[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.
—Mauro Zukin, MD, and colleagues
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 de Câncer, 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 the Journal of Clinical Oncology, showed that combination treatment was associated with improved overall survival in this patient population.1
“This study was the first multicenter investigator initiated phase III trial completed in Brazil,” Dr. Zukin told The ASCO Post. “We collaborated since the inception with Dr. Rogerio Lilenbaum from the Yale Cancer Center, who presented the trial results at the ASCO 2012 Annual Meeting.”
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 at 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 (35% and 37% ≥ 70 years) and most were male (59% and 63%), had stage IV disease (95% and 94%), had weight loss ≥ 5% (54% and 58%), and were current or former smokers (77.5% in both); 80% and 82.5% of patients had adenocarcinoma. Similar proportions of patients in both groups had hypertension (45% in both), chronic obstructive pulmonary disease (18% and 12%), and diabetes (8% and 13%) as comorbidities.
Combination Treatment Prolongs 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).
The median number of treatment cycles was four in both groups, although fewer patients in the pemetrexed group completed the prescribed four cycles (54% vs 71%, P = .012). The major reasons for discontinuation of study treatment in the pemetrexed and combination groups included early death (14.7% vs 9.7%), early progression (15.7% vs 7.8%), clinical deterioration (12.7% vs 6.8%), and toxicity (0% vs 1.9%).
Approximately 35% 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%).
Subgroup analyses showed median overall survival benefit of combination therapy among elderly patients (9.9 vs 5.3 months, HR = 0.49, P = .006), never-smokers (9.4 vs 4.2 months, HR = 0.54, P = .069), and current/former smokers (8.8 vs 5.6 months, HR = 0.65, P = .01). Median survival of patients at the center enrolling the greatest number of patients (n = 119) was 7.9 months compared with 5.8 months for the other sites (HR = 1.00, P = .991).
An exploratory analysis according to number of comorbidities showed no significant differences in median overall survival among patients with no comorbidities (n = 69, 6.9 months), one comorbidity (n = 89, 6.3 months), or more than one comorbidity (n = 62, 8.2 months).
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, as was the frequency of grade 3 or 4 nausea/emesis (4.9% vs 1.0%). Febrile neutropenia occurred in 2.9% of pemetrexed patients and 1.0% of combination patients. Grade 3 or 4 dyspnea was more common in the pemetrexed group (10.8% vs 5.8%), and was thought to reflect disease manifestation rather than treatment toxicity.
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.” ■
Disclosure: Dr. Zukin reported no potential conflicts of interest. For full disclosures of all study authors, visit jco.ascopubs.org.
1. Zukin M, Barrios CH, Pereira JR, et al: Randomized phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced non–small-cell lung cancer and Eastern Cooperative Oncology Group performance status of 2. J Clin Oncol. June 17, 2013.