Immunotherapy Before Noon Linked to Improved Survival in mRCC

Patients who received at least 20% of their immunotherapy treatments before noon for metastatic renal cell carcinoma (mRCC) had improved survival compared with those who did not meet a 20% threshold for early-day treatment, according to new findings.

Connections between circadian rhythm and the body’s immune system have been established for decades, say the authors, who were primarily from Emory’s Winship Cancer Institute in Atlanta, Georgia. They cited work that showed how lymphocyte counts fluctuate throughout the day, as does the secretion of proinflammatory cytokines, leading to studies of how the time of day affects patients’ responses to chemotherapy in colorectal cancer as well as the likelihood of certain adverse effects.

In this study, outcomes were evaluated among 201 patients with mRCC who were treated with ICIs | Image Credit: moodboard- stock.adobe.com

As immunotherapy became standard of care across a variety of cancers, the authors had previously established that administering immune checkpoint inhibitors (ICIs) was associated with improved progression-free survival (PFS) and overall survival (OS) in metastatic melanoma. Because these therapies are now the bedrock of care in mRCC, they sought to answer whether time of day affected outcomes in administering therapy for this group of patients.

The current study, published recently in Journal of Immunotherapy for Cancer, evaluated outcomes for 201 patients with mRCC who were treated with ICIs at Winship Cancer Institute from 2015 through 2020. Of the group, 51 patients received at least 20% of their treatments before noon, while 50 received less than 20% before noon. The ICI treatments across both groups included nivolumab (58%), nivolumab plus ipilimumab (34%), and pembrolizumab (8%).

Researchers evaluated patient records by noting the time stamp included on the infusion order; as noted by the authors, time stamps were “automatically generated when infusion clinic staff had fulfilled a physician order and initiated ICI infusion.” In cases where patients received more than 1 type of immunotherapy, researchers used the time stamp for the first infusion.

Looking at outcomes based only on groups by the time therapy was given, those with at least 20% of immunotherapy treatments before noon had longer PFS and OS than those whose immunotherapy treatments occurred before noon less than 20% of the time. There was 33% improved PFS for those with more morning appointments (HR, 0.67; 95 CI, 0.48-0.94; P = .020). The OS was 43% better for the group with more morning appointments (HR, 0.57; 95% CI, 0.34-0.95; P = .033)

Results were consistent in a multivariate analysis that included age, gender, performance status, patients’ International Metastatic RCC Database Consortium Risk Score, disease histology, and the presence of bone, brain, and liver metastases. In the multivariate analysis, the group with more treatments before noon had a 30% advantage in PFS (HR, 0.70; 95% CI, 0.50-0.98; P = .040) and a 43% edge in OS (HR, 0.57, 95% CI 0.33 to 0.98; P = .043).

Of note, “Administration of ICI in the first-line setting and choice of initial ICI did not impact outcomes.”

The authors found that among patients who had higher levels of early day immunotherapy administration, 64% had 1 of their first 2 treatment cycles before noon; among those with fewer cycles before noon, only 7% had 1 of their first 2 treatment cycles before noon. Investigators repeated a biomarker analysis from their earlier study in metastatic melanoma, which confirmed their observation that administering ICIs earlier in the day “may induce a more robust systemic immune response that confers improved patient outcomes.”

The authors noted that patients were given wide latitude to set their own schedules, and studies that more actively manage when ICIs are given are needed. “While the interplay between circadian rhythm and immunotherapy remains an area of active investigation, the findings presented herein justify further development of randomized studies that more concretely establish time-of-day optimization strategies for ICI management for patients with mRCC.”

Reference

Patel JS, Woo Y, Draper A, et al. Impact of immunotherapy time-of-day infusion on survival and immunologic correlates in patients with metastatic renal cell carcinoma: a multicenter cohort analysis. J Immunother Cancer. 2024;12(3):e008011. doi:10.1136/jitc-2023-008011