CHICAGO – Coupling carboplatin chemotherapy with pemetrexed significantly improved survival in the subset of hard-to-treat patients with advanced non–small cell lung cancer and an Eastern Cooperative Oncology Group performance status of 2.
Progression-free survival increased from a median of 3.0 months to 5.9 months (hazard ratio, 0.46; P less than .001), and overall survival from 5.6 months to 9.1 months (HR, 0.57; P = .001) with the addition of carboplatin to pemetrexed (Alimta), according to final results of a phase III trial.
Patrice Wendling/IMNG Medical Media
Dr. Rogerio Lilenbaum
This represents a 43% reduction in the risk of death, with 43% of patients on the combination alive at 12 months vs. 18% on single-agent pemetrexed. None of the patients had received prior chemotherapy.
The results can be generalized to patients of all histologic subtypes who have an ECOG performance status of 2, Dr. Rogerio Lilenbaum said at the annual meeting of the American Society of Clinical Oncology.
"Although carboplatin plus pemetrexed may be a particularly suitable regimen in this population because of its safety profile, we do not think these results are unique to this regimen or nonsquamous patients," he said.
"Given the magnitude of the benefit seen in this study, and the immediate applicability of these data to clinical practice, we urge the appropriate organizations to revise their guidelines, which to this date, by and large, still recommend single-agent therapy for these patients."
Patients with non–small cell lung cancer (NSCLC) and an ECOG performance status (PS) of 2 are ambulatory and can care for themselves, but are unable to work. The optimal management strategy for these patients remains unresolved in the wake of mixed results from several phase III trials, including the IFCT-0501 (Intergroupe Francophone de Cancerologie Thoracique 1501) trial of carboplatin and paclitaxel vs. vinorelbine or gemcitabine (Gemzar) monotherapy (Lancet 2011;378:1079-88) and the U.S. Oncology trial of gemcitabine plus carboplatin vs. gemcitabine (J. Clin. Oncol. 2009;27:5808-15).
In contrast, the current results were so robust that one audience member asked whether they were "contaminated" with better–performance status patients.
Discussant Dr. Gregory P. Kalemkerian, codirector of thoracic oncology at the University of Michigan in Ann Arbor, said the results clearly demonstrate – as other trials have suggested – that two-drug regimens can improve response rate and survival, and should be an option in PS 2 patients.
He applauded the investigators for choosing a tolerable regimen and avoiding the "cult of cisplatin," but went on to say that PS 2 denotes a very heterogeneous population. Thus, single-agent therapy should remain an option for very elderly patients, those with excessive comorbidities, and those who do not tolerate a two-drug therapy.
He faulted the team for not providing quality-of-life data, and said that "supportive care with a focus on palliation of symptoms is imperative for all patients, because quality of life is really key."
Median Follow-Up Was 6 Months
Investigators at eight centers in Brazil and one in the United States stratified 203 chemotherapy-naive patients with stage IIIB or IV advanced non–small cell lung cancer by stage, age, and weight loss, and then randomly assigned them to pemetrexed 500 mg/m2 or the same pemetrexed dose plus carboplatin AUC (area under the curve) 5 every 3 weeks for 4 cycles. All patients received folic acid, vitamin B12 and dexamethasone. The protocol was amended in May 2009 to exclude patients with squamous cell histology for which pemetrexed is not indicated.
Median follow-up was 6.1 months in all patients. Their median age was 65 years, 95% had stage IV disease, two-thirds were former smokers, and 81% had adenocarcinoma histology. Squamous cell histology was slightly imbalanced at 11% of the single-agent and 3% of the pemetrexed/carboplatin arm, but the difference was not significant. The median number of cycles was four in both arms.
The overall response rate was 24% with the combination vs. 10.5% with pemetrexed alone (P less than .029), despite the fact that 33.3% and 23.3% of patients, respectively, did not reach the point of a formal response assessment, said Dr. Lilenbaum, chair of solid tumor oncology at the Cleveland Clinic Florida in Weston.
Analysis Redone to Exclude Squamous Cell
The investigators repeated the survival analysis excluding patients with squamous cell or unknown histology, and the hazard ratios were nearly identical to the intent-to-treat population for both progression-free and overall survival (HR, 0.45 and 0.59, respectively).
Subgroup analyses revealed a significant reduction in the risk of death with pemetrexed plus carboplatin in elderly patients (HR, 0.49; P less than .015) and never smokers (HR, 0.47; P less than .035), he said.