First-line Carboplatin plus Pemetrexed Improves Survival vs Pemetrexed Alone in Patients with Advanced NSCLC and Poor Performance Status
A significant proportion of patients with advanced non–small cell lung cancer (NSCLC) have poor performance status, and optimal clinical management of these patients has not been established. In an attempt to help define optimal chemotherapy in such patients, Mauro Zukin, MD, of Instituto Nacional do Cancer, Rio de Janeiro, and colleagues conducted a phase III trial of first-line carboplatin plus pemetrexed (Alimta) vs pemetrexed alone in patients with Eastern Cooperative Oncology Group (ECOG) performance status of 2. The study, recently reported in Journal of Clinical Oncology, showed that combination treatment was associated with improved overall survival in this patient population.
Study Details
In the trial, conducted in eight centers in Brazil and one in the United States, 205 patients with advanced NSCLC, ECOG performance status of 2, no prior chemotherapy, and adequate organ function were randomly assigned to receive pemetrexed 500 mg/m2 alone (n = 102) or in combination with carboplatin AUC 5 (n = 103) every 3 weeks for four cycles. Initially, patients could have any histology, with the protocol subsequently being amended to permit enrollment of only patients with nonsquamous histology. Patients in both the pemetrexed and combination groups had a median age of 65 years and most were male (59% and 63%), had stage IV disease (95% and 94%), and were current or former smokers (77.5% in both groups); 80% and 82.5% of patients had adenocarcinoma. Similar proportions of patients in both groups had hypertension, chronic obstructive pulmonary disease, and diabetes as comorbidities.
Combination Treatment Prolongs Overall Survival
Median follow-up was 27.5 months. Median overall survival was 9.3 months in the combination group vs 5.3 months in the pemetrexed group (hazard ratio [HR] = 0.62, P = .001). One-year overall survival rates were 40.1% and 21.9%, respectively. Analysis of overall survival excluding patients with squamous cell carcinoma and unknown histology yielded similar results (HR = 0.65, P = .007). Progression-free survival was also significantly prolonged in the combination group (median 5.8 vs 2.8 months; HR = 0.46, P < .001). Objective response occurred in significantly more combination group patients (23.8% vs 10.3% among evaluable patients; P = .032).
Approximately 35% percent of patients in both groups received second-line therapy, with more of these patients in the pemetrexed group receiving platinum-based therapy (69% vs 39%) and more in the combination group receiving docetaxel (28% vs 8%).
Toxicities
Hematologic toxicity was mild and rates of grade 3 or 4 nonhematologic toxicities were low in both groups. The frequencies of grade 3 or 4 anemia (11.7% vs 3.9%), neutropenia (6.8% vs 1.0%), and thrombocytopenia (1.0% vs 0%) were higher in the combination group. Febrile neutropenia occurred in 2.9% of pemetrexed patients and 1.0% of combination patients. Four treatment-related deaths occurred in the combination group (due to renal failure, sepsis, pneumonia, and thrombocytopenia) compared with none in the pemetrexed group. Treatment delays (45% vs 21%) and dose reductions (4% vs 3%) were more common in the combination group.
The authors noted that they particularly wanted to address a practice pattern in which patients with poor performance status are given inferior regimens and thus have poorer outcomes, a pattern that tends to reinforce the view that treatment is of limited benefit in such patients. They concluded, “[O]ur study provides strong evidence that combination chemotherapy is superior to single-agent therapy in all relevant clinical end points. Our results suggest it should be offered to patients with an ECOG performance status of 2.”
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