The combination of carboplatin plus pemetrexed with pemetrexed maintenance was noninferior to docetaxel, with prolonged survival and an improved safety profile, among elderly patients with nonsquamous non-small cell lung cancer (NSCLC), according to results of the phase 3 JCOG1210/WJOG7813L trial.1
“To the best of our knowledge, our study is the first phase 3 randomized clinical trial specifically designed for patients 75 years and older with advanced nonsquamous NSCLC,” the authors wrote.
Although more than one-third of newly diagnosed lung cancer patients are 75 years or older, clinical trials that include this age group are limited. A prior study demonstrated that docetaxel was superior to vinorelbine in this age group. However, given that pemetrexed is generally well-tolerated, the purpose of this study was to determine if its combination with carboplatin were noninferior to docetaxel monotherapy.
This open-label, multicenter, phase 3 trial conducted in Japan randomly assigned 433 patients 75 years or older with chemotherapy-naive nonsquamous NSCLC to receive carboplatin plus pemetrexed followed by pemetrexed maintenance therapy or docetaxel. The chemotherapy doublet was administered as 4 cycles of carboplatin (area under the curve of 5) and 500 mg/m2 of pemetrexed every 3 weeks; the same dose of pemetrexed for 3 weeks was used for maintenance. Docetaxel was administered as 60 mg/m2 every 3 weeks, which the authors acknowledged was a lower dose than the standard 75 mg/m2 used in Western countries. Prior immunotherapy or targeted therapy was allowed for patients with actionable alterations.
The primary endpoint was OS, with noninferiority defined as a median OS of 2 or more months shorter than the docetaxel arm with a margin of 1.154 on a hazard ratio (HR) scale. Secondary endpoints included progression-free survival (PFS), response rate among patients with measurable lesions, symptoms score, and toxicities.
Baseline characteristics were balanced between the 2 arms, and the median age was 78 years (range, 75-88 years). OF the 97% of patients with known EGFR status, 21.9% were positive for a sensitizing EGFR mutation and were previously treated with at least 1 EGFR tyrosine kinase inhibitor.
The carboplatin/pemetrexed group demonstrated significantly prolonged OS at 18.7 months (95% CI, 16.0-21.9) compared with 15.5 months (95% CI, 13.6-18.4) in the docetaxel arm (HR, 0.85; 95% CI, 0.68-1.06; noninferiority P =.003). Although the chemotherapy doublet met the prespecified criteria for noninferiority, it did not meet the superiority criteria. Two-year OS rates were 40% with carboplatin and pemetrexed compared with 33.4% with docetaxel.
PFS was also prolonged with carboplatin plus pemetrexed, with a median of 6.4 months (95% CI, 5.4-7.7) compared with 4.3 months (95% CI, 4.0-4.9) with docetaxel (HR; 0.74; 95% CI, 0.61-0.90). The overall response rate was also higher in the combination group at 36.8% compared with 28.2% in the docetaxel group. Quality-of-life scores from baseline to 18 weeks were similar between groups.
The carboplatin plus pemetrexed group experienced a lower incidence of grade 3 to grade 4 leukopenia, neutropenia, but higher rates of thrombocytopenia and anemia, compared with the docetaxel group. Dose reductions were required in 22.7% of patients in the combination group compared with 61.3% of patients in the docetaxel group. Discontinuation rates due to adverse events were similar between the docetaxel and carboplatin plus pemetrexed groups (26.2% and 23.4%, respectively).
According to the authors, among elderly patients with nonsquamous NSCLC, carboplatin plus pemetrexed “provides a clinically significant benefit with regard to its effectiveness and tolerability.” They suggest that “this combination should therefore be considered as a standard option for treatment in this setting.”
Okamoto I, Nokihara H, Nomura S, et al. Comparison of carboplatin plus pemetrexed followed by maintenance pemetrexed with docetaxel monotherapy in elderly patients with advanced nonsquamous non–small cell lung cancer. A phase 3 randomized clinical trial [published online March 12, 2020]. JAMA Oncol. doi: 10.1001/jamaoncol.2019.6828