Update: Nature Medicine has notified readers that its editors will investigate concerns raised regarding some study findings and inconsistencies in the trial.

Administering immunochemotherapy earlier in the day may improve survival outcomes in certain patients with advanced non-small cell lung cancer (NSCLC), according to results of the prospective, randomized phase 3 LungTIME-C01 trial.

Researchers from China found that giving immunochemotherapy before 3:00 PM was associated with delayed disease progression of nearly 6 months and a median overall survival benefit of about 11 months compared with administration later in the day — a benefit likely due to circadian-regulated immune cell activity.

The prospective findings, published in Nature Medicine, add to retrospective studies suggesting that infusions of immunochemotherapy earlier in the day may improve efficacy in a variety of tumor types.

This new study is “genuinely noteworthy and not just ‘more evidence that timing matters,’” said Adam J. Schoenfeld, MD, thoracic medical oncologist, Memorial Sloan Kettering Cancer Center, New York City, who wasn’t involved in the research.

Schoenfeld noted that most prior studies in this space have been retrospective and therefore vulnerable to confounding and selection bias, which can distort outcomes.

“This is the first large, randomized study I’ve seen addressing this question,” and the magnitude of benefit is “striking,” said Schoenfeld.

Two key questions arising from the findings are whether the data are practice-changing and, if so, whether it’s actually feasible to provide immunochemotherapy earlier in the day.

On the practice-changing question, Schoenfeld said “potentially.” But “I’d frame it as ‘practice-informing now’ and ‘practice-changing once confirmed,’” he told Medscape Medical News.

On the question of practicality, Schoenfeld believes that it is likely feasible, but scheduling could pose challenges, and implementation may vary by institution.

Inside the New Data

In an earlier retrospective study, the research team found that patients with extensive-stage small cell lung cancer receiving immunochemotherapy before 3:00 PM demonstrated improved progression-free survival (PFS) and overall survival compared to peers treated later in the day, as reported by Medscape Medical News. 

In the current trial, the researchers aimed to validate whether the timing of immunochemotherapy matters using a prospective trial design and assessing outcomes in patients with advanced NSCLC. Overall, 210 patients with treatment-naive stage IIIC-IV NSCLC who lacked driver mutations were randomly allocated (1:1) to receive the first four treatment cycles of anti-PD-1 therapy (pembrolizumab or sintilimab) either before 3:00 PM (early group) or after 3:00 PM (late group). Chemotherapy was infused about 30 minutes after immunotherapy. After the first four cycles, patients received maintenance therapy with unstipulated infusion times.

After a median follow-up of 28.7 months, median PFS was 11.3 months in the early group vs 5.7 months in the late group (hazard ratio [HR], 0.40; P < .001), reported the authors led by Zhe Huang, MD, with Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University in Changsha, China.

Median overall survival was 28.0 months in the early group and 16.8 months in the late group (HR, 0.42; P < .001), though the overall survival had not yet matured. 

The researchers also observed no significant between-group differences in immune-related adverse events. 

Earlier infusions were associated with increased levels of circulating CD8+ T cells and a higher ratio of activated vs exhausted CD8+ T cells, which “likely reflect increased cytotoxic activity and may partly explain the improved clinical efficacy observed” in the early group, the authors explained. 

A Signal That’s Hard to Ignore

The study provides yet another “signal” that earlier is better, “and that’s hard to ignore,” said David Spigel, MD, president and chief medical officer of Sarah Cannon Research Institute, Nashville, Tennessee. Spigel wasn’t involved in the research.

Spigel cited a recent study that found chimeric antigen receptor-T cell therapy for large B-cell lymphoma was more effective when infused in the morning. In that study, patients treated before noon showed a 51% 1-year PFS rate compared to 35% for those treated after 12:00 PM.

However, Spigel noted that in practice, immunotherapy scheduling can depend on logistic factors.

For instance, “If I’m giving somebody immunotherapy with chemotherapy, we can’t give that later in the day. It takes too long, so we have to bring them in early,” Spigel explained. “If they’re just getting immunotherapy, which is a short infusion, you might be more likely to push those to later in the day.” But he noted that this study “would argue maybe we should rethink that.”

Spigel also explained that the 3:00 PM cutoff time used in the study for the early vs late administration may not be meaningful in many US clinics “because almost everyone’s treatments are done before 3 PM.”

If adopted, Schoenfeld told Medscape Medical News that implementation of earlier vs later immunotherapy infusions will likely vary by center.

“Tighter sequencing can be operationally challenging (scheduling, coordination across teams, capacity constraints), but it’s feasible, particularly if the benefit proves reproducible and we better define which patients stand to gain most,” he said.

Schoenfeld also said that prospective confirmation in other geographic settings will be important.

“Because this study was conducted in China, we’ll want to see whether the findings generalize across different patient populations and health systems before it becomes universal standard practice,” he told Medscape Medical News.

The study had no commercial funding. Huang, Schoenfeld, and Spigel reported no relevant disclosures.