Administering chemoimmunotherapy at an earlier time of day improved progression-free survival (PFS) and overall survival (OS) compared with treatment later in the day, according to data from a phase 3 trial (NCT05549037) published in Nature Medicine.1

Findings showed a median PFS of 11.3 months (95% CI, 9.2-13.4) among patients who received treatment earlier in the day compared with 5.7 months (95% CI, 5.2-6.2) among those who underwent treatment at a late time of day (HR, 0.40; 95% CI, 0.29-0.55; P <.001). Additionally, the PFS rates at 1 year were 47.6% (95% CI, 39.0%-58.2%) vs 19.0% (95% CI, 12.8%-28.3%) in each respective group. The median OS was 28.0 months (95% CI, not evaluable [NE]-NE) vs 16.8 months (95% CI, 13.7-19.9) in each group (HR, 0.42; 95% CI, 0.29-0.60; P <.001).

Based on univariate and multivariate analyses, time of day treatment administration and PD-L1 tumor proportion score (TPS) were the only relevant factors that predicted PFS and OS outcomes. The objective response rate (ORR) was 69.5% (95% CI, 60.6%-78.5%) in the early treatment group vs 56.2% (95% CI, 46.5%-65.8%) in the late therapy group (P = .046).

“These findings have important implications for the routine clinical use of immunochemotherapy, offering a simple and cost-neutral strategy that can be readily implemented without imposing additional financial burden on the health care system,” lead study author Zhe Huang, from the Early Phase Clinical Trial Center in the Department of Investigational Cancer Therapeutics at Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine at Central South University in Changsha, China; and the Department of Pathology in the School of Basic Medical Science at Central South University, wrote with coauthors in the publication.1 “[I]nfusion of immunochemotherapy at early [time of day] improves PFS and OS in patients with advanced NSCLC. Future clinical trials of immunotherapy should, at a minimum, document infusion time and may also consider incorporating infusion time as a stratification factor.”

In this prospective, single-center, open-label study, patients were randomly assigned to receive chemoimmunotherapy before 3:00 PM EST in the early time of day group (n = 105) or after 3:00 PM EST in the late time of day group (n = 105). Patients received pembrolizumab (Keytruda) or sintilimab (Tyvyt) every 3 weeks until disease progression, death, or intolerable toxicity. Investigators also administered carboplatin area under the curve 5 and nab-paclitaxel at 200 mg/m2 to patients with squamous cell carcinoma, while those with histologically confirmed adenocarcinoma received carboplatin area under the curve 5 plus pemetrexed at 500 mg/m2.

The trial’s primary end point was PFS based on blinded independent review committee assessment. Secondary end points included OS and ORR.

Patients 18 to 75 years old with histologically or cytologically confirmed metastatic NSCLC and a lack of EGFR, ALK, and ROS1 mutations were eligible for enrollment on the trial.2 Other eligibility criteria included having an ECOG performance status of 0 or 1, a life expectancy of at least 12 weeks, and adequate bone marrow hematopoiesis and organ function.

The median age was 61 years (range, 33-80) in the early treatment group and 60 years (range, 34-77) in the late treatment group. In each respective group, most patients were male (90.5% vs 90.5%) and previously smoked (80.0% vs 82.9%). Most patients across both groups had an ECOG performance status of 1 (63.8% vs 69.5%), squamous disease (57.1% vs 53.3%), stage IV disease (77.1% vs 83.8%), no brain metastases (86.7% vs 84.8%), no liver metastases (94.3% vs 90.5%), treatment with sintilimab (77.1% vs 77.1%), and a PD-L1 TPS of less than 1% (39.0% vs 44.8%).

In the early and late time of day groups, respectively, the most common treatment-related adverse effects (TRAEs) of any grade included leukopenia (44.8% vs 28.6%), anemia (43.8% vs 42.9%), and thrombocytopenia (21.0%). The most common immune-related AEs in each group included rash (12.4% vs 16.2%) and hypothyroidism (11.4% vs 10.5%).

ReferencesHuang Z, Zeng L, Ruan Z, et al. Time-of-day immunochemotherapy in nonsmall cell lung cancer: a randomized phase 3 trial. Nat Med. Published online February 2, 2026. doi:10.1038/s41591-025-04181-wEffect of time-of-day (ToD) for immunochemotherapy on PFS in NSCLC (PACIFIC15). ClinicalTrials.gov. Updated February 19, 2025. Accessed February 2, 2026. https://tinyurl.com/ycwraff9