MAINTENANCE PEMETREXED PLUS BEST SUPPORTIVE CARE VS PLACEBO PLUS BEST SUPPORTIVE CARE: A RANDOMIZED PHASE III STUDY IN ADVANCED NSCLC

Belani CP, Brodowicz T, Ciuleanu T, Kim JH, Krzakowski M, Laack E, Wu YL, Peterson P, Krejcy K, Zielinski C; Penn State Hershey Cancer Institute , Hershey, PA; Medical University Vienna General Hospital and CECOG, Vienna, Austria; Oncology Institute Ion Chiricuta and CECOG, Cluj, Romania; Yonsei Cancer Center, Seoul, Republic of Korea; Centre of Oncology-Institute and CECOG, Warsaw, Poland; University Cancer Center Hamburg, Eppendorf, Germany; Guangdong Province People's Hospital, Guangzhou, China; Eli Lilly and Company, Indianapolis, IN; Eli Lilly Regional Operations, Vienna, Austria; Medical University of Vienna and Austria and CECOG, Vienna, Austria.

Platinum-based doublet chemotherapy is the cornerstone of care for patients with advanced non–small cell lung cancer (NSCLC) because it provides symptomatic relief, modestly prolongs survival, and improves quality of life, compared with supportive care alone.¹ Patients whose tumors respond to platinum-based, first-line therapy generally do not receive further treatment after 4 to 6 chemotherapy cycles²; unfortunately, however, patients with stage IV disease inevitably develop drug resistance, which ultimately results in disease progression.¹ Thus, many patients with advanced disease must eventually undergo second-line therapy with docetaxel, pemetrexed, or erlotinib, all of which have been proven effective for the management of advanced NSCLC.³

Pemetrexed is an anti-folate agent that exerts its cytotoxic effect through the inhibition of thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase, enzymes that are involved in DNA synthesis and folate metabolism.⁴ In a large, phase II trial, single-agent pemetrexed was shown to be active in recurrent and progressive NSCLC.⁵ Furthermore, a phase III trial comparing the safety and efficacy of pemetrexed and docetaxel in patients with advanced NSCLC found that treatment with pemetrexed resulted in clinically equivalent efficacy outcomes, but with significantly fewer adverse effects. Specifically, the 1-year survival rate for each treatment arm was 29.7%, but patients receiving docetaxel were more likely to have grade 3 or 4 neutropenia, febrile neutropenia, neutropenia with infections, and hospitalizations for drug-related adverse events compared with patients receiving pemetrexed.⁶

Given pemetrexed’s proven efficacy and tolerability in the second-line setting, a randomized, double-blind, phase III clinical study was conducted to evaluate the efficacy and safety of pemetrexed as maintenance therapy in patients with stage IIIB/IV NSCLC. Patients who did not experience disease progression following 4 cycles of platinum-based chemotherapy other than with pemetrexed were randomized to receive pemetrexed (500 mg/m² on day 1) with best supportive care (BSC) or placebo with BSC in 21-day cycles until disease progression. Additionally, all patients were treated with vitamin B₁₂ and folic acid⁷ because these vitamin deficiencies are associated with an increased frequency of pemetrexed-related adverse events (ie, neutropenia, diarrhea, nausea, vomiting, mucositis, and skin rash).⁸ Patients also received prophylactic dexamethasone to reduce the occurrence of severe skin rash.

Of the 663 patients who were randomized in this study, 441 received pemetrexed and 222 received placebo. Overall, patients treated with pemetrexed achieved a significantly better overall survival (OS) time than those given placebo (13.4 months vs 10.6 months; hazard ratio [HR] = 0.79; confidence interval, 0.65–0.95; P = .012). Pemetrexed patients also experienced a longer progression-free survival (PFS; 4.3 months vs 2.6 months; HR = 0.50; P <.0001) and a greater response rate (51.7% vs 33.3%; P <.001) than placebo patients. Histological subanalysis (ie, squamous cell carcinoma vs non-squamous cell carcinoma) revealed that these improvements were only demonstrated in patients with a non-squamous histology. Specifically, OS time in this patient population was 15.5 months for the pemetrexed arm, compared to 10.3 months for the placebo arm (HR = 0.70; P = .02); the pemetrexed group had a PFS time of 4.37 months, compared to 1.84 months for the placebo group (HR = 0.47; P <.00001). Patients with non-squamous cell carcinoma who were treated with pemetrexed also had a greater response rate than those who received placebo (54.3% vs 26.6%; P <.001). Finally, drug-related severe or life-threatening toxicities (ie, fatigue and neutropenia) occurred more frequently in the pemetrexed group than in the placebo group (16% vs 4%; P <.001); however, there were no pemetrexed-related deaths. Investigators concluded that pemetrexed is safe and effective for use as maintenance therapy in patients with advanced non-squamous NSCLC who respond to initial chemotherapy.

Investigators should have clearly defined BSC, in order to allow readers to better understand the types of treatment that patients in the trial may have received after they progressed on their initial treatment. Overall, however, this study was effectively designed to illustrate the role of pemetrexed for maintenance therapy of NSCLC. Because patients treated with platinum-based chemotherapy often experience disease progression, PFS was an appropriate end point to evaluate. Additionally, the decision to perform a histological subanalysis helped to provide important conclusions regarding the utility of pemetrexed in specific patient populations. This study establishes the value of pemetrexed for maintenance therapy of advanced NSCLC; further evaluation must be done to determine how soon this medication should be commenced, following completion of first-line treatment.

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