/postoperative adjuvant chemotherapy or EGFR-tyrosine kinase inhibitor (TKI), with stage IIIB, stage IV, or recurrence disease after surgery; have measurable lesion that met the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [8]; be aged from 20 to 74 years; ECOG performance status of 0 or 1; and have adequate organ function within 1 week before study entry. The laboratory value requirements were as follows: hemoglobin level ≥ 9 g/dl, absolute neutrophil count ≥1500/mm3, platelet count ≥100,000/mm3, serum bilirubin levels < 1.5 mg/dl, serum aspartate aminotransferase and alanine aminotransferase levels < 100 IU/l, and serum creatinine levels < 1.5 mg/dl; have an estimated life expectancy of at least 90 days; and have signed the document of informed consent.
Patients were not eligible if they had metastases of the central nervous system or prior therapies for brain metastasis; had received radiotherapy for lung lesions; had a history of cardiac effusion that required treatment; had another active malignancy; had a history of hemoptysis or hemosputum; had a complication related to a bleeding episode, such as bleeding diathesis, an evidence of major thoracic blood vessel involvement, an evidence of cavity formation in the lung lesion, or an evidence of thrombosis; needed an anti-thrombosis drug during the study or were administered an anti-thrombosis drug within 10 days before enrollment; had a history of brain vascular disease with symptom, gastrointestinal perforation, diverticulitis, or fistula, symptomatic heart failure, unstable angina or arrhythmia that required treatment, cardiac infarction within 1 year before enrollment, any evidence of interstitial lung disease, superior vena cava syndrome, a cord compression, a serious non-healing wound or unhealed bone fracture, an uncontrollable ulcer, uncontrollable hypertension, or a serious concomitant active infection that needed antibiotics; had known sensitivity to any component of platinum or monoclonal antibody drugs; or pregnancy or lactation.
The current study (UMIN000005569) was planned on the basis of the Declaration of Helsinki and Good Clinical Practice guidelines and was approved by the institutional review boards of all participating hospitals. Signed informed consent forms were obtained from the patients.
Treatment and evaluation
Prior to the administration of pemetrexed, all patients received folic acid and vitamin B12 supplementation and standard premedication with dexamethasone [2, 9, 10]. Patients received induction chemotherapy on day 1 of each 21-day cycle comprising cisplatin (75 mg/m2), pemetrexed (500 mg/m2), and bevacizumab (15 mg/kg). Induction chemotherapy was repeated every 3 weeks for a maximum of four cycles. After completion of at least three cycles of induction chemotherapy, patients underwent maintenance chemotherapy on day 1 of the 21-day cycle comprising pemetrexed (500 mg/m2) and bevacizumab (15 mg/kg). Every 3 weeks, maintenance chemotherapy was repeated until disease progression or intolerance.
Using the National Cancer Institute Common Toxicity Criteria version 4.0, patients were evaluated every 21 days to assess toxicity. Tumor response was assessed using computed tomography; it was performed every 6 weeks for 24 weeks and every 6 weeks thereafter until disease progression. The original RECIST criteria (version 1.1) were used to assess the response [8]. Central review of radiologic assessment was not performed.
Statistical methods
PFS, defined as the time from enrollment to disease progression (as assessed by the investigator) or to death, was the primary endpoint of the study. OS, objective response rate, and toxicity were the secondary endpoints. A median PFS of at least 7 months compared with the historic rate of 4.8 months [5] would be considered as a favorable outcome. We estimated that 35 patients were needed to achieve an 80% power with a one-sided 0.1 level test in this single-stage, single-arm trial. An intent-to-treat approach was followed for analyzing all data. Kaplan–Meier method was used to calculate survival distributions. All statistical analyses were performed using the Statistical Package for the Social Sciences software (version 24.0; IBM, Armonk, NY, USA). A p value of < 0.05 was considered to be significant.