TOPLINE

A real-world study found that adding pemetrexed to maintenance pembrolizumab in advanced NSCLC was not associated with improved survival but did increase severe adverse events.

METHODOLOGY

• Maintenance therapy with pembrolizumab and pemetrexed is guideline-recommended for patients with advanced, nononcogene-driven NSCLC, but there’s some evidence that dropping the pemetrexed component has no effect on survival outcomes. Real-world data comparing combined and pembrolizumab-only maintenance therapy have been lacking.
• Researchers conducted a retrospective propensity score-weighted analysis using Veterans Affairs (VA) data. They included 622 patients with metastatic or recurrent nonsquamous NSCLC who completed four cycles of carboplatin or cisplatin, pemetrexed, and pembrolizumab induction therapy between 2017 and 2024. Most patients (473) received pemetrexed/pembrolizumab maintenance, while 149 received pembrolizumab alone.
• Propensity weighting was applied to adjust for baseline imbalances incorporating demographics, geographic factors, patient clinical factors (smoking status, BMI, comorbidities, performance status, and induction therapy tolerance), and disease characteristics (including histology, PD-L1 expression, stage at diagnosis, brain metastasis, and tumor response to induction).
• The primary outcome was overall survival, and the secondary outcome was time to next treatment (a surrogate for progression-free survival). Adverse events during maintenance therapy and treatment costs were also assessed.

TAKEAWAY

• Over roughly 3.5 years of follow-up, median overall survival was 18 months in the pembrolizumab-only group and 17.7 months in the pemetrexed/pembrolizumab group. After propensity weighting, combination therapy was not associated with improved overall survival compared with pembrolizumab alone (adjusted hazard ratio [aHR], 1.06; P = .62). Similarly, there was no improvement in time to next treatment (aHR, 1.17; P = .19).
• In contrast, pemetrexed/pembrolizumab was associated with increased risks for grade 3 or higher acute kidney injury (aHR, 3.35; P = .04), neutropenia (aHR, 2.86; P = .004), and anemia (aHR, 1.65; P = .01).
• Subgroup analyses by PD-L1 expression did not identify significant differences in survival between treatment groups — although the aHR for pemetrexed/pembrolizumab vs pembrolizumab alone was 0.83 in the subgroup with PD-L1 < 1% (95% CI, 0.51-1.34).
• Estimated US government spending on maintenance pemetrexed (across the VA, Medicare, and Medicaid) totaled more than $1.5 billion from 2017 to 2022. Use and spending rose markedly in 2019 with the publication of the KEYNOTE-189 trial and the inclusion of maintenance pemetrexed in treatment guidelines.

IN PRACTICE

“Our findings raise questions about maintenance pemetrexed’s necessity in the immune checkpoint inhibitor era, especially for patients whose tumors are PD-L1 ≥ 1%,” the study authors wrote. Clinical trials comparing the effectiveness of combination and pembrolizumab-only maintenance therapy are warranted, they concluded.

SOURCE

The study, led by Garth W. Strohbehn, MD, Veterans Affairs Center for Clinical Management Research and Rogel Cancer Center, Michigan Medicine, Ann Arbor, Michigan, was published online in JCO Oncology Practice.

LIMITATIONS

Residual confounding remains possible despite propensity score adjustment. The study was conducted in a predominantly male VA population, which may limit generalizability to other populations. The analysis did not assess private payer spending and indirect costs such as adverse event management, thus underestimating true costs.

DISCLOSURES

The study was supported by the VA and the University of Michigan, Ann Arbor, Michigan. Strohbehn disclosed having financial relationships with VIVIO Health, Merck, and AstraZeneca. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.