Bevacizumab/Pemetrexed Maintenance Increases Progression-Free Survival vs Bevacizumab Alone in Advanced Nonsquamous NSCLC 

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Maintenance therapy is associated with improved survival in non–small cell lung cancer (NSCLC), but few studies have compared active agents in this setting. In a phase III trial (AVAPERL trial) reported in the Journal of Clinical Oncology by Fabrice Barlesi, MD, PhD, of Aix Marseille University–Assistance Publique Hôpitaux de Marseille, and colleagues, patients with advanced nonsquamous NSCLC who had disease control after first-line treatment with platinum-based chemotherapy plus bevacizumab (Avastin) had significantly prolonged progression-free survival with maintenance bevacizumab/pemetrexed (Alimta) compared with bevacizumab alone.1 Toxicity was increased with bevacizumab/pemetrexed, although no new safety signals were observed.

Study Details

In this open-label multicenter trial, 376 patients with advanced nonsquamous NSCLC received first-line bevacizumab 7.5 mg/kg, cisplatin 75 mg/m2, and pemetrexed 500 mg/m2 once every 3 weeks for four cycles. Of these, 269 (72%) achieved disease control (response in 23% and stable disease in 49%) and 253 (67%) were randomly assigned to receive maintenance bevacizumab 7.5 mg/kg alone (n = 125) or with pemetrexed 500 mg/m2 (n = 128) once every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival from the time of randomization. 

For the bevacizumab/pemetrexed and bevacizumab groups, median age was 60 years in both (< 65 years for 70% of both), 58% and 57% of patients were male, Eastern Cooperative Oncology Group performance status at randomization was 0 or 1 in 98% and 94%, 94% and 89% had stage IV disease, 86% and 92% had adenocarcinoma, 75% and 74% were current or former smokers, 37% and 36% had centrally located lung tumors, and 5% and 6% had a cavitated tumor.

Prolonged Progression-Free Survival

At a median follow-up of 8.1 months, progression-free survival from the time of randomization was 7.4 months in the bevacizumab/pemetrexed group vs 3.7 months in the bevacizumab group (hazard ratio [HR] = 0.48, P < .001) in an analysis stratified by sex, smoking status, and induction response. The outcome was similar on stratified analysis of progression-free survival from first induction (median, 10.2 vs 6.6 months, HR = 0.50, P < .001). Progression-free survival was prolonged in the bevacizumab/pemetrexed group both among patients with partial response (8.6 vs 3.9 months, HR = 0.42, P < .001) and those with stable disease (6.8 vs 3.3 months, HR = 0.63, P = .036) after induction, and progression-free survival benefit also extended across age, performance status, and smoking history subgroups.

After progression, 39% of patients in the bevacizumab/pemetrexed group and 57% of those in the bevacizumab group received subsequent treatment, with the most common being tyrosine kinase inhibitors (26% and 33%) and taxanes (12% and 28%).

Overall Survival and Response Rates

Median overall survival from randomization was not yet reached in the  bevacizumab/pemetrexed group and 12.8 months in the bevacizumab group (HR = 0.75, P = .219). After median follow-up of 10.9 months from time of first induction, median overall survival was not reached in the bevacizumab/pemetrexed group and 15.7 months in the bevacizumab group (HR = 0.75, P < .23).

The best overall response rates (all partial responses) during the induction and maintenance period were 55.5% in the bevacizumab/pemetrexed group and 50.0% in the bevacizumab group (P = .878). Median duration of response (9.2 vs 5.7 months, P = .006) and median duration of disease control (7.8 vs 4.9 months, P < .001) were significantly longer in the bevacizumab/pemetrexed group. A preliminary analysis of health-related quality of life found no significant differences between patients in the maintenance arms; full quality-of-life results are to be reported elsewhere.


Any grade, grade ≥ 3, and serious adverse events were more common with bevacizumab/pemetrexed maintenance. The most common adverse events of any grade during maintenance treatment were nausea (23% and 12%), hypertension (22% and 18%), and asthenia (14% and 8%); hemoptysis of any grade occurred in 2.4% and 1.7% of patents.

Grade ≥ 3 adverse events occurred in 38% of bevacizumab/pemetrexed patients and 22% of bevacizumab patients, including hematologic toxicities in 10% and 0% and nonhematologic toxicities in 31% and 22%; the most common were neutropenia (5.6%), hypertension (4.8%), and anemia (3.2%) in the bevacizumab/pemetrexed group and hypertension and dyspnea (2.5% each) in the bevacizumab group. There were no cases of grade ≥ 3 pulmonary hemorrhage in either group, and no treatment-related deaths were observed. 

Serious hematologic adverse events occurred in 1.6% of the bevacizumab/pemetrexed group and in 0% of the bevacizumab group, and serious nonhematologic adverse events occurred in 17% and 13%, respectively; the most common events were pneumonia (1.6%) and pulmonary embolism (0.8%) in the bevacizumab/pemetrexed group and pulmonary embolism (1.7%) in the bevacizumab group. Adverse events led to discontinuation of bevacizumab in 9% of the bevacizumab group and to discontinuation of bevacizumab in 18% and pemetrexed in 17% of the bevacizumab/pemetrexed group.

The investigators concluded, “In an unselected population of patients with nonsquamous NSCLC who had achieved disease control with platinum-based chemotherapy plus bevacizumab, bevacizumab plus pemetrexed maintenance was associated with a significant progression-free survival benefit compared with bevacizumab alone. The combination was well tolerated.” ■

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1. Barlesi F, Scherpereel A, Rittmeyer A, et al: Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non–small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol. July 8, 2013 (early release online).

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