Study Questions Role of Maintenance Pemetrexed in Advanced Nonsquamous NSCLC

A retrospective cohort study presented at the 2025 World Conference on Lung Cancer raises questions about the necessity of combining maintenance pemetrexed (Alimta) with pembrolizumab (Keytruda) in the treatment of advanced nonsquamous non–small cell lung cancer (NSCLC).¹

Although the combination has been considered a standard of care since the KEYNOTE-189 (NCT02578680) trial, the findings, which were presented by researchers from the VA National Oncology Program and other VA-based researchers, suggest that maintenance pemetrexed may not provide additional survival benefits when used alongside pembrolizumab alone.

The KEYNOTE-189 trial established the efficacy of adding pembrolizumab to carboplatin and pemetrexed in both induction and maintenance phases of treatment for patients with advanced/metastatic nonsquamous NSCLC. However, the trial design left unresolved whether maintenance pemetrexed provides incremental benefit when combined with pembrolizumab in the maintenance setting. Despite this uncertainty, maintenance pemetrexed has remained a guideline-recommended option in the immunotherapy era.

The researchers retrospectively analyzed a cohort of 62 veterans with advanced nonsquamous NSCLC who had completed 4 cycles of induction therapy with carboplatin, pemetrexed, and pembrolizumab. Patients were then treated with either maintenance pemetrexed/pembrolizumab (n=473) or pembrolizumab alone (n=149).

The primary end point was overall survival (OS), while secondary outcomes included time-to-next treatment (TTNT) and the incidence of grade ≥3 adverse events of special interest. In addition, the study examined the financial impact of pemetrexed maintenance therapy, estimating US federal government payer spending from 2017 to 2022.

The study noted no significant difference in OS between the 2 groups, with a median OS of 18.1 months (95% CI, 13.9-28.6) for pembrolizumab alone versus 17.7 months (95% CI, 16.4-19.9) for pemetrexed/pembrolizumab.

Similarly, no significant difference was observed in TTNT, with an adjusted hazard ratio of 1.17 for pemetrexed/pembrolizumab versus pembrolizumab alone (95% CI, 0.93-1.48; P=.19).

However, the addition of pemetrexed was associated with a higher rate of severe toxicity (95% CI, 1.44-3.05; P=.004), and higher costs.

The study underscores the need to reassess the role of legacy therapies in modern combination treatment regimens. As oncology continues to evolve, the researchers pointed out the importance of carefully evaluating the contributions of individual treatment components, particularly at the time of regulatory approval.

Reference

1. Maintenance pemetrexed/pembrolizumab vs maintenance pembrolizumab alone in advanced non-squamous non-small cell lung cancer. P2.10.01. Presented at: 2025 World Conference on Lung Cancer. September 6-9, 2025; Barcelona, Spain.