In a Japanese phase III trial reported in the Journal of Clinical Oncology, Seto et al found that the addition of maintenance pemetrexed to bevacizumab did not significantly improve overall survival in patients with previously untreated, advanced nonsquamous non–small cell lung cancer (NSCLC) without confirmed activating EGFR mutations. Progression-free survival was improved with the combination, and a survival benefit was observed among patients with known EGFR wild-type disease.

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Study Details

The open-label, multicenter COMPASS (WJOG5610L) trial enrolled patients without confirmed EGFR 19 deletion or L858R mutation between September 2010 and September 2015. Nine hundred and seven patients received induction therapy with carboplatin area under the curve = 6, pemetrexed at 500 mg/m², and bevacizumab at 15 mg/kg once every 3 weeks for 4 cycles. Those without disease progression (n = 599) were randomly assigned to receive maintenance therapy with pemetrexed at 500 mg/m² plus bevacizumab at 15 mg/kg (n = 298) or bevacizumab at 15 mg/kg (n = 301) once every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was overall survival following randomization.

Overall Survival

Median follow-up after randomization was 59.9 months. Median overall survival was 23.3 months in the pemetrexed/bevacizumab group vs 19.6 months in the bevacizumab group (hazard ratio [HR] = 0.87, P = .069). In the pemetrexed/bevacizumab and bevacizumab groups, 2% and 3% of patients, respectively, had uncommon EGFR mutations or unknown status and 6% and 7% could not be evaluated for EGFR status. Among 274 (92%) vs 265 (90%) patients with known wild-type EGFR status, median overall survival was 23.3 months vs 18.8 months (HR = 0.82, P = .020). Among all patients, median progression-free survival was 5.7 vs 4.0 months (HR = 0.67, P < .001).

Subsequent treatment was received by 84% of patients in the pemetrexed/bevacizumab group vs 91% of patients in the bevacizumab group, including docetaxel and nab-paclitaxel in 103 vs 104 patients, a taxane with anti-angiogenic agents in 43 vs 46, and immune checkpoint inhibitors in 19 vs 12 patients.

Safety

The authors noted that safety data were consistent with previous reports of the treatment regimens. During maintenance treatment, the most common grade ≥ 3 adverse events in the pemetrexed/bevacizumab group were low neutrophil count (14.0% vs 1.0% in the bevacizumab group), hypertension (12% vs 17%), low white blood cell count (5% vs 0%), and proteinuria (5% vs 9%). Four deaths considered related to treatment occurred during maintenance therapy with pemetrexed/bevacizumab, with causes consisting of interstitial pneumonitis in two patients, alveolar hemorrhage in one patient, and lung infection in one patient. 

The investigators concluded: “In terms of the primary endpoint of [overall survival], no statistically significant benefit was observed; however, [progression-free survival] in the total patient population and [overall survival] in patients with wild-type EGFR was prolonged with the addition of pemetrexed to bevacizumab maintenance therapy.”

Takashi Seto, MD, of the Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Eli Lilly Japan KK. For full disclosures of the study authors, visit ascopubs.org.