In lung cancer patients receiving immune checkpoint inhibitors (ICIs), survival is not necessarily better when treatment is administered in the morning vs in the afternoon, according to the i-TIMES study.
In a meta-analysis of patient-level data from positive phase II/III trials involving lung cancer patients treated with atezolizumab alone or in combination with chemotherapy vs chemotherapy alone, the median overall survival (OS) was 17.3 months among those who received the first two cycles of ICIs before 12 noon (early) vs 16 months among those who received the first two cycles of ICIs after 12 noon (late). [ELCC 2026, abstract LBA2]
The i-TIMES study met its primary objective, demonstrating noninferiority of late vs early intravenous administration of the first two ICI cycles with respect to OS (hazard ratio, 1.039, 95 percent confidence interval [CI], 0.925–1.168), with the upper bound of the 95 percent CI below the prespecified limit of 1.18, reported first study author Dr Solange Peters from the University of Lausanne, Switzerland, at a proffered paper session in the annual ELCC meeting.
“These results suggest that intravenous ICI treatment timing within the day is unlikely to represent an independent determinant of ICI efficacy in patients with lung cancer,” Peters said. “In this context, any potential chronotherapy effect appears limited in magnitude and of uncertain clinical relevance.”
Molecular circadian clocks
The hypothesis that morning administration of immunotherapy could improve clinical outcomes rests on the principle of chronotherapy.
“Chronotherapy is an emerging therapeutic strategy that leverages the principles of circadian biology to optimize the timing of medical treatments, ultimately aiming to enhance their efficacy while minimizing side effects,” Peters explained.
This circadian biology, according to Peters, involves the regulation of leukocyte trafficking and CD8⁺ T-cell activation through rhythmic control of chemokine signalling and immune gene expression by BMAL1–CLOCK transcriptional programs. [Trends Cell Biol 2021;31:940-950; Sci Immunol 2022;7:eabm2465]
“ICIs rely on adaptive immune activation, with preclinical and translational data suggesting higher immune activation in the morning, potentially enhancing antitumour responses,” she added. [Nature 2023;621:868-876]
The findings of i-TIMES support a “flexible and pragmatic approach to treatment scheduling, without compromising clinical outcomes,” Peters said. “Ongoing developments of subcutaneous formulations of ICIs should definitively terminate all remaining related investigational efforts.”
The i-TIMES study
In the study, Peters and colleagues performed a propensity-score matched analysis in a large cohort of patients from eight company-sponsored international randomized controlled phase II/III trials in the advanced/metastatic lung cancer setting. The primary endpoint was OS.
A total of 3,060 patients were included in the meta-analysis. ICI was administered early in 1,244 patients (41 percent) and late in 964 (32 percent); the remaining 852 patients (28 percent) who received 1 cycle of ICI early and 1 cycle late. The median follow-up was 42.6 months.
The propensity-score matched population consisted of 775 patients each in the early and late groups. The median age was 65 and 62 years, respectively, and 65 percent were male. ECOG PS was 0/1, and 59 percent had squamous lung cancer. Between 16 percent and 17 percent of patients had liver metastases, and between 5 percent and 7 percent had brain metastases.