In the phase III PARAMOUNT trial, pemetrexed (Alimta) continuation maintenance therapy significantly reduced the risk of disease progression by 38% compared with placebo after pemetrexed/cisplatin induction in patients with advanced nonsquamous non–small cell lung cancer (NSCLC). Final overall survival results were recently reported in the Journal of Clinical Oncology by Luis G. Paz-Ares, MD, of University Hospital Virgen del Rocío in Seville and colleagues, with pemetrexed maintenance being associated with a significant 22% reduction in risk of death.1 Updated safety results yielded no new findings, with drug-related grade 3 or 4 anemia, fatigue, and neutropenia being relatively infrequent but more common with pemetrexed.
In the PARAMOUNT trial, 939 patients with advanced nonsquamous NSCLC received four cycles of pemetrexed/cisplatin induction therapy; 539 patients with no disease progression and Eastern Cooperative Oncology Group performance status 0 or 1 were then randomly assigned to maintenance pemetrexed (500 mg/m2 on day 1 of 21-day cycles, n = 359) or placebo (n = 180).
The mean number of maintenance cycles was 7.9 (range, 1–44) for pemetrexed patients and 5.0 (range, 1–38) for placebo patients. After a median follow-up of 12.5 months for all patients and 24.3 months for surviving patients, median overall survival was 13.9 months in the pemetrexed group and 11.0 months in the placebo group (hazard ratio [HR] = 0.78, P = .0195). One- and 2-year overall survival rates were 58% vs 32% and 45% vs 21%, respectively (both P < .05). Median overall survival from the time of induction was 16.9 vs 14.0 months (HR = 0.78, P = .0191).
Hazard ratios for overall survival consistently favored pemetrexed for all patient subgroups (disease stage IIIB or IV, performance status at randomization, male or female, smoker or nonsmoker, age, and adenocarcinoma or other histology). Overall survival was numerically improved among patients with response on induction therapy (HR = 0.81, 95% confidence interval [CI] = 0.59–1.11) and those with stable disease on induction therapy (HR = 0.76, 95% CI = 0.57–1.01); the study was not powered to detect differences between these subgroups.
In total, 64% of pemetrexed patients and 72% of placebo patients received additional therapy, with types of therapy being well matched between groups except for the more frequent use of docetaxel in the placebo group (43% vs 32%). The majority of patients received an approved second-line treatment (either docetaxel or erlotinib [Tarceva]).
Pemetrexed maintenance was associated with significantly greater frequency of drug-related grade 3 or 4 anemia (6.4% vs 0.6%), neutropenia (5.8% vs 0%), and fatigue (4.7% vs 1.1%). The most frequent drug-related grade 1 or 2 adverse events in the pemetrexed group were fatigue (17.5%), nausea (13.4%), and anemia (11.7%); grade 1 or 2 adverse events that were significantly more common with pemetrexed were anemia, neutropenia, leukopenia, increased AST, fatigue, nausea, vomiting, mucositis/stomatitis in oral cavity, anorexia, eye watering, and fever.
Treatment was discontinued due to potentially drug-related adverse events in 12.0% of pemetrexed patients and 4.4% of placebo patients. Three deaths considered potentially drug-related occurred during maintenance treatment, due to pneumonia in one pemetrexed patient and sudden death–not otherwise specified and respiratory arrest in two placebo patients.
There were no significant differences between patients receiving more than six cycles of pemetrexed and those receiving fewer cycles with regard to toxicity of any grade or drug-related grade 3 or 4 laboratory toxicity; longer exposure was associated with a numeric increase in grade 3 or 4 neutropenia (9% vs 4%, P = .062). Grade 3 or 4 infections occurred in 1.5% of patients receiving more than six cycles and 1.5% of those receiving six or fewer.
The authors emphasized that since not all patients require maintenance therapy, as is shown by patients receiving placebo for multiple cycles without showing disease progression, additional studies are needed to identify patients who would benefit most from such treatment.
They concluded, “Certainly, our understanding of optimal use of maintenance therapy will be furthered when several ongoing clinical trials are completed over the next few years. Then and now, the decision to use maintenance therapy should be based on an individualized approach that includes patient-specific factors and wishes. The results of the PARAMOUNT study provide evidence to direct those choices by providing new data on the benefits/risks of maintenance pemetrexed, supporting the use of continuation maintenance pemetrexed for patients with advanced nonsquamous NSCLC.”
The study was supported by Eli Lilly. ■
Disclosure: For full disclosures of the study authors, visit jco.ascopubs.org.
1. Paz-Ares LG, de Marinis F, Dediu M, et al: PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non–small-cell lung cancer. J Clin Oncol. July 8, 2013 (early release online).