Effect of immunotherapy and time-of-day infusion chronomodulation on survival in advanced cancers.

Abstract

1588 Background: Emerging clinical studies report correlation of time-of-day infusion (TOI) to immunotherapy outcomes and the intricate interplay of the human circadian rhythm and cancer and immunotherapy exposure. Preclinical and clinical studies have shown cancer chronotherapy to play important role in transcriptional rhythmicity of oncogenic process. We evaluated the association of TOI and immunotherapy outcomes in a large cohort to determine impact of TOI on overall survival (OS) and progression free survival (PFS). Methods: We reviewed charts of patients with solid tumors who received immunotherapy, specifically anti programmed cell death protein 1 (PD1) and anti-programmed death-ligand 1 (PD-L1) agents at MD Anderson Cancer Center. Infusion times were divided into two hours cohorts from 8am-8pm and one overnight cohort from 8pm-8am. Accelerated failure time models were used to model OS (log-normal distribution) and PFS (Weibull distribution) with relation to TOI after adjusting for factors such as age, gender, tumor type and prednisone > 10mg daily use within 1 month of immunotherapy initiation to minimize confounding factors. Results: Of 6151 patients with advanced tumors, 4441 patients received immunotherapy therapy after adjusting for minimum 140 patients in each tumor cohort from 10/15/2016 until 10/15/2021. Tumor types included advanced lung cancer (31.4%), melanoma (28.7%), renal (14.4%), breast (7.6%), colon (6.2%), liver cancer (3.9%) and head and neck (H&N) cancers (2.8%). Median age was 63 (15-99) with 58% males and 42% female. 1894 (43%) patients received investigational agents and 2547 (57%) received standard of care therapies. Mechanism of action of various agents: anti PD1, anti-PDL1, TGF-βRII and anti-PDL1, anti-PD-1 with OX40+ T Cell activation, PD-1 / PD-L1 bispecific antibody, PD-L1 dependent 4-1BB agonist and anti PD-1 and CTLA-4 activity. Among all patients, median OS was 26.4 months while median PFS was 4.8 months. Preponderance of immunotherapy TOI occurred between 12-2pm and 2-4pm in all patients. Patients receiving overnight TOI with lung, renal and breast cancer demonstrated significantly (p < 0.05) poorer OS compared to TOI (10am-4pm) whereas in melanoma, significantly lower OS was seen with overnight, 8-10am and 6-8pm compared to 10am-4pm TOIs. Among H&N cancer patients, early TOI (8-10am) was associated with significantly lower OS compared to afternoon TOI (12pm-4pm). PFS trends were less distinct than for OS but showed a slighted inverted tendency towards lower PFS following daytime TOI. Conclusions: In this large cohort of patients treated with immunotherapy, clinically significant association of TOI with overall survival is seen. These intriguing findings warrant prospective validation in a future randomized trial to harness the role of chronomodulation of cancer therapies for improving outcomes.

Effect of immunotherapy-infusion time of day on survival of patients with advanced cancers: a study-level meta-analysis

“…The search found 16 studies, including 8 articles in peer-reviewed international journals 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 and 8 congress abstracts, which were presented as poster communications at major international congresses. 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 Three abstracts were discarded because the data 40 were updated in a subsequently published article, 26 or detailed HR data were not reported. 34 , 35 All 13 retained study reports consisted of retrospective evaluations of ToD ICI administration effects.…”

“… 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 Three abstracts were discarded because the data 40 were updated in a subsequently published article, 26 or detailed HR data were not reported. 34 , 35 All 13 retained study reports consisted of retrospective evaluations of ToD ICI administration effects. They involved patients receiving ICIs for metastatic lung cancer, 26 , 27 , 28 , 36 , 39 malignant melanoma, 25 , 30 , 32 urothelial cancer, 33 renal cell carcinoma, 29 , 37 , 38 and esophageal carcinoma.…”

Therapeutically targeting the unique disease landscape of pediatric high-grade gliomas

“…Despite its clinical relevance being unknown in pediatric patients and its utilization potentially being quite difficult in younger patients with inconsistent sleep cycles, chronotherapy may provide a novel avenue for optimizing the efficacy of pre-existing drugs at significantly lower concentrations to eliminate toxicity while enhancing the therapeutic capacity of compounds discovered in the future. Immunotherapy may be one such approach to benefit from chronotherapy with research increasingly hinting at the immune system being circadian regulated with the time of treatment influencing overall survival (72). Investigations into artificially manipulating local factors associated with circadian rhythm may also be beneficial for administering drugs outside the hours discussed in these studies.…”

Smart drug delivery systems to overcome drug resistance in cancer immunotherapy

“…Cancer immunotherapy has become a major area of research in cancer treatment during the last decade owing to the documented extraordinary success in treating or managing tumors 1 – 4 . Cancer immunotherapy is a treatment strategy to keep cancer under control and eliminate cancer by reactivating and maintaining the immune system to identify and eliminate tumor cells.…”